Clinical Oncology News - December 2009 - Special Edition Vol. 12 No. 2 by McMahon Group

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM

2009 • VOL. 12 • NO. 2

SPECIAL EDITION WWW.CMEZONE.COM

SOLID TUMORS

The Bone Continuum Of Cancer: Early to Advanced Stage Disease Larissa A. Korde, MD, MPH Julie R. Gralow, MD

Evolving Treatment Paradigms in NonSmall Cell Lung Cancer Mona Lisa Alattar, MD Kathryn A. Gold, MD Edward S. Kim, MD

Chemotherapy Options In the Management Of Platinum-Resistant Recurrent Ovarian Cancer Marcela G. del Carmen, MD, MPH

HEMATOLOGIC DISEASE

Recent Therapeutic Advances in the Management Of Patients With The Myelodysplastic Syndromes

Management of Cutaneous T-Cell Lymphoma Frederick Lansigan, MD Francine M. Foss, MD

Current Challenges In the Management Of Chronic Myelogenous Leukemia Brandon Hamilton, MD Michael R. Savona, MD

Harry P. Erba, MD, PhD

SUPPORTIVE CARE

Safe Handling Of Hazardous Drugs: Reviewing Standards For Worker Protection Luci A. Power, MS, RPh Martha Polovich, MN, RN, AOCN

Guide to the Prevention Of Chemotherapy Medication Errors: Strategies To Prevent Chemotherapy Errors

Guidelines for the Management of Febrile Neutropenia Michael Gabay, PharmD, JD, BCPS Maria Tanzi, PharmD

Dwight D. Kloth, PharmD, FCCP, BCOP

Treatment of Nausea And Vomiting in the Oncology Setting David G. Frame, PharmD William Leslie, MD

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From the EDITORS Dear Reader: We hope you enjoy this issue of Clinical Oncology News Special Edition, which contains 10 educational reviews that are intended to serve as lasting clinical references. This issue includes several totally new educational reviews covering key areas of oncology. For example, Evolving Treatment Paradigms in Non-small Cell Lung Cancer discusses the emerging roles of biomarkers and maintenance therapy in this setting. Chemotherapy Options in the Management of Platinum-resistant Recurrent Ovarian Cancer reviews the current pharmacologic options for this difficult-to-treat population. In addition, we hope you enjoy our new reviews on the management of febrile neutropenia and management options for treatment-related bone loss and bone metastases. The issue also provides reader favorites, including an updated version of The Management of Chronic Myelogenous Leukemia and the Guide to the Prevention of Chemotherapy Medication Errors: Strategies To Prevent Chemotherapy Errors. Do you have ideas for new reviews? We would love to hear them. Send us your feedback on these educational reviews or suggest ideas for new reviews by e-mailing korourke@mcmahonmed.com. We greatly appreciate your input. Sincerely, Kate O’Rourke, Editor

McMahon Publishing is a 37-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Copyright © 2009 by McMahon Publishing, New York, NY 10036. All rights reserved. Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Postage paid at New York, NY, and at additional mailing offices. www.mcmahonmed.com POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036.

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CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 2

TABLE of CONTENTS WWW.CMEZONE.COM

Solid Tumors

Hematologic Disease The Bone Continuum of Cancer: Early to Advanced Stage Disease

Larissa A. Korde, MD, MPH Assistant Professor

Brandon Hamilton, MD

Julie R. Gralow, MD

Fellow Division of Hematology, Oncology and Bone Marrow Transplantation San Antonio Military Medical Center San Antonio, Texas

Director of Breast Medical Oncology Associate Professor Department of Medicine Division of Oncology University of Washington Seattle Cancer Care Alliance Fred Hutchinson Cancer Research Center Seattle, Washington

Current Challenges in the Management of Chronic Myelogenous Leukemia

Evolving Treatment Paradigms In Non-Small Cell Lung Cancer Mona Lisa Alattar, MD

Kathryn A. Gold, MD

Internal Medicine Resident The University of Texas Health Science Center Houston, Texas

Medical Oncology Fellow Division of Cancer Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas

Michael R. Savona, MD Attending Physician Clinical Assistant Professor of Internal Medicine University of Texas Health Science Center San Antonio San Antonio, Texas

Supportive Care

Edward S. Kim, MD Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas M. D. Anderson Cancer Center Houston, Texas

Safe Handling Of Hazardous Drugs: Reviewing Standards For Worker Protection Luci A. Power, MS, RPh Senior Pharmacy Consultant Power Enterprises San Francisco, California

Martha Polovich, MN, RN, AOCN

Chemotherapy Options In the Management Of Platinum-Resistant Recurrent Ovarian Cancer Marcela G. del Carmen, MD, MPH

Associate Director Clinical Practice Duke Oncology Network Durham, North Carolina

107

Associate Professor of OB-GYN and Reproductive Biology Harvard Medical School Clinical Director Gillette Center for Gynecologic Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts

Dwight D. Kloth, PharmD, FCCP, BCOP Director of Pharmacy Fox Chase Cancer Center Philadelphia, Pennsylvania

Hematologic Disease

119 49

Recent Advances in the Management of Patients With The Myelodysplastic Syndromes

Guidelines for the Management of Febrile Neutropenia Michael Gabay PharmD, JD, BCPS Director Drug Information Group and Prior Authorization Services Clinical Assistant Professor

Harry P. Erba, MD, PhD

Maria Tanzi PharmD

Associate Professor of Internal Medicine University of Michigan Ann Arbor, Michigan

Clinical Assistant Professor, Drug Information Group

Management of Cutaneous T-Cell Lymphoma Frederick Lansigan, MD

Guide to the Prevention of Chemotherapy Medication Errors: Strategies To Prevent Chemotherapy Errors

University of Illinois at Chicago College of Pharmacy Chicago, Illinois

129

Treatment of Nausea And Vomiting In the Oncology Setting

Assistant Professor of Medicine Hematology and Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

David G. Frame, PharmD

Francine M. Foss, MD

William Leslie, MD

Professor of Medicine Hematological Malignancies Medical Oncology Yale Cancer Center New Haven, Connecticut

Assistant Professor of Medicine Rush University Medical Center Chicago, Illinois

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Clinical Assistant Professor of Pharmacy The University of Michigan College of Pharmacy Ann Arbor, Michigan

APPROVED for first-line metastatic NSCLC and first- and second-line MCRC

Raising the survival standard as observed in pivotal Phase III trials1-4 First-line

First-line

NSCLC

MCRC

Primary Endpoint: OS

10.3 12.3 months months vs

Chemotherapy*

Avastin + chemotherapy*

19%

Second-line

15.6 20.3 months months

10.8 13.0 months months

Chemotherapy*

Avastin + chemotherapy*

Chemotherapy*

30%

Avastin + chemotherapy*

20%

increase†

P=0.013 Study E4599

P<0.001 Study 2107

P=0.001 Study E3200

Avastin is recognized by the NCCN‡ as a standard of care for appropriate patient types in combination with first-line IV chemotherapy5,6

*Chemotherapy regimens with Avastin-based therapy: Study E4599, paclitaxel/carboplatin; Study 2107, IFL; Study E3200, FOLFOX4. † Difference statistically significant. Hazard ratios for survival: Study E4599, HR=0.80; Study 2107, HR=0.66; Study E3200, HR=0.75. ‡ National Comprehensive Cancer Network.

Indications Avastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer. Avastin, in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Avastin administration can result in the development of GI perforation, in some cases resulting in fatality. GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin. Permanently discontinue Avastin therapy in patients with GI perforation. Wound healing complication: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. Permanently discontinue Avastin therapy in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery has not been determined. Hemorrhage: Severe, and in some cases fatal, pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin. Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood). Permanently discontinue Avastin in patients with serious hemorrhage and initiate aggressive medical management. Additional serious adverse events included non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic–other, and headache. Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. March 2008. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 5. The NCCN Colon Cancer Clinical Practice Guidelines in Oncology (Version 1.2008). ©2007 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org. 6. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version2.2008). ©2008 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

9151100

Printed in USA.

www.avastin.com

Brought to you by

Ready for an EHR?

Tips for Selecting the Right System

ncentives in the American Recovery and Reinvestment Act of 2009 are enticing many oncologists to invest in Electronic Health Record (EHR) systems. So, how do you know which system is right for your practice?

Plan the Process Evaluating and implementing an EHR system is a significant endeavor, not only financially but also from a change management perspective. Determine who will lead the charge and assemble a team with representation from physicians, nurses, administration and research, if applicable. Set specific goals and clearly outline the evaluation process.

Set Your Priorities Each team member will likely have different priorities for key functions of the system. Physicians may want a system that facilitates treatment decision support, regimen management, and efficient clinical documentation. Nurses may focus on easy access to patient records, regimen scheduling and admixture information. Administrators may be most interested in financial opportunities such as revenue cycle enhancement and charge capture functionality. Defining and prioritizing these wants and needs will aid evaluating each vendor’s system.

Decide Between Oncology-specific or General EHR System Some EHR systems are general, for use in any type of physician practice, and may offer an oncology module geared toward supporting the specific requirements of oncology practices. Other systems are oncology-specific, meaning they are completely developed around

the oncology workflow and are only implemented in oncology practices. Assess the priorities your team has established to determine which type of system will best meet your goals. For example, if treatment decision support is a priority, an oncology-specific system that includes tumor-staging tools, chemotherapy dosing and administration, toxicity assessment and management, and tools for protocol management should provide the support you need. If your practice offers clinical trials or routinely screens patients for trials, an EHR system with oncology-specific clinical trial management components can help increase patient accruals by automatically screening for potential study enrollment.

Evaluate Experience Increased demand for EHR systems has led to an influx of vendors entering the market. Although this offers more choices, you’ll want to be sure to choose a vendor with proven experience implementing these systems in other oncology practices. Many practices discover that the costs of implementation, both in time and money, far exceed what they had expected when third-party vendors are required to facilitate the process. Instead, an EHR vendor with an in-house implementation team that has already brought thousands of users onto its EHR platform is more likely to follow a proven and robust implementation process that minimizes patient disruption and increases the chance of implementation success. Additionally, partner with a vendor with clinical experience who will easily understand your practice’s specific

Cynthia Chavez is Vice President of iKnowMed, a division of US Oncology. In this role, Chavez oversees the development and implementation of the electronic health record system iKnowMed, an oncology-specific EHR software application acquired by US Oncology in 2004. Implemented by more than 900 oncology providers and thousands of staff to date, iKnowMed is now being offered to the greater oncology community. This application is supported by a technical team based in Berkeley, Calif. and Houston, Texas, along with a nationwide team focused on implementation and customer support. Prior to working with US Oncology, Chavez was practice director at Rocky Mountain Cancer Centers for five years. As practice director, Chavez managed cancer centers throughout the Denver metro area. In this role she was also responsible for selecting and managing the implementation of an EHR for the cancer centers. She has also worked with Steadman Hawkins Clinic in Colorado as a practice administrator.

Questions to Ask EHR Vendors • How long has your EHR been available to community oncology practices? • How many systems have you implemented in oncology practices? • What clinical background does your team have? • Is your implementation team on staff, or is it outsourced? • Are upgrades included in the scope of services? • Will you train our staff at our practice?

workflow. One-on-one training for physicians, as well as customized training specific to the respective staff positions and workflow, reduces time away from patient care and ensures a deeper understanding of the EHR system throughout the practice.

Look for a Long-term Relationship Your relationship with the selected vendor will not stop once the product has been installed. In fact, training and ongoing support are vital for a successful transition into the world of EHR. Training should be held at your practice by the vendor. Be wary of “train the trainer” scenarios or training via Web casts, and make sure sufficient training and support are included in the scope of the proposal. When evaluating proposals, sometimes it pays to look for what’s missing in addition to what’s included. The benefits of EHR to the entire healthcare system are phenomenal. With the right commitment and forethought, your practice can ensure a smooth adoption of this technology and be at the forefront of a future that includes nationwide EHR. —Cindy Chavez, Vice President of iKnowMed at US Oncology

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

The Bone Continuum of Cancer: Early to Advanced Stage Disease LARISSA A. KORDE, MD, MPH Assistant Professor

JULIE R. GRALOW, MD Director of Breast Medical Oncology Associate Professor Department of Medicine Division of Oncology University of Washington Seattle Cancer Care Alliance Fred Hutchinson Cancer Research Center Seattle, Washington

t is estimated that nearly 1.5 million people will be diagnosed with cancer in the United States in 2009.1 Survival

rates of many cancers are improving, leading to an emerging population of individuals living with cancer.

Bone health is an increasingly important issue in patients with cancer, for both those who have developed metastatic disease in the bone and those receiving treatment to prevent recurrence that can affect bone health. This article reviews the risk factors and management options for treatment-related bone loss, factors associated with, and treatment of, bone metastases, and emerging strategies for prevention of bone recurrence. The American Cancer Society estimates that there will be 192,370 new cases of invasive breast cancer and 192,280 new cases of prostate cancer in the United States in 2009. In addition, it is estimated that 219,440 individuals will develop lung cancer.1 Although a large number of these individuals will not develop metastatic disease, the incidence of bone metastases among those who develop distant disease is 73% for patients with breast cancer, 68% for patients with prostate cancer, and 30% to 40% for those with lung cancer.2 The median survival

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

time for patients with bone metastases from breast and prostate cancer is on the order of several years3,4; in contrast, survival for metastatic lung cancer is measured in months. Other cancers also can give rise to bony involvement; nearly 100% of cases of multiple myeloma involve the bone, and carcinomas of the thyroid and kidney also commonly give rise to bone metastases.2 Complications of bone metastases include bone pain, bone marrow suppression, hypercalcemia, nerve compression, and pathologic fracture, all of which can place significant and complex demands on the health care system. Furthermore, a number of cancer treatments, including hormone therapy, systemic glucocorticoids, and chemotherapy in premenopausal women (leading to premature menopause) can cause accelerated bone loss, resulting in osteoporotic fracture, pain, and adverse effects on quality of life. Oncologic and non-oncologic risk factors for osteoporosis are listed in Table 1.

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 0 0 9 â&#x20AC;˘ N O. 2

Table 1. Risk Factors for Osteoporotic Fractures Non-Oncologic

Oncologic

Age

Treatment-induced menopause

Frequent falls

Hormonally active medication use: • Androgen deprivation therapy • Ovarian function suppression • Aromatase inhibitors

Family history of osteoporosis Personal history of fragility fracture Rheumatoid arthritis Low body mass index Smoking

Other medications: • Glucocorticoids

Alcohol consumption

The management of bone health in patients with cancer requires an understanding of normal bone metabolism and how it is affected by metastatic disease and cancer treatments, including chemotherapy and hormone therapy. Bone is a dynamic tissue, undergoing continuous remodeling throughout life. Bone homeostasis is maintained by a balance of bone matrix and mineral resorption, mediated by osteoclasts, and bone formation, controlled by osteoblasts. Bone remodeling is regulated by both locally acting cytokines, such as receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG), and systemic hormones, including calcitonin, parathyroid hormone, insulin-like growth factor-1, and platelet-derived growth factor (Table 2).5 Systemically, parathyroid hormone, calcitonin, calcitriol, and vitamin D work together to maintain serum calcium levels by regulating bone resorption. Steroid hormones such as glucocorticoids, estrogens, and androgens also contribute to bone growth and maintenance. Local regulation of bone turnover is mediated via the OPG/RANKL/ RANK system. RANKL binds to RANK on the surface of osteoclastic precursor cells, causing maturation and differentiation, and thus is critical for survival of mature osteoclasts. OPG inhibits this process by binding RANKL, decreasing osteoclast formation and survival, resulting in decreased bone resorption. Cytokines such as tumor necrosis factor-α and interleukin-10 also modulate bone turnover, primarily by stimulating production of macrophage colony-stimulating factor and increasing RANKL expression.

Evaluation and Treatment of Osteoporosis Bone health is generally evaluated by bone mineral density (BMD) levels, and usually is assessed using dualenergy x-ray absorptiometry (DEXA) scanning of the hip and spine. Significant variation in DEXA measurements can exist due to differences in calibration and detectors used, and thus serial monitoring of BMD should be performed using the same piece of equipment and the

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

same reference standards. BMD can be expressed in absolute terms (grams per square centimeter) or, more commonly, it is described on a relative scale as the difference in standard deviations from the expected BMD for the patient’s age and sex (Z-score) or from that of “young normal” adults of the same sex (T-score). The World Health Organization (WHO) defines a normal BMD as that within one standard deviation of a young normal adult value (T-score of >1.0); a T-score of –1.0 to –2.5 is considered osteopenia; and a T-score of less than –2.5 constitutes osteoporosis.6 It is estimated that fracture risk doubles for each standard deviation reduction in BMD.7 Age is an important additional risk factor for fracture. Recently, the WHO developed a risk assessment tool (FRAX) that combines BMD measures with other clinical risk factors for fracture, including age, to provide estimates of 10-year risk for fracture.8 Current Medicare guidelines recommend therapeutic intervention if a patient has a 10-year FRAX risk of 3% for hip fractures and more than 20% for all major fractures. Cancer patients with elevated risk for bone loss and fracture should be evaluated periodically to assess the impact of their cancer treatment on bone mass. Initial strategies for prevention and treatment of bone loss include lifestyle modifications such as performing regular weight-bearing exercises, strength training and balance exercises, avoiding tobacco, and limiting alcohol intake. In addition, all patients should be counseled to ensure adequate intake of calcium (at least 1,200 mg/d for all individuals older than 50 years of age and those with risk factors for osteoporosis) and vitamin D (800-1,000 IU/d).9 Preventing falls is key to reducing fractures. Therapeutic intervention (described below) should be strongly considered for patients with a T-score below –2.0, particularly in those with additional risk factors for fracture. An algorithm for the management of cancer patients at risk for bone loss is shown in Figure 1. The optimal duration of therapy for osteoporosis is unknown.

Bone Health in Breast Cancer AROMATASE INHIBITOR–INDUCED BONE LOSS A number of cancer therapies can significantly affect bone health. Aromatase inhibitors (AIs) have become increasingly common as adjuvant therapy for hormone receptor–positive breast cancer in postmenopausal women. AIs inhibit peripheral conversion of androgen to estrogen, resulting in a rapid decrease in circulating estrogen levels and thus accelerated bone loss and increased risk for fracture. In the large adjuvant trials comparing AIs, such as anastrozole (Arimidex, AstraZeneca), with tamoxifen, absolute rates of fracture among patients treated with AIs were 1% to 3% higher than those among tamoxifen-treated patients.10-12 In the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial, in which patients were randomized to 5 years of either anastrozole or tamoxifen, fracture rates after discontinuation of therapy were similar, suggesting that the increased risk for fracture with AI therapy is not permanent.11 The MA17 trial, which compared 5 years of letrozole to placebo after completion of 5 years of tamoxifen, showed a nonsignificant difference in the incidence of a new diagnosis of osteoporosis in the 2 arms (5.8% for letrozole vs 4.5% for placebo; P=0.07), whereas fracture rates were similar in the 2 groups.13 This suggests that the difference in fracture rates between AIs and tamoxifen may be predominantly due to a bone-protective effect of tamoxifen rather than a detrimental effect of AIs. In a prospective substudy of the ATAC trial that assessed BMD changes among 197 women, the median change in lumbar spine BMD was –6.08% in anastrozole-treated women and 2.77% in tamoxifen-treated women. Importantly, in that study, no patients with normal bone density at baseline developed osteoporosis during the 5 years of therapy, and 5% of patients with osteopenia at baseline became osteoporotic.14 Among AI-treated patients, older age and baseline osteopenia have been identified as risk factors for fracture. Several studies have evaluated the impact of oral and IV bisphosphonate therapy on BMD in women undergoing adjuvant AI therapy for breast cancer. In SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE), women receiving anastrozole were assigned to therapy based on baseline T-scores: Patients with a low-risk T-score (>–1.0) received no additional therapy; those with a T-score between –1.0 and –2.0 were randomized to risedronate or placebo; and those with a T-score less than –2.0 were treated with risedronate. Over 24 months, risedronate at a dose of 35 mg weekly resulted in favorable effects on BMD.15 The ARIBON trial (effect of oral ibandronate on anastrozole-induced bone loss) used a similar design (patients with a T-score of –1.0 to –2.5 were randomized to either ibandronate or placebo). In that study, the addition of ibandronate (Boniva, Roche) to anastrozole led to a significant increase in BMD at the spine and hip after 1 year of therapy.16 The Zometa-Femara Adjuvant Synergy Trials (Z-FAST and Zo-FAST) evaluated the

Table 2. Effects of Systemic Hormones On RANK/RANKL/OPG System Hormone

Effect on RANKL

Transforming growth factor-β

Effect on OPG ↑

Parathyroid hormone

↑

1,25 dihydroxyvitamin 2D

↑

Glucorticoids

↑

Estrogen

↓

↓ ↑

Basic fibroblast growth factor

↑

↓

Prostaglandin E2

↓

↑

efficacy of immediate versus delayed initiation of zoledronic acid (Zometa, Novartis) in preventing AI-associated bone loss. Patients in the immediate arm received zoledronic acid every 6 months beginning at initiation of AI therapy; those in the delayed arm received zoledronic acid only if they developed clinically significant bone loss (T-score <–2.0) or fracture. In a pooled analysis of approximately 1,600 patients treated in these 2 trials, immediate use of zoledronic acid was significantly associated with preservation of BMD,17 although fracture rates were not significantly different between the 2 arms. No trials to date have compared oral with IV bisphosphonates for this indication, but taken together, these data suggest that both formulations of bisphosphonates can mitigate the bone loss associated with AI therapy. Another agent being assessed for its effects on AIinduced bone loss is denosumab, in development by Amgen. Denosumab, humanized monoclonal antibody to RANKL (which enhances osteoclast production and survival, resulting in increased bone resorption), has been assessed in a Phase II placebo-controlled study of adjuvant therapy for nonmetastatic breast cancer.18 Patients in the treatment arm received 60 mg of denosumab subcutaneously every 6 months for 2 years. At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group compared with the placebo group (P<0.0001), and increases were also seen in BMD at the hip and radius.

CHEMOTHERAPY-INDUCED OVARIAN FAILURE Premenopausal women with early-stage breast cancer who receive adjuvant chemotherapy generally experience at least temporary amenorrhea, and more than 50% will experience premature ovarian failure19-21;

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risk for ovarian failure increases with increasing age at diagnosis and with type of treatment.22 Several studies have reported accelerated bone loss as a consequence of chemotherapy-induced premature ovarian failure. In a prospective study by Shapiro et al, 71% of young women undergoing adjuvant chemotherapy experienced ovarian suppression, and in these patients a highly significant loss of bone density was seen in the lumbar spine at 6 months.23 Additional data suggest that bone loss associated with chemotherapy-induced menopause is several times higher than that seen with natural menopause or with AI treatment in postmenopausal women.9 Oral clodronate (Bonefos, Berlex) and risedronate have been studied in the setting of chemotherapyinduced ovarian failure. Compared with placebo, both agents imparted about a 2% to 3% absolute improvement in BMD.24,25 Zoledronic acid was evaluated in the Cancer and Leukemia Group B (CALGB) 79809 study, in which premenopausal women beginning adjuvant chemotherapy were randomized to immediate versus delayed administration of zoledronic acid.26 At 12 months, patients in the immediate treatment arm had a 2.6% improvement in BMD, whereas those in the delayed arm, who had not yet received zoledronic acid, experienced a 6.4% loss of BMD. Intravenous zoledronic acid also is effective for minimizing bone loss in women receiving ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist.27 Although these results are positive, no studies to date have shown an impact of bisphosphonate therapy on reducing fracture rates in this population.

EFFECT OF BISPHOSPHONATE THERAPY ON RISK FOR RECURRENCE In addition to beneficial effects on bone health, emerging evidence suggests that bisphosphonates also may have antitumor and antimetastatic properties. Possible mechanisms include inhibition of angiogenesis and tumor cell invasion, induction of apoptosis, and immunomodulatory effects. 28,29 Early studies assessing the effect of clodronate on risk for recurrence produced promising yet conflicting results.30 A recent meta-analysis of trials using oral clodronate in the adjuvant setting did not show improvements in overall or recurrence-free survival.31 However, there was marked heterogeneity among the trials and wide confidence intervals (CIs) around their hazard ratio (HR). The ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12) studied the effect of adding zoledronic acid to endocrine therapy in 1,800 premenopausal women with stage I or II breast cancer.32 All patients received ovarian suppression for 3 years with goserelin (Zoladex, AstraZeneca), and patients were randomized in a 2 × 2 design to receive tamoxifen versus anastrozole, with or without zoledronic acid (4 mg every 6 months). After a median followup of 47.8 months, the addition of zoledronic acid resulted in an absolute reduction of 3.2% in the risk for

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disease recurrence versus endocrine therapy without zoledronic acid (HR, 0.64; 95% CI, 0.46-0.91; P=0.01). Furthermore, subset analyses of the site of recurrence revealed reductions in the incidences of distant recurrences, locoregional recurrences, and contralateral breast cancer, although the overall number of recurrences in both arms is small to date. Results from several other studies examining the question of whether bisphosphonates affect disease recurrence are expected in the near future. The National Surgical Adjuvant Breast and Bowel Project Study 34 (NSABP B34) randomized 3,300 women with stage I or II breast cancer to 3 years of clodronate or placebo. The trial closed to accrual in March 2004, but the results have not yet been reported because the requisite number of events has not been reached. The AZURE trial is testing a “more intensive” dosing regimen of zoledronic acid (monthly for 6 months, followed by every3-month dosing and finally every-6-month dosing to complete 5 years) versus control in women receiving chemotherapy and/or endocrine therapy for the treatment of stage II or III breast cancer. This study closed to accrual in January 2006 and will likely report results sometime in 2010. The ongoing SWOG 0307 (Southwest Oncology Group Study 0307) trial is comparing the efficacy of “more intensive” IV zoledronic acid with oral clodronate and ibandronate in premenopausal and postmenopausal women with stage I to III breast cancer receiving standard adjuvant systemic therapy. In summary, breast cancer patients on AI therapy, and those who undergo premature menopause due to chemotherapy, experience accelerated bone loss and are at increased risk for osteoporosis and bone fracture. BMD in these patients should be monitored with serial DEXA scans, and treatment should be considered for women with a T-score less than –2.0 or additional risk factors for fracture. Both oral and IV bisphosphonates have been shown to mitigate bone loss associated with cancer therapy, and data also suggest that these agents may protect against recurrence. Recently closed and currently accruing clinical trials will help to further elucidate the effect of bisphosphonates on recurrence of breast cancer.

Bone Health in Prostate Cancer Prostate cancer is the most common malignancy among men in the United States.1 Prostate cancer growth is driven by endogenous androgens, and thus androgen deprivation therapy (ADT), by either surgical orchiectomy or administration of GnRH agonists is commonly used for this disease. ADT lowers testosterone levels, leading to the desired therapeutic effect, but because estradiol is produced from testosterone via aromatase activity, ADT also reduces estradiol levels. A number of studies have shown that men treated with ADT for prostate cancer exhibit accelerated bone loss.33-37 A Medicare claims-based study evaluated the relationship between GnRH agonist use and fracture risk, and found that GnRH agonist use was associated with a faster time to fracture

Cancer patients at increased risk for bone loss and fracture due to therapy or age

History and physical examination, BMD screening, FRAX analysis

Lifestyle modification, calcium, and vitamin D supplementation

T-score >–1.0

T-score between –1.0 and –1.5

T-score between –1.5 and –2.0

T-score between >–2.0 FRAX 10-y risk >20% for major fracture or >3% for hip fracture

Consider checking 25(OH) vitamin D level

Consider pharmacologic therapy

Strongly consider pharmacologic therapy

Repeat DEXA scan every 2 y

Figure 1. Algorithm for management of bone health in cancer patients at risk for bone loss. BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; FRAX, World Health Organization Fracture Risk Assessment Tool; OH, hydroxyvitamin

and a significantly increased risk for hip, femur, and vertebral fractures.37 Similarly, a SEER (Surveillance, Epidemiology and End Results) study, which included 50,000 men with prostate cancer, showed that men treated with ADT had an approximately 7% higher absolute rate of fractures compared with men who did not receive ADT; there also was a statistically significant association between the number of doses of GnRH agonist and fracture risk.36 A number of therapeutic agents have been evaluated for the prevention of ADT-associated bone loss. In a randomized study of pamidronate in men receiving ADT for prostate cancer, pamidronate-treated patients had no significant change in BMD, whereas untreated patients had a decrease in BMD.38 In one study evaluating zoledronic acid given every 3 months, mean lumbar spine density improved by 5.6% in patients treated with zoledronic acid, and decreased by 2.2% in placebo patients.39 In a study evaluating a single yearly dose of zoledronic acid, lumbar spine and hip BMD increased by 4.0% and 0.7%, respectively, in men receiving zoledronic acid, and decreased by 3.1% and 1.9% in the placebo arm.40 One study has evaluated oral alendronate in patients with nonmetastatic prostate cancer who were receiving ADT; this study showed a 3.7% increase in BMD in men receiving weekly oral therapy for 1 year.41 Although there are no studies examining the effect of bisphosphonate therapy on fracture risk, these data provide evidence that treatment can effectively reduce

bone loss in men receiving ADT for prostate cancer. However, the optimal agent and dosing schedule have yet to be defined. Numerous other agents have been evaluated in the setting of ADT-induced bone loss, including raloxifene (Evista, Lilly), a selective estrogen receptor modulator (SERM) that is approved for treatment and prevention of osteoporosis in postmenopausal women,42 and toremifene (Fareston, Shire), a SERM approved for treatment of advanced breast cancer.43,44 Additionally, several trials evaluating the role of denosumab for both prevention of bone loss and treatment of bone metastases are expected to report results in the next several years. In conclusion, ADT for prostate cancer can result in significant morbidity associated with bone loss and increased risk for fracture. Strategies to reduce morbidity include patient education, lifestyle modifications such as weight-bearing exercises, supplementation with calcium and vitamin D, screening for osteoporosis, and when appropriate, medical intervention to mitigate ADT-induced bone loss. Future trials will help to establish evidence-based guidelines for prevention of osteoporotic fracture in prostate cancer survivors.

Bisphosphonate Toxicities Oral bisphosphonates can cause mucosal irritation of the upper gastrointestinal tract, leading to esophagitis or esophageal ulceration. Recommendations to reduce the risk for esophagitis include swallowing the

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60 52

Prevalence of Event

Pathologic fracture

Radiation therapy

Surgical intervention

Spinal cord compression

37 34

30 25 22

20 11

8 3

0 Breast (24 mo)

Prostate (24 mo)

Multiple Myeloma (21 mo)

Other Solid Tumors Including NSCLC (21 mo)

Figure 2. Prevalence of skeletal-related events in patients with metastatic bone disease not treated with bisphosphonates. NSCLC, non-small cell lung cancer Based on references 53-56.

medication with 180 to 240 mL of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop.45 IV bisphosphonates can cause renal toxicity and thus are generally not recommended for use in patients with creatinine clearance less than 30 mL per minute.46 The risk for renal toxicity is likely related to dose, infusion rate, and hydration. Osteonecrosis of the jaw (ONJ) has recently emerged as a complication of bisphosphonate treatment. The incidence of ONJ appears highest in patients receiving monthly IV bisphosphonates for the treatment of bone metastases.47 However, ONJ also has been reported in trials of bisphosphonates in the adjuvant setting48 and rarely, in patients taking oral bisphosphonates.49 Dental extraction appears to be the strongest risk factor for ONJ in bisphosphonate-treated patients; thus, dental examination and prophylactic measures should be performed prior to initiating therapy, and invasive oral surgery should be approached with caution during bisphosphonate treatment.50

Bone Metastases Normal bone homeostasis is maintained by a balance of osteoblastic and osteoclastic activity. Metastatic bone disease associated with breast cancer is often predominantly osteolytic, whereas bony lesions due to prostate cancer are generally osteoblastic. However, bone metastases are frequently heterogeneous, with histologic evidence of both osteolytic and osteoblastic features.51

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Patients with bone metastases are at risk for skeletal-related events (SREs), which include fracture, need for radiation to bone, spinal cord compromise, hypercalcemia, or surgery. In a study conducted in the United Kingdom, SREs accounted for 63% of hospital costs for patients with metastatic breast cancer.52 In addition, bone metastases often cause significant pain, with attendant negative effects on quality of life. Figure 2 illustrates the prevalence of SREs in patients with metastatic bone disease not treated with bisphosphonates.53-56 The mainstay of oncologic care for bone metastases is control of tumor burden, which typically involves chemotherapy and/or hormone therapy. Surgery and radiation also can be used for local control of specific bony lesions. Bisphosphonates commonly are used as systemic therapy for patients with bony involvement of metastatic cancer. In clinical trials in breast cancer patients, pamidronate and zoledronic acid have been shown to reduce the frequency of skeletal morbidity. In a placebo-controlled trial in breast cancer, pamidronate increased the time to skeletal complications (12.7 vs 7 months; P<0.0001) and reduced the incidence of SREs (51% vs 64%; P<0.001).55 In a trial of patients with metastatic breast cancer and multiple myeloma, zoledronic acid appeared to be at least as effective as pamidronate.57 The overall incidence of hypercalcemia and the median time to first SRE were similar with the 2 agents. In contrast, the percentage of patients requiring radiotherapy to the bone was lower in patients treated with zoledronic acid (19% vs 24%; P=0.037), and the overall incidence of skeletal complications was 16% lower with zoledronic acid (P=0.030).

Table 3. Results of Phase III Trials Comparing Denosumab to Zoledronic Acid in Metastatic Cancer

Hazard Ratio

Number of ONJ cases (D vs. ZA)

Not reached vs 26.5 mo

0.82 (0.70-0.95)

20 vs 14

20.6 vs. 16.3 mo

0.84 (0.71-0.98)

10 vs 11

Trial

Population

Time to 1st SRE (D vs ZA)

Stoppeck et al65

2,046

Breast cancer patients with bone metastates

Henry et al66

1,776

Bone metastates due to solid tumor (non-breast, non-prostate) or multiple myeloma

D, denosumab; ONJ, osteonecrosis of the jaw; SRE, skeletal-related event; ZA, zoledronic acid

The American Society for Clinical Oncology clinical practice guidelines for breast cancer suggest that patients with radiographic evidence of bone metastases should receive therapy with either zoledronic acid or pamidronate at 3- to 4-week intervals.58 In some countries, oral therapy with either clodronate or ibandronate is also an approved therapeutic option. An estimated 65% to 75% of patients with advanced prostate cancer experience an SRE and their median 5-year survival is 25%.52 Although bone metastases in prostate cancer are primarily osteoblastic, studies show that bone resorption also is elevated in prostate cancer, suggesting substantial osteoclastic activity. Clodronate and pamidronate have been studied in the setting of metastatic prostate cancer, with disappointing results. Clodronate treatment did not improve pain relief or quality of life in 2 placebo-controlled trials,59,60 and pamidronate was not more effective than placebo for pain control or reduction of SREs.61 Zoledronic acid is the only bisphosphonate with proven clinical benefit in reducing skeletal complications in men with hormonerefractory prostate cancer. In a Phase III placebo-controlled trial, zoledronic acid reduced the incidence of skeletal complications (44.2% vs 33.2%; P=0.021) and delayed the onset of first SRE.62 In addition, decreases were seen in fracture, spinal cord compression, antineoplastic therapy, and need for radiation therapy and surgery in patients receiving zoledronic acid compared with placebo. In a randomized, placebo-controlled trial of zoledronic acid in patients with bone metastases from lung cancer or other solid tumors, zoledronic acid reduced the rate of SREs (HR, 0.732; P=0.017) and significantly increased the time to first SRE.63 The optimal duration and dosing interval for bisphosphonate therapy in the metastatic setting is not well defined. ASCO guidelines recommend continuing bisphosphonate therapy indefinitely or until there is a substantial decline in the patientâ&#x20AC;&#x2122;s performance status.58 The consensus of the National Comprehensive Cancer Network task force is that the decision to

continue bisphosphonate therapy should be reconsidered at 2 years, and that discontinuation should be considered in patients who have no active disease or who have experienced a significant deterioration in renal function.9 Two ongoing clinical trials, OPTIMIZE 2 and CALGB 70604, are evaluating optimal dosing intervals in women with metastatic breast cancer, either up front or after a year of monthly dosing. A third trial, BISMARK (Cost-effective use of BISphosphonates in metastatic bone disease: a comparison of bone MARKer directed zoledronic acid), is evaluating the use of bone resorption markers to determine dosing intervals versus standard monthly dosing.

Emerging Therapies for Patients With Bone Metastases Within the bone microenvironment, RANKL secretion by stromal cells and osteoblasts is stimulated by tumor cells, resulting in increased osteoclast differentiation, function, and survival.64 Results of a Phase III trial comparing denosumab to zoledronic acid in 2,046 women with metastatic breast cancer to bone were reported in September 2009 at the European Society of Medical Oncology meeting.65 Patients were randomly assigned to subcutaneous denosumab or IV zoledronic acid on a monthly schedule. Denosumab significantly delayed the time to first and subsequent on-study SRE (P=0.001). Adverse events due to toxicity were similar in the 2 groups. Although overall toxicities were similar, the incidence of ONJ was numerically, but not statistically, higher in denosumab-treated patients than in zoledronic acidâ&#x20AC;&#x201C;treated patients (2% vs 1.4%). In a second Phase III trial of denosumab versus zoledronic acid in patients with solid tumors (not including breast or prostate) or multiple myeloma, the median time to first SRE was 20.6 months for patients receiving denosumab and 16.3 months for patients receiving zoledronic acid (HR, 0.84; 95% CI, 0.71-0.98).66 This result was statistically significant for noninferiority (P=0.0007). Table 3 summarizes data from these 2 trials. Another trial, of

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zoledronic acid versus denosumab in metastatic prostate cancer, has yet to be reported. Although the widespread use of bisphosphonates has resulted in a decrease in the incidence of SREs, complications of bone metastases, including pain, fracture, and decreased mobility, can have a significant impact on quality of life. Localized therapies, including radiation and surgery, can be used for palliation and for prevention of an impending event. Radiation therapy results in response rates from 60% to 70%, and can provide complete pain relief in up to 30% of patients.67,68 Surgical management can relieve pain, provide stabilization, and prevent impending fracture or cord compression. General criteria for lesions with high risk for fracture include lytic lesions greater than 2.5 cm, lesions encompassing more than 50% of the bone diameter, or the presence of lesser trochanter avulsion. Surgery also can be considered for impending fractures that include a lesion in a weight-bearing area and for readily identifiable painful lesions that are refractory to external beam radiation therapy.9

Conclusion Bone health is an increasingly important issue for cancer patients and their health care providers. An understanding of factors associated with cancer therapy-induced bone loss and its treatment are essential to providing quality care to cancer survivors. Strategies to reduce morbidity include education, lifestyle modifications, calcium and vitamin D supplementation, screening for osteoporosis, and when appropriate, initiation of drug therapy. For patients on bisphosphonate therapy, careful monitoring for side effects is essential. Emerging data suggest that in addition to effectively treating cancer therapy-induced bone loss, bisphosphonates may impact risk for recurrence in patients with early-stage breast cancer. Bone metastases are common in a number of solid tumors and in patients with multiple myeloma. In patients with documented bone metastases, SREs lead to significant morbidity and adversely affect quality of life. Treatment should consist of a multidisciplinary approach, including systemic anticancer therapy, osteoclast-targeted therapy such as bisphosphonates, pain control, and possibly surgery and radiation for local control. Emerging strategies, including novel bone-targeted

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agents such as denosumab, are being evaluated and may contribute to the management of patients with metastatic bone disease.

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35. Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol. 1999;161(4):1219-1222, PMID: 100818873. 36. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352(2):154-164, PMID: 15647578. 37. Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol. 2005;23(31):7897-7903, PMID: 16258089. 38. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345(13):948-955, PMID: 11575286. 39. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169(6):2008-2012, PMID: 12771706. 40. Michaelson MD, Kaufman DS, Lee H, et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007;25(9):1038-1042, PMID: 17369566. 41. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of onceweekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007;146(6):416-424, PMID: 17371886.

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42. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89(8):3841-3846, PMID: 15292315. 43. Smith MR, Malkowicz SB, Chu F, et al. Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol. 2008;179(1):152-155, PMID: 18001802. 44. Smith MR, Malkowicz SB, Chu F, et al. Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study. J Clin Oncol. 2008;26(11):1824-1829, PMID: 18398147. 45. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335(14):1016-1021, PMID: 8793925. 46. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med. 2003;349(17):1676-1679; PMID: 14573746. 47. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park). 2006;20(9):1053-1062; discussion 1065-1056, PMID: 16986349. 48. Coleman R TH, Cameron D, Bell R, et al. Zoledronic acid is well tolerated and can be safely administered with adjuvant chemotherapy—first safety data from the AZURE trial (BIG01/04). Br Ca Res Treat. 2006;100(suppl 1): Abstract 2080. 49. King AE, Umland EM. Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy. 2008;28(5):667-677, PMID: 18447663. 50. Weitzman R, Sauter N, Eriksen EF, et al. Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients—May 2006. Crit Rev Oncol Hematol. 2007;62(2):148-152, PMID: 17336086. 51. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12(20 Pt 2):6213s-6216s, PMID: 17062703.

57. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, doubleblind, multicenter, comparative trial. Cancer. 2003;98(8):1735-1744, PMID: 14534891. 58. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21(21):4042-4057, PMID: 12963702. 59. Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst. 2003;95(17):1300-1311, PMID: 12953084. 60. Ernst DS, Tannock IF, Winquist EW, et al. Randomized, doubleblind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol. 2003;21(17):3335-3342, PMID: 12947070. 61. Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebocontrolled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003;21(23):4277-4284, PMID: 14581438. 62. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468, PMID: 123559855. 63. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol. 2003;21(16):3150-3157, PMID: 12915606.

52. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 suppl):1588-1594, PMID: 9362426.

64. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25(28):4431-4437, PMID: 17785705.

53. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol. 1998;16(2):593-602, PMID: 9469347.

65. Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Can Suppl. 2009;7(3): Abstract 2LBA.

54. Body JJ, Diel IJ, Bell R, et al. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain. 2004;111(3):306-312, PMID: 15363874. 55. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88(5):1082-1090, PMID: 10699899. 56. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004;100(12):2613-2621, PMID: 15197804.

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66. Henry D, von Moos R, Vadhan-Raj S, et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Can Suppl. 2009;7(3);11. Abstract 20LBA. 67. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25(11):1423-1436, PMID: 17416863. 68. Wu JS, Wong R, Johnston M, Bezjak A, Whelan T. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55(3):594605, PMID: 12573746.

SOLID TUMORS Head and Neck

Post-Treatment Pain Associated With Recurrence, Survival in Head and Neck Cancer Patients Pain that occurs within the first year after treatment for head and neck cancer is strongly associated with recurrence and survival, according to a recent study of the relationship of post-treatment pain to outcomes (Arch Otolaryngol Head Neck Surg 2009;135:789-794). Post-treatment pain may be the first sign of cancer recurrence, but patients may underreport pain and health professionals are not always aware of the predictive importance of pain, according to the authors. “This study points out the critical importance of monitoring and managing patients’ pain on a regular basis during routine oncologic surveillance. Health care providers should know that when routine monitoring indicates abnormal pain—that is, new-onset, increased severity or persistent pain that should have subsided—the first step should involve a detailed evaluation for recurrent disease,” said Gerry F. Funk, MD, director of the Division of Head and Neck Oncology and professor of otolaryngology-head and neck surgery at the University of Iowa Hospitals and Clinics in Iowa City, and senior author of the study. If there is no evidence of cancer recurrence in a patient with high levels of posttreatment pain, then patients should receive state-of-the-art pain management using a multidisciplinary approach and a dedicated pain-management system, he continued.

those who reported no or low pain.

Pain and Survival Five-year disease-specific survival rates for patients with no/low post-treatment pain were significantly higher than for those in the intermediate/high pain group (81.8% vs. 65.1%, respectively; P=0.04). A multivariate analysis found that age, tumor site, treatment modality and recurrence within one year were independently associated with disease-specific survival. A subsequent multivariate analysis omitting recurrence found that post-treatment pain, age and type of treatment were predictors of disease-specific survival.

Pain and Recurrence Data were prospectively gathered from the University of Iowa’s Head and Neck Cancer Outcomes Assessment Project on 339 patients with head and neck cancer and a valid pain score enrolled between February 1998 and October 2001. Of these patients, 233 were men (68.7%) and the mean age was 60.8 years. Most of the patients had primary cancer (84.4%), nearly 60% of which was advanced-stage disease. The main treatment was surgery alone (37.2%) or surgery plus radiotherapy (37.7%). During the first year of follow-up, the percentage of patients who reported no pain increased from 45.9% pre-treatment to 61.4% at 12 months post-treatment. But the percentage of patients who reported high levels of pain remained relatively constant from pre- to post-treatment, at about 10%. A further analysis was based on 191 of 339 patients (56.3%) with sufficient data on recurrence within the first 12 months. Multivariate analysis showed that pain and tumor sites were independent predictors of first-year recurrence. Patients who reported intermediate or high levels of pain were almost four times as likely to have a recurrence than

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

“Recurrence was removed from the subsequent multivariate analysis because it was significantly associated with posttreatment pain,” Dr. Funk explained. A second multivariate analysis excluding first-year recurrence status showed that post-treatment pain, in addition to age and stage of cancer, was an independent predictor of survival. Patients who reported an intermediate/high pain level were 2.5 times more likely to die of their disease within the first five years of diagnosis than patients who reported no/low pain. A subset of patients with high levels of post-treatment pain did not develop a recurrence within the first year. A post hoc analysis of this subgroup suggested that undetected, persistent disease was the cause of post-treatment pain in this subset. “Five-year, disease-specific survival in the subgroup with high levels of post-treatment pain and no recurrence within the first year [64%] was quite similar to that of patients who had neither pain nor recurrence [69.7%], while patients with both high levels of pain and recurrence within the first year see SURVIVAL, page 25

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 0 9 • N O. 2

Indication ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer.

WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE ONSOLIS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. This should be considered when prescribing or dispensing ONSOLIS in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances, which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with other oral transmucosal fentanyl products have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. ONSOLIS is contraindicated for use in opioid non-tolerant patients including those using opioids intermittently, on an as needed basis. ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with other fentanyl products. When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS. Patients beginning treatment with ONSOLIS must begin with titration from the 200 mcg dose [see Dosage and Administration (2)]. When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic proﬁle of ONSOLIS compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. Special care must be used when dosing ONSOLIS. If the breakthrough pain episode is not relieved, patients should wait at least 2 hours before taking another dose [see Dosage and Administration (2)]. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. All ONSOLIS ﬁlms must be kept out of the reach of children [see Patient Counseling Information (17)]. The concomitant use of ONSOLIS with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression [see Drug Interactions (7)]. Because of the risk for misuse, abuse, and overdose, ONSOLIS is available only through a restricted distribution program, called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. To enroll in the FOCUS Program, call 1-877-466-7654 (1-877-4ONSOLIS) or visit www.OnsolisFocus.com [see Warnings and Precautions (5.3.1)].

Important Safety Information The most serious adverse reactions associated with all opioids including ONSOLIS™ are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression In ONSOLIS™ trials, the most common adverse events (frequency ≥10%) were nausea, vomiting, dizziness, anemia, dehydration, peripheral edema, dyspnea, and somnolence Please see Boxed Warning and brief summary of Prescribing Information on adjacent pages. 1. Onsolis™ [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc.; 2009.

Printed in the USA.

10/09

BEM9064

Introducing Onsolisâ&#x201E;˘

Unique Delivery System A fentanyl buccal delivery system now approved for the management of breakthrough pain in opioid-tolerant adult patients with cancer.1

200 mcg

400 mcg

600 mcg

800 mcg

Thin (0.26 mm) soluble ďŹ lm shown actual size

New

www.onsolis.com

1200 mcg

ONSOLIS™ (fentanyl buccal soluble film), CII Brief Summary: Please see full prescribing information. PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT WARNINGS IN THIS LABEL. WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE ONSOLIS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. This should be considered when prescribing or dispensing ONSOLIS in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances, which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with other oral transmucosal fentanyl products have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. ONSOLIS is contraindicated for use in opioid non-tolerant patients including those using opioids intermittently, on an as needed basis. ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with other fentanyl products. When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS. Patients beginning treatment with ONSOLIS must begin with titration from the 200 mcg dose [see Dosage and Administration (2)]. When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of ONSOLIS compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. Special care must be used when dosing ONSOLIS. If the breakthrough pain episode is not relieved, patients should wait at least 2 hours before taking another dose [see Dosage and Administration (2)]. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. All ONSOLIS films must be kept out of the reach of children [see Patient Counseling Information (17)]. The concomitant use of ONSOLIS with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression [see Drug Interactions (7)]. Because of the risk for misuse, abuse, and overdose, ONSOLIS is available only through a restricted distribution program, called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. To enroll in the FOCUS Program, call 1-877-466-7654 (1-877-4ONSOLIS) or visit www.OnsolisFocus.com [see Warnings and Precautions (5.3.1)]. INDICATIONS AND USAGE ONSOLIS (fentanyl buccal soluble film) is an opioid analgesic indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. This product must not be used in opioid non-tolerant patients because life-threatening respiratory depression could occur in patients not taking chronic opiates. For this reason, ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. CONTRAINDICATIONS Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. This product must not be used in opioid non-tolerant patients. Patients considered opioid tolerant are those who are taking at least: 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer. ONSOLIS is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl. Anaphylaxis and hypersensitivity have been reported in association with the use of other oral transmucosal fentanyl products. DOSAGE AND ADMINISTRATION As with all opioids, the safety of patients using such products is dependent on healthcare professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use. Only prescribers enrolled in the FOCUS Program may prescribe ONSOLIS [see Warnings and Precautions (5.3.1)]. Dose Titration The goal of dose titration is to find the individual patient’s effective and tolerable dose. The dose of ONSOLIS is not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and MUST be determined by dose titration. Starting Dose: Individually titrate ONSOLIS to a dose that provides adequate analgesia with tolerable side effects. All patients MUST begin treatment using one 200 mcg ONSOLIS film. Due to differences in pharmacokinetic properties and individual variability, patients switching from another oral transmucosal fentanyl product must be started on no greater than 200 mcg of ONSOLIS. When prescribing, do not switch patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS

as ONSOLIS is not equivalent on a mcg per mcg basis with any other fentanyl product. ONSOLIS is NOT a generic version of any other oral transmucosal fentanyl product. From the initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia. If adequate pain relief is not achieved after one 200 mcg ONSOLIS film, titrate using multiples of the 200 mcg ONSOLIS film (for doses of 400, 600, or 800 mcg). Increase the dose by 200 mcg in each subsequent episode until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Do not use more than four of the 200 mcg ONSOLIS films simultaneously. When multiple 200 mcg ONSOLIS films are used, they should not be placed on top of each other and may be placed on both sides of the mouth. If adequate pain relief is not achieved after 800 mcg ONSOLIS (i.e., four 200 mcg ONSOLIS films), and the patient has tolerated the 800 mcg dose, treat the next episode by using one 1200 mcg ONSOLIS film. Doses above 1200 mcg ONSOLIS should not be used. Once adequate pain relief is achieved with a dose between 200 and 800 mcg ONSOLIS, the patient should use or safely dispose of all remaining 200 mcg ONSOLIS films [see Disposal of ONSOLIS (16.2)]. Patients who require 1200 mcg ONSOLIS, should dispose of all remaining unused 200 mcg ONSOLIS films [see Disposal of ONSOLIS (16.2)]. The patient should then get a prescription for ONSOLIS films of the dose determined by titration (i.e., 200, 400, 600, 800, or 1200 mcg) to treat subsequent episodes. Single doses should be separated by at least 2 hours. ONSOLIS should only be used once per breakthrough cancer pain episode, i.e., ONSOLIS should not be redosed within an episode. During any episode of breakthrough cancer pain, if adequate pain relief is not achieved after ONSOLIS, the patient may use a rescue medication (after 30 minutes) as directed by their healthcare provider. Dose Titration ONSOLIS is available in five dosage strengths: 200, 400, 600, 800, and 1200 mcg

The initial dose is 200 mcg ONSOLIS Titrate by incrementally increasing the dose once per episode Fentanyl dose

200 mcg

Using Using

400 mcg

600 mcg

800 mcg

200 mcg ONSOLIS ﬁlm(s) 1

1200 mcg 1200 mcg ONSOLIS ﬁlm 1

If adequate pain relief is achieved, treat subsequent breakthrough cancer pain episodes using the determined dose. ONSOLIS should only be used once per episode. ONSOLIS dosing should be separated by at least 2 hours. During any episode, if adequate pain relief is not achieved within 30 minutes, the patient may use a rescue medication as directed.

Dosage Adjustment During maintenance treatment, if the prescribed dose no longer adequately manages the breakthrough cancer pain episode for several consecutive episodes, increase the dose of ONSOLIS as described in Dose Titration (2.1). Once a successful dose has been found, each episode is treated with a single film. ONSOLIS should be limited to four or fewer doses per day. Consider increasing the dose of the around-the-clock opioid medicine used for persistent cancer pain in patients experiencing more than four breakthrough cancer pain episodes daily. Administration of ONSOLIS Use the tongue to wet the inside of the cheek or rinse the mouth with water to wet the area for placement of ONSOLIS. Open the ONSOLIS package immediately prior to product use. Place the entire ONSOLIS film near the tip of a dry finger with the pink side facing up and hold in place. Place the pink side of the ONSOLIS film against the inside of the cheek. Press and hold the ONSOLIS film in place for 5 seconds. The ONSOLIS film should stay in place on its own after this period. Liquids may be consumed after 5 minutes. An ONSOLIS film, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when used as directed [see Clinical Pharmacology – Pharmacokinetics (12.3)]. The ONSOLIS film should not be cut or torn prior to use. The ONSOLIS film will dissolve within 15 to 30 minutes after application. The film should not be manipulated with the tongue or finger(s) and eating food should be avoided until the film has dissolved. WARNINGS AND PRECAUTIONS See Boxed Warning - WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE Respiratory Depression (Hypoventilation) Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in ONSOLIS. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. Patient/Caregiver Instructions Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. Patients and their caregivers must be instructed to keep ONSOLIS out of the reach of children. [see How Supplied (16.3), Storage and Handling (16.1), and Patient Counseling Information (17)]. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. ONSOLIS Dispensing When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of ONSOLIS compared to other fentanyl products (e.g., see Figure 1) that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is NOT a generic version of any other transmucosal fentanyl product.

ONSOLIS Distribution Program ONSOLIS is available only through a restricted distribution program called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. This program provides educational materials, patient counseling and facilitated distribution of the drug. To enroll in the FOCUS Program, call 1-877-466-7654 (1-877-4ONSOLIS) or visit www.OnsolisFocus.com. Prescribers and patients are required to understand the risks of therapy with ONSOLIS. Prescribers are required to understand the information in the prescribing information and to:

receives the Medication Guide

Additive CNS Depressant Effects The concomitant use of ONSOLIS with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with inhibitors of the cytochrome P450 3A4 (CYP3A4) isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)]. Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of ONSOLIS if warranted. Effects on Ability to Drive and Use Machines Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking ONSOLIS of these dangers and counsel them accordingly.

Table 2 lists, by successful dose, adverse reactions with an overall frequency of ≥5% that occurred during long-term treatment (i.e., the double-blind or open-label maintenance periods).

Table 2 Adverse Reactions Which Occurred During Long-Term Treatment at a Frequency of ≥5% System Organ Class, Preferred Term, n (%) Gastrointestinal Nausea

ONSOLIS Dose (mcg) 200 (N=23)

400 (N=59)

600 (N=79)

800 (N=91)

1200 (N=81)

>1200 (N=28)

Total (N=213)

2 (9)

6 (10)

8 (10)

12 (13)

26 (32)

4 (14)

56 (26)

Vomiting

1 (4)

5 (8)

9 (11)

8 (9)

23 (28)

3 (11)

45 (21)

Constipation

2 (9)

4 (7)

4 (5)

4 (4)

6 (7)

4 (14)

23 (11)

Diarrhea

1 (4)

1 (2)

4 (5)

4 (4)

10 (12)

19 (9)

Dry mouth

1 (4)

4 (7)

3 (4)

2 (2)

3 (4)

1 (4)

14 (7)

3 (4)

1 (1)

7 (9)

1 (4)

11 (5)

General/administration site Asthenia 0

6 (10)

3 (4)

8 (9)

7 (9)

4 (14)

28 (13)

Fatigue

2 (9)

6 (10)

1 (1)

7 (8)

7 (9)

3 (11)

25 (12)

Investigations Weight decreased

3 (13)

Abdominal pain

2 (3)

5 (5)

5 (6)

1 (4)

15 (7)

Metabolism/nutrition Dehydration 1 (4)

4 (7)

6 (8)

5 (5)

10 (12)

3 (11)

28 (13)

Decreased appetite

4 (7)

4 (5)

6 (7)

2 (2)

2 (7)

18 (8)

4 (4)

6 (7)

1 (4)

17 (8)

Chronic Pulmonary Disease Because potent opioids can cause respiratory depression, titrate ONSOLIS with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. In such patients, even normal therapeutic doses of ONSOLIS may further decrease respiratory drive to the point of respiratory failure.

Anorexia

2 (9)

1 (2)

3 (4)

Nervous system Dizziness

2 (9)

4 (7)

2 (3)

3 (3)

10 (12)

2 (7)

23 (11)

Headache

2 (9)

1 (2)

3 (4)

9 (10)

7 (9)

20 (9)

Head Injuries and Increased Intracranial Pressure Administer ONSOLIS with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

Somnolence

2 (9)

4 (5)

2 (2)

3 (4)

3 (11)

14 (7) 18 (8)

Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use ONSOLIS with caution in patients with bradyarrhythmias.

Psychiatric Confusional state

1 (4)

4 (5)

4 (4)

6 (7)

4 (14)

Depression

3 (5)

1 (1)

4 (4)

7 (9)

3 (11)

18 (8)

Insomnia

2 (3)

3 (3)

4 (5)

2 (7)

12 (6)

1 (4)

1 (2)

2 (3)

3 (3)

3 (4)

1 (4)

11 (5)

Anxiety Respiratory

MAO Inhibitors ONSOLIS is not recommended for use in patients who have received MAO inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Dyspnea

3 (13)

4 (7)

3 (4)

8 (9)

6 (7)

3 (11)

26 (12)

Cough

1 (4)

3 (4)

5 (5)

6 (7)

1 (4)

15 (7)

ADVERSE REACTIONS Clinical Studies Experience The safety of ONSOLIS has been evaluated in 306 opioid tolerant patients with breakthrough cancer pain in the efficacy study and an open-label safety study. The mean duration of therapy was 115 days, with 32 patients treated for more than 1 year. The adverse reactions seen with ONSOLIS are typical opioid side effects in a population with cancer. Frequently, opioid-associated adverse reactions will cease or decrease in intensity with continued use of ONSOLIS. Expect opioid side effects and manage them accordingly. The most serious adverse reactions associated with all opioids including ONSOLIS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression. Because the clinical trials of ONSOLIS were designed to evaluate safety and efficacy in treating patients with breakthrough pain associated with cancer, all patients were also taking concomitant opioids, such as sustainedrelease morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse event among patients who received ONSOLIS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of ONSOLIS therapy, or cancer-related symptoms. Adverse reactions are included regardless of severity. Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 lists, by maximum dose received, adverse reactions with an overall frequency of 5% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schedules used in these studies. Adverse reactions are listed in descending order of frequency within each body system.

Hypotension

3 (5)

3 (4)

1 (1)

3 (4)

1 (4)

11 (5)

Table 1 Adverse Reactions Which Occurred During Titration at a Frequency of ≥5% System Organ Class, Preferred Term, n (%)

ONSOLIS Dose (mcg) 200 (N=303)

400 (N=257)

600 (N=207)

800 (N=138)

1200 (N=79)

>1200 (N=9)

Total (N=306)

Gastrointestinal Disorders Nausea

16 (5)

12 (5)

6 (3)

5 (4)

4 (5)

42 (14)

Vomiting

7 (2)

9 (4)

8 (4)

2 (1)

26 (8)

Nervous System Disorders Dizziness

5 (2)

6 (3)

2 (1)

4 (5)

22 (7)

Somnolence

6 (2)

2 (1)

4 (2)

2 (1)

4 (5)

1 (11)

17 (6)

Vascular

In a mucositis study, a group of patients (n=7) with Grade 1 oral mucositis and a matched group of control patients (n=7) without oral mucositis were included in a clinical trial designed to support the safety of ONSOLIS. The adverse event profile was similar in both subsets of patients. There was no evidence that ONSOLIS caused or worsened oral mucosal irritation or pain in either study group. The duration of exposure to ONSOLIS varied greatly, and included open-label and double-blind studies. The adverse reactions listed below represent those that were reported by ≥1% of patients from two clinical trials (the titration and post-titration periods) while receiving ONSOLIS. Events are classified by system organ class. Cardiac disorders: tachycardia vision blurred, diplopia Gastrointestinal disorders: nausea, vomiting, constipation, diarrhea, dry mouth, abdominal pain, dyspepsia, dysphagia, abdominal distension, intestinal obstruction, flatulence General disorders and administration site conditions: asthenia, fatigue, malaise Injury, poisoning and procedural complications: fall, contusion Investigations: weight decreased, blood pressure increased Metabolism and nutrition disorders: dehydration, decreased appetite, anorexia Nervous system disorders: dizziness, somnolence, headache, lethargy, amnesia, sedation Psychiatric disorders: confusional state, depression, insomnia, anxiety, hallucination, agitation, mental status changes Renal and urinary disorders: urinary retention Respiratory, thoracic and mediastinal disorders: dyspnea, cough Skin and subcutaneous tissue disorders: pruritus, rash Vascular disorders: hypotension, hot flush, deep vein thrombosis, hypertension DRUG INTERACTIONS Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when ONSOLIS is given concurrently with agents that affect CYP3A4 activity. The concomitant use of ONSOLIS with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving ONSOLIS who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done conservatively [see Warnings and Precautions (5.4)]. The concomitant use of ONSOLIS with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of ONSOLIS. Patients receiving ONSOLIS who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of decreased ONSOLIS activity and the dose of ONSOLIS should be adjusted accordingly.

USE IN SPECIFIC POPULATIONS Pregnancy – Category C There are no adequate and well-controlled studies in pregnant women. ONSOLIS should be used during pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome. In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for ONSOLIS. Fentanyl citrate was not teratogenic when administered to pregnant animals. In published studies, pregnant rats were treated with fentanyl (10, 100, or 500 mcg/kg/day) via implanted microosmotic minipumps from Day 7 to 21 of their 21 day gestation period. Fentanyl was not teratogenic at doses up to 500 mcg/kg/day [approximately 3-times the maximum recommended human dose (MRHD) of 1200 mcg for ONSOLIS per breakthrough cancer pain episode]. Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation Day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/ day group, but was not teratogenic

Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. OVERDOSAGE Clinical Presentation The manifestations of ONSOLIS overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation [see Clinical Pharmacology – Pharmacodynamics (12.2)]. Immediate Management Immediate management of opioid overdose includes removal of the ONSOLIS film, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, ventilatory and circulatory status. Treatment of Overdosage (Accidental Ingestion) in the Opioid NON-Tolerant Person Provide ventilatory support, obtain intravenous access, and employ naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist’s action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use. Treatment of Overdose in Opioid Tolerant Patients Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

Labor and Delivery Fentanyl readily passes across the placenta to the fetus; therefore, use of ONSOLIS during labor and delivery is not recommended.

General Considerations for Overdose Management of severe ONSOLIS overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient’s airway is secure. In the presence of hypoventilation or apnea, assist or control ventilation, and administer oxygen as indicated.

Nursing Mothers Fentanyl is excreted in human milk; therefore, ONSOLIS should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using ONSOLIS.

Although muscle rigidity interfering with respiration has not been seen following the use of ONSOLIS, this is possible with fentanyl and other opioids. If it occurs, manage by the use of assisted or controlled ventilation, by the administration of an opioid antagonist, and, as a ﬁnal alternative, by the administration of a neuromuscular blocking agent.

Pediatric Use Safety and efﬁcacy in pediatric patients below the age of 18 years have not been established.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl.

Geriatric Use Of the 306 opioid tolerant patients with breakthrough cancer pain in clinical studies of ONSOLIS, 98 (32.0%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those <65 years. No clinically meaningful difference was noted in the safety proﬁle of the group 65 years of age and older as compared to younger patients in ONSOLIS clinical trials.

Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously compared with the younger population. Therefore, exercise caution when individually titrating ONSOLIS in elderly patients to provide adequate efﬁcacy while minimizing risk.

PATIENT COUNSELING INFORMATION See Medication Guide (17.3) for speciﬁc patient instructions.

Patients with Renal or Hepatic Impairment Insufﬁcient information exists to make recommendations regarding the use of ONSOLIS in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. It is recommended that ONSOLIS be titrated to clinical effect for all patients with special care taken in patients with severe renal or hepatic disease. Gender Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse reactions. DRUG ABUSE AND DEPENDENCE Controlled Substance Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. ONSOLIS may be subject to misuse, abuse and addiction. Abuse and Addiction Manage the handling of ONSOLIS to minimize the risk of abuse, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see How Supplied (16.3) and Storage and Handling (16.1)]. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors inﬂuencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since ONSOLIS may be abused for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of patients, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse of this product. Dependence Guide the administration of ONSOLIS by the response of the patient. Physical dependence is not ordinarily a concern when one is treating a patient with chronic cancer pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain. Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine).

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for ONSOLIS.

Patient/Caregiver Instructions Patients will need to be enrolled in the FOCUS Program to receive ONSOLIS. The patient will receive their prescription via a traceable courier (with proof of delivery and adult signature required). The patient will receive a counseling call at the time of the first prescription to verify that they are opioid tolerant and discuss how to use the drug. Provide patients and their caregivers with a Medication Guide for ONSOLIS (17.3). Patients and their caregivers must be instructed that ONSOLIS contains medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Patients and their caregivers must be instructed to keep ONSOLIS out of the reach of children. Patients and members of their household must be instructed to dispose of any unneeded films remaining from a prescription as soon as possible [see How Supplied (16.3) and Storage and Handling (16.1)]. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. Disposal of Unneeded ONSOLIS Films Patients and members of their household must be instructed on the safe disposal of any unneeded films remaining from a prescription as soon as they are no longer needed. To dispose of the unneeded ONSOLIS films: 1. Remove the ONSOLIS film from its foil package. 2. Drop the ONSOLIS film into the toilet. 3. Repeat steps 1 and 2 for each ONSOLIS film. Flush the toilet after all unneeded films have been put into the toilet. Do not flush the ONSOLIS foil packages or cartons down the toilet [see How Supplied (16.3) and Storage and Handling (16.1)]. Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ONSOLIS are provided in the Medication Guide (17.3). Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered. In the event that a caregiver requires additional assistance in disposing of excess unneeded films that remain in the home after a patient has expired, instruct them to call Meda Pharmaceuticals Inc. at 1-800-526-3840 or seek assistance from their local Drug Enforcement Agency (DEA) office.

MEDA Pharmaceuticals MEDA Pharmaceuticals Inc. Somerset, NJ 08873 ONSOLIS™ is a registered trademark of Meda Pharmaceuticals Inc

SOLID TUMORS Head and Neck

SURVIVAL continued from page 19

had a low rate of five-year, disease-specific survival [18.5%],” Dr. Funk said. The instrument used to capture pain did not discriminate between head and neck pain and pain elsewhere in the body. Another weakness of the study was a lack of information on comorbidities. Furthermore, levels of pain in the study were measured at a given point in time rather than across time, which would be the best indicator of the association between pain and recurrence.

Health care providers should know that when routine monitoring indicates abnormal pain—that is, new-onset, increased severity or persistent pain that should have subsided—the first step should involve a detailed evaluation for recurrent disease.’ –Gerry F. Funk, MD

Valuable Project and Excellent Study Barbara Murphy, MD, had high praise for Dr. Funk’s study and for the University of Iowa’s Head and Neck Cancer Outcomes Assessment Project. Dr. Murphy is director of the Pain and Symptom Management Program and leader of the head and neck cancer research team at Vanderbilt-Ingram Cancer Center in Nashville, Tenn. “The Iowa Outcomes Project is exceptional. It has provided clinicians with invaluable information on the long-term sequelae of symptoms and functional deficits in the head and neck cancer patient population,” she said. “This excellent study adds to the literature demonstrating that chronic pain has adverse health effects.” The association between chronic pain and decreased survival, although established, is not well understood. “There are lots of theories [about why pain decreases survival]. Further

study is clearly needed to elucidate the biological mechanisms that underlie the adverse health outcomes of chronic pain,” Dr. Murphy said. Dr. Murphy agreed with the authors of the study that chronic pain is not well studied in head and neck cancer patients, and she emphasized that about one in five head and neck cancer patients have long-term chronic pain: 10% severe pain and 10% moderate pain. “This number—one of five—is clinically important. Clinicians need to recognize that follow-up for head and neck cancer patients should include a thorough pain assessment,” Dr. Murphy said. “The study also demonstrates the importance of aggressive management of chronic pain.” —Alice Goodman

Colorectal

New Blood Tests for GI Cancers Likely BERLIN—Two investigative teams reported promising results for potential blood tests for detection of colorectal and possibly other gastrointestinal cancers, at the joint 2009 Congress of the European Cancer Organisation and European Society for Medical Oncology. The tests could make detection of colorectal cancer (CRC) simpler, and could aid in prognosis and monitoring of patients with the disease, investigators said. Joost Louwagie, PhD, from OncoMethylome Sciences headquartered in Liège, Belgium, described the performance of several tumor markers in the first multicenter feasibility study of a DNA methylation test. Researchers collected blood before surgery from 124 patients with CRC and from 444 controls undergoing screening colonoscopy. DNA was extracted from plasma and tested for the presence of DNA methylation of specific genes. DNA methylation is involved in the regulation of protein expression, and methylation or silencing of key genes has been linked to the initiation and progression of tumors,

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Dr. Louwagie explained. “We optimized the methods of DNA extraction and methylation detection so we could detect low levels of methylated genes in persons with CRC,” he said, “and we were able to find a high frequency of two newly reported genes, SYNE1 and FOXE1, in CRC patients. The same genes occurred infrequently in noncancerous individuals.” The sensitivity and specificity for the combination of SYNE1 and FOXE1 were 58% and 90%, respectively, in the first test group and were 56% and 91%, respectively, in a validation set, Dr. Louwagie reported. By disease stage, sensitivity was 41% for stage I, 80% for stage II, 50% for stage III and 100% for stage IV tumors. When a larger volume of plasma was used (>3.3 mL), sensitivity rose to 77% overall and specificity was 91%, he added. These methylation gene markers are now being validated in a large CRC screening study of 7,000 patients. “And we are currently talking to several partners about distribution rights” for the test, which would provide an additional “patient-friendly” screening modality, he said. In a different study, German investigators also reported promising results from a blood test in patients with colon, see BLOOD TESTS, page 72

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SOLID TUMORS Breast

For Patients With Breast Cancer ...

Eight Things Clinicians Should Know About Neoadjuvant Therapy What have we learned about neoadjuvant chemotherapy (NAC) over the past 30 years? Although NAC for breast cancer has not been shown to improve survival in all patients, compelling reasons asons still exist for using it, as long as patients are selectcted carefully. Researchers are investigating neodjuvant therapies increasingly tailored to patients and cancer types. At a recent symposium, J. Michael Dixon, MD, FRCS, professor of surgery, consultant surgeon and clinical director, Breakthrough Research Unit, Edinburgh Breast Unit, Western General Hospital, Edinburgh, Unit-ed Kingdom, offered a list of observations for oncologists. “I’m going to give you eight things you might not know about that might be useful,” Dr. Dixon said. 1. “Neoadjuvant therapy may improve disease survival and overall survival, especially in young women, compared with the same adjuvant chemotherapy.” In the National Surgi-cal Adjuvant Breast and Bowel Project trial B-18, 18, which compared NAC with chemotherapy after ter sursur gery, data are now available on disease-free survival out to 16 years. When the survival curve is plotted from 10 to 15 years, “the curves significantly diverge in favor of NAC,” Dr. Dixon said. “Younger women have a significant benefit in terms of overall survival but older women appear to do worse with NAC.” 2. “Neoadjuvant therapy, when you downstage disease, does not increase the rate of subsequent local recurrence if that patient is converted from mastectomy to breast-conserving surgery,” Dr. Dixon said. A meta-analysis showed a 13% excess of local recurrences in women converting from mastectomy to breast-conserving surgery, but there were more young women in that group (Br J Surg 2007:94;11891200, PMID: 17701939). “We know that young age in itself is a factor affecting local recurrence.” 3. “Neoadjuvant chemotherapy has no effect on surgical complications, and importantly, it significantly decreases overall infectious complications compared with adjuvant chemotherapy,” Dr. Dixon said. Data from a meta-analysis showed fewer surgical complications with NAC, and a 31% reduction in infections. 4. Breast-conserving surgery may be safe in select women with inflammatory breast cancer post-NAC. Example: a 40-year-old patient presented with invasive ductal carcinoma with edema and inflammation, grade 3, HER2-positive, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative. She received four cycles of FEC (fluorouracil [5FU], epirubicin and cyclophosphamide), and four cycles of docetaxel (Taxotere, Sanofi-Aventis) and trastuzumab (Herceptin, Genentech). Imaging revealed a complete response (CR). “It’s gone. No disease. At surgery, there was no disease in the sentinel nodes or the breast,” Dr. Dixon said. His hospital has used this approach with 17 similar patients over the past decade; all received wide local excisions, and at median follow-up of 39 months, no local

recurrences were reported. 5. There is less pathologic CR with NAC when the tumor is ER-positive than when it is ER-negative. Data from a big series at the University of Texas M.D. Anderson Cancer Center, Housto Houston, shows a pathologic CR of 8% in ER-positive tumors, but much higher—24%—for ERne negative cancers (J Clin Oncol 2006;24:103710 1044, PMID: 16505422). 6. NAC and neoadjuvant endocrine therapy h have similar efficacy in older, postmenopausal women with ER-positive cancers. One small stu study compared the two types of therapy in 121 ssuch patients randomized to NAC or neoadju juvant anastrozole (Arimidex, AstraZeneca) a and exemestane (Aromasin, Pfizer; Cancer 2 2007;110:244-254, PMID: 17538978). The clinical response rates, mammographic response rrates, pathologic CR and local recurrence rrates were identical in the two groups. “The sa same can’t be said of the side effects,” Dr. Dixon said. The NAC group experienced neutropenia, fe febrial neutropenia, neuropathy, alopecia and cardiotoxic cardiotoxicity. The endocrine group experienced some fatigue, vaginal bleeding, arthralgia and myalgia. 7. The optimal duration of neoadjuvant hormonal therapy may be longer than that for NAC. “We treated 224 patients (with neoadjuvant letrozole [Femara, Novartis]). About 57% were eligible for breast-conserving surgery by three months, but by continuing between six and 12 months, we got almost three-fourths to breast-conserving surgery,” Dr. Dixon said, noting that this is a far better figure than has ever been recorded with NAC. “And interestingly, 12% say, ‘I’m not going to have that surgery,’ they remain on the drug, and they’re well.” 8. Histology changes are different between NAC and neoadjuvant endocrine therapy because the two treatments work differently. Central scarring occurs in 60% of patients who receive endocrine therapy, as opposed to 4% in patients who receive NAC. A scattered pattern, with widespread poorly cellular tissue, shows up in 18% of NAC patients, and in 6% of neoadjuvant endocrine therapy patients. “We see more [pathologic] CRs [with NAC], but you very often see with chemotherapy the sort of patterns we don’t like as surgeons; it’s shot through the cancer but left scattered cells.” So who should get what? “Neoadjuvant chemotherapy is great for triple HER2-negative, ER-negative cancers,” Dr. Dixon said, “but you should probably only give it to higher-risk, ER-positive women.” Invasive lobular cancers are difficult to treat with NAC but do well with endocrine therapy. For endocrine therapy, “you want to choose ER-rich cancers. Older women, but some younger patients with significant morbidities are also good candidates,” as well as patients with a delayed diagnosis; neoadjuvant endocrine therapy can be used with good effect in ER-rich inflammatory cancers. “The great thing about hormone therapy is that it’s targeted. Chemotherapy isn’t targeted,” Dr. Dixon said. “We need more targeted therapies.” —Monica J. Smith

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Chart your course with ALIMTA. visit www.ALIMTA.com

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Evolving Treatment Paradigms in

Non-Small Cell Lung Cancer

MONA LISA ALATTAR, MD

KATHRYN A. GOLD, MD

EDWARD S. KIM, MD

Internal Medicine Resident The University of Texas Health Science Center Houston, Texas

Medical Oncology Fellow Division of Cancer Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas

Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas M. D. Anderson Cancer Center Houston, Texas

ung cancer is the most common cause of cancer-related death in the United States, accounting for 30% and 26% of all cancer deaths in men and women, respectively, and exceeding the

predicted death rates for breast and colorectal cancers combined.1 Non-small cell lung cancer (NSCLC), the most common histologic type of lung cancer, accounts for more than 80% of lung cancers.

Locally resectable NSCLC can be cured with surgical intervention. However, less than one-third of patients present with localized disease; the majority presents with advanced incurable disease. Overall survival (OS) in patients with advanced disease has modestly improved over the past few decades through advances in chemotherapy; median OS has improved by approximately 2 months, providing 1-year survival rates of about 30% compared with 10% with supportive care. More recently, the advent of newer chemotherapy regimens has increased median survival times

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

with standard doublet chemotherapy regimens to 8 to 11 months.2 The addition of biological agents and efforts to focus treatment populations have further increased efficacy, with median survival times in some studies exceeding 12 months.3 While previous studies of cytotoxic chemotherapy demonstrated no improvement in outcome when regimens were administered for more than 4 to 6 cycles, recent studies in the maintenance setting indicate that more prolonged therapy may be desirable.4 As treatment strategies evolve and chemotherapies and

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 0 0 9 â&#x20AC;˘ N O. 2

biological therapies are being increasingly integrated, a more personalized approach should be used to provide the most effective and least toxic treatments to NSCLC patients.

Conventional Chemotherapy In patients with advanced NSCLC with good performance status (PS)—PS 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale—platinum-based doublet regimens constitute the mainstay of chemotherapy.5 Based on a meta-analysis showing a survival benefit in patients treated with cisplatin,6 in 1996, the American Society of Clinical Oncology (ASCO) devised guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and good PS. For patients with incurable disease, however, quality of life (QoL) is an important concern. The considerable toxicity of cisplatin-based regimens has prompted efforts to develop better-tolerated, equally efficacious treatments. To this end, trials have considered the use of newer agents, either as monotherapy or in combination regimens, and the use of carboplatin in lieu of cisplatin in doublet regimens. In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum agent. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-Aventis), paclitaxel, and, more recently, pemetrexed (Alimta, Lilly). A large trial comparing cisplatinpaclitaxel to 3 other regimens—carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabine—showed that all 4 regimens are equivalent.5 Notably, results from the Phase III study by Scagliotti et al, the largest ever performed in first-line NSCLC treatment (N=1,725), confirmed a statistically significant survival advantage for nonsquamous cell patients treated with cisplatin-pemetrexed, compared with cisplatingemcitabine (median OS, 11.8 vs 10.4 months, respectively; hazard ratio [HR], 0.81; P=0.005).7 This is the first Phase III trial that showed a survival difference based on histology.

Newer Targeted Therapies With the advent of new targeted therapies, first-line chemotherapy for advanced NSCLC is changing. Given limited OS prolongation with current chemotherapy regimens, new drug development has focused on the goals of improving tolerance, QoL, and ease of administration while maintaining comparable efficacy to standard first-line therapy. The Phase III ECOG 4599 trial evaluated first-line platinum doublet therapy with and without the anti-VEGF (vascular endothelial growth factor) antibody bevacizumab (Avastin, Genentech).3 This trial evaluated carboplatin and paclitaxel versus carboplatin and paclitaxel plus bevacizumab as initial therapy and as maintenance in patients with advanced NSCLC. Chemotherapy was

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administered every 3 weeks for 6 cycles, and then maintenance bevacizumab was administered every 3 weeks until disease progression or intolerable side effects occurred. Median survival increased by more than 2 months, with significant improvements in response rate (35% vs 15%) and progression-free survival (PFS; 6.2 mo vs 4.5 mo). The pivotal FLEX (First-Line Erbitux in Lung Cancer) trial compared the cisplatin-vinorelbine doublet plus cetuximab (Erbitux, Bristol-Myers Squibb) versus cisplatin and vinorelbine alone and showed that OS was significantly improved in the cetuximab-containing arm in patients with advanced epidermal growth factor receptor (EGFR)-detectable NSCLC.8 Further analysis of the FLEX data showed that gender, ethnicity, PS, histologic subtype, and smoking status had prognostic significance for patients with advanced NSCLC. Specifically, women had longer survival than men (12.7 vs 9.3 mo), Asians had a longer survival than whites (median, 19.5 vs 9.6 mo), and patients with a higher PS and those who never smoked had better prognoses than patients with lower PS and smokers. Data presented at ASCO in 2009 expanded on prognostic factors and molecular predictors of OS outcome from the FLEX trial. In one analysis of FLEX data, KRAS mutational status was found not to be predictive for cetuximab efficacy; however, patients taking cetuximab who developed an acne-like rash had a longer median OS than those without acne-like rash (15.0 vs 8.8 mo; HR, 0.63; 95% confidence interval [CI], 0.52-0.77; P<0.001).9 Improvements in OS seen with molecular targeted therapies against VEGF and EGFR combined with platinum doublets in patients with advanced NSCLC (E4599, FLEX)3,8 have led to further investigation of the combined effects. A Southwest Oncology Group (SWOG 0536) Phase II study combined 4 drugs—cetuximab, bevacizumab, carboplatin, and paclitaxel—for up to 6 cycles followed by maintenance bevacizumab weekly until disease progression.10 The primary end point was the frequency and severity of hemorrhagic toxicities that were grade 4 or higher in patients with advancedstage nonsquamous cell NSCLC. Combining carboplatin, paclitaxel, cetuximab, and bevacizumab resulted in a safe and tolerable safety profile, with a 2% incidence of hemorrhage that was grade 4 or higher (95% CI, 0-7%). Biomarkers from patients receiving this highly active regimen are being assessed via tissue (EGFR FISH [fluorescence in situ hybridization] and KRAS) and blood (cytokine/angiogenic profiling) analyses. Additional Phase III studies—INTEREST (Iressa Nonsmall cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) and IPASS (First-line Iressa Versus Carboplatin/Paclitaxel in Asia)—have compared biological therapy alternatives to traditional chemotherapeutic agents with favorable outcomes. INTEREST is a randomized Phase III trial comparing gefitinib (Iressa, AstraZeneca) with docetaxel in previously treated patients with NSCLC.11 The main objective of INTEREST was to compare OS, along with analyses to assess noninferiority of gefitinib in the maintenance

Table. Selected Trials of Maintenance Therapy in Advanced NSCLC Clinical Trial

Treatment Arms

PFS, mo

Median OS, mo

Fidias et al18 (JCO 2009)

GC then immediate docetaxel GC then delayed docetaxel

309

5.6 (P=0.001) 2.7

12.3 (P=0.0853) 9.7

Capuzzo et al (SATURN)19

CT then E CT then P

438 451

E significantly increased PFS longer than P (P<0.001)

12 11

Pemetrexed + BSC P + BSC

441 222

Overall/NSQ/SQ 4.3/4.37/2.43 2.6/1.84/2.50

Overall/NSQ/SQ 13.4/15.5/9.9 10.6/10.3/10.8

CT + B then B + P CT + B then B + E

768

3.7 4.8

Belani et al20

Miller et al21 (ATLAS)

B, bevacizumab; BSC, best supportive care; CT, first-line platinum-based chemotherapy; E, erlotinib; GC, gemcitabine-carboplatin; NA, not available; NSQ, nonsquamous histology; OS, overall survival; P, placebo; PFS, progression-free survival; SQ, squamous histology

setting in the overall protocol population and superiority in patients with an increased number of EGFR gene copies in the intent-to-treat population. Results showed noninferiority of gefitinib compared with docetaxel for OS (7.6 months in the gefitinib arm versus 8 months in the docetaxel arm; 593 vs 576 events; HR, 1.020; 95% CI, 0.905-1.150). However, in patients with a high number of EGFR gene copies, gefitinib did not show superiority for OS (median survival, 8.4 vs 7.5 months; 72 vs 71 events; HR, 1.09; 95% CI, 0.78-1.51; P=0.62). Recent data from the IPASS trial have shown that the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib was a valid up-front therapy for advanced NSCLC in nonsmokers or former light smokers with adenocarcinoma in Asia.12 The large IPASS study compared primarily PFS in Chinese patients with advanced NSCLC who received gefitinib or carboplatin-paclitaxel. The IPASS population consisted of 1,217 chemotherapy-na誰ve never smokers or light exsmokers with World Health Organization PS 0-2, adenocarcinoma histology, and stage IIIB/IV disease. The patients on gefitinib exceeded the primary end point of PFS advantage versus carboplatin-paclitaxel (HR, 0.741; 95% CI, 0.651-0.845; P<0.0001). Also, preliminary OS (28% maturity; follow-up ongoing) was similar for gefitinib and carboplatin-paclitaxel, but QoL improvement rates were higher with gefitinib than with carboplatin-paclitaxel, with a more favorable tolerability profile. In IPASS, EGFR mutational status appeared to be a strong biomarker for gefitinib efficacy, with statistically significant improvement in PFS compared with carboplatin-paclitaxel. A shorter cumulative smoking history has been shown to be predictive of EGFR mutations; this characteristic may warrant early genetic screening to tailor therapy.13 This highlights a need for a paradigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy.

Maintenance Therapy: Treat Until Disease Progression Debate continues about delayed (second- or thirdline) versus immediate (maintenance) chemotherapy in patients who have already received first-line therapy. Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in metastatic NSCLC (Table).14-21 Maintenance chemotherapy could be either continuation of one or more of the initial chemotherapy agents or the addition of a new chemotherapeutic or targeted agent. In a large, multicenter Phase III trial, Fidias et al compared docetaxel given immediately for up to 6 cycles in patients without disease progression after initial chemotherapy, with docetaxel given on disease progression (a comparison of immediate versus delayed docetaxel).18 Maintenance docetaxel was associated with a statistically significant improvement in PFS and a trend toward improvement in OS. Several large Phase III trials of maintenance therapy presented at the 2009 ASCO annual meeting used either erlotinib (Tarceva, OSI Pharmaceuticals), erlotinib plus bevacizumab, or pemetrexed as maintenance therapy. The large Phase III SATURN trial tested erlotinib maintenance vs placebo after platinum-based doublet chemotherapy in stage IIIB/IV NSCLC. The SATURN trial met its primary end point of PFS, with results showing significantly increased PFS with erlotinib in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001) as well as improved OS (12 vs 11 months).19 Another large Phase III trial evaluated pemetrexed, an attractive option for maintenance therapy because of its favorable tolerability profile. Preliminary results from this trial of 663 patients with advanced NSCLC who did not progress on an initial platinum-based doublet showed

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Adenocarcinoma or nonsquamous

EGFR mutationpositive

Gefitinib Erlotinib

Squamous

EGFR mutationnegative or unknown

Bevacizumab + chemotherapy doublet a

Chemotherapy doublet with or without cetuximab a

Non-bevacizumab chemotherapy doublet (pemetrexed-based) a

Maintenance therapy Pemetrexed a Erlotinib with or without bevacizumab Docetaxel

Disease Progression

Salvage therapy Consider clinical trial

Figure. Proposed algorithm for treatment of NSCLC. a

FDA-approved regimens

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer

that pemetrexed maintenance resulted in significantly better OS than placebo (13.4 vs 10.6 months, respectively [HR, 0.79; 95% CI, 0.65-0.95; P=0.012]).20 There was also a significantly increased PFS in patients who received pemetrexed maintenance instead of placebo (P<0.0001). Pemetrexedâ&#x20AC;&#x2122;s efficacy, favorable tolerability profile, ease of administration, and now, OS benefits make it appealing as a maintenance drug in advanced NSCLC. In July 2009, the FDA approved pemetrexed for maintenance treatment of patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy. Although most studies discussing maintenance options at ASCO 2009 tested nonâ&#x20AC;&#x201C;cross-resistant regimens, the ATLAS Phase III trial compared bevacizumab therapy with or without erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of advanced NSCLC.21 The ATLAS study, the first to evaluate combination versus single-agent maintenance therapy options, showed significant improvement in PFS in the combination therapy group (4.8 vs 3.7 months; HR, 0.722; 95% CI, 0.592-0.881; P=0.0012).

Biomarkers and Therapy Now that there are more options for treatment of NSCLC, it is important to look for predictors of efficacy

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so that the right therapy can be given to the appropriate patient. In clinical practice, phenotypic factors such as the lack of or light smoking history, histology, or ethnicity may help determine the choice of therapy. However, genotypic explanations still are being pursued.

HISTOLOGY MATTERS In 2007, a retrospective analysis using subset histology data from a Phase III study in 571 patients with previously treated advanced NSCLC22 identified a statistically significant improvement in OS for nonsquamous patients treated with pemetrexed, compared with those treated with docetaxel (median OS, 9.3 vs 8 months, respectively; HR, 0.778; P=0.048).23 In addition, prespecified analyses to examine efficacy according to NSCLC histology in 2 subsequent Phase III studies of pemetrexed as first-line and maintenance treatment confirmed these results.4,7 Scagliotti et al conducted the first prospective study to show survival differences based on histology.7 OS was significantly superior for cisplatin-pemetrexed versus cisplatin-gemcitabine in patients with adenocarcinoma (n=847; 12.6 vs 10.9 months, respectively) and large cell carcinoma histology (n=153; 10.4 vs 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with

cisplatin-gemcitabine compared with cisplatin-pemetrexed (n=473; 10.8 vs 9.4 months, respectively).24 Later, Belani reported a benefit for patients with nonsquamous histology treated with pemetrexed, which is a thymidylate synthase (TS)-inhibiting agent.20 In NSCLC, baseline TS levels are higher in squamous cell carcinoma compared with adenocarcinoma.25 Data on TS expression recently have been broadened to include undifferentiated large cell carcinoma. In a study presented at ASCO 2009, Scagliotti et al evaluated mRNA and protein levels among large cell and squamous cell carcinoma and adenocarcinoma samples.26 Significantly higher median TS levels were detected in the large cell and squamous cell carcinoma samples compared with the adenocarcinoma samples (large cell carcinoma: P<0.001 for both mRNA and protein values; squamous cell carcinoma: P=0.002 for mRNA, P<0.001 for protein).

EGFR, VEGF,

AND

KRAS

Somatic mutations in the tyrosine kinase domains of 2 ERBB (epidermal growth factor receptor) genes— the EGFR and HER2 (human epidermal growth factor receptor 2) genes—have been found in a number of lung adenocarcinomas. EGFR mutations are associated with sensitivity to the TKIs gefitinib27-29 and erlotinib.30 However, markers of resistance to EGFR inhibitors have also been identified.31,32 Approximately 15% to 30% of lung adenocarcinomas contain activating mutations in the KRAS gene and may be associated with unfavorable outcomes.33 Unlike in colon cancer, in lung cancer, mutations in KRAS are not associated with a lack of sensitivity to either of the EGFR inhibitors.34 So, although SATURN demonstrated improved PFS in advanced NSCLC patients with EGFR mutations with EGFR inhibitor maintenance therapy, KRAS had no predictive value for erlotinib therapy.

BIOMARKER PREDICTABILITY The Phase II S0536 study showing combined carboplatin, paclitaxel, cetuximab plus bevacizumab demonstrated safety, tolerability, and encouraging efficacy in advanced NSCLC.10 Further biomarker studies in S0536 are under way, including tissue (EGFR FISH and KRAS) and blood (cytokine/angiogenic profiling) analyses, with the hope of validating the combination of chemotherapy with EGFR and VEGF inhibition and EGFR FISH as a predictive biomarker (SWOG 0819).

BROADER GENOTYPE TESTING Beyond the paradigm of genotype testing for EGFR and KRAS mutations, newer molecular profiling (EML4ALK and insulin-like growth factors [IGFs]) associated with lung cancer are leading to Phase I trials for molecular targeted therapy. Specifically, EML4-ALK is a novel fusion oncogene in NSCLC.35 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. At ASCO 2009, Shaw showed that EML4-ALK mutations result in a similar clinical profile

as seen in patients with EGFR mutations and are particularly frequent in light or never smokers (100% vs 43%; P<0.001); however, unlike EGFR mutations, they are found more often in males (61% vs 30%; P=0.015).36 Patients with EML4-ALK mutations did not benefit from EGFR TKIs; there were no responses in the ALK cohort. A Phase I trial has begun testing the ALK inhibitor PF-02341066,37 and promising initial data have allowed early development of a Phase III trial of an ALK inhibitor with docetaxel as second-line therapy. IGF receptors also are showing promise as a target in the treatment of NSCLC.38 CP-751871 (Pfizer), an anti-IGF-1R receptor antibody, was tested in combination with chemotherapy in treatment-naïve patients with advanced NSCLC. Updated results presented at ASCO 2008 showed a significant response of 51% in the CP-751871 arm.39 Of particular significance is the impressive 72% response seen in the subgroup of patients with squamous cell histology. In view of these results, a Phase III trial will test CP-751871 with a platinum-based doublet in the first-line setting.

Conclusion It is exciting to see paradigms in first-line and maintenance settings of advanced NSCLC evolving toward targeted molecular therapies with better tolerability profiles. Based on recent studies, new standards of management in advanced NSCLC must be considered, evaluating the roles of histology, maintenance therapy, and testing for mutations in EGFR (Figure). Each patient with NSCLC presents a unique challenge, and therapy should be directed by more than just PS. Agents targeting EGFR, VEGF, IGF-1 receptor, and ALK pathways in NSCLC have demonstrated that different lung cancers respond differently to therapy. Efforts must continue to understand the biology of individual tumors by emphasizing tissue-based clinical trials to create patient-specific therapy.40

References 1.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225-249, PMID: 19474385.

2. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials for patients with advanced non-small-cell lung cancer; sobering results. J Clin Oncol. 2001;19(6):1734-1742, PMID: 11251004. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550, PMID: 17167137. 4. Ciuleanu TE, Brodowicz T, Belani CP, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study. J Clin Oncol. 2008;26:426(suppl): Abstract 8011. 5. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98, PMID: 11784875. 6. Non-small Cell Lung Cancer Collaborative Group (NSCL-CG). Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311(7010):899-909, PMID: 7580546. continued on page 36

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Which patient is at risk?

One in three patients may be compromised by chemotherapy-induced neutropenia Nearly one in three chemotherapy patients (29.3% overall) are impacted by febrile or severe neutropenia, according to a recent prospective registry of 2,692 patients that included all major tumor types.1 Data showed that neutropenia risk was greatest in the first cycle, but persisted throughout cycles 2 and 3.*1 A separate, retrospective analysis demonstrated that a longer duration of severe neutropenia was directly related to an increased risk of febrile neutropenia.2

What are some immediate consequences?

Figure. Inpatient mortality for patients hospitalized due to febrile neutropenia by number of comorbidities4 60 Inpatient mortality (%)

Why does neutropenia matter?

50.6 38.6

21.4 20

10.3

9.5 2.6 0

Immediate complications of neutropenia can include infection and fever, which may require hospitalization. The projected incidence of neutropenia-related hospitalizations is over 60,000 cases per year in the US, according to one retrospective analysis.3 Short-term consequences of febrile neutropenia–related hospitalization may include prolonged lengths of stay, related costs, and the risk of inpatient mortality.4 In another retrospective database analysis (N = 41,779), the mean inpatient mortality rate for febrile neutropenia– related hospitalization was 9.5% overall (n = 3,967).4 Researchers found that inpatient mortality increased with the number of comorbidities, climbing from 21% for those with 2 comorbidities (n = 1,255 of 5,865) to over 50% for patients with 4 or more (n = 181 of 358) (see Figure).4

What are potential long-term consequences? Dose delays and reductions due to severe and febrile neutropenia impact treatment plans, which can threaten outcomes for some patients.5-9 Retrospective analyses support the hypothesis that delivery of chemotherapy at the recommended dose intensity is an important factor in determining patient survival in some tumor types.9-13 In these studies, adhering to planned treatments significantly increased survival rates in both non-Hodgkin’s lymphoma (NHL) and early-stage breast cancer patients.9-13 The retrospective NHL analysis demonstrated significantly improved median survival (7.08 years) for patients who received > 90% average relative dose intensity of CHOP-21 compared with those who received ≤ 90% (n = 210; P = 0.002).9

Overall

2 Comorbidities

Retrospective analysis of claims data from 115 member-institutions of the University HealthSystem Consortium, including discharge summaries and charges for all adult (≥ 18 years) cancer patients hospitalized for febrile neutropenia between 1995 and 2000 (N = 41,779). Comorbidities included congestive heart failure, other heart diseases, lung disease, liver disease, renal disease, diabetes mellitus, cerebrovascular disease, peripheral vascular disease, deep venous thrombosis, pulmonary embolism, anemia, or a transfusion requirement.

How can you be certain if your patient is at risk? When neutropenia occurs, as it does for nearly one in three patients, treatment goals may be unintentionally compromised and serious consequences may ensue, including death.1,3-9,14 Take steps to determine which patients are at risk. • Consider the febrile neutropenia risk potential for the chemotherapeutics administered, alone or in combination • Assess patient risk factors including comorbidities (eg, age ≥ 65, poor performance status, poor nutritional status, COPD, cardiovascular disease, diabetes mellitus, etc) • Evaluate each patient prior to each cycle

To request a febrile neutropenia Risk Assessment Checklist, email: FNchecklist@amgen.com.

Assess the risk.

*Crawford et al, J Natl Compr Canc Netw, 2008. Nationwide, prospective registry study conducted in 115 community-based, randomly selected, IRB-approved sites, evaluating the incidence and timing of neutropenia and neutropenic events in the first cycle and in cycles 2–3. References: 1. Crawford J, et al, for the Awareness of Neutropenia in Chemotherapy Study Group. J Natl Compr Canc Netw. 2008;6:109-118. 2. Meza L, et al. Proc Am Soc Clin Oncol. 2002;21: Abstract 2840. 3. Caggiano V, et al. Cancer. 2005;103:1916-1924. 4. Kuderer N, et al. Cancer. 2006;106:2258-2266. 5. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 6. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 7. Link B, et al. Cancer. 2001;92:1354-1367. 8. Picozzi V, et al. Oncology. 2001;15:1296-1306. 9. Bosly A, et al. Ann Hematol. 2008;87:277-283. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 12. Bonadonna G, et al. BMJ. 2005;330:217-222. 13. Kwak L, et al. J Clin Oncol. 1990;8:963-977. 14. Lyman G. J Natl Compr Canc Netw. 2009;7:99-108.

continued from page 33

7. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551, PMID: 18506025. 8. Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(suppl): Abstract 3. 9. Pirker R, Rodrigues-Pereira J, Szczesna A, et al. Prognostic factors in advanced NSCLC: experience from the FLEX trial. J Clin Oncol. 2009;27(15 suppl): Abstract 8083. 10. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD3.5.5. Presented at the 2009 IASLC World Congress on Lung Cancer; San Francisco, CA; July 31-August 4, 2009. 11. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized Phase III trial. Lancet. 2008;372(9652):1809-1818, PMID: 19027483. 12. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957, PMID: 19692680. 13. Jida M, Toyooka S, Mitsudomi T, et al. Usefulness of cumulative smoking dose for identifying the EGFR mutation and patients with non-small-cell lung cancer for gefitinib treatment. Cancer Sci. 2009;100(10):1931-1934, PMID: 19650855. 14. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV nonsmall-cell lung cancer. J Clin Oncol. 2002;20(5):1335-1343, PMID: 11870177.

Oncol. 2004;22(9):1589-1597, PMID: 15117980. 23. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): P2-328. J Thorac Oncol. 2007;2(8):S851: Abstract P2-328. 24. Scagliotti G, Purvish P, von Pawel J, et al. Phase III study of pemetrexed plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC): PRS-03. J Thorac Oncol. 2007;2(8):S306: Abstract PRS-03. 25. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107(7):1589-1596, PMID: 16955506. 26. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27:15(suppl): Abstract 7521. 27. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139, PMID: 15118073. 28. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500, PMID: 15118125. 29. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311, PMID: 15329413. 30. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144, PMID: 16014883.

15. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25(33):5233-5239, PMID:18024869.

31. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792, PMID: 15728811.

16. Westeel V, Quoix E, Moro-Sibilot D, et al. Randomized study of maintenance vinorelbine in responders with advanced nonsmall cell lung cancer. J Natl Cancer Inst. 2005;97(7):499-506, PMID: 15812075.

32. Morgillo F, Kim WY, Kim ES, Ciardello F, Waun KH, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13(9):2795-2803, PMID: 17473213.

17. Sculier JP, Lafitte JJ, Lecomte J, et al. A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol. 2007;18(6): 1037-1042, PMID: 17404152.

33. Rodenhuis S, Slebos RJ. The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990;142(6 Pt 2):S27-S30, PMID: 2252272.

18. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-598, PMID: 19075278. 19. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27:15(suppl): Abstract 8001. 20. Belani CP, Brodowicz T, Ciuleanu T, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: a randomized phase III study in advanced nonsmall cell lung cancer (NSCLC). J Clin Oncol. 2009;27:18(suppl): Abstract CRA8000. 21. Miller VA, O’Connor P, Soh C, et al. A randomized, doubleblind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;2718PLS CONFIRM(suppl): Abstract LBA8002. 22. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–smallcell lung cancer previously treated with chemotherapy. J Clin

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34. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):e17, PMID: 15696205. 35. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature. 2007;448(7153):561-566, PMID: 17625570. 36. Shaw AT, Costa D, Mino-Kenudson M, et al. Clinicopathologic features of EML4-ALK mutant lung cancer. J Clin Oncol. 2009;27:15(suppl): Abstract 11021. 37. Kwak EL, Camidge DR, Clark J, et al. Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066. J Clin Oncol. 2009;27:15(suppl): Abstract 3509. 38. Karp DD, Paz-Ares LG, Blakely LJ, et al. Efficacy of the anti-insulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2007;25;(18 suppl): Abstract 7506. 39. Karp DD, Paz-Ares LG, Novello S, et al. High activity of the antiIGF-IR antibody CP-751,871 in combination with paclitaxel and carboplatin in squamous NSCLC. J Clin Oncol. 2008;26(suppl): Abstract 8015. 40. Kim ES, Herbst RS, Lee JJ, et al. Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program. J Clin Oncol. 2009;27(15 suppl): Abstract 8024.

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION BRIEF SUMMARY (OVARIAN). For complete safety please consult the package insert for complete prescribing information. INDICATION AND USAGE: THERAPEUTIC INDICATION—Ovarian Cancer—Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. CLINICAL STUDIES: Ovarian Cancer—Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS). The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms. CONTRAINDICATION: Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see Allergic under ADVERSE REACTIONS). WARNINGS: Caution—Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES in the full Prescribing Information). Hematology—Gemzar can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. See DOSAGE AND ADMINISTRATION in the full Prescribing Information for recommended dose adjustments. Pulmonary—Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Renal—Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS (see Renal under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Hepatic—Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Pregnancy—Pregnancy Category D. Gemzar can cause fetal harm when administered to a pregnant woman. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to the fetus. PRECAUTIONS: General—Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle. Laboratory Tests—Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected (see DOSAGE AND ADMINISTRATION in the full Prescribing Information). Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300 the human dose on a mg/m2 basis). Pregnancy—Category D. See WARNINGS. Nursing Mothers—It is not known whether Gemzar or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Gemzar in nursing infants, the mother should be warned and a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the potential risk to the infant. Elderly Patients—Gemzar clearance is affected by age (see CLINICAL PHARMACOLOGY in the full Prescribing Information). There is no evidence, however, that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. Gender—Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY in the full Prescribing Information). In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in women. In general, in single-agent studies of Gemzar, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. Pediatric Patients—The effectiveness of Gemzar in pediatric patients has not been demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial. Patients with Renal or Hepatic Impairment—Gemzar should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency. GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

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Drug Interactions—No specific drug interaction studies have been conducted. For information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug Interactions under CLINICAL PHARMACOLOGY. Radiation Therapy—A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar. Non-concurrent (given >7 days apart)—Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or ≤7 days apart)—Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types. ADVERSE REACTIONS: Combination Use in Ovarian Cancer—In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse events between arms (10.9% versus 9.8%, respectively). Table 1 presents the adverse events (all grades) occurring in ≥10% of patients in the ovarian cancer study. Table 1: Adverse Events From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 b Laboratory Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 38 15 RBC Transfusions c c 9 3 Platelet Transfusions Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Neuropathy-sensory 29 1 0 27 2 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Anorexia 16 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. In addition to blood product transfusions as listed in Table 1, myelosuppression was also managed with hematopoetic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse events, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse events (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Post-marketing experience—The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar. Cardiovascular—Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders—Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin—Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic—Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Pulmonary—Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal—Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported (see Radiation Therapy under PRECAUTIONS). Dosage and administration: Gemzar is for intravenous use only. Please consult full prescribing information for complete dosage and administration guidelines.

Literature revised May 7, 2007 PV 4067 AMP

PRINTED IN USA

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What are her options when her ovarian cancer has recurred? GEMZAR/carboplatin is one option for 2nd-line treatment of your patients with platinum-sensitive* advanced ovarian cancer. Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

GEMZAR in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

Overall response rate (%)†

Median progression-free survival (months) GEMZAR plus Carboplatin

95% Cl (8.0-9.7) (N=178)

Carboplatin 95% Cl (5.2-7.1) (N=178)

(p=0.0038)

GEMZAR plus Carboplatin (N=178)

8.6

5.8 6

(p=0.0016)

Carboplatin (N=178)

10%

47.2%

30.9% 20%

30%

40%

50%

patients are defined as patients who develop disease progression ≥6 months after receiving first-line platinum-based chemotherapy. Investigator-reviewed.

* Platinum-sensitive †

The overall survival difference between GEMZAR/carboplatin (18.0 months) vs carboplatin (17.3 months) was not significant (p=0.8977). Select Important Safety Information GEMZAR should not be administered to patients with known hypersensitivity to this drug. Infusion times of GEMZAR longer than 60 minutes and more frequent than weekly dosing have been shown to increase toxicity. Pulmonary toxicity has been reported. In cases of severe lung toxicity, GEMZAR therapy should be discontinued immediately and appropriate supportive care measures instituted. Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of GEMZAR. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs. GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman. Use caution in patients with pre-existing renal impairment or hepatic insufficiency. Administration of GEMZAR may exacerbate underlying hepatic insufficiency. The optimum regimen for safe administration of GEMZAR with therapeutic doses of radiation has not yet been determined in all tumor types. GEMZAR has radiosensitizing activity and radiation recall reactions have been reported. It is not known whether GEMZAR or its metabolites are excreted in GEMZAR® is a registered trademark of Eli Lilly and Company. GC58321 0509 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

human milk. The effectiveness of GEMZAR in pediatric patients has not been demonstrated. The toxicities of GEMZAR observed in pediatric patients were similar to those reported in adults. GEMZAR clearance is affected by age as well as gender. Patients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Abbreviated Adverse Events (% incidence) The most severe adverse events (Grades 3/4) with GEMZAR plus carboplatin versus carboplatin alone, respectively, for the treatment of patients with advanced ovarian cancer were neutropenia (71 vs 12); thrombocytopenia (35 vs 11); leukopenia (53 vs 7); anemia (28 vs 11); nausea (6 vs 3); vomiting (6 vs 3); and constipation (7 vs 3). The most common adverse events (all Grades) were neutropenia (90 vs 58); leukopenia (86 vs 70); anemia (86 vs 75); thrombocytopenia (78 vs 57); RBC transfusion (38 vs 15); alopecia (49 vs 17); neuropathy/sensory (29 vs 27); nausea (69 vs 61); fatigue (40 vs 32); vomiting (46 vs 36); diarrhea (25 vs 14); and constipation (42 vs 37). For additional safety information, please see Brief Summary of Prescribing Information on adjacent page. For more information about cancer treatment with GEMZAR, visit GEMZAR.com.

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Chemotherapy Options in the Management of

Platinum-Resistant Recurrent Ovarian Cancer MARCELA G.

DEL

CARMEN, MD, MPH

n estimated 75% of women with ovarian cancer present with advanced (stage III or IV)

disease. For women in stages III or IV with a low volume of residual disease (all lesions <2 cm in size), the risk for recurrence after primary surgery is 60% to 70%; however, for women with large-volume residual disease, the risk is estimated at 80% to 85%.1

The selection of therapy for women with recurrent disease is in large part determined by response to first-line therapy. Specifically, recurrent ovarian cancer has been dichotomized to either platinum-sensitive (progressionfree interval [PFI], >6 months) or platinum-resistant (PFI, â&#x2030;¤6 months),2,3 with PFI predicting expected response rate (RR) and duration of response (Table 1).4 Regardless of the treatment selected, recurrent ovarian cancer remains incurable, and the goals of therapy should focus on palliation of cancer-related symptoms, prolongation of life, and maintenance of quality of life. This review will focus on the medical treatment, specifically chemotherapy options, available for women with platinum-resistant disease.

Timing and Type of Treatment Recurrent ovarian cancer may be detected based on new symptoms or the results of imaging studies, or may

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

be suspected in an asymptomatic patient with a rising serum concentration of tumor marker, CA-125.5,6 Given that recurrent disease is not curable, the therapeutic goals of the patient should help guide decisions about second-line therapy.7 In women with symptomatic recurrences, immediate institution of therapy may be indicated as a means to palliate cancer-related symptoms. Timing of therapy in women with asymptomatic recurrences (rising CA-125) is more controversial. Advocates of immediate treatment maintain that small-volume disease is more likely to respond to early intervention.8-10 This argument is less likely to be true for patients with platinum-resistant disease. Those advocating delayed treatment argue that, because the goal is palliation and given the lack of data that early intervention improves survival, therapy should be deferred until symptom onset.11 This controversy was addressed in a recent prospective study of 1,442 women with ovarian cancer. Patients

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 0 0 9 â&#x20AC;˘ N O. 2

Table 1. Characteristics of PlatinumSensitive and Platinum-Resistant Recurrent Ovarian Cancer Platinum-Sensitive Disease PFI >6 mo

considered. Another consideration is combination versus single-agent therapy. Although higher response rates and longer 2- to 3-month progression-free survival (PFS) generally are seen with the use of combination regimens,13-15 combination therapy is associated with higher toxicity and no improvement in overall survival (OS) when compared with single-agent therapy.13-15

Available Chemotherapy Options TAXANES

High probability of responding again to platinum-based treatment

Several drugs have documented activity in platinumresistant disease. In Phase II and III clinical trials, singleagent paclitaxel resulted in objective responses in 22% to 30% of patients.16-19 Several dosing and scheduling regimens for paclitaxel have been investigated. Table 2 describes some of these options.20-23 Single-agent docetaxel (Taxotere, Sanofi-Aventis) is more toxic and less effective than paclitaxel.24,25 In a Phase II trial of 60 patients with platinum-resistant disease, a 22% objective RR was seen, with a 2.5-month median response duration.24 Grade 4 neutropenia was reported in 75% of the women treated with docetaxel.24

Platinum-Resistant Disease PFI <6 mo Progression during platinum-based therapy (platinum-refractory disease) Stable disease as best response to platinumbased therapy Poorer prognosis, less likely to respond to second-line therapy PFI, progression-free interval

PEGYLATED LIPOSOMAL DOXORUBICIN were in complete clinical remission from their cancer, with a normal CA-125 level after completion of primary surgical and platinum-based systemic therapies.12 Investigators and patients were blinded. Participants had their serum CA-125 assayed every 3 months. Women whose CA-125 rose to a level twice above the upper limit of normal and remained asymptomatic (n=527) were randomized to immediate treatment or treatment at clinical or symptomatic recurrence. Preliminary analysis shows that women randomized to immediate therapy initiated chemotherapy a median of 5 months earlier. At 57-month follow-up, survival and remission duration were comparable between the 2 arms. Quality of life was worse for the women undergoing immediate treatment. Whether treatment is initiated immediately or delayed, nonâ&#x20AC;&#x201C;cross-resistant agents should be

In a Phase III trial, pegylated liposomal doxorubicin (PLD; Doxil, Ortho Biotech) was compared with topotecan (Hycamtin, GlaxoSmithKline) in women with recurrent ovarian cancer, following one platinum-containing regimen.26,27 A similar overall RR (20% vs 17%), time to progression (22 vs 20 weeks), and median OS (66 vs 56 weeks) were documented with each regimen.26 A significant OS advantage was noted at longer follow-up among patients treated with PLD, especially those with platinumsensitive disease (hazard ratio, 0.82; 95% confidence interval, 0.68-1.0).27 When compared with topotecan, PLD was associated with lower rates of neutropenia, anemia, and thrombocytopenia and higher rates of handâ&#x20AC;&#x201C;foot syndrome and stomatitis.27 Preliminary review of data from a Phase III trial comparing PLD with paclitaxel indicates that the regimens were similar in terms of response rates, PFI,

Table 2. Dosing and Scheduling Options for Paclitaxel Dose, mg/m2

Scheduling

Infusion Time, h

Observations

Author

135

Every 3 wk

3 or 24

RR similar for 135 and 175 mg/m2 doses; 3-h infusion associated with less myelosuppression, more neurotoxicity

Eisenhauer20

175

Every 3 wk

3 or 24

3-h infusion associated with less myelosuppression, more neurotoxicity

Eisenhauer20

Weekly

Toxicity, especially myelosuppression, minimized when compared with every 3 wk schedule; predominant toxicities: asthenia, peripheral neuropathy

Markman21 Kita22 Markman23

RR, response rate

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Table 3. Dosing and Scheduling Regimen Options for Topotecan Dose, mg/m2

Scheduling

RR, %

Toxicity

Author

1.5

Days 1-5 (consecutive, every 28 d)

15-20

70%-80% grade 4 neutropenia; 25% febrile neutropenia, with or without infection; efficacy preserved with less hematologic toxicity at 1 mg/m2, days 1-5 (consecutive) dose

Gordon26 McGuire33 Bookman35 Kudelka36 Hoskins37

Days 1-3 (consecutive, every 28 d)

24-32

90% grade 3-4 neutropenia; 8% febrile neutropenia

Brown38 Herzog39

Days 1, 8, 15 (every 28 d)

20-27

<10% grade 3 or 4 neutropenia

Safra40 Abushahin41

and OS.28 Handâ&#x20AC;&#x201C;foot syndrome is seen in 20% of patients treated with PLD at a dose of 50 mg/m2 every 4 weeks.29 Similar efficacy with lower toxicity has been seen at lower doses (35-40 mg/m2 every 4 weeks).30,31

TOPOTECAN Topotecan is another agent with similar efficacy to paclitaxel and PLD in the treatment of platinum-resistant recurrent ovarian cancer.32 Its use usually is associated with some degree of myelosuppression, especially neutropenia.26,33 Concomitant use of amifostine (Ethyol, MedImmune Oncology) with topotecan in heavily pretreated patients has been reported to lower the risk for hematologic toxicity.34 Table 3 lists some of the available regimens for topotecan.26,33,35-41

mg/m2 given weekly for 3 out of every 4 weeks, was associated with a 19% response rate.42 In a nonequivalency trial comparing gemcitabine with PLD, no significant differences were seen between the 2 agents with respect to overall RRs (6.1% vs 8.3%), median PFS (3.6 vs 3.1 months), and median OS (12.7 vs 13.5 months).43 Gemcitabine in combination with PLD appears to be a welltolerated active regimen. In a study of 31 patients with platinum-resistant or refractory disease, a 33% objective RR was seen with this combination.44 Grade 3 or 4 neutropenia was seen in 25% of patients, underscoring the previously noted recommendation to consider single-agent therapy in the setting of platinum-resistant recurrence.

OTHER AGENTS GEMCITABINE Gemcitabine (Gemzar, Lilly), which is approved in combination with carboplatin for the treatment of platinum-sensitive recurrent ovarian cancer, also has been studied as a single-agent therapy in the setting of platinum-resistant disease. In a study of 50 patients with recurrent ovarian cancer, gemcitabine, at a dose of 800

Table 4 lists some of the other single-agent chemotherapy options appropriate for treating platinum-resistant disease.45-50

Conclusions Because recurrent ovarian cancer is not curable, the goals of therapy should focus on palliation of cancer-

Table 4. Additional Single-Agent Options for Platinum-Resistant Disease Agent

ORR, %

Toxicity

Author

Vinorelbine

3-29

Neutropenia, anemia, and worsening paresthesia

Sorensen45 Burger46

Oral etoposide

18-27

Leukopenia, neutropenia, thrombocytopenia, anemia

Slayton47 Rose48

Ifosfamide

Myelosuppression, nephrotoxicity, central nervous system toxicity

Markman49

Pemetrexed (Alimta, Lilly)

Myelosuppression

Miller50

ORR, overall response rate

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

related symptoms, extension of life, and maintenance of quality of life. In patients with platinum-resistant ovarian cancer, RRs are low and prognosis is generally poor. For most of these patients, single-agent therapy rather than combination therapy generally is recommended. There are few published studies of combination therapy in this setting,13-15 and no studies to date have compared combination regimens to sequential single-agent therapy. Combination therapies are associated with a higher response rate but greater toxicity. Single-agent therapy offers a potential balance between efficacy of treatment and an acceptable toxicity profile. Numerous agents have been shown to be active in the setting of platinum-resistant ovarian cancer. RRs for these agents are similar. The choice of therapy should take into consideration the agentâ&#x20AC;&#x2122;s sideeffect profile, previously encountered toxicity with other therapies, and convenience of drug administration. For some patients, consideration should be given to nonchemotherapeutic treatments. For example, biologics or targeted therapies (such as bevacizumab [Avastin, Genentech]) or hormones (such as tamoxifen) may be appropriate therapeutic choices for some patients with platinum-resistant recurrent ovarian cancer.

References 1.

Young RC, Walton LA, Ellenberg SS, et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med. 1990;322(15):1021-1027, PMID: 2181310.

2. Thigpen JT, Vance RB, Khansur T. Second-line chemotherapy for recurrent carcinoma of the ovary. Cancer. 1993;71(4 suppl):15591564, PMID: 8094320. 3. Markman M, Markman J, Webster K, et al. Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol. 2004;22(15):3120-3125, PMID: 15284263. 4. Pujade-Lauraine E, Paraiso D, Cure H, et al. Predicting the effectiveness of chemotherapy (Cx) in patients with recurrent ovarian cancer (ROC): a GINECO study. J Clin Oncol. 2002;21(suppl):Abstract 829. 5. Liu PY, Alberts DS, Monk BJ, Brady M, Moon J, Markman M. An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. J Clin Oncol. 2007;25(24):3615-3620, PMID: 17704410.

8. Cantu MG, Buda A, Parma G, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubucin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol. 2002;20(5):1232-1237, PMID: 11870165. 9. Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389-393, PMID: 1999708. 10. Ferrandina G, Ludovisi M, De Vicenzo R, et al. Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study. Ann Oncol. 2007;18(8):1348-1353, PMID: 17470449. 11. Canistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24): 2519-2529, PMID: 15590954. 12. Rustin GJ, van der Burg ME, et al. A randomized trial in ovarian cancer (OC) or early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials). J Clin Oncol. 2009;27(suppl):Abstract 1. 13. Karaoglu A, Arslan UY, Ozkan M, et al. Efficacy and toxicity of gemcitabine and pegylated liposomal doxorubicin in recurrent platinum-resistant/refractory epithelial ovarian cancer. Asian Pac J Cancer Prev. 2009;10(1):63-66, PMID: 19469626. 14. Skarlos DV, Kalofonos HP, Foutzilas G, et al. Gemcitabine plus pegylated liposomal doxorubicin in patients with advanced epithelial ovarian cancer resistant/refractory to platinum and/or taxanes. A HeCOG phase II study. Anticancer Res. 2005;25(4):3103-3108, PMID: 16080573. 15. Pectasides D, Xiros N, Papaxoines G, et al. Gemcitabine and pegylated liposomal doxorubicin alternating with cisplatin plus cyclophosphamide in platinum refractory/resistant, paclitaxel-pretreated, ovarian carcinoma. Gynecol Oncol. 2008;108(1):47-52, PMID: 17915300. 16. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273-279, PMID: 2569287. 17. Einzig AI, Wiernik PH, Sasloff J, Runowicz CD, Goldberg GL. Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol. 1992;10(11):17481753, PMID: 1357110. 18. Thigpen JT, Blessing JA, Ball H, Hummel SJ, Barrett RJ. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol. 1994;12(9):1748-1753, PMID: 7916038. 19. Kohn EC, Sarosy G, Bicher A, et al. Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst. 1994;86(1):18-24, PMID: 7505830. 20. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol. 1994;12(12):2654-2666, PMID: 7989941.

6. Santillan A, Garg R, Zahurak ML, et al. Risk of epithelial ovarian cancer recurrence in patients with rising serum CA-125 levels within the normal range. J Clin Oncol. 2005;23(36):9338-9343, PMID: 16361633.

21. Markman M, Hall J, Spitz D, et al. Phase II trial of weekly singleagent paclitaxel in platinum/paclitaxel-refactory ovarian cancer. J Clin Oncol. 2002;20(9):2365-2369, PMID: 11981009.

7. Doyle C, Crump M, Pintilie M, Oza AM. Does palliative chemotherapy palliate? Evaluation of expectations, outcomes, and costs in women receiving chemotherapy for advanced ovarian cancer. J Clin Oncol. 2001;19(5):1266-1274, PMID: 11230467.

22. Kita L, Kikuchi Y, Takano M, et al. The effect of single weekly paclitaxel in heavily pretreated patients with recurrent or persistent advanced ovarian cancer. Gynecol Oncol. 2004;92(3):813-818, PMID: 14984946.

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23. Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101(3):436-440, PMID: 16325893. 24. Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88(2):130-135, PMID: 12586591. 25. Markman M, Zanotti K, Webster K, et al. Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum. Gynecol Oncol. 2003;91(3):573-576, PMID: 14675679. 26. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322, PMID: 11454878. 27. Gordon AN, Teitelbaum A. Overall survival advantage for pegylated liposomal doxorubicin compared to topotecan in epithelial ovarian cancer. Eur J Cancer. 2003;12(suppl):Abstract 157.

ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol. 1998;16(6):2233-2237, PMID: 9626225. 38. Brown JV 3rd, Peters WA 3rd, Rettenmaier MA, et al. Threeconsecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer. Gynecol Oncol. 2003;88(2):136-140, PMID: 12586592. 39. Herzog TJ, Powel MA, Rader JS, Gibb R, Mutch DG. Phase II evaluation of a 3-day infusion of topotecan in patients with recurrent ovarian or primary peritoneal cancer. Gynecol Oncol. 2006;103(2):637-641, PMID: 16781766. 40. Safra T, Menczer J, Bernstein R, et al. Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Gynecol Oncol. 2007;105(1):205-210, PMID: 17239430. 41. Abushahin G, Singh DK, Lurain JR, Grendys EC, Rademaker AW, Schink JC. Weekly topotecan for recurrent platinum resistant ovarian cancer. Gynecol Oncol. 2008;108(1):53-57, PMID: 17904208.

28. O’Byrne KJ, Bliss P, Graham JD, et al. A phase III study of Doxil/ Caelyx versus paclitaxel in platinum-treated, taxane-naïve relapsed ovarian cancer. Proc Am Soc Clin Oncol. 2002;21:Abstract 808.

42. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (2’,2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst. 1994;86(20):1530-1533, PMID: 7932808.

29. Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol. 1997;15(3):987-993, PMID: 9060537.

43. Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25(19):2811-2818, PMID: 17602086.

30. Rose PG, Maxson JH, Fusco N, Mossbruger K, Rodriguez M. Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol. 2001;82(2):323-328, PMID: 11531287. 31. Markman M, Kennedy A, Webster K, Peterson G, Kulp B, Belinson J. Phase 2 trial of liposomal doxorubicin (40 mg/m2) in platinum/ paclitaxel-refactory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol. 2000;78(3 pt 1): 369-372, PMID: 10985896. 32. Peng L, Cheng X, Wu T. Topotecan for ovarian cancer. Cochrane Database Syst Rev. 2008;CD005589. 33. McGuire WP, Blessing JA, Bookman MA, Lentz SS, Dunton CJ. Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2000;18(5): 1062-1067, PMID: 100694558. 34. Gold MA, Walker JL, Berek JS, Hallum AV 3rd, Garcia DJ, Alberts DS. Amifostine pretreatment for protection against topotecaninduced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies. Gynecol Oncol. 2003;90(2):325-330, PMID: 12893194. 35. Bookman MA, Malmstrom H, Bolis G, et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that combined cisplatin or carboplatin and paclitaxel. J Clin Oncol. 1998;16(10):3345-3352, PMID: 9779711. 36. Kudelka AP, Tresukosol D, Edwards CL, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol. 1996;14(5):1552-1557, PMID: 8622071. 37. Hoskins P, Eisenhauer E, Beare S, et al. Randomized phase II study of two schedules of topotecan in previously treated patients with

44. Petru E, Angleitner-Boubenizek L, Reinthaller A, et al. Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and -resistant ovarian cancer after previous platinum-taxane therapy: a phase II Austrian AGO study. Gynecol Oncol. 2006;102(2):226-229, PMID: 16443259. 45. Sorensen P, Hoyer M, Jakobsen A, Malmstrom H, Havsten H, Bertelsen K. Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma. Gynecol Oncol. 2001;81(1):58-62, PMID: 11277650. 46. Burger RA, DiSaia PJ, Roberts JA, et al. Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol. 1999;72(2):148-153, PMID: 10021293. 47. Slayton RE, Creasman WT, Petty W, Bundy B, Blessing JA. Phase II trial of VP-16-213 in the treatment of advanced squamous cell carcinoma of the cervix and adenocarcinoma of the ovary: a Gynecologic Oncology Group Study. Cancer Treat Rep. 1979; 63(11-12):2089-2092, PMID: 526942. 48. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16(2):405-410, PMID: 9469322. 49. Markman M, Hakes T, Reichman B, et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992;10(2):243-248, PMID: 1732425. 50. Miller DS, Blessing JA, Krasner CN, Mannel RJ. A phase II evaluation of pemetrexed (LY231514, IND#40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecology Oncology Group. J Clin Oncol. 2008;26(suppl):Abstract 5524.

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In the treatment of higher-risk MDS *…

A Breakthrough in S U R V I V A L VIDAZA® is the ﬁrst and only agent proven to extend overall survival vs CCR1 VIDAZA nearly doubled the 2-year overall survival rate1 1.0 0.9 Log–Rank P =.0001 HR=0.58 (95% CI, 0.43–0.77)

Proportion Surviving

0.8 0.7 0.6

24.5 months

0.5

15.0 months

0.4

VIDAZA

0.3

CCR

0.2 0.1 0.0 0

15 20 25 Time (Months) From Randomization

Study 4, the Survival Study (AZA-001), was a phase 3, prospective, international, multicenter, randomized, controlled, parallel-group, noncrossover study of 358 adult (≥18 years) patients with higher-risk MDS (IPSS Intermediate-2 or High), and FAB-deﬁned refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEB-T†), or dysplastic-type chronic myelomonocytic leukemia (CMMoL), using modiﬁed FAB criteria. Patients were randomized to receive either VIDAZA (75 mg/m2 SC daily for 7 days each 28-day cycle) + BSC (transfusions, antibiotics, G-CSF for neutropenic infection), or 1 of 3 CCR. CCR treatments included BSC alone; L-DAC (20 mg/m2 SC daily for 14 days every 28 to 42 days); or 7+3 chemotherapy (induction with cytarabine 100-200 mg/m2/d by continuous IV infusion over 7 days plus an anthracycline days 1-3 [plus a maximum of 2 consolidation cycles]). CCR were preselected by study investigators. The primary end point of the study was overall survival.1

• In the Survival Study, median overall survival was 24.5 months for patients on VIDAZA vs 15 months for patients on CCR (P =.0001; HR=0.58 [95% CI, 0.43-0.77])1 • VIDAZA nearly doubled the 2-year overall survival rate vs CCR1,2 – 51% survival for VIDAZA vs 26% survival for CCR (24.6% difference, 95% CI, 13.1-36.1)1,2 • Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity – Patients receiving VIDAZA were treated for a median of 9 cycles (range 1 to 39)1 – Patients should be monitored for hematologic response and renal toxicities, with dosage delay or reduction as appropriate • CCR included BSC or L-DAC or 7+3 chemotherapy1 Abbreviations: BSC, best supportive care; CCR, conventional care regimens; FAB, French-American-British classification for MDS; L-DAC, low-dose cytarabine; MDS, myelodysplastic syndromes. *Higher-risk MDS is Intermediate-2– and High-risk MDS per International Prognostic Scoring System (IPSS). † Bone marrow blast count ≥20% is classified by the WHO as AML.3 The investigators in the Survival Study classified RAEB-T as blasts 21%-29%.2

VIDAZA® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

Important Safety Information • VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors • In Studies 1 and 2, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), and malaise (10.9%). In Study 3, the most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%) • In Study 4, the most commonly occurring adverse reactions were thrombocytopenia (69.7%), neutropenia (65.7%), anemia (51.4%), constipation (50.3%), nausea (48.0%), injection site erythema (42.9%), and pyrexia (30.3%). The most commonly occurring Grade 3/4 adverse reactions were neutropenia (61.1%), thrombocytopenia (58.3%), leukopenia (14.9%), anemia (13.7%), and febrile neutropenia (12.6%) • Because treatment with VIDAZA is associated with anemia, neutropenia, and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle • Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function • VIDAZA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be apprised of the potential hazard to the fetus. Men should be advised not to father a child while receiving VIDAZA • Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother Please see Brief Summary of full Prescribing Information on following pages. References: 1. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. 2. Data on file, Celgene Corporation. 3. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999;10(12):1419-1432.

Proven Results. Extended Survival.

VIDAZA速 (azacitidine for injection) The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE 1.1 Myelodysplastic Syndromes (MDS) VIDAZA速 is indicated for treatment of patients with the following FrenchAmerican-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). 4 CONTRAINDICATIONS 4.1 Advanced Malignant Hepatic Tumors VIDAZA is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2)]. 4.2 Hypersensitivity to Azacitidine or Mannitol VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. 5 WARNINGS AND PRECAUTIONS 5.1 Anemia, Neutropenia and Thrombocytopenia Treatment with VIDAZA is associated with anemia, neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response [see Dosage and Administration (2.3) in full prescribing information]. 5.2 Severe Preexisting Hepatic Impairment Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Contraindications (4.1)]. Safety and effectiveness of VIDAZA in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials. 5.3 Renal Abnormalities Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held [see Dosage and Administration (2.4) in full prescribing information]. Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys [see Dosage and Administration (2.4, 2.5) in full prescribing information]. Safety and effectiveness of VIDAZA in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials. 5.4 Monitoring Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. 5.5 Pregnancy Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine caused congenital malformations in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5.6 Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females [see Nonclinical Toxicology (13)].

6 ADVERSE REACTIONS 6.1 Overview Adverse Reactions Described in Other Labeling Sections: anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma [see Warnings and Precautions (5.1, 5.2, 5.3)]. Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia. 6.2 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to VIDAZA in 443 MDS patients from 4 clinical studies. Study 1 was a supportivecare controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) [see Clinical Studies (14)]. In Studies 1, 2 and 3, a total of 268 patients were exposed to VIDAZA, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). VIDAZA was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2. In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to VIDAZA. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily VIDAZA doses of 75 mg/m2. Table 1 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC VIDAZA Treated Patients; Studies 1 and 2) Number (%) of Patients Observationc System Organ Class All VIDAZAb Preferred Terma (N=220) (N=92) Blood and lymphatic system disorders Anemia 153 (69.5) 59 (64.1) Anemia aggravated 12 (5.5) 5 (5.4) Febrile neutropenia 36 (16.4) 4 (4.3) Leukopenia 106 (48.2) 27 (29.3) Neutropenia 71 (32.3) 10 (10.9) Thrombocytopenia 144 (65.5) 42 (45.7) Gastrointestinal disorders Abdominal tenderness 26 (11.8) 1 (1.1) Constipation 74 (33.6) 6 (6.5) Diarrhea 80 (36.4) 13 (14.1) Gingival bleeding 21 (9.5) 4 (4.3) Loose stools 12 (5.5) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Nausea 155 (70.5) 16 (17.4) Stomatitis 17 (7.7) 0 Vomiting 119 (54.1) 5 (5.4) continued

Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC VIDAZA Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class All VIDAZAb Observationc a Preferred Term (N=220) (N=92) General disorders and administration site conditions Chest pain 36 (16.4) 5 (5.4) Injection site bruising 31 (14.1) 0 Injection site erythema 77 (35.0) 0 Injection site granuloma 11 (5.0) 0 Injection site pain 50 (22.7) 0 Injection site pigmentation changes 11 (5.0) 0 Injection site pruritus 15 (6.8) 0 Injection site reaction 30 (13.6) 0 Injection site swelling 11 (5.0) 0 Lethargy 17 (7.7) 2 (2.2) Malaise 24 (10.9) 1 (1.1) Pyrexia 114 (51.8) 28 (30.4) Infections and infestations Nasopharyngitis 32 (14.5) 3 (3.3) Pneumonia 24 (10.9) 5 (5.4) Upper respiratory tract infection 28 (12.7) 4 (4.3) Injury, poisoning, and procedural complications Post procedural hemorrhage 13 (5.9) 1 (1.1) Metabolism and nutrition disorders Anorexia 45 (20.5) 6 (6.5) Musculoskeletal and connective tissue disorders Arthralgia 49 (22.3) 3 (3.3) Chest wall pain 11 (5.0) 0 Myalgia 35 (15.9) 2 (2.2) Nervous system disorders Dizziness 41 (18.6) 5 (5.4) Headache 48 (21.8) 10 (10.9) Psychiatric disorders Anxiety 29 (13.2) 3 (3.3) Insomnia 24 (10.9) 4 (4.3) Respiratory, thoracic and mediastinal disorders Dyspnea 64 (29.1) 11 (12.0) Skin and subcutaneous tissue disorders Dry skin 11 (5.0) 1 (1.1) Ecchymosis 67 (30.5) 14 (15.2) Erythema 37 (16.8) 4 (4.3) Rash 31 (14.1) 9 (9.8) Skin nodule 11 (5.0) 1 (1.1) Urticaria 13 (5.9) 1 (1.1) Vascular disorders Hematoma 19 (8.6) 0 Hypotension 15 (6.8) 2 (2.2) Petechiae 52 (23.6) 8 (8.7) a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to VIDAZA, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA. Table 2 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).

Table 2: Most Frequently Observed Adverse Reactions ( 5.0% in the VIDAZA Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) Number (%) of Patients Any Grade Grade 3/4 Best Best Supportive Supportive System Organ Class VIDAZA Care Only VIDAZA Care Only Preferred Terma (N=175) (N=102) (N=175) (N=102) Blood and lymphatic system disorders Anemia 90 (51.4) 45 (44.1) 24 (13.7) 9 (8.8) Febrile neutropenia 24 (13.7) 10 (9.8) 22 (12.6) 7 (6.9) Leukopenia 32 (18.3) 2 (2.0) 26 (14.9) 1 (1.0) Neutropenia 115 (65.7) 29 (28.4) 107 (61.1) 22 (21.6) Thrombocytopenia 122 (69.7) 35 (34.3) 102 (58.3) 29 (28.4) Gastrointestinal disorders Abdominal pain 22 (12.6) 7 (6.9) 7 (4.0) 0 Constipation 88 (50.3) 8 (7.8) 2 (1.1) 0 Dyspepsia 10 (5.7) 2 (2.0) 0 0 Nausea 84 (48.0) 12 (11.8) 3 (1.7) 0 Vomiting 47 (26.9) 7 (6.9) 0 0 General disorders and administration site conditions Fatigue 42 (24.0) 12 (11.8) 6 (3.4) 2 (2.0) Injection site bruising 9 (5.1) 0 0 0 Injection site erythema 75 (42.9) 0 0 0 Injection site hematoma 11 (6.3) 0 0 0 Injection site induration 9 (5.1) 0 0 0 Injection site pain 33 (18.9) 0 0 0 Injection site rash 10 (5.7) 0 0 0 Injection site reaction 51 (29.1) 0 1 (0.6) 0 Pyrexia 53 (30.3) 18 (17.6) 8 (4.6) 1 (1.0) Infections and infestations Rhinitis 10 (5.7) 1 (1.0) 0 0 Upper respiratory tract infection 16 (9.1) 4 (3.9) 3 (1.7) 0 Urinary tract infection 15 (8.6) 3 (2.9) 3 (1.7) 0 Investigations Weight decreased 14 (8.0) 0 1 (0.6) 0 Metabolism and nutrition disorders Hypokalemia 11 (6.3) 3 (2.9) 3 (1.7) 3 (2.9) Nervous system disorders Lethargy 13 (7.4) 2 (2.0) 0 1 (1.0) Psychiatric disorders Anxiety 9 (5.1) 1 (1.0) 0 0 Insomnia 15 (8.6) 3 (2.9) 0 0 Renal and urinary disorders Hematuria 11 (6.3) 2 (2.0) 4 (2.3) 1 (1.0) Respiratory, thoracic and mediastinal disorders Dyspnea 26 (14.9) 5 (4.9) 6 (3.4) 2 (2.0) Dyspnea exertional 9 (5.1) 1 (1.0) 0 0 Pharyngolaryngeal pain 11 (6.3) 3 (2.9) 0 0 Skin and subcutaneous tissue disorders Erythema 13 (7.4) 3 (2.9) 0 0 Petechiae 20 (11.4) 4 (3.9) 2 (1.1) 0 Pruritus 21 (12.0) 2 (2.0) 0 0 Rash 18 (10.3) 1 (1.0) 0 0 Vascular disorders Hypertension 15 (8.6) 4 (3.9) 2 (1.1) 2 (2.0) a Multiple reports of the same preferred term from a patient were only counted once within each treatment.

In Studies 1, 2 and 4 with SC administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment. Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy. Eye disorders: eye hemorrhage. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. Renal and urinary disorders: loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. 6.3 Postmarketing Experience Adverse reactions identified from spontaneous reports have been similar to those reported during clinical trials with VIDAZA. 7 DRUG INTERACTIONS No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted [see Clinical Pharmacology (12.3) in the full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Female partners of male patients receiving VIDAZA should not become pregnant [see Nonclinical Toxicology (13)]. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities). 8.3 Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in

animal studies and the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients. Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Dosage and Administration (2.5) in full prescribing information and Warnings and Precautions (5.3)]. 8.6 Gender Differences There were no clinically relevant differences in safety and efficacy based on gender. 8.7 Race Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible. 13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. 17 PATIENT COUNSELING INFORMATION Instruct patients to inform their physician about any underlying liver or renal disease. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with VIDAZA. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother. Advise men not to father a child while receiving treatment with VIDAZA. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Or Baxter Oncology GmbH Bedford, OH 44146 33790 Halle/Westfalen Germany VidPlyPI.001 BS 08/08

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Recent Therapeutic Advances in the Management of

Patients With the Myelodysplastic Syndromes HARRY P. ERBA, MD, PHD Associate Professor of Internal Medicine University of Michigan Ann Arbor, Michigan

he myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow failure disorders. Patients typically present with peripheral blood cytopenias and (typically)

hyperplastic bone marrow with dysplastic cellular elements.

Patients may present with signs or symptoms of cytopenias, such as fatigue, dyspnea, recurrent infections, and hemorrhage, or the disease may be discovered at the time of routine blood counts. Clinicians should be aware that patients with MDS are at risk for progressing to acute myeloid leukemia (AML), arbitrarily defined as the accumulation of myeloblasts to more than 20% of the nucleated cells of the bone marrow or peripheral blood. The etiology of the ineffective hematopoiesis is complex and likely multifactorial. Our fragmented knowledge of the pathogenesis of MDS has not yet led to rational selection of therapeutic interventions for individual patients.

Factors Influencing Survival A number of clinical and laboratory features are known to influence the survival of patients with MDS and their risk for progression to AML. The International MDS Risk

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

Assessment Workshop (IMRAW) developed a prognostic model for patients with MDS.1 Based on a multivariate analysis, 3 clinical factors were included in the International Prognostic Scoring System (IPSS): percentage of bone marrow blasts, bone marrow karyotype, and number of cytopenias. Patients can be divided into 4 prognostic groups with median survival ranging from 5.7 years (low risk) to 0.4 years (high risk). It is important to remember that this model was based on patients who had their type of MDS identified by the French-American-British (FAB) classification system. Patients with treatment-related MDS were excluded from this prognostic model. An alternative prognostic scheme for de novo MDS patients has recently been published based on the World Health Organization (WHO) classification of disease that relies on bone marrow karyotype and transfusion requirements to categorize the type of MDS.2

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 0 0 9 â&#x20AC;˘ N O. 2

Based on a review of the Surveillance Epidemiology and End Results (SEER) database, there were 14,648 estimated cases of MDS in the United States in 2003, or 3.1 cases per 100,000 Americans.3 It is likely that the SEER database underestimates the true incidence of MDS because the incidence of MDS increases with advancing age and older patients may not undergo diagnostic bone marrow examination for evaluation of cytopenias. For example, there were 7.4 cases per 100,000 people between the ages of 60 and 69 compared with 36.3 cases per 100,000 in individuals who were 80 years of age or older. Patient age, along with associated comorbid conditions and performance status, is arguably the most important factor influencing the choice of therapeutic goal: palliation alone, palliation with prolongation of survival, or curative intent.

Hematopoietic Stem Cell Transplantation Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative therapeutic option for patients with MDS. However, prospective clinical trials have not yet identified the optimal timing of allo-HSCT. The IPSS has been shown to be predictive of outcomes (survival and relapse) for patients who receive allo-HSCT. However, there is significant risk for early treatment-related mortality associated with allo-HSCT. Investigators addressed this problem by performing an analysis examining the optimal timing of bone marrow transplantation for patients younger than 60 who received sibling donor allo-HSCT with myeloablative conditioning regimens, and comparing these patients with patients who received supportive care alone.4 The transplantation cohort was composed of patients taken from the International Bone Marrow Transplant Registry (IBMTR) and patients seen at the Fred Hutchinson Cancer Research Center (FHCRC). Data on the outcome of patients not undergoing transplantation was mined from the IMRAW database. For low- and intermediate-1–risk MDS, delayed allo-HSCT was associated with maximal life expectancy; immediate allo-HSCT for intermediate-2– and high-risk patients was associated with maximal life expectancy. Risk was assessed using the IPSS.4 This retrospective analysis has several important limitations. For example, the median age of patients in the IMRAW was significantly older (49.8 years) than that of the patients who received allo-HSCT (IBMTR, 39.4 years and FHCRC, 45.6 years). There were likely other clinical differences between patients in these 2 databases that could affect survival, such as comorbid illnesses and performance status. Patients in the analysis underwent alloHSCT between 1990 and 1999. Since that time, there have been improvements in supportive care offered to patients undergoing HSCT, thus resulting in improved patient outcomes. Likewise, patients with MDS can receive therapy that may affect their survival (see below). Finally, the analysis was limited to patients under the age of 60 and does not include patients receiving reduced-intensity conditioning regimens or alternative donors.

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Supportive Care: Erythropoietin-Stimulating Agents The erythropoietin-stimulating agents (ESAs) epoetin alfa (Epogen, Amgen; Procrit, Ortho Biotech) and darbepoetin (Aranesp, Amgen) have been shown to decrease red blood cell (RBC) transfusion requirements in MDS patients. Patients with lower RBC transfusion requirements, lower endogenous erythropoietin (EPO) levels, and low-grade MDS are more likely to have an erythroid response.5,6 Erythroid responses also are more durable in patients with low- and intermediate-1–risk disease than in patients with higher-risk disease.7 In fact, superior survival was seen in MDS patients treated with erythropoietin and granulocyte colony-stimulating factor (G-CSF) in Nordic clinical trials compared with MDS patients receiving RBC transfusions without ESAs in Pavia, Italy.8 Therefore, ESAs have been recommended in the supportive care of select MDS patients with anemia.9 However, recent randomized trials have demonstrated increased risk for thromboembolic complications and inferior survival in patients with carcinoma receiving ESAs,10,11 raising concern about the use of ESAs in oncology patients, including those with MDS. The Eastern Cooperative Oncology Group has published a prospective, randomized trial comparing daily EPO with or without G-CSF, to RBC transfusion support alone.12 Between December 1997 and June 2004, 110 MDS patients were enrolled and were evaluable. Baseline demographics of the study population were as follows: age older than 65 years, 85%; refractory anemia (RA)/refractory anemia with ringed sideroblasts (RARS), 72%; EPO level at least 200 mU/mL, 69%; lowor intermediate-1–risk, 83%. There was no statistical difference in the patient demographics between the 2 treatment groups. Following 4 months of therapy, the erythroid response rates (based on 2006 International Working Group [IWG] criteria) were 34% with EPO and 6% without (P=0.001). Erythroid responses were less likely in patients with serum EPO levels greater than 200 mU/mL and those with refractory anemia with excess blasts (RAEB), type 1 (ie, 5%-10% marrow blasts). Additional erythroid responses were seen when G-CSF was given and the dose of EPO was increased. The overall survival (OS) and time to leukemic transformation of patients randomized to supportive care alone versus to EPO/G-CSF was not statistically different. There was a single deep venous thrombosis identified among the 53 patients randomized to receive EPO. Therefore, EPO is effective for the treatment of MDS patients—especially those with low-grade MDS, low or intermediate-1–risk disease and low endogenous EPO levels—and it is not associated with increased risk for mortality or leukemic transformation.

Immunosuppressive Therapy Laboratory investigation of bone marrow samples from patients with MDS suggests that immune dysregulation may contribute to the pathogenesis of the

1.0 0.9

Proportion Surviving

0.8 Azacitidine 0.7

Conventional care

0.6 0.5 0.4 0.3 0.2 P=0.0001

0.1 0 0

Time From Randomization (mo)

Number at risk Azacitidine

179

152

130

Conventional care

179

132

cytopenias. In a Phase II National Institutes of Health (NIH) study, 61 patients with MDS were treated with antithymocyte globulin (ATG), 40 mg/kg per day administered for 4 consecutive days.13 The investigators found that 34% of patients became RBC transfusion-independent within 8 months of therapy, with 76% of these responders remaining transfusion-independent at 5 years. Neutrophil and platelet responses also were observed. The factors predictive of response were younger age, RA subtype, and lower platelet counts. Hypercellular marrow and abnormal karyotype were associated with lack of response. Subsequent analyses showed that expression of the HLA-DR15 (a serologic split of DR2) predicts for response to ATG in MDS patients.14 Expression of HLA-DR15, younger age, and shorter duration of RBC transfusion requirement all predicted for response to ATG in multivariate analysis. The NIH group described a predictive model of response based on these 3 factors.15 The long-term outcome of MDS patients treated with immunosuppressive therapy has been recently described.16 Patients with de novo MDS (N=129) were treated in 1 of 3 trials with ATG, cyclosporine (CSA), or a combination of both. The majority of patients (n=110) had low- and intermediate-1–risk MDS. Complete or partial responses were observed in 30% of patients: 24% with ATG alone, 45% with ATG plus CSA, and 8% with CSA alone. The response rate was significantly better in intermediate-1–risk patients treated with ATG/CSA versus ATG alone (54% vs 29%; P=0.004). In multivariate

analysis, age as a continuous variable and expression of HLA-DR15 were the most significant variables affecting response. The survival and risk for leukemic transformation of patients treated with immunosuppressive therapy was compared with the same long-term outcomes in patients included in the IMRAW. OS in intermediate-1–risk MDS patients who were at least 60 years of age was superior for the IST cohort compared to the patients who received supportive care alone in IMRAW (median survival >8.1 vs 5.2 years; P=0.001). Likewise, the proportion of patients developing AML was lower in the intermediate-1–risk patients treated with immunosuppressive therapy compared with the IMRAW cohort. Because there was no difference in survival or risk for leukemic transformation between older patients in the immunosuppressive therapy and IMRAW cohorts, lack of response to immunosuppressive therapy likely does not adversely affect the long-term outcome of MDS patients.

Lenalidomide Lenalidomide (Revlimid, Celgene) has been approved by the FDA for the treatment of low- and intermediate1–risk MDS patient with del(5q). In 4 different studies (including the pivotal trial MDS 003), 168 MDS patients with del(5q) were treated with lenalidomide.17 The median age of these patients was 71 years, with a female predominance. The majority had previously received EPO (74%) and was receiving 2 or more units of RBC every 4 weeks (71%). It also is important to remember that only a minority of these patients had any degree of

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neutropenia or thrombocytopenia. Sixty-eight percent of patients became RBC transfusion-independent, with a median time to RBC transfusion independence of 4.7 weeks. Response was not affected by IPPS or karyotype complexity. The median duration of response was 2.2 years. However, responses were longer in patients with low-risk disease and the 5q– syndrome. Lenalidomide appears to be cytotoxic to the 5q– clone, with complete cytogenetic responses observed in 50% of the patients, likely explaining the initial period of treatment-related myelosuppression in responders. Lenalidomide also is active in patients with low- and intermediate-1–risk MDS without del(5q). However, the rate of RBC transfusion independence is 26% and the median duration of RBC transfusion independence is 41 weeks.18 Again, the prognostic risk group and karyotype were not predictive of response. Myelosuppression was observed but was not associated with response. Identification of non-del(5q) MDS patients who are more likely to benefit from lenalidomide would avoid the potential toxicities of this agent in the majority of these patients who are unlikely to respond. Recently, Ebert et al identified a gene expression signature predictive of response to lenalidomide in patients with MDS.19 Bone marrow samples of lenalidomide-responders with or without del(5q) tend to underexpress a number of genes involved in normal erythroid differentiation. It is interesting to note that patients with the 5q– syndrome often have bone marrow erythroid hypoplasia. Because the RNA was isolated from whole bone marrow aspirate samples without cell selection, it can be speculated that erythroid hypoplasia also may predict for response. However, an association of erythroid response with marrow erythogenesis has not been reported. Major erythroid responses also were observed in a few patients with higher risk MDS with del(5q) treated with lenalidomide in the MDS 003 study. Recently, Ades et al reported the results of a Phase II study of lenalidomide in patients with intermediate-2– and high-risk MDS.20 Forty-seven patients were treated with lenalidomide 10 mg daily for 21 days of a 28-day cycle. Although this was a high-risk group of patients, 38% had an absolute neutrophil count below 1,000 cells/mcL and 57% had a platelet count less than 100,000 cells/mcL. The majority (81%) had either RAEB-2 or AML by WHO criteria; 40% had high-risk disease and 19% had del(5q) as an isolated cytogenetic abnormality. Of the 47 patients, 13 (28%) had a response, including 7 patients (15%) with a complete remission (CR). Nine patients had a complete cytogenetic remission. However, CR was only seen in the patients with a baseline platelet count above 100,000 cells/mcL and del(5q) alone or with a single other change. There was a trend for a higher CR rate in patients with marrow blast counts less than 20%. Myelosuppression was the major toxicity with many patients requiring hospitalization for treatment of complications. Although lenalidomide clearly exerts a cytotoxic effect on the del(5q) MDS clone, this agent should be used cautiously in del(5q) MDS patients with

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intermediate-2– and high-risk disease. The goal of therapy for patients with intermediate-2– and high-risk MDS is palliation of symptoms as well as improvement in expected survival. The Phase II studies of lenalidomide in MDS patients have not shown a survival benefit.

DNA Methyltransferase Inhibitors: Azacitidine and Decitabine Azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Eisai) are both FDA-approved for the treatment of MDS. These agents both cause DNA hypomethylation, which alters global chromatin structure, resulting in reactivation of gene expression. However, it still is not known for certain if responses are solely due to this mechanism of action. Azacitidine was the first drug approved for the treatment of all FAB subtypes of MDS in 2004. Using IWG response criteria, CRs, partial remissions (PRs), and hematologic responses were observed in 10%, 1%, and 36%, respectively, of MDS patients treated in the CALGB 9221 study.21 Patients receiving azacitidine either at study entry or within 6 months of study entry had a superior OS compared with patients receiving supportive care alone during this time.22 Azacitidine is the only agent that has been shown to improve the survival of MDS patients compared with other conventional care regimens, including supportive care alone.23 The AZA-001 study randomly assigned patients to azacitidine 75 mg/m2 per day for 7 consecutive days or a conventional care regimen (supportive care, low-dose cytarabine, or anthracycline and cytarabine induction chemotherapy). The conventional care regimen was selected by the treating physician prior to randomization. Patients assigned to intensive chemotherapy were more likely to be younger than age 65, to have high-risk disease, and to have AML by WHO criteria. Treatment with azacitidine continued as long as there was no evidence of progression or unacceptable toxicity; the median number of cycles was 9. Only patients with intermediate-2– and high-risk disease by IPSS and with RAEB and RAEB in transformation (RAEB-T) by FAB criteria were treated in this study. The median survival of patients was significantly longer in the azacitidinetreated group compared with the conventional care regimens (24.5 vs 15 months, P=0.0001; Figure 1). A survival benefit was observed even in patients over age 75, as well as in patients with high-risk disease, poorrisk cytogenetics including monosomy 7 or del(7q), and marrow blast counts between 21% and 30%. CRs and PRs were seen in 29% of azacitidine-treated patients; 49% of patients had hematologic improvement (HI). Patients achieving HI with azacitidine had a superior survival compared with patients achieving the same response with the conventional care regimens.24 Treatment with 7 consecutive days of azacitidine is inconvenient. A randomized Phase II study investigated 3 different doses and schedules of azacitidine: 75 mg/m2 per day for 7 days with a 2-day weekend break, 50 mg/m2 per day for 10 days with a 2-day break, and 75 mg/m2 per day for 5 days (Figure 2).25 The median age of patients

100 AZA 5-2-2

AZA 5-2-5

AZA 5

% of Patients

0 Any Hematologic Improvement

Red Blood Cell Transfusion Independence

Grade 3/4 Neutropenia

Figure 2. Comparison of three azacitidine (AZA) regimens. Based on reference 25.

in each treatment arm was 73, 76, and 76 years, respectively. The IPSS was not reported, but slightly more than 50% of patients in each arm had low-grade MDS by FAB criteria, and only 4 of the 151 patients had RAEB in transformation. There was no obvious difference in rates of HI (44%-56%) or RBC transfusion independence (50%-64%) between the 3 schedules. Marrow CRs and PRs were not reported because follow-up bone marrow exams were not required in the protocol. However, patients receiving the 5-day schedule were less likely to have treatment-emergent hematologic toxicity. The majority of hematologic responses and transfusion independence occurred within 2 cycles of therapy. However, it is not certain that this 5-day schedule would also lead to a survival advantage in intermediate-2– and high-risk patients. Decitabine also was approved for the treatment of MDS patients based on responses seen in a Phase III study.26 Both de novo and secondary MDS patients with intermediate-1–, intermediate-2– and high-risk disease were treated with IV decitabine 15 mg/m2 over 3 hours every 8 hours for 3 consecutive days. The median number of cycles delivered was 3. The rates of CR, PR, and HI were 9%, 8%, and 13%, respectively. However, there was no difference in survival without leukemic transformation between decitabine-treated patients and those receiving supportive care alone. The European Organisation for Research and Treatment of Cancer (EORTC) recently reported a Phase III study of the same dose and schedule of decitabine compared with supportive care alone in 233 MDS patients over the age of 60 with

intermediate- and high-risk disease.27 The median number of cycles was 4, and no patient received more than 8 cycles by study design. Patients who achieved a CR only received 2 additional cycles of therapy. The rates of CR, PR, and HI were 13%, 6%, and 15%, respectively. Again, there was no difference in OS or survival without leukemic transformation between the 2 treatment arms. The discontinuation of decitabine after at most 8 cycles may have affected the ability to demonstrate a survival advantage over supportive care alone. A lower total dose of decitabine (100 mg/m2 per cycle) was evaluated in a randomized Phase II study conducted at the University of Texas M.D. Anderson Cancer Center in Houston.28 Among the 95 patients, median age was 65 years; 24% of patients had less than 5% blasts and only 6% had 21% to 30% blasts. The patients received 1 of 3 schedules of decitabine. Those receiving IV decitabine 20 mg/m2 per day for 5 consecutive days had a CR rate of 39%. The results of this singlecenter study led to the multicenter ADOPT (Alternative Dosing for Outpatient Treatment) trial,29 in which 99 patients received decitabine 20 mg/m2 per day for 5 days on an outpatient basis. The median number of cycles delivered was 5. The median age of the patients was 72 years; 37% had RA or RARS; 53% had intermediate-1–risk, 46% had intermediate-2– and high-risk disease; 49% had good-risk karyotypes; 42% had less than 5% marrow blasts. The CR rate was 17%, marrow CR was 15%, PR was 0%, and HI was seen in 18%; 33% of RBC transfusion-dependent patients became independent of transfusion. Half of the patients experienced a

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cytogenetic remission. The response was not affected by IPSS or FAB subtypes. Decitabine and azacitidine are both clearly effective therapies for MDS patients. The M.D. Anderson Cancer Center and ADOPT trials have demonstrated activity of decitabine in patients with treatment-related MDS. Decitabine 20 mg/m2 per day for 5 days is a more convenient outpatient dosing regimen than the higher total dose tested in the 2 Phase III studies of decitabine. However, the population of patients treated in the M.D. Anderson Cancer Center and ADOPT trials appears to be different from the population of patients treated in the EORTC study or the AZA-001 study. The former studies include a higher proportion of patients with lower-grade and lower-risk disease. The studies also differ slightly in the response criteria. Although achievement of marrow CR does demonstrate activity, these patients may not have achieved HI.30 Therefore, it is difficult to determine the effect of marrow CR on the quality of life. Finally, the improvement in survival observed with azacitidine may well be due to maintenance therapy. The median number of cycles of therapy in the single-center and multicenter trials of the 5-day decitabine regimen was less than that of the AZA-001 study.

Conclusions The majority of patients with MDS are older and not candidates for curative therapies. There are now 3 FDAapproved drugs for the treatment of these patients. Azacitidine 75 mg/m2 per day for 7 days is the only treatment that has been shown to improve the survival of intermediate-2– and high-risk MDS patients. Decitabine and azacitidine appear to be effective in the setting of high-risk clinical features, such as high-risk karyotype and treatment-related disease. Nonetheless, responses are only observed in at most half of patients treated with the DNA methyltransferase inhibitors, and the responses are not durable even with maintenance therapy. Although maintenance therapy with azacitidine and decitabine is felt to be important, the value of

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maintenance has not yet been demonstrated in a randomized trial. The degree of cross-resistance between azacitidine and decitabine remains uncertain. These and many other unanswered questions remain in the treatment of MDS. It is appropriate to consider therapy on well-designed clinical trials for the majority of MDS patients. Combinations of the DNA methyltransferase inhibitors with other agents, such as the histone deacetylase inhibitors and lenalidomide, are actively being explored to continue to improve the outcome of MDS patients.

References 1.

Greenberg P, Cox C, Le Beau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088, PMID: 9058730.

2. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2008;25(23):3503-3510, PMID:17687155. 3. Rollinson DE, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER program. Blood. 2006;108(11). Abstract 247. 4. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104(2):579-585, PMID: 15039286. 5. Hellström-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Brit J Haemat. 1995;89(1):67-71, PMID: 7833279 6. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haemat. 2003;120(6):1037-1046, PMID:12648074. 7. Jädersten M, Montgomery SM, Dybedal I, et al. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106(3):803-811, PMID: 15840690. 8. Jädersten M, Malcovati L, Dybedal I. et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008;26(21):3607-3613, PMID: 18559873.

9. Greenberg PL, Attar E, Battiwalla M, et al. Myelodysplastic syndromes. J Natl Compr Canc Netw. 2008;6(9):902-926, PMID: 18926100. 10. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-smallcell lung cancer with disease-related anemia. J Clin Oncol. 2007;25(9):1027-1032, PMID: 17312332. 11. Smith RE Jr, Aapro MS, Ludwig H, et al. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2008;26(7):1040-1050, PMID: 18227526. 12. Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase III trial by the Eastern Cooperative Oncology Group (E1996). Blood. 2009;114(12) 2393-2400, PMID: 19564636. 13. Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002;137(3):156-163, PMID: 12160363. 14. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100(5):1570-1574, PMID: 12176872. 15. Saunthararajah Y, Nakamura R, Wesley R, et al. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102(8):3025-3027, PMID: 12829603.

syndromes with 5q deletion: results of a phase 2 study. Blood 2009;113(17):3947:3952, PMID: 18987358. 21. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24(24);3895-3903, PMID: 16921040. 22. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20(10):2429-2440, PMID: 12011120. 23. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232, PMID, 19230772. 24. List AF, Fenaux P, Mufti GJ, et al. Effect of azacitidine on overall survival in higher-risk myelodysplastic syndromes without complete remission. J Clin Oncol. 2008;26(15s): Abstract 7006. 25. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27(11):1850-1856, PMID: 19255328. 26. Kantarijian H, Issa JP, Rosenfield CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803, PMID: 16532500.

16. Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008;26(15):2505-2511, PMID: 18413642.

27. Wijermans P, Suciu S, Baila L, et al. Low dose decitabine versus best supportive care in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy:final results of the randomized phase III study of the EORTC Leukemia and German MDS Study Groups. Blood. 2008; 112(11): Abstract 226.

17. List AF, Dewald GW, Bennett JM, et al. Long-term clinical benefit of lenalidomide (Revlimid) treatment in patients with myelodysplastic syndrome and chromosome deletion 5q. Blood. 2006;108(11): Abstract 251

28. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52-57, PMID: 16882708.

18. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111(1):86-93, PMID: 17893227. 19. Ebert BL, Galili N, Tamayo P, et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLOS Med 5(2):e35, PMID: 18271621. 20. AdĂ¨s L, Boehrer S, Prebet T, et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic

29. Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 2009;27(23):3842-3848, PMID: 19528372. 30. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425, PMID: 16609072.

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Management of

Cutaneous T-Cell Lymphoma FREDERICK LANSIGAN, MD Assistant Professor of Medicine Hematology and Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

FRANCINE M. FOSS, MD Professor of Medicine Hematological Malignancies Medical Oncology Yale Cancer Center New Haven, Connecticut

utaneous T-cell lymphoma (CTCL), a heterogeneous group of lymphoproliferative diseases characterized by infiltration of the skin by malignant T-cells, comprises approximately

4% of the non-Hodgkin’s lymphomas in the United States.

The classification of cutaneous lymphomas describes several subtypes of CTCL: mycosis fungoides (MF), its variants, and the Sézary syndrome (SS), which comprise 44% of cases; the CD30+ lymphomas, such as anaplastic large cell lymphoma of the skin and lymphomatoid papulosis; and aggressive forms of peripheral T-cell lymphoma (PTCL), including PTCL-unspecified, panniculitic T-cell lymphoma, and natural killer (NK)/T-cell lymphomas of the skin.1 According to a recent review of the SEER (Surveillance, Epidemiology and End Results) database and other registries, the incidence of CTCL is on the rise. It is estimated that 6.4 per 1 million people will be diagnosed with CTCL annually.2 Patients with early-stage disease frequently have an indolent clinical course; however, those with advanced stages have a shortened survival. An accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit. More conservative treatment strategies in the initial management of CTCL have

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

led to newer biologic and targeted therapies. MF, the most common form of CTCL, is considered a more indolent form of the disease, whereas SS is a more aggressive leukemic form with both blood and skin involvement. The skin manifestations of CTCL are multiple and include patches or plaques, cutaneous tumors, ulcerations or fissuring of the skin, patchy or diffuse erythroderma, and exfoliation. Generally, early-stage MF evolves slowly from patch-plaque disease to more aggressive forms, including cutaneous tumors, erythroderma, and visceral involvement. The diagnoses of MF and SS are based on the presence of characteristic malignant T-cells with cerebriform or convoluted nuclear contours in the epidermis and dermis. The malignant cells may occur in clusters with a perinuclear halo, called a Pautrier’s microabscess. In early-stage disease, infiltration may be minimal and diagnosis may be based on immunophenotypic features of the T-cells, including loss of normal antigen expression or the presence of clonal T-cell receptors in genotypic analysis.

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 0 0 9 • N O. 2

Table 1. Tumor-Node-Metastasis-Blood Classification and Clinical Staging System for Mycosis Fungoides and Sézary Syndrome

T1: Limited Patch/Plaque (<10% BSA)

N0: Nodes clinically uninvolved

N1: Nodes enlarged, histologically uninvolved

IIA

N2–3: Nodes clinically normal (N2) or enlarged (N3), histologically involved

IVA

N0–3: Visceral involvement

IVB

T2: Generalized Patch/Plaque (≥10% BSA)

T3 Tumor

T4 Erythroderma

IIB

IIIA IIIB

B: Classification not incorporated in the clinical stage B0: Absence of significant peripheral blood Sézary cells B1: Presence of significant peripheral blood Sézary cells BSA, body surface area Adapted from reference 3.

Clinical Staging and Prognosis of MF and SS

Skin-Directed Therapies

Staging of patients with MF and SS is essential both for its prognostic value and for decisions in management. The most commonly used staging system for MF/ SS is based on a tumor-node-metastasis-blood (TNMB) classification (Table 1).3 When MF is grouped by stage, patients with patch-plaque disease (stages IA, IB, and IIA) have an excellent survival of more than 12 years; those with tumors or erythroderma (stages IIB/III) have a median survival of approximately 4 years; and those with stage IV, which includes patients with lymph node or visceral involvement, have a median survival of less than 3 years.4 SS also has a median survival of less than 3 years.5,6 Many patients die not from their disease but from infectious complications, which are likely due to impaired immunity, as well as immunosuppressive effects of systemic therapies.

Patients with early-stage MF often present with disease limited to the skin without systemic involvement, that is, patch-plaque disease. These patients usually have an intact cellular immune response, so that treatment with skin-directed agents often is sufficient to induce clearing of disease and can produce effective long-term responses in roughly 60% of cases. Intermediate- and high-potency topical corticosteroids produce clinical remission in 25% to 63% of patients, but the duration of benefit may be short.8 Long-term use of topical steroids, especially over a large body surface area, can suppress endogenous cortisol secretion in approximately 15% of patients treated, and can cause cutaneous atrophy. Oral corticosteroids also are effective; however, they can cause the unwanted side effects of osteoporosis, adrenal suppression, altered glucose metabolism, and steroid-induced myopathies. Topical nitrogen mustard (mechlorethamine; Mustargen, Ovation), an alkylating agent that damages cellular DNA and induces apoptosis, is available in an ointmentbased preparation and can be very effective in palliating skin lesions in patients in all stages of disease, even when systemic treatment for CTCL is being administered. It has been shown to produce complete response (CR) rates of 26% to 76% in stage I disease, and 22% to 49% in stage III disease.9 Some patients with stage IA disease may be cured; however, relapses are frequent even when therapy is continued after remission. One limitation of topical nitrogen mustard therapy is that it is not widely available and must be prepared by a compounding pharmacy. Side effects of nitrogen mustard include irritant reactions, and up to 40% of patients develop contact hypersensitivity. Nitrogen mustard is carcinogenic and

Treatment Decisions about initial or subsequent therapies should be made based on disease stage, overall prognosis, and quality of life for the patient. For early-stage patients in whom remission is likely, the goal should be to avoid long-term treatment-related toxicities; for patients with aggressive disease, approaches often include skindirected as well as systemic therapies, including biologic or targeted therapy. For younger patients with highly refractory or advanced disease, allogeneic stem cell transplantation provides a potentially curative treatment. The sequence of treatment frequently depends on the experience of the treating physicians and institution, as well as patient preference. Treatment algorithms for MF/SS include combined or sequential therapies with multiple skin-directed and systemic agents (Table 2).7

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Table 2. Treatment Algorithms According to Disease Stage Stage

Initial Therapy

Relapsed/Refractory Disease

Skin-directed therapy

Additional skin-directed therapya OR Skin-directed therapya with biologicb or single-agent therapyc

IB/IIA

Skin-directed therapya and/or biologic therapyb

Skin-directed therapya plus biologic therapyb OR Single-agent therapyc

IIB

Skin-directed therapy (PUVA, electron beam radiation therapy) plus biologic therapyb OR Single-agent therapyc

Multimodality combinations: skin-directed therapya plus single-agent therapyc or biologic therapyb OR Multiagent therapyd OR Allogeneic stem cell transplantation

IIIA/B

ECP with or without skin-directed therapya OR Multimodality combinations with systemic or biologic therapyb

Multimodality combinations with single-agent therapyc or multiagent therapyd OR Allogeneic stem cell transplantation

IVA/B

Single-agent therapyc OR Combination biologic therapyb OR Multiagent therapyd

Salvage chemotherapy OR Allogeneic stem cell transplantation

Skin-directed therapy: topical steroids (intermediate and high potency); topical nitrogen mustard or bischloroethylnitrosourea ointment or aqueous solution; topical retinoids (bexarotene gel, tazarotene cream and gel); phototherapy (UVB for patch or thin plaque, PUVA for thick plaque); electron beam radiation (localized for limited disease, total skin for extensive skin involvement).

Biologic therapy: interferon-alfa; retinoids (bexarotene, 13-cis retinoic acid, all-trans-retinoic acid); ECP; alemtuzumab.

Single-agent therapy: methotrexate (low-dose oral or intravenous); denileukin diftitox; HDAC inhibitor (vorinostat); liposomal doxorubicin; gemcitabine; pentostatin; etoposide; cyclophosphamide; bortezomib; temozolomide.

Multiagent combination therapies: biologic combinations (PUVA, UVB, or ECP plus retinoids with or without interferon); denileukin diftitox plus bexarotene; retinoids plus interferon; PUVA, UVB, or ECP with HDAC inhibitor (under investigation); cytotoxic multiagent regimens (gemcitabine, vinorelbine; liposomal doxorubicin; EPOCH; hyper-CVAD; ICE; etoposide, methylprednisolone, cytarabine, cisplatin).

ECP, extracorporeal photopheresis; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and oral prednisone; HDAC, histone deacetylase; hyper-CVAD, cyclophosphamide, mesna, vincristine, doxorubicin, dexamethasone, filgrastim, methotrexate, leucovorin, cytarabine, methylprednisolone; ICE, ifosfamide, carboplatin, and etoposide; PUVA, psoralen plus ultraviolet A; UVB, ultraviolet B Adapted from reference 7.

secondary cutaneous malignancies, such as squamous and basal cell carcinomas, have been attributed to its long-term use.10 Retinoids have demonstrated efficacy in the treatment of MF/SS and have antiproliferative, antiangiogenic, immune-modulating, and cellular effects.11 Bexarotene, a novel RXR-retinoid (rexinoid), has shown biological activity in both a topical formulation, bexarotene gel (Targretin Gel, Eisai) and an oral formulation (Targretin, Eisai; see below) in patients with early and advanced MF/SS. It is very effective in patients with patch-plaque disease. In clinical trials of bexarotene gel, 44% to 64% of patients with stage I MF responded.12 The median time to response was 4.5 months, and the median duration of response was 23 months. The major

toxicity of bexarotene gel is cutaneous hypersensitivity and increased redness or itching. Often, alternating applications of corticosteroids and bexarotene can alleviate these effects. Phototherapy with psoralen plus ultraviolet A radiation (PUVA) is a skin-directed therapy that causes apoptosis of infiltrating tumor cells and mononuclear cells, including Langerhanâ&#x20AC;&#x2122;s cells, which support CTCL survival in the skin microenvironment.13 Retrospective studies of PUVA monotherapy demonstrated response rates from 50% to 63%, with 50% of responders showing sustained remissions, although most of the responders were patients with stage I disease.14,15 Prolonged use of PUVA has been associated with skin erythema and secondary malignancies, including melanoma and

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squamous and basal cell carcinomas.14 Ultraviolet B radiation (UVB) has a lower penetration into the skin and is selectively absorbed in the epidermis. UVB has been shown to induce CR in 71% of early-stage MF patients, with a median duration of 22 months; however, fewer durable responses were seen in patients with significantly infiltrated plaque-stage CTCL.16 Narrowband UVB can penetrate deeper in the dermis and is not associated with secondary skin cancers.17-19 The choice of lightdirected therapy is based on many factors, including depth of the infiltrate as well as risk for secondary skin changes in the individual patient. Total skin electron beam therapy (TSEBT) is a therapeutic modality in which electron radiation is administered to the entire skin surface. TSEBT is usually administered over a course of 9 to 12 weeks. Due to the limited penetration by electrons, systemic toxicity is rare. TSEBT, which is often used for patients with extensive skin involvement, can be combined with adjuvant systemic modalities such as retinoids, PUVA, or photopheresis, or with nodal radiation approaches.20-24 The response rate is high for early-stage disease (90%-95%), and the therapy is curative for patients with stage IA disease.25-28 Long-term toxicity includes anhydrosis, telangiectasia, and secondary skin cancers. TSEBT also is effective as palliative therapy in patients with aggressive, extensive disease, including patients with erythroderma. Spot radiation is often employed for palliation in patients with cutaneous tumors, ulcerations, or fissures. Radiation recall may occur when radiation-sensitizing agents such as gemcitabine, adriamycin, or liposomal doxorubicin are administered concurrently with, or within weeks of, TSEBT, and this should be avoided.

Systemic Therapy Systemic therapies for MF/SS often are employed in patients with stage IIB or higher disease, or in patients with early-stage disease who have become refractory to skin-directed therapies or have developed dose-limiting toxicities to UV or ionizing radiation (Table 3). For these patients, many systemic treatments, including novel agents, are widely acceptable. Often, systemic agents are administered in combination with topical therapies.

EXTRACORPOREAL PHOTOPHERESIS Extracorporeal photopheresis (ECP) is a treatment for MF/SS that involves leukapheresis to isolate mononuclear cells, which are then exposed ex vivo to UVA in the presence of methoxypsoralen and reinfused into the patient.29 Methoxypsoralen incorporates into DNA, and in the presence of ultraviolet light induces strand breaks, and, subsequently, apopotosis.30 Circulating T-cells and Sézary leukemia cells are susceptible to UVA-induced apoptosis. The mechanism of action of ECP is believed to be related to the induction of apoptosis in clonal Sézary T-cells, leading to uptake and processing of tumor antigens by immature dendritic cells generated from the effects of the ECP process on circulating monocytoid dendritic cell precursors.31,32

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Edelson et al reported the first results with ECP in 1987, with a response rate of 73% in relapsed MF/SS patients, including those with erythrodermic MF, SS, or nodal involvement.33 Other studies have shown similar responses to ECP monotherapy; however, the best responders seem to be patients with a short duration of disease, an absence of bulky lymphadenopathy, and low Sézary counts, and who have not received immunosuppressive chemotherapy.34,35 ECP is well tolerated and often is the first systemic therapy used in patients with erythrodermic CTCL. Maximal response may take as long as 4 to 6 months, and many patients remain on therapy for 1 year or longer. The timing of ECP treatments varies; generally patients receive 2 consecutive treatments once per month as well as an escalated schedule of 2 consecutive treatments every other week. Response is measured by reduction in overall skin tumor burden, a decrease in circulating Sézary cells, and restoration of a normal CD4/CD8 ratio. Combinations of ECP with other systemic agents, such as interferon-γ (IFN-γ) or bexarotene, and other treatment modalities, such as TSEBT or PUVA, have demonstrated efficacy and may reduce the time to response.

CYTOKINE THERAPIES Because the host immune response plays a pivotal role in the immune surveillance and clearing of CTCL cells, biologic agents such as cytokines can be used to augment the immune response. IFN-α was first shown to have activity in CTCL in 1984 by Bunn et al.36 Heavily treated patients with advanced disease were treated with IFN-α and showed a 45% objective response rate. Subsequent studies confirmed activity in early- and latestage disease patients, with 73% response in stages IA to IIA, and 60% response in stages IIB to IVA, many of them durable.37 The acute toxicities of IFN-α, which include fever, chills, arthralgias, myalgias, and malaise, usually dissipate after the first week of treatment. Chronic toxicities such as fatigue, anorexia, weight loss, and mood lability improve over time or with dose modification. In the practical management of early-stage CTCL, IFN-α can be used as an adjunct to topical therapy, or after failure of skin-directed agents. Combinations of IFN-α with ECP,38 and IFN with PUVA, oral retinoids, and cytotoxic chemotherapy39 have also shown encouraging results. The dosing of IFN-α and the administration schedule used have varied among clinical studies. In most instances, low doses of 3 million to 10 million units are administered 2 or 3 times per week, and the schedule and dose are tailored to individual patient response and toxicities. IFN-γ also has shown efficacy in patients with earlyand advanced-stage CTCL when administered with photopheresis. Because Sézary cells are associated with a Th2 cytokine profile, there is a deficit of IFN-γ in the microenvironment of the malignant cells, and the malignant cells are resistant to its effects.40 Administration of recombinant IFN-γ to local tumor sites has been studied using TG-1042, a replication-deficient adenovirus type 5 that carries the IFN-γ gene, for the potential treatment of

CTCL and cutaneous B-cell lymphoma (CBCL).41 A Phase I/II clinical trial in CTCL and CBCL was recently completed and a Phase II clinical trial is under way. Another strategy to increase IFN-Îł production in CTCL cells is to administer recombinant human IL-12 (rhIL-12). A clinical study of rhIL-12 in early MF (stages IA-IIA) was conducted in which rhIL-12 was administered biweekly (100 ng/kg for 2 wk, 300 ng/kg thereafter) to 23 MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) who had failed previous therapies.42 Ten of the 23 patients (43%) achieved partial response (PR); 7 (30%) achieved minor response; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve patients (52%) ultimately progressed, with a mean time to progressive disease of 57 days (range, 28-805). Adverse events included constitutional symptoms of asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, as well as elevated aspartate and alanine aminotransferase levels. One patient died from hemolytic anemia.

RETINOID THERAPY In a clinical trial of heavily pretreated patients with refractory CTCL, oral monotherapy with bexarotene resulted in response rates of 54% in early-stage and 45% in advanced-stage disease patients.43 The median response duration was 299 days with continuous dosing of 300 mg/m2 per day, and responses occurred in patients in all groups (57% in stage IIB, 32% in stage III, 44% in stage IVA, and 40% in stage IVB), including those with large cell transformation. Pruritus decreased significantly in the treated patients and led to overall improvement in quality of life. The major toxicities of bexarotene included elevations in serum lipids and cholesterol and suppression of thyroid function. Elevations in lipids occurred rapidly, within 2 to 4 weeks, and required the use of lipidlowering agents in the majority of patients. Patients on bexarotene also developed a dose-dependent central hypothyroidism with low levels of thyroid-stimulating hormone and free thyroxin within weeks of starting the medication. Symptoms of hypothyroidism may be subtle because they include fatigue/asthenia, depression, cold intolerance, and constipation. Levothyroxine was found to alleviate these symptoms and improve tolerance of treatment. Oral bexarotene often is started at a low dose (150-300 mg/d) and titrated to achieve therapeutic effect. Laboratory studies should be performed weekly until lipids and thyroid function are stable and then performed monthly during therapy.

Targeted Therapy DENILEUKIN DIFTITOX Denileukin diftitox (Ontak, Eisai) is a fusion protein toxin that targets interleukin-2 (IL-2) receptorâ&#x20AC;&#x201C;bearing cells, including CTCL cells. In October 2008, the FDA granted full approval to denileukin diftitox for the treatment of persistent or recurrent CTCL in patients whose malignant cells express the CD25 component of the IL-2

Table 3. Treatment of CTCL With Systemic Chemotherapy

Treatment

Response Rate, %

Duration of Response, mo

Bortezomib66

7-14

Cladribine62-64

13-38

3-4

EPOCH67

Fludarabine59

7.5

Gemcitabine57

Pegylated liposomal doxorubicin65

Pentostatin60

2-4

EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, oral prednisone

receptor. The previously granted accelerated approval was converted to full approval based on a priority review of data from a Phase III, randomized placebo-controlled study (N=144) that verified its clinical benefit.44 The study by Negro-Vilar et al showed that treatment with denileukin diftitox in either the 9 or 18 mcg/kg per day dosage yielded a significantly increased overall response rate (ORR) compared with placebo (37% and 46% vs 15%; P=0.002 and P=0.03, respectively). The 9-mcg/kg per day dose contributed to a 58% reduction in the risk for disease progression and the 18-mcg/kg per day dose resulted in a 73% risk reduction. Physicians administering this medication should be aware of potentially serious side effects, including infusion reactions, capillary leak syndrome, and loss of visual acuity. The FDA boxed warning states that denileukin diftitox should only be administered in a facility equipped and staffed for cardiopulmonary resuscitation and that treatment should be immediately and permanently discontinued if there are serious infusion reactions. The incidence of infusion reactions in 3 clinical studies (N=234) was 70.5%; in 8.1% of patients, the reactions were considered serious. Premedication with dexamethasone, diphenhydramine, and acetaminophen reduces the incidence of infusion reactions. Additionally, because of the risk for potentially fatal capillary leak syndrome, patients should be monitored for weight changes, edema, blood pressure, and serum albumin levels before and during denileukin diftitox therapy. The most common adverse reactions were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea, and pruritus. All the adverse events in the pivotal Phase III trial were most severe during the first 2 cycles of treatment and then diminished significantly.

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Denileukin diftitox was administered in combination with oral bexarotene in a Phase I trial in patients with relapsed or refractory MF/SS.45 It was demonstrated that oral bexarotene upregulates the expression of the IL-2 receptor and thus may potentiate the effects of denileukin diftitox. The ORR was 70%, and responders included patients who had stable disease or no response on denileukin diftitox alone. The combination was well tolerated, with no overlapping adverse events. The lowest effective dose of bexarotene in the combination trial was 150 mg daily.

MONOCLONAL ANTIBODIES Unmodified monoclonal antibodies have also demonstrated efficacy in the treatment of CTCL. Alemtuzumab (Campath, Bayer) is a humanized monoclonal antibody directed against the CD52 antigen, which is abundantly expressed on all normal and most malignant T lymphocytes. Alemtuzumab has been administered at a dose of 30 mg 3 times a week until maximum response in patients with CTCL and other T-cell malignancies.46,47 Apart from first-dose reactions, which were common, treatment was well tolerated, with the main complications being infection and viral reactivation associated with the prolonged lymphopenia, and cardiac toxicities. There was a report of large cell transformation of CTCL after treatment with alemtuzumab. In both SS and MF patients, ORRs were high. Zanolimumab (Genmab) is a humanized monoclonal antibody directed against CD4. In a Phase I study, patients with treatment-refractory CD4+ CTCL were treated with escalating doses of zanolimumab (early-stage disease, 280 and 560 mg; advanced-stage disease, 280 and 980 mg). Responses were seen in both MF and SS patients, and the ORR in the high-dose groups was 56%, with a median response of 81 weeks.48 Adverse events included low-grade infections and eczematous dermatitis. Depletion of normal CD4+ cells occurred.

administered HDAC inhibitor that has shown promising results in CTCL. Preliminary results of a Phase II study of panobinostat in bexarotene-na誰ve and bexarotenetreated patients have been reported.52 Eleven of 66 evaluable patients (16.7%) who had received bexarotene and were given panobinostat orally at a dose of 20 mg on days 1, 3, and 5, had confirmed responses, including 2 CRs. Of 35 bexarotene-na誰ve patients, 4 (11.4%) had a confirmed response. Median duration of response ranged from 9.25 to 11 months. Thrombocytopenia and neutropenia were the most common grade 3 or 4 toxicities. Another HDAC inhibitor, romidepsin (Istodax, Gloucester Pharmaceuticals), demonstrated activity in CTCL patients in a National Cancer Institute study published in 2001.53 The response rate was 30% and response durations of 8 to 14 months or longer were reported in refractory, heavily pretreated patients.53 More recently, preliminary results of a Phase II, open-label, multiarm, multicenter study of romidepsin in 71 patients with relapsed or refractory CTCL were reported.54 Romidepsin was administered at a dose of 14 mg/m2 as a 4-hour infusion on days 1, 8, and 15 every 28 days. Patients had a median of 2 previous treatments. For 63 patients who received at least 2 cycles of therapy, the ORR was 40% (CR, 6%; PR, 33%). The median time to response was 1.8 months, and the median duration of response was 11 months or longer. Because earlier studies demonstrated that romidepsin may be associated with electrocardiogram changes, specifically QTc prolongation, extensive electrocardiographic and cardiac monitoring was performed during the study. Independent review of electrocardiograms showed a median increase in QTcF of 6 to 7 ms, which was not clinically significant, and no patient developed symptomatic arrhythmia.54 On Nov. 5, 2009, the FDA approved romidepsin for the treatment of CTCL in patients who have received at least 1 prior systemic therapy.

HISTONE DEACETYLASE INHIBITORS Epigenetic modulation has emerged as a novel therapeutic approach for patients with T-cell lymphomas. Histone deacetylase (HDAC) inhibitors prevent the removal of the acetyl modification from lysine residues, leading to a more open chromatin structure and to global alterations in gene expression.49 Vorinostat (Zolinza, Merck), an oral HDAC inhibitor, was approved by the FDA in 2006 for the treatment of the skin manifestations of MF and SS. In a Phase II trial of vorinostat given at different doses and schedules, responses were seen in 30% of the patients; 42% experienced relief of pruritus.50 A multicenter Phase IIB trial using 400 mg vorinostat daily also showed an ORR of 30% with one CR.51 The median time to response was 2 months, and the response duration was 9.8 months or longer. The most common side effects were diarrhea, nausea, fatigue, and anorexia. Asymptomatic QTc prolongation was observed on serial electrocardiograms in 4% of patients but was not clinically significant. Panobinostat (Novartis) is another orally

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PRALATREXATE: A NOVEL TARGETED ANTIFOLATE Pralatrexate (Folotyn, Allos) is a novel targeted antifolate with a high affinity for the reduced folate carrier. Cancer cells overexpress the reduced folate carrier RFC-1, and thus selectively accumulate the drug. Once inside the cells, pralatrexate interferes with the action of dihydrofolate reductase (DHFR), a key enzyme involved in the synthesis of deoxythymidine and the purine DNA nucleotides, which leads to cell death. A recent Phase II trial of pralatrexate (PROPEL) was completed in patients with aggressive PTCL, and the reported response rate in refractory patients was 27%. A multicenter, open-label, Phase I, dose-finding study of pralatrexate is ongoing in patients with CTCL who have failed at least one previous systemic therapy.55 Nine of 17 (53%) evaluable patients achieved a response, including PR in 7 patients and CR in 2 patients. Responding patients had previously received up to 8 treatment regimens. This study is designed as a dose de-escalating study, and is ongoing to identify a dose and schedule (2 out of 3 weeks or 3 out of 4 weeks)

of pralatrexate that can result in maintained responses with minimal toxicity. The most common toxicities of pralatrexate include mucositis and stomatitis and bone marrow suppression. On Sept. 25, 2009, the FDA granted accelerated approval to pralatrexate for the treatment of relapsed or refractory PTCL based on the results of the PROPEL trial.

FORODESINE: A NOVEL PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR Forodesine (BioCryst) is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of dGTP, resulting in apoptosis in T lymphocytes. During a Phase I, open-label dose-escalation study of oral forodesine, 9 doses (40-320 mg/m2 daily) were administered to patients with refractory CTCL via IV infusion for 30 minutes (day 1), followed 24 hours later by doses every 12 hours (days 2-5); 3 courses were given at 16-day intervals. Of 13 CTCL patients treated, 9 had an improvement in skin or a decrease in the absolute number of Sézary cells.56 The most frequent adverse events were nausea, fatigue, and reversible lymphopenia. A Phase II study is under way in patients with relapsed or refractory CTCL.

CYTOTOXIC CHEMOTHERAPY If the agents described fail to control indolent disease, or if there is rapidly progressing or aggressive de novo disease, more potent chemotherapy is warranted. Because of the chronic nature of the disease, single-agent chemotherapy that allows the sequential use of these agents is preferred. Gemcitabine (Gemzar, Lilly) has demonstrated impressive clinical activity in advanced and refractory CTCL, with a 70% response rate and a median response duration of 8 months.57 The incidence of grade 3 neutropenia was 25%. In a study of chemotherapy-naïve patients treated with 1,200 mg/m2, the response rate was 70%, with 5 CRs.57,58 Other purine analogues, including fludarabine, cladribine (Leustatin, Ortho Biotech), and pentostatin, also have demonstrated efficacy.59-64 Pegylated liposomal doxorubicin (Doxil, Centocor Ortho Biotech) was associated with an ORR of 88%, a CR rate of 42%, and a disease-free survival of 13 months.65 With the exception of infusion-related events, liposomal doxorubicin was well tolerated. Responders received up to 18 cycles of pegylated liposomal doxorubicin. Bortezomib (Velcade, Millennium) administered on a weekly schedule was reported recently to have an impressive response rate of 67% in patients who had recurring MF/SS.66 All responses were durable, lasting from 7 to 14 months or longer. Overall, the drug was well tolerated, with no grade 4 toxicity, and combination therapy studies are under way. Despite numerous treatment alternatives, many patients who have advanced MF/SS rapidly become refractory to therapy, presumably because of drug resistance. Responses to combination chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine,

and prednisolone are high, but response durations are short. Infusion chemotherapy with etoposide, vincristine, doxorubicin, cyclophosphamide, along with oral prednisone (EPOCH) was studied in heavily pretreated CTCL patients and resulted in an ORR of 80%, with a CR rate of 27%.67 The median progression-free survival was 8 months, and Sézary cells were undetectable in 2 of 6 patients who had SS. Other intensive lymphoma salvage regimens likewise have demonstrated responses, albeit with significant toxicity related to immunosuppression.

Hematopoietic Stem Cell Transplantation Hematopoietic stem cell transplantation offers CTCL patients a chance for long-term cure. High-dose chemotherapy and autologous stem cell transplantation have yielded disappointing results.68 Allogeneic stem cell transplantation provides the advantages of a sustained immune-mediated graft-versus-lymphoma effect and a graft that is uncontaminated with tumor cells but with the risk for peritransplantation morbidity and mortality. Allogeneic transplantation including reduced-intensity conditioning regimens for MF and SS demonstrates a graft-versus-tumor effect and long-term remissions in selected patients.69 The timing of allogeneic stem cell transplantation is also an important factor to consider. In patients who have a large disease burden or who have had multiple previous relapses, allogeneic transplantation should be considered earlier in the disease course if a human leukocyte antigen–matched donor is identified.

Conclusion Although several treatments have shown efficacy in the management of CTCL, very few patients are cured of their disease. The overall goals of treatment for most patients are to reduce the disease burden with minimal toxicity from treatment, palliate the symptoms of pruritus and compromised skin integument, and prevent infection and immunosuppression. As the role of biologic agents is becoming better understood, new combination strategies can be designed and tested.

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6. Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. 2002;46(1):95-106, PMID: 11756953. 7. Lansigan F, Choi J, Foss FM. Cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 2008;22(5):979-996, PMID: 18954747. 8. Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for mycosis fungoides. Experience in 79 patients. Arch Dermatol. 1998;134(8):949-954, PMID: 9722724. 9. Hoppe RT, Abel EA, Deneau DG, Price NM. Mycosis fungoides: management with topical nitrogen mustard. J Clin Oncol. 1987;5(11):1796-1803, PMID: 3681368. 10. Vonderheid EC, Tan ET, Kantor AF, Shrager L, Micaily B, Van Scott EJ. Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. J Am Acad Dermatol. 1989;20(3):416-428, PMID: 2537348. 11. Mahrle G, Thiele B. Retinoids in cutaneous T cell lymphomas. Dermatologica. 1987;175(suppl 1):145-150, PMID: 3500880. 12. Breneman D, Duvic M, Kuzel T, Yocum R, Truglia J, Stevens VJ. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002;138(3):325-332, PMID: 11902983. 13. Takemori N, Hirai K. [Significance of PUVA therapy for adult T-cell leukemia/lymphoma—PUVA therapy can induce apoptosis in leukemic cells]. Hum Cell. 1995;8(3):121-126, PMID: 8652448. 14. Abel EA, Sendagorta E, Hoppe RT, Hu CH. PUVA treatment of erythrodermic and plaque-type mycosis fungoides. Ten-year follow-up study. Arch Dermatol. 1987;123(7):897-901, PMID: 3606168. 15. Honigsmann H, Brenner W, Rauschmeier W, Konrad K, Wolff K. Photochemotherapy for cutaneous T cell lymphoma. A follow-up study. J Am Acad Dermatol. 1984;10(2 pt 1):238-245, PMID: 6609177. 16. Ramsay DL, Lish KM, Yalowitz CB, Soter NA. Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol. 1992;128(7):931-933, PMID: 1626959. 17. Clark C, Dawe RS, Evans AT, Lowe G, Ferguson J. Narrowband TL-01 phototherapy for patch-stage mycosis fungoides. Arch Dermatol. 2000;136(6):748-752, PMID: 10871938. 18. Gathers RC, Scherschun L, Malick F, Fivenson DP, Lim HW. Narrowband UVB phototherapy for early-stage mycosis fungoides. J Am Acad Dermatol. 2002;47(2):191-197, PMID: 12140464. 19. Hofer A, Cerroni L, Kerl H, Wolf P. Narrowband (311-nm) UV-B therapy for small plaque parapsoriasis and early-stage mycosis fungoides. Arch Dermatol. 1999;135(11):1377-1380, PMID: 10566837. 20. Duvic M, Lemak NA, Redman JR, et al. Combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;34(6):1022-1029, PMID: 8647968. 21. Jones G, McLean J, Rosenthal D, Roberts J, Sauder DN. Combined treatment with oral etretinate and electron beam therapy in patients with cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). J Am Acad Dermatol. 1992;26(6):960-967, PMID: 1607416. 22. Micaily B, Campbell O, Moser C, Vonderheid EC, Brady LW. Total skin electron beam and total nodal irradiation of cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys. 1991;20(4):809-813, PMID: 2004959.

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23. Price NM. Topical mechlorethamine. Cutaneous changes in patients with mycosis fungoides after its administration. Arch Dermatol. 1977;113(10):1387-1389, PMID: 911166. 24. Wilson LD, Licata AL, Braverman IM, et al. Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy. Int J Radiat Oncol Biol Phys. 1995;32(4):987-995, PMID: 7607973. 25. Hoppe RT. Total skin electron beam therapy in the management of mycosis fungoides. Front Radiat Ther Oncol. 1991;25:80-89; discussion 132-133, PMID: 1908426. 26. Jones GW, Rosenthal D, Wilson LD. Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sezary syndrome). Cancer. 1999;85(9):1985-1995, PMID: 10223240. 27. Quiros PA, Jones GW, Kacinski BM, et al. Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys. 1997;38(5):1027-1035, PMID: 9276369. 28. Wilson LD, Quiros PA, Kolenik SA, et al. Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35(1):69-73, PMID: 8682967. 29. Knobler RM. Photopheresis—extracorporeal irradiation of 8-MOP containing blood—a new therapeutic modality. Blut. 1987;54(4):247-250, PMID: 3493819. 30. Gasparro FP, Chan G, Edelson RL. Phototherapy and photopharmacology. Yale J Biol Med. 1985;58(6):519-534, PMID: 3832664. 31. Edelson RL. Cutaneous T cell lymphoma: the helping hand of dendritic cells. Ann N Y Acad Sci. 2001;941:1-11, PMID: 11594563. 32. Berger CL, Hanlon D, Kanada D, et al. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood. 2002;99:2929-2939, PMID: 11929784. 33. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. 1987;316(6):297-303, PMID: 3543674. 34. Zic JA, Miller JL, Stricklin GP, King LE Jr. The North American experience with photopheresis. Ther Apher. 1999;3(1):50-62, PMID: 10079806. 35. Zic J, Arzubiaga C, Salhany KE, et al. Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol. 1992;27(5 pt 1):729-736, PMID: 1430395. 36. Bunn PA Jr, Foon KA, Ihde DC, et al. Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med. 1984;101(4):484-487, PMID: 6332565. 37. Olsen EA, Rosen ST, Vollmer RT, et al. Interferon alfa-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol. 1989;20(3):395-407, PMID: 2783939. 38. Dippel E, Schrag H, Goerdt S, Orfanos CE. Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma. Lancet. 1997;350(9070):32-33, PMID: 9217723. 39. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther. 2003;16(4):311-321, PMID: 14686974. 40. Dummer R, Dobbeling U, Geertsen R, Willers J, Burg G, Pavlovic J. Interferon resistance of cutaneous T-cell lymphoma-derived

clonal T-helper 2 cells allows selective viral replication. Blood. 2001;97(2):523-527, PMID: 11154232. 41. Urosevic M. Drug evaluation: TG-1042, an adenovirus-mediated IFNgamma gene delivery for the intratumoral therapy of primary cutaneous lymphomas. Curr Opin Investig Drugs. 2007;8(6): 493-498, PMID: 17621880. 42. Duvic M, Sherman ML, Wood GS, et al. A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides. J Am Acad Dermatol. 2006;55(5):807-813, PMID: 17052486. 43. Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001;19(9):2456-2471, PMID: 11331325. 44. Negro-Vilar A, Dziewanowska A, Groves ES, et al. Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL). J Clin Oncol. 2007;25(18 suppl):Abstract 8026. 45. Foss F, Demierre MF, DiVenuti G. A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2005;106(2):454-457, PMID: 15811959. 46. Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood. 2003;101(11):42674272, PMID: 12543862. 47. Kennedy GA, Seymour JF, Wolf M, et al. Treatment of patients with advanced mycosis fungoides and Sezary syndrome with alemtuzumab. Eur J Haematol. 2003;71(4):250-256, PMID: 12950233. 48. Kim YH, Duvic M, Obitz E, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood. 2007;109(11):4655-4662, PMID: 17311990. 49. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287-299, PMID: 12120280. 50. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31-39, PMID: 16960145. 51. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109-3115, PMID: 17577020. 52. Duvic M, Becker JC, Dalle S, et al. Phase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous T-cell lymphoma (CTCL). ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1005. 53. Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001;98(9):2865-2868, PMID: 11675364. 54. Bates S, Piekarz R, Wright J, et al. Final clinical results of a Phase 2 NCI multicenter study of romidepsin in recurrent cutaneous T-cell lymphoma (molecular analyses included). ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1568.

55. Horwitz SM, Duvic M, Kim Y, et al. Pralatrexate (PDX) is active in cutaneous T-cell lymphoma: preliminary results of a multi-center dose-finding trial. ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1569. 56. Duvic M, Forero-Torres A, Foss F, Olsen E, Pinter-Brown L, Kim Y. Long-term treatment of CTCL with the oral PNP inhibitor, forodesine. J Clin Oncol. 2009;27(suppl 15s):Abstract 8552. 57. Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol. 2000;18(13):2603-2606, PMID: 10893292. 58. Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer. 2005;104(11):2437-2441, PMID: 16216001. 59. Von Hoff DD, Dahlberg S, Hartstock RJ, Eyre HJ. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group study. J Natl Cancer Inst. 1990;82(16):1353-1355, PMID: 1696322. 60. Kurzrock R, Pilat S, Duvic M. Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol. 1999;17(10):3117-3121, PMID: 10506607. 61. Foss FM, Ihde DC, Breneman DL, et al. Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. J Clin Oncol. 1992;10(12):1907-1913, PMID: 1453206. 62. Kuzel TM, Hurria A, Samuelson E, et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood. 1996;87(3):906-911, PMID: 8562961. 63. Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood. 1992;80(3):587-592, PMID: 1353380. 64. Oâ&#x20AC;&#x2122;Brien S, Kurzrock R, Duvic M, et al. 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders. Blood. 1994;84(3):733-738, PMID: 7913841. 65. Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer. 2003;98(5):993-1001, PMID: 12942567. 66. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(27):4293-4297, PMID: 17709797. 67. Akpek G, Koh HK, Bogen S, Oâ&#x20AC;&#x2122;Hara C, Foss FM. Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Cancer. 1999;86(7):1368-1376, PMID: 10506727. 68. Olavarria E, Child F, Woolford A, et al. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol. 2001;114(3):624-631, PMID: 11552988. 69. Herbert KE, Spencer A, Grigg A, Ryan G, McCormack C, Prince HM. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34(6):521-525, PMID: 15286686.

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DOSE MODIFICATION GUIDELINES For dose modiﬁcation guidelines, please see Brief Summary of Prescribing Information on following pages.

BOXED WARNING: HEPATOTOXICITY TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.

IMPORTANT SAFETY INFORMATION Decreased Left Ventricular Ejection Fraction—TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Conﬁrm normal LVEF before starting TYKERB, and continue evaluations during treatment. Patients With Severe Hepatic Impairment—If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered. Diarrhea—Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with antidiarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and ﬂuids and interruption or discontinuation of therapy with TYKERB. Interstitial Lung Disease/Pneumonitis—TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥grade 3 (NCI CTCAE), TYKERB should be discontinued. QT Prolongation—TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered. Pregnancy—Pregnancy Category D: TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions—The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%). The most common grade 3 and 4 adverse reactions (NCI CTCAE v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%). References: 1. TYKERB Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2008. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.1.2010. www.nccn.org. Accessed October 20, 2009.

www.TYKERB.com 1-866-4-TYKERB 1-866-489-5372

IN HER2+ METASTATIC BREAST CANCER (MBC)

WHEN FIRST-LINE THERAPY FAILS*

TREAT HER DIFFERENTLY WITH TYKERB *TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1

Proven After 1st-line MBC

Dosage & Administration

2010 NCCN CLINICAL PRACTICE GUIDELINES TYKERB + capecitabine is listed as a preferred regimen for second-line treatment of HER2+ MBC patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab2

28% TO 43% REDUCTION IN RISK OF PROGRESSION TYKERB plus capecitabine reduced risk of progression 28% to 43% vs capecitabine alone†1 †

TYKERB was studied in a phase 3 trial of 399 women with HER2+ MBC; ≈95% of patients had prior treatment with an anthracycline, a taxane, and trastuzumab. Patients were randomized to either: TYKERB 1250 mg orally daily throughout the trial + capecitabine 2000 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=198); or capecitabine 2500 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=201). Primary end point was time to progression (time from randomization until objective tumor progression or death due to breast cancer).1

Please see Brief Summary of Prescribing Information on adjacent pages.

TYKERB® (lapatinib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).] 1

INDICATIONS AND USAGE TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. 2 2.1

DOSAGE AND ADMINISTRATION Recommended Dosing The recommended dose of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see Clinical Pharmacology (12.3) of full prescribing information]. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. 2.2

Dose Modification Guidelines Cardiac Events: TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. TYKERB may be restarted at a reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic. Hepatic Impairment: Patients with severe hepatic impairment (ChildPugh Class C) should have their dose of TYKERB reduced. A dose reduction to 750 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).] Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2).] Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be considered when patients develop ≥Grade 2 NCI CTC toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB should be restarted at a lower dose (1,000 mg/day). See manufacturer’s prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity. 4

CONTRAINDICATIONS None. See manufacturer’s prescribing information for capecitabine contraindications. 5 5.1

WARNINGS AND PRECAUTIONS Decreased Left Ventricular Ejection Fraction TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if TYKERB is to be administered to patients with conditions that could impair left ventricular function. LVEF

should be evaluated in all patients prior to initiation of treatment with TYKERB to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with TYKERB to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)]. 5.2

Hepatotoxicity Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB [see Adverse Reactions (6.1)]. 5.3

Patients with Severe Hepatic Impairment If TYKERB is to be administered to patients with severe pre-existing hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)]. 5.4

Diarrhea Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB. 5.5

Interstitial Lung Disease/Pneumonitis Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1)]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE). 5.6

QT Prolongation QT prolongation measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4) of full prescribing information]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration. The prescriber should consider baseline and ontreatment electrocardiograms with QT measurement. 5.7

Pregnancy Pregnancy Category D TYKERB can cause fetal harm when administered to a pregnant woman. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC). Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations. There are no adequate and well-controlled studies with TYKERB in pregnant women. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6 6.1

ADVERSE REACTIONS Clinical Trials Experience The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14) of full prescribing information.] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be

directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication. The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2. Table 1. Adverse Reactions Occurring in ≥10% of Patients

Reactions

TYKERB 1,250 mg/day Capecitabine + Capecitabine 2,500 mg/m2/day 2,000 mg/m2/day (N = 191) (N = 198) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % %

Gastrointestinal disorders Diarrhea 65 13 1 40 10 0 Nausea 44 2 0 43 2 0 Vomiting 26 2 0 21 2 0 Stomatitis 14 0 0 11 <1 0 Dyspepsia 11 <1 0 3 0 0 Skin and subcutaneous tissue disorders Palmar-plantar 53 12 0 51 14 0 erythrodysesthesia Rashb 28 2 0 14 1 0 Dry skin 10 0 0 6 0 0 General disorders and administrative site conditions Mucosal inflammation 15 0 0 12 2 0 Musculoskeletal and connective tissue disorders Pain in extremity 12 1 0 7 <1 0 Back pain 11 1 0 6 <1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 12 3 0 8 2 0 Psychiatric disorders Insomnia 10 <1 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine group. Table 2. Selected Laboratory Abnormalities

signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See Warnings and Precautions (5.1).] Hepatotoxicity: Lapatinib has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)]. Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Warnings and Precautions (5.5)]. 7 DRUG INTERACTIONS 7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown. Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised. 7.2

Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)]. Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%. 7.3

Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised. 7.4

Other Chemotherapy Agents In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine). 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.7)].

8.3

Nursing Mothers It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TYKERB, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4

TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m2/day Parameters

Capecitabine 2,500 mg/m2/day

All Grade Grade All Grade Grade 4 Gradesa 3 4 Gradesa 3 % % % % % %

Hematologic Hemoglobin 56 <1 0 53 1 0 Platelets 18 <1 0 17 <1 <1 Neutrophils 22 3 <1 31 2 1 Hepatic Total Bilirubin 45 4 0 30 3 0 AST 49 2 <1 43 2 0 ALT 37 2 0 33 1 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as

Pediatric Use The safety and effectiveness of TYKERB in pediatric patients have not been established. 8.5

Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine (N = 198), 17% were 65 years of age and older, and 1% were 75 years of age and older. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6

Renal Impairment Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with TYKERB in patients with severe renal impairment. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys. 8.7

Hepatic Impairment The pharmacokinetics of lapatinib were examined in subjects with preexisting moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure

(AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, respectively. Administration of TYKERB in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe pre-existing hepatic impairment [see Dosage and Administration (2.2)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].

clinical exposure based on AUC, respectively).

17.2 Diarrhea Patients should be informed that TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with TYKERB.

OVERDOSAGE There is no known antidote for overdoses of TYKERB. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of TYKERB could result in serum concentrations exceeding those observed in clinical trials and could result in increased toxicity. Therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose. There has been a report of one patient who took 3,000 mg of TYKERB for 10 days. This patient had Grade 3 diarrhea and vomiting on Day 10. The event resolved following IV hydration and interruption of treatment with TYKERB and letrozole. Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with lapatinib are ongoing. Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays. There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (17.6) of full prescribing information.

17.1 Decreased Left Ventricular Ejection Fraction Patients should be informed that TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB.

17.3 Drug Interactions TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products. 17.4 Food Patients should be informed of the importance of taking TYKERB at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food. 17.5 Divided Dosing The dose of TYKERB should not be divided. Patients should be advised of the importance of taking TYKERB once daily, in contrast to capecitabine which is taken twice daily. TYKERB is a registered trademark of GlaxoSmithKline.

SOLID TUMORS Colorectal

BLOOD TESTS

These methylation gene markers are now being validated in a large CRC screening study of 7,000 patients. ‘And we are currently talking to several partners about distribution rights.’

continued from page 25

rectal or gastric cancers. Ulrike Stein, PhD, from the ECRC Charité University of Medicine and the Max-Delbrück Center for Molecular Medicine in Berlin, said the test not only detects malignancy but also can help predict the likelihood for metastasis in patients with a cancer diagnosis. Dr. Stein and her colleagues looked for the presence of an S100A4 transcript by isolating RNA from plasma samples of 466 patients with colon, rectal and gastric cancers, as well as 51 matched controls. “We found that S100A4 mRNA was present at significantly higher levels in the group of cancer patients than in tumorfree controls,” she reported, “and levels were even higher in patients with metastases. More importantly, prospective analysis of the data showed that patients who developed metastases had higher S100A4 levels at baseline than those whose disease did not metastasize.” Additionally, in patients followed over time, recurrences were significantly less likely in patients with low S100A4 levels than in those with the highest levels, for all the tumor

—Joost Louwagie, PhD

types, Dr. Stein added. The S100A4 transcript has been known to enhance the metastatic capability of cancer cells, she said, but the problem has been the expense and complexity of establishing its existence in a tumor. Dr. Stein and her group will now attempt to correlate S100A4 transcript levels in the blood with patient survival after three or more years of follow-up. Such a correlation would lead the way to identifying patients with more aggressive disease that might need more intensive treatment.

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 0 9 • N O. 2

—Caroline Helwick

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Guide to Cancer Therapeutic Regimens 2009 Pocket Guide The use of cancer therapeutic agents in combination is well established. The knowledge of cell kinetics and the pharmacology of antitumor agents have allowed the clinician to use combination therapy to maximize tumor cell kill with minimal or acceptable toxicity to the patient.

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Current Challenges in the Management of

Chronic Myelogenous Leukemia BRANDON HAMILTON, MD Fellow Division of Hematology Oncology and Blood and Marrow Transplantation San Antonio Military Medical Center San Antonio, Texas

MICHAEL R. SAVONA, MD Attending Physician Clinical Assistant Professor of Internal Medicine University of Texas Health Science Center San Antonio San Antonio, Texas

hronic myelogenous leukemia (CML) is the first clonal disorder recognized to be driven by a dominant acquired genetic mutation.1-4 That mutation, the Philadelphia chromosome, t(9;22)(q34;q11)—the reciprocal

translocation and fusion of the Abelson kinase (ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22—encodes for BCR-ABL tyrosine kinase, the molecular machinery behind CML.

Imatinib mesylate (Gleevec, Novartis), the first inhibitor of BCR-ABL kinase, has revolutionized the treatment of, and the outlook for, patients with CML since its introduction in the late 1990s.5 This review discusses the use of imatinib and other tyrosine kinase inhibitors (TKIs) in the treatment of CML, offering treatment recommendations based on emerging resistance data and information about the nuances of the various TKIs. In addition, it discusses new tactics to address resistance and the pressing need to further target primitive CML stem cells for any potential hope for cure.

Imatinib Trials of imatinib showing significant activity in chronic-phase (CP) patients who were previously treated

C L IN IC A L O N COLOGY NEWS SPECI AL EDI TI ON 200 9 • NO. 2

with interferon-α (IFN) and in patients with advanced stages of the disease (eg, accelerated phase [AP] and blast crisis [BC]) led to FDA approval of imatinib for previously treated patients with CML.6-9 The use of imatinib was then explored in newly diagnosed CML patients in IRIS (International Randomized Study of Interferon-alpha plus cytarabine versus ST1571), which compared the drug with the standard of care at the time (IFN-α plus cytarabine). Imatinib markedly increased cytogenetic response rates with an improved toxicity profile, leading to its approval as first-line therapy for CML.10,11 At the time, limited information existed on the durability of the remissions, the impact on survival, and the nature of resistance. A large body of data has since become available, and complete hematologic response

INDE P E NDE NT LY DE V E LOP E D BY MC MAH ON P U B L I S H I N G

(CHR) and complete cytogenetic response (CCyR) are seen in 94% and 87% of newly diagnosed patients treated with imatinib, respectively.12 These benchmarks are important because patients who do not develop at least a partial cytogenetic response account for most (more than 70%) of resistant disease, and, ultimately, the majority of the disease-related mortality.13 Long-term outcome of therapy is not clear; however, prior to 1990, the median survival of patients with CML was approximately 4 years, so the impact of imatinib on survival appears to be dramatic (Figure 1).14 Disease-free survival (DFS) and overall survival (OS) have been reported to be 94% and 86%, respectively, after more than 7 years.15 Since IRIS randomization, fewer than 5% of patients have died due to progression of CML. Early studies of imatinib in advanced disease revealed modest, dose-dependent responses in AP8 and BC CML.9,16,17 Outcomes are clearly less favorable in the advanced stages of CML, but imatinib may still have a role in combination with cytotoxic agents, and perhaps as part of a strategy that uses several treatment modalities including cytotoxic agents, allogeneic stem cell transplantation (SCT), newer TKIs, and other pathway-targeted therapies. Perhaps the greatest reward with regard to advanced-stage CML is the dramatic reduction of its prevalence with imatinib therapy.

and improved survival relative to patients who failed to achieve this response.11 This response is measured via classic karyotyping with a metaphase spread, or with interphase cytogenetic analysis via fluorescence in situ hybridization (FISH) assays. FISH can be performed on peripheral blood, and can be useful during diagnosis to identify rare cases of Philadelphia (Ph) chromosomeâ&#x20AC;&#x201C; negative BCR-ABLâ&#x20AC;&#x201C;positive CML, Ph amplification, or other variant chromosomal aberrations.13 The development of real-time quantitative polymerase chain reaction (RQ-PCR) amplification assays, which quantify the ratio of BCR-ABL transcripts and a common gene transcript (typically ABL), has provided a tool to detect and quantify minimal residual disease.18 Quantification of mRNA from BCR-ABL has been incorporated in the prospective studies of imatinib in CML, and has helped to further characterize the kinetics of treatment response. Although the majority of CP CML patients who receive TKI therapy will achieve the desired clinical response, it is critical to monitor response to therapy at regular intervals because failure to respond and loss of response are harbingers of poor outcome.12 After 7 years of analysis of the IRIS data, it has become clear that the time needed to reach cytogenetic response has prognostic significance. For example, at 6 months, event-free survival was less than 60% for patients with no cytogenetic response, and greater than 90% for patients with CCyR. Similarly, if the CCyR is less than 35% at 12 months, then the chance of achieving a CCyR at 2 years decreases to 20%.12 After achieving a CCyR, some patients will have rising protein levels by RQ-PCR during surveillance, but the significance of this is unclear. In a University of Texas M.D. Anderson

Monitoring Therapy and Speed of Response Cytogenetic monitoring was established as a preferred method for following therapy outcomes in CML when it was demonstrated that patients treated with IFN who achieve CCyR had a lower risk for disease progression

Patients Without Event, %

100 90 80 70 60 50 40

Survival: deaths associated with CML

Overall Survival

20 10 0 0

Months Since Randomization

Figure 1. Overall survival in IRIS (ITT principle): imatinib arm. ITT, intent to treat Based on reference 14.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 1. Definition of Treatment Failure and Suboptimal Response For Previously Untreated Chronic Phase CML Patients Time From Start Of Imatinib,a mo

Recommended Follow-up

Failure

Suboptimal Responseb

Monitor for CHRc; RQ-PCRd; with or without FISH

No HR

<CHR

Monitor for CHRc Bone marrow biopsye RQ-PCRd

<CHR or no CyR

<PCyR (Ph+ >35%)

Monitor for CHRc; RQ-PCRd; with or without FISH

<CHR or no CyR

<PCyR (Ph+ >35%)

Monitor for CHRc Bone marrow biopsye RQ-PCRd

<PCyR (Ph+ >35%)

<CCyR

Monitor for CHRc RQ-PCRd

<CCyR

<MMR

400 mg/d Consider mutational analysis for any suboptimal response or treatment failure. c Monitor for CHR every 2 wk until achieved. d Monitor every 3 mo during therapy. e Every 6 mo until CCyR achieved, then as indicated. b

CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myelogenous leukemia; CyR, cytogenetic response; FISH, fluorescence in situ hybridization; MMR, major molecular response; PCyR, partial cytogenetic response; RQ-PCR, real-time quantitative polymerase chain reaction

Cancer Center cohort of patients who had achieved a CCyR while taking imatinib but had an increase in their minimal molecular disease by RQ-PCR, 13 of 116 (11%) had disease progression.19 It seems clear that there is prognostic value in achieving at least a major molecular response (MMR); however, patients who have CCyR with minimal residual molecular disease, or evidence of a modest increase in molecular disease while retaining a CCyR, may not be relapsing but should be monitored closely. Various schemes have been employed to monitor patients while they are receiving TKI therapy. After initiating therapy, physicians should monitor for hematologic toxicity and measure hematologic response weekly or more frequently if necessary. Conventional karyotyping (metaphase cytogenetics) of bone marrow should be completed prior to therapy, and every 6 months until a CCyR is attained. More frequent FISH analysis of peripheral blood can lead to clearer establishment of CCyR and thus lend prognostic utility, but there is a lack of clear guidance from the literature on the continued utility of FISH at short intervals if conventional karyotyping already is performed. Once a CCyR has been achieved, conventional cytogenetics can be conducted annually until an MMR has been attained, and then as clinically indicated. Molecular testing should be performed every 3 months during therapy and should continue for at least 3 to 5 years, even in the setting of complete molecular response (CMR), because a small number of patients with MMR or CMR lose molecular response and

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

eventually relapse.20 An extended interval between follow-ups can be considered for patients with CMR after several years of stable disease control. Mutational analyses should be performed for treatment failure (including patients with a significant rise in BCR-ABL transcript levels) and suboptimal response (Table 1).13,21,22

Mechanisms of Resistance While most CML patients initially respond to TKI therapy, nearly 4% of newly diagnosed CP patients are resistant to imatinib, and up to 18% lose response or become intolerant of the drug.12,16 Long-term follow-up reveals a declining rate of resistance over time, with a near negligible rate of resistance in patients who achieve a timely CCyR.23 Presumably, the greater resistance seen in the first year of therapy is in patients with late CP CML who may have been developing advanced disease at the time of their diagnosis. Approximately one-half of imatinib resistance is BCR-ABL-dependent or secondary to clones expressing mutant forms of BCR-ABL. Point mutations in the ABL kinase domain decrease imatinibâ&#x20AC;&#x2122;s ability to bind to this region. Other mutations (eg, P-loop, C-helix, activation loop, and C terminal lobe mutations) lead to conformational changes in the kinase. There are more than 100 described mutations of BCR-ABL tyrosine kinase.24-26 Four of them account for more than 70% of all mutations identified (Y253F, E255V, T315I, and M351T).27 Of these common mutations, BCR-T315I confers significant

resistance to imatinib therapy and to the second-generation TKIs as well. TKI therapy eliminates mature but not primitive CML cells. The low replicative indices of these primitive cells define an inherent refractoriness to growth/ cell cycle-specific therapy; these cells are not resistant but refractory to TKIs. Refractoriness of CML stem cells implies acquisition of the complete characteristics of the stem cell in an affected clone or the insertion of the malignant genotype into a normal hematopoietic stem cell (HSC), leading to quiescence and a protected reservoir for the Ph chromosome.22 Primitive refractory CML cells exist even in patients in CMR, whereas BCRABL-independent resistance implies acquisition of cellular machinery that enables the progeny cell to exert the leukemic phenotype beyond strict regulation of a refractory CML stem cell. BCR-ABL-independent resistant CML cells are armed with defenses against apoptosis, including increased drug efflux and deactivation, overexpression of other oncogenes (c-Myc, Lyn kinase), amplification of the fusion gene, and activation of epigenetic pathways.28,29

High-Dose Imatinib Although the maximum tolerated dose has not been reached for imatinib, patients with CCyR or MMR have higher trough levels of drug than those who lack response to imatinib.30 Additionally, Shah et al demonstrated that some BCR-ABL mutations confer only relative resistance and these patients respond to higher doses of imatinib.31 Higher doses of imatinib can lead to greater rates of cytogenetic and molecular responses,32,33 and early use of high-dose imatinib in patients who are TKI-naĂŻve may improve the overall molecular response rate, and reduce the risk for emergence of imatinib-resistant clones. For these reasons, higher doses of imatinib could be considered during the first year of therapy, either from initiation of therapy or after failure to achieve adequate timely cytogenetic and molecular responses. The advantages of high-dose imatinib therapy, however, also must be considered in the context of an increase in hematologic and nonhematologic toxicities. Likewise, although dose escalation may saturate the cell and override steric hindrance,31,34 the changes incurred by some BCR-ABL mutants cannot be overcome with a greater concentration of imatinib,35 and, thus, increasing the dose of imatinib may not be appropriate for some mutations.17 Guidance on use of higher doses of imatinib may be improved by measuring trough levels during treatment30 or evaluating polymorphisms in the P450 (CYP3A4) liver enzyme that is primarily responsible for drug metabolism.17 In the future, the potential of pharmacogenomics may help determine appropriate doses for individual patients, and standardized tests will be readily available to clinicians.

Second-line Therapies Dasatinib (Sprycel, Bristol-Myers Squibb) has potent inhibitory activity against BCR-ABL, KIT, PDGFR, and

the Src family tyrosine kinases, binding to both the active and inactive conformation of the ABL kinase domain.36 This less stringent binding requirement is thought to be responsible for dasatinibâ&#x20AC;&#x2122;s activity against most imatinib-resistant kinase domain mutations.17 Dasatinib showed early activity in both CP and advanced CML in imatinib-resistant patients, with CHR achieved in 92% of CP patients, and major hematologic response in 70% with AP CML.37 Given these findings, a series of trials was initiated to evaluate the efficacy of dasatinib for CP, advanced CML, and Ph-positive acute lymphocytic leukemia. Nearly 200 CP patients with treatment failure or intolerance to imatinib were given 70 mg of dasatinib twice daily, and 53% reached CCyR.38 These responses were maintained in 86% of imatinib-resistant patients at 24-month follow-up. Patients with advanced disease also responded to dasatinib.39-41 Discontinuation of therapy occurred in 9% of patients because of adverse events, most commonly myelosuppression and pleural effusion.38 As mentioned previously, escalating the dose of imatinib (to 800 mg) daily overcomes resistance to imatinib in some cases.26 In a randomized crossover study comparing high-dose imatinib and dasatinib, CCyR was achieved in 40% of the dasatinib group and 16% of the high-dose imatinib group. Further markers of disease response were similarly favorable in the dasatinib group, and, notably, failure rates rose among patients who crossed over from the dasatinib to the high-dose imatinib group and fell among patients who crossed over from the high-dose imatinib to the dasatinib group.17 Given the cytopenias and pleural effusions seen with the early use of dasatinib, alternative dosing has been explored, and dasatinib at a dose of 100 mg once daily seems to have similar efficacy but significantly less toxicity than the 70-mg twice-daily dose.42 Nevertheless, the 70-mg twice-daily dosing schema should be maintained for patients with advanced CML. Dasatinib is ineffective against the T315I mutation, and likely has limited activity against other mutations including Q252H, V299L, and F317L,43 which have variable sensitivity to imatinib and other second-generation kinase inhibitors. Nilotinib (AMN107, Novartis) binds to the inactive conformation of the ABL kinase approximately 30-fold more potently than imatinib,44 and also has increased activity with the KIT and PDGF receptor kinases, but, unlike dasatinib, nilotinib has no activity against the Src family kinases. Like dasatinib, this drug was shown to have activity in dose-finding experiments for patients who were resistant to or intolerant of imatinib.45 These results were confirmed in a follow-up Phase II trial in which 321 patients with CP CML resistant to, or intolerant of, imatinib were treated with nilotinib at a dose of 400 mg twice daily. At the time, the rate of CHR was 77% and the rate of major cytogenetic response was 57% (with 41% CCyR).46 Patients experienced the hematologic side effects of imatinib, but they did not have significant fluid retention or subsequent effects that can lead to imatinib intolerance.47 Nilotinib has

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been tested in advanced CML as well, and it appears to have similar efficacy to dasatinib.48 Both dasatinib and nilotinib are being studied in the first-line setting,49 but the roles of these agents in previously untreated CML are not well defined, and they should be reserved for clinical trials. In vitro mutational analyses reveal that these second-generation TKIs are ineffective against BCRABL T315I but differentially potent against variable mutations (Table 2).38,46,50 The mutational analyses from early clinical studies seem to correlate with this, with dasatinib superior to nilotinib for Y253F, F359V, and E255V, and the converse for L248V, V299L, and F486S.17,37,45,51 Given differing side-effect profiles and mutation sensitivities for each drug, one may develop a rational approach for dealing with imatinib failure. Specifically, when imatinib treatment failure occurs, selection of a second agent can be directed by mutational analysis. Alternative TKIs, such as bosutinib (SKI606), may have a role against specific mutations such as Q252H and L384M.50

fails to respond to second-generation agents, great effort has been invested in the development of agents capable of inhibiting the BCR-ABL T315I mutant kinase. The T315I mutation occurs via the substitution of a threonine residue by isoleucine, placing the bulky isoleucine side chain within the imatinib binding site of the ABL kinase. This resultant steric hindrance is believed to be the basis for resistance to first- and second-generation TKIs.52 Aurora/ABL kinase inhibitors (AKIs) are able to overcome the resistance of T315I because they do not bind as deeply to the hydrophobic pocket of the ABL kinase; through this shallow binding, they can avoid the steric hindrance of this isoleucine side chain. There are many AKIs undergoing both preclinical and clinical study, and several including MK-0457 seem to lead to clinical response in patients with the T315I mutation.53 A quickly expanding understanding of intracellular signaling in CML has led to exploration of both tyrosine kinaseâ&#x20AC;&#x201C;specific, and BCR-ABL-independent targets for therapy, and this is reviewed thoroughly elsewhere.54,55 These agents remain investigational but hold promise in the therapy of de novo and resistant CML.

The T315I Problem and Investigational Options Stem Cell Transplantation

In the Phase I trials of dasatinib and nilotinib, the T315I mutation prevented response to either agent.37,45 As BCR-ABL T315I represents 10% to 15% of all BCR-ABL mutations in patients who fail imatinib,21 and it likewise

Allogeneic SCT remains a viable option for patients with resistant disease. In a large retrospective review of more than 1,480 CML patients receiving allogeneic

Table 2. Rational Approach for Choosing Second-line TKIs for Common ABL Mutations After Imatinib Failure Mutation

Dasatinib

Nilotinib

Recommended Second-line Therapy

Q252H

MCyR38

Not tested

Dasatinib or nilotinib

Y253F

CCyR Sensitive in vitro50

CHR Moderate resistance in vitro50

Dasatinib

T315I

No response50

No response46

Clinical trial or allogeneic stem cell transplantation

F317L

CCyR38 Resistance in vitro50

CHR46 Moderate resistance in vitro50

Dasatinib or nilotinib

F359V

CCyR38 Sensitive in vitro50

MCyR46 Resistance in vitro50

Dasatinib or nilotinib

H396R

CHR38 Sensitive in vitro50

CCyR46 Moderate resistance in vitro50

Dasatinib or nilotinib

E255V

CHR38 Moderate resistance in vitro50

High resistance in vitro50

Dasatinib

E279K

Sensitive in vitro50

CCyR46 Sensitive in vitro50

Dasatinib or nilotinib

V299L

Resistance in vitro50

Sensitive in vitro50

Nilotinib

F486S

Moderate resistance in vitro50

Sensitive in vitro50

Nilotinib

CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; MCyR, major cytogenetic response; TKI, tyrosine kinase inhibitor

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Independence From Addiction to BCR-ABL

Blast Crisis

Accelerated Phase

Anaplastic Threshold

Oncogenic Addiction to BCR-ABL

Late Chronic Phase

Genetic Instability

Early Chronic Phase

Time

Figure 2. Addiction to BCR-ABL, and avoiding the anaplastic threshold. The natural history of chronic myelogenous leukemia most commonly includes an indolent progression with disease susceptible to suppression from tyrosine kinase inhibitors (TKIs). During this period, the disease is “addicted” to the oncogenic events stimulated by BCR-ABL. If the disease is left unchecked, it will progress to a more disorganized state marked by increased genetic instability. At some point during disease progression, the anaplastic threshold is reached and the disease is sufficiently disorganized and is driven independent of input from BCR-ABL tyrosine kinase. At this point, the disease is no longer addicted to BCR-ABL, and the therapeutic value of BCR-ABL-targeted TKIs is vastly diminished. Based on reference 22.

SCT, OS was 47% at 8 years, with a relapse rate of 33% at 5 years.56 Mutational analyses were not available for these patients, and many received transplants prior to imatinib; however, reason and early data suggest that the alloimmune effect brought about by HSC transplantation may have equivalent potency against T315I mutation.57 For patients with CML and a T315I mutation, either allogeneic SCT or enrollment in a clinical trial is recommended.

Approaching the Anaplastic Threshold Left unchecked (ie, without TKI inhibition of its progeny), the progeny of the refractory CML stem cells develop secondary genetic aberrations and progressively more powerful leukemic genotypes58 in the inevitable sequelae of advanced disease. Typically, in CP, when patients are likely to have a response to TKIs, their disease is below the anaplastic threshold (Figure 2). In more advanced disease, it seems that CML progeny cells can acquire the “stem cell–like” feature of self-renewal.59 As the disease progresses and genetic instability increases, pro-growth and antiapoptotic cellular functions of the CML cells may surpass signals for senescence, irrespective of the contribution of BCR-ABL tyrosine kinase. Here, above the anaplastic threshold, BCR-ABL is, potentially, superfluous to the progression of the disease, and for this reason, early-generation TKIs are largely ineffective.22 As the ability to match leukemic phenotypes with leukemic genotypes improves, tailor-made TKI therapy

may increase responses among patients with advanced disease. However, the complexity and genetic heterogeneity seen in blastic CML and acute leukemias suggest that the best treatment for advanced disease is avoiding it with timely, effective treatment of the disease before the anaplastic threshold is reached.60 There is mounting evidence of the compounding inertia of the disease, even in CP. In a corollary to the IRIS trial, for example, patients who had previously failed IFN were then treated with imatinib and followed for 6 years. Unlike the previously undiagnosed patients of IRIS, this cohort included patients who were months, and often years, from their original diagnoses. At 6 years of follow-up, 57% of patients maintain a CCyR61 (vs 87% in IRIS),12 implying further progression of CP CML nearer to this anaplastic threshold.

Conclusion The speed of drug development for CML is a testament to the power of laboratory investigation into the molecular mechanism of this disease. However, TKIs are not without toxicities; they are not sufficiently effective in a significant minority of patients; and, perhaps most cogently, as of yet they rarely eradicate or cure the disease, demanding lifelong continuation of treatment. As experience grows with the use of this type of therapy, investigation into the pathogenesis of CML and potential strategies for therapy improvement continue to arrive. Soon, molecular fingerprinting of individual tumors including mutational analysis, assays of protein

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expression related to drug metabolism, and other factors influencing the disease will allow for tailoring of multifaceted therapy to individual patients. Combinations of agents, a rational approach to choosing second-line therapy, and a focus on eradication—not just suppression—of CML by better understanding the CML stem cell should be a focus of the next several years of CML research.

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25. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002;62(15):4236-4243, PMID: 12154025.

11. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349(15):1423-1432, PMID: 14534335.

26. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117-125, PMID: 12204532.

12. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23(6):1054-1061, PMID: 19282833. 13. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809-1820, PMID: 16709930. 14. O’Brien SG,Guilhot F, Goldman JM, et al. International Randomized Study of Interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML CP) treated with

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27. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112(13):4808-4817, PMID: 19064740. 28. Kantarjian HM, Giles F, Quintas-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13(4):1089-1097, PMID: 17317816. 29. Lee SM, Bae JH, Kim MJ, et al. Bcr-Abl-independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors. J Pharmacol Exp Ther. 2007;322(3):1084-1092, PMID: 17569822. 30. Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses

to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496-3499, PMID: 17192396. 31. Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101(11):4611-4614, PMID: 12576318. 32. Kantarjian H, Talpaz M, Oâ&#x20AC;&#x2122;Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103(8):2873-2878, PMID: 15070658. 33. Piazza RG, Magistroni V, Andreoni F, et al. Imatinib dose increase up to 1200 mg daily can induce new durable complete cytogenetic remissions in relapsed Ph+ chronic myeloid leukemia patients. Leukemia. 2005;19(11):1985-1987, PMID: 16121215. 34. Morel F, Bris MJ, Herry A, et al. Double minutes containing amplified bcr-abl fusion gene in a case of chronic myeloid leukemia treated by imatinib. Eur J Haematol. 2003;70(4):235-239, PMID: 12950231. 35. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96(3):1070-1079, PMID: 10910924. 36. Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110(12):4055-4063, PMID: 17720881. 37. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541, PMID: 16775234. 38. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303-2309, PMID: 17138817. 39. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200-1206, PMID: 18401416. 40. Rea D, Dombret H, Kim DW, et al. Dasatinib efficacy in patients with imatinib-resistant/-intolerant chronic myeloid leukemia in accelerated phase: 24-month data from START-A. Haematologica. 2008;93(s1): 391. Abstract 0982. 41. Saglio G. Dasatinib efficacy in patients with imatinib-resistant/intolerant chronic myeloid leukemia in blast phase: 24-month data from the START program. Haematologica. 2008;93(s1):349. Abstract 0880. 42. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26(19):3204-3212, PMID: 18541900. 43. Muller MC. Dasatinib treatment of chronic phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009; Epub ahead of print, PMID: 19779040. 44. Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Crit Rev Oncol Hematol. 2006;57(2):145-164, PMID: 16213151. 45. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542-2551, PMID: 16775235. 46. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res. 2008;14(17):5325-5331, PMID: 18765523.

47. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540-3546, PMID: 17715389. 48. le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834-1839, PMID: 18048643. 49. Cortes J, Oâ&#x20AC;&#x2122;Brien S, Jabbour E, et al. Efficacy of nilotinib (AMN107) in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts). 2007;110: Abstract 29. 50. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469-471, PMID: 19075254. 51. Soverini S, Gnani A, Colarossi S, et al. Long-term mutation follow-up of Philadelphia-chromosome positive leukemia patients treated with second-generation tyrosine kinase inhibitors after imatinib failure shows that newly acquired Bcr-Abl kinase domain mutations leading to relapse are mainly detected during the first year. Blood (ASH Annual Meeting Abstracts). 2008;112: Abstract 2118. 52. Azam M, Nardi V, Shakespeare WC, et al. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance. Proc Natl Acad Sci U S A. 2006;103(24):9244-9249, PMID: 16754879. 53. Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood. 2007;109(2):500-502, PMID: 16990603. 54. Cooper S, Giles F, Savona M. Overcoming resistance in chronic myelogenous leukemia. Leuk Lymphoma. 2009;50(11):1785-1792. In press. 55. Quintas-Cardama A, Cortes J. Therapeutic options against BCRABL1 T315I-positive chronic myelogenous leukemia. Clin Cancer Res. 2008;14(14):4392-4399, PMID: 18628453. 56. Gratwohl A, Hermans J, Niederwieser D, et al. Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 1993;12(5):509-516, PMID: 8298562. 57. Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood. 2006;108(4):1421-1423, PMID: 16601247. 58. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103(8):2794-2799, PMID: 16477019. 59. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657-667, PMID: 153006667. 60. Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110-114, PMID: 18408710. 61. Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. 2008;111(3):1039-1043, PMID: 17932248.

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POLICY & MANAGEMENT CPOE

CPOE in Ambulatory Setting Comes With Growing Pains MIAMI–Clinicians thinking of starting computerized physician order entry (CPOE) in an ambulatory oncology infusion setting should know that although it is definitely doable, it also can be a challenge to implement. Michael J. Anderson, MD, president and CEO of Commonwealth Hematology-Oncology, P.C., said that his practice, which is a community practice of 25 MDs, 11 nurse practitioners in 7 practice settings in Massachusetts, has been using a computer physician order entry system for approximately 10 years and has found it to be invaluable for diminishing errors and following quality matrices. “It is a significant improvement in communication between physicians, nurses, and the pharmacy, as well as being a legible record of the patient’s treatment,” Dr. Anderson said. At the most recent annual meeting of the Hematology/Oncology Pharmacy Association (HOPA), Joseph Barletti, PharmD, the ambulatory oncology manager at Montefiore Medical Center, Einstein Division, in New York City, discussed the challenges of implementing a CPOE in an ambulatory oncology setting. “As with anything new, there is a learning curve associated with setting up a computerized physician order entry system in the outpatient oncology department,” Dr. Barletti said. Montefiore has had a CPOE system in place for approximately 10 years; the only part of the hospital that was not using the system was ambulatory oncology, he explained. Deciding that the time was right to implement CPOE in their outpatient clinic, Montefiore physicians, pharmacists, nurses and information technology staff got together to build the system, which went live in May 2008. At the HOPA meeting, Dr. Barletti discussed a retrospective chart review of 67 patients to determine if the CPOE process duplicated the efficiency of the former paper process. “In the past, we would get paper orders from the physicians and we would then enter the orders ourselves into the electronic system. That doesn’t take a lot of time, but still you can shave off that time. Plus you don’t have to worry about figuring out a physician’s handwriting,” Dr. Barletti said.

A Host of Problems Uncovered The review, which covered the first three months of experience with the CPOE system after all users had become familiar with it, identified several overall problems that could reduce the effectiveness of the e-prescribing tool: • incorrect/omitted demographic information • incorrect/omitted dosing information • nonadherence to institutional co-signature policy • orders entered under wrong patient accounts • incorrect/incomplete electronic nursing documentation Additionally, several problems were uncovered that were specific to the 67 patient charts reviewed: • 2% of the charts had no orders entered

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• • • • • • • • • •

20% had incorrectly entered orders 8% omitted entry of demographic information 19% had incorrect dosing information 15% had the wrong dose calculated 4% had incorrect diluents or quantity of diluents 10% had incorrect or omitted dose rate of infusion 12% had orders not co-signed by a physician 2% had orders that were entered in the incorrect account 2% had incorrect documentation by the RN 6% had no documentation of dose administration by RN “We found out that some of the attending physicians weren’t co-signing their orders electronically in a timely fashion, so we could not go ahead [with administering the chemotherapy] until that was done. This would mean that the patient would have to wait longer in the chair, so a one-hour infusion would turn into a two-hour infusion because we had to wait for the attending to co-sign the order,” Dr. Barletti said. Another issue was the failure to enter dosage ranges. “Most drugs are dosed by body surface area, which includes height and weight. We would get the order and we would just see the total dose of drug for the patient but we wouldn’t see the dosage range. So it would take us longer to figure out the dose that the physician actually wanted and what he or she was basing it on,” he said. There also were instances where the nurses were not charting certain drugs, or did not document that they had completed the infusion. “For instance, a patient came in on June 1 for infusion. The nurse would chart that but would forget to document that it had finished, so when you go back on July 14, you look in the computer and the drug is still infusing,” Dr. Barletti said. At least one success became apparent during the chart review process—the use of pharmacist-created drug “order sets” for the most common chemotherapy regimens. “When chemotherapy is given, it’s never usually just one drug; it’s typically two, three or four drugs, and these are all given at specific times, so we made up these order sets to make it as easy as possible for the physicians to enter the drugs,” Dr. Barletti said. “We had regimens under various icons for breast, lung, colon and so on,” he explained. “This development had a positive impact on CPOE implementation.” Dr. Barletti concluded that implementation and maintenance of CPOE is an ongoing process and it is imperative that the institution allow enough time and resources—both financial and human—for training. Valerie Moussou, PharmD, an oncology pharmacist at Kaiser Permanente—Ventura, Calif., said that adding CPOE in oncology care areas “is definitely the way to go. If the process is userfriendly, it can greatly help in reducing dosing errors, alerting practitioners of things that should be followed or checked on before ordering chemotherapy and providing a template for treatment. It increases patient safety and can be more efficient.” —Fran Lowry

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 0 9 • N O. 2

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Safe Handling Of Hazardous Drugs: Reviewing Standards for Worker Protection LUCI A. POWER, MS, RPH

MARTHA POLOVICH, MN, RN, AOCN

Senior Pharmacy Consultant Power Enterprises San Francisco, California

Associate Director Clinical Practice Duke Oncology Network Durham, North Carolina

s a new generation of health care

workers joins those already engaged in patient care, it is

essential that they understand the occupational risks associated with the handling of hazardous drugs and the need for training in proper techniques for all handling activities to reduce occupational exposure to hazardous drugs.

These drugs, which include antineoplastic agents, antiviral agents, biological modifiers, hormones, and others, provide therapeutic benefit to patients but may result in adverse effects for healthy workers.1-4 Potential health risks for workers who compound and administer these drugs include adverse reproductive outcomes and the development of cancer.5 This review emphasizes new information about this well-recognized issue. It focuses on activities of the National Institute for Occupational Safety and Health (NIOSH) and the 2008 revision of United States Pharmacopeia (USP) Chapter <797> that mandates compliance with environmental, engineering, and training standards for worker protection.

Routes of Occupational Exposure Many studies have documented both surface and worker contamination with hazardous drugs.6-13 Standard

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work practices for handling injectable drugs generate powder and liquid aerosols from vials and syringes. This drug residue may contaminate the air and surfaces in the work area.6-8,14,15 It also has been shown that many hazardous drug vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.16 Certain hazardous drugs have been shown to vaporize at room temperature, resulting in drug contamination in the air.17-19 Workers may breathe contaminated air or touch contaminated surfaces and absorb hazardous drugs. Drug uptake also may occur through the ingestion of contaminated food or drink that is improperly located in or near drug-handling areas. Additionally, the transfer of contaminated residue from hands to mouth may result in the ingestion of hazardous drugs.

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Needlesticks with hazardous-drug contaminated needles or cuts from glass fragments of vials or ampules may also trigger exposure by injection.

Guidelines for the Safe Handling Of Hazardous Drugs Guidelines for the safe handling of hazardous drugs have been issued by numerous groups since 1980. The Occupational Safety and Health Administration (OSHA) issued guidelines in 1986,20 updated them in 1995,21 and made them available online in 1999.22 The American Society of Health-System Pharmacists (ASHP) published guidelines on the safe handling of cytotoxic agents as Technical Assistance Bulletins in 1985 and 1990, and new guidelines on hazardous drugs in 2006.23-25 The Oncology Nursing Society (ONS), in an attempt to influence nursing practice and protect its members from exposure, published guidelines for safe handling and also developed an extensive educational program based on “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice.”26-28

Continuing Exposure Adverse health effects and chances for exposure have been demonstrated among health care workers for more than 2 decades. Studies of surface and worker contamination conducted in the late 1990s and the early years of this decade continued to document exposure.6-8,10,14,15 Some possible reasons for the problem include new workers’ lack of awareness of the issue, a lack of vigilance in work practices, poor adherence to the use of personal protective equipment (PPE),2933 and other potential sources of contamination that have yet to be discovered.30 In 2000, NIOSH convened a working group of interested individuals to examine the issue of occupational exposure of health care workers to hazardous drugs. The Hazardous Drug Safe Handling Working Group was composed of representatives from government (OSHA, NIOSH, and FDA), industry, pharmaceutical manufacturers, academia, membership organizations (eg, American Nurses Association [ANA], ASHP, and ONS), and union leaders whose members handle hazardous drugs. The Working Group assessed existing information and formulated a plan to increase affected workers’ awareness of the risks and to reduce those risks. In 2004, as a result of the efforts of the Working Group, NIOSH issued “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”34 This NIOSH Alert is similar to the OSHA documents in that it is a guidance document without enforcement authority. However, the recommendations in the NIOSH Alert and the OSHA Technical Manuals may be enforced by OSHA under the general duty clause of the Occupational Safety and Health (OSH) Act, which sets safety and health standards for US workers. Employers subject to the OSH Act have a general duty to provide work and a workplace free from recognized, serious hazards.35 NIOSH actively continues to increase awareness of

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this issue by maintaining 2 Safety and Health Topic pages online: “Hazardous Drug Exposures in Health Care”36 and “Occupational Exposure to Antineoplastic Agents.”37 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications. In 2007, the USP released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.38 This revision of the 2004 standard includes a section specific to the compounding of hazardous drugs and is coordinated with much of the 2004 NIOSH Alert. More importantly, the USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of hazardous drugs are compounded, not just hospitals and clinics.

Defining Hazardous Drugs A number of drug types that are potent and toxic to patients have the potential to cause adverse effects in persons exposed to them occupationally. In 1990, ASHP attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”24 for the first time using the term “hazardous drug” in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety concerns and to be compatible with the then newly developed OSHA Hazard Communication Standard (HCS).39,40 The HCS is intended to ensure that employers and workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken. The HCS defines a “hazardous chemical” as any chemical that poses a physical or health hazard. It further defines a “health hazard” as any chemical for which statistically significant evidence from at least one study conducted in accordance with established scientific principles is available to indicate that it may cause acute or chronic health effects in exposed employees. The HCS further notes that the term “health hazard” includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects. ASHP has used similar criteria to define hazardous drugs.23,24 Data on the side effects of a drug are collected during both the premarket investigational phase of the drug and clinical use. These data may reasonably be used to infer “health hazards” in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define hazardous drugs24: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer (IARC); • teratogenicity or fertility impairment in animal

Table 1. Comparison of 2004 NIOSH and 1990 ASHP Definitions NIOSH

ASHP

Carcinogenicity

Carcinogenicity in animal models, in the patient population, or both as reported by the International Agency for Research on Cancer

Teratogenicity or developmental toxicity

Teratogenicity in animal studies or in treated patients

Reproductive toxicity

Fertility impairment in animal studies or in treated patients

Organ toxicity at low doses

Evidence of serious organ or other toxicity at low doses in animal models or treated patients

Genotoxicity

Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)

Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health Originally published in reference 23 © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (RO939)

studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients. ASHP’s criteria for hazardous drugs were revised by NIOSH for the 2004 Hazardous Drug Alert. USP Chapter <797> has adopted the following definition of hazardous drugs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.38 NIOSH has adopted a mechanism both to review its hazardous drug criteria and to judge newly FDAapproved drugs against these criteria on a regular basis. In 2007, a group of experts met to review the drugs that have been approved by the FDA since 2004 to evaluate which should be considered hazardous. Sixty-two drugs from many different therapeutic categories met at least 1 criterion of the hazardous definition in the preliminary analysis by NIOSH.41 The final list will be published when it is approved by the Office of Management and Budget (T. Connor, personal communication, July 10, 2008). Once published, the complete list will include nearly 200 pharmacologic agents available in the United States that are deemed hazardous to health care workers. The current NIOSH list of drugs that should be considered hazardous can be found in Appendix A of the NIOSH Alert.42 Table 1 compares the 2004 NIOSH and 1990 ASHP definitions of hazardous drugs.

Recommendations Recommendations for the safe handling of hazardous drugs have been available since the early 1980s. As more research has been conducted and more groups have

been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns; and USP Chapter <797> deals exclusively with sterile compounding. All guidelines agree that to reduce exposure to hazardous drugs in the occupational setting, a comprehensive safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative controls, environmental and engineering controls, work practice controls, and PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate other risks from occupational exposure.43

ADMINISTRATIVE CONTROLS Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of hazardous drug handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the ongoing monitoring of adherence to policies judiciously established. USP Chapter <797> emphasizes administrative controls for the safe compounding of hazardous drugs by mandating conditions that protect health care workers and other personnel in preparation and storage areas. Further requirements include extensive training of all

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personnel who handle hazardous drugs in the storage, handling, and disposal of such drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing specific hazardous drug preparation techniques. Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of hazardous drugs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new hazardous drug that enters the marketplace. Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposure. OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2007, NIOSH released â&#x20AC;&#x153;Workplace Solution: Medical Surveillance for Health Care Workers Exposed to Hazardous Drugs,â&#x20AC;? which provides direction for establishing such a program and the elements that should be included.44 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks of handling hazardous drugs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle hazardous drugs.

ENVIRONMENTAL

AND

ENGINEERING CONTROLS

The recent revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of hazardous drugs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments. Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which hazardous drugs are compounded. Hazardous drugs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns of volatilization at room temperature, storage is preferably within a containment area such as a negativepressure room with sufficient exhaust ventilation and at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants. An International Organization for Standardization (ISO) class 5 primary engineering control (PEC) is required for hazardous drug compounding to prevent

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microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of hazardous drug aerosols or residue. Appropriate PECs for compounding sterile hazardous drug preparations include class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) meeting or exceeding the standards set forth in USP Chapter <797>. Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP hazardous drug guidelines. The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile hazardous drug preparations (CACIs). To meet the criteria of USP Chapter <797>, an isolator must provide isolation from the room and maintain ISO class 5 air quality within the cabinet during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during material transfer in and out of the isolator. Recovery time to ISO class 5 air in the main chamber must be documented after material is transferred in and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time. A CACI meeting all of these conditions, as detailed in USP Chapter <797>, is exempt from the requirement of placing the CACI in an ISO class 7 buffer area. For hazardous drug compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A class II BSC has an open front and depends on an air barrier to prevent hazardous drug contamination from escaping the cabinet.45 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.46 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO class 5 compounding environment within the class II BSC. A class II BSC or CACI not meeting the conditions listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and has air quality of ISO class 7. Optimally, this area should be at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas, thus providing inward airflow to contain airborne drug. Optimally, a PEC used for compounding sterile hazardous drug preparations should be 100% vented to the outside air through high-efficiency particulate air (HEPA) filtration. All environments where sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more than 50% of the ACPH in that environment. The ISO class 7 buffer area and ante-area must be supplied with HEPA-filtered air providing a total of at least 30 ACPH.

Table 2. Comparison of the NIOSH, ASHP, and USP Chapter <797> Recommendations for the Hazardous Drug–Compounding Environment NIOSH

ASHP

USP Chapter <797>

Storage environment

Store hazardous drugs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Segregate hazardous drug inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Hazardous drugs shall be stored separately from other inventory, preferably within a containment area such as a negative-pressure room.

Compounding

Prepare hazardous drugs in an area that is devoted to that purpose alone and is restricted to authorized personnel.

Hazardous drugs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements.

Hazardous drugs shall be prepared in a PEC, which shall be placed in an ISO class 7 area that is physically separated from other preparation areas.

Ventilation

Where feasible, exhaust 100% of the filtered air to the outside.

Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.

Storage: area should have exhaust ventilation of at least 12 air changes per hour. Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.

ASHP, American Society of Health-System Pharmacists; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 23, 33, and 38.

Table 3 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for hazardous drug PECs.

WORK PRACTICE CONTROLS Work practices must be designed to minimize the generation of hazardous drug contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill. The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of hazardous drugs.47 These techniques, when performed accurately, minimize the escape of drug from vials and ampules. Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the powder and liquid drug residue that escapes from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced to make the compounding process more efficient. One study documents the effectiveness of one of these devices, but the investigators used only a visual inspection process because no sensitive drug assays

were available at the time of the study.48 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in an adjunct device, generically named by NIOSH in the 2004 Alert as a “closed-system drug-transfer device” (CSTD). NIOSH defines a CSTD as a drug-transfer device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.34 These systems provide some of the benefits of the earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of IV push and IV infusion doses, which had not been available previously. Numerous studies using hazardous drug marker drugs have demonstrated the effectiveness of a CSTD in reducing hazardous drug contamination in the workplace.6,14,15 At clinical practice sites representing inpatient and outpatient compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.6,14,15,49 USP Chapter <797> similarly defines CSTDs as “vial-

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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <797> Recommendations for Primary Engineering Controls NIOSH

ASHP

USP Chapter <797>

Primary engineering controls

• Aseptic containment ventilation control class II BSC-type B2 is preferred. • Class III BSC or CACI

• Class II BSC-type B2 with outside exhaust is preferred. • Total exhaust is required if the hazardous drug is known to be volatile. • Class III BSC or CACI

• BSC or CACI that meets or exceeds the standards for CACI in USP Chapter <797>

Ventilation

• Do not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment if a drug is volatile.

• Without special design considerations, class II BSCs are not recommended in traditional, positive-pressure clean rooms.

• BSCs and CACIs optimally should be 100% vented to the outside air through HEPA filtration.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; USP, United States Pharmacopeia Based on references 23, 33, and 38.

transfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within the ISO class 5 environment of a BSC or CACI. In facilities that prepare a low volume of hazardous drugs, the use of 2 tiers of containment (eg, a CSTD within a BSC or a CACI that is located in a non–negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet. Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of hazardous drugs. Any device marketed as a CSTD should be clinically tested.

been made based on several studies.51,52 See Table 4 for a comparison of PPE recommendations. During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks), a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves. Appropriate PPE must be worn when the sterile compounding of hazardous drugs is performed in a BSC or CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile hazardous drug–tested gloves.

PERSONAL PROTECTIVE EQUIPMENT

New Technologies

In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and the hazardous drug during episodes of potential contact. This is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness. Glove and gown materials should be able to withstand permeation by a selection of hazardous drugs. Several hazardous drugs require nonaqueous diluents for patient use, which may permeate PPE more readily than others. The American Society for Testing and Materials has developed a standard for testing chemotherapy gloves.50 There is no standard for chemotherapy gowns, but recommendations have

Technologic advances include robotic automation that can compound sterile doses of hazardous and nonhazardous drugs. By replacing the human compounder, these robots reduce the occupational exposure of health care workers during the compounding process. Robotic units provide contained ISO class 5 environments and use techniques to reduce the generation of hazardous drug residue during compounding. Robots operate with sophisticated mechanics and software and provide a degree of accuracy and patient safety not available with manual compounding. CytoCare from Health Robotics, IntelliFill Chemo from ForHealth Technologies, Inc, and RIVA (Robotic IV Administration) from Intelligent Hospital Systems all

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Table 4. Comparison of NIOSH, OSHA, ASHP, And USP Chapter <797> Recommendations for PPE

General handling

NIOSH/OSHA

ASHP

USP Chapter <797>

• Use double gloving for all activities involving hazardous drugs.

• Wear double gloves for all activities involving hazardous drugs. • Guidelines for the safe handling of hazardous drugs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.

• Hazardous drugs shall be handled with caution at all times with the use of appropriate chemotherapy gloves during receiving, distributing, stocking, taking inventory, preparing for administration, and disposal.

OSHA: • Protective equipment, including PPE for eyes, face, head, and extremities, protective clothing, respiratory devices, and protective shields and barriers shall be provided, used, and maintained in a sanitary and reliable condition wherever it is necessary by reason of hazards of processes or environment, chemical hazards, radiologic hazards, or mechanical irritants encountered in a manner capable of causing injury or impairment in the function of any part of the body through absorption, inhalation, or physical contact.

Receiving and storage

• Wear chemotherapy gloves, protective clothing, and eye protection when opening containers to unpack hazardous drugs.

• Gloves must be worn at all times when drug packaging, cartons, and vials are handled, including during the performance of inventory control procedures and the gathering of hazardous drugs.

Compounding

• Wear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs. • Make sure that gloves are labeled as chemotherapy gloves. • Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).

• Select disposable gowns of material tested to be protective against the hazardous drugs to be used. • Coated gowns must not be worn for longer than 3 hours during compounding and must be changed immediately when damaged or contaminated. • Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area.

• Wear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration.

• Gowns worn during administration should be changed when the patient care area is left and immediately if contaminated.

Administration

Sterile compounding: • Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves. Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; OSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 22, 23, 33, and 38.

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provide robotic solutions to the compounding of sterile preparations of hazardous drugs. Like most technology, these robots are not perfect. They require human staff to load and clean them. Hazardous drug contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection and the decontamination of hazardous drug residue. No particular cleaner has been shown to effectively deactivate all known hazardous drugs,11 so routine cleaning and spill control are still challenges to the health care personnel working with these robots. The robots help only with the compounding process, leaving the workers administering hazardous drugs without protection. Spill control and waste handling also remain issues for human workers to address.

Conclusion Despite almost 3 decades of data on the adverse health effects of occupational exposure to hazardous drugs, skepticism about the risks continues, as evidenced by the lack of programmatic controls for reducing exposure. NIOSH has renewed its dedication to this health risk by continuing to promote worker awareness of safety. USP Chapter <797> has elevated many of the NIOSH recommendations to a standard, ensuring both awareness and compliance with at least the compounding segment of safety program controls. Each new generation of health care workers needs to be educated about the risks of handling hazardous drugs and the importance of training in the proper techniques to reduce their exposure. Employers and employees must implement all aspects of hazardous drug safety programs to reduce occupational exposure and its potential adverse effects.

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Ng LM, Jaffe N. Possible hazards of handling antineoplastic drugs. Pediatrics. 1970;46(4):648-649.

2. Crudi CB, Stephens BL, Maier P. Possible occupational hazards associated with the preparation/administration of antineoplastic agents. NITA. 1982;5(4):264-265. 3. Baker ES, Connor TH. Monitoring occupational exposure to cancer chemotherapy drugs. Am J Health Syst Pharm. 1996;53(22):2713-2723. 4. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers. Evaluation of methods for monitoring occupational exposure to cytostatic drugs. Drug Saf. 1999;20(4):347-359. http://www. communityoncology.net/journal/abstracts/0205397.html. Accessed September 25, 2008. 5. Martin S. The adverse health effect of occupational exposure to hazardous drugs. Community Oncol. 2005;2(5):397-440. 6. Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60(22):2314-2320. 7.

Nygren O, Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health. 1997;70(3):209-214.

8. Pethran A, Schierl R, Hauff K, Grimm CH, Boos KS, Nowak D. Uptake of antineoplastic agents in pharmacy and hospital personnel. Part I: monitoring of urinary concentrations. Int Arch Occup Environ Health. 2003;76(1):5-10. 9. Sessink PJ, Van de Kerkhof MCA, Anzion RB, Noordhoek J, Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health. 1994;49(3):165-169. 10. Sessink PJ, Boer KA, Scheefhals AP, Anzion RB, Bos RP. Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-112. 11. Dorr RT, Alberts DS. Topical absorption and inactivation of cytotoxic anticancer agents in vitro. Cancer. 1992;70(4 suppl):983-987. 12. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health. 1997;70(3):205-208. 13. Sessink PJ, Wittenhorst BCJ, Anzion RB, Bos RP. Exposure of pharmacy technicians to antineoplastic agents: reevaluation after additional protective measures. Arch Environ Health. 1997;52(3):240-244. 14. Vandenbroucke J, Robays H. How to protect environment and employees against cytotoxic agents, the UZ Ghent experience. J Oncol Pharm Pract. 2001;6(4):146-152. 15. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63(18):1736-1744. 16. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm. 2005;62(5):475-484. 17. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470(1):85-92. 18. Opiolka S, Schmidt KG, Kiffmeyer TK, Schoppe G. Determination of vapor pressure of cytotoxic drugs and its effects on occupational safety. J Oncol Pharm Pract. 2000;6:15. Abstract. 19. Kiffmeyer TK, Kube C, Opiolka S, Schmidt KG, Schoppe G, Sessink PJ. Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety. Pharm J. 2002;268:331-337. 20. Yodaiken RE, Bennett D. OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Occupational Safety and Health Administration. Am J Hosp Pharm. 1986;43(5):1193-1204. 21. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21. 22. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (TED 1-0.15A Sec VI Chap 2); 1999. http://www.osha.gov/dts/ osta/otm/otm_vi/otm_vi_2.html. Accessed November 12, 2009. 23. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63(12):1172-1191. 24. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049.

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25. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals. Am J Hosp Pharm. 1985;42(1):131-137. 26. Brown KA, Esper P, Kelleher LO, O’Neil JEB, Polovich M, White JM, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 2001. 27. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Press; 2005. 28. Mahon SM, Casperson DS, Yackzan S, et al. Safe handling practices of cytotoxic drugs: the results of a chapter survey. Oncol Nurs Forum. 1994;21(7):1157-1165. 29. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum. 2003;30(4):575-581. 30. Nieweg R, de Boer M, Dubbleman R, et al. Safe handling of antineoplastic drugs. Results of a survey. Cancer Nurs. 1994;17(6):501-511. 31. Valanis B, McNeil V, Driscoll K. Staff members’ compliance with their facility’s antineoplastic drug handling policy. Oncol Nurs Forum. 1991;18(3):571-576. 32. Valanis B, Vollmer WM, Labuhn K, Glass A, Corelle C. Antineoplastic drug handling protection after OSHA guidelines. Comparison by profession, handling activity, and work site. J Occup Med. 1992;34(2):149-155. 33. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004165. Washington, DC: NIOSH; 2004. http://www.cdc.gov/niosh/ docs/2004-165/. Accessed November 12, 2009. 34. Code of Federal Regulations. Title 29—Labor. Subtitle B—Regulations Relating to Labor. Chapter VII—Occupational Safety and Health Administration, Department of Labor. Part 1910—Occupational Safety and Health Standards. Subpart A—General. Article 1910.2—Definitions. Washington, DC: US Government Printing Office; 2004. http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&tpl=/ecfrbrowse/Title29/29cfr1910_main_02.tpl. Accessed November 12, 2009. 35. National Institute for Occupational Safety and Health. NIOSH safety and health topic: hazardous drug exposures in health care. http://www.cdc.gov/niosh/topics/hazdrug. Accessed November 12, 2009. 36. National Institute for Occupational Safety and Health. NIOSH safety and health topic: occupational exposure to antineoplastic products. http://www.cdc.gov/niosh/topics/antineoplastic/. Accessed November 12, 2009. 37. US Pharmacopeial Convention. Chapter <797> Pharmaceutical compounding—sterile preparations. In: The United States Pharmacopeia, 31st rev, and The National Formulary, 26th ed. Rockville, MD: US Pharmacopeial Convention; 2008. 38. Occupational Safety and Health Administration. Hazard Communication-59:6126-6184. http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=federal_register&p_id=13349. Accessed November 12, 2009. 39. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10099. Accessed November 12, 2009. 40. National Institute for Occupational Safety and Health. Draft document for public review and comment: process for updating the list of hazardous drugs (Appendix A) for the NIOSH Alert on Hazardous Drugs. NIOSH Docket #105. http://www.cdc.gov/niosh/review/

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public/105/default.html. Accessed November 12, 2009. 41. National Institute for Occupational Safety and Health. NIOSH Publication No. 2004-165: Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Appendix A. drugs considered hazardous. http://www.cdc.gov/ niosh/docs/2004-165/2004-165d.html#o. Accessed November 12, 2009. 42. US Department of Labor. 1998. OSHA 3143. Informational booklet on industrial hygiene. http://www.osha.gov/Publications/ OSHA3143/OSHA3143.htm. Accessed November 12, 2009. 43. National Institute for Occupational Safety and Health. Medical surveillance for healthcare workers exposed to hazardous drugs. NIOSH Publication No. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/. Accessed November 12, 2009. 44. NSF International. NSF/ANSI 49-2007: NSF 49 Class II (Laminar Flow) Biosafety Cabinetry. Ann Arbor, MI: NSF International; 2007. 45. Clark RP, Goff MR. The potassium iodide method for determining protection factors in open-fronted microbiological safety cabinets. J Appl Bacteriol. 1981;51(3):439-460. 46. Wilson JP, Solimando DA Jr. Aseptic technique as a safety precaution in the preparation of antineoplastic agents. Hosp Pharm. 1981;16(11):575-576, 579-581. 47. Hoy RH, Stump LM. Effect of an air venting filter device on aerosol production from vials. Am J Health Syst Pharm. 1984;41(2):324-326. 48. Connor TH, Anderson RW, Sessink PJ, Broadfield L, Power LA. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health Syst Pharm. 1999;56(14):1427-1432. 49. American Society for Testing and Materials. D 6978-05 standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. West Conshohocken, PA: American Society for Testing and Materials; 2005. 50. Connor TH. Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs. Am J Health Syst Pharm. 1999;56(23):2450-2453. 51. Harrison BR, Kloos MD. Penetration and splash protection of six disposable gown materials against fifteen antineoplastic drugs. J Oncol Pharm Pract. 1999;5(2):61-66. 52. Connor TH. An evaluation of the permeability of disposable polypropylene-based protective gowns to a battery of cancer chemotherapy drugs. Appl Occup Environ Hyg. 1993;8:785-789.

Suggested Reading American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63(12):1172-1191. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004-165. Washington, DC: NIOSH; 2004. http://www.cdc.gov/niosh/docs/ 2004-165/. Accessed November 12, 2009. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21. Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Press; 2009.

Your Complete Advanced Aseptic Compounding™ Solutions Provider Containment Technologies Group, Inc. encompasses much more than just superior compounding aseptic isolator technology. We have grown to become your one-stop provider for all of your USP<797> needs. We are known for our expertise in CAI’s and CACI’s with our Mobile Isolation Chamber (MIC) family of isolators (MIC-Single, MIC-Dual, MIC-TPN and MIC-EDU Systems). We offer service plans and complete certification programs including viable and non-viable testing for all of your pharmacy and laboratory primary engineering control needs. On-site training is included with every MIC purchase. We also provide customized training from our diverse educational curriculum. We also offer an extensive stock of pharmacy supplies. These supplies can be ordered in any quantity from just one piece to multiple cases. Please contact CTG, Inc. for all your USP<797> needs.

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速

ABRAXANE delivers efficacy* to make more possible

速

nab defined: nab technology exploits the natural properties of albumin, facilitating the delivery of water-insoluble compounds to the tumor.

*In a pivotal randomized phase III trial in metastatic breast cancer patients,

ABRAXANE delivered nearly double the overall response rate vs solvent-based paclitaxel1 Reconciled target lesion response rates (TLRR)* in the randomized phase III clinical trial in metastatic breast cancer patients1

21.5% vs 11.1%

15.5% vs 8.4%

For all study patients (P=.003).1 95% Cl, 16.2% to 26.7% for ABRAXANE 95% Cl, 6.9% to 15.1% for solvent-based paclitaxel

For study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy (P=NS).1 95% Cl, 9.3% to 21.8% for ABRAXANE 95% Cl, 3.9% to 12.9% for solvent-based paclitaxel

*Reconciled TLRR in the randomized, open-label, phase III trial was the rigorous protocol-specific primary end point based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. (Tumor response was assessed using Response Evaluation Criteria in Solid Tumors [RECIST].)2 It is well established that reconciled TLRR are lower than investigator-reported response rates typically reported in the scientific literature.3

BOUND AND DETERMINED

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

IMPORTANT SAFETY INFORMATION WARNING: ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Dose adjustment is recommended for patients with moderate to severe hepatic impairment. The need for further dose adjustments in subsequent courses should be based on individual tolerance. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy. ABRAXANE contains albumin (human), a derivative of human blood. Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for 7 days or

more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended. Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension. In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%; severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%). Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), ﬂuid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see the Brief Summary of the ABRAXANE full prescribing information on the next page. References: 1. ABRAXANE [prescribing information]. Bridgewater, NJ: Abraxis BioScience, LLC; September 2009. 2. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-7803. 3. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205-216. All Abraxis BioScience, LLC. corporate names, names of services, and names of products referred to herein are trade names, service marks, and/or trademarks that are owned by or licensed to Abraxis BioScience, its divisions or its afﬁliates, unless otherwise noted. ©2009 Abraxis BioScience, LLC. All Rights Reserved. AB 1427 10/09 Printed in USA

Table1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule (cont.) Percent of Patients ABRAXANE® Paclitaxel Injection 175/3hc,d 260/30minb (n=229) (n=225) Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 f Severe Symptoms 10 2 Myalgia / Arthralgia Any Symptoms 44 49 8 4 Severe Symptomsf Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 0 <1 Severe Symptomsf Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 Severe Symptomsf 4 1 Diarrhea Any Symptoms 27 15 <1 1 Severe Symptomsf Mucositis Any Symptoms 7 6 Severe Symptomsf <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1

Rx Only

Brief Summary of Full Prescribing Information. WARNING ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of < 1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D : ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m 2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability). Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see CLINICAL PHARMACOLOGY). Hematology ABRAXANE® therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE and ADMINISTRATION). Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE and ADMINISTRATION). Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Hepatic Impairment) Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS). Pregnancy: Teratogenic Effects: Pregnancy Category D : (See WARNINGS section). Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE® therapy. Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. Geriatric use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. Ability to Drive and Use Machines Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines. ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE® or paclitaxel injection for the treatment of metastatic breast cancer. Table1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L < 0.5 x 109/L Thrombocytopenia < 100 x 109/L < 50 x 109/L Anemia < 11 g/dL < 8 g/dL Infections Febrile Neutropenia Bleeding Hypersensitivity Reactione All Severef Cardiovascular Vital Sign Changesg Bradycardia Hypotension Severe Cardiovascular Eventsf Abnormal ECG All patients Patients with Normal Baseline

80 9

82 22

2 <1

3 <1

33 1 24 2 2

25 <1 20 1 2

4 0

12 2

<1 5 3

<1 5 4

60 35

52 30

a b c d e

f g

Based on worst grade. ABRAXANE dose in mg/m2/duration in minutes. paclitaxel injection dose in mg/m2/duration in hours. paclitaxel injection pts received premedication. Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. Severe events are defined as at least grade 3 toxicity. During study drug dosing.

Myelosuppression and sensory neuropathy were dose related. Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE ® in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy. Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Cranial nerve palsies and vocal cord paresis have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage. Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE® administration, and resolved within a few days. Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise. Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Accidental Exposure No reports of accidental exposure to ABRAXANE® have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 4. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely. (See CLINICAL PHARMACOLOGY: Hepatic Impairment and PRECAUTIONS: Hepatic Impairment) Table 4: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels

Bilirubin Levels

Mild

<10 x ULN

>ULN to ≤ 1.25 x ULN

Moderate

<10 x ULN

Severe

<10 x ULN > 10 x ULN

AND OR

260 mg/m2

1.26 to 2.0 x ULN

200 mg/m2

2.01 to 5.0 x ULN

130 mg/m2 b

> 5.0 x ULN

not eligible

Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance.

Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. Preparation and Administration Precautions ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE® contacts mucous membranes, the membranes should be flushed thoroughly with water. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions (see PRECAUTIONS: Injection Site Reaction). No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Preparation for Intravenous Administration ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. 6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL) The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE® into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours. HOW SUPPLIED: Product No. 103450 NDC No. 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006 REFERENCES: 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication No. 83-2621. For sale by the Superintendent of Documents, US Government NIH Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):15901592. 3. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm, 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm, 1996; 53:1669-1686. 8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41. This Brief Summary is based on the ABRAXANE Full Prescribing Information Revised: September 2009

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some

ABRAXANE a

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Part 2 of a 2-Part Series

Guide to the Prevention of

Chemotherapy Medication Errors: Strategies To Prevent Chemotherapy Errors DWIGHT D. KLOTH, PHARMD, FCCP, BCOP Director of Pharmacy Fox Chase Cancer Center Philadelphia, Pennsylvania

edication error prevention is a critical goal for pharmacists, nurses,

and physicians in all treatment settings—especially in oncology.

Antineoplastic agents have a lower therapeutic index and safety margin than do other drug classes. Additionally, in cancer chemotherapy, the dose, dosing interval, and even the route of administration may vary as a function of the tumor type and the stage of disease. Chemotherapy-related medication errors, such as the administration of a 10-fold higher dose as a result of a transcription error, or the intrathecal administration of drugs that only should be administered by IV infusion, are potentially fatal.1-4 In 2006, the Institute of Medicine (IOM) released the landmark report Preventing Medication Errors,5 which stated that “medication errors harm at least 1.5 million patients every year in hospitals, long-term care facilities, and outpatient clinics, resulting in billions of dollars in additional medical costs.” To help prevent medication errors, the committee recommended that all organizations implement an electronic prescribing and dispensing system by 2010. Additionally, the report contained several other important recommendations pertinent to facilities that treat patients with cancer: • monitor medication safety literature; • develop and implement a structured error-avoidance plan;

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• establish a routine procedure for double-checking filled prescriptions; • designate a practice-wide medication safety officer with widespread authority and responsibility to improve care; • create a safer work environment by looking at lighting and noise levels, minimizing distractions, and improving drug storage areas by separating lookalike/sound-alike medications; • continuously evaluate technology and automation to reduce medication errors; • be assertive in requesting resources to promote accurate medication prescribing, processing, dispensing, and administration; and • involve patients in an aggressive education and reconciliation program. This 2-part educational review is intended to help clinicians develop practical strategies to recognize and

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 0 9 • N O. 2

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Table 1. Helpful DOs and DO NOTs for Writing Chemotherapy/Medication Orders DOs DO

always double-check the dose against the actual drug regimen or protocol.

always use the full name (generic preferred over the trade name) of the drug.

prescribe all drug doses clearly in terms of dose (eg, micrograms, mg, grams, etc).

use a leading zero when the dose is less than 1 unit/mg/gram, etc (ie, an order of .1 mg may be read as 1 mg; write 0.1 mg).

avoid excessive attempts at precision and round chemotherapy doses greater than 5 mg to the nearest integer or nearest reasonable amount (ie, for fluorouracil, write 525 mg, NOT 521.6 mg; for carboplatin, write 925 mg, NOT 919.57 mg; for cisplatin, write 125 mg, NOT 126.4 mg).a

date all orders with month, day, and year. For inpatient orders, also include time of day.

use body surface area (BSA)–based dosing (ie, mg/m2 or g/m2, or when applicable, mcg/kg), giving the daily dose and the specific number of days it is to be given. DO NOT write the course dose—unless the daily dose is written as well. For example, in a patient with a BSA of 1.5 m2, cisplatin 20 mg/m2 per day for 5 days = 30 mg per day for 5 days = 100 mg/m2 per course = 150 mg per course.

list a route of administration and an infusion duration for intravenous solutions.

include patient’s current height, weight, and BSA with the chemotherapy order.

print critical information such as drug names, doses, etc.

double-check all drug names and doses and verify that they are what you intend the patient to receive before signing.

make sure that the medication order sheet has the correct patient’s name on it, either handwritten or stamped by addressograph plate. DO NOT leave orders on a blank order sheet for subsequent stamping by an addressograph plate.

prevent chemotherapy medication errors. Part 1, which appeared in the July/August issue, includes information on selected publicized chemotherapy errors and their outcomes as well as examples of potential causes of errors, such as look-alike/sound-alike drug names and the use of handwritten orders. This part discusses how health care professionals can assess the risk for medication errors at their own institutions and practice sites and offers strategies to help prevent such errors. Because nearly all authorities recommend implementation of an electronic order entry system, this guide discusses the use of technology and computerization (eg, computerized prescriber order entry [CPOE] and bar coding) in medication error prevention, including the advantages of and caveats to these technologies.

Strategies To Prevent Cancer Chemotherapy Errors The helpful rules illustrated in Table 1 have been in existence at Fox Chase Cancer Center (FCCC) for more than 10 years, and the strategies listed in Table 2 are important steps toward improving patient safety drawn from both the literature and clinical experience.6-19

CHEMOTHERAPY ORDER FORMS In the absence of a functional CPOE system, the use of a standardized preprinted order form is a highly effective

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tool. Such a form should be used for both parenteral and oral anticancer drugs, and must be approved by the institution’s pharmacy and therapeutics committee. It should include the protocol number and treatment arm if applicable; cycle number; patient age, weight, height, and body surface area; pertinent laboratory data; hydration fluids; antiemetics and other premedications; and supportive medications. Multiday regimens should be written in a format that specifies the dose per meter squared, per dose, and/or per day. Consistent with best practices and Joint Commission requirements, dangerous abbreviations such as “U” and “qd” should never be used.

DRUG INFORMATION

AND

DOSING GUIDELINES

Informational guidelines about conventional and investigational chemotherapy must be readily available. For example, electronic guidelines for each drug should list information such as the drug’s common indication and clinical use, pharmacologic category, principal adverse effects, reconstitution directions, storage/ stability, preparation/administration guidelines, incompatibilities, usual doses, clinical considerations (including standardized antiemetic, hydration, and supportive medications), and dose adjustment guidelines for renal or hepatic dysfunction. Maximum single- and total-course doses should be established at each institution and entered into the

Table 1. Helpful DOs and DO NOTs for Writing Chemotherapy/Medication Orders DO NOTs DO NOT

designate drug by brand names, nicknames, company names, or abbreviations. For example, does Paraplatin refer to cisplatin or carboplatin? Does CPT-11 refer to cisplatin or irinotecan? Similarly, “Aredia” (pamidronate), when written, could be misunderstood to be “Adria”b (doxorubicin), or vice versa. Ideally, always use generic rather than trade names.

DO NOT

use a trailing zero when writing an order (eg, an order of 10.0 mg may be read as 100 mg; simply write 10 mg).

DO NOT

use a leading decimal. DO write 0.1 mg—not .1 mg, which may be misread as 1 mg and cause a 10-fold overdose.

DO NOT

use dangerous abbreviations. Using “U” for units may be read as “0” and the patient could receive a 10-fold overdose (eg, “5U of insulin” could be read as “50 of insulin”).

DO NOT

refer to drugs by common name of drug class. For example, does “platinum” mean cisplatin or carboplatin?

DO NOT

use a soft felt-tip pen. When orders are written on multilayer carbonless paper, copies of the drug order may be illegible or invisible.

DO NOT

sign a blank copy of a medication order for an allied health professional (eg, RN, RPh, or RT) to fill in later. Medication orders should reflect information directly intended and checked by the licensed prescriber.

DO NOT

give verbal orders for chemotherapy.

DO NOT

abbreviate “daily” as “qd,” which has been mistaken for “qid.” Similarly, DO NOT abbreviate “every other day” as “qod.”

DO NOT

write drug orders in terms of number of ampules or vials. Drugs may come in more than one vial or ampule size, leading to administration of doses not intended by the prescriber. For example, both carboplatin and cisplatin come in 3 different vial sizes over a 10-fold size range.

DO NOT

use outdated laboratory information when writing orders. Current lab data might indicate a change in renal or hepatic function and a required dose modification might be missed, leading to an incorrect dose.

Rationale: Federal requirements mandate that commercial drug concentrations be between 95% and 105% of labeled strength; in addition, expiration dating procedures are based on ≤10% degradation over time, so for an ordered dose of 127.4 mg, even when Nursing and Pharmacy perform their functions flawlessly, the dose actually received by the patient is somewhere in the range of 114 to 134 mg. b Shortened form of Adriamycin. Adapted from references 6 and 7.

pharmacy computer system.19 The limits should be communicated during employee orientation programs and at regularly scheduled in-service education programs and should be available in all clinical areas in written or electronic versions, or in both. Pharmacists should take a leadership role in organizing and presenting such educational sessions for prescribers and nurses who administer drugs. Illustrating actual medication errors that have happened at their practice site is an effective tool for describing the consequences of nonstandard prescribing methods. One very effective tool is dissemination of the ISMP Medication Safety Alert! to clinical staff, with an accompanying summary highlighting the most compelling and/or most relevant articles in that particular issue. Additionally, prescribers’ vocabulary should be standardized, and the dose-verification process should have as many verification steps as possible. The prescriber who writes the order, the pharmacist who prepares it, and the nurse who administers the drug should calculate all doses independently. An important but often underappreciated issue is the evaluation of errors when oral chemotherapy is

administered. Many practice sites do not have the typical redundant verification steps seen when a parenteral antineoplastic drug is administered because the responsibility of the proper medication administration belongs to the patient or caregiver rather than to a health care professional.20 Prescribing and administration medication errors occurred in nearly 10% of oral chemotherapeutic drugs administered on an outpatient basis to 69 children with acute lymphoblastic leukemia.21 Finally, verbal orders for the initiation of chemotherapy should not be permitted under any circumstance.

PUNITIVE VERSUS NONPUNITIVE ENVIRONMENTS An important consideration that recently has been appreciated is the issue of punitive versus nonpunitive cultures. Medication errors predominantly are system dependent rather than the result of negligence by a specific individual. A punitive focus on individuals involved in a medication error is dangerous. It inhibits open discussion about errors, creates a defensive and reactive environment, and hinders careful and unbiased consideration of the system-based root causes of errors.22,23 However, a “no-blame” or “blame-free” culture fails to

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Table 2. Strategies To Prevent Cancer Chemotherapy Errors

(continued)

Mandate the use of preprinted order forms that standardize practice and “force functions.” Implement prescribing guidelines. • Use full drug names (generic preferred, trade names generally less desirable), and ban drug name abbreviations. Express doses in mg whenever possible, use a recent body surface area with each order, avoid trailing zeros (after a decimal point), and use leading zeros (before a decimal point). • Ban the use of felt-tip pens. • Ban the use of dangerous, error-prone abbreviations such as U, μg, and qd. • Require that multiday regimens be in a format that specifies the dose per meter squared (m2) per day, dose per day, and number of days of therapy. Ban verbal orders for the initiation of chemotherapy. • Although verbal orders are never appropriate for initiation of chemotherapy, verbal orders to immediately stop a chemotherapy infusion may in some cases be the only appropriate step in the event of an acute ADR, when it is imperative to immediately stop the administration of the chemotherapy and initiate appropriate therapy for the ADR. Work diligently to develop a CPOE system. • CPOE systems should interface directly with all pharmacy systems and meet the institution’s specific needs. • Pharmacists must be integral members of implementation teams for automated prescribing and administration systems. Make drug information available electronically, and train all members of the team to use electronic drug information. • Develop unique drug guidelines that address the institution’s dose information, infusion, hydration, antiemetic, and supportive care parameters, and update this information as often as necessary. Ensure that critically important laboratory results are available before drug dispensing and administration with real-time interfaces. Assess the clarity of a manufacturer’s vial, syringe, and other labels with the goal of avoiding confusion. • Formulary decisions of multisource products should consider labeling. When adding drugs to the formulary, publicize the name similarity to those of preexisting agents and any differences between the drugs. Realize that errors can and will happen at your institution, and then create a culture of safety. • Discuss all errors in a formal multidisciplinary environment in a nonpunitive manner. • Develop a medication process improvement committee or a patient safety committee that is regularly attended by leadership in medicine, pharmacy, nursing, administration, and quality improvement. • Develop a mechanism to ensure that dangerous drugs, particularly the vinca alkaloids and doxorubicin, cannot be given intrathecally. Be supportive of pharmacists, nurses, and physicians who make errors. • Sincerely ask them for solutions to avoid a recurrence of the error. Recognize that, in general, most medication errors are fostered by system deficiencies; ask staff members for suggestions that could make the system stronger and less prone to allowing a similar error in the future. Cultivate a teamwork relationship with the chief or president of the medical staff so that you have an ally if a confrontation arises in which patient safety is threatened and the physician involved is refractory to following safe practices. Ensure that Pharmacy is well represented on the institutional review board and all other applicable committees that govern clinical research at your institution. Distribute the ISMP Medication Safety Alert! to medical, nursing, pharmacy, and quality improvement staff, and conduct an educational program on medication error prevention regularly. • Review actual errors that have occurred at your practice site; the patient’s name and all health care worker identifiers should be removed if politically necessary. (If the handwriting of the prescriber would reveal the prescriber’s identity, rewrite the order to preserve anonymity.) Conduct educational programs such as a Grand Rounds-type of presentation on medication error prevention for the full medical staff annually, or more often as necessary. Monitor and publicize errors that are described in Joint Commission Sentinel Event Alerts. Develop tools to assess competency of new staff and annually ensure and document the competency of existing staff. If chemotherapy orders are written by fellows or other physicians in training, require that they be cosigned by an attending faculty member before being considered valid. Consider possible ways to involve patients in the medication safety program. Incorporate medication error prevention education, appropriately targeted, into new staff orientation for all clinical staff, including ward secretaries as well as nurses, pharmacists, and physicians. ADR, adverse drug reaction; CPOE, computerized prescriber order entry; ISMP, Institute for Safe Medication Practices Adapted from reference 6.

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discipline individuals who repeatedly make unsafe behavioral choices or go against established policies and procedures.24,25 The safety culture in health care has been like a pendulum during the past decade. It has gone from a “name, shame, and blame” philosophy (punitive) to one of “amnesty for all” (nonpunitive). Health care now is gradually settling at a reasonable middle ground—a “just culture”—that is fair to health care professionals and effective in reducing safety risks.26 All workers need to know that safety is valued in their organization and that they should have ongoing discussions about risks and ways to avoid them. Managers are continuously looking for systems, technology, and policies that provide the opportunity for workers to improve outcomes.26 A paradigm shift is required for successful prevention of cancer chemotherapy errors. To avoid recurrence of errors, it is essential to conduct open interdisciplinary discussions of all errors and near-misses. Anonymous error reporting using an intranet site may be effective at increasing such reporting and institutional evaluation. Individuals who make errors should be sincerely thanked for reporting them, rather than being punished. A structured interdisciplinary team should review all actual and potential medication errors to resolve the miscommunication that often is a leading cause of problems and to look for practice trends.

THE PATIENT’S ROLE Because patients often are the last line of defense against an error, they should be well educated about the names of their drugs, the route of administration, the planned treatment schedule, and the color of the infusion. Patients should be encouraged to remind caregivers to verify their identity (eg, check their wristband or home address) and ask questions about their chemotherapy. Health care professionals must listen carefully to what patients tell them.

Technology: Computerized Prescriber Order Entry Essential features of a safe medication system include electronic prescribing, automated dispensing machines, the addition of clinical indications to prescriptions, smart IV pumps, point-of-care systems, appointment of an institutional medication safety officer, and reporting and analysis of medication errors in a national database.27 The potential benefits of using a CPOE system include creating standardized order sets, automating clinical decision support, reducing errors by decreasing time to refill orders, checking doses against online clinical information, eliminating lost and illegible orders, improving coding for research protocol and outcomes analysis, evaluating clinical interventions, and resolving billing issues.28

CUSTOMIZING

CPOE SYSTEM

To maximize the safety benefits for an individual practice site, CPOE systems initially must be robust and well designed yet highly customizable according to the needs of the institution; therefore, before implementing a CPOE

system, the specific needs of the practice site should be assessed. Unfortunately, very few institutions have the internal resources to build a suitable CPOE system and must purchase a system “off the shelf” or enter into a development agreement with a commercial vendor. This is problematic because many commercial computer software vendors believe that their product is the best on the market, that no additional features or modifications are necessary for their product, and that all end-users have the same needs and should use the same software.28 An additional complication is that some enterprise-wide or CPOE software vendors “strongly encourage” their customers to migrate in entirety to their corporate product line of software, even if the hospital may already use a superior product (eg, a pharmacy computer system) from a different vendor.28 When working with such software vendors, reaching an agreement on the necessary aspects of CPOE can be very difficult and/or associated with extensive delays. Even when a vendor agrees in principle to a certain feature or modification, their interpretation of what that means may differ from the interpretation of clinicians in medicine, pharmacy, and nursing. Important questions that should be considered before purchasing a CPOE system can be found in the patient safety section of the American Society of Health-System Pharmacist (ASHP) Web site (www.ashp.org).8 As new therapies (agents or combination regimens) are developed and new data become available, it is possible that previously designed custom order sets will either require some level of modification or even become completely outmoded. Examples of such developments may include the incorporation of new cytotoxic agents into existing regimens, incorporation of extensions of regimens for metastatic disease into the adjuvant or neoadjuvant setting, and changes in supportive care medications such as antiemetics, growth factors, etc. At FCCC, chemotherapy order forms (presently a combination of paper-based and online/interactive, printable PDF templates) are reviewed periodically and revised as dictated by developments in therapies. Readers are encouraged to consider annual or other periodic reviews of any CPOE templates to ensure that the CPOE system in use remains accurate and up to date, using concepts such as those listed below: 1. Terminology specific to chemotherapy, such as “cycle,” “parameter,” “protocol,” and “regimen,” must be clearly defined. 2. A multidisciplinary team, including physician service chiefs within medical oncology, should establish and approve a wide variety of standardized chemotherapy regimens from actual institutional experience and evidence-based guidelines. The National Comprehensive Cancer Network compendia of clinical practice guidelines (available at www.nccn.org) are an excellent resource because the guidelines are differentiated by tumor type and stage of disease. Ideally, order sets should be available for all CPOE users on a multiple-column grid that lists each drug of the specified continued on page 114

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Breakthrough cancer pain

A Closer Look at

Identifying the Problem Cancer pain is a serious healthcare problem A number of studies conducted over the past 20 to 25 years have demonstrated that pain is undertreated in nearly half of patients with cancer.1-5 Recently, the Global Results Presentation conducted by European Pain in Cancer (EPIC) reported that many patients with cancer experience moderate-to-severe pain every day. Pain so severe, it is often described as “intolerable.”4 This type of cancer pain can be enduring and relentless.5 In addition to its severity, cancer pain is common throughout the entire course of disease. About a third of cancer patients experience pain at diagnosis, more than half experience pain during active treatment, and the majority experience pain with advanced disease.6 Relatively low utilization rates of opioids have been reported among patients with metastatic cancer in their final year of life. Although published clinical guidelines recommend the use of opioids in this setting, this suggests that for many patients with advanced cancer, pain may be suboptimally treated.5 Cancer pain is one of the most feared consequences of cancer. Pain is believed to be part of “having cancer.”4 Although family members are supportive, they cannot fully comprehend the intensity of the pain or the patient’s suffering.4

Untreated or undertreated pain has a profound impact on emotional distress.3 Patients with pain have an increased incidence of psychological factors (ie, depression and anxiety), which intensify the pain experience, and patients with cancer pain who present with psychiatric symptoms might actually be showing symptoms of uncontrolled pain.3 Unrelieved, cancer pain destroys quality of life.4 It adversely affects psychological and physical well-being.7 Pain interferes with functioning, forces some patients to stop working, interferes with thinking or concentration, requires patients to rely heavily on other people, and prevents patients from caring for themselves or others.4 Patients who experience persistent pain report a significant reduction in their ability to sleep, perform daily activities, engage in relationships with others, and enjoy life.5 Pain also affects the family’s ability to provide appropriate support.2 According to the National Cancer Institute, there is a low priority given to cancer pain treatment.8 Physicians are trained to focus on prolonging life and achieving a cure, rather than assessing pain8 or alleviating suffering.3

A D V E R T I S E M E N T

Recognizing breakthrough cancer pain In basic terms, many patients with cancer experience 2 types of cancer pain: persistent pain and breakthrough pain. Persistent pain is chronic, constant, and continuous—requiring around-the-clock (baseline) medication. Breakthrough pain is pain that “breaks through” the baseline pain medication and is described as moderate to severe. Breakthrough cancer pain is different from persistent cancer pain. Breakthrough pain maybe episodic, spontaneous, or provoked, and it is often difficult to treat.6 Its onset, duration, and frequency differ as well.6 As such, it requires different medication9,10 and a treatment strategy tailored for the individual patient.9

Pain Intensity

Breakthrough Cancer Pain9,11,12

AROUND-THE-CLOCK OPIOID MEDICATION

PERSISTENT CANCER PAIN Time

Artist’s rendering derived from Fishbain DA. Am J Manag Care. 2008;14(5 suppl 1):S123-S128; Portenoy RK, et al. Pain. 1990;41:273281; Shoemaker SA, et al. Poster presented at the 25th Annual Meeting of the American Academy of Pain Medicine. Honolulu, HI; January 28-31, 2009

Although there is no unanimous agreement on the definition of the term “breakthrough cancer pain,” it is often described as transient worsening of ongoing, steady, or persistent pain in cancer patients.6 In addition, the onset, duration, frequency, and intensity of breakthrough cancer pain differ widely from episode-to-episode and from patient-to-patient, making it difficult to generalize or characterize.5 Nearly half of breakthrough cancer pain episodes have a sudden or intense onset.6 The duration of these episodes varies from 15 minutes to hours. The frequency of breakthrough cancer pain episodes ranges from 4 to 7 per day and pain intensity may differ between episodes.6

In a number of studies, 50% to 70% of cancer patients with pain have breakthrough cancer pain.6 More importantly, in a recent study of patients using prescription analgesia, 64% report their medicine is not adequate to control their pain.4

Breakthrough cancer pain must be identified in order to treat it appropriately Many healthcare professionals recognize the fact that cancer pain and breakthrough cancer pain in particular are serious healthcare problems. To help identify breakthrough cancer pain, it is critically important to start the conversation with the patient and fully understand the patient’s needs before an individualized treatment regimen for relief can begin.

Next in the Series: “Closing the Gap by Opening the Dialogue” References: 1. Cleeland CS. The impact of pain on the patient with cancer. Cancer. 1984;54 (11 suppl):2635-2641. 2. Levin DN, Cleeland CS, Dar R. Public attitudes toward cancer pain. Cancer. 1985;56:2337-2339. 3. Breitbart W. Psychiatric management of cancer pain. Cancer. 1989;63(11 suppl):2336-2342. 4. European Pain in Cancer (EPIC) Global Results Presentation. EPIC Steering Group Presentation. July 2007. www.paineurope.com/files/ Final%20Results%20Presentation.ppt. Accessed July 20, 2009. 5. Berger A, Dukes E, Smith M, et al. Use of oral and transdermal opioids among patients with metastatic cancer during the last year of life. J Pain Symptom Manage. 2003;26(2):723-730. 6. Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms. Eur J Pain. 2005;9(2):195-206. 7. Ferrell BR, Wisdom C, Wenzl C. Quality of life as an outcome variable in the management of cancer pain. Cancer. 1989;63(11 suppl):2321-2327. 8. National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/ supportivecare/pain/HealthProfessional/page2. Accessed March 25, 2009. 9. Fishbain DA. Pharmacotherapeutic management of breakthrough pain in patients with chronic persistent pain. Am J Manag Care. 2008;14(5 suppl 1): S123-S128. 10. Palos GR, Ashing-Giwa KT. The importance of community and culture in the comprehensive management of pain. Pain Practitioner. 2007;17(2):10-16. 11. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41:273-281. 12. Shoemaker SA, Bruns D, Portenoy RK. Characteristics and impact of breakthrough pain (BTP) in noncancer- and cancer-related chronic pain managed by clinicians who are not pain specialists. Poster presented at the 25th Annual Meeting of the American Academy of Pain Medicine. Honolulu, HI; January 28-31, 2009.

Table 3. Questions for Institutional Self-Assessment Of a Chemotherapy Error Prevention Program ❑ Do health care providers at your institution constantly monitor the external medication and medical error literature (eg, the ISMP Medication Safety Newsletter, etc) to be aware of potential risks to your patients based on events elsewhere? If so, do ongoing risk assessment discussions occur at your institution so that risk reduction strategies, as necessary, can be implemented? ❑ Does your institution/practice site prohibit abbreviations of chemotherapy drug names (generic or trade) on chemotherapy order sheets? ❑ Did your institution organize multidisciplinary reviews or task forces/committees to analyze medication control systems in the wake of recently publicized tragic chemotherapy errors? ❑ Does your institution have maximum dose guidelines/ceilings for chemotherapy? ❑ In your opinion, does your pharmacy computer system aid rather than hinder pharmacy department–driven medication safety programs at your institution? ❑ Does your institutional computer system help rather than hinder medical and medication error prevention by allowing prescribers and other staff to conveniently and accurately access necessary patient data? ❑ When/if your institution were to have a severe medication error, would the administrative response, in your opinion, be analytical (root-cause analysis) rather than punitive? ❑ Has your institution established guidelines concerning increasingly complex protocols (investigational or FDAapproved) using monoclonal antibodies (cold and radiolabeled), gene therapy, etc? ❑ Have you made any significant revisions to your chemotherapy medication order forms? ❑ For multiday chemotherapy orders, do your institutional or site guidelines require nomenclature of “drug X ____ mg per m2 per day = ____ mg for ____ days” and prohibit expressing the dosage as “the cycle drug dose over ____ days”? ❑ Has your institution taken steps, above and beyond using supplemental warning stickers and extra zip lock bag containers, to prevent inadvertent intrathecal administration of vinca alkaloids, including vinCRIStine? ❑ Are your medical and nursing staff educated about the need to keep vinca alkaloid doses away from any patient scheduled for a lumbar puncture? ❑ Does your institution have a documented final 2-person check procedure (eg, nurse and pharmacist or 2 nurses) where the prepared drug dose is compared one final time to the source document (ie, physician order, either written or electronic)? Based on references 4, 6, 20, 24, and 29.

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regimen and accompanying supportive care medications. The grid should contain patient-specific parameters, such as height, weight, and body surface area; the treatment cycle number and regimen start date; and hydration fluids, antiemetics, colony-stimulating factors, and other associated medications to be given both before and after chemotherapy administration. 3. The system should be able to apply policies and procedures designed to minimize medication errors (eg, a policy and procedure for rounding parenteral chemotherapy doses between 101 and 500 mg to the nearest 10 mg when appropriate). 4. A CPOE system should be programmed to notify prescribers when a patient has received a specified cumulative lifetime dose of a specific chemotherapy agent, such as doxorubicin or bleomycin, and these data should include any doses administered at other locations prior to the transfer of the patient to the current institution. 5. The system should be programmed to prevent prescribers from entering contraindicated routes of administration (eg, intrathecal administration of vincristine or doxorubicin and intramuscular administration of most antineoplastics).

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6. A catalogue of all “physician’s order sets,” including complete drug names, dosages, diluent fluid volumes, administration rates, and duration of administration for chemotherapy and supportive care agents, must be maintained and available to all prescribers. Such order sets have been described as a successful multidisciplinary approach to reducing chemotherapy errors.29

CAVEATS

CPOE SYSTEMS

CPOE systems are designed to decrease the risk for chemotherapy-related medication errors. However, they are not designed to replace physicians, pharmacists, or nurses, and staff reduction should not be a goal of CPOE system implementation. CPOE systems are neither a panacea nor the sole solution for preventing medication errors. Studies have illustrated that total reliance on a CPOE system not only has failed to improve safety, but has presented new risks for serious errors, as well as lifethreatening results for patients.30,31 In 2005, a systematic study using explicit, standard criteria on a random sample of all admissions during a 20-week period found persistently significant rates of adverse drug events at a highly computerized, 110-bed tertiary care Veterans Administration hospital.32 Medication errors contributed

to 27% of those adverse drug events. Of those medication errors, 61% occurred at the ordering stage, 25% at monitoring, 13% on administration, 1% at dispensing, and none at transcription. In addition to these types of data, the IOM Committee on Identifying and Preventing Medication Errors received testimony from Bruce Bagley, MD, medical director for Quality Improvement for the American Academy of Family Physicians, in which he stated, “Just putting a system in or buying the right software is not the answer. Getting your whole culture to change the way they do their work, supported by the new opportunities that are available through electronic health records, is really the key.”33 Although CPOE offers significant, additional protection against medication errors, its implementation can be an arduous task with a long adaptation period. Additionally, a CPOE system clearly requires a substantial investment in resources. For treatment settings that have not converted to electronic formats (or cannot convert because of a lack of resources), standardized, preprinted order forms are effective tools to reduce the occurrence of chemotherapy errors.6 Like electronic order forms, paper forms must include pertinent patient information, required laboratory monitoring, supportive care and other special medication orders, and proper delineation of the chemotherapeutic regimen to be administered (full drug name [no abbreviations], dose per meter squared or dose per kilogram, calculated dose, frequency, route of administration, day[s] to be given, and cumulative cycle dose per meter squared or dose per kilogram [to validate that the calculated dose and the number of doses ordered will equal the cycle dose specified in the given regimen]).

Technology: Bar Coding In addition to CPOE, bar coding has been promoted as an important step in medication error reduction by enhancing medication administration.34-38 Many issues in the successful implementation of bar coding are similar to those in the development of CPOE—for example, multidisciplinary involvement, vendor selection and support, product capabilities, and protocols for use. Bar-coding systems must be properly designed and implemented. In an era of seemingly daily drug shortages, on a practical level, it is quite possible that bar coding may be too brand- or vendor-specific. Bar-code scanners do not recognize medications the same way that humans can recognize that a different brand or vial description of a particular generic medication is still the correct medication and dose. There must be a functional interface between systems for drug prescribing, dispensing, and administration.

Institutional Self-Assessment The resolve by oncology caregivers to prevent patient harm must be absolute. It is important for all institutions to assess their own error prevention strategies, both as a baseline at one time point as well as continuously, especially if an error or a near-miss occurs. It also

is important for organizations to consider errors that occurred elsewhere to be a potential risk at their site. The ISMP newsletter Medication Safety Alert! is an exceptional resource that provides excellent examples of reported errors and near-miss events. Most settings find the alerts to be extremely helpful. The alerts can be accessed at ISMP’s Web site (www.ismp.org) or via published tabulations of the ISMP’s surveys on medication safety processes.39

Conclusion Cancer care is exceedingly complex and continues to change. Oncology caregivers face the challenges of increasing workloads, staff vacancies resulting from nurse and pharmacist shortages, institutional financial pressures attributable to managed care, reimbursement cutbacks and other economic challenges, increased regulatory burdens such as HIPAA and compliance regulations, and an expanding armamentarium of cytotoxics and targeted biologic therapies. Without question, oncology patients are among the most complex to care for and receive the most medications at the majority of hospitals. Despite these enormous pressures, health care’s resolve to prevent patient harm should be absolute and a team effort between the medicine, pharmacy, nursing, and laboratory staffs. It is clear that the appropriate use of technology is vital to increasing patient safety, but it is important that the technological tools used are carefully thought out and constructed to reflect the needs and characteristics of the specific organization where they are to be used. A “one-size-fits-all” approach by a computer software vendor may hamper safety efforts and create rather than reduce risk. Prevention of chemotherapy errors is a matter of remaining vigilant, having systems in place to expose mistakes and talk openly about ways to avoid them, and fostering a culture among co-workers who recognize that there is a mandate from the top levels of an organization that error prevention is an absolute priority. No one wants to wait for a tragedy to occur—each system must prioritize safety as a core value through its leadership and must commit resources for a cultural change that invites open discussion of errors.

References 1.

Beckwith MC, Tyler LS. Preventing medication errors with antineoplastic agents, part 1. Hosp Pharm. 2000;35(5):511-524.

2. Womer RB, Tracy E, Soo-Hoo W, Bicket B, Bitaranto S, Barnsteiner JH. Multidisciplinary systems approach to chemotherapy safety: rebuilding processes and holding the gains. J Clin Oncol. 2002;20(24):4705-4712, PMID: 12488417. 3. Müller T. Typical medication errors in oncology: analysis and prevention strategies. Onkologie. 2003;26(6):539-544, PMID: 14704927. 4. Schulmeister L. Preventing chemotherapy errors. Oncologist. 2006;11(5):463-468, PMID: 16720846. 5. Aspden P, Wolcott J, Bootman JL, Cronenwett LR, eds, for the Committee on Identifying and Preventing Medication Errors. Preventing Medication Errors: Quality Chasm Series. Washington, DC: National Academy Press; 2006.

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6. Kloth DD. Prevention of chemotherapy medication errors. J Pharm Pract. 2002;15(1):17-31. 7. Institute for Safe Medication Practices. ISMP’s List of Error-Prone Abbreviations, Symbols, and Dose Designations. http://www.ismp. org/Tools/errorproneabbreviations.pdf. Accessed October 26, 2009. 8. ASHP Council on Professional Affairs. ASHP guidelines on preventing medication errors with antineoplastic agents. Am J Health Syst Pharm. 2002;59(17):1648-1668, PMID: 12229895. 9. Cohen MR, Anderson RW, Attilio RM, Green L, Muller RJ, Pruemer JM. Preventing medication errors in cancer chemotherapy. Am J Health Syst Pharm. 1996;53(7):737-746, PMID: 8697025. 10. Sano HS, Waddell JA, Solimando DA, Doulaveris P, Myhand R. Study of the effect of standardized chemotherapy order forms on prescribing errors and anti-emetic cost. J Oncol Pharm Pract. 2005;11(1):21-30, PMID: 16460600.

24. Institute for Safe Medication Practices. Our long journey towards a safety-minded just culture. Part I: where we’ve been. http://www. ismp.org/Newsletters/acutecare/articles/20060907.asp. Accessed October 26, 2009. 25. Global Aviation Information Network (GAIN). A roadmap to a just culture: enhancing the safety environment. September 2004. http://www.flightsafety.org/files/just_culture.pdf. Accessed October 26, 2009. 26. Institute for Safe Medication Practices. Our long journey towards a safety-minded just culture. Part II: where we’re going. http://www. ismp.org/Newsletters/acutecare/articles/20060921.asp. Accessed October 26, 2009. 27. Kelly WN, Rucker TD. Compelling features of a safe medicationuse system. Am J Health Syst Pharm. 2006;63(15):1461-1468, PMID: 16849713.

11. Kozakiewicz JM, Benis LJ, Fisher SM, Marseglia JB. Safe chemotherapy administration: using failure mode and effects analysis in computerized prescriber order entry. Am J Health Sys Pharm. 2005;62(17):1813-1816, PMID: 16120742.

28. Gray MD, Felkey BG. Computerized prescriber order-entry systems: evaluation, selection, and implementation. Am J Health Syst Pharm. 2004;61(2):190-197, PMID: 14750404.

12. Sheridan-Leos N, Schulmeister L, Hartranft S. Failure mode and effect analysis: a technique to prevent chemotherapy errors. Clin J Oncol Nurs. 2006;10(3):393-398, PMID: 16789584.

29. Dinning C, Branowicki P, O’Neill JB, Marino BL, Billett A. Chemotherapy error reduction: a multidisciplinary approach to create templated order sets. J Pediatr Oncol Nurs. 2005;22(1):20-30, PMID: 15574723.

13. Attilio RM. Caring enough to understand: the road to oncology medication error prevention. Hosp Pharm. 1996;31:17-26. 14. Cohen MR. Medication error: clarify laboratory test results given by telephone. Nursing. 1981;11(11):63, PMID: 6914487. 15. Cohen MR, Senders J, Davis NM. Failure mode and effects analysis: a novel approach to avoiding dangerous medication errors and accidents. Hosp Pharm. 1994;29(4):319-330. 16. Cohen MR. Medication-error reporting: banish a system that blames. Nursing. 1996;26(1):15, PMID: 8632840. 17. Cohen MR. Why error reporting systems should be voluntary [editorial]. BMJ. 2000;320(7237):728-729, PMID: 10720338. 18. McCarthy ID, Cohen MR, Kateiva J, McAllister JC 3rd, Ploetz PA. What should a pharmacy manager do when a serious medication error occurs? A panel discussion. Am J Hosp Pharm. 1992;49(6):1405-1412, PMID: 1529980. 19. DuBeshter B, Griggs J, Angel C, Loughner J. Chemotherapy dose limits set by users of a computer order entry system. Hosp Pharm. 2006;41:136-142. 20. Birner A. Safe administration of oral chemotherapy. Clin J Oncol Nurs. 2003;7(2):158-162, PMID: 12696211. 21. Bennett C. Is jail the answer for fatal negligence? Guardian (UK). September 25, 2003. http://www.guardian.co.uk/uk/2003/sep/25/ ukcrime.comment. Accessed October 26, 2009. 22. Stump LS. Re-engineering the medication error-reporting process: removing the blame and improving the system. Am J Health Syst Pharm. 2000;57(suppl 4):S10-S17, PMID: 11148939. 23. Accelerating Change Today. Reducing medial errors and improving patient safety: success stories from the front lines of medicine. National Coalition of Health Care and Institute for Healthcare Improvement. February 2000. http://www.nchc.org/documents/ medical_errors.pdf. Accessed October 26, 2009.

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30. Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293(10):1197-1203, PMID: 15755942. 31. McNutt RA, Abrams R, Arons DC; Patient Safety Committee. Patient safety efforts should focus on medical errors. JAMA. 2002;287(15):1997-2001, PMID: 11960545. 32. Nebeker JR, Hoffman JM, Weir CR, Bennett CL, Hurdle JF. High rates of adverse drug events in a highly computerized hospital. Arch Intern Med. 2005;165(10):1111-1116, PMID: 15911723. 33. Young D. IOM panel reviews lessons for medication safety. Am J Health Syst Pharm. 2005;62(13):1340-1342, PMID: 15972369. 34. Kester M. Bar coding at the bedside: New England hospital implements an automated point-of-care medication administration system to reduce medication errors and their associated complications. Health Manag Technol. 2004;25(5):42-44, PMID: 15154143. 35. Neuenschwander M, Cohen MR, Vaida AJ, Patchett JA, Kelly J, Trohimovich B. Practical guide to bar coding for patient medication safety. Am J Health Syst Pharm. 2003;60(8):768-779, PMID: 12749163. 36. Greenly M, Gugerty B. How bar coding reduces medication errors. Nursing. 2002;32(5)2:70, PMID: 12035658. 37. Scalise D. Medication safety. Bar coding: the forgotten technology. Hosp Health Netw. 2002;76(4):16, PMID: 11924556. 38. Tribble DA. Bar coding a must for patient safety. Am J Health Syst Pharm. 2002;59(7):667, discussion 667-668, PMID: 11974399. 39. Smetzer JL, Vaida AJ, Cohen MR, Tranum D, Pittman MA, Armstrong CW. Findings from the ISMP Medication Safety Self-Assessment for hospitals. Jt Comm J Qual Saf. 2003;29(11):586-597, PMID: 14619351.

For a pocket guide version of The Guide to the Prevention of Chemotherapy Medication Errors, visit www.CLINICALONCOLOGY.COM

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Guidelines for the Management of

Febrile Neutropenia MICHAEL GABAY PHARMD, JD, BCPS Director, Drug Information Group and Prior Authorization Services Clinical Assistant Professor

MARIA TANZI PHARMD Clinical Assistant Professor, Drug Information Group University of Illinois at Chicago College of Pharmacy Chicago, Illinois

or patients receiving chemotherapy, febrile neutropenia often is associated with immediate hospitalization and

institution of empiric broad-spectrum antibiotic therapy.1 Although the condition remains a major source of morbidity and mortality, improvements in treatment have significantly improved outcomes.2

Historically, mortality was extremely high—rates approached 90% in a 1962 study involving patients with gram-negative bacteremia and severe underlying disease.3 More recent data from the Surveillance and Control of Pathogens of Epidemiologic Importance Project found mortality rates of 33.4% with coagulase-negative staphylococci, 22.8% with methicillin-susceptible Staphylococcus aureus, and 17.7% with methicillin-resistant S. aureus (MRSA) bloodstream infections in 2,340 patients with underlying malignancies.4 Although the definition of febrile neutropenia varies within clinical studies, both the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN) define fever as a single oral temperature of at least 38.3˚C (101˚F) without any obvious environmental cause.5,6 In addition, a febrile state is defined as a temperature of at least 38˚C (100.4˚C) for

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

at least 1 hour. An absolute neutrophil count (ANC) fewer than 1,000 cells/mcL or fewer than 500 cells/mcL often is used to define neutropenia.1 The lower the neutrophil count, the greater the risk for infection.5 Beyond the quantity of neutrophils, the duration of neutropenia also can impact infection risk. A protracted neutropenic state can significantly increase the potential for infection.

Causes of Neutropenia And Infectious Complications The neutropenia observed in patients with malignancy usually is the direct result of cancer chemotherapy.7 Neutropenia can be so severe that subsequent cycles may be delayed or require dose reductions, thereby potentially impacting the efficacy of the chemotherapy regimen in the future.8 Certain single-agent and combination regimens carry a high (>20%) risk for

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Table 1. Chemotherapy Regimens at High Risk for Febrile Neutropeniaa Cancer Type

Regimen

Bladder

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin)

Breast

Docetaxel plus trastuzumab AT (doxorubicin plus paclitaxel or docetaxel) TAC (docetaxel, doxorubicin, cyclophosphamide

Esophageal and gastric

Docetaxel-cisplatin-fluorouracil

Non-Hodgkinâ&#x20AC;&#x2122;s Lymphoma

ICE (ifosfamide, carboplatin, etoposide) CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone) DHAP (dexamethasone, cisplatin, cytarabine) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

Melanoma

Dacarbazine-based combinations

Myelodysplastic syndrome

Decitabine

Ovarian

Topotecan Paclitaxel or docetaxel

Pancreatic

Gemcitabine-docetaxel

Sarcoma

MAID (mesna, doxorubicin, ifosfamide, dacarbazine)

Small cell lung

Topotecan

Testicular

VeIP (vinblastine, ifosfamide, cisplatin) VIP (etoposide, ifosfamide, cisplatin) BEP (bleomycin, etoposide, cisplatin) TIP (paclitaxel, ifosfamide, cisplatin)

Does not contain all high-risk regimens.

Based on reference 9.

febrile neutropenia. Table 1 contains examples of such chemotherapy regimens.9 In patients with malignancy who develop febrile neutropenia, a variety of pathogens may be responsible for infectious complications. Bacteria are the primary causes of initial infection early in the course of febrile neutropenia.6 The predominant categories of bacterial pathogens identified as the source of infection have changed over time.10 In the late 1950s and early 1960s, gram-positive organisms, such as S. aureus, commonly were recognized as causative agents. Since that time, the primary bacterial cause underlying febrile neutropenia has fluctuated back and forth from gram-negative organisms (ie, Escherichia coli, Klebsiella spp, and Pseudomonas spp) in the late 1960s and early 1970s to gram-positive organisms in the 1990s, to an emergence of gram-negative organisms again in the new millennium. Today, coagulase-negative staphylococci, S. aureus, viridans group streptococci, and enterococci

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are the most common gram-positive pathogens6 and E. coli, Klebsiella spp, Enterobacter spp, and P. aeruginosa are the most common gram-negative species. Fungal infections such as Candida and Aspergillus can occur later in the course of prolonged neutropenia.

Patient Risk Assessment Assessments of the risk for neutropenia and infectious complications are important components in the care of patients with malignancy. These assessments not only evaluate which patients may be at risk for febrile neutropenia but also attempt to predict the probability of serious complications and whether a low-risk individual may safely receive outpatient treatment with oral antibiotics.6 A variety of risk models have been studied to identify patient-, disease-, and treatment-related factors associated with the risk for developing neutropenia and its associated complications.11 In addition to risk models, studies

of individual risk factors also have been conducted to aid in identifying patients at greatest risk.12 Although there is no consensus nomogram for risk assessment, the NCCN has developed a risk categorization for patients based on disease, chemotherapy regimen, patient risk factors, and treatment intent (ie, curative vs palliative).9 This scheme categorizes patients as having either a high (>20%), intermediate (10%-20%), or low (<10%) risk for developing febrile neutropenia. Table 2 lists patient risk factors for experiencing a poor clinical outcome or infectionassociated complications, as noted in the 2009 NCCN Myeloid Growth Factor guidelines.9 The identification of patients at low risk who may be treated on an outpatient basis with oral antibiotic therapy is an important consideration in the management of febrile neutropenia. The Multinational Association for Supportive Care in Cancer (MASCC) risk scoring index (Table 3)13 accurately identifies those at low risk for complications associated with febrile neutropenia who may then be treated with a more convenient and cost-effective option. The MASCC index was validated in a prospective, multinational study where a MASCC score of at least 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%.13 In addition, the IDSA and the NCCN have identified various individual factors that favor a low risk for severe infection among patients with neutropenia (Table 4).5,6

Table 2. Risk Factors for Poor Clinical Outcomes or InfectionAssociated Complications Sepsis syndrome Age 65 y or older Severe neutropenia, defined as an absolute neutrophil count <100 cells/mcL Neutropenia lasting >10 d Pneumonia Invasive fungal infection Other clinically documented infections Hospitalization at the time of fever Based on reference 9.

Table 3. MASCC Risk Scoring Indexa Extent of illness (choose 1) No symptoms (5 points) Mild symptoms (5 points)

Clinical Presentation Febrile neutropenia should be suspected in any patient who has received chemotherapy in the prior 4 to 6 weeks and presents with a fever or a general feeling of malaise.14 An infection may be present in these patients even without fever because a lack of neutrophils may negatively impact the ability to mount a sufficient immune response. A thorough history and physical examination should be completed to identify the site of infection; however, a definitive infection site may never be discovered.14,15 This examination should include the skin, mucous membranes, fundi, sinuses, and the perianal area.15 All peripheral and central catheter sites should be inspected for signs of infection. The date and the medications involved in the most recent chemotherapy treatment should be obtained. In addition, any history of prior prophylactic antibiotics should be noted because this therapy could alter the patientâ&#x20AC;&#x2122;s microflora and influence subsequent antibiotic choice.14 Initial laboratory evaluations include a complete blood count with differential, liver function tests, lipase, a complete chemistry panel, and a full set of cultures (ie, sputum, blood, and urine).15 Cultures should be drawn from every peripheral and central access point. Chest radiographs should be obtained even in patients without obvious pulmonary symptoms. If local signs or symptoms exist, consider acquiring additional imaging studies or laboratory tests that may provide more information regarding symptom etiology. Although patients may present with only fever and malaise, signs and symptoms

Moderate symptoms (3 points) No hypotension (5 points) No chronic obstructive pulmonary disease (4 points) Solid tumor or no fungal infection (4 points) No dehydration (3 points) Outpatient at onset of fever (3 points) Age <60 y (2 points) a A score of 21 or higher indicates the patient is likely to be at low risk for complications.

MASCC, Multinational Association for Supportive Care in Cancer Based on reference 13.

of sepsis, such as hypotension and cardiopulmonary compromise, also may occur during initial presentation.14,15

Management and Treatment USE OF ANTIMICROBIALS As discussed previously, patients with neutropenia are at risk for developing serious infections that can have a substantial impact on morbidity and mortality. Therefore, therapies aimed at eliminating the most likely infectious pathogens are the primary treatments used for managing patients with febrile neutropenia. In 2002, the IDSA published guidelines on the use of antimicrobial agents

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Table 4. Factors Favoring Low Risk for Severe Infection in Patients With Neutropeniaa IDSA 2002 Guidelines

NCCN 2009 Guidelines

• Absolute neutrophil count of ≥100 cells/mcL

• No high-risk factorsa AND most of the following: • Outpatient status at the time of development of fever • No associated acute comorbid illnesses • Anticipated short duration of severe neutropenia, defined as <7d • Good performance status • No renal or hepatic insufficiency OR • A score of ≥21 on the MASCC Risk Index (see Table 3)

• Absolute monocyte count of ≥100 cells/mcL • Normal findings on a chest radiograph • Nearly normal renal and hepatic function tests • Duration of neutropenia is <7d • Resolution of neutropenia expected in <10 d • No IV catheter-site infection • Early evidence of bone marrow recovery • Malignancy in remission • Peak temperature of <39˚C • No neurologic or mental changes • No appearance of illness • No abdominal pain • No comorbid conditions such as shock, hypoxia, pneumonia or other deep-organ infection, vomiting, or diarrhea a

High-risk factors are listed on page FEV-3 of v.2.2009 of the NCCN Practice Guidelines for the Prevention and Treatment of Cancer-Related Infections. IDSA, Infectious Diseases Society of America; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network Based on references 5 and 6.

in neutropenic patients with cancer.5 An update to these guidelines is expected in 2010. More recently, the NCCN published guidelines on the prevention and treatment of cancer-related infections.6 Both sets of guidelines recommend that empiric antimicrobial therapy be initiated in all neutropenic patients at the onset of fever. The selection of empiric therapy should be based on a variety of factors such as a patient’s infectious risk, potential sites of infection, and local antimicrobial sensitivity and resistant patterns (Table 5).6 For patients at low risk for complications (Tables 4 and 5), oral antimicrobial therapy can be given.5,6 Both sets of guidelines recommend an oral regimen that contains ciprofloxacin plus amoxicillin-clavulanate. The NCCN recommends ciprofloxacin plus clindamycin for patients with a penicillin allergy.6 If fluoroquinolone prophylaxis was used, the NCCN guidelines recommend against oral therapy. Outpatient management may be appropriate for low-risk patients who meet certain criteria, such as consenting to home care, having a telephone, having access to emergency facilities, having an adequate and supportive home environment, and being within 1-hour travel time to a medical facility or physician’s office. Patients at high risk for severe infections should be treated in the hospital with IV antimicrobials, according to the IDSA and NCCN guidelines.5,6 Both guidelines recommend various monotherapy and combination

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regimens, with vancomycin recommended for select patients (Table 6). Some of the monotherapy and combination regimens differ between the 2 sets of guidelines. For monotherapy, the NCCN guidelines state that ceftazidime has weak gram-positive coverage and is associated with increased breakthrough infections, suggesting that the utility of this agent is limited.6 With respect to vancomycin as empiric therapy, the IDSA recommends that this agent be used for patients with clinically suspected serious catheter-related infections, known colonization with penicillin- and cephalosporin-resistant pneumococci or MRSA, positive results of a blood culture for gram-positive bacteria before final identification and susceptibility testing, or hypotension or other evidence of cardiovascular impairment.5 The NCCN guidelines recommend that vancomycin be used for patients meeting any of the same criteria as the IDSA guidelines, in addition to patients with a soft tissue infection or those with risk factors for viridans group streptococcal bacteremia.6 The NCCN guidelines strongly recommend against the use of empiric vancomycin for patients not meeting these criteria because of concerns about resistance and breakthrough infections. These guidelines also comment on the use of agents such as linezolid (Zyvox, Pharmacia), daptomycin (Cubicin, Cubist), and quinupristin-dalfopristin (Synercid, Monarch) and state that use of these antimicrobials should be limited to specific situations

Table 5. Factors Influencing Initial Antimicrobial Selection

Table 6. Empiric Antimicrobial Therapy for Febrile Neutropenia

Infection risk assessment (ie, low vs high risk)

IDSA 2002 Guidelines

NCCN 2009 Guidelines

Antimicrobial susceptibilities of pathogens isolated locally

Monotherapy

• Imipenem/cilastatin

The most commonly potentially infecting organisms, including antimicrobial-resistant pathogens, such as ESBL-producing gram-negative rods or VRE

• Meropenem

• Cefepime

• Piperacillin/tazobactam

• Ceftazidime

• Cefepime • Ceftazidime (limited utility)

Colonization or previous infection with MRSA Potential site of the infection

Combination therapy

Importance of broad spectrum antimicrobial coverage that includes antipseudomonal coverage

• Aminoglycoside plus antipseudomonal penicillin

Previous antimicrobial use Clinical instability such as organ dysfunction, hypotension

• Aminoglycoside plus antipseudomonal penicillin with or without β-lactamase • Aminoglycoside plus inhibitor cefepime, ceftazidime, or carbapenem • Aminoglycoside plus cefepime or ceftazidime

Drug allergy ESBL, extended spectrum β-lactamase; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus Based on reference 6.

involving infections caused by documented vancomycinresistant organisms or for patients in whom vancomycin is not an option. Patients with febrile neutropenia who are clinically unstable, such as those with sepsis, should be initiated on combination therapy that includes a broad-spectrum β-lactam (eg, imipenem-cilastatin, meropenem, or piperacillin-tazobactam [Zosyn, Wyeth]) plus an aminoglycoside and vancomycin.6 The addition of antifungal therapy (eg, fluconazole or an echinocandin) also should be considered for patients not receiving antifungal prophylaxis. Alterations in the initial empiric regimen are needed for patients who are not responding to therapy.5,6 The NCCN guidelines recommend assessing the appropriateness of antimicrobials for isolated pathogens in patients with documented infection who are not responding to empiric therapy.6 In addition, for patients with fever of unknown origin who are unstable, antimicrobials should be broadened to include coverage of anaerobes, resistant gram-negative rods and gram-positive organisms, and Candida. Empiric antifungal therapy is generally initiated after 4 to 7 days in patients who remain febrile. The NCCN guidelines state that the duration of antimicrobial therapy is determined by several factors such as the underlying site of infection, causative organisms, and the patient’s clinical condition, response to treatment, and time to neutrophil recovery.6 For patients with fever of unknown origin, antimicrobial therapy is generally continued until the ANC is at least 500 cells/mcL, assuming

Combination therapy

• Ciprofloxacin plus antipseudomonal penicillin Vancomycin (for select patients)

Vancomycin (for select patients)

• Vancomycin plus cefepime, ceftazidime, or carbapenem with or without aminoglycoside

• Monotherapy or combination therapy

IDSA, Infectious Diseases Society of America; NCCN, National Comprehensive Cancer Network Based on references 5 and 6.

the patient is afebrile for at least 24 hours before discontinuation. For patients with documented infections, the NCCN guidelines acknowledge that most clinicians treat patients until the ANC recovers to 500 cells/mcL or more, but they recommend using a defined course of therapy appropriate for the specific infection. The durations for antimicrobial therapies suggested in the NCCN guidelines are summarized in Table 7.6 The duration of antimicrobial therapy is treated differently in the IDSA guidelines.5 The IDSA guidelines state that if no infection is identified after 3 days of treatment, the neutrophil count is at least 500 cells/mcL for 2 consecutive days, and the patient has been afebrile for at least 48 hours, antimicrobials can be stopped. The guidelines also recommend that for patients with prolonged neutropenia, therapy can be stopped in low-risk patients who are clinically well and afebrile for 5 to 7 days. Antimicrobial therapy can be stopped after 2 weeks in patients with persistent fever on day 3 and prolonged neutropenia, as long as no documented infection is found and the patient is clinically stable.

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Infection

Duration of Therapy

Skin and soft tissue

7-14 d

Blood stream infections Gram-negative Gram-positive

10-14 d 7-14 d

Antifungal prophylaxis with fluconazole and antiviral prophylaxis with acyclovir or ganciclovir are recommended for patients undergoing allogenic hematopoietic stem cell transplantation. The NCCN guidelines include a detailed discussion on antimicrobial prophylaxis, which is beyond the scope of this review; however, key recommendations include fluoroquinolone prophylaxis, with levofloxacin (Levaquin, Ortho-McNeil-Janssen) as the preferred agent for patients expected to have neutropenia for more than 7 days, and TMP-SMX for patients at risk for Pneumocystis jiroveci infections.

Sinusitis

10-21 d

PROPHYLACTIC USE

Bacterial pneumonia

10-21 d

Table 7. Suggested Durations Of Antimicrobial Therapy for Patients With Documented Infections

Fungal (mold and yeast) Candida

Minimum of 2 wk after first negative blood culture

Mold (eg, Aspergillus)

Minimum of 12 wk

Viral Herpes simplex/Varicella zoster Influenza

7-10 d 5-10 d

Based on reference 6.

PROPHYLACTIC ANTIMICROBIALS Both the IDSA and NCCN guidelines comment on the use of antimicrobial prophylaxis for afebrile neutropenic patients.5,6 The IDSA guidelines recommend against the routine use of antimicrobial prophylaxis because of emerging resistance.5 Antimicrobial prophylaxis with trimethoprim-sulfamethoxazole (TMPSMX) is only recommended to prevent Pneumocystis jiroveci pneumonitis in patients at risk for this infection.

COLONY-STIMULATING FACTORS

Reducing the incidence, severity, and duration of neutropenia is another important treatment strategy used for managing patients with febrile neutropenia. Colony-stimulating factors (CSFs) are used to prevent neutropenia in patients who are receiving myelosuppressive chemotherapy.16 These agents regulate the proliferation, differentiation, maturation, and functional activation of neutrophils. The CSFs are classified into 2 groups: granulocyte-CSFs (filgrastim [Neupogen, Amgen] and pegfilgrastim [Neulasta, Amgen]) and a granulocyte-macrophage CSF (sargramostim [Leukine, Genzyme]).17-19 The labeled indications for filgrastim, pegfilgrastim, and sargramostim vary; a summary of these indications is presented in Table 8.17-19 Filgrastim should be initiated 24 to 72 hours after completion of chemotherapy at a daily dose of 5 mcg/kg.17 Therapy should be continued through the post-nadir recovery to normal or near-normal levels. Filgrastim should not be given the same day chemotherapy is administered. Pegfilgrastim should also be initiated 24 to 72 hours after the completion of chemotherapy and not administered on the same day chemotherapy is given.18 Pegfilgrastim is given as one dose of 6 mg per treatment cycle. Sargramostim is given at a dose of 250 mcg/m2

Table 8. Labeled Indications for CSFs CSFs

FDA-Approved Indications

Filgrastim (Neupogen, Amgen)

• • • • •

Pegfilgrastim (Neulasta, Amgen)

• Cancer patients receiving myelosuppressive chemotherapy

Sargramostim (Leukine, Genzyme)

• • • •

Cancer patients receiving myelosuppressive chemotherapy Patients with AML receiving induction or consolidation chemotherapy Cancer patients receiving BMT Patients undergoing peripheral blood progenitor cell collection and therapy Patients with severe chronic neutropenia

Patients with AML receiving induction or consolidation chemotherapy Patients undergoing peripheral blood progenitor cell collection and therapy Cancer patients receiving BMT Use in BMT failure or engraftment delay

AML, acute myeloid leukemia; BMT, bone marrow transplant; CSFs, colony-stimulating factors Based on references 17-19.

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Table 9. ASCO Recommendations on Use of CSFs As primary prophylaxis of febrile neutropenia for patients at high risk based on age, medical history, disease characteristics, and risk for myelotoxicity associated with a chemotherapy regimen. For patients undergoing nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications due to bone marrow compromise or other comorbidities. As secondary prophylaxis in patients who have previously experienced an episode of febrile neutropenia (without primary prophylaxis) when a reduction in dose of chemotherapy is not appropriate. Use can be considered as adjunctive treatment of febrile neutropenia for patients at high-risk for infectious complications. To allow for a modest to moderate increase in dose-density and dose-intensity of chemotherapy regimens. As an adjunct to progenitor-cell transplantation. For reduction of neutropenia in patients with AML with initial or repeat induction chemotherapy or completion of consolidation therapy. To increase ANC in patients with myelodysplastic syndrome. Following completion of initial induction therapy or first post-remission course of chemotherapy for ALL. For limited use with refractory or relapsed AML (data suggest only a few shortened days of neutropenia can be expected). As prophylaxis in patients 65 y and older with diffuse aggressive lymphoma undergoing CHOP or more aggressive regimens. For patients being treated with lethal doses of total body radiotherapy. For pediatric patients, CSFs can be used for primary prophylaxis and as secondary prophylaxis or as adjunctive therapy for high-risk patients; the risk for secondary myeloid leukemia or myelodysplastic syndrome should be considered in children with ALL. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ANC, absolute neutrophil count; ASCO, American Society of Clinical Oncology; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CSFs, colony-stimulating factors Based on reference 16.

per day, also initiated 24 to 72 hours after the completion of chemotherapy, and continued through the post-nadir recovery period.19 The American Society of Clinical Oncology (ASCO) guidelines recommend that use of sargramostim is limited to its labeled indications.16

RECOMMENDATIONS

FOR

USE

CSFS

In 2006, ASCO published an update to its 2000 recommendation on the use of CSFs.16 Data have shown that prophylactic use of CSFs reduces the incidence, length, and severity of chemotherapy-related neutropenia, and decreases rates of infection.20,21 Use of CSFs is recommended as primary prophylaxis of febrile neutropenia for patients at high risk based on age, medical history, disease characteristics, and risk for myelotoxicity associated with a chemotherapy regimen. Available data support the use of CSFs with chemotherapy regimens that have a 20% or greater risk for febrile neutropenia (Table 1). In addition, CSFs may be beneficial for patients undergoing nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications. A summary

of ASCOâ&#x20AC;&#x2122;s recommendations is presented in Table 9.16 The CSFs are not recommended for routine treatment of afebrile neutropenia and use should be avoided in patients receiving a combination of chemotherapy and radiation. The 2009 recommendations from NCCN on the use of CSFs are summarized in Table 10.9 These guidelines, which are similar to the ASCO guidelines, also recommend the prophylactic use of CSFs with chemotherapy regimens that have a 20% or greater risk for febrile neutropenia. In addition, patients are considered to be at high risk if they experienced a previous neutropenic complication in the immediate previous cycle with no plan to reduce the dose intensity of the chemotherapy regimen. When deciding if CSFs should be used, clinicians are encouraged to consider the intent of the chemotherapy regimen. For example, is therapy curative or is it being used for symptom control? For patients in the intermediate-risk category (10%-20%), NCCN recommends that if the risk is based on patient-specific factors, then use of CSFs is reasonable. However, if the intermediate risk is based on the chemotherapy

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Table 10. NCCN Recommendations on CSFs for Febrile Neutropenia

Risk for Febrile Neutropenia

Use of CSF

High (>20%)

CSF

Intermediate (10%-20%)

May be considered

Low (<10%)

No CSFa

No CSF

Only consider CSF if a patient is at significant risk for serious medical consequences of febrile neutropenia, including death.

CSFs, colony-stimulating factors; NCCN, National Comprehensive Cancer Network Based on reference 9.

regimen, then use of less myelosuppressive therapies or a dose reduction should be considered.

Conclusion Febrile neutropenia remains a significant source of morbidity and mortality for patients receiving chemotherapy. Risk factors and models have been evaluated to aid in determining which patients may be at high risk for complications and which patients may be at low risk and therefore benefit from treatment with more cost-effective and convenient medication regimens. The IDSA and NCCN have developed guidelines for the prevention and treatment of infections associated with febrile neutropenia. In addition, the NCCN and ASCO have published guidelines regarding the appropriate use of myeloid growth factors for this condition. Appropriate therapy in selected patients can significantly improve outcomes and reduce complications of febrile neutropenia.

References 1.

Lyman G. Kuderer NM. Epidemiology of febrile neutropenia. Support Cancer Ther. 2003;1(1):23-35, PMID: 18628128.

Cancer. 2004;100(2):228-237, PMID: 14716755. 8. Lyman G. Risks and consequences of chemotherapy-induced neutropenia. Clin Cornerstone. 2006;8(suppl 5):S12-S18, PMID: 17379159. 9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Myeloid growth factors (v.1.2009). http://www. nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf. Accessed November 11, 2009. 10. Ellis M. Febrile neutropenia. Ann NY Acad Sci. 2008;1138:329-350, PMID: 18837909. 11. Lyman GH. Risk assessment in oncology clinical practice. From risk factors to risk models. Oncology (Williston Park). 2003;17(suppl 11):8-13, PMID: 14682113. 12. Lyman GH, Lyman CH, Agboola O, for the ANC study group. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10(6):427-437, PMID: 15967836. 13. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051, PMID: 10944139. 14. Walji N, Chan AK, Peake DR. Common acute oncological emergencies: diagnosis, investigation, and management. Postgrad Med J. 2008;84(994):418-427, PMID: 18832403.

2. Viscoli C, Vanier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis. 2005;40(suppl 4):S240-S245, PMID: 15768329.

15. Adelberg DE, Bishop MR. Emergencies related to cancer chemotherapy and hematopoietic stem cell transplantation. Emerg Med Clin N Am. 2009;27(2):311-331, PMID: 1947314.

3. McCabe WR, Jackson GG. Gram-negative bacteremia. II. Clinical, laboratory, and therapeutic observations. Arch Intern Med. 1962;110(6):856-864.

16. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205, PMID: 16682719.

4. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis. 2003;36(9):1103-1110, PMID: 12715303. 5. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34(6):730-751, PMID: 11850858. 6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related Infections (v.2.2009). http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed November 10, 2009. 7. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management.

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17. Neupogen [package insert]. Thousand Oaks, CA: Amgen; 2007. 18. Neulasta [package insert]. Thousand Oaks, CA: Amgen; 2008. 19. Leukine [package insert]. Seattle, WA: Bayer; 2008. 20. Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;(4):CD003189, PMID: 18843642. 21. Sung L, Nathan PC, Alibhai SM, Tomlinson GA, Beyene J. Metaanalysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med. 2007;147(6):400-411, PMID: 17876022.

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and ﬂatulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

STRONG. FROM THE START.

HELP ESTABLISH A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When your patients experience acute chemotherapyinduced nausea and vomiting (CINV) during their ﬁrst cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: Starts strong to prevent CINV4 A single IV dose lasts up to 5 days after MEC4,5* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

www.ALOXI.com

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Treatment of

Nausea and Vomiting In the Oncology Setting DAVID G. FRAME, PHARMD Clinical Assistant Professor of Pharmacy The University of Michigan College of Pharmacy Ann Arbor, Michigan

WILLIAM LESLIE, MD Assistant Professor of Medicine Rush University Medical Center Chicago, Illinois

he American Society of Clinical Oncology,1 the European

Society of Medical Oncology,2 the Multinational Association of Supportive Care in Cancer,3 and the National

Comprehensive Cancer Network4 all provide antiemetic guidelines.

This review will focus on the most updated versions of these guidelines, which are very similar. By summarizing the guideline recommendations for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) and radiation-induced nausea and vomiting (RINV), this review will assist physicians, pharmacists, and nurses in the selection of the most appropriate antiemetic regimens for patients receiving chemotherapy or radiation therapy. The guidelines are described below and are outlined in Tables 1 and 2. The Figure is a useful algorithm describing the recommended course of antiemetic care.

Anticipatory Nausea and Vomiting Each of the guidelines recommend the use of psychological techniques to prevent anticipatory nausea and vomiting; benzodiazepines can be used as an alternative or in addition to psychological techniques, if needed. Because anticipatory nausea and vomiting is a learned response, the best prevention for it is aggres-

I N D E P E N D E N TL Y DEVELOPED BY MCMAHON PUBLI SHI NG

sive prevention of acute and delayed nausea and vomiting with each course of chemotherapy or radiation.

Acute-Onset CINV HIGHLY EMETOGENIC CHEMOTHERAPY For prevention of acute-onset CINV in patients treated with highly emetogenic agents, a 3-drug regimen that includes a single dose of a serotonin (5-HT3)–receptor antagonist, dexamethasone, and aprepitant (Emend, Merck) or its prodrug, fosaprepitant (Emend, Merck) is recommended. The 5-HT3–receptor antagonists include dolasetron (Anzemet, Sanofi-Aventis/Organon), granisetron, ondansetron, and palonosetron (Aloxi, Eisai). Additional therapy with lorazepam and/or an H2 antagonist or proton pump inhibitor (PPI) may be considered.

MODERATELY EMETOGENIC CHEMOTHERAPY For patients treated with moderately emetogenic agents, a 5-HT3–receptor antagonist plus dexamethasone is recommended. Aprepitant or fosaprepitant

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should be added for patients receiving additional agents of moderate risk such as carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, and methotrexate. Lorazepam and/or an H2 antagonist or PPI also may be considered.

dexamethasone and aprepitant or fosaprepitant is recommended. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

MODERATELY EMETOGENIC CHEMOTHERAPY LOW EMETOGENIC CHEMOTHERAPY For patients treated with agents with low emetogenic potential, a low dose of a single agent, such as a dexamethasone, or a dopamine antagonist, such as metoclopramide or prochlorperazine, is recommended.

MINIMALLY EMETOGENIC CHEMOTHERAPY Routine antiemetic prophylaxis is not recommended in patients with no history of nausea and vomiting who are treated with minimally emetogenic chemotherapy.

MULTIDAY CHEMOTHERAPY For patients receiving a multiday regimen with a moderately or highly emetogenic agent, a daily regimen of a 5-HT3–receptor antagonist (or palonosetron 0.25 mg IV on days 1, 3, and 5) and dexamethasone is recommended. Aprepitant or fosaprepitant may be added (for up to 5 days) if a regimen is likely to be associated with significant delayed CINV. Lorazepam and/or an H2 antagonist or PPI also may be considered.

Delayed-Onset CINV HIGHLY EMETOGENIC CHEMOTHERAPY To prevent delayed-onset CINV in patients treated with highly emetogenic regimens, a combination of

Antiemetic prophylaxis should only be used for moderately emetogenic chemotherapy known to be associated with a significant incidence of delayed nausea and vomiting. In this circumstance, if aprepitant or fosaprepitant was not used in the prevention of acute nausea and vomiting, it is recommended that oral dexamethasone be used. A 5-HT3–receptor antagonist could be used as an alternative to dexamethasone. For patients treated with aprepitant or fosaprepitant, dexamethasone, and a 5-HT 3– receptor antagonist for the prevention of acute nausea and vomiting, it is recommended that aprepitant or fosaprepitant with or without dexamethasone be given for delayed CINV. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

MULTIDAY CHEMOTHERAPY To prevent delayed-onset CINV, the use of dexamethasone is recommended; however, aprepitant or fosaprepitant may be added if patients are considered at significant risk. The granisetron transdermal patch (Sancuso, ProStrakan) is approved for use in chemotherapy regimens of up to 5 days duration.

Table 1. Treatment Recommendations for CINV Type of N/V

Recommended Therapy

Anticipatory N/V

• Psychological techniques • Alternative: benzodiazepines (alone or in combination with psychological techniques)

Acute-onset N/V with highly emetogenic chemotherapy

• 5-HT3–receptor antagonist, dexamethasone, and aprepitant or fosaprepitant

Acute-onset N/V with moderately emetogenic chemotherapy

• 5-HT3–receptor antagonist plus dexamethasone

Acute-onset N/V with low emetogenic chemotherapy

• Single agent such as a dopamine antagonist or a low-dose corticosteroid

Acute-onset N/V with minimally emetogenic chemotherapy

• No routine use of antiemetics unless patient has a history of N/V

• 5-HT3–receptor antagonist, dexamethasone, and aprepitant or fosaprepitant if ≥2 moderate-risk chemotherapeutic agents

Delayed-onset N/V with highly emetogenic • Dexamethasone and aprepitant chemotherapy Delayed-onset N/V with moderately emetogenic chemotherapy

• Oral dexamethasone (plus aprepitant if used for acute N/V) • Alternative: 5-HT3–receptor antagonist

CINV, chemotherapy-induced nausea and vomiting; 5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting

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Table 2. Treatment Recommendations for RINV Level of Radiation Emetogenicity

Recommended Therapy

Highly emetogenic

• 5-HT3–receptor antagonist plus dexamethasone

Moderately emetogenic irradiation of upper abdomen

• 5-HT3–receptor antagonist

Low emetogenic

• Rescue with a 5-HT3–receptor antagonist if patient experiences N/V • Prophylaxis with a 5-HT3–receptor antagonist before future radiation therapy

Minimally emetogenic

• Rescue with a dopamine antagonist or 5-HT3–receptor antagonist

5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting; RINV, radiation-induced nausea and vomiting

RINV HIGHLY EMETOGENIC RADIATION THERAPY To prevent RINV in patients treated with highly emetogenic radiation therapy, the use of a 5-HT3– receptor antagonist combined with dexamethasone is recommended.

MODERATELY EMETOGENIC RADIATION THERAPY For patients treated with moderately emetogenic radiation therapy to the upper abdomen, a 5-HT3– receptor antagonist is recommended.

MILDLY EMETOGENIC RADIATION THERAPY If a patient experiences nausea and vomiting after mildly emetogenic radiation therapy, routine prophylaxis is not recommended; however, rescue and subsequent prophylaxis with a 5-HT3–receptor antagonist is suggested.

MINIMALLY EMETOGENIC RADIATION THERAPY For patients who experience nausea and vomiting after minimally emetogenic radiation therapy, routine prophylaxis is not recommended, but rescue and subsequent prophylaxis with a dopamine antagonist or a 5-HT3–receptor antagonist is the standard of care.

Dosing of Antiemetic Agents The consensus is that there are no proven clinically relevant differences in the effectiveness of the available 5-HT3–receptor antagonists for preventing acute nausea and vomiting when they are given as recommended. The dosing guidelines for these agents are shown in Table 3. The recommended dosing of dexamethasone, aprepitant, and fosaprepitant is shown in Table 4. The dose of dexamethasone should be reduced by approximately 50% when it is used with aprepitant or fosaprepitant to avoid a drug interaction.5 There are several possible interactions with aprepitant and fosaprepitant. Since they are inhibitors of cytochrome P-450 (CYP) 3A4, they should not be

used concurrently with agents that are metabolized by CYP3A4 because this could cause elevated plasma concentrations of these drugs and potentially serious or life-threatening reactions.5 Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, etoposide, ifosfamide, imatinib (Gleevec, Novartis), irinotecan, paclitaxel, vinblastine, vincristine, and vinorelbine. Also, aprepitant and fosaprepitant have been shown to partially inhibit cyclophosphamide bioactivation and thiotepa metabolism. Coadministration of aprepitant or fosaprepitant with warfarin also may result in a clinically significant decrease in the international normalized ratio (INR).5 In patients receiving long-term warfarin therapy, the INR should be closely monitored for 2 weeks after initiation of the 3-day regimen of aprepitant or fosaprepitant with each chemotherapy cycle. In addition, the efficacy of hormonal contraceptives may be reduced during the 28 days after administration of the last dose of aprepitant or fosaprepitant.6,7 Alternative or backup methods of contraception should be used during treatment and for 1 month following the last dose of aprepitant or fosaprepitant.

Breakthrough Nausea and Vomiting When the primary antiemetic regimen fails to appropriately control nausea and vomiting, another agent with a different mechanism of action should be added. Phenothiazines, substituted benzamides, and butyrophenones have antidopaminergic and anticholinergic properties and are often effective when a 5-HT3–receptor antagonist has failed. Most chemotherapy agents, except for carboplatin and cyclophosphamide, generally cause an early release of serotonin, which is why 5-HT3–receptor antagonists have the greatest efficacy against acute-onset nausea and vomiting.8 Dopaminergic pathways and substance P may be more involved in delayed-onset nausea and vomiting. Although the butyrophenones are effective, the recent warning of QT prolongation and potential torsades de pointes with droperidol has I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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Individual Patient Risk Assessment • History of N/V • Age • Anxiety • History of motion sickness • Gender • Hydration status

Anticipatory N/V or high anxiety level

• Psychological techniques • ± Benzodiazepines

Chemotherapy

Single dose of 5-HT3 – receptor antagonist IV or PO + dexamethasone 10 mg IV + aprepitant 125 mg Highly emetogenic

Moderately emetogenic

Mildly emetogenic

Minimally emetogenic

Prophylactic prechemotherapy antiemetic regimen for acute-onset N/V

Single dose of 5-HT3 –receptor antagonist IV or PO + dexamethasone 8 mg IV + aprepitant 125 mg PO if ≥2 moderately emetogenic agents

Prophylactic postchemotherapy antiemetic regimen for chemotherapy associated with delayed-onset N/V

Dexamethasone 8 mg daily x 3-4 days + aprepitant 80 mg PO x 2 days

Dexamethasone 8 mg daily x 2-3 days + aprepitant 80 mg PO x 2 days if used for acute N/V

Dexamethasone 4-8 mg IV

Treatment of breakthrough N/V

None recommended unless patient has a history of N/V

Adjunctive therapy: benzodiazepines, cannabinoids

Second-line therapy: use agent of different class (eg, phenothiazine or butyrophenone)

Figure. Treatment algorithm for chemotherapy-induced nausea and vomiting. 5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting

required an electrocardiographic evaluation before its use.9 Standard doses of metoclopramide may be effective in combination but not alone.10 Thus, the phenothiazines often are used as primary agents for second-line therapy. Also approved for use as second-line therapy are the cannabinoids dronabinol (Marinol, Solvay) and nabilone (Cesamet, Valeant). These agents have complex effects on the central nervous system (CNS), and it is thought that the antiemetic effect is caused by an interaction with the cannabinoid receptors (CB1), which are present throughout the central and peripheral nervous system. Both of these agents were studied in the 1980s, before the availability of the 5-HT3–receptor antagonists. In randomized trials, both cannabinoids were more effective than prochlorperazine. In one study, the combination of dronabinol and prochlorperazine was more effective than either agent alone.11 A meta-analysis also concluded that the cannabinoids were more effective than many conventional antiemetics, including prochlorperazine and metoclopramide.12 Adverse effects, particularly related to the CNS, occurred significantly more often with cannabinoids. Some were considered potentially beneficial (sedation and euphoria), whereas others were considered harmful (dizziness and dysphoria). Withdrawals resulting from adverse effects also were more common

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with cannabinoids. In contrast to dronabinol, nabilone has a longer duration of action, less frequent dosing, and an apparent lack of P450 enzyme inhibition, which may make it more convenient to use.13 Adjunctive therapy with benzodiazepines also may be considered, although these agents have never been proven to be effective as single agents. They may be more effective when used as adjunctive anxiolytic agents. Antihistamines also are generally ineffective as single agents, but may provide value in combination with other antiemetic agents, especially in patients with a history of motion sickness.14 Some patients also may benefit from nonpharmacologic approaches such as relaxation techniques, biofeedback, acupressure, and music therapy.

New Directions In a Phase II trial, treatment with the atypical antipsychotic olanzapine (Zyprexa, Lilly) resulted in a 100% complete response rate (no emesis, no rescue) in the acute phase in 30 patients receiving cyclophosphamide, doxorubicin, and/or cisplatin.15 Olanzapine was begun 2 days before chemotherapy, was combined with granisetron and dexamethasone on day 1 of chemotherapy, and was added to dexamethasone on days 2 to 4 after chemotherapy. The complete response rate for the delayed period was 80%. Although this was a small

Table 3. Recommended Doses of 5-HT3–Receptor Antagonists for Acute Emesis Agent

Route

Dose

Dolasetron IV (Anzemet, Sanofi-Aventis/Organon) Oral

100 mg or 1.8 mg/kg

Granisetron

1 mg or 0.01 mg/kg

Oral

2 mg (or 1 mga)

(Sancuso, ProStrakan)

Transdermal patch

52 cm2 containing 34.3 mg

Ondansetron

8 mg or 0.15 mg/kg

Oral

16 mgb

0.25 mg

Oral

0.5 mg

Palonosetron (Aloxi, MGI Pharma)

100 mg

The 1-mg dose is preferred by some panelists; it has been evaluated in a small randomized study of moderately emetogenic chemotherapy and in a Phase II study of highly emetogenic chemotherapy.

Randomized studies have tested an 8-mg twice-daily schedule.

5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3)

study, the high response rates are encouraging and may be the result of olanzapine’s effects on multiple neurotransmitters, including dopamine at D1, D2, D3, and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at α1-adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors.15

Economics When agents within a class have similar efficacy, as with the 5-HT3–receptor antagonists, part of the decision of which agent to use involves cost. In December 2006, generic ondansetron became available, substantially decreasing the cost of this agent. When evaluating cost to the health care system and the patient portion of payment for these agents, this generic option must be considered. However, this should not change decisions about when 5-HT3–receptor antagonists should be administered or the dose. Based on the pharmacology of this agent, it does not mean that a higher dose or more days would be appropriate because of the reduced cost. It also does not mean that it is necessarily appropriate to use a 5-HT3–receptor antagonist in place of dexamethasone or dexamethasone plus aprepitant or fosaprepitant for delayed nausea and vomiting because there are few data evaluating the efficacy differences. Studies evaluating 5-HT3–receptor antagonists alone in the delayed phase have not shown significant overall efficacy.

in this review of the prevention and treatment of CINV and RINV. Because of individual variations in response, neurotransmitter release, and drug metabolism, the efficacy of a certain antiemetic may be decreased, or its toxicity increased. These guidelines should be considered general recommendations, but one must remember that treatment should always be individualized, especially when nausea and vomiting have not been completely controlled. The 5-HT3–receptor antagonists plus dexamethasone have significantly improved the control of acute nausea and vomiting. The control of delayed nausea and vomiting continues to be more difficult. Recent studies have shown that aprepitant or fosaprepitant may improve results with several types of chemotherapy regimens. However, there is still much work to be done to continue to improve outcomes for many patients receiving chemotherapy or radiation therapy.

References 1.

Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24(18):2932-2947, PMID: 167117289.

2. ESMO Guidelines Working Group, Herrstedt J. Chemotherapyinduced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol. 2007;18(suppl 2):ii83-ii85, PMID: 17491061.

Conclusion

3. Roila F, Hesketh PJ, Herrstedt J, et al. Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol. 2006;17(1):20-28. Recommendation and slides updated March 2008: http://www.mascc.org. Accessed November 10, 2009.

The recommendations in the major antiemetic consensus guidelines are very similar and are represented

4. Ettinger DS, Bierman PJ, Bradbury B, et al. Antiemesis. J Natl Compr Canc Netw. 2007;5(1):12-33, PMID: 17239323.

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Table 4. Recommended Dosing of Dexamethasone, Aprepitant, and Fosaprepitant Dexamethasonea

Type of Emesis

Dosing and Schedule

High risk

Acute

20 mg once

Delayed

8 mg/d for 3-4 d

Acute

8 mg once

Delayed

8 mg/d for 2-3 db

Low risk

Acute

4-8 mg once

Aprepitant/Fosaprepitant

Type of Emesis

Dosing and Schedule

Acute

125 mg orally or 115 mg IV, once

Delayed

80 mg/d orally, for 2 d

Moderate risk

The dose of dexamethasone should be reduced by 50% when it is given with aprepitant to avoid a drug interaction.

Many consensus panelists give the dosage as 4 mg twice daily.

5. Shadle CR, Lee Y, Majumdar AK, et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol. 2004;44(3):215-223, PMID: 14973304.

Dando TM, Perry CM. Aprepitant or fosaprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs. 2004;64(7):777-794.

6. Emend (aprepitant) [prescribing information]. Whitehouse Station, NJ: Merck & Company; April 2008.

De Wit R, Herrstedt J, Rapoport B, et al. Addition of the oral NK1 antagonist aprepitant or fosaprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol. 2003;21(22):4105-4111.

7. Emend (fosaprepitant dimeglumine) [prescribing information]. Whitehouse Station, NJ: Merck & Company; February 2009. 8. Minami M, Endo T, Hirafuji M, et al. Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity. Pharmacol Ther. 2003;99(2): 149-165, PMID: 12888110. 9. Keefe DL. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern? Oncologist. 2002;7(1):65-72, PMID: 11854548. 10. Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs. 1983;25(suppl 1):63-73, PMID: 6682376. 11. Slatkin NE. Cannabinoids in the treatment of chemotherapyinduced nausea and vomiting: beyond prevention of acute emesis. J Support Oncol. 2007;5(5 suppl 3):1-9, PMID: 17566383. 12. Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001;323(7303):16-21, PMID: 11440936. 13. Ware MA, Daeninck P, Maida V. A review of nabilone in the treatment of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manag. 2008:4(1):99-107, PMID: 18728826. 14. Morrow GR. Susceptibility to motion sickness and the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Cancer Treat Rep. 1984;68(9): 1177-1178, PMID: 6332674. 15. Navari RM, Einhorn LH, Loehrer PJ Sr. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Ca. 2007;15(11):1285-1291, PMID: 17375339.

Suggested Readings Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepitant or fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer. 2003;97(9):2290-2300.

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Eisenberg P, Figueroa-Vadillo J, Zamora R, et al; 99-04 Palonosetron Study Group. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a Phase III, single-dose trial versus dolasetron. Cancer. 2003;98(11):2473-2482. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol. 2007;18(2):233-240. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant or fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatinâ&#x20AC;&#x201D;the Aprepitant or fosaprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-4119. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol. 2000;18(19):3409-3422. Martin CG, Rubenstein EB, Elting LS, Kim YJ, Osoba D. Measuring chemotherapy-induced nausea and emesis. Cancer. 2003;98:645-655. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin-1 receptor antagonist aprepitant or fosaprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74(1):17-24. Mertens WC, Higby DJ, Brown D, et al. Improving the care of patients with regard to chemotherapy-induced nausea and emesis: the effect of feedback to clinicians on adherence to antiemetic prescribing guidelines. J Clin Oncol. 2003;21(7):1373-1378. Navari RM. Role of neurokinin-1 receptor antagonists in chemotherapy-induced emesis: summary of clinical trials. Cancer Invest. 2004;22(4):569-576. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist. 2003;8(2):187-198.

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration]. INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information]. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Adverse Reactions] Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Immediately and permanently discontinue Vectibix infusion in patients experiencing severe (grade 3 or 4) infusion reactions. Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to grade 2 within 1 month, permanently discontinue Vectibix. If dermatologic toxicity improves to grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Preparation and Administration: Do not administer Vectibix as an intravenous push or bolus. Preparation Prepare the solution for infusion, using aseptic technique, as follows: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix if discoloration is observed. Withdraw the necessary amount of Vectibix for a dose of 6 mg/kg. Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. Mix diluted solution by gentle inversion. Do not shake. Administration Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. Vectibix must be administered via infusion pump. – Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. – Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes. Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4). Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix [see Dosage and Administration]. Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Dermatologic Toxicity [see Boxed Warning, and Warnings and Precautions] Infusion Reactions [see Boxed Warning, and Warnings and Precautions] Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] Pulmonary Fibrosis [see Warnings and Precautions] Electrolyte Depletion/Monitoring [see Warnings and Precautions] Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in 5% of Patients With a Between-Group Difference of 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing experience: The following adverse reaction has been identified during post-approval use of panitumumab. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Angioedema DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17 -estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight). Animal Toxicology and/or Pharmacology: Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose. Reproductive and Developmental Toxicology: Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight). PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], Diarrhea and dehydration [see Warnings and Precautions], Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], Pregnancy or nursing [see Use in Specific Populations]. Advise patients of the need for: Periodic monitoring of electrolytes [see Warnings and Precautions], Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v8, 7/2009 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006-2009 Amgen Inc. All rights reserved.

Based on independent review of disease progression, a statistically significant prolongation in PFS was observed in patients receiving Vectibix® plus BSC vs those patients receiving BSC alone1,2 100%

90%

Kaplan-Meier Plot of PFS Time as Determined by the Independent Review Committee1,2

80%

Proportion Event Free

The first fully human anti-EGFR monoclonal antibody

70%

Treatment Group Vectibix® + BSC (n=231) BSC Alone (n=232)

P < 0.0001

60% 50% 40% 30% 20% 10% 0% 0

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 5

232 209 175 149 75 41 31 20 17 11

Infusion reactions

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.

Q2W dosing

INDICATION: Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following, fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations. Important Safety Information including Boxed WARNINGS:

Prolonged PFS

*Correlation with safety and efficacy is unknown

231 217 209 197 118 85 76 65 49 41 40 40 31 22 19 19 13 8 7

Weeks Subjects at risk: Vectibix® + BSC BSC Alone

Statistically significant prolongation in PFS time vs BSC alone1,2 The recommended dose of Vectibix® is 6 mg/kg administered over 60 minutes (for doses over 1000 mg infuse over 90 minutes) as an intravenous infusion every 14 days1 The use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1 ~1% incidence of severe infusion reactions reported1 - See Important Safety Information including Boxed WARNINGS for infusion reactions

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy, and appropriate treatment instituted, as needed. Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Dermatologic, mucosal, and ocular toxicities were also reported. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page. References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;13:1658-1664.

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