APRIL 2011 VOL 2 NO 2 by Value-Based Cancer Care

APRIL 2011 VOL 2 NO 2

www.ValueBasedCancerCare.com

Prominent Oncologist Applauds NCCN Expert Panel Considers Value, Utilization of Molecular First Conference of AVBCC Stakeholder Integration Crucial for Personalized Medicine Interview with Al B. Benson, III, MD, FACP Professor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Immediate Past President, ACCC; and Immediate Past Chair, Board of Directors, NCCN

n March 29-30, 2011, approximately 200 oncologists, payers, managed care executives, and drug manufacturers gathered in Philadelphia for the First Annual Conference of the Association for Value-Based Cancer Care. VBCC asked Dr Benson to share his thoughts on the conference and some of the issues it provoked.

Testing in Clinical Practice Will ultimately reduce costs, toxicities from inappropriate treatments By Audrey Andrews

Q: From your vantage point at the top of academic, clinical, and research expertise in oncology, did you find this conference of benefit? Did the meeting provide value to the variety of healthcare stakeholders attending it, including community oncologists, payers, and manufacturers? Dr Benson: Absolutely. There is a general concern in healthcare that instead of encouraging people to work together to discuss these very serious issues in healthcare delivery, there are efforts to force people to distance themselves, particularly from industry, and work in silos, which is not in the public’s interest. We need a very transparent process that allows people to understand these various associations but also to understand that solving so many complex healthcare issues will take everybody working together. The fact that we are having a forum with this conference, where clinicians and third-party carriers are discussing issues together, where the pharmaceutical industry and the diagnostic indus-

Hollywood, FL—The number of molecular tests to assess the potential efficacy of cancer therapies for an individual patient is rapidly increasing, but their value and validity in cancer care remain controversial. An expert panel at the 2011 National Comprehensive Cancer Network (NCCN) Annual Conference discussed how to regulate the tests done, the need for better data to determine their value and cost-effectiveness, as well as new approaches to optimal uses. Lee Newcomer, MD, MHA, Senior Vice President of Oncology Services at UnitedHealthcare, framed the discussion, noting that “evidence” for a good assay comprises 3 points:

Continued on page 16

Washington, DC—Oncologists must plan for and invest in future trends and expected growth using available evidence-based information, said Rebecca Booi, PhD, Director of Cancer Solutions at Sg2, during the 2011 Association of Community Cancer Centers 37th Annual National Meeting.

AVBCC Conference | March 29-30 | Philadelphia

• Analytic validity: Do you get the same result 99 times out of 100? • Clinical validity: Is what you’re measuring going to result in a valid change? Continued on page 8

Preparing for Future Trends in Cancer Care Impact of survivorship, technology on care delivery By Daniel Denvir The boom in cancer survivors, already near 12 million today, will be a crucial factor in reshaping the face of cancer care. The survivorship population is expected to grow by 80% over the next decade, as cancer treatments improve and the baby boomers age Continued on page 18

INSIDE

VALUE PROPOSITIONS

VBCC PERSPECTIVE

Value of vitamin D in cancer prevention . . . . . . . . . . . . . . . . . . . . . . . . . . 3

The potential of personalized medicine for targeted therapies . 28

MEETING COVERAGE

HEALTH POLICY

NCCN annual conference . . . . . . . . . 8 ACCC annual meeting . . . . . . . . . . . 17 Genitourinary cancers symposium . . . . . . . . . . . . . . . . . . . . . . 25 HOPA annual meeting . . . . . . . . . . . 38 Gastrointestinal cancers symposium . . . . . . . . . . . . . . . . . . . . . . 48

Implications of CMS’s decision on Provenge . . . . . . . . . . . 28 ODAC on the accelerated approvals process . . . . . . . . . . . . . . . 30 BEST PRACTICES

The value of EHRs for leading oncology networks . . . . . . . . . . . . . . 36

ÂŠ Centocor Ortho Biotech Products, L.P. 2011 2/11 08A11004B

FDA UPDATES FDA Approved First Generic Docetaxel The US Food and Drug Administration (FDA) approved docetaxel injection (Hospira)—the first generic formulation of Taxotere (sanofi-aventis). Generic docetaxel is already available in Europe and Australia. Docetaxel, an antineoplastic chemotherapy medication, is indicated for

the treatment of several cancers at different stages, including metastatic and adjuvant breast cancer; metastatic androgen-independent prostate cancer; advanced non–small-cell lung cancer; advanced gastric adenocarcinoma; and locally advanced squamous-cell carcinoma of the head and neck. Unlike the original brand-name drug, which requires a 2-step prepara-

tion method, the new generic formulation comes in a single-vial formulation. According to Thomas Moore, Hospira president, in addition to the potential cost-savings, another valuable feature of the generic formulation is its “differentiated delivery system, designed to enhance caregiver safety.” Docetaxel will be available in 20-mg, 80-mg, and 160-mg vials at the origi-

VALUE PROPOSITIONS IOM Questions Value of Vitamin D in Cancer Prevention

Academic Institutions Join Oncology Drug Development

Many reports have suggested the potential benefit of vitamin D in cancer prevention. Now the Institute of Medicine (IOM) has issued a statement (online, March 23, 2011, N Engl J Med) questioning the causality between vitamin D and cancer. Lead author JoAnn Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, said, “Given that the potential role of vitamin D in cancer prevention has been widely touted, many people were surprised that cancer-related considerations didn’t figure prominently” in the recent IOM report on vitamin D and overall health. A careful review of the “evidence regarding vitamin D’s role in preventing cancer, however, revealed that the research is inconsistent and doesn't establish a cause– effect relationship,” according to the IOM. It is important to remember that no large-scale randomized clinical trials have yet investigated this link, and therefore a negative conclusion regarding the potential link between vitamin D and cancer prevention is just as premature as a positive conclusion. It has taken researchers years to acknowledge the benefits of vitamin D for overall well-being. Large trials investigating the association between vitamin D and cancer are ongoing, but results will not be available for another 5 or 6 years.

A new spirit of collaboration between manufacturers and academic centers suggests the high value seen by all in pursuing research and development (R&D) in oncology.

New Assay for Tumor Stem Cells Potential Game Changer A new editorial published in the Journal of Clinical Oncology (Wicha MS, et al, March 21, 2011) highlights the potential benefits of a new assay for measuring circulating tumor cells (CTCs) in the bloodstream of patients with cancer. This assay uses genetic markers to identify cancer cells, including stem-like cells. Cancer stem cells are the cells with the “greatest invasive and metastatic capacity” within the tumor, according to the editorialists. The most widely used assay in the United States for identifying CTCs, CellSearch, has limited utility because of “low sensitivity and poor specificity,” Wicha and colleagues write. A report of a new investigational assay published in the same issue of the journal does “establish the highly reproducible analytic validity of this assay in patients with colorectal cancers,” say Wicha and colleagues. This assay, they add, “could have enormous utility for directing adjuvant therapy for patients with this disease.”

• Yale Medical School and Gilead Sciences. Gilead Sciences, which until now focused much of its efforts on drugs for HIV/AIDS, has recently announced it has joined the search for the Holy Grail in cancer therapies. According to a report in the Wall Street Journal (April 1, 2011), Gilead has contracted with Yale University School of Medicine to focus on new cancer drugs. Gilead will pay Yale Medical School $40 million to apply its research expertise in cancer and genomic medicine based in its Cancer Biology Institute to develop new oncolytics over a 4-year period. If successful, this effort could be extended to 10 years, to the tune of $100 million. The explosion in new targeted therapies for cancer that are currently in development (see article on colorectal cancer therapies, page 49, this issue) is clearly driving this new venture, which will make use of some of the best research and clinical expertise in the country to advance the future cancer therapies. • Nuclea Biotech and Boston Medical Center focus on diagnostics for prostate/breast cancer. A new promising partnership between biomarker pioneer Nuclea Biotechnologies and Boston Medical Center (BMC), one of Boston’s leading teaching hospitals, is a new collaborative effort to advance personalized medicine for prostate cancer. According to Drug Discovery News (2011[7]; www.drugdiscoverynews.com/index.php? newsarticle=4679), Nuclea will pay BMC almost $1.5 million in the next 3 years to support R&D for new genetic diagnostics and radiologic modalities for earlystage tumors. The value in this collaboration is the ready access each company brings to the tools and knowledge of each partner to enhance this research effort. “We would like to come up with our first diagnostic test within a year,” said Patrick Muraca, Nuclea’s president and CEO. “The new testing modality in gene protein expression, combined with radiologic testing tools, will help confirm the presence of cancers.”

nal 10-mg/mL concentration. (March 9, 2011)

Ipilimumab a Powerful New Targeted Drug for Advanced Melanoma Applying its priority review route, the FDA approved the biologic medication ipilimumab (Yervoy; BristolMyers Squibb) as a second-line therapy for the treatment of advanced melanoma. Ipilimumab is the first drug that has shown improved overall survival (OS) in late-stage disease, and is the first drug approved for this patient population in the past 13 years. This new targeted therapy represents a new class of drug, known as a targeted T-cell antibody. It works by blocking cytotoxic T-lymphocyte–associated antigen 4, which enhances antitumor T-cell response. In 2010, an estimated 68,130 new cases of melanoma were diagnosed in the United States, resulting in approximately 8700 deaths, according to the National Cancer Institute. Late-stage melanoma has very few treatment options, and none has so far shown improved OS. Ipilimumab “is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The pivotal study (study 020) was conducted in previously treated unresectable patients with stage III or stage IV melanoma. Patients receiving the combination of ipilimumab and a peptide vaccine had a median survival of 10 months compared with 6.4 months with the vaccine alone. Ongoing follow-up of patients who received ipilimumab shows that complete responses can continue for >6 years in some patients. However, only 10.9% of the patients receiving ipilimumab (N = 676) showed complete or partial response, as with other targeted therapies, which work on subsets of patients. A new study (study 024) has now shown that ipilimumab is also effective in previously untreated patients with metastatic melanoma. In this study, ipilimumab chemotherapy (dacarbazine) improved OS compared with chemotherapy alone. Ipilimumab is associated with severe adverse events, which may require immunosuppressive therapy with steroids. Because of the potential for life-threatening complications, patients receiving this drug may require a multidisciplinary team to manage them. The common adverse effects associated with ipilimumab include fatigue, Continued on page 4

VOL. 2

NO. 2

www.ValueBasedCancerCare.com

FROM THE LITERATURE National Projections: 27% Rise in Cost of Cancer Care in 2020 The constant change in the incidence of cancer, the rate of survival, and treatment practices have led investigators to estimate anew the cost of cancer care in the United States (which is currently based on 2003 estimates). In this new analysis (Mariotto AB, et al. J Natl Cancer Inst. 2011;103: 1-12), investigators used projections

based on phase of cancer care and tumor sites for 13 cancer types in men and 16 types in women between 2010 and 2020. The prevalence rate was based on Surveillance, Epidemiology, and End Results (SEER) program data. Net annual costs were estimated from recent Medicare-SEER claims through 2006. All costs were adjusted to 2010 dollars. Sensitivity analysis was used

to assess future trends of cancer rates and costs. Cancer survivorship numbers are 13.8 million in 2010 compared with 18.1 million in 2020; associated costs for cancer are $124.57 billion in 2010, $157.77 billion in 2020—a 27% increase in costs. The largest increases involve the continuing phase of care for prostate cancer (42%) and breast cancer in women (32%). If the costs

increase by 2% in the first year of cancer care and last year of life, overall 2020 cancer costs will total $173 billion, a 39% increase from 2010. The costs for the top 5 cancer types in 2010 were: • Female breast: $16.50 billion • Colorectal: $14.14 billion • Lymphoma: $12.14 billion • Lung: $12.12 billion • Prostate: $11.85 billion.

FDA UPDATES Ipilimumab...Continued from page 3

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe-to-fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. (March 25, 2011)

Act before febrile neutropenia strikes

Peginterferon Alfa-2b for Metastatic Melanoma after Definitive Surgical Resection

Potential consequences of febrile neutropenia may be serious and can impact patient care

The FDA approved peginterferon alfa-2b (Sylatron; Schering Corporation) for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy. The recommended dose and schedule for Sylatron is 6 µg/kg/week, subcutaneously for 8 doses, followed by 3 µg/kg/week subcutaneously. The maximum treatment period is 5 years. The approval was based on a single, 5-year trial, EORTC 18991, an openlabel, multicenter trial with 1256 patients. Patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes were randomized to peginterferon alfa-2b or to 5-year observation. The primary end point, relapse-free survival (RFS), was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. Based on 696 RFS events, an improvement in RFS for peginterferon alfa-2b– treated patients was observed. The estimated median RFS was 34.8 months with the active treatment and 25.5 months in the observation arm. After 525 deaths during the study, no difference in OS was seen between the 2 groups. The most common (>60%) grade 1-4 adverse reactions in the peginterferon alfa-2b group were fatigue, increased alanine transaminase, increased aspartate aminotransferase, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. A total of 33% of patients receiving therapy discontinued treatment because of adverse events. (March 29, 2011) ■

VALUE-BASED CANCER CARE

First- and every-cycle Neulasta® achieved: Q 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

April 2011

MC49047-A-1

04-10

www.neulasta.com

VOL. 2

NO. 2

FROM THE LITERATURE KRAS Mutation Predicts Treatment Outcomes of Anti-EGFR Therapies Mutation in the KRAS gene has been shown to prevent the benefit of antiepithelial growth factor receptor (EGFR) therapy in patients with colorectal cancer (CRC) in previous studies. Ongoing randomized clinical studies are now investigating whether KRAS testing can help predict survival outcomes in

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

patients with advanced CRC who are receiving cetuximab (Erbitux) or panitumumab (Vectibix) therapy. In a new meta-analysis (Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49), 45 publications were eligible for analysis, representing 24 nonoverlapping studies. Of these, 4 were reanalyses of randomized controlled trials of antiEGFR therapy compared with best supportive care or with chemotherapy

randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of 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 Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. 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 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following detail in other sections of the Brief Summary: factors: (1) seriousness of the reaction, (2) reported frequency • Splenic Rupture [See Warnings and Precautions] of the reaction, or (3) strength of causal relationship to Neulasta. • Acute Respiratory Distress Syndrome [See Warnings Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis • Use in Patients with Sickle Cell Disorders [See Warnings [see Warnings and Precautions] and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Potential for Tumor Growth Stimulatory Effects on Malignant including anaphylaxis, skin rash, and urticaria, Sweet’s Cells [See Warnings and Precautions] syndrome, generalized erythema and flushing [see Warnings The most common adverse reactions occurring in ≥ 5% of and Precautions] patients and with a between-group difference of ≥ 5% higher Respiratory, thoracic, and mediastinal disorder: ARDS in the pegfilgrastim arm in placebo controlled clinical trials [see Warnings and Precautions] are bone pain and pain in extremity. General disorders and administration site conditions: Clinical Trials Experience Injection site reactions Because clinical trials are conducted under widely varying Skin and subcutaneous tissue disorders: Cutaneous vasculitis conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical DRUG INTERACTIONS trials of another drug and may not reflect the rates observed in No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity clinical practice. Neulasta clinical trials safety data are based upon 932 patients of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider receiving Neulasta in seven randomized clinical trials. The these findings when interpreting bone-imaging results. population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and USE IN SPECIFIC POPULATIONS 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy tumors (n = 53) and lymphoma (n = 56) received Neulasta Pregnancy Category C after nonmyeloablative cytotoxic chemotherapy. Most patients There are no adequate and well-controlled studies in pregnant received a single 100 mcg/kg (n = 259) or a single 6 mg women. Pegfilgrastim was embryotoxic and increased pregnancy (n = 546) dose per chemotherapy cycle over 4 cycles. loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on The following adverse reaction data in Table 1 are from a

VOL. 2

NO. 2

alone, from which no significant benefit was found in overall survival (OS) or progression-free survival (PFS) in patients with KRAS mutations. The 22 studies with nonoverlapping populations showed a specificity of 0.49 (positive likelihood ratio, 7.35) and a sensitivity of 0.93 (negative likelihood ratio, 0.55). This meta-analysis of patients with CRC with or without the KRAS muta-

body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 12.0

MC45288-B

tion who were treated with anti-EGFR therapy shows that OS is almost 80% longer in those with wild-type KRAS. Furthermore, median PFS or time to progression was shorter in patients with KRAS-positive tumors than with the wild-type KRAS. This high positivity ratio suggests that KRAS mutations are a strong predictor of reduced survival, disease progression, and treatment failure. This study corroborates the warning on the US Food and Drug Administration (FDA) labeling that restricts the use of anti-EGFR antibody therapy to patients with CRC who test negative for KRAS mutations.

Denosumab a New Option for Preventing Skeletal-Related Events in Advanced Cancer In metastatic bone disease or myeloma, bisphosphonates such as zoledronic acid (Zometa) are used to delay or prevent skeletal-related events (SREs). Although zoledronic acid is effective in delaying the onset of SREs, it is administered intravenously and can lead to treatment-associated renal complications and acute-phase reactions. Results of a phase 3 randomized, double-blind, double-dummy study comparing the use of denosumab (Xgeva) with zoledronic acid showed that denosumab may be a more flexible option (Henry DH, et al. J Clin Oncol. 2011;29:1125-1132). A total of 1776 patients with solid tumors and bone metastases or with osteolytic lesions from myeloma were randomized to subcutaneous denosumab and an intravenous (IV) placebo or to IV zoledronic acid and a subcutaneous placebo. The primary end point was a noninferiority comparison of the 2 treatments based on the time to a first SRE (ie, pathologic fracture, radiotherapy or surgery, or spinal cord compression). At 34 months, denosumab was noninferior (trending toward significance) to zoledronic acid (hazard ratio, 0.84; P = .0007) in delaying the onset of a first SRE in patients with advanced cancer and bone metastasis or myeloma. The overall survival and disease progression rates were similar between the 2 drugs, as were those of most adverse events. Hypocalcemia occurred more often with denosumab; acute-phase SREs after the first dose, and adverse renal events occurred more often with zoledronic acid. The researchers concluded that in the treatment of bone metastasis, denosumab offers the convenience of subcutaneous administration, without monitoring for renal or acute-phase reactions. The FDA approved denosumab last year for the prevention of SREs in patients with metastatic cancer. ■

www.ValueBasedCancerCare.com

IN THIS ISSUE Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara Reiman lara@engagehc.com 732-992-1892 Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886 Phil Pawelko phil@greenhillhc.com 732-992-1887 Cristopher Pires cris@engagehc.com 732-992-1896 Senior Production Manager Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. BPA Worldwide membership applied for August 2010. Contact Information: For subscription and reprint information please contact: circulation@valuebasedcare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. Address all editorial correspondence to: editor@valuebasedcare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

NCCN CONFERENCE Value, Utilization of Molecular Testing Clinical Guidelines Updates More...

ACCC MEETING The New HITECH Rules for Medical Practices Debating the Role of Pathways, Guidelines More...

GENITOURINARY CANCERS SYMPOSIUM Abiraterone Acetate Improves Survival in Prostate Cancer PSA Not Needed More than 10 Years after Prostatectomy More...

GASTROINTESTINAL CANCERS SYMPOSIUM Novel Pathways for Colorectal Cancer Therapies Hypertension a Good Sign with Sunitinib More...

HEALTH POLICY Implications of CMS’s Coverage Decision on Provenge ODAC to Tighten Accelerated Approvals for Cancer Drugs More...

VBCC PERSPECTIVE The Promise of Personalized Medicine for Targeted Therapies

HOPA ANNUAL MEETING

CONTINUING EDUCATION

Making Oncolytics Worth the Cost Strategies to Cut Costs in Oncology Practice

VTE Prevention Strategies for Patients with Cancer

VBCC Editorial Board Al B. Benson III, MD FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Immediate Past President, ACCC Past Chair, NCCN Board of Director Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD ITA Partners Philadelphia, PA Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

VALUE-BASED CANCER CARE

April 2011

Section Editor

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT David Hom, MBA Solucia Farmington, CT Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL Ira Klein, MD, MBA Aetna Hartford, CT

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Foley Hoag Washington, DC Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Naimish Pandya, MD University of Maryland Baltimore, MD Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

VOL. 2

NO. 2

Oncogenic BRAF: A new potential therapeutic target EGFR

1,2

EGFR

RAS

BRAF MEK

ERK

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2: ~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6 In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com To contact your account manager for more information on BRAF visit: genentechmm.com References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

Demonstrating the Value of Innovation ÂŠ2011 Genentech, Inc., So. San Francisco, CA MCM0000269700 02/11

A Member of the Roche Group

NCCN ANNUAL CONFERENCE

NCCN Expert Panel Considers Value, Utilization of... • Clinical utility: Is there something you can do with the information? Regulatory Standards Lacking for Test Validity Panelists agreed that greater regulatory standards are needed for molecular tests. “One of the major problems we’re facing is the heterogeneity and variability of these tests,” noted Andrew C. von Eschenbach, MD, former Commissioner of the US Food and Drug Administration (FDA) and Director of the National Cancer Institute, and currently Senior Director for Strategic Initiatives at the Center for Health Transformation. “It’s going to get even more complex as we develop other markers in the area of proteomics and metabolomics. So we’re laying a foundation here, and it’s important that we get it right, because we’re going to have to build on it,” Dr von Eschenbach said. “Molecular tests are regulated by how they are marketed, not by claims for what the test can do. If a test is marketed as a kit, it is regulated by the FDA. If it tests for certain things—an example is the test that screens the blood supply—it is regulated by the FDA. The FDA would like to regulate on the basis of the claims being made around the test, but they have not stepped in to do that,” said Scott Gottlieb, MD, former FDA Deputy Commissioner and now a fellow at the American Enterprise Institute. “What has concerned the FDA is that regulation follows, not necessarily the complexity of the test or the claims being made around it, but how the test is being marketed,” Dr Gottlieb said. “So if a test is marketed as a kit, it has to be FDA-approved. If it is being performed as a laboratory service inside a CLIA [Clinical Laboratory Improvement Amendments] laboratory, it is regulated by CLIA and could escape FDA regulation.” Because of the variability in their performance and minimal regulation, the accuracy of current test results may be questionable, said panel moderator Clifford Goodman, PhD, of the Lewin Group. Dr Newcomer added that 30% of the results from the original trastuzumab registration trial were found to be inaccurate. “This means that 1 of 3 breast cancer patients in the community may be getting the wrong result.” That is, women with a falsepositive HER2 test result “would be getting a year’s worth of therapy that would not be helpful,” Dr Newcomer noted. Those with false-negative results “would be missing a year of very valuable therapy that could save her life.”

Nevertheless, the use of molecular testing in breast cancer has become routine. According to Dr Newcomer, in certain subsets of patients with breast cancer, 94% of the treatment decisions are made based on the risk score of the Oncotype DX molecular test.

“Determining how important the test result is to the clinical decision that needs to be made is best left to the clinical community.” —Scott Gottlieb, MD

Better regulatory oversight of the analytic validity of molecular testing would be expected to correct some of these failings and improve clinical confidence, the panel agreed. Dr von Eschenbach reiterated the need to ensure the consistency of the tests’ claims and results, regardless of where they are performed, as well as allowing the FDA to develop the infrastructure necessary “to bring order out of chaos.” Dr von Eschenbach stressed the “tremendous amount of resistance on the part of developers, because of the belief that if you placed these tests in the hands of the FDA for regulation, that—by its very nature—would undermine innovation, create significant barriers to progress….I don’t say that those concerns are not well-founded, but I do say that those concerns can easily or systematically be overcome.”

“We are aspiring to an era of personalized medicine, but we aren’t there yet.” —Michael Kolodziej, MD “We need to put it in the hands of the agency that has the scientific infrastructure to be able to make scientific decisions about these tests, as well as be able to judge their clinical utility,” Dr von Eschenbach argued. Dr Gottlieb also supports having the FDA, or CLIA, regulate analytic validity of testing. According to Dr Gottlieb, there is movement in this direction. Within the next 12 to 24 months, a new regulatory scheme will be applied to molecular

VALUE-BASED CANCER CARE

April 2011

testing based on work being done at the FDA and on Capitol Hill at this time. Nevertheless, “The keystone of the debate is whether or not a regulatory authority should be regulating the clinical validity and the clinical utility,” Dr Gottlieb said. “Determining how important the test result is to the clinical decision that needs to be made is best left to the clinical community.” Mark G. Kris, MD, Chief of the Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, agreed that this is best left to the research community. “It is our job as clinical researchers to provide the data that regulators and payers need to make decisions,” he said. Toward Personalized Medicine Dr Goodman asked, “How do we know that these molecular tests work?” Dr Kris, who specializes in treating lung cancer, has been a fervent advocate of molecular testing and has spearheaded much research on its clinical application. He noted 2 instances in which DNA-based testing is firmly driving treatment decisions—testing for the epidermal growth factor receptor (EGFR) in advanced lung cancer and for the KRAS gene in colorectal cancer. In these settings, genetic assays can clearly predict whether a certain targeted agent will be effective in a given patient. Patients with the KRAS mutation have virtually no chance of responding to the EGFR inhibitors cetuximab (Erbitux) or panitumumab (Vectibix), whereas there is a “decent chance” of tumor shrinkage with these drugs in patents lacking the mutation. In patients with lung cancer, there is a 70% response to treatment with the EGFR inhibitor gefitinib (Iressa) for those with EGFR mutations compared with just 1% in those without the mutation. “Molecular testing is now part of standard guidelines and labeling for these 2 drugs,” Dr Kris said. But Michael Kolodziej, MD, Chief of Oncology, St. Peter’s Hospital, Albany, NY, said he sees obstacles to utilizing even established molecular tests in his practice. Some tests do not lead to treatments that make a clear difference in patient survival; he experiences difficulties and delays in obtaining tissue specimens needed to perform the molecular tests. “We are aspiring to an era of personalized medicine, but we aren’t there yet,” he said. At Memorial Sloan-Kettering Cancer Center and a handful of other major cancer centers, oncologists have an easier time with testing. At SloanKettering, patients with non–small-

Continued from cover

cell lung cancer (NSCLC) routinely undergo a panel of genetic tests, Dr Kris reported, acknowledging that just 1 of the 8 tests in the multiplex assay is backed by phase 3 clinical trial evidence. Insufficient Evidence, Patient Education The concern that data supporting molecular and genetic testing are immature was echoed by the panel. “There is evidence, evidence with practical hurdle, and inadequate evidence. EGFR mutational analysis is evidence, but we will not order other tests without good evidence—New England Journal of Medicine level of evidence,” said Dr Kolodziej. Louis B. Jacques, MD, Director of the Coverage and Analysis Group, Centers for Medicare & Medicaid Services, agreed that clinicians and payers cannot always be certain a given test works. “What we mean by knowing a test works is the same thing that you mean when you look at your 13-yearold and you say, ‘You’re going to be a successful adult.’...The challenge for us is we are looking at this vast array of, say, 8000 adolescents and are being asked to prepay a Harvard education for all of them. And what we don’t know now, because they are adolescents and the evidence about them has not matured, is whether Harvard may be the wrong place for many of them.”

“However, while the United States is leading the world in terms of what molecular testing means for patient care and outcomes, we still don’t have enough information.” —Elizabeth Thompson Patient advocate Elizabeth Thompson, who is with the Susan G. Komen for the Cure organization, agreed. “Cancer treatment at NCCN institutions centers on a group of people looking at a wide variety of factors, and these tests are one part of the decision-making module,” she said. “However, while the United States is leading the world in terms of what molecular testing means for patient care and outcomes, we still don’t have enough information.” Continued on page 9

VOL. 2

NO. 2

NCCN ANNUAL CONFERENCE

NCCN 2011 Clinical Guidelines Updates By Audrey Andrews Hollywood, FL—Chairpersons of the various National Comprehensive Cancer Network (NCCN) tumor panels presented clinical practice updates at the recent 16th Annual Conference of the NCCN. Key updates, and relevant discussions, are highlighted.

Key Changes in Breast Cancer Recommendations Pivotal research in 2010 led to changes that are immediately applicable to clinical practice in breast cancer, said panel chair Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Palo Alto, CA. Pharmacotherapy Despite the recent controversy regarding the US Food and Drug Administration (FDA) recommendation to remove the metastatic breast

cancer indication for bevacizumab (Avastin), the NCCN affirmed the combination of bevacizumab and paclitaxel in its treatment guidelines. The panel members were not as confident in the use of bevacizumab with other approved chemotherapy agents. The NCCN decision was based on the argument that “if the data were compelling 2 years ago, they are compelling enough today,” Dr Carlson said. The panel, however, did add a footnote to the guidelines, acknowledging that the use of the drug does not improve overall survival (OS) and only “modestly improves time to progression and response rates.” Eribulin (Halaven), a cytotoxic agent, is now a “preferred” agent for women with previously treated metastatic breast cancer, based on the

2010 EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) trial, in which 762 patients were randomized to treatment by physicians’ choice or to eribulin. One-year OS was 53.9% for the eribulin arm versus 43.7% for the treatment by physicians’ choice arm, and median OS was 13.12 months versus 10.65 months, representing a 19% risk reduction with the new agent. The addition of denosumab (Xgeva) in this patient population to help prevent skeletal-related events was based on a study presented at the American Society of Clinical Oncology 2010 meeting (abstract 1024) showing 23% fewer skeletal-related events, versus zoledronic acid (Zometa), although OS and disease-free survival were similar to the control group.

Other Changes The panel also recommends that the metastatic breast cancer work-up include the determination of hormonal and HER2/neu status “if unknown, originally negative, or not overexpressed.” This was based on growing evidence showing discordance between primary and recurrent disease. “This recommendation is likely to get stronger as these data are formally published,” Dr Carlson added. Representing a significant departure from current clinical practice, the panel has given a thumbs-down to complete axillary lymph node dissection in women with clinically nodenegative T1-T2 tumors, and <3 involved sentinel lymph nodes who undergo surgery and radiation therapy. This change is based on the landContinued on page 10

NCCN Expert Panel Considers Value, Utilization of... Ms Thompson added that for many patients, these tests are “confusing and challenging.” Educated patients are aware of these tests and frequently request them, but still have trouble applying them to their specific situations. They often report that their Oncotype DX recurrence risk score is low, yet their oncologist still advocates chemotherapy. “Patients call us and say, ‘This is what the test said, but this is what my doctor is saying. What should I do?’ Generally, we refer people to a major medical center for a second opinion,” Ms Thompson said. Dr Newcomer, however, said his data show that 94% of oncologists follow the recommendations for a low-risk score. “At the end of the day,” Dr Kolodziej said, “I am a cautious optimist. There will prove to be value in some molecular testing, and it will prove to be predictive of response to a specific therapy.” Dr Gottlieb agreed, “If there were no value inherent in these tests, I don’t think they would exist.” Is There Value for the Dollar? Is the value of the result obtained with molecular testing worth the high cost of the average assay? This may be hard to determine. The price of testing varies tremendously. For example, EGFR mutation testing costs approximately $800 at Memorial SloanKettering, and this cost also covers testing for an additional 7 gene muta-

VOL. 2

NO. 2

“These tests are becoming mechanisms for saving money and improving outcomes for our patients. We need to make sure we have the mechanisms in place to make decisions about what is the right treatment, at the right dose, done for the right reason.” —Andrew C. von Eschenbach, MD tions found in NSCLC, Dr Kris noted. Other genetic tests, however, are considerably more expensive. “What Dr Kris does not see is the 180-genomic panel that I also get billed for on a routine lung cancer patient,” Dr Newcomer said. “Those tests are 98% unproven.” Dr Newcomer stressed that “a small set of genes can belong together; that makes perfect sense. But we have both ends of the spectrum—people who are being reasonable, and those who are expanding those panels dramatically with no evidence whatsoever. I worry that decisions will be made based on those other 180 tests and they won’t be evidence-based.” Moving forward, he said, “We need to be led by the first precept in medicine: first, do no harm….We are all desperately eager to make these genetic tests work, but we cannot get ahead of ourselves, or we will hurt patients in the interim. We need to organize to get the data. We need to

find out what works and doesn’t work, and patiently collect that before we eagerly accept or embrace all of this new technology.” Attempting to put the issue of cost into perspective, Dr Jacques reminded the audience that “everything about cancer is expensive,” including chemotherapy, hospitalization, and the treatment of serious adverse events. Other panelists suggested that the benefit will become clear in the longrun. “There is no question that both from a theoretic and an emerging practical perspective, these tests are a methodology for saving money in healthcare,” Dr von Eschenbach noted. The application of molecular testing will reduce unnecessary spending for insufficient or inappropriate therapy, he maintained. The actual cost of a genetic test, however, is just part of the economic discussion, the discussion made clear. Dr Newcomer revealed some surprising problems with regard to billing.

Continued from page 8

“The current system does not itemize the tests, and the coding system is antiquated,” he said. “It just says ‘genetic test,’ which doesn’t allow us to assess either the upfront costs or the downstream benefits that might result from this kind of testing.” Dr Newcomer and other third-party payers do not always know where these reimbursement dollars are going. “I have no idea what I am spending, or what I am actually getting, when we reimburse for genetic testing,” Dr Newcomer said. Dr Jacques agreed, “Anything short of clinical utility casts a giant pall of uncertainty over, frankly, whether I ought to be paying for this.” Dr Gottlieb also noted that logistics issues cited by the clinicians (getting the specimen from the pathology department to the laboratory performing the test) will also become moot, as more integrated entities become the norm. “Anatomical pathologists are consolidating themselves and also purchasing these molecular diagnostic companies,” he pointed out. This should smooth out the process. Dr von Eschenbach summarized the views expressed by the panel, stating, “These tests are becoming mechanisms for saving money and improving outcomes for our patients. We need to make sure we have the mechanisms in place to make decisions about what is the right treatment, at the right dose, done for the right reason.” ■

www.ValueBasedCancerCare.com

NCCN ANNUAL CONFERENCE

NCCN 2011 Clinical Guidelines Updates... mark American College of Surgeons Oncology Group Z0011 study (Giuliano AE, et al. JAMA. 2011;305:569-575), which found no difference in locoregional recurrences, disease-free survival or OS between patients who underwent complete dissection and those who had a sentinel lymph node dissection only.

“Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time.” —Robert W. Carlson, MD “The panel decided to add the recommendation to the main guidelines based on this single randomized trial,” Dr Carlson said. The recommendation is intended only for this well-defined subset of the patient population. Finally, citing discrepancies between major studies, the panel did not recommend that patients be tested for the CYP2D6 polymorphism, which has been implicated in resistance to tamoxifen. “The current NCCN guidelines are silent on this issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time,” he said.

Prostate Cancer Update The question of active surveillance or immediate treatment for a subset of men with prostate cancer was the focus of the updated guidelines for prostate cancer. James L. Mohler, MD, Roswell Park Cancer Institute, discussed the recommendation for more rigorous monitoring of men opting for active surveillance (or watchful waiting) and new treatment options for advanced prostate cancer. “The NCCN remains concerned about overdiagnosis and overtreatment of prostate cancer, as growing evidence suggests that overtreatment commits too many men to side effects that outweigh a very small risk of prostate cancer death,” Dr Mohler said. Active surveillance is a viable option for many men with very low risk or even low risk of progression. In 2010, the guidelines established the “very-low-risk” category, which incorporated the strictest criteria for clinically insignificant prostate cancer. This recommendation is for active surveillance as the sole initial treatment for

men meeting these criteria who have a life expectancy of >20 years. Men at low risk for prostate cancer and a life expectancy of <10 years should also be recommended for active surveillance, the guidelines state. The 2011 guidelines made active surveillance monitoring more rigorous for men in the very-low-risk category: with a life expectancy of <20 years, prostate-specific antigen (PSA) should be measured at least every 6 months, a prostate examination must be done at least every 12 months, and repeat biopsies should be considered as often as every 12 months. Dr Mohler noted conundrums related to active surveillance and PSA testing, including overtreatment rates, clinical risks associated with biopsies, and differing criteria for active surveillance and disease progression in large clinical series. All need to be taken into consideration in treatment decisions. “Ultimately, this decision must be based on careful individualized weighting of a number of factors, and is an option that needs to be thoroughly discussed,” Dr Mohler said. Pharmacotherapy A significant change was the addition of sipuleucel-T (Provenge) as an immunotherapy option for a subset of men with recurrent metastatic prostate cancer, based on an observed OS advantage. “The guidelines have been modified to include sipuleucel-T as a category 1 recommendation. It is appropriate as salvage treatment for patients with castration-recurrent cancer who have minimally symptomatic disease, a performance status of 0 or 1, and a life expectancy of at least 6 months,” Dr Mohler noted. The panel also voted to include cabazitaxel (Jevtana) as a new secondline option for men with castrationrecurrent metastatic disease who fail docetaxel (Taxotere), also based on observed OS advantage. Finally, denosumab was added as an alternative to zoledronic acid (Zometa) for the prevention of skeletal-related events. The choice of agent for bone protection, however, depends on the presence of comorbidities and whether the patient has been treated with zoledronic acid previously, he emphasized.

Non–Small-Cell Lung Cancer The use of epidermal growth factor receptor (EGFR) mutations and histologic subtype to tailor therapy are pivotal updates to the non–smallcell lung cancer (NSCLC) guidelines, said David S. Ettinger, MD, Sidney

VALUE-BASED CANCER CARE

April 2011

Continued from page 9

Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore. Molecular Diagnostic Testing The 2011 NCCN guidelines have changed the evaluation process for systemic therapy for recurrent or metastatic disease to first establish the histologic subtype and then perform EGFR testing based on that subtype. Treatment recommendations for advanced NSCLC should be tailored based on these determinations. “We are heading toward the era of mutation driving the therapy, and it’s extremely important for our patients,” said Dr Ettinger. Therefore, a major change is evident in the molecular diagnostics section. Updated information on EGFR and KRAS gene status, as well as a new addition on EML4-ALK is included. More than 60,000 new cases of NSCLC annually are estimated to be driven by these gene mutations, Dr Ettinger said. EGFR testing is now a category 1 recommendation for adenocarcinoma, large cell, and NSCLC not-otherwisespecified (NOS), but this is not recommended for squamous-cell carcinoma. Dr Ettinger emphasized the need to acquire tissue for genetic testing in NSCLC: “Histology matters, and NOS is unacceptable.” All patients who have adenocarcinoma should undergo studies for molecular mutations. Although there is yet no standard method for detecting EML4-ALK in NSCLC, polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization are being evaluated. Pharmacotherapy Bevacizumab plus a platinum doublet (for patients who received firstline erlotinib [Tarceva] and have adenocarcinoma) was added as a treatment option. Bevacizumab plus paclitaxel/carboplatin (Taxol/Paraplatin) may be an effective option for nonsquamous-cell tumors but not squamous-cell tumors. Bevacizumab is changing the landscape of treatment of stage IV disease, Dr Ettinger said. Crizotinib, an agent targeting EML4ALK, may change the prognosis of the 5% to 10% of patients with this mutation. A recent clinical trial of patients with EML4-ALK+ adenocarcinoma showed robust responses to this novel agent (Kwak EL, et al. N Engl J Med. 2010;363:1693-1703). Updated results of this study will be important.

Non-Hodgkin Lymphoma A new guideline for posttransplant

lymphoproliferative disease (PTLD) and the promotion to a category 1 recommendation for 2 therapies for follicular lymphoma took center stage in non-Hodgkin lymphoma. “PTLD has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation,” said Andrew D. Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center, NY. Understanding PTLD has helped to identify high-risk patients. “The single biggest risk factor for PTLD is the presence of an Epstein-Barr virus [EBV] mismatch between the recipient and the donor,” Dr Zelenetz said. “The time from organ transplant is critically important, with most of these lesions developing within the first year.”

“PTLD has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation.” —Andrew D. Zelenetz, MD, PhD The NCCN guidelines for PTLD recommend certain tests as either “essential” or “useful in selected cases.” Among the essential tests are histopathology, immunophenotyping, and the EBV-ISH assay. EBV viral load may be useful in selected cases. Depending on the PTLD subtype, recommended treatment options include the reduction of immunosuppression, which is effective in 23% to 64% of patients, and single-agent rituximab (Rituxan), particularly for early and polymorphic lesions, where responses may reach 90%. “I would reserve chemoimmunotherapy for patients in whom other simpler maneuvers have failed,” Dr Zelenetz said.

Category 1 for 2 Follicular Lymphoma Therapies Significant changes in follicular lymphoma are centered on the upgrading of 2 therapies from lower-level recommendations to category 1 (the highest ranking). This includes the combination of bendamustine (Treanda) and rituximab (B-R) for first-line treatment, and rituximab maintenance and radioimmunotherapy (90Y ibritumomab tiuxetan [Zevalin]) following firstremission treatment. In the 2009 pivotal trial comparing B-R plus standard therapy with CHOP (cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone [DeltaContinued on page 11

VOL. 2

NO. 2

NCCN ANNUAL CONFERENCE

NCCN 2011 Clinical Guidelines... sone]) plus rituximab (CHOP-R), B-R significantly improved progressionfree survival (PFS) and complete response rates versus CHOP-R, although there was no difference in OS. Radioimmunotherapy after chemotherapy and rituximab maintenance are now more strongly recommended based on an improvement in PFS following first-remission therapy, although no improvement was seen in OS. Observation is still an appropriate approach in the NCCN algorithm for the initial treatment of follicular lymphoma. “No maintenance strategy in [follicular lymphoma] has yet demonstrated a benefit in OS,” Dr Zelenetz said; therefore, delayed treatment remains a viable option. He emphasized the importance of individualized treatment for this patient population.

New First-Line Rx for Chronic Myelogenous Leukemia Second-generation tyrosine kinase inhibitors, now approved for first-line therapy for chronic myelogenous leukemia (CML), offer newly diagnosed patients more options and are now recommended by the NCCN, said Susan O’Brien, MD, University of Texas M. D. Anderson Cancer Center. The addition of nilotinib (Tasigna) and dasatinib (Sprycel) as first-line options in addition to imatinib (Gleevec) is a key update to the CML guidelines. In recent studies, dasatinib and nilotinib were associated with significantly improved response rates and reductions in accelerated or blast phase at 12 months. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, major molecular responses were achieved at 24 months by >60% of newly diagnosed patients treated with nilotinib versus 37% of patients receiving imatinib, and <2% of nilotinib-treated patients progressed to accelerated phase or blast crisis versus 4% to 6% with imatinib. “This is the most clinically relevant data in the short-term, because transformation heralds a very poor prognosis,” Dr O’Brien noted. Other studies reported at ASH reached similar conclusions. Dr O’Brien said the data show that the 2 newer agents are “almost identical” in improving short-term end points, although their impact on PFS and OS has not been established. With 3 approved front-line agents, oncologists can either start patients on a newer drug from the start or reserve the newer agents for salvage therapy, for which they have proved very effective. ■

VOL. 2

NO. 2

at-a-glance NCCN 2011 Guidelines Update Breast Cancer ➤ The new cytotoxic agent eribulin was added as an option for metastatic disease ➤ Denosumab was added as an option for preventing skeletalrelated events in patients with bone metastases ➤ Bevacizumab, in combination with paclitaxel, was reaffirmed as an option for metastatic disease ➤ Determination of hormonal status and HER2/neu status is recommended for patients with metastatic disease Chronic Myelogenous Leukemia ➤ Nilotinib and dasatinib were added as first-line treatment options, but their impact on PFS and OS has not been established Head and Neck Cancer ➤ Human papillomavirus is a growing concern in head and neck cancers, and testing for the virus was added as a recommendation in work-up ➤ New algorithm for mucosal melanoma; treatment should follow the guidelines for malignant melanoma Malignant Melanoma ➤ In defining clinical stage IB melanoma, mitotic index has replaced Clark level; Clark level is optional on the pathologist’s report ➤ The presence of any mitosis (mitotic rate ≥1 mm2) in a thin melanoma (≤1 mm) upstages the patient to stage IB and has implications for sentinel lymph node biopsy (SLNB) ➤ SLNB should be discussed and offered to patients with stage IA or II melanomas; the threshold for considering SLNB is a risk of recurrence of approximately 7% ➤ For follow-up of patients with stage IIA or lower melanoma, the updated guidelines place less emphasis on routine blood work and cross-sectional imaging Multiple Myeloma ➤ The regimen of bortezomib/cyclophosphamide/dexamethasone became a category 2A option for induction therapy in the transplant setting, and lenalidomide/bortezomib/ dexamethasone was listed as promising category 2B alternative

Continued from page 10

➤ Lenalidomide maintenance, which nearly doubles PFS, has been added as a new option after autologous stem-cell transplant ➤ Melphalan/prednisone/ lenalidomide and bortezomib/ dexamethasone became category 2A options in the nontransplant setting ➤ Cyclophosphamide/bortezomib/ dexamethasone and cyclophosphamide/lenalidomide/dexamethasone were added as category 2A salvage treatment option Non-Hodgkin’s Lymphoma ➤ A new guideline for PTLD ➤ Recommended treatment options for PTLD include reduction of immunosuppression, single-agent rituximab, and chemoimmunotherapy ➤ Category 1 recommended treatments for follicular lymphoma now include bendamustine/ rituximab for first-line treatment and rituximab maintenance and radioimmunotherapy for after firstremission treatment Non–Small-Cell Lung Cancer ➤ Testing for EGFR is now category 1 recommendation for adenocarcinoma, large-cell, and NSCLC nototherwise-specified, but is not recommended for squamous-cell carcinoma ➤ Mutational status—particularly EGFR, KRAS, and EML4-ALK— affects the choice of treatment options ➤ The use of surgery after induction therapy for patients with stage IIIA (N2) disease is debated; the benefit of surgery in this heterogeneic group remains unclear ➤ Patients with a single lymph node <3 cm can be considered for a multimodality approach that includes surgical resection Ovarian Cancer ➤ Women with borderline epithelial ovarian cancer of low malignant potential should be primarily managed surgically ➤ For women wishing to maintain fertility, surgery should be limited to unilateral salpingo-oophorectomy, and standard debulking surgery is recommended for those not concerned about fertility preservation ➤ Stage II, III, or IV epithelial ovarian cancer should have intraperitoneal chemotherapy first-line; updated recommendations include dose-

dense paclitaxel as a possible treatment option, although this may be more toxic ➤ The NCCN has decided to delay recommending the addition of bevacizumab to carboplatin/ paclitaxel up front; participation in clinical trials is encouraged ➤ Discussion of the pros and cons of monitoring CA-125 levels is recommended, based on data showing a lack of survival benefit when treatment for relapse was initiated on a rise in CA-125 ➤ Recommendations were added for the management of infusion drug reactions Prostate Cancer ➤ A new “very-low-risk” category incorporates very strict criteria for clinically insignificant prostate cancer ➤ Active surveillance is recommended as the sole initial treatment for men meeting the criteria for very-low-risk disease who have a life expectancy of >20 years ➤ More rigorous active surveillance monitoring for men in the verylow-risk category ➤ Active surveillance should be recommended for men with lowrisk prostate cancer and a life expectancy of <10 years ➤ Sipuleucel-T was added as an immunotherapy option for asymptomatic or minimally symptomatic castrationrecurrent metastatic disease in patients with ≥6 months’ life expectancy ➤ Cabazitaxel is a new secondline option for castration-recurrent metastatic disease after progression with docetaxel ➤ Denosumab is an alternative to zoledronic acid for the prevention of skeletal-related events Sarcoma ➤ The recommended management of the desmoid tumor subtype of sarcoma changed to reflect the recommendation to follow these patients carefully if their tumors are small and not located on the trunk and if surgery would lead to excessive morbidity ➤ Several changes in staging include the reclassifying of lymph nodes as stage III rather than stage IV disease

www.ValueBasedCancer.com

BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Important Safety Information for

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

insufficiency should avoid taking NSAIDs with short elimination halflives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatmentrelated hematologic and GI toxicities.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

ALIMTA (pemetrexed for injection) Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration. Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. The safety and effectiveness of ALIMTA in pediatric patients have not been established. Dose adjustments may be necessary in patients with hepatic insufficiency. Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence): The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6). For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

insideALIMTA.com

% E 9.6.=;.A.- /8; 273.,=287 # $& #) 8; ,8695.=. <*/.=B 95.*<. ,87<>5= =1. />55 ";.<,;2+270 7/8;6*=287

% ! $ &$

87<:>*68>< 87 $6*55 .55 >70 *7,.; C 86+27*=287 @2=1 2<95*=27 & 3= 38.3-+>/. 38 -97,38+>398 A3>2 -3=:6+>38 >2/<+:C 09< >2/ 383>3+6 ></+>7/8> 90 :+>3/8>= A3>2 69-+66C +.@+8-/. 9< 7/>+=>+>3- 898=;?+79?= 898 =7+66 -/66 6?81 -+8-/<

262=*=287< 8/ &<. & 3= 89> 38.3-+>/. 09< >2/ ></+>7/8> 90 :+>3/8>= A3>2 =;?+79?= -/66 898 =7+66 -/66 6?81 -+8-/< .## ('*'! ( /0"'#. '* /&# $0(( -#.!-' '*% *$+-) /'+* !$ $%# % ! 86+27*=287 &<. @2=1 2<95*=27 !98=;?+79?= !98 %7+66 /66 ?81 +8-/< &2/ </-977/8./. .9=/ 90 & 3= 71 7 +.7383=>/</. += +8 38><+@/89?= 380?=398 9@/< 738?>/= 98 +C 90 /+-2 .+C -C-6/ &2/ </-977/8./. .9=/ 90 -3=:6+>38 3= 71 7 380?=/. 9@/< 29?<= ,/1388381 +::<9B37+>/6C 738?>/= +0>/< >2/ /8. 90 & +.7383=><+>398 #+>3/8>= =29?6. </-/3@/ +::<9:<3+>/ 2C.<+>398 :<39< >9 +8. 9< +0>/< </-/3@381 -3=:6+>38 %// -3=:6+>38 :+-5+1/ 38=/<> 09< 79</ 3809<7+>398 ";.6.-2,*=287 #.026.7 (3>+738 %?::6/7/8>+>398 &9 </.?-/ >9B3-3>C :+>3/8>= ></+>/. A3>2 & 7?=> ,/ 38=><?->/. >9 >+5/ + 69A .9=/ 9<+6 0963- +-3. :</:+<+>398 9< 7?6>3@3>+738 A3>2 0963- +-3. 98 + .+36C ,+=3= > 6/+=> .+36C .9=/= 90 0963- +-3. 7?=> ,/ >+5/8 .?<381 >2/ .+C :/<39. :</-/.381 >2/ H<=> .9=/ 90 & +8. .9=381 =29?6. -98>38?/ .?<381 >2/ 0?66 -9?<=/ 90 >2/<+:C +8. 09< .+C= +0>/< >2/ 6+=> .9=/ 90 & #+>3/8>= 7?=> +6=9 </-/3@/ 98/ 38><+7?=-?6+< 384/->398 90 @3>+738 .?<381 >2/ A//5 :</-/.381 >2/ H<=> .9=/ 90 & +8. /@/<C -C-6/= >2/</+0>/< %?,=/;?/8> @3>+738 384/->398= 7+C ,/ 13@/8 >2/ =+7/ .+C += & 8 -6383-+6 ><3+6= >2/ .9=/ 90 0963- +-3. =>?.3/. <+81/. 0<97 >9 7-1 +8. >2/ .9=/ 90 @3>+738 A+= 7-1 &2/ 79=> -977986C ?=/. .9=/ 90 9<+6 0963- +-3. 38 -6383-+6 ><3+6= A+= 7-1 .## -*'*%. *" -#! 0/'+*. 9<>3-9=>/<93. %538 <+=2 2+= ,//8 </:9<>/. 79</ 0</;?/8>6C 38 :+>3/8>= 89> :</></+>/. A3>2 + -9<>3-9=>/<93. #</></+>7/8> A3>2 ./B+7/>2+=98/ 9< /;?3@+6/8> </.?-/= >2/ 38-3./8-/ +8. =/@/<3>C 90 -?>+8/9?= </+->398 8 -6383-+6 ><3+6= ./B+7/>2+=98/ 71 A+= 13@/8 ,C 79?>2 >A3-/ .+36C >2/ .+C ,/09</ >2/ .+C 90 +8. >2/ .+C +0>/< & +.7383=><+>398 .## -*'*%. *" -#! 0/'+*. *+8;*=8;B 872=8;270 *7- 8<. #.->,=287 2<,87=27>*=287 #.,866.7-*=287< 983>9<381 97:6/>/ ,699. -/66 -9?8>= 38-6?.381 :6+>/6/> -9?8>= =29?6. ,/ :/<09<7/. 98 +66 :+>3/8>= </-/3@381 & #+>3/8>= =29?6. ,/ 7983>9</. 09< 8+.3< +8. </-9@/<C A23-2 A/</ >/=>/. 38 >2/ -6383-+6 =>?.C ,/09</ /+-2 .9=/ +8. 98 .+C= +8. 90 /+-2 -C-6/ #+>3/8>= =29?6. 89> ,/138 + 8/A -C-6/ 90 ></+>7/8> ?86/== >2/ ! 3= â&#x2030;¥ -/66= 77 >2/ :6+>/6/> -9?8> 3= â&#x2030;¥ -/66= 77 +8. -</+>3838/ -6/+<+8-/ 3= â&#x2030;¥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â&#x2030;¥ 77

-3=:6+>38 !+.3< :6+>/6/>= 77 A3>29?> ,6//.381 </1+<.6/== 90 8+.3< ! 90 :</@39?= .9=/ :/7/></B/. +8. -3=:6+>38 !+.3< :6+>/6/>= 77 A3>2 ,6//.381+ </1+<.6/== 90 8+.3< ! 90 :</@39?= .9=/ :/7/></B/. +8. -3=:6+>38 + &2/=/ -<3>/<3+ 7//> >2/ & @/<=398 ! ./H83>398 90 â&#x2030;¥ & <+./ ,6//.381 0 :+>3/8>= ./@/69: 8982/7+>96913- >9B3-3>3/= /B-6?.381 8/?<9>9B3-3>C â&#x2030;¥ <+./ ></+>7/8> =29?6. ,/ A3>22/6. ?8>36 </=96?>398 >9 6/== >2+8 9< /;?+6 >9 >2/ :+>3/8>G= :</ >2/<+:C @+6?/ &</+>7/8> =29?6. ,/ </=?7/. +--9<.381 >9 1?3./638/= 38 &+,6/ %*+5. 8<. #.->,=287 /8; % *7- 2<95*=27 C 871.6*=85802, %8A2,2=2.<* + 8<. 8/ % 60 6 8<. 8/ 2<95*=27 60 6 8C <+./ 9< >9B3-3>3/= /B-/:> 7?-9=3>3= 90 :</@39?= .9=/ 90 :</@39?= .9=/ 8C .3+<<2/+ </;?3<381 29=:3>+63D+>398 90 :</@39?= .9=/ 90 :</@39?= .9=/ 3<</=:/->3@/ 90 <+./ 9< <+./ 9< .3+<<2/+ <+./ 9< 7?-9=3>3= 90 :</@39?= .9=/

90 :</@39?= .9=/ + ! 97798 &9B3-3>C <3>/<3+ & , B-6?.381 8/?<9>9B3-3>C .## &+,6/ 8 >2/ /@/8> 90 8/?<9>9B3-3>C >2/ </-977/8./. .9=/ +.4?=>7/8>= 09< & +8. -3=:6+>38 +</ ./=-<3,/. 38 &+,6/ #+>3/8>= =29?6. .3=-98>38?/ >2/<+:C 30 <+./ 9< 8/?<9>9B3-3>C 3= /B:/<3/8-/. %*+5. 8<. #.->,=287 /8; % <2705. *0.7= 8; 27 ,86+27*=287 *7- 2<95*=27 C .>;8=8A2,2=B % ;*-. 8<. 8/ % 60 6 8<. 8/ 2<95*=27 60 6

90 :</@39?= .9=/

90 :</@39?= .9=/ 90 :</@39?= .9=/ 3=-98>38?+>398 $/-977/8.+>398 & >2/<+:C =29?6. ,/ .3=-98>38?/. 30 + :+>3/8> /B:/<3/8-/= +8C 2/7+>96913- 9< 8982/7+>96913- <+./ 9< >9B3-3>C +0>/< .9=/ </.?->398= 9< 377/.3+>/6C 30 <+./ 9< 8/?<9>9B3-3>C 3= 9,=/<@/. $/8+66C 7:+3</. #+>3/8>= 8 -6383-+6 =>?.3/= :+>3/8>= A3>2 -</+>3838/ -6/+<+8-/ â&#x2030;¥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â&#x2030;¥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â&#x2030;¥ -/66= 77 >2/ :6+>/6/> -9?8> 3= â&#x2030;¥ -/66= 77 +8. -</+>3838/ -6/+<+8-/ 3= â&#x2030;¥ 7 738 .## +. %# *" ")'*'./- /'+* ";.07*7,B *=.08;B +=/. 98 3>= 7/-2+83=7 90 +->398 & -+8 -+?=/ 0/>+6 2+<7 A2/8 +.7383=>/</. >9 + :</18+8> A97+8 #/7/></B/. +.7383=>/</. 38><+:/<3>98/+66C >9 73-/ .?<381 9<1+891/8/=3= A+= /7,<C9>9B3- 0/>9>9B3- +8. >/<+>91/83- 38 73-/ +> 1</+>/< >2+8

<. >2/ </-977/8./. 2?7+8 .9=/ 0 & 3= ?=/. .?<381 :</18+8-C 9< 30 >2/ :+>3/8> ,/-97/= :</18+8> A236/ >+5381 >23= .<?1 >2/ :+>3/8> =29?6. ,/ +::<3=/. 90 >2/ :9>/8>3+6 2+D+<. >9 >2/ 0/>?= )97/8 90 -236.,/+<381 :9>/8>3+6 =29?6. ,/ +.@3=/. >9 +@93. ,/-97381 :</18+8> )97/8 =29?6. ,/ +.@3=/. >9 ?=/ /00/->3@/ -98><+-/:>3@/ 7/+=?</= >9 :</@/8> :</18+8-C .?<381 ></+>7/8> A3>2 & .## .# '* ,#!'3! +,0( /'+*. %12;- $9*,. 5>2&2/ /00/-> 90 >23<. =:+-/ I?3. =?-2 += :6/?<+6 /00?=398 +8. +=-3>/= 98 & 3= ?8589A8 8 :+>3/8>= A3>2 -6383-+66C =3183H-+8> >23<. =:+-/ I?3. -98=3./<+>398 =29?6. ,/ 13@/8 >9 .<+38381 >2/ /00?=398 :<39< >9 & +.7383=><+>398 ' #$ # % ! $ 5272,*5 %;2*5< A9.;2.7,. /-+?=/ -6383-+6 ><3+6= +</ -98.?->/. ?8./< A3./6C @+<C381 -98.3>398= +.@/<=/ </+->398= <+>/= -+889> ,/ .3</->6C -97:+</. >9 <+>/= 38 9>2/< -6383-+6 ><3+6= +8. 7+C 89> </I/-> >2/ <+>/= 9,=/<@/. 38 -6383-+6 :<+->3-/ 8 -6383-+6 ><3+6= >2/ 79=> -97798 +.@/<=/ </+->398= 38-3./8-/ â&#x2030;¥ A/</ 0+>31?/ 8+?=/+ +8. +89</B3+ ..3>398+6 -97798 +.@/<=/ </+->398= 38-3./8-/ â&#x2030;¥ 38-6?./. @973>381 8/?><9:/83+ 6/?59:/83+ +8/73+ =>97+>3>3= :2+<C813>3= >2<97,9-C>9:/83+ +8. -98=>3:+>398 !98 %7+66 /66 ?81 +8-/< !% F 97,38+>398 A3>2 3=:6+>38 &+,6/ :<9@3./= >2/ 0</;?/8-C +8. =/@/<3>C 90 +.@/<=/ </+->398= >2+> 2+@/ ,//8 </:9<>/. 38 90 :+>3/8>= A3>2 !% A29 A/</ <+8.973D/. >9 =>?.C +8. </-/3@/. & :6?= -3=:6+>38 +8. :+>3/8>= A3>2 !% A29 A/</ <+8.973D/. >9 =>?.C +8. </-/3@/. 1/7-3>+,38/ :6?= -3=:6+>38 66 :+>3/8>= </-/3@/. =>?.C >2/<+:C += 383>3+6 ></+>7/8> 09< 69-+66C +.@+8-/. 9< 7/>+=>+>3- !% +8. :+>3/8>= 38 ,9>2 ></+>7/8> 1<9?:= A/</ 0?66C =?::6/7/8>/. A3>2 0963- +-3. +8. @3>+738 %*+5. -?.;<. #.*,=287< 27 >55B $>995.6.7=.- "*=2.7=< #.,.2?270 % 95>< 2<95*=27 27 $ * % ,2<95*=27 .6,2=*+27. ,2<95*=27 #.*,=287+ 55 ;*-.< ;*-. 55 ;*-.< ;*-. %8A2,2=B %8A2,2=B %8A2,2=B %8A2,2=B 55 -?.;<. #.*,=287<

*+8;*=8;B .6*=85802,

8/73+

!/?><9:/83+

/?59:/83+

&2<97,9-C>9:/83+ #.7*5 </+>3838/ /6/@+>398

5272,*5 87<=2=>=287*5 $B69=86< +>31?/

*<=;827=.<=27*5

!+?=/+

(973>381

89</B3+

98=>3:+>398

%>97+>3>3= #2+<C813>3=

3+<<2/+ C=:/:=3+ /+<>,?<8 .>;8580B !/?<9:+>2C =/8=9<C

&+=>/ .3=>?<,+8-/ .;6*=8580B $427 69:/-3+

$+=2 /=;?+7+>398

+ 9< >2/ :?<:9=/ 90 >23= >+,6/ + -?> 900 90 A+= ?=/. 09< 38-6?=398 90 +66 /@/8>= A2/</ >2/ </:9<>/< -98=3./</. + :9==3,6/ </6+>398=23: >9 & , $/0/< >9 ! & <3>/<3+ @/<=398 09< /+-2 <+./ 90 >9B3-3>C --9<.381 >9 ! & <3>/<3+ @/<=398 >23= +.@/<=/ /@/8> >/<7 =29?6. 986C ,/ </:9<>/. += <+./ 9< !9 -6383-+66C </6/@+8> .300/</8-/= 38 +.@/<=/ </+->398= A/</ =//8 38 :+>3/8>= ,+=/. 98 23=>9691C 8 +..3>398 >9 >2/ 69A/< 38-3./8-/ 90 2/7+>96913- >9B3-3>C 98 >2/ & +8. -3=:6+>38 +<7 ?=/ 90 ><+8=0?=398= $ +8. :6+>/6/> +8. 2/7+>9:93/>3- 1<9A>2 0+->9<= A+= 69A/< 38 >2/ & +8. -3=:6+>38 +<7 -97:+</. >9 >2/ 1/7-3>+,38/ +8. -3=:6+>38 +<7 &2/ 09669A381 +..3>398+6 +.@/<=/ </+->398= A/</ 9,=/<@/. 38 :+>3/8>= A3>2 898 =7+66 -/66 6?81 -+8-/< <+8.976C +==318/. >9 </-/3@/ & :6?= -3=:6+>38 7,2-.7,. =8 +"2 . &+(# F 0/,<36/ 8/?><9:/83+ 380/->398 :C</B3+ #*#- ( '.+-"#-. F ./2C.<+>398 #/ +('.) *" 0/-'/'+* F 38-</+=/. %& 38-</+=/. & #* ( F -</+>3838/ -6/+<+8-/ ./-</+=/ </8+6 0+36?</ ,#!' ( #*.#. F -984?8->3@3>3= 7,2-.7,. .<< =1*7 -"'+1 .!0( - F +<<2C>273+ #*#- ( '.+-"#-. F -2/=> :+38 #/ +('.) *" 0/-'/'+* F 38-</+=/. & #0-+(+%2 F 79>9< 8/?<9:+>2C --2=287*5 5272,*5 %;2*5< A9.;2.7,. -<9== -6383-+6 ><3+6= =/:=3= A23-2 38 =97/ -+=/= A+= 0+>+6 9--?<</. 38 +::<9B37+>/6C 90 :+>3/8>= "8<= *;4.=270 A9.;2.7,. &2/ 09669A381 +.@/<=/ </+->398= 2+@/ ,//8 3./8>3H/. .?<381 :9=> +::<9@+6 ?=/ 90 & /-+?=/ >2/=/ & E :/7/></B/. 09< 384/->398 #( #

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â&#x2030;¥ 8 849 ,@?4:9 >3:@7/ -0 @>0/ B309 ,/8494>?0=492 4-@;=:109 .:9.@==09?7D B4?3 !' ?: ;,?409?> B4?3 847/ ?: 8:/0=,?0 =09,7 49>@1I.409.D .=0,?49490 .70,=,9.0 1=:8 ?: 8 849 + %"'" % ! *& (%( . "' ,! -%% * + *" "' ' (*& ,"(' #?30= "& > $,?409?> B4?3 847/ ?: 8:/0=,?0 =09,7 49>@1I.409.D >3:@7/ ,A:4/ ?,6492 "& > B4?3 >3:=? 074849,?4:9 3,71 74A0> 1:= , ;0=4:/ :1 /,D> -01:=0 ?30 /,D :1 ,9/ /,D> 1:77:B492 ,/8494>?=,?4:9 :1 !' 9 ?30 ,->09.0 :1 /,?, =02,=/492 ;:?09?4,7 49?0=,.?4:9 -0?B009 !' ,9/ "& > B4?3 7:920= 3,71 74A0> ,77 ;,?409?> ?,6492 ?30>0 "& > >3:@7/ 49?0==@;? /:>492 1:= ,? 70,>? /,D> -01:=0 ?30 /,D :1 ,9/ /,D> 1:77:B492 !' ,/8494>?=,?4:9 1 .:9.:84?,9? ,/8494>?=,?4:9 :1 ,9 "& 4> 90.0>>,=D ;,?409?> >3:@7/ -0 8:94?:=0/ .7:>07D 1:= ?:C4.4?D 0>;0.4,77D 8D07:>@;;=0>>4:9 =09,7 ,9/ 2,>?=:49?0>?49,7 ?:C4.4?D *3-4262:.( 47,5 !' 4> ;=48,=47D 074849,?0/ @9.3,920/ =09,77D ,> , =0>@7? :1 27:80=@7,= I7?=,?4:9 ,9/ ?@-@7,= >0.=0?4:9 :9.:84?,9? ,/8494>?=,?4:9 :1 90;3=:?:C4. /=@2> .:@7/ =0>@7? 49 /07,D0/ .70,=,9.0 :1 !' :9.:84?,9? ,/8494>?=,?4:9 :1 >@->?,9.0> ?3,? ,=0 ,7>: ?@-@7,=7D >0.=0?0/ 0 2 ;=:-090.4/ .:@7/ ;:?09?4,77D =0>@7? 49 /07,D0/ .70,=,9.0 :1 !' #! ! # " ! 4*,1'1(; * ,( '" ,+ $=029,9.D ,?02:=D + *'"' + ' * -,"('+ ,>0/ :9 4?> 80.3,94>8 :1 ,.?4:9 !' .,9 .,@>0 10?,7 3,=8 B309 ,/8494>?0=0/ ?: , ;=029,9? B:8,9 '30=0 ,=0 9: ,/0<@,?0 ,9/ B077 .:9?=:770/ >?@/40> :1 !' 49 ;=029,9? B:809 $080?=0C0/ B,> 08-=D:?:C4. 10?:?:C4. ,9/ ?0=,?:2094. 49 84.0 9 84.0 =0;0,?0/ 49?=,;0=4?:90,7 /:>0> :1 ;080?=0C0/ B309 24A09 /@=492 :=2,9:2090>4> .,@>0/ 10?,7 8,71:=8,?4:9> 49.:8;70?0 :>>4I.,?4:9 :1 ?,7@> ,9/ >6@77 -:90 ,-:@?

=/ ?30 =0.:8809/0/ 49?=,A09:@> 3@8,9 /:>0 :9 , 82 8 -,>4> ,9/ .701? ;,7,?0

=/ ?30 =0.:8809/0/ 49?=,A09:@> 3@8,9 /:>0 :9 , 82 8 -,>4> 8-=D:?:C4.4?D B,> .3,=,.?0=4E0/ -D 49.=0,>0/ 08-=D: 10?,7 /0,?3> ,9/ =0/@.0/ 74??0= >4E0> 1 !' 4> @>0/ /@=492 ;=029,9.D := 41 ?30 ;,?409? -0.:80> ;=029,9? B3470 ?,6492 ?34> /=@2 ?30 ;,?409? >3:@7/ -0 ,;;=4>0/ :1 ?30 ;:?09?4,7 3,E,=/ ?: ?30 10?@> *:809 :1 .347/-0,=492 ;:?09?4,7 >3:@7/ -0 ,/A4>0/ ?: @>0 0110.?4A0 .:9?=,.0;?4A0 80,>@=0> ?: ;=0A09? ;=029,9.D /@=492 ?30 ?=0,?809? B4?3 !' 745.1, 26-*45 ? 4> 9:? 69:B9 B30?30= !' := 4?> 80?,-:74?0> ,=0 0C.=0?0/ 49 3@8,9 8476 0.,@>0 8,9D /=@2> ,=0 0C.=0?0/ 49 3@8,9 8476 ,9/ -0.,@>0 :1 ?30 ;:?09?4,7 1:= >0=4:@> ,/A0=>0 =0,.?4:9> 49 9@=>492 491,9?> 1=:8 !' , /0.4>4:9 >3:@7/ -0 8,/0 ?: /4>.:9?49@0 9@=>492 := /4>.:9?49@0 ?30 /=@2 ?,6492 49?: ,..:@9? ?30 48;:=?,9.0 :1 ?30 /=@2 1:= ?30 8:?30= *).'64.( #5* '30 >,10?D ,9/ 0110.?4A090>> :1 !' 49 ;0/4,?=4. ;,?409?> 3,A0 9:? -009 0>?,-74>30/ *4.'64.( #5* !' 4> 69:B9 ?: -0 >@->?,9?4,77D 0C.=0?0/ -D ?30 64/90D ,9/ ?30 =4>6 :1 ,/A0=>0 =0,.?4:9> ?: ?34> /=@2 8,D -0 2=0,?0= 49 ;,?409?> B4?3 48;,4=0/ =09,7 1@9.?4:9 0.,@>0 07/0=7D ;,?409?> ,=0 8:=0 74607D ?: 3,A0 /0.=0,>0/ =09,7 1@9.?4:9 .,=0 >3:@7/ -0 ?,609 49 /:>0 >070.?4:9 %09,7 1@9.?4:9 8:94?:=492 4> =0.:8809/0/ B4?3 ,/8494>?=,?4:9 :1 !' ": /:>0 =0/@.?4:9> :?30= ?3,9 ?3:>0 =0.:8809/0/ 1:= ,77 ;,?409?> ,=0 90.0>>,=D 1:= ;,?409?> D0,=> :1 ,20 := :7/0= + (+ ' &"'"+,* ,"(' 9 ?30 494?4,7 ?=0,?809? 9:9 >8,77 .077 7@92 .,9.0= .7494.,7 ?=4,7 :1 ;,?409?> ?=0,?0/ B4?3 !' ;7@> .4>;7,?49 B0=0 â&#x2030;¥ D0,=> ,9/ =,/0 90@?=:;094, B,> 2=0,?0= ,> .:8;,=0/ ?: ;,?409?> D0,=> A0=>@>

:= ;,?409?> D0,=> ?30 % 1:= :A0=,77 >@=A4A,7 B,> ,9/ 1:= ;,?409?> â&#x2030;¥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

,>? &:@?30,>? >4,9> ,9/ :?30=> := ,@.,>4,9> ?30 % 1:= :A0=,77 >@=A4A,7 B,> 1:= ,>? &:@?30,>? >4,9> ?30 % B,> ,9/ 1:= :?30=> ?30 % B,> 49 ?30 49?09? ?: ?=0,? ;:;@7,?4:9 $ ! '30=0 3,A0 -009 10B .,>0> :1 !' :A0=/:>0 %0;:=?0/ ?:C4.4?40> 49.7@/0/ 90@?=:;094, ,9084, ?3=:8-:.D?:;094, 8@.:>4?4> ,9/ =,>3 9?4.4;,?0/ .:8;74.,?4:9> :1 :A0=/:>0 49.7@/0 -:90 8,==:B >@;;=0>>4:9 ,> 8,9410>?0/ -D 90@?=:;094, ?3=:8-:.D?:;094, ,9/ ,9084, 9 ,//4?4:9 4910.?4:9 B4?3 := B4?3:@? 10A0= /4,==30, ,9/ 8@.:>4?4> 8,D -0 >009 1 ,9 :A0=/:>0 :..@=> 2090=,7 >@;;:=?4A0 80,>@=0> >3:@7/ -0 49>?4?@?0/ ,> /0080/ 90.0>>,=D -D ?30 ?=0,?492 ;3D>4.4,9 9 .7494.,7 ?=4,7> 70@.:A:=49 B,> ;0=84??0/ 1:= ' =,/0 70@6:;094, 7,>?492 â&#x2030;¥ /,D> ' =,/0 90@?=:;094, 7,>?492 â&#x2030;¥ /,D> ,9/ 4880/4,?07D 1:= ' =,/0 ?3=:8-:.D?:;094, -700/492 ,>>:.4,?0/ B4?3 =,/0 ?3=:8-:.D?:;094, := =,/0 := 8@.:>4?4> '30 1:77:B492 49?=,A09:@> /:>0> ,9/ >.30/@70> :1 70@.:A:=49 B0=0 =0.:8809/0/ 1:= 49?=,A09:@> @>0 82 8 49?=,A09:@>7D :9.0 1:77:B0/ -D 70@.:A:=49 82 8 49?=,A09:@>7D 0A0=D 3:@=> 1:= /,D> '30 ,-474?D :1 !' ?: -0 /4,7DE0/ 4> @969:B9 " % & '4(.12,*1*5.5 76',*1*5.5 03'.40*16 2+ *46./.6; ": .,=.49:2094.4?D >?@/40> 3,A0 -009 .:9/@.?0/ B4?3 ;080?=0C0/ $080?=0C0/ B,> .7,>?:2094. 49 ?30 49 A4A: 84.=:9@.70@> ,>>,D 49 8:@>0 -:90 8,==:B -@? B,> 9:? 8@?,2094. 49 8@7?4;70 49 A4?=: ?0>?> 80> ,>>,D # .077 ,>>,D $080?=0C0/ ,/8494>?0=0/ ,? 4 A /:>0> :1 82 62 /,D := 2=0,?0= ?: 8,70 84.0 ,-:@? ?30 =0.:8809/0/ 3@8,9 /:>0 :9 , 82 8 -,>4> =0>@7?0/ 49 =0/@.0/ 10=?474?D 3D;:>;0=84, ,9/ ?0>?4.@7,= ,?=:;3D " " # ! " &00 ;;=:A0/ $,?409? ,-07492 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: =0,/ ?30 ;,?409? ;,.6,20 49>0=? .,=01@77D

**) +24 2/.( (.) '1) $.6'0.1

$,?409?> ?=0,?0/ B4?3 !' 8@>? -0 49>?=@.?0/ ?: ?,60 1:74. ,.4/ ,9/ A4?,849 ,> , ;=:;3D7,.?4. 80,>@=0 ?: =0/@.0 ?=0,?809? =07,?0/ 308,?:7:24. ,9/ 2,>?=:49?0>?49,7 ?:C4.4?D + (+ ' &"'"+,* ,"(' 29 /22) *// 27165 $,?409?> >3:@7/ -0 ,/0<@,?07D 491:=80/ :1 ?30 =4>6 :1 7:B -7::/ .077 .:@9?> ,9/ 49>?=@.?0/ ?: 4880/4,?07D .:9?,.? ?304= ;3D>4.4,9 >3:@7/ ,9D >429 :1 4910.?4:9 /0A07:; 49.7@/492 10A0= $,?409?> >3:@7/ ,7>: .:9?,.? ?304= ;3D>4.4,9 41 -700/492 := >D8;?:8> :1 ,9084, :..@= '5642.16*56.1'/ ++*(65 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: .:9?,.? ?304= ;3D>4.4,9 41 ;0=>4>?09? A:84?492 /4,==30, := >429> :1 /03D/=,?4:9 ,;;0,= 21(20.6'16 *).('6.215 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: 491:=8 ?30 ;3D>4.4,9 41 ?30D ,=0 ?,6492 ,9D .:9.:84?,9? ;=0>.=4;?4:9 := :A0= ?30 .:@9?0= 80/4.,?4:9> 49.7@/492 ?3:>0 1:= ;,49 := 4917,88,?4:9 >@.3 ,> 9:9 >?0=:4/,7 ,9?4 4917,88,?:=D /=@2> + *- ', * ,"('+ "2 4*3246 !#! " $ ! " ! (216'(6 /. .//; '1) 203'1; '6 .//; : 24 '6 24 999 +)' ,28 0*)9'6(-

!' F ;080?=0C0/ 1:= 4950.?4:9

$) !$

4?0=,?@=0 =0A4>0/ @2@>?

/. .//; '1) 203'1; 1).'1'32/.5 #! :;D=423? G 74 477D ,9/ :8;,9D 77 =423?> =0>0=A0/ $) !$

$% "' " (& $) !$

AVBCC ANNUAL CONFERENCE See also VBCC Perspective, page 28

Prominent Oncologist Applauds First Conference... try are talking with insurers, with clinicians—there is hope that this type of communication has great potential for each of these critical groups in healthcare delivery to understand where each component is coming from, and understand each other’s issues, which we trust over the long-run will lead to creative solutions. To try to put people in “good guy, bad guy” categories is not productive for anyone. If we look at the drug development side, the pharmaceutical industry clearly needs the expertise that comes from clinicians in terms of trial development, particularly regarding integration of biological principles and disease-specific expertise. We need the ongoing scientific expertise from laboratory scientists, from imaging experts, as well as from drug developers—all working together to design the very best trials. These include the trials done through the public sector, that is, the National Cancer Institute, including the cooperative groups. Such interactions are absolutely essential, because the drugs after all are coming from industry. But for the industry trials also, we want the very best trials developed across the board. We want trials that will bring forward important human biological data to help us better select patients who are more likely to benefit from the various drugs under development. And this is going to take encouragement; an environment where people are communicating with each other. Q: Does it also relate to payers or policymakers? Dr Benson: Indeed. Insurance carriers, including our policymakers and government agencies, clearly need to comprehend what it takes to deliver effective oncologic care. There is the need to understand how we can offer this care to the greatest number of people—access is a critical issue—and how can we make sure that we are using the resources to the best advantage for the patient. They need to understand that we are making progress in our ability to select patients who will have the best opportunity to benefit from these therapies, although we certainly have much more work ahead of us to accomplish this goal across disease sites. At the same time, we should make it clear when an agent is not going to provide benefit for the patient. In addition, to more effectively use imaging, we need to look at risks and benefits, to be able to decide when to order particular scans, and so on. The

effective use of imaging requires strategic thinking for each patient to decide what is the intended goal, what we are going to learn from imaging, how is this imaging going to affect the care delivered, and will it result in altered decision-making. In other words we need to get people to think more carefully what tests—diagnostics and imaging alike—will truly add benefit. Some tests of course are clearly for safety, and we have to consider what will help us make sure that an

the advances in providing care, we may end up spending the same amount but getting better outcomes from the dollars we spend. At least we would know that we are getting value. We would project that value in healthcare delivery could have other ramifications, such as keeping more people gainfully employed, so that they are able to care for themselves and their families, as well as contribute to the overall economy.

To effectively achieve the goal of personalized medicine, we have to have everyone in the healthcare enterprise engaged to understand and to help get us to our goal. We hope to see much more interaction among the multiple stakeholders of the healthcare system, as has been evident at this conference.

intervention is being safely administered. Other issues are to look at the effectiveness of the therapy, and to look for recurrence, with the understanding that if we find recurrence, we are going to intervene in an attempt to enhance outcome. Q: This is directly relevant to a key issue in oncology—personalized medicine. Did the conference have any relevance to this? Dr Benson: Yes, it goes hand in hand. To effectively achieve the goal of personalized medicine, you have to have everyone in the healthcare enterprise engaged to understand and to help get us to our goal. That requires an environment that encourages innovation on the one hand, even though innovation may come at a cost. On the other hand, if innovative strategies help us with much better patient selection, in the long-run we are at the very minimum using dollars more effectively, but we could also have huge cost-savings. Perhaps those cost-savings need to be invested in other components of healthcare, so that our overall health expenditure may not actually decrease. Given our expanding and aging population and

VALUE-BASED CANCER CARE

April 2011

Furthermore, expanded innovation should lead to more jobs, more industry to enhance the economy, and more development of infrastructure. There are so many permutations that we could foresee, but if we do not have everybody getting together and talking about these issues, we are not going to have the optimal solutions. Q: Where do you see personalized medicine today, and where will it be in, say, 5 years? Are we moving in the right direction? Dr Benson: I think we are clearly moving in the right direction, because if we look at the past 5 years, I don’t think people could have predicted the advancements that we see now. We already have more biologic factors we are able to use, at least in some circumstances, for patient selection. Our technology—the laboratory technology, the informatics technology—is all developing at a very fast rate. And these kinds of developments enable us to do a lot of the work in terms of understanding human biology. If we just look at the tumor assessment technology, where in the past people might have only been able to do experiments with fresh tissue, now a huge amount of work can be done

Continued from cover from tumor bank material, for example. And because there is increasing understanding of human tumor biology, we hope that in the long-run this will drive drug development. I don’t think we could have predicted the role of KRAS in colon cancer, for example. The expectation is that this process will accelerate. With the economic concerns, however, one question is whether we will continue to recognize that investing in healthcare innovation is absolutely critical, because not only will it lead to better understanding of human disease, it should also lead to far better ways to deliver healthcare and to deliver appropriate treatments to people who will benefit from them. Q: You mentioned value earlier, which is not an easy issue. How do you understand value in cancer? Are we talking about survival, reduced costs? Some people say that a treatment that prolongs life for 1 or 2 weeks does not really provide value. Dr Benson: That is part of the problem when people are talking about outcomes, and why we need different paradigms for clinical trial design. Currently, when we evaluate a treatment, we have eligibility criteria, but these are still for the most part very broad. We know that cancers, even within a given stage, are very heterogeneous. There are multiple biological pathways that are engaged in the same tumor, and we know that within a given group of patients, outcomes vary considerably. In such a situation, we know that an intervention is not going to benefit a certain percentage of patients. We are designing the trial so that we project that a certain number of patients will benefit, which will show that the drug has activity for at least some people in that group. So when we look at the statistics, we are looking at this diverse population, and until we can truly separate those who will not benefit, and those who have a high likelihood of benefit, we are not getting the full value of the intervention. When people make a comment such as, “well, it only extends survival for this limited period of time,” that is true in a broader collection of people who were participating in the trial; but, clearly there are some individuals who got great benefit—yet we are unable to adequately select those who would benefit and those who would not. These trials that typically have relatively unselected populations of Continued on page 20

VOL. 2

NO. 2

ACCC ANNUAL MEETING

Implementing the HITECH Rules in Oncology Practices By Daniel Denvir Washington, DC—The American Recovery and Reinvestment Act (AARA) of 2009 provides up to $27 billion over 10 years for the Centers for Medicare & Medicaid Services to offer cash incentives to encourage providers to make the switch to electronic health records (EHRs), said Gena Cook, CEO, Navigating Cancer, a web-based company dedicated to oncology services.

about the cost of EHRs, she said it is better to reap the incentives now than get hit with penalties later. To receive federal funds, providers must demonstrate “meaningful use” of EHRs. The

objectives constituting meaningful use will be implemented in 3 stages. The 3 Implementation Stages Stage 1, which has 20 objectives, has

been released; it includes providing patients with a clinical summary and timely electronic access to records. The objectives for stage 2 for 2013 Continued on page 18

ARZERRA HCPCS Code J9302 Announcing a NEW J-Code for ARZERRA ARZERRA will have a permanent HCPCS code effective January 1, 2011 “This is a part of healthcare reform, where the train has already left the station… and physicians can start… receiving payments this year.”

The new J9302 Code replaces miscellaneous HCPCS Codes J9999, J3590, J3490, and C9260 that most providers have used to bill for ARZERRA to date

—Gena Cook Financial Implications Speaking at the 2011 Association of Community Cancer Centers annual meeting, Ms Cook emphasized that the focus should be on “meaningful” adoption of EHRs for improving patient care, according to the ARRA. Providers are encouraged to move quickly to understand the coming changes resulting from implementation of the AARA and the Health Information Technology for Economic and Clinical Health (HITECH) Act, which falls under it. By 2015, providers who continue to use paper records instead of EHRs could have their Medicare reimbursements reduced, she said. “What people aren’t thinking about is what that really means. As you adopt technology into your office, what does that mean for patients and their families?” she asked. “This is a part of healthcare reform, where the train has already left the station. This has bipartisan support, and physicians can start…receiving payments this year.” Addressing providers’ concerns

VOL. 2

NO. 2

HCPCS code

Description

Effective

J9302

Injection, ofatumumab, 10mg

January 1, 2011

Contact your GSK representative for additional information or visit www.ARZERRA.com.

www.ValueBasedCancer.com

ACCC ANNUAL MEETING

Preparing for Future Trends... and join Medicare (the population most susceptible to cancer). The settings where care is delivered will also change, according to Dr Booi, with technological advances driving treatment from inpatient to outpatient settings. “It will also expand the number of treatments that are given,” she says, “as we look at more multimodality treatments and more complex interventions.” Epidemiologic trends in relation to cancer are mixed—smoking is down, but obesity continues to rise, and both trends will have an impact on cancer rates and outcomes, considering the link of these conditions to cancer. Growth in Technologies Two technologies have particular growth potential—interventional oncology, which speeds recovery and lowers the risk for complication, will be a “huge opportunity for growth and a great source of program differentiation for cancer centers.” Stereotactic body radiation therapy, allowing for highdose and high-accuracy treatment, is the second anticipated growth area. Screening. The recession has depressed the use of certain cancer treatments, most notably preventive screening for colorectal cancer and mammography. However, the healthcare reform has eliminated patient cost-sharing for many preventive screenings, so utilization of these services can be expected to grow. Dr Booi predicts a 39% increase in mammography utilization over the next decade.

Surgical intervention. Increased screening and an aging population will, in turn, boost surgical intervention. “This is a big revenue opportunity,” she says. “The performance strategy for colorectal cancer is to increase your screening rates, because this is

“The performance strategy for colorectal cancer is to increase your screening rates, because this is going to drive downstream utilization of surgical resections….There are a lot of opportunities in this technology revolution that we can incorporate into the way we deliver care.” —Rebecca Booi, PhD

going to drive downstream utilization of surgical resections, which we know have favorable margins.” Chemotherapy. Chemotherapy is another opportunity for growth. Evidence also suggests that chemotherapy will grow by 38%, thanks to more “complex and targeted” therapies. “What does this mean for planning? I think on the inpatient side, it means be careful; don’t overplan for demand that you may not see. And on the outpatient side, it means also be careful, but in terms of efficiency,” Dr Booi said.

Continued from cover

Imaging. Positron-emission tomography (PET) will also likely see robust growth. After the National PET Registry study determined that PET improved treatment planning, the Centers for Medicare & Medicaid Services expanded coverage for PET. Dr Booi expressed skepticism over the prospects for proton beam therapy. “Is adopting proton beam therapy a performance strategy for cancer centers?” she asked. Her reference to the $100-million to $150-million imaging machines provoked a laugh from the audience. “Well, maybe. Maybe not.” Coordinated Care and Utilization Dr Booi predicts that the increasing pressure to move toward coordinated care models such as accountable care organizations and bundled payments will ultimately decrease utilization, because improved communication will result in fewer duplicate tests and better outpatient self-care. “If you’re communicating better, if you’re improving hand-offs, then your patients are probably better managing their diseases, they’re not being exposed to duplicate or unnecessary tests, and they’re probably being better educated about managing their symptoms in the outpatient setting. So they’re not being readmitted for complications like nausea or dehydration as a result of their treatment.” Dr Booi endorses the utilization of “time frames” to diminish wasteful backlogs in the treatment process and reduce patient anxiety. This is something that cancer centers can market to

Implementing the HITECH Rules... may include implementing patient reminders, providing discharge instructions, and secure online messaging. Providers may be compelled to have 20% of their patients using web portals, Ms Cook said. Providers must ensure that a vendor is Health and Human Services–certified. By 2015, stage 3 could require further patient engagement, electronic selfmanagement tools, EHR exchanging data with personal health records, among other objectives. This process provides an opportunity to better engage patients in the treatment process. “Think about empowering your patient to be a part of care,” Ms Cook said. Patient portals have already been implemented by some groups: 35% of Kaiser Permanente patients and 60%

of Group Health patients now use the portals. “Not only do they give patients electronic access to their health information, but they give them tools to manage a lot of transactions within health,” Ms Cook said. “Their patient portals allow patients to request appointments, request prescription refills, and to do online consults for simple things.” Patient–Provider Communication Responding to a question on patients misinterpreting their raw medical data, Ms Cook noted that having EHRs does not mean giving patients access “to the entire chart” or their entire information. Continuity-of-care documents and continuity-of-care records are becoming the standard for communication

VALUE-BASED CANCER CARE

April 2011

Continued from page 17

between provider and patient and between provider and provider. Ms Cook cited a recent Pew Internet

“What people aren’t thinking about is what that really means. As you adopt technology into your office, what does that mean for patients and their families?” —Gena Cook

Research study (www.pewinternet. org/Press-Releases/2011/HealthTopics.aspx), which found that search-

patients; “we’ll get you in and out quickly.” She cited Gundersen Lutheran Center in La Crosse, WI, which reduced treatment to turnaround time to 7 days, resulting in fewer negative biopsies. In Memphis, TN, the Baptist Hospital for Women decreased turnaround times without adding staff or equipment by establishing an online preregistration portal and shifting business hours to better meet patient demand. The Cleveland Clinic, which suffered from long wait times for chemotherapy, introduced targeted scheduling to address inefficiencies in infusion suites. The patient satisfaction rate soared to 98%. Technology-Driven Oncology Dr Booi anticipates strong growth in seeking treatment for prostate cancer, especially in the outpatient setting; much of this will be made up with reimbursable electronic visits, she expects. “I can imagine that this is kind of hard to grapple with. But think about 2 years ago, could you have imagined an iPad if you weren’t Steve Jobs? And could you have imagined that today, iPads are being used for check-ins at cancer centers, for patient education, to keep patients entertained during treatment?” Dr Booi strongly believes that technology will revolutionize cancer care. “There are a lot of opportunities in this technology revolution that we can incorporate into the way we deliver care,” she said. ■

See also article on page 36 ing for health information is the third most popular activity online. In addition, a study published in the Journal of Medical Internet Research showed that 75% of patients wanted online access to medical records, laboratory results, and appointment scheduling (Adler KG. Web portals in primary care: an evaluation of patient readiness and willingness to pay for online services. J Med Internet Res. 2006;8:e26). Patient privacy and security are major concerns, and privacy advocates are pushing the government to take steps to strengthen data safeguards. But the HITECH Act makes EHRs a certainty, and providers should act proactively to implement a system that works best for their practice. ■

VOL. 2

NO. 2

ONE QUESTION FOR

IS RIGHT

EVERY PATIENT. IS THERE A HISTORY OF BREAST OR OVARIAN CANCER? As a health care professional, you have the power to identify women at risk for hereditary breast and ovarian cancer (HBOC) by asking every one of your patients this simple question. BRACAnalysis®—a test that identifies the BRCA mutations that cause most cases of HBOC—can help you identify patients in need of special attention and take steps to reduce their cancer risk. While you are empowering your patients and their families with valuable information, you are also able to individualize medical management for better patient care.

JUST ASK IF SHE HAS A PERSONAL AND/OR FAMILY HISTORY OF:* Breast cancer before age 50 Ovarian cancer at any age Two primary breast cancers in an individual at any age Both breast and ovarian cancer in an individual at any age Male breast cancer at any age Two or more breast cancers in a family, one under age 50 Women of Ashkenazi Jewish descent with breast or ovarian cancer at any age A previously identified BRCA mutation in the family *Assessment criteria based on medical society guidelines. For these individual medical society guidelines go to www.myriadpro.com/guidelines For reference and supporting data on risk factors and medical management visit www.myriadpro.com/references

TO LEARN MORE OR TO ORDER BRACAnalysis MATERIALS FOR YOUR PRACTICE, PLEASE CONTACT YOUR MYRIAD REPRESENTATIVE AT 800-469-7423. Myriad Genetic Laboratories, Inc. 320 Wakara Way Salt Lake City, UT 84108 Myriad, the Myriad logo, BRACAnalysis, and the Just Ask logo are either trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and other jurisdictions. ©2010 Myriad Genetic Laboratories, Inc.

www.bracnow.com

ACCC ANNUAL MEETING

Oncologists Debate the Place of Pathways and Guidelines in Clinical Practice Are these tools compromising physicians’ autonomy and patient variability? By Daniel Denvir Washington, DC—Physicians are tugged in different directions by patients, payers, and society at large (expressed via the legal system), with expectations involving physician autonomy, best practices, adherence to local standards of care, as well as national guidelines. At the 2011 Association of Community Cancer Centers Annual Meeting, oncologists debated the increasing role of pathways and guidelines in clinical practice. Variation in Treatment Not Always a Bad Thing Cary A. Presant, MD, FACP, an oncologist at the Wilshire Oncology Medical Group at the California Cancer Medical Center and Professor of Clinical Medicine at the University of Southern California Keck School of Medicine, said that the 3 major trends in medicine today—physician autonomy, guidelines or pathways, and personalized medicine—often seem to be in conflict with one another. Physician autonomy goes to the core of the profession, back to the Hippocratic Oath of treating the patient to the “best of my ability and judgment,” Dr Presant said. “Physician autonomy should not be let go of

in a setting where everyone seems to be moving toward guidelines and pathways,” Dr Presant said. “Whatever is working seems to change very quickly. Therefore, basing the guideline on what has been working may be basing the guideline on something that is really unsustainable,” he reiterated.

“The development and use of evidence-based medicine by physicians allows for physician autonomy and continues to apply the logic of Level I understanding of treatments, which allows for there to be even more personalized care.” —Roy A. Beveridge, MD A clinical oncologist is able to account for factors such as the presence of multiple comorbidities that guidelines may not sufficiently take into account, or to analyze increasingly sophisticated genetic testing. In this sense, physician autonomy and personalized medicine can go hand in hand. “Society,” accord-

Prominent Oncologist Applauds First Conference... Continued from page 16

patients can show the potential for that drug for a much better selected group of patients, and that should lead to more research to get to the point where we can identify the people who will benefit. With cancer medicine we are often dealing with a continuum, and that is where the concept of incremental benefit comes in—if you have multiple regimens with incremental benefits for individuals, that can lead to prolongation of overall survival. Everyone would love to see a therapy that greatly improves the cure rate and greatly improves overall survival. That clearly is possible if we can better define populations of people where that may happen. But to get there, it is going to take much more profound understanding of human biology. Continuing to invest

in drug development has to go hand in hand with understanding tumor biology. In summary, the design of clinical trials will undergo a change in paradigm, where we are not just entering hundreds or even thousands of patients on a given trial, but rather on studies that are much more focused with selective populations, which will be to everyone’s advantage in terms of risk versus benefit, efficacy, and resource utilization. People need to be speaking the same language and understand these principles. That takes all components of the healthcare enterprise to support these collaborative strategies. We hope to see much more interaction among the multiple stakeholders of the healthcare system, as has been evident at this conference. ■

VALUE-BASED CANCER CARE

April 2011

ing to Dr Presant, “grants doctors that autonomy.” It is well established that guidelines or pathways seek to diminish the variation in treatment, which can lead to poor care and higher costs. This variation, however, is not simply a result of bad providers, Dr Presant claims; many physicians disagree about what works best. Imposing a single standard can often be counterproductive. The narrowness of clinical trials further makes it difficult to generalize some standards to a broader patient population, he said, noting that guideline authors often have undisclosed conflicts of interest. “Decisions cannot be made by one single guideline, or by a computer, or by one single laboratory evaluation.” Pathways Allow for Patient Variation Presenting the other side of this debate, Roy A. Beveridge, MD, Executive Vice President and Medical Director at US Oncology, said he did not perceive such tension between pathways and physician autonomy, or personal medicine. “In the pathways as they are now, there are already provisions made for those patients who have premenopausal or postmenopausal breast cancer; those patients who are PR [progesterone receptor} positive or PR nega-

at a glance ➤ Pathways and guidelines are increasingly seen as the future of oncology practice ➤ Some oncologists worry that guidelines and pathways may be compromising physician autonomy to address patient variability and best practices ➤ By contrast, other oncologists believe that clinical guidelines and pathways incorporate the principles of patient variability and differentiation in accordance with personal medicine ➤ The use of Level I Pathways lowered outpatient costs by 35% for patients treated for non–small-cell lung cancer in one study, without compromising overall survival

“Physician autonomy should not be let go of in a setting where everyone seems to be moving toward guidelines and pathways. Whatever is working seems to change very quickly. Therefore, basing the guideline on what has been working may be basing the guideline on something that is really unsustainable.” —Cary A. Presant, MD, FACP tive; those patients with colon cancer who are KRAS positive and KRAS negative; those patients with certain chromosomal abnormalities in terms of leukemia or in terms of myeloma,” Dr Beveridge said. US Oncology, a cancer healthcare network with 460 community cancer practices in 39 states, has developed Level I Pathways known as Innovent Oncology (www.innoventoncology. com). Innovent Oncology is continuously developed and maintained by US Oncology member physicians, who access the system through a web portal and electronic health records. “The development and use of evidence-based medicine by physicians allows for physician autonomy and continues to apply the logic of Level I understanding of treatments, which allows for there to be even more personalized care,” Dr Beveridge said. A study completed by Aetna showed that providers using the Level I Pathways lowered outpatient costs by 35% for patients treated for non– small-cell lung cancer, and these patients had the same 12-month overall survival rate as patients not managed with this pathway. Dr Beveridge also countered concerns that effective treatments are being put aside because of cost; the best evidence-based treatment available is always considered first line, and if 2 treatments have equal efficacy, toxicity will be taken into account to determine use. If efficacy and toxicity are equal, the cost to patient and payer will be considered as a pathway guide. Innovent Oncology also encourages patient accrual to clinical trials; insufficient patient participation in clinical trials continues to hinder drug research and development, according to Dr Beveridge. ■

VOL. 2

NO. 2

ACCC ANNUAL MEETING

Accelerating Growth in REMS Programs a Challenge for Oncologists By Daniel Denvir

ddressing the 2011 Association of Community Cancer Centers annual meeting attendees, Timothy Tyler, PharmD, FCSHP, Director of Pharmacy Services at the Desert Regional Medical Center Comprehensive Cancer Center, Palm Springs, CA, outlined the considerable demands and complications that have been added to oncology care with the introduction of the Risk Evaluation and Mitigation Strategies (REMS) program for high-risk drugs. Many of these are cancer drugs, Dr Tyler said, and the US Food and Drug Administration (FDA) has much work to do to calm provider fears and confusion. “REMS presents very significant challenges for a lot of stakeholders,” said Dr Tyler. “Providers in community cancer centers have a fair number of these drugs.” He participated in a National Comprehensive Cancer Network (NCCN) working group on REMS, which developed a white paper on increasing concerns in the oncology community, including: • Increased and nonreimbursed workload for physicians, pharmacists, and nurses • A misleading focus on risks, not balanced against a discussion of benefits • Lack of clarity and plain language in patient communication • Concern that onerous REMS programs could make it potentially less likely for a provider to prescribe a drug and limit legitimate off-label use. The NCCN group, however, also recognized the potential for improved patient safety, citing examples in recent years of major problems with prescription drugs (eg, Vioxx), which is lending a sense of urgency to drug safety. The FDA may now require manufacturers to develop REMS for both existing and new drugs.

Risk a Familiar Face in Oncology The oncology community is uniquely well positioned to mitigate risk, despite the widespread use of oncology drugs for off-label indications, he said. “The basic concern was that for years we’ve had black box warnings, we’ve had contraindications,” said Dr Tyler. “In the oncology community, because we tend to go off label, the incorrect or correct assumption was that we’re not paying attention. I would say that because of the toxicities of the agents we’re dealing with, and the fragility of the patients, we

VOL. 2

NO. 2

tend to be a little more in tune than other populations.” Nurses and pharmacists, for example, already use a double-check system when administering chemotherapy. The high toxicity of oncology drugs means that providers are already experienced in discussing risks with patients. The most common REMS requirement is medication guides. Drugs that pose a high-risk level can be required to include a communication plan for providers. And oncology pharmacy directors are now inundated with these. “I get a stack of those a month,” he complained, but “how else do you communicate with the prescribing community?” Dr Tyler asked. In the most high-risk cases, an element to assure safe use (ETASU) can be required, which can mandate prescriber training, certification, or credentials. Manufacturers or Providers? There is also concern that although the FDA can only exercise control over manufacturers, it is the providers who will actually implement REMS in the clinical setting. “They don’t really have any sticks or carrots. They’re just trying to do what’s best by the product. Their biggest concern is having their drug withdrawn from the market, which is the FDA’s ultimate trump card,” Dr Tyler noted. In 2010, an FDA panel decisively rejected proposed REMS for opioids, insisting on a more exacting standard that required training and not merely education. The panel was responding to growing concern about the widespread abuse of drugs such as Oxycontin.

“It is realistic to think that REMS can help. But as the number and complexity of these things start to skyrocket, challenges of both prescribing and dispensing drugs are going to increase.” —Timothy Tyler, PharmD, FCSHP

“The biggest drug category that’s been looked at is opioids,” Dr Tyler pointed out. “We use opioids like candy in the oncology community. There are problems, but what’s the best way to solve them?” A Staggering Growth The number of drugs subject to REMS is growing rapidly, from 136 in September 2010 to 177 in March 2011, covering 113 unique entities (Table). All 177 drugs required a medication guide, 43 required a communication plan, and 21 required an ETASU. Of

Table REMS Programs: September 2010 through March 2011 September 29, 2010

March 2, 2011

REMS programs: 136a

REMS programs: 177a

Used in hematology/oncology: 6

Used in hematology/oncology: 11

Non-orals: 1

Non-orals: 6

Traditional drugs: 0

Support hematology/oncology: 31

Support hematology/oncology: 46

Used in outpatient clinic: 11 (18 if adding antibiotics)

Used in outpatient clinic: 18 (25 if adding antibiotics)

Total REMS: 55 (~40%)

Total REMS: 82 (~46%)

Excluding deemed status and valid as of February 19, 2011. REMS indicates Risk Evaluation and Mitigation Strategy. Courtesy of Timothy Tyler, PharmD, FCSHP.

those requiring an ETASU, 12 are used in the cancer center setting; 11 are of vital interest to oncology; and all except interferon are oral medications. All REMS were created or have been modified over the past 18 months. An additional 46 drugs are related to hematology/oncology, 18 of which have a place in infusion centers, and 25 include antibiotics. “If you’re involved in outpatient care, you could see up to 82 of these at the present moment. That’s kind of a staggering number,” Dr Tyler pointed out. Traditional chemotherapy has yet to be subjected to REMS, but it is possible that it could. This would pose serious challenges to the oncology community. “It is an overwhelming force coming at you. And in the physician office setting and the hospital setting, they don’t have a lot of slack,” he said. Dr Tyler cited a report saying that 33% of new molecular entities and biologic products approved by the FDA in the first half of 2010 had REMS required. “All the paperwork we need to do is not reimbursable. We might end up doing a lot to comply with the REMS, but there’s no added revenue. And I may spend an extra 2 to 3 hours on a patient,” Dr Tyler noted. Streamlining the Process Electronic medical records and web technology could play an important role in streamlining REMS. “Efficiencies become ever more important,” he said, so “electronic records, electronic information, is certainly one of those areas that is making it potentially easier for us to be compliant.” The NCCN working group recommended streamlining the process and ensuring that the burden does not become overwhelming, calling on the FDA and manufacturers to standardize risk categories and accompanying REMS, and to deliver that information through an online clearinghouse. Dr Tyler reports that the FDA seemed to understand the problems during a 2010 meeting. He suggests, however, that Congress may ultimately need to consider amending the FDA Amendments Act. “It is realistic to think that REMS can help,” Dr Tyler said. “But as the number and complexity of these things start to skyrocket, challenges of both prescribing and dispensing drugs are going to increase.” ■

www.ValueBasedCancer.com

in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s va ral l y le n l M unt tag ye re e lo at m ed a

If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT IMPORTANT 33-YEAR -YEAR U UPDATEPDATE- S SUSTAINED USTAINED BENEFIT BENEFIT UPDATED VISTA* OVERALL (OS) A ANALYSIS: NALY YS SIS: VcMP MP U PDATED VISTA* OVERALL SURVIVAL SURVIVAL (OS) VcMP† vvss MP ((36.7-month 36.7-month median median follow-up) follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Patients Patients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier estimate. estimate. Kaplan-Meier

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

Please see Brief Summary for VELCADE on the next page of this advertisement.

www.VELCADE.com

Brief Summary INDICATIONS: VELCADE (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. ®

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved. Printed in USA V1215 12/09

GENITOURINARY CANCERS SYMPOSIUM

Abiraterone Acetate Prolongs Survival in Metastatic Prostate Cancer Potential game changer for men with this disease By Debra Wood, RN Orlando, FL—Abiraterone acetate holds promise of improving survival in patients with metastatic castrationresistant prostate cancer across multiple patient subgroups, according to Howard I. Scher, MD, chief of the Genitourinary Oncology Service, Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering Cancer Center, New York City, who reported results of a trial at the session “Prostate Cancer for the Recurrent Disease” at the 2011 Genitourinary Cancers Symposium. “Abiraterone acetate prolongs overall survival of men with metastatic castration-resistant prostate cancer who have progressed after docetaxel-based chemotherapy, with a 35% reduction in mortality,” said Dr Scher. The drug is currently under review by the US Food and Drug Administration (FDA) and the manufacturer said that an FDA decision is expected later this year. Early clinical studies suggested abiraterone acetate, a selective androgen

biosynthesis inhibitor blocking the action of CYP17, restrains persistent androgen synthesis from adrenal and intratumoral sources, thereby suppressing a growth stimulus for metastatic castration-resistant prostate cancer. In a randomized, double-blind study, Dr Scher and an international team compared abiraterone acetate 1000 mg daily and prednisone 5 mg twice daily with placebo and prednisone in 1195 men with metastatic castration-resistant prostate cancer, progressing after receiving docetaxelbased chemotherapy. Patients previously treated with ketoconazole or more than 2 previous chemotherapy regimens were excluded from the study. The 2 cohorts were well balanced in terms of age, race, performance status, pain, previous chemotherapy regimens, type of progression, and extent of disease. In August 2010, after interim results showed significant improved overall survival in the active cohort, the study was unblinded, and men in the place-

“Abiraterone acetate prolongs overall survival of men with metastatic castration-resistant prostate cancer who have progressed after docetaxel-based chemotherapy, with a 35% reduction in mortality.” —Howard I. Scher, MD bo group were offered abiraterone acetate. “The favorable effect on overall survival was observed across multiple patient subgroups, including those with 1 prior chemotherapy, visceral disease, as well as a pain intensity of 4 or greater,” Dr Scher said. Nicholas J. Vogelzang, MD, head of the Section of Genitourinary Cancer at the Nevada Cancer Institute in Las Vegas, said at the meeting that continuing the long trial was a waste of lives and money, because the researchers, of which he was an investigator, saw the agent was active after 10 to 12 patients. Adverse events were similar in the 2 cohorts. Fluid retention and hypokalemia were the 2 most common adverse

Mutational Analysis Leads Search for New Treatments for Bladder Cancer Orlando, FL—Novel therapies are desperately needed for bladder cancer, a common malignancy with a poor prognosis for advanced disease, said Matthew I. Milowsky, MD, medical oncologist at Memorial SloanKettering Cancer Center (MSKCC), New York City, at the 2011 Genitourinary Cancers Symposium. “Bladder cancer is an absolutely devastating disease, and the molecular characterization of these tumors is exciting,” Dr Milowsky said. Understanding of genetic mutations associated with bladder cancer will lead to targeted therapies, already used in other cancer types. “If we are able to understand the molecular alterations that occur, then we can use multiple therapies targeting those alterations,” he said. “We are not there yet, but we are getting close.” A number of genes associated with bladder cancer are known to har bor mutations, according to Dr Milowsky. Low-grade, genomically stable lesions are characterized by upfront alterations in fibroblast growth factor 3 (FGFR3) and the

VOL. 2

NO. 2

HRAS gene, whereas high-grade, invasive tumors are characterized upfront by alterations in tumor suppressors, such as p53, Rb, and PTEN genes, with a subgroup of tumors having mutations and overexpression of FGFR3. FGFR3 mutations are present in approximately 15% of invasive bladder tumors, and overexpression occurs in approximately 40% of invasive tumors. The MSKCC Bladder Cancer Oncogenome Project uses mutational profiling, structural variation, and methylation events to identify known driver alterations for guiding treatment or trial selection and to identify genetic drivers in patients in whom no known driver alteration has been identified. The team profiled select mutations from 137 high-grade bladder cancer specimens. They found FGFR3 mutations in 16 samples, BRAF mutations in 2 of the tumors, PIK3CA mutations in 17 specimens and Tp53 mutations in 19 samples. Dr Milowsky said it was possible to identify morphologies using microscopy and sort out patients with FGFR3 mutations for clinical trials, and

he foresees a time when a physician can perform a core biopsy, subject it to a biomarker analysis, and use an agent to target the molecular alterations. Novel agents are being investigated for genitourinary cancer targeting FGFR3, PIK3CA, and BRAF, and have shown promising activity in other diseases. For example, TKI258 (dovitinib lactate) is a potent inhibitor of fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptor tyrosine kinases, which is now in clinical trials for

reactions in the abiraterone group, but they were typically low grade. There was a slight 2% increase in cardiac disorders, primarily tachycardia and atrial fibrillation, in the treatment group, but Dr Scher said, the cardiac conditions were easily managed. A. Oliver Sartor, MD, Professor of Medicine at Tulane University in New Orleans and co-chair of the session, commented that abiraterone acetate will be a “game changer” in treating men with metastatic castration-resistant prostate cancer. “It will provide a new alternative for patients with castration-resistant prostate disease postdiagnosis,” Dr Sartor said. “It will change practice.” ■

“If we are able to understand the molecular alterations that occur, then we can use multiple therapies targeting those alterations. We are not there yet, but we are getting close.” —Matthew I. Milowsky, MD urothelial carcinoma. Other agents targeting the epidermal growth factor receptor/HER2 pathway are approved for other cancers.—DW ■

CyberKnife Cost-Effective in the Long-Term Orlando, FL—Although the cost of CyberKnife to treat prostate cancer is initially higher than surgery—an equally effective therapy—patients experience a better quality of life with CyberKnife than with other treatment modalities and have lower lifetime costs compared with radiation and proton therapies.

CyberKnife uses image-guided stereotactic radiosurgery to target tumors and requires fewer visits than needed with external beam radiation. Researchers at Innovus, San Francisco, used a Markov model to compare payer and societal costs associated with surgery, CyberKnife, Continued on page 26

www.ValueBasedCancer.com

GENITOURINARY CANCERS SYMPOSIUM

Large Study Rules PSA Test Unnecessary >10 Years after Radical Prostatectomy Clinicians urged to counsel patients based on this evidence By Debra Wood, RN Orlando, FL—Most cases of prostate cancer biochemical recurrence after radical prostatectomy occurs within 10 years of surgery, and men who progress after that period are less likely to develop metastasis or die from prostate cancer, according to results of a large study conducted by a team of experts at Johns Hopkins Medical School. The team concluded that clinicians could counsel patients about risks but stop prostate-specific antigen (PSA) testing 10 years postoperative. Stacy Loeb, MD, chief urology resident at Johns Hopkins, reported on their findings at the 2011 Genitourinary Cancers Symposium. “It’s reasonable to stop PSA testing 10 years after the radical prostatectomy,” Dr Loeb said, adding that this is

the first large study with long-term follow-up to evaluate the need for PSA, which can provoke great anxiety. “There are financial burdens and psychological complications of” repeating the test. Large Study, Clear Results Dr Loeb and colleagues studied 10,609 men with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins between 1978 and 2009, did not receive hormonal therapy before surgery, and had accessible data about follow-up care. At some point, 1648 men (15.5%) developed biochemical recurrence. “The vast majority [of recurrences] occurred within the first 5 years, and

Potential New Options for Neuroendocrine Prostate Cancer Orlando, FL—Very little is known about the underlying biology of neuroendocrine prostate cancer, an aggressive form of the disease that can arise on its own or from an existing prostate adenocarcinoma. Patients typically die within 1 year of diagnosis, despite aggressive chemotherapy. New research suggests a clonal origin of neuroendocrine prostate cancers from prostate adenocarcinoma and possible treatment targets. At the 2011 Genitourinary Cancers Symposium, Himisha Beltran, MD, a fellow at Weill Cornell Medical College, NY, reported about the use of next-generation RNA sequencing and oligonucleotide arrays to profile neuroendocrine prostate cancer, prostate adenocarcinoma, and benign prostate samples to assess for specific gene expression. “We found Aurora kinase A changes in neuroendocrine prostate cancers,” Dr Beltran said. She was presented with the Merit Award for Young Scientists at the meeting. Aurora kinase A, a cell-cycle kinase, was overexpressed in the neuroendocrine prostate cancer samples, and included a gene amplification of Aurora kinases and N-myc. “The functional distribution shows they cooperate and can induce the

neuroendocrine phenotype in adenocarcinoma cells involved in progression,” Dr Beltran said. Only 5% of the prostate adenocarcinoma samples had an Aurora kinase or N-myc alteration, and it was not found in any of the benign samples.

“Treatment with a kinase inhibitor should prove effective for neuroendocrine prostate cancer.” —Himisha Beltran, MD The researchers observed in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in the neuroendocrine prostate cancer samples but not in the adenocarcinoma samples. Neuroendocrine marker expression was suppressed in the treated xenografts. “Treatment with a kinase inhibitor should prove effective for neuroendocrine prostate cancer,” Dr Beltran concluded.—DW ■

VALUE-BASED CANCER CARE

April 2011

“It’s reasonable to stop PSA testing 10 years after the radical prostatectomy. There are financial burdens and psychological complications of” repeating the test. —Stacy Loeb, MD

then it dramatically dropped off,” Dr Loeb pointed out. “Only 6.4% of the recurrences were after 10 years. There were very few of them.” Supporting the team’s conclusion that PSA was not necessary after 10 years were their data showing that: • Men with early recurrences were more likely to develop metastasis than men with late recurrences • Men who progressed early on were more likely to die from prostate cancer than other men • Among the men with a Gleason score of 6 with late recurrence, no one subsequently died. “Late recurrences are of a more

indolent fashion, most likely related to the tumor biology,” Dr Loeb emphasized. “It is so slow for the recurrence. It takes a long time to develop into a clinical event.” Dr Loeb said she hoped other prostate cancer experts with long-term data will analyze those cases and help to develop a guideline for PSA testing, indicating that it is safe to stop PSA screening if the cancer is undetectable after 10 years. “We’re also interested in looking to see if we can space it [the testing] out more, perhaps every 2 or 5 years, which would decrease cost and anxiety,” Dr Loeb said. ■

CyberKnife Cost-Effective... Continued from page 25 intensity-modulated radiation therapy (IMRT), and proton therapy and their related adverse events in patients aged ≥65 years with prostate cancer. Societal costs include items associated with a productive life and paid for by the individual or family. “Surgery is cheaper, but is CyberKnife better?” asked Anju Parthan, PhD, Senior Project Manager for Health Economics & Outcomes Research at Innovus. “It costs more, but you can have improved quality of life,” she commented. All possible combinations of gastrointestinal, genitourinary, and sexual dysfunction long-term toxicities were included. Toxicity probabilities were obtained from the pooled results of multiple studies. Costs were assigned based on published sources. The model projected lifetime costs and quality-adjusted life-years (QALYs) for each treatment. Total lifetime costs from a payer perspective were: • $25,904 for CyberKnife • $22,295 for surgery • $38,915 for IMRT

• $58,100 for proton therapy. The incremental cost per QALY gained with CyberKnife over surgery was $9200 from a payer perspective and $4800 from a societal perspective. Dr Parthan said, “$9200 is a small dollar value in the threshold of what payers are willing to pay for quality of life.” That threshold “is in the $50,000 to $100,000 range in the United States.” At a threshold of $50,000 per QALY, CyberKnife was cost-effective from a payer perspective 84% of the time. Dr Parthan added that a head-tohead trial ideally would be used to determine the most cost-effective treatment, but limitations associated with randomization do not make that possible. Therefore, the research company conducted a sensitivity analysis and concluded that CyberKnife is a costeffective strategy compared with surgery, and that its costs are less, with better quality of life, than external beam radiation therapy or proton therapy.—DW ■

VOL. 2

NO. 2

COMING IN AUGUST

ASCO 2011: Payersâ&#x20AC;&#x2122; Perspectives

News and analysis, including coverage of plenary sessions, keynotes, abstracts, posters, and latebreaking sessions To Subscribe: www.AHDBonline.com Space reservations due 7/1 Materials due 7/15

ADVERTISING OPPORTUNITIES AVAILABLE PUBLISHER

ASSOCIATE PUBLISHER

Nicholas Englezos nick@engagehc.com 732.992.1884

Maurice Nogueira maurice@engagehc.com 732.992.1895

DIRECTOR, CLIENT SERVICES Mark Timko mark@engagehc.com 732.992.1897

VBCC PERSPECTIVE

The Potential for Personalized Medicine to Improve the Value of Targeted Therapy See also article on page 49

By Yu-Ning Wong, MD, MSCE, Medical Oncologist, Fox Chase Cancer Center, Philadelphia, PA, and Editorial Board Member of Value-Based Cancer Care

or all the talk about personalized medicine, in most cases the tools we have in oncology are more often disease site–focused than personalized. Each tumor type has a list of potentially active agents. For example, in kidney cancer, I can talk to my patients about sunitinib (Sutent), pazopanib (Votrient), bevacizumab (Avastin) and interferon, sorafenib (Nexavar), temsirolimus (Torisel), and everolimus (Afinitor). However, I cannot tell an individual patient which agent has the best probability of working for him or her. And when I see patients who have unexpected outcomes, I am often left wondering, what makes this person different? Why did he/she have such a dramatic response? Or, why has the disease progressed so quickly? In a perfect world, we would submit a piece of tumor tissue or a blood sample to the laboratory and receive a report that outlines the best treatment for that specific patient. Rather than thinking of a patient’s tumor as lung cancer or breast cancer, we would think about tumors in terms of their molecular markers and their potential for response to a particular targeted therapy. This would allow us to improve the value of the targeted therapy. Patients

able time treating them with agents that have no benefit and that can cause toxicity (both physical and financial).

Novel molecular tests have most value when validated data demonstrate that they improve outcomes through better patient selection. Currently only 5% of American patients enroll in clinical trials; this slow pace delays the completion of studies and the translation of new knowledge into practice. would only be treated with medications that were expected to help them, and clinicians would not waste valu-

Notable Examples Two notable examples illustrate how we can achieve our goal of practicing personalized medicine. The Oncotype DX assay measures the expression of 21 genes to calculate a recurrence score for women with early-stage breast cancer, allowing oncologists to identify who is most likely to experience a recurrence and who is most likely to benefit from chemotherapy, in an effort to reduce the risk of cancer recurrence. The assay is also a valuable tool in identifying women who are destined to do well without chemotherapy and can be spared its toxicity. In patients with advanced colorectal cancer, KRAS testing has helped to identify patients with advanced colorectal cancer who are unlikely to respond to agents targeting the epidermal growth factor receptor, such as panitumumab (Vectibix) or cetuximab (Erbitux). What the Oncotype DX assay and KRAS testing have in common is that their clinical utility was established using banked specimens from clinical trials. When used in the appropriate patient population, we now know

how to interpret these test results, and how to use the information to guide clinical practice, by identifying appropriate candidates for therapy. Novel molecular tests have most value when validated data demonstrate that they improve outcomes through better patient selection compared with established clinical criteria. The Value of Clinical Trials To optimize the potential value of personalized medicine, physicians and payers need to encourage patients to enroll in clinical trials. Currently only 5% of American patients enroll in clinical trials; this slow pace delays the completion of studies and the translation of new knowledge into practice. Providers should encourage eligible patients to explore clinical trials early in their disease course, instead of as a last-resort option. Payers should eliminate barriers to clinical trial coverage. Otherwise, countless patients will continue to be treated with standard therapy. When treatment is given outside of clinical trials, no primary data are collected or specimens banked. This information is critical to the development of new molecular tests to further personalize medicine and improve the value of treatment for future patients. ■

HEALTH POLICY

CMS’s Coverage Decision on Provenge: Implications for Payers By Dalia Buffery, MA, ABD

n March 30, 2011, the Centers for Medicare & Medicaid Services (CMS) announced its highly anticipated proposed national coverage decision concerning the prostate cancer immunotherapy sipuleucel-T (Provenge; Dendreon). The biologic medication (which is often labeled a “vaccine” because of its immunotherapeutic properties but is rather a therapeutic, not a prophylactic, product) was approved by the US Food and Drug Administration (FDA) in April 2010 for the treatment of men with asymptomatic or mildly symptomatic metastatic prostate cancer. According to the CMS proposed decision, Medicare will reimburse payers for the FDA-approved indication for the drug and leave the coverage deci-

sion for off-label uses to its contractors. CMS “proposes that the evidence is adequate to conclude that the use of [the] autologous cellular immunotherapy treatment—sipuleucel-T; Provenge improves health outcomes for Medicare beneficiaries with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer, and thus is reasonable and necessary for that indication” (www.cms.gov). With the cost of this therapy estimated at $93,000 per patient, this product, like many recent cancer products, raises yet again the question of value for therapies that extend life by weeks or months (the drug appears to extend life on average by approximately 4 months, although it is possible that in

VALUE-BASED CANCER CARE

April 2011

a subset of patients this time could be extended considerably). On the FDA approval of the drug, CMS instructed the Medicare Evidence Development and Coverage Advisory Committee to review the evidence from clinical trials as part of its coverage determination, an unusual step for CMS, considering the proximity of this process to FDA approval. Off-Label Use So far no evidence is available to support the use of Provenge for offlabel uses in patients with prostate cancer. In what is considered an unexpected move, CMS has left the coverage decision for off-label use to payers’ discretion. CMS says that this is in an effort to

allow access to the drug to patients in clinical trials that involve off-label uses, with the hope “that unlabeled uses in the near future will take place only in the context of bona fide clinical studies,” discouraging providers from prescribing it independent of clinical trials. “If this turns out to be an overly optimistic viewpoint,” however, CMS may reconsider this strategy to make sure the Medicare coverage “is restricted to uses that are supported by robust evidence.” Nevertheless, it is quite likely that this decision also signals CMS’s hope that payers will use the same evidence-based criteria to refuse to pay for off-label uses of the drug, again visà-vis its cost and the increasingly limContinued on page 29

VOL. 2

NO. 2

HEALTH POLICY

CMS’s Coverage Decision on Provenge... ited resources for regional plans. In fact, it can also be argued that in its statement cited above, CMS is sending a message to the company that offlabel uses should be limited to clinical trials only at this point. It may also be sending a message to other developers of oncology products that it would be looking at off-label uses more carefully in the future. Time will tell.

patients. The company expects that many patients in the registry are likely to be Medicare patients, which will present the opportunity “to compare across age-groups.” The company’s patient registry

Continued from page 28

will also support analysis of whether black men could benefit more than other groups from Provenge. This is in response to comments by CMS of an underrepresentation of black men in clinical trials of this drug (which is

not an uncommon situation in clinical trials conducted by many pharmaceutical companies), although the prostate cancer mortality rate among black men is double that of white men. ■

It can be argued that CMS is sending a message to the company that offlabel uses should be limited to clinical trials only at this point. It may also be sending a message to other developers of oncology products that it would be looking at offlabel uses more carefully in the future. VBCC Perspectives Revisited Commenting on the question of offlabel use after the approval of the drug last year in the October issue of VBCC, Lee Newcomer, MD, VBCC editorial board member and Business Leader of Oncology Services for UnitedHealthcare, said, “Using the therapy for patients who do not meet the precise indications is simply conducting a $93,000 clinical trial with 1 subject.” A second VBCC editorial member, Yu-Ning Wong, MD, MSCE, Assistant Professor at Fox Chase Cancer Center, noted that “Oncologists are trained to counsel patients about risks and benefits, including treatment-associated survival improvement and toxicities. However…physicians are ill prepared to add the ‘cost and value’ dimension to these discussions.” Patient Registry to Provide Additional Data After its recent decision, CMS has announced it is “requesting public comments on this proposed determination pursuant to section 1862 (l) of the Act. After considering the public comments, we will make a final determination and issue a final decision memorandum.” CMS is expected to issue its final ruling by June 30, 2011. In its February 24, 2011, letter to CMS, Dendreon noted it would analyze its patient registry with the goal of providing long-term real-world information for various subgroups of

VOL. 2

NO. 2

With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology offers health plans and oncology practices a comprehensive solution that enhances the quality and consistency of patient care. With evidence-based medicine as the foundation of the program, we further help patients by providing direct, personalized support and education between office visits as well as advance care planning regarding future treatment and care preferences. Through this patient-centric approach, we help health plans and oncology practices collaborate by aligning incentives to drive better patient outcomes as well as encourage the efficient use of healthcare resources. After all, isn’t cancer a disease we should manage together? To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.

www.ValueBasedCancer.com

HEALTH POLICY

ODAC Supports Tightening Up Accelerated Approvals for New Cancer Drugs Lax approach to postmarketing trials at issue By Daniel Denvir

n February 8, 2011, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voiced its support for tightening up the agency’s accelerated approval process for new cancer drugs. The agency has been criticized for failing to police the program, allowing drug companies that did not complete required postmarketing studies to keep the drugs on the market for years. ODAC must strike a difficult balance, ensuring patients’ expedited access to potentially life-saving medications, while keeping potentially toxic and untested treatments off the market. Lee Newcomer, MD, UnitedHealth Group Senior Vice President for Oncology, supported the move. “The FDA’s first responsibility is determining safety and effectiveness,” he told Value-Based Cancer Care (VBCC). “They compromised on the standards to allow access to potentially important drugs, but they still have the obligation to ensure that the drugs did meet standards.”

Postmarketing Issues The committee quizzed 4 drug companies that had not yet completed postmarketing trials on drugs approved for 6 different indications, and discussed the following common concerns: • The prevalence of single-arm trials over randomized clinical trials • The timing of postmarketing trials • The number of trials that should be required • Holding pharmaceutical companies accountable when they depend on cooperative group trials conducted by others. “Water tends to seek its lowest level,” said Richard Pazdur, MD, FDA Director of Oncology Drug Products. “And we frequently find sponsors coming in and saying, ‘Dr Pazdur, what’s the fewest number of patients and the lowest response rate that you’ll take?’ That’s problematic for us.” The accelerated approval program has expedited the availability of drugs that show early benefit on surrogate end points (eg, response rate and duration). The approval is conditioned on results of postmarketing trials meeting a definitive end point. In September 2009, a Government

Accountability Office report criticized the FDA for allowing pharmaceutical companies to drag out postmarketing trials. Failing to complete such trials is now a federal violation subject to

“While 10% of oncology indications approved under accelerated approval were unable to prove a benefit, this should not be thought of as a failure.” —Paul Kluetz, MD

financial penalties. Although the FDA has yet to issue such a fine, the pressure is growing for heightened scrutiny. The recent case of Avastin (bevacizumab) is one such example. “While there’s no regulatory definition of due diligence related to the completion of postmarketing clinical trial requirements,” said Paul Kluetz, MD, Medical Officer at the FDA Division of Drug Oncology Products, “most would agree that over 7 years of marketing, an unproved drug, with at least some level of toxicity, is suboptimal.” Barriers cited by drug companies include:

panies have not been able to prove 5 indications. Pro and Con Unlike the FDA’s accelerated approval process, the European “conditional approval” process must be renewed annually. By contrast, this ODAC meeting was its first since 2005 to review postmarketing requirements. Silvana Martino, DO, Director, The Angeles Clinic Breast Cancer Program, strongly criticized the FDA. “I’m very disappointed that this process of approval has really become a screening process,” she said. “Everyone’s interested in ‘what is the least that we have to offer.’ I think that this committee and the FDA and others have allowed that to become the mood of science within the field of oncology...where we are willing to accept drugs with the most minimal evidence….We’re dealing with drugs that have barely any activity.” Acknowledging the need for change, Dr Kluetz nevertheless insisted that, “While accelerated approval allows for earlier marketing of promising drugs, it does come at the expense of increased uncertainty,” he said. “And while 10% of oncology indications approved under accelerated approval were unable to prove a benefit, this should not be thought of as a

“The FDA’s first responsibility is determining safety and effectiveness. They compromised on the standards to allow access to potentially important drugs, but they still have the obligation to ensure that the drugs did meet standards.” —Lee Newcomer, MD

• Shifting standards of care • Difficulty of enrolling patients in a randomized trial of a drug that has already received the FDA’s imprimatur. According to Dr Kluetz, 49 new indications for 37 oncology drug products have been approved since the program was expanded to oncology drugs in 1996. Of these drugs, 27 have completed required trials with a verified clinical benefit; in addition, com-

VALUE-BASED CANCER CARE

April 2011

failure….The tradeoff is for earlier availability of promising agents for severe and life-threatening diseases.” Jeff Allen, PhD, Executive Director of Friends of Cancer Research, supports the program and cautioned against an overreaction. “The accelerated approval process has historically shown to be an important tool to provide patients with timely access to highly beneficial treatments,” he told VBCC.

“The FDA should have the appropriate authority to ensure confirmatory trials are efficiently conducted. But there needs to remain a level of flexibility that allows the FDA and sponsors to develop the desired evidence in such trials. A blanket requirement for randomized controlled trials may not be the most appropriate approach in all cases,” said Dr Allen.

“The accelerated approval process has historically shown to be an important tool to provide patients with timely access to highly beneficial treatments.” —Jeff Allen, PhD

What Type of Postmarketing Trials? Single-Arm Trials Members of the panel agreed that single-arm studies should be limited, acknowledging that those could be useful in researching treatments for rare cancers. Of the cancer drugs approved under the accelerated approval program, 20 were based on randomized clinical trials and 29 on singlearm studies. “There seems to be a real possibility in a lot of these situations for running a randomized trial,” said Ralph D’Agostino, PhD, Boston University Professor and Chair of Mathematics and Statistics. “And that should be the first item on the table.” With increased focus on molecular therapies and subpopulations of patients, randomization may not always be possible. “I don’t think anyone would be interested in giving patients a drug that doesn’t work, but if an exceptional case comes along with truly outstanding results, there may be better approaches to sufficiently demonstrate efficacy,” said Dr Allen. Confirmatory Trials The ODAC members unanimously agreed that the FDA should require companies to complete 2 clinical trials to prove benefit after receiving accelerated approval. According to Dr Pazdur, oncology is alone in requiring only 1 trial. Continued on page 31

VOL. 2

NO. 2

CANCER DRUGS

Cancer Drugs and Life Expectancy Focus of Health Economist Based on an interview with Frank R. Lichtenberg, PhD

ate last year, Frank R. Lichtenberg, PhD, Courtney C. Brown Professor of Business at the Columbia University Graduate School of Business, NY, was awarded the 2010 Garfield Economic Impact Award, which is given annually to recognize the work of economists who demonstrate how medical and health research impacts the economy. The award was given specifically for his study, “The Effect of New Cancer Drug Approvals on the Life Expectancy of American Cancer Patients, 1978-2004.”1 Cancer Drug Costs Lower Than Expected This award-winning study showed that cancer drugs that were introduced between 1978 and 2004 increased the life expectancy of American patients with cancer by almost 1 year, and that the cost of this additional year is <$7000 per patient, much lower than previous estimates of what Americans are willing to pay for an additional year of life.1 Given the recent, and increasingly expensive, developments in cancer drug therapies, that annual cost sounds low, but Dr Lichtenberg explains that his is “a historical study. Most of the drugs taken by patients with cancer are not brand new drugs.

In general, most drugs…are 20 years old, are off patent, and available in generic form. Therapy, then, becomes much less expensive.” However, “Most new therapies are extremely expensive,” he acknowledged, “but the number of patients using them is relatively small compared with the overall population of patients with cancer.”

“Where there has been the most rapid utilization of advanced imaging, we have also had the largest reductions in cancer mortality.” —Frank R. Lichtenberg, PhD To back up this contention, Dr Lichtenberg cited ongoing work in which he has analyzed data on the top 6 drugs used in 2008—4 of them were launched before 1984. And the 2 top drugs were launched before 1996 (unpublished data). “The point is that the most commonly used drugs are not the brand new ones, and they don’t account for a large fraction of total drug expenditure. If new drugs were widely used,” he acknowledged,

ODAC Supports Tightening... Continued from page 30 “It’s a basic principle of science,” noted Dr Newcomer. “Any observation should be confirmed by an independent observer.” Timing. Most ODAC members supported requiring that postmarketing trials be under way at the time of accelerated approval. Cooperative groups. ODAC members voiced support for making it necessary for only 1 of 2 confirmatory trials to be conducted through cooperative groups. Pharmaceutical companies cannot cede responsibility to cooperative groups, which carry out such studies for their own purposes. There was concern over GlaxoSmith-Kline’s failure to fulfill postmarketing requirements in trials for Bexxar (tositumomab and iodine 131 I tositumomab) therapy to treat

VOL. 2

NO. 2

relapsed and refractory low-grade follicular lymphoma. Two postmarketing commitments were delayed and 1 is ongoing. One of the trials set out to compare Bexxar and rituximab (Rituxan) and had trouble accruing sufficient patients, seeking FDA permission to shift to a study that is already being carried out by the Southwest Oncology Group. “We cannot be in a situation where a regulatory requirement is transferred to a third party,” said Dr Pazdur. But some on the panel emphasized that cooperative groups had been successful, particularly in pediatrics. Dr Newcomer echoed the concern, cautioning against too much rigidity. “The key is doing a good study,” he said, “not the organizational structure under which it is accomplished.” ■

“they would indeed push costs through the roof.” Currently, cancer drugs account for 5% of total drug expenditure, according to Dr Lichtenberg, and drugs account for about one tenth of total healthcare expenditure. So cancer drugs may account for half of 1% of total healthcare expenditure, he suggested. Innovation and Cancer Survival The connection between innovation and patient longevity is a major aspect of Dr Lichtenberg’s work. His previous research has shown that in some parts of the United States, new drugs have been adopted faster than in others, and in those states, there tended to be faster growth in life expectancy.2 In another study looking at 5 European countries, he found slower drug uptake in the United Kingdom relative to other countries in Europe (including France, Spain, and Germany); perhaps not surprisingly therefore, survival in the United Kingdom has been worse.3 This slower drug uptake in the United Kingdom may be related to NICE (National Institute for Health and Clinical Excellence), which carefully controls drug use based on costs, but Dr Lichtenberg acknowledged that he has not studied this formally. Dr Lichtenberg is currently working on a paper looking at innovation in pharmaceuticals and diagnostic imaging and the impact of innovation in these 2 sectors on cancer mortality.4 Overall, imaging innovation and drug innovation jointly explain about 75% of the decline in cancer mortality. “Where there has been the most rapid utilization of advanced imaging, we have also had the largest reductions in cancer mortality,” Dr Lichtenberg elaborated. “In fact, the survival gains from advanced imaging may be even larger than the survival gains from chemotherapy innovation.” The Value of Cancer Therapies In terms of whether the economist and the oncologist might actually work together, Dr Lichtenberg acknowledged, “I’m not too closely connected to the oncology community. I’ve occasionally interacted with ASCO [American Society of Clinical Oncology] and other organizations, but my approach is more from 30,000 feet.” With regard to the physician–patient

“We cannot expect patients or physicians to be too concerned about costs if they are not bearing those costs.” —Frank R. Lichtenberg, PhD

discussions on the value of cancer therapies, he recognizes the differences in perspective between economists and patients. “In principle, economists believe that as a society we should consider benefits and costs. This is what comparative effectiveness is about.” But in terms of an individual patient, “a Medicare patient doesn’t care what that organization pays [for a treatment], only what he as an individual pays.” Cost discussions with patients are relevant, Dr Lichtenberg noted, especially for very expensive therapies. And if the government is paying for these medications (as in the case of Medicare Part D), there is no reason why the government cannot exercise a role in terms of reimbursement, he suggested. Clearly, insurance affects decisionmaking; when people have insurance, they are not price-sensitive, and this can lead to excessive utilization of therapies that are not necessarily worthwhile. “We cannot expect patients or physicians to be too concerned about costs if they are not bearing those costs,” Dr Lichtenberg concluded. ■ References 1. Lichtenberg FR. The effect of new cancer drug approvals on the life expectancy of American cancer patients, 1978-2004. Econ Innovation N Technol. 2009;18: 407-428. 2. Lichtenberg FR. The Quality of Medical Care, Behavioral Risk Factors, and Longevity Growth. NBER Working Paper No. 15068. Issued June 2009. www.nber.org/papers/w15068. Accessed December 13, 2010. 3. Lichtenberg FR. The effect of cancer drug vintage on cancer survival and mortality. Ann Oncol. 2007;18 (suppl 3):iii67–iii77. 4. Lichtenberg FR. Has medical innovation reduced cancer mortality? NBER Working Paper No. 15880. Issued April 2010. www.nber.org/papers/w15880. Accessed December 13, 2010.

www.ValueBasedCancer.com

In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

1.9

4.9

months

Placebo 40

Afinitor 20

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2 BSC=best supportive care.

â&#x20AC;

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 2.5 mg 5 mg 10 mg

Printed in U.S.A.

10/10

AFI-1002330

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. • Infections [see Warnings and Precautions (5.2)]. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 Pneumonitisc 14 4

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

Hematology Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness 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 [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

ONCOLOGY BEST PRACTICES

The Value of EHR Best Practices for Leading Oncology Networks See also HITECH article, page 17 By Gerard M. Nussbaum and Laura K. Rehfeld Mr Nussbaum is Director of Technology Services, and Ms Rehfeld is a manager in Kurt Salmon’s Healthcare Group

recent survey by Kurt Salmon of best practices among leading oncology networks in the country (www.kurtsalmon.com/ oncology) suggests that the use of electronic health records (EHRs) in the most successful networks improves the flow of information between providers by using fewer, more robust systems with multiple access points, including EHRs, physician portals, and access through handheld devices. The study included more than 132 inpatient oncology sites within regional oncology networks across the United States. It surveyed oncology leaders about current and planned levels of oncology network development. The participants (who requested confidentiality as a condition for participation) represent some of the largest and most respected oncology centers in the United States today. The goal of the study was to provide oncology networks information about the level of EHRs and information technology (IT) in oncology practices. Questions included: • What are the current “best practices” in EHR and IT systems? • How do other oncology networks organize their IT resources and secure funding? • In what ways will the systems develop over the next 3 to 5 years?

Characteristics of Best Practices Characteristics of leading oncology networks with EHR best practices include dedicated staff and increased dedication to developing EHR and common IT systems across network sites; for example, it is rare that these networks would have disparate registry software. Most have also implemented common systems within specific functional areas; for example, all radiation oncology is on one system and inpatient care is on another system (Table). A key characteristic is their priority for developing a common EHR across all elements of oncology care, with IT goals and budgets that span multiple years. Although multiple IT systems will continue to exist, leading oncology networks bridge the gap with interfaces, health information exchange solutions, and physician portals. Given the specialized needs of oncology, leading networks focus on an oncology-specific EHR that supports tight integration with clinical modali-

ties. They recognize the immense opportunity of IT systems to link realtime clinical EHR with the longitudinal tumor registry to research clinical outcomes and protocol effectiveness.

to the network. The regular planning and budgeting cycle encourages the development of multiyear EHR initiatives, with some certainty that the goals can be achieved.

“Until there is a broad-based adoption of electronic health records, our ability to understand issues of quality, equity, and cost will be limited. Information technology is seen as critical to improving oncology patient care.” —Paul Browne

To facilitate clinical information flow today, leading networks complement IT resources with a clinical coordinator who serves as the central point to ensure information is gathered, cataloged, entered into IT systems, and disseminated to members of the oncology care team. Clinical records are often received in various media. The clinical coordinator incorporates all these into the central EHR. Clinical coordinators also facilitate the sharing of updates and patient status with referring physicians, who may not have access to the central EHR. Leading oncology networks expect the role of the clinical coordinator will continue to be essential well into the future, although their role will likely change. They also have a stable funding model and budget to support centralized functions and network goals. This is accomplished in 1 of 2 ways: network sites contribute to a common budget or the system allocates funding

Oncology EHR Development Despite the widely held belief that most oncology networks have robust EHR capabilities, this is not the case. Very few have achieved the desired level of IT sophistication; the vast majority continue to operate in a largely paper-based care universe. Given the predominance of paper-based manual systems, it is no surprise that oncology networks see expanding their EHR capabilities as a high priority. For example, Paul Browne, Senior Vice President and CIO, Trinity Health, said, “Until there is a broadbased adoption of electronic health records, our ability to understand issues of quality, equity, and cost will be limited. Information technology is seen as critical to improving oncology patient care.” Most oncology networks have a common vision to move to a single oncology EHR. One reason so few have adopted a single EHR to date is the limitations of current systems. No

Table Clinical and IT Components in Oncology Networks Oncology networks, %

Leading oncology networks, %

A single EHR

100

A single system for imaging, laboratory, and testinga

100

A single tumor registry system

100

Common clinical protocolsb

100

Oncology Network has

System may be integrated within a single EHR or separate. Network has achieved common clinical protocols above adoption of standard guidelines, such as the National Cancer Institute Community Cancer Centers Program best practices. EHR indicates electronic health record; IT, information technology. Source: Kurt Salmon research of 132 inpatient oncology sites organized within regional networks across the US, 2010. www.kurtsalmon.com/oncology. b

VALUE-BASED CANCER CARE

April 2011

vendor has developed a comprehensive, mature oncology EHR platform that is fully integrated with an enterprise EHR, thus requiring networks to piece together different systems to support medical oncology, radiation oncology, inpatient care, and tumor registry functions. In the rare cases where a single oncology EHR exists, it is usually achieved through niche solutions tied to treatment modalities and is only partially integrated with the hospital’s enterprise EHR. Throughout the study, networks expressed the goal of developing a unified oncology EHR among the sites, interfaced to the enterprise EHRs, and leveraging health information exchange to connect external providers. Given the current and near-term future capabilities of enterprise EHR solutions, leading oncology networks will likely live in an interfaced world, electronically exchanging clinical information between general enterprise EHR solutions and specialized oncology EHR solutions. Greater Value in Oncology Care The majority of oncology networks have implemented some portion of the best practices. All networks express a desire to move toward a more complete set of systems and resources and common EHR solutions; however, many lack the funding and organizational cohesiveness to implement desired staffing models or IT solutions. The main factors in the best practices for creating a common EHR include (1) a central guiding body comprised of network leadership and site clinicians that set the EHR plan and garner support from individual network sites; and (2) financial resources dedicated to oncology EHR. Leading networks view implementation of an EHR as a requirement to advance clinical care coordination for demonstrating better outcomes, lowering cost, and increasing the value of care. As such, these networks create multiyear plans and budgets to support EHR development. We expect many networks to adopt this viewpoint over the next few years and invest in IT systems, interfaces, and health information exchange as a way to create growth and value in the future. ■

VOL. 2

NO. 2

THANK YOU to the sponsors and to the nearly 200 oncologists, payers, and attendees who made AVBCCâ&#x20AC;&#x2122;s First Annual Stakeholder Integration Conference in Philadelphia a great success

Complete conference coverage coming in the July 2011 issue

HOPA ANNUAL MEETING

Making Cancer Drugs Worth the Cost Efficacy and safety are the real “business” of medicine By Christin Melton Salt Lake City, UT—When it comes to cancer, “how much is too much?” is a common question. At the John G. Kuhn Keynote Lecture at the 2011 Hematology/Oncology Pharmacy Association annual meeting titled “The Cost of Cancer Therapy,” speaker Tito Fojo, MD, PhD, with the National Cancer Institute (NCI), said cost is not the real issue. “If you frame the argument in terms of cost, you’re going to lose it,” he said. Dr Fojo said the real issue is “about how effective drugs are and how toxic drugs are.”

“If you frame the argument in terms of cost, you’re going to lose it”; the real issue is “about how effective drugs are and how toxic drugs are.” —Tito Fojo, MD, PhD

Dr Fojo offered examples of drugs used in clinical situations that not only fail to improve survival but actually harm patients, such as cetuximab (Erbitux) for patients with metastatic colorectal cancer (CRC) and bevacizumab (Avastin) for patients with breast cancer. He acknowledged that controversy surrounds these examples

and not everyone shares his views, including Giuseppe Giaccone, MD, PhD, his supervisor at NCI and a member of the American Society of Clinical Oncology (ASCO) panel responsible for adding the combination of cetuximab and paclitaxel (Taxol) to the ASCO guidelines for first-line therapy of metastatic CRC. These therapies are also included in the National Comprehensive Cancer Network treatment guidelines. The Unmet Promise of Personalized Medicine Dr Fojo’s review of the pivotal trials used to support the US Food and Drug Administration (FDA) approval of cetuximab in metastatic CRC and bevacizumab in breast cancer underscores important considerations for various stakeholders when considering drug development and use. “Our drug development, drug approval, and drug consumption strategies need better focus,” he said, lamenting that despite the decade that has elapsed since imatinib (Gleevec) ushered in the “targeted therapy revolution,” too many treatments are still used indiscriminately in broad patient populations. Dr Fojo sees room for improvement at all levels—academia, the pharmaceutical industry, government agencies such as the FDA, and clinicians treating patients with cancer. All are responsi-

Successful Strategies for Drug Cost-Containment in Oncology Practice Salt Lake City, UT—Before establishing measures your oncology practice can implement to lower costs, review your physicians’ prescribing habits, identify causes of drug waste, and look for outlays that are not captured in reimbursement channels, said Bhavesh Shah, RPh, BCOP, a clinical pharmacy specialist with Boston Medical Center (BMC) at the 2011 Hematology/Oncology Pharmacist Association meeting. He outlined successful examples of cost-saving strategies that BMC has adopted. The Benefit of Dose-Rounding Rounding the dose of certain oncology biologics to within 10% of the

amount ordered is one successful measure. The purpose is: • Ensure the drug is measured accurately • Minimize drug waste • Maximize cost avoidance. The 10 drugs that are the most amenable to dose-rounding are listed in the Table (page 40). “For any order that comes through the pharmacy, the pharmacist can round the dose to the nearest vile size for the concentration,” said Mr Shah. The exceptions include when the difference between the ordered dose and the nearest vile size exceeds 10%. “That’s when we try to round it to the

VALUE-BASED CANCER CARE

Continued on page 40

April 2011

ble for “our failure to deliver on the promise of personalized medicine.” The example of cetuximab supports Dr Fojo’s contention that drugs must be analyzed prospectively to identify predictive markers before initiating trials. Four years after cetuximab’s 2004 FDA approval, a study published in the New England Journal of Medicine showed it was ineffective in patients with mutated KRAS. In 2009, ASCO issued its Provisional Clinical Opinion recommending KRAS testing before

“Our drug development, drug approval, and drug consumption strategies need better focus.” —Tito Fojo, MD, PhD

prescribing cetuximab, but left it as a voluntary option. Cetuximab inhibits epidermal growth factor receptor (EGFR), and “as early as 1990, Bert Vogelstein at Hopkins had reported that as many as 50% of colorectal patients harbored KRAS,” Dr Fojo said. In 1998, KRAS was reported to be in the EGFR signaling pathway. “Despite this, we went ahead and conducted studies without looking at this prospectively.” Continued investigation into the causes of poor response to cetuximab among some patients with wild-type KRAS will likely reduce the viable patient population even further. “Eventually, we’ll be able to identify the 80% of patients that do not benefit, and give it only to the 20% who benefit substantially, and a drug that was marginal to begin with will become highly effective,” said Dr Fojo. What Constitutes an Acceptable Improvement? “Increasingly, therapies that demonstrate at best marginal improvement are being used in the treatment of cancer,” he noted. With breast cancer, we may even be going backward, with the controversy over bevacizumab. He emphasized that his views did not represent those of the NCI. Dr Fojo faulted the decision to approve bevacizumab based on data from the E2100 study, which suggested that adding it to paclitaxel significantly prolonged progression-free survival (PFS) but not overall survival (OS).

Although the study showed nonsignificant improvement in OS favoring bevacizumab, “Nonsignificant improvement is no improvement,” he said, adding that it was unusual for a study to reflect major discordance between PFS and OS. Dr Fojo and colleague published a review of major studies published since 1996 with a significant improvement in PFS or OS and found “tight correlation between the two” (Lancet Oncol. 2010;11:1117-1119). He therefore believes E2100 is an outlier. Even if bevacizumab does improve PFS, “delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms,” he said. Toxicities Studies need to focus more on whether regimens used are harming patients. In E2100, patients treated with bevacizumab had more than twice as many adverse events as the control group. Dr Fojo believes that toxicity is unacceptable when a treatment fails to improve OS and is very expensive, but he acknowledged that many breast cancer specialists disagree. The FLEX trial, investigating cetuximab in metastatic CRC, also found high rates of grade 3 and 4 toxicities, particularly severe skin reactions. With the growing use of oral therapies for cancer, it is important that studies not overlook the grade 1 and 2 toxicities, he said. “The scale was developed for chemotherapy, but when you are taking a drug every day for months on end, a grade 1 or 2 event can be very difficult.” Although cost is relevant for drugs that cause serious adverse effects but demonstrate minimal efficacy, Dr Fojo said it comes down to the notion that you do not harm patients for little improvement in survival. Various attempts to combine therapies have hurt patients, without helping them; he called for an end to this “incremental approach” to treatment. Finding better treatments requires determining the settings in which the drugs work best, but also the ones in which they do not work. This would require major journals to give greater weight to negative studies, he said, which are often relegated to secondand third-tier journals. It also requires expanding incentives for pharmaceutical companies to take a more personalized approach to drug development, where rewards are likely to be less lucrative. ■

VOL. 2

NO. 2

HOPA ANNUAL MEETING

Successful Strategies for Drug Cost-Containment...

Continued from page 38

nearest concentration size available.” Dose-rounding is only as effective as the level of adherence by pharmacy clinicians. A retrospective study (J Oncol Pharm Pract. 2010 Mar 23 [Epub ahead of print]) showed that a 3month pilot program to round doses for orders of 7 anticancer biologics would have produced a 42% reduction in drug wastage and $24,434 in savings (in 2005 dollars) had there been 100% compliance with the program. Instead, because the dose-rounding protocol was not used in 29 of the 126 orders, savings amounted to only $15,922. It is important to include measures for monitoring adherence. Chemotherapy Infusion The following strategies implemented at BMC for chemotherapy infusion have led to hundreds of thousands of dollars in annual savings. Shift Inpatient to Outpatient Administration Encourage your physicians to shift from inpatient to outpatient chemotherapy administration. “We developed this because a lot of chemotherapy was being administered in the hospital, primarily due to convenience, where we got reimbursed by DRGs [diagnostic-related groups] but not based on what the patient was actually receiving,” Mr Shah said. Under Medicare, inpatient claims can list only 1 DRG, whereas outpatient claims permit multiple ambulatory payment classifications (APCs). Chemotherapy drugs are also not bundled under APCs, allowing for greater reimbursement. “Now, we always push our physicians to do it on the day of, or the day after, hospital release, so we can capture that cost,” he said, adding that orders for inhospital chemotherapy administration declined by 50%. Test Rituximab before Infusion Another new policy at BMC is to test the dose of rituximab (Rituxan) before starting infusion. Mr Shah said that 80% of patients receiving rituximab will have a reaction to their first infusion, which leads to discontinuation and drug waste. In 2009, infusion reactions resulted in $50,000 in wasted rituximab. “We implemented a test dose for each patient, and we saw a drastic decline in waste of rituximab,” he said. The test dose is 100 mg and is administered to all patients at BMC who are scheduled for rituximab infusion and have not received the drug for at least 6 months. In 2010, BMC saved approximately $2000 per patient using rituximab.

Table 10 Anticancer Agents Amenable to Dose-Rounding Drug

Rounding amount

Infliximab

Nearest 100 mg

Bevacizumab

Nearest 100 mg

Rituximab

Nearest 100 mg

Docetaxel

Nearest 20 mg

Pemetrexed

Nearest 100 mg

Cetuximab

Nearest 100 mg

Oxaliplatin

Nearest 5 mg or 50 mg

Gemcitabine

Nearest 200 mg

Panitumumab

Nearest 20 mg or 100 mg

Bendamustine

Nearest 25 mg

Follow Guidelines for Pegfilgrastim When Mr Shah and his colleagues were seeking ways to reduce costs, they observed that orders for pegfilgrastim (Neulasta) had increased. Based on published data, they thought it might be safe to delay administration of white blood cell growth factor support for patients treated with paclitaxel (Taxol). They tested this on 10 patients prescribed 4 cycles of paclitaxel (175 mg/m2 every 2 weeks), and administered a single dose of pegfilgrastim with the first dose of the second cycle of paclitaxel. All patients completed therapy without delay, with no neutropenic events or hospitalizations. Mr Shah speculated that delaying pefilgrastim led to less bone pain from paclitaxel-induced arthralgia. It also cut costs by $60,000.

“We implemented a test dose for each patient and we saw a drastic decline in waste of rituximab.” —Bhavesh Shah, RPh, BCOP

He noted that pegfilgrastim was sometimes administered as primary prophylaxis in situations inconsistent with established practice guidelines. “There was a lot of inappropriate utilization, in metastatic prostate cancer, stage IV non–small-cell lung cancer [NSCLC], and metastatic colon cancer,” said Mr Shah. They requested that physicians stop using growth factor support when the intent was not curative and use dose reductions or delays instead. Physicians were also

VALUE-BASED CANCER CARE

April 2011

told to stop giving it to patients receiving chemotherapy with curative intent and an associated incidence of febrile neutropenia <20%. To adhere to evidence-based guidelines for pegfilgrastim, BMC required physicians to administer it in the adjuvant setting for patients with colorectal cancer (CRC) and NSCLC, the neoadjuvant setting for patients with solid tumors whose operative procedure had curative intent, and for patients with a malignancy related to AIDS. Even with these measures, BMC decreased expenditures by $250,000 annually, which does not factor in potential cost-savings from ensuring that all appropriate patients received the drug. Rapid Infusion for Improved Utilization Mr Shah noted that no formal economic analysis has ever been done on the cost-effectiveness of rapid infusion. Agents to consider for rapid infusion include rituximab, bevacizumab (Avastin), trastuzumab (Herceptin), cetuximab (Erbitux), as well as lowmolecular-weight (LMW) iron dextran (INFeD). “This can increase your resource utilization,” he said. One 2007 study tested a 90-minute rituximab infusion in more than 1200 patients, a 0% rate of grade 3/4 toxicity related to the faster infusion was observed. Other studies found 30minute infusions of trastuzumab and bevacizumab and 60-minute infusions of cetuximab and LMW iron dextran to be relatively safe. A higher rate of adverse events was seen in patients allergic to >2 drugs who received LMW iron dextran. Mr Shah cautioned that Dexderm—another form of iron dextran—should not be used in a rapid fashion.

“I think rapid infusions are great. It totally increases the volume for your clinic and decreases the absentees, and you can get your patients out faster,” Mr Shah said; it also increases satisfaction among patients and nurses. Cetuximab versus Panitumumab BMC switched from cetuximab to the lower-cost panitumumab (Vectibix) for CRC based on studies showing little difference in overall response rate or survival. Although the cost per 100 mg is higher for panitumumab than for cetuximab ($618.81 vs $367.83, respectively), cetuximab requires an 8vial loading dose. A BMC 4-week cost analysis of panitumumab averaged $5953.70 compared with $8460.09 for cetuximab. In addition, reimbursement from the Centers for Medicare & Medicaid Services (CMS) was higher for panitumumab than for cetuximab ($49.737/10 mg vs $87.326/10 mg). Other cost-savings with panitumumab included reduced chair time, because it can be administered every 2 weeks, and the reduction in febrile neutropenia treatment.

“We had about $20,000 in waste that we saved last year using these programs.” —Bhavesh Shah, RPh, BCOP

Handling Waste BMC takes advantage of bio-oncology spoilage programs offered by pharmaceutical companies. “They’re not well known, and you have to actually call, but...it’s pretty easy,” he said. “We had about $20,000 in waste that we saved last year using these programs. Fill out a form and they send you a check for the drug that’s been wasted.” Adopting such programs allows you to request reimbursement from CMS for “discarded drug/biological remaining in a single-use product after administering what is reasonable and necessary for the patient’s condition” (per Pub. 100-04, Chapter 17, Section 40 in the Medicare Claims Processing Manual). Mr Shah said, “There’s a JW code that mirrors the J code you’re billing for.” CMS requires documenting the cause of waste in the patient’s medical record, which BMC has implemented to recover those costs. When looking for ways to save costs, patient safety is the most important consideration, he said.—CM ■

VOL. 2

NO. 2

For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages. VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information]. INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information]. WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 <500/mm3 10 (4.2%) 146 (62.1%) Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%) <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

10.2

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. 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. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. 0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

CONTINUING EDUCATION

Improving the Prevention and Treatment of Venous Thromboembolism in Cancer: The Strategic Role of the Health-System Pharmacist PROGRAM P10076E

REGISTERED PHARMACY DESIGNATION

Initial Release Date: April 22, 2011 • Expiration Date: April 22, 2012. Estimated time to complete activity: 1 hour.

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-11-021-H01-P.

SPONSOR

This activity is sponsored by Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC. TARGET AUDIENCE

This activity was developed for health-system pharmacists and oncology pharmacists. LEARNING OBJECTIVES

• Explain the epidemiology and risk factors of venous thromboembolism (VTE) in cancer • Summarize current evidence-based guidelines for prevention and treatment of VTE in cancer, with special attention to the differences and similarities across guidelines • Discuss key data from randomized clinical trials of low-molecular-weight heparins in prevention of recurrent VTE in cancer • Describe emerging strategies in VTE prophylaxis and treatment COMMERCIAL SUPPORT ACKNOWLEDGMENT

This activity is supported by an educational grant from sanofi-aventis. INSTRUCTIONS FOR CREDIT

There is no fee for this activity. To receive credit, participants must read this CE activity in its entirety and complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/p10076E.html.Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@mlicme.org.

DISCLOSURES

Before the activity, all faculty and anyone that is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Paul Dobesh, PharmD, FCCP, BCPS, is a consultant to Ortho-McNeil and sanofi-aventis. Gary M. Owens, MD, is a consultant to Auxilium, Biosense Webster, Centocor Ortho Biotech, Eli Lilly, Genentech, and Novartis. Gary C. Yee, PharmD, FCCP, BCOP, is on the advisory board for Amgen. Nancy Nesser, JD, PharmD, a reviewer for MLI, has nothing to disclose. DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred.

Venous Thromboembolism a Major Concern in Patients with Cancer By Gary M. Owens, MD, President, Gary Owens Associates, Philadelphia, PA

he risk of venous thromboembolism (VTE) in the general population is substantial, with an approximate incidence of 1 VTE case per 1000 individuals. This translates to more than 200,000 new cases annually in the United States.1 More important, almost 30% of patients with VTE will die within 30 days of the initial diagnosis.1 Although not all those deaths are directly related to VTE or its sequelae, approximately 20% of those dying within this 30-day period will be caused by pulmonary embolism (PE).1 Despite significant advances in the diagnosis and management of VTE, its incidence has not substantially changed since the 1980s.1 The risk of having VTE is elevated by a number of factors, including1: • Central venous catheter/transvenous pacemaker • Hospital or nursing home confinement • Hormone replacement therapy • Increasing age • Male sex • Malignancy

• Neurologic disease with extremity paresis • Oral contraceptives • Pregnancy • Previous superficial vein thrombosis • Surgery • Trauma • Varicose veins. Venous Thromboembolism and Malignancy VTE may be a presenting sign of an occult malignancy. Of all new cases of VTE, approximately 20% are associated with active malignancy.2 It is remarkable to note that patients with cancer have a 4- to 6-fold higher risk for VTE compared with patients without cancer.3 Therefore, otherwise healthy adults presenting with VTE without an obvious cause may warrant additional testing to rule out occult malignancies. VTE is also a major concern for patients with cancer, and it must be considered a serious complication of an already-diagnosed cancer. For

VALUE-BASED CANCER CARE

April 2011

patients with cancer, the incidence of VTE approaches 1 in 200 patients.4 Approximately 20% of VTE cases occur in patients with cancer,2 which means that cancer-related cases of VTE account for more than 40,000 of the 200,000 cases seen annually in the United States. Fifteen percent of patients with cancer will have symptomatic, diagnosed VTE, and, astoundingly, almost 50% of patients with cancer are found to have VTE at postmortem examination.5 The risk of VTE in patients with cancer is compounded by the fact that many patients in this population are older people, aged >55 years. VTE is the second leading cause of death in hospitalized patients with cancer, and the risk of death from VTE in patients with cancer is 3- to 8-fold higher than in comparable patients without cancer.6 Furthermore, patients with cancer and symptomatic deepvein thrombosis (DVT) exhibit a high risk for recurrent DVT/PE that persists for many years after the initial episode.7

Other Risk Factors Other factors that increase the risk for VTE in patients with cancer include the type of malignancy. In men, tumors of the prostate, colon, lung, and brain are among the cancer types with the highest risk for VTE. In women, breast, ovarian, and lung cancers are associated with increased VTE risk.4,8 Hematologic malignancies, such as lymphoma and multiple myeloma, especially when the latter disease is treated with immunomodulators, have a very high risk for VTE events.4 Finally, VTE increases the risk for cancer-related death in hospitalized patients.9 The Figure illustrates that the percentage of patients who suffer in-hospital death is higher with either metastatic or nonmetastatic disease when VTE is a comorbid condition.9 The risk for VTE is certainly increased in patients diagnosed with a malignancy. That risk can further be compounded by such factors as the treatment of the disease by selected

VOL. 2

NO. 2

CONTINUING EDUCATION Figure VTE and Inpatient Mortality No VTE

VTE

Mortality, %

14 12 10 8 6 4 2 0 All (N = 66,016)

Nonmetastatic (N = 20,591)

Metastatic (N = 17,360)

Hospital deaths VTE indicates venous thromboembolism. Adapted with permission from Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

chemotherapeutic agents, the placement of a centrally dwelling catheter, or even by surgical procedures targeted at removing the lesion. It is therefore essential that oncologists and other providers caring for patients with cancer are aware of these risks and take steps to prevent and to aggressively manage cancerrelated VTE. At a minimum, physicians must actively intervene to prevent VTE in patients with cancer who are undergoing surgery or who are hospitalized. In addition, strong consideration should be given to consider preventive therapies for high-risk ambulatory patients with cancer (eg, patients with myeloma receiving immunomodulatory therapy) and to engage in long-term treatment (>6 months) for patients with cancer who have VTE to prevent VTE recurrence. ■

References 1. Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost. 2002;28(suppl 2):3-13. 2. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162:1245-1248. 3. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815. 4. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation. 2003;107(23 suppl 1):I-17-I-21. 5. El-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment. Oncologist. 2007;12:518-523. 6. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 1999;159:445-453. 7. Prandoni P, Lensing AW, Cogo A, et al. The longterm clinical course of acute deep vein thrombosis. Ann Intern Med. 1996;125:1-7. 8. Heit JA. Cancer and venous thromboembolism: scope of the problem. Cancer Control. 2005;12(suppl 1):5-10. 9. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:484-490.

Guidelines for the Prevention and Treatment of Venous Thromboembolism in Cancer By Gary C. Yee, PharmD, FCCP, BCOP, Professor of Pharmacy Practice and Associate Dean for Academic Affairs, College of Pharmacy, University of Nebraska Medical Center, Omaha, and a member of the utilization management committee and national pharmacy & therapeutics committee for a large pharmacy benefits manager

everal international organizations have developed clinical practice guidelines for the prevention and treatment of venous thromboembolism (VTE) in patients with cancer.1 In the United States, 3 organizations have developed guidelines for VTE—the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN).2-4 The guidelines differ in their scope and methods used to develop the guideline. The ACCP and ASCO guidelines are based on a systematic review and formal evaluation of study quality. The first NCCN guideline was based on a systematic review, but annual revisions are based on review of recently published research and responses to questions asked by clinicians at member institutions.1 The ASCO and NCCN guidelines are limited to the prevention and treatment of VTE in patients with cancer.

Prevention of Venous Thromboembolism The ACCP, ASCO, and NCCN guidelines agree that all hospitalized patients with cancer, including those undergoing surgery, should receive prophylactic anticoagulation (in the absence of contraindications).2-4 Recommended agents include low-dose unfractionated heparin, low-molecular-weight heparin (LMWH), or fonda-

VOL. 2

NO. 2

parinux. Patients undergoing major abdominal or pelvic surgery should receive prolonged prophylaxis (ie, up to 4 weeks). For ambulatory cancer patients, the ACCP, ASCO, and NCCN guidelines agree that routine VTE prophylaxis is not recommended. The ASCO and NCCN guidelines list certain high-risk patient groups that are exceptions to the recommendation (Table). Although the ASCO and NCCN guidelines consider those who are receiving thalidomide or lenalidomide with chemotherapy or dexamethasone as high-risk patients, the NCCN guideline adds specific information on dexamethasone dose and incorporates a risk assessment model and recommendations developed by an international group of experts.5 In contrast to other VTE risk assessment models, that risk assessment model was developed specifically for patients with multiple myeloma who are treated with thalidomide or lenalidomide. The recommended agents for VTE in high-risk patients vary depending on the guideline and risk category. The ASCO guideline does not list aspirin as a recommended prophylactic agent, probably because its literature search only included randomized controlled trials published through the end of 2006.3 The NCCN guideline recommends LMWH or full-dose warfarin for most patients, but lists aspirin as an option for selected patients (eg, low-

Table Comparison of Guidelines for the Prevention of VTE in Ambulatory Patients with Cancer

Definition of highrisk patients

ASCO

NCCN

Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone

Select patients receiving highly thrombotic antiangiogenic therapy (ie, multiple myeloma patients receiving thalidomide/lenalidomide and high-dose dexamethasone [≥480 mg/month]), doxorubicin, or multiagent chemotherapy) Myeloma patients with ≥2 individual or myeloma risk factors

Recommended agent(s)

LMWH or warfarin (INR ~1.5)

LMWH (eg, enoxaparin 40 mg subcutaneous every 24 hr) or warfarin (INR 2-3) Low-risk myeloma outpatients: aspirin (81-325 mg/day)

ASCO indicates American Society of Clinical Oncology; INR, international normalized ratio; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolism.

risk myeloma outpatients).4 This variability in the guideline recommendations reflects the lack of rigorous evidence on the prevention of VTE in patients with multiple myeloma. Guideline recommendations are likely to change as the results of randomized controlled trials are published. For example, Palumbo and colleagues recently reported the results of a randomized controlled comparison of aspirin (100

mg/day), fixed low-dose warfarin (1.25 mg/day), or LMWH (enoxaparin 40 mg/day) as VTE prophylaxis in 667 patients with multiple myeloma treated with thalidomidebased regimens.6 Of 659 analyzed patients, 43 (6.5%) developed an event, a composite end point that included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 Continued on page 46

www.ValueBasedCancer.com

CONTINUING EDUCATION

Guidelines for the Prevention and Treatment... months of treatment. The event rate for the different thromboprophylaxis arms was not significantly different. Validated risk assessment models are also needed to predict the risk of VTE in patients with multiple myeloma. Treatment of Venous Thromboembolism The ACCP, ASCO, and NCCN guidelines agree that all patients with cancer and established VTE should be treated with anticoagulation.2-4 Recommended agents include unfractionated heparin, LMWH, or fondaparin-

ux, and the recommended duration of initial therapy is a minimum of 5 days. Long-term therapy with LMWH is recommended for up to 6 months. Each of the guidelines recommends that anticoagulation be continued for longer than 6 months in selected patients with cancer. The ACCP guideline recommends “subsequent anticoagulation with LMWH or warfarin indefinitely or until the cancer is resolved” (grade 1C recommendation).2 The ASCO guideline states that “indefinite anticoagulation should be considered for selected patients with

Continued from page 45

active cancer, such as those with metastatic disease and those receiving chemotherapy” (panel consensus).3 The NCCN guideline recommends indefinite anticoagulation if the patient has active cancer or persistent risk factors. ■ References 1. Khorana AA, Streiff MB, Farge D, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guideline panels and call to action. J Clin Oncol. 2009;27:4919-4926. 2. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-

Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):454S-545S. 3. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505. 4. National Comprehensive Cancer Network. Venous thromboembolic disease. Version 1. 2011. www.nccn. org/professionals/physician_gls/pdf/vte.pdf. Accessed April 14, 2011. 5. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22: 414-423. 6. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:986-993.

Case Scenarios in the Prevention and Treatment of VTE in Patients with Cancer By Paul Dobesh, PharmD, FCCP, BCPS, Professor of Pharmacy Practice, University of Nebraska Medical Center College of Pharmacy, Omaha

Case Scenario 1 J. B. is a 54-year-old obese man recently diagnosed with stage III colon cancer. He is admitted today for surgical resection of the involved bowel segment and will subsequently receive FOLFOX (5FU, leucovorin, and oxaliplatin) as adjuvant chemotherapy. He has no history of cancer or thromboembolic events. Is thromboembolism a concern in this patient?

atients with cancer undergoing surgical procedures are at higher risk for the development of venous thromboembolism (VTE) compared with patients without cancer undergoing similar surgical procedures.1,2 Patients with cancer undergoing surgery are considered to be one of the highest risk groups for the development of VTE, with event rates similar to those in patients undergoing orthopedic surgery.3,4 This high risk for VTE is because patients undergoing cancer surgery end up with all 3 parts of Virchow’s triad: venous stasis, vascular damage, and a hypercoagulable state. Therefore, VTE prophylaxis in these patients is very recommended.3,4 The decision on what to use for prophylaxis has also been extensively studied. In the Enoxaparin in Cancer (ENOXACAN) study, 631 patients undergoing elective abdominal or pelvic surgery for cancer were randomized to enoxaparin 40 mg subcutaneously once daily or to unfractionated heparin (UFH) 5000 units subcutaneously 3 times daily.5 The first dose of anticoagulant was given 2 hours before surgery and

continued for 10 days. The primary end point of the ENOXACAN study was the incidence of total VTE determined by venography. Although the primary end point was reduced by almost 20% at 10 days with the use of enoxaparin compared with UFH, this difference was not significant (14.7% vs 18.2%). There was also no significant difference in the incidence of total bleeding or major bleeding (4.1% vs 2.9%) between the groups. In the Canadian Colorectal DVT Prophylaxis Trial, 1349 patients undergoing colorectal surgery were randomized to the same regimens of enoxaparin and UFH6 as in the ENOXACAN study. In this Canadian study, 35% of the patients (n = 475) were undergoing colorectal surgery for cancer. In this subgroup, the incidence of VTE was 13.9% in the enoxaparin group compared with 16.9% in the UFH group.6 The efficacy and safety between using a low-molecular-weight heparin (LMWH) or UFH for in-hospital VTE prophylaxis in patients undergoing surgery for cancer has been evaluated in a meta-analysis.7 This meta-analysis included 14 randomized trials that compared these regimens in surgical cancer patients. Although patients receiving LMWH did not demonstrate any reduction in mortality (relative risk [RR], 0.89; 95% confidence interval [CI], 0.61-1.28), there was a significant reduction in deep-vein thrombosis (DVT) with the use of LMWH (RR, 0.72; 95% CI, 0.55-0.94). Most of this overall benefit to the use of LMWH was in the comparison to patients receiving UFH twice daily (RR, 0.66; 95% CI, 0.44-0.99), with less difference demonstrated in comparison to UFH

VALUE-BASED CANCER CARE

April 2011

3 times daily (RR, 0.78; 95% CI, 0.531.15). There was also no significant difference between the 2 regimens with regard to minor or major bleeding.7 Another important question that arises with the use of VTE prophylaxis in patients having cancer surgery is the appropriate duration of prophylaxis. Although VTE prophylaxis for most indications is usually given for the duration of hospitalization or until the patient is mobile, data suggest that a longer duration is indicated in patients undergoing surgery for cancer.

Another important question that arises with the use of VTE prophylaxis in patients having cancer surgery is the appropriate duration of prophylaxis. The ENOXACAN II study evaluated patients undergoing gastrointestinal tract, genitourinary tract, or female reproductive organ cancer surgery.8 All patients received enoxaparin 40 mg subcutaneously once daily for 6 to 10 days. Patients (n = 332) were then randomized in a double-blind fashion to continue taking enoxaparin at the same dose or placebo for an additional 21 days. The primary end point was the incidence of venographic VTE at 1 month, which was significantly reduced by 60% with the use of enoxaparin compared with placebo (4.8% vs 12%; P = .02), as well as a 60% reduction in proximal DVT (0.6% vs 1.8%). This significant 60% reduction in the primary end point was still evident at

the 3-month follow-up (5.5% vs 13.8%; P = .01). The use of extended prophylaxis with enoxaparin did not produce a significant increase in any bleeding event (5.1% vs 3.6%) or major bleeding (0% vs 0.4%) compared with placebo.8 These results have been confirmed by 2 additional studies.9,10 The Cancer, Bemiparin, and Surgery Evaluation (CANBESURE) study randomized 703 patients undergoing abdominal or pelvic surgery for cancer to bemiparin 3500 IU subcutaneously once daily or placebo after completing 6 to 10 days of bemiparin (same dose).9 At 3-month follow-up, major VTE was reduced by more than 80% with the use of extended bemiparin compared with placebo (0.8% vs 4.6%; P = .010). Major bleeding was not significantly different between the groups (0.6% vs 0.3%; P = .572).9 The Fragmin After Major Abdominal Surgery (FAME) trial was slightly different in that it enrolled all patients undergoing abdominal surgery and had an open-label design.10 Patients were randomized to dalteparin 5000 IU subcutaneously once daily for 7 days or 28 days. Overall, VTE events were significantly reduced with extendedduration dalteparin prophylaxis at the 1-month follow-up (7.3% vs 16.3%; P = .012). Although 58% of the patients in the FAME trial had abdominal surgery for cancer, the results for the subgroup of patients with cancer are not provided. Minor and major bleeding were not significantly increased with the extended duration of VTE prophylaxis. Based on the results of these studies, extended VTE prophylaxis is recommended for patients undergoing abdominal or pelvic surgery for cancer.3,4 Continued on page 47

VOL. 2

NO. 2

CONTINUING EDUCATION

Case Scenarios in the Prevention and Treatment... Case Scenario 2 A. K. is a 42-year-old woman diagnosed with stage IIB breast cancer. She had a lumpectomy with surgical axillary staging and has since been receiving radiation and chemotherapy. Two months into therapy, she presents to the hospital with right lower-leg pain, swelling, and tenderness. A duplex ultrasound is positive for proximal DVT. What should be the approach to treatment in this patient?

he treatment of VTE in patients with cancer requires a different approach compared with that for the patient without cancer. The typical patient without cancer who has VTE receives an injectable anticoagulant and warfarin together for a minimum of 4 days and until the international normalized ratio (INR) becomes therapeutic in the range of 2 to 3. At that time, the injectable anticoagulant (UFH, LMWH, or fondaparinux) is then discontinued and the patient continues taking warfarin for at least 3 to 6 months, depending on the etiology of the VTE.4 In patients with cancer, the management should be an LMWH for 3 to 6 months, without the typical initiation of warfarin. This different management strategy is srongly recommended in clinical guidelines and supported by well-conducted randomized clinical trials. Although dalteparin is currently the only LMWH to be approved by the US Food and Drug Administration for treatment of VTE in patients with cancer, all 3 LMWHs available in the United States have clinical evidence to support their use for VTE therapy. Tinzaparin was compared with a standard vitamin K antagonist in the treatment of VTE in the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE).11 In the LITE trial, 200 patients with cancer with acute symptomatic proximal vein thrombosis were randomized in an open-label fashion to tinzaparin 175 IU/kg subcutaneously once daily for 3 months or to UFH intravenous bolus and infusion overlapped with warfarin until day 6 and the INR was therapeutic (2-3), with warfarin continued for 3 months. At 3 months, the incidence of recurrent VTE was reduced by 40% in the tinzaparin group compared with the usual-care group, but this did not achieve significance (6% vs 10%). Patients receiving tinzaparin did have a

VOL. 2

NO. 2

significant 56% reduction in recurrent VTE at the end of 12 months (7% vs 16%; P = .04). The incidence of minor bleeding, major bleeding, and death were similar between the groups.11 In another study, enoxaparin 1.5 mg/kg subcutaneously once daily for 3 months was compared with the same dose of enoxaparin overlapped with warfarin for at least 4 days, with warfarin continued at an INR of 2 to 3 for 3 months.12 The 146 patients with cancer in this trial were diagnosed with pulmonary embolism (PE) and/or DVT and then randomized to 1 of the 2 treatment groups in an open-label fashion. The primary outcome of recurrent VTE and major bleeding at 3 months occurred in 10.5% of enoxaparin patients and 21.1% of warfarin patients (P = .09). While mortality was cut by more than 50% with the use of enoxaparin compared with warfarin (11.3% vs 22.7%; P = .07), this trial was not large enough to find a significant difference in mortality. Fatal bleeding was significantly reduced with the use of enoxaparin compared with warfarin (0% vs 8%; P = .03), whereas other major bleeding did not achieve statistical significance (9% vs 17%; P = .07).12 Dalteparin was compared with warfarin therapy for treatment of PE and/or DVT in patients with cancer in the Comparison of Low-MolecularWeight Heparin versus Oral Anticoagulant Therapy for Long-Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) trial.13 Patients in the CLOT trial (n = 676) were randomized in an open-label fashion for 6 months of anticoagulant therapy. Patients randomized to dalteparin received 200 IU/kg (maximum dose of 18,000 IU) subcutaneously once daily for 1 month, and then approximately 150 IU/kg subcutaneously once daily for the remaining 5 months. The usualcare patients received dalteparin 200 IU/kg (maximum dose of 18,000 IU) subcutaneously once daily overlapped with a vitamin K antagonist for at least 5 days, and the INR was therapeutic (2-3), with the vitamin K antagonist continued for the remaining 6 months. At 6 months, the primary end point of recurrent VTE was significantly reduced by 50% with the use of dalteparin compared with usual care (8% vs 16%; P = .002). Mortality was not reduced at 6 months with the use of dalteparin compared with usual care (39% vs 41%; P = .53), and major bleeding was also not different between the groups (6% vs 4%; P = .27).13 In a 12-month follow-up of the CLOT trial, mortality was 59% in both

Continued from page 46

groups (P = .62). In this trial, in 75% of the patients with metastases, the mortality rate with dalteparin was similar to that of usual care (72% vs 69%; P = .46).14 In the 25% of patients without metastases, there was a 45% significant reduction in mortality with the use of dalteparin compared with usual care (20% vs 36%; P = .03).14 Although these data are from a post hoc analysis of the data, it clearly requires further study in a larger patient sample. One of the major questions that remains unanswered from clinical trials is what to do after the initial 6month treatment with LMWH? There are at least 4 options: 1. Give no further anticoagulation therapy 2. Continue anticoagulation with warfarin (INR 2-3) 3. Continue anticoagulation with treatment doses of LMWH 4. Continue anticoagulation with prophylaxis doses of LMWH. Future research will need to focus on answering the best approach for continued therapy, if it is needed at all.

Case Scenario 3 M. S. is a 65-year-old man with newly diagnosed pancreatic cancer. The oncology team has decided to initiate treatment with gemcitabine and radiation. He has no history of thrombophilia or VTE, but the team wishes to discuss the possible risks and benefits of primary prevention in this patient.

urrent guidelines do not support the use of primary VTE prophylaxis in patients with cancer. Despite the current lack of a recommendation, clinical trials have begun to demonstrate a benefit in primary prophylaxis in certain patients at high risk for cancer. A number of trials have evaluated the ability of LMWH to prevent mortality in patients without a current VTE event.15-19 One study evaluated the LMWH nadroparin for 6 weeks in patients with metastasized or locally advanced solid tumors.15 Patients were randomized to placebo or to therapeutic weight-adjusted nadroparin subcutaneously twice daily for the first 2 weeks and then once daily for another 4 weeks. Median survival was 8.0 months for patients receiving nadroparin compared with 6.6 months for patients receiving placebo (P = .021). Major bleeding was not significantly increased with the use of nadroparin (3% vs 1%; P = .021).15

Although these results with nadroparin seem impressive, other trials of LMWH for improvement in survival in patients with cancer have not repeated these same findings. The Improving with Nadroparin the Prognosis in Advanced Cancer Treatment (INPACT) trial evaluated 503 patients with hormone-refractory prostate cancer within 6 months of diagnosis (41%), locally advanced pancreatic cancer within 3 months of diagnosis (26%), or nonâ&#x20AC;&#x201C; small-cell lung carcinoma (stage IIIB) within 3 months of diagnosis (33%).16 Patients in the INPACT trial were randomized to observation or subcutaneous nadroparin. The nadroparin regimen consisted of full-dose treatment for 2 weeks, followed by half-dose treatment for 4 weeks. Nadroparin was then given in up to 6 cycles of no nadroparin for 4 weeks followed by full dose for 2 weeks. All-cause mortality was not different between the nadroparin and observation patients (57% vs 61%). These results were consistent across all types of cancer included in the trial. One limitation to the trial is the use of open-label nadroparin for the treatment of VTE in 30% of the observation patients.16 In the FAMOUS trial, subcutaneous dalteparin 5000 IU once daily or placebo was given for 1 year to 385 patients with advanced malignancy.17 Mortality at 1, 2, and 3 years was not different between the groups (P = .19).17 Trials evaluating LMWH for the primary prevention of VTE have recently been more consistent than the trials evaluating mortality. In the Prophylaxis of Thromboembolism During Chemotherapy (PROTECHT) trial, 1150 patients with metastatic or locally advanced solid organ cancer were randomized in a double-blind fashion 2:1 to a prophylaxis dose of nadroparin (3800 IU) subcutaneously once daily or placebo for the duration of chemother-

Despite the current lack of a recommendation, clinical trials have begun to demonstrate a benefit in primary prophylaxis in certain patients at high risk for cancer. apy (maximum of 4 months).18 The primary end point of venous or arterial thromboembolic events was reduced by almost 50% with the use of nadroparin compared with placebo (2% vs 3.9%; P = .02). The benefit was Continued on page 48

www.ValueBasedCancer.com

CONTINUING EDUCATION

Case Scenarios in the Prevention and Treatment... provided without a significant increase in major (0.7% vs 0%; P = .18) or minor (7.4% vs 7.9%) bleeding.18 In the CONKO-004 trial 312 chemotherapy-naïve patients with advanced pancreatic cancer were randomized to observation or enoxaparin 1 mg/kg subcutaneously once daily for 12 weeks followed by enoxaparin 40 mg subcutaneously once daily.19 At the end of the initial 12 weeks of therapy, the primary end point of symptomatic VTE was reduced by 87% with the use of enoxaparin (1.3% vs 9.9%; P <.01). This provides a number needed to treat of only 12 patients to prevent one symptomatic VTE with the use of enoxaparin in this patient population. The incidence of bleeding was not significantly increased during this 12week period with the use of enoxaparin (3.8% vs 2.6%; P = .6). After the median follow-up period of 30 weeks, the lower dose of enoxaparin still provided a significant reduction in symptomatic VTE (5% vs 14.5%; P <.05). The incidence in bleeding was increased in both groups compared with the 12week assessment, but the difference was still not statistically significant (6.3% vs 9.9%).19 Results of the Evaluation of AVE5026

in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy (SAVEONCO) trial should be available by mid-2011. This is the largest trial to evaluate the primary VTE prophylaxis in patients with cancer. The SAVEONCO trial is set to randomize 3200 patients to semuloparin 20 mg subcutaneously once daily or placebo for 3 to 7 months. Semuloparin is an ultra-LMWH with an anti-Xa to anti-IIa ratio of more than 30:1 compared with most LMWHs that have a ratio of 3:1 or 4:1.20 Semuloparin has a half-life of 16 to 20 hours, which allows for oncedaily administration. Semuloparin has already demonstrated efficacy and safety in patients undergoing orthopedic and abdominal surgery.20 If the results of the SAVE-ONCO trial demonstrate a significant benefit of primary VTE prophylaxis, as seen in the PROTECHT and CONKO-004 trials, a change in the guidelines supporting primary VTE prophylaxis in appropriate patients with cancer may be warranted. ■ References 1. Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost.

Continued from page 47

1997;78:126-132. 2. Rahr HB, Sørensen JV. Venous thromboembolism and cancer. Blood Coagul Fibrinolysis. 1992;3:451-460. 3. Nicolaides A, Arcelus J, Belcaro G, et al. Prevention of venous thromboembolism. European Consensus Statement, 1-5 November 1991, developed at Oakley Court Hotel, Windsor, UK. Int Angiol. 1992;11:151-159. 4. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):381S-453S. 5. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicenter trial with venographic assessment. ENOXACAN Study Group. Br J Surg. 1997;84:1099-1103. 6. McLeod RS, Geerts WH, Sniderman KW, et al, for the Canadian Colorectal Surgery DVT Prophylaxis Trial. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Results of the Canadian Colorectal DVT Prophylaxis Trial: a randomized, double-blind trial. Ann Surg. 2001;233:438-444. 7. Akl EA, Terrenato I, Barba M, et al. Low-molecularweight heparin vs unfractionated heparin for perioperative thromboprophylaxis in patients with cancer: a systematic review and meta-analysis. Arch Intern Med. 2008;168:1261-1269. 8. Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975-980. 9. Kakkar VV, Balibrea JL, Martínez-González J, et al, for the CANBESURE Study Group. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J Thromb Haemost. 2010;8:1223-1229. 10. Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, et al, for the FAME Investigators. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4:2384-2390. 11. Hull RD, Pineo GF, Brant RF, et al, for the LITE Trial

Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119:1062-1072. 12. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162:1729-1735. 13. Lee AYY, Levine MN, Baker RI, et al, for the CLOT Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. 14. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low-molecular-weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129. 15. Klerk CPW, Smorenburg SM, Otten H-M, et al. The effect of low-molecular-weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23:2130-2135. 16. Buller HR, Prins MH. The effect of the low-molecular-weight heparin nadroparin on the survival in patients with cancer: a randomized trial (for the INPACT Investigators). J Thromb Haemost. 2009;7(suppl 2):1203. Abstract LB-MO-004. 17. Kakkar AK, Levine MN, Kadziola Z, et al. Low-molecular-weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol. 2004;22:1944-1948. 18. Agnelli G, Gussoni G, Bianchini C, et al, for the PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009;10:943-949. 19. Riess HB, Pelzer U, Opitz B, et al. A prospective, randomized trial of chemotherapy with and without the low molecular weight heparin (LMWH) enoxaparin in advanced pancreatic cancer patients. J Thromb Haemost. 2009;7(suppl 2):1203. Abstract LB-MO-003. 20. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523-1532.

GASTROINTESTINAL CANCERS SYMPOSIUM

Competing Tests for Colorectal Cancer Risk Recurrence By Caroline Helwick San Francisco, CA—The optimal treatment of early-stage colorectal cancer (CRC) is not well-established. At the 2011 Gastrointestinal Cancers Symposium, several studies presented involved molecular assays that stratify patients according to a tumor’s genetic profile. 18-Gene ColoPrint Assay Outperforms Clinical Variables One study reported validation results from an 18-gene assay. “The ColoPrint facilitates the identification of patients with stage II CRC with a low risk of recurrence and who therefore don’t need chemotherapy,” said Robert Rosenberg, MD, PhD, of Technical University Munich. Of the 27% of patients who were classified as high-risk by the ColoPrint assay, 80.5% were free of distant metastases at 5 years compared with 94.9% of those classified as low-risk. This test also outperformed the clinical parameters recommended by the American Society of Clinical Oncology for patients with stage II CRC. “No other prognostic genetic profile in col-

orectal cancer has been subjected to a second validation,” Dr Rosenberg said. Studies are under way in this country and internationally. Commenting on this assay, Wells Messersmith, MD, Director of the Gastrointestinal Medical Oncology Program at the University of Colorado, Denver, was concerned that this test only tells us who not to treat. “I want a test that tells me who to treat, and the ColoPrint assay only tells me who I probably should not be treating—the good-risk patients. I also want to know the subset of ‘poor-risk’

at a glance ➤ Gene assays that identify a particular tumor’s genetic profile could help guide chemotherapy ➤ This represents an alternative to evaluating each patient’s clinical criteria ➤ Whether these genetic tests will be reimbursed by all payers is still unclear

VALUE-BASED CANCER CARE

April 2011

patients who will benefit from adjuvant chemotherapy.”

“It is more clinically significant and cost-effective to define who is at high risk for recurrence.” —Peter F. Lenehan, MD, PhD

5-Gene OncoDefender Validated, Superior to NCCN Guidelines A 5-gene assay claims to be doing that. First validation results for the OncoDefender were announced at the meeting by Peter F. Lenehan, MD, PhD, Chief Medical Officer of Everist Genomics, Ann Arbor, MI, who evaluated this test at 3 Mayo Clinic sites. The study included 115 patients with stage I and II CRC treated only by surgery. The 5-gene test differentiated the risk of recurrence among earlystage patients more accurately than did estimates using the National Comprehensive Cancer Network

guidelines. The test correctly classified 32 of 46 patients with recurrence, and 38 patients of 69 without. High-risk patients had a significantly greater probability of recurrence than low-risk patients. Dr Lenehan said the OncoDefender stands out among a growing list of competitors in higher positive predictive value and better sensitivity. Most tests have good negative predictive value, he said. “It is more clinically significant and cost-effective to define who is at high risk for recurrence. Our test can say with more confidence that a patient has a tumor that is aggressive and will recur.” He added, “Our test is the first to also target stage I patients.” Approximately 15% of patients with stage I disease will turn out to have aggressive disease. OncoDefender should become available soon, at a cost of $3400, with a patient assistance program. Gene assays used in breast cancer cost $3000 to $4000. The Oncotype DX Recurrence Score is already available for CRC, but it is not reimbursed by all payers. ■

VOL. 2

NO. 2

GASTROINTESTINAL CANCERS SYMPOSIUM

Future of Colorectal Cancer Therapy: Novel Targeted Pathways Personalized medicine key to explosion in drug development