Clinical Oncology Special Edition

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McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM

2010 • VOL. 13 • NO. 1

SPECIAL EDITION SOLID TUMORS

Management of Platinum-Sensitive Recurrent Ovarian Cancer

Evolving Treatment Paradigms in NSCLC

Marcela G. del Carmen, MD, MPH

Edward S. Kim, MD

Dilemmas in the Management of Treatment-Naïve Patients With Metastatic RCC Saby George, MD

Margaret E. M. Van Meter, MD Tige Stading, MBA

Bone Issues in Breast Cancer Larissa A. Korde, MD, MPH Julie R. Gralow, MD

Ronald M. Bukowski, MD

HEMATOLOGIC DISEASE

Recent Therapeutic Advances in the Management of Patients With MDS

Stem Cell Transplantation for MM: Do We Still Need It? Shaji Kumar, MD

Harry P. Erba, MD, PhD

Diagnosis and Treatment of Mycosis Fungoides and Sézary Syndrome

Maximizing Therapy for Chronic Phase CML Michael R. Savona, MD

Frederick Lansigan, MD Francine Foss, MD

SUPPORTIVE CARE

Safe Handling of Hazardous Drugs Luci A. Power, MS, RPh Martha Polovich, PhD, RN, AOCN

ChemotherapyInduced Nausea and Vomiting Lisa A. Thompson, PharmD Cindy L. O’Bryant, PharmD, BCOP

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

*1 *The CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B lymphocytes) and on B-cell CLL.

Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions.

Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients

on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions.

Cytopenias Prolonged ( 1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in preexisting neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture.

Hepatitis B Reactivation Hepatitis B reactivation, including fulminant hepatitis and death, occurs with other monoclonal antibodies

To learn more, please visit www.ARZERRA.com

directed against CD20. Screen patients at high risk of hepatitis B virus (HBV) infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. InsuďŹƒcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis.

Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected.

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

Most Common Adverse Reactions In the pivotal study (n=154) the most common adverse reactions ( 10%) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%),

diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

Most Common Serious Adverse Reactions In patients who received an infusion of 2,000 mg of ARZERRA, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia.

A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the udarabine- and alemtuzumab-refractory group was 17%.

Please see Brief Summary of Prescribing Information on adjacent pages.

Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.

BRIEF SUMMARY ARZERRATM (ofatumumab) Injection, for intravenous infusion

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset of Study 1 (MedDRA 9.0)

The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ARZERRATM (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14) of full prescribing information]. No data demonstrate an improvement in disease related symptoms or increased survival with ARZERRA. 4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. 5.4 Hepatitis B Reactivation Hepatitis B reactivation, including fulminant hepatitis and death, occurs with other monoclonal antibodies directed against CD20. Screen patients at high risk of hepatitis B virus (HBV) infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment.

Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. 5.6 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONS The most common adverse reactions (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions in Study 1 were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical Trials Experience The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data described in Table 1 and other sections below are derived from 154 patients in Study 1. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were White.

Total Population (n = 154) Body System/ Adverse Event

All Grades %

Grade ≥3 %

Fludarabine- and AlemtuzumabRefractory (n = 59) All Grade Grades ≥3 % %

Infections and infestations Pneumoniaa 23 14 25 15 Upper respiratory tract 11 0 3 0 infection Bronchitis 11 <1 19 2 Sepsisb 8 8 10 10 Nasopharyngitis 8 0 8 0 Herpes zoster 6 1 7 2 Sinusitis 5 2 3 2 Blood and lymphatic system disorders Anemia 16 5 17 8 Psychiatric disorders Insomnia 7 0 10 0 Nervous system disorders Headache 6 0 7 0 Cardiovascular disorders Hypertension 5 0 8 0 Hypotension 5 0 3 0 Tachycardia 5 <1 7 2 Respiratory, thoracic, and mediastinal disorders Cough 19 0 19 0 Dyspnea 14 2 19 5 Gastrointestinal disorders Diarrhea 18 0 19 0 Nausea 11 0 12 0 Skin and subcutaneous tissue disorders Rashc 14 <1 17 2 Urticaria 8 0 5 0 Hyperhidrosis 5 0 5 0 Musculoskeletal and connective tissue disorders Back pain 8 1 12 2 Muscle spasms 5 0 3 0 General disorders and administration site conditions Pyrexia 20 3 25 5 Fatigue 15 0 15 0 Edema peripheral 9 <1 8 2 Chills 8 0 10 0 a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. c Rash includes rash, rash macular, and rash vesicular.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections.

A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from patients with CLL in Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period.

Results were negative in 46 patients after the 8th infusion and in 33 patients after the 12th infusion. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short-term and long-term effects of perinatal B-cell depletion in offspring following in-utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)].

8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation.

Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information].

8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab.

The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

©2009, GlaxoSmithKline. All rights reserved.

October 2009 ARZ:1BRS ©2010 The GlaxoSmithKline Group of Companies.

All rights reserved. Printed in USA. AZA013R0 March 2010

TABLE of CONTENTS Solid Tumors

Hematologic Disease Chemotherapy Options in the Management of PlatinumSensitive Recurrent Ovarian Cancer

13

69

Shaji Kumar, MD

Marcela G. del Carmen, MD, MPH

Associate Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota

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

Evolving Treatment Paradigms in Non-Small Cell Lung Cancer

75

Margaret E. M. Van Meter, MD

24

Stem Cell Transplantation For Multiple Myeloma: Do We Still Need It?

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

Updates in the Diagnosis and Treatment of Mycosis Fungoides and Sézary Syndrome Frederick Lansigan, MD Assistant Professor of Medicine, Hematology and Oncology, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

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

Tige Stading, MBA Graduate Student, Harvard University, Cambridge, Massachusetts

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

83 Dilemmas in the Management of Treatment-Naïve Patients With Metastatic Renal Cell Carcinoma

39

Maximizing Therapy for Chronic Phase Chronic Myelogenous Leukemia Michael R. Savona, MD Clinical Assistant Professor of Internal Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Supportive Care

Saby George, MD Medical Oncology Fellow Cancer Therapy & Research Center, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas

Ronald M. Bukowski, MD Professor Emeritus Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio

93

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

Martha Polovich, PhD, RN, AOCN Associate Director, Clinical Practice, Duke Oncology Network, Durham, North Carolina

Bone Issues in Breast Cancer Larissa A. Korde, MD MPH

51

Assistant Professor of Medicine

Julie R. Gralow, MD Professor of Medicine Division of Medical Oncology, University of Washington and Seattle Cancer Care Alliance, Seattle, Washington

104

Chemotherapy-Induced Nausea and Vomiting: Guideline Summary and Clinical Challenges Lisa A. Thompson, PharmD Assistant Professor

Cindy L. O’Bryant, PharmD, BCOP Associate Professor Department of Clinical Pharmacy, School of Pharmacy, University of Colorado Denver, Aurora, Colorado

Hematologic Disease Recent Therapeutic Advances in the Management of Patients With the Myelodysplastic Syndromes

58

Harry P. Erba, MD, PhD Associate Professor of Internal Medicine, University of Michigan, Ann Arbor, Michigan

6

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

Guidelines for the Management of Febrile Neutropenia

115

Michael Gabay, PharmD, JD, BCPS Director, Drug Information Group and Prior Authorization Services, Clinical Assistant Professor

Maria Tanzi, PharmD Clinical Assistant Professor, Drug Information Group University of Illinois at Chicago, College of Pharmacy, Chicago, Illinois

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls.

The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

©2010 Genentech USA, Inc.

All rights reserved.

9151102

(01/10)

Printed in USA.

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.

[See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with and resolved without medical intervention. Grade 1 or 2 hemorrhagic gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy following a venous thromboembolic event. Among these patients, an additional The overall incidence of Grade 3–4 venous thromboembolic events in following Grade 3–4 venous thromboembolic events was higher in intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving presented in Table 1.

AVASTIN® (bevacizumab) Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI-CTC Grade 3-4 Events Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 Arm 1

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6%

52% 43% 40% 32% 24% 24%

47% 35% 29% 30% 17% 19%

2% 1%

7% 6%

4% 1%

Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs.

3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.

0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

may be influenced by several factors, including sample handling, timing of

Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving α) plus Avastin compared to 304 patients receiving α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving α α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 α α + Placebo) Preferred term* Gastrointestinal disorders Diarrhea General disorders and administration site conditions

α (n = 304) 16%

α + Avastin (n = 337)

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

21%

Investigations Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Myalgia Back pain Nervous system disorders Headache Renal and urinary disorders Proteinuria Respiratory, thoracic and mediastinal disorders Epistaxis Dysphonia Vascular disorders Hypertension

reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. 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.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia

31%

36%

14% 6%

19% 12%

16%

24%

3%

20%

4% 0%

27% 5%

9%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the α α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Manufactured by: Genentech, Inc. 94080-4990

7453214 4835706 © 2009 Genentech, Inc

From the EDITORS Dear Readers:

T

his issue of Clinical Oncology News Special Edition contains reviews covering many areass of oncology practice. Our mix of new reviews and perennial favorites with the latest updates offers something for everyone. One new review by Saby George, MD, and Ronald Bukowski, MD, focuses on patients with treatment-naïve metastatic renal cell cancer.

Drs. George and Bukowski describe the pace of new treatments approved in this setting over the past 5 or 6 years, and the latest data on the progress of these new therapies.

Another featured offering in this issue is a commentary by Shaji Kumar, MD, discussing the role of stem cell transplantation for patients with multiple myeloma in the era of new treatments for this disease. Reviewing historical data on transplantation before the new drugs were approved as well as emerging data, Dr. Kumar makes a case for the continued value of transplantation. Another new review provides recommendations for preventing and treating nausea and vomiting, with specific suggestions for special populations such as those receiving multiday regimens and those receiving oral chemotherapeutic agents. It is our hope that the reviews on these pages will support you in your daily practice of improving the lives of patients with cancer.

Kate O’Rourke, Editor

Sincerely, Sarah Tilyou, Senior Editor

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Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

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For more information about GEMZAR, talk with your doctor or visit GEMZAR.com.

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Chemotherapy Options in the Management of

Platinum-Sensitive Recurrent Ovarian Cancer MARCELA G.

DEL

CARMEN, MD, MPH

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

E

pithelial ovarian cancer is the most lethal gynecologic malignancy, with an estimated 5-year survival

of 45% for all stages of the disease, and 18.6% for stage IV.1 Approximately 75% of women with ovarian cancer present with stage III or IV disease.

Women with low-volume residual stage III or IV disease (all lesions <2 cm) have a 60% to 70% risk for recurrence following primary surgery. The presence of large-volume residual disease increases that percentage to 80% to 85%.2 Such recurrences are incurable, so the goals of therapy should be palliation of cancer-related symptoms, prolongation of life, and maintenance of quality of life.

Response to first-line therapy influences the choice of therapy for women with recurrent ovarian cancer and predicts how a tumor will respond to treatment in the recurrent setting. Recurrent ovarian cancer has been dichotomized as being either platinum-sensitive (progression-free interval [PFI] >6 months) or platinum-resistant (PFI â&#x2030;¤6 months).3,4 A patientâ&#x20AC;&#x2122;s PFI predicts response rate (RR) and duration of response.5 This review will focus on the medical treatment, specifically chemotherapy options, available for women with platinum-sensitive disease. The management strategy for women with platinum-resistant disease was formally discussed in a previous issue (Clinical Oncology News Special Edition 2009;12[2]:39-43).

The Importance of Treatment Timing Recurrent disease may be heralded by the onset of

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

new symptoms, radiological evidence of recurrence in an asymptomatic patient, or rising CA-125 levels predating radiological detection or symptoms by several months.6,7 Although formal definitions of ovarian cancer recurrence and progression have been described, based on both clinical and CA-125 criteria, many women present with either an asymptomatic, radiological recurrence or an asymptomatic rise in CA-125 without a radiographic correlate.7,8 Given that recurrent disease is incurable, the goals of therapy outlined earlier should guide decisions about initiation of second-line therapy.9 In patients with symptomatic recurrence, immediate institution of treatment may be justified and warranted to palliate cancer-related symptoms. For women with asymptomatic recurrences (eg, those with no symptoms but with rising CA-125), the timing of therapy is much more controversial. Researchers who advocate immediate treatment argue that patients with small-volume disease are more likely to achieve a complete response if they are treated early.1012 Advocates for delaying treatment argue that because the increases in complete responses have not been translated into improved survival,13 the goal is still palliation and therapy should be deferred until symptom onset.

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 1 0

13

Table 1. Role of Platinum-Free Interval in Predicting Future Response to Treatment Treatment-Free Interval, mo

Response Rate, %

Pathologic Complete Response, %

5-12

27

5

13-24

33

11

>24

59

22

The controversy over the appropriate time to start therapy was addressed in Rustin et al’s recent prospective study of 1,442 women with ovarian cancer.14 The trial was conducted among patients in complete clinical remission from their cancer, with a normal CA-125 level following completion of primary surgical and platinum-based systemic therapy. Both the investigators and patients were blinded. Serum CA-125 levels were checked every 3 months. Women whose CA-125 rose to a level twice above the upper limit of normal but who remained asymptomatic (n=527) were randomly assigned to receive immediate treatment or treatment upon clinical or symptomatic recurrence. Women randomized to immediate therapy initiated chemotherapy a median of 5 months earlier than those treated upon recurrence. Survival and remission duration were comparable between the 2 arms at 57-month follow-up. However, quality of life was worse for the women undergoing immediate treatment. The investigators concluded that early institution of second-line therapy did not benefit patients and advocated for treatment to be delayed until symptoms develop or patients have signs of recurrent disease.

Importance of Platinum-Free Disease Interval Table 1 summarizes the importance that the length of the treatment-free interval plays in predicting response to platinum therapy in the recurrent setting.11 In general, platinum-sensitive recurrent ovarian cancer is treated with a platinum-agent, alone or in combination with another agent. The process of determining whether to use single-agent therapy or combination therapy should consider patients’ performance status, other comorbidities, and previous toxicities with other therapies. If combination therapy is elected, the specific combination regimen should be chosen to optimize outcome and minimize overlapping toxicities.

Treatment Regimen Selection A Phase II trial randomly assigning patients with platinum-sensitive recurrences to either single-agent paclitaxel or combination therapy with cisplatin, doxorubicin, and cyclophosphamide documented similar overall response rates between the 2 regimens (45% vs 55%) but showed that the platinum-containing combination

14

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

was associated with significant increases in response duration (16 vs 9 months) and median survival (35 vs 26 months; hazard ratio [HR], 0.58; 95% confidence interval, 0.34-0.98; P=0.043).10 These results illustrate the importance of platinum agents in the management of women with platinum-sensitive recurrent disease.

The choice of whether to use a single platinum agent or a platinum-containing combination is somewhat controversial. Combination regimens are associated with a longer response rate, and PFI.15-19 The paclitaxel-carboplatin combination has been shown to lead to a longer overall survival (OS) compared with platinum alone.

However, combination therapy is more toxic.15 Selection of single-agent platinum versus combination platinum-containing regimens also should take into account patients’ performance status and previously encountered chemotherapy toxicities.

Combination Regimens In 2 parallel, randomized Phase III trials, 802 women with platinum-sensitive recurrent ovarian cancer were treated with a single-agent platinum versus paclitaxel in combination with a platinum agent. The combination regimen was associated with an improved OS (HR, 0.82), a 2-year survival benefit of 7%, and a 5-month improvement in median survival (29 vs 24 months).15 The combination regimen had a progression-free survival (PFS) with an HR of 0.76, and an absolute 10% difference in 1-year PFS (50% vs 40%).15 However, the combination also was associated with a higher incidence of grade 2 to 4 neurologic toxicity (20% vs 1%) and alopecia (86% vs 25%).15 Importantly, 30% of patients had been treated with platinum alone in the primary setting. Table 2 shows results of Phase III trials of several platinum-containing combinations, including carboplatin plus pegylated liposomal doxorubicin (PLD; Doxil, Centocor/Ortho Biotech), carboplatin plus gemcitabine (Gemzar, Lilly), and carboplatin plus paclitaxel.16-18 Non–platinum-based combination regimens are another emerging option for patients with platinumsensitive disease. In a Phase III randomized trial of PLD alone versus PLD combined with the marine-derived alkaloid trabectedin (Yondelis, Ortho), the combination regimen resulted in improved PFS.19

Single-Agent Chemotherapy Beyond Second Line Numerous single-agent therapeutic options exist for patients with ovarian cancer who have had progression of disease on platinum-based second-line therapy.

Table 3 lists some chemotherapeutic options and their documented response rates. The higher response rates are for patients with platinum-sensitive disease.20-41 Bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that targets vascular endothelial growth factor, has been studied in several Phase II studies, alone and in combination with cytotoxic chemotherapy.

It has been shown to be an active agent in patients with recurrent ovarian cancer (Table 4).42-44 However, studies

Table 2. Results of Platinum-Containing Combination Phase III Trials Regimen

Number of Patients

RR, %

PFS, mo

OS, mo

Toxicity

Reference 16

Carboplatin Carboplatin + gemcitabine

356

31 47

5.8 8.6

17.3 18

Combination associated with higher hematologic toxicity

Carboplatin Carboplatin + PLD

61a

32 67

8 12

18 26

Combination associated with 17 higher hematologic toxicity, constipation, and hand–foot syndrome

Carboplatin + PLD Carboplatin + paclitaxel

976

11.3 9.4

PLD-carboplatin combination had fewer infusion reactions, less alopecia, and less neurotoxicity

18

PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin; RR, response rate a 61 of 900 planned patients were accrued, significantly limiting the power of the study.

indicate that there is a risk for gastrointestinal complications with this agent; specifically, perforations have been estimated to be 5% to 7%.42-45 Some have suggested that bevacizumab be used only in patients without clinical symptoms of bowel obstruction, computed tomography scan evidence of bowel involvement, or evidence of rectosigmoid involvement on pelvic examination.46 Bevacizamab’s role has yet to be determined. Single-agent bevacizumab may be an appropriate third-, fourth-, and even fifth-line treatment in carefully selected patients. Combination regimens using bevacizumab

remain investigational until more data on their efficacy and safety is available. Interestingly, bevacizumab has been shown to improve PFS in patients undergoing primary treatment. Roche has announced that patients in GOG (Gynecologic Oncology Group) study 218, randomized to bevacizumab in combination with chemotherapy, and also receiving bevacizumab maintenance therapy, had greater PFS than women who were administered chemotherapy alone. The final study results will be presented at the 2010 American Society of Clinical Oncologists meeting.47

Table 3. Single-Agent Treatment Options in Recurrent Ovarian Cancer Agent

ORR, %

Toxicity (Grades 3 and 4)

Reference

Paclitaxel

21-53

Neutropenia, anemia, GI, neurologic, fatigue, dyspnea, infection, pulmonary

20-23

Gemcitabine (Gemzar, Lilly)

14-22

Neutropenia, anemia, thrombocytopenia, nausea/ vomiting, fatigue

24-26

PLD (Doxil, Centocor/Ortho Biotech)

11-28

Hand–foot syndrome, stomatitis

27-31

Topotecan (Hycamtin, GlaxoSmithKline)

15-32

Neutropenia, anemia, thrombocytopenia

27, 28, 32, 33

Vinorelbine

3-29

Neutropenia, anemia, worsening parasthesia

34, 35

Etoposide (oral)

18-27

Neutropenia, leukopenia, anemia, thrombocytopenia

36, 37

Docetaxel

7-28

Neutropenia, leukopenia

38, 39

Ifosfamide

10

Myeolosuppression, nephrotoxicity, central nervous system toxicity

40

Pemetrexed (Alimta, Lilly)

21

Myelosuppression

41

GI, gastrointestinal; ORR, overall response rate; PLD, pegylated liposomal doxorubicin

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15

Table 4. Bevacizumab Trials in Ovarian Cancer Reference 42 (N=63)

Reference 43 (N=29)

Reference 44 (N=44)

Study treatment

Single-agent bevacizumab 15 mg/kg q3wk

Bevacizumab 10 mg/kg q2wk plus low-dose oral cytoxan

Single-agent bevacizumab 15 mg/kg q3wk

Prior treatment setting

Relapsed platinum disease, up to 2 prior regimens

Relapsed platinum disease with post-platinum maximum of 2 regimens

Resistant to platinum, and PLD/topotecan, up to 3 regimens total

Efficacy 6-mo PFS, % ORR, %

39 18

57 28

27.4 16

Gastrointestinal perforation, N (%)

0

2 (3%)

5 (11%)

ORR, overall response rate; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin

Conclusions Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrences treated with a platinumbased agent. Platinum-containing combination regimens are associated with higher response rates and PFI. Paclitaxel in combination with carboplatin has been reported to have an improved OS compared to carboplatin alone.

The choice of single-agent versus combination therapy should take into account the patientsâ&#x20AC;&#x2122; performance status, other comorbidites and previous toxicities with other therapies. If combination therapy is elected, the specific combination regimen chosen should also take into consideration these factors to optimize outcome and minimize overlapping toxicities. For patients whose cancer progresses after platinum retreatment, numerous other agents have been shown to be effective in palliating cancer-related symptoms and extending life. The future may include the use of non-platinum combinations, as well as targeted therapies such as bevacizumab in combination with cytotoxic agents.

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26. Petru E, Angleitner-Boubenizek L, Reinthaller A, et al. Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and –resistant ovarian cancer after previous platinum-taxane therapy: a phase II Austrian AGO study. Gynecol Oncol. 2006;102(2): 226-229, PMID: 16443259.

27. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322, PMID: 11454878.

28. Gordon AN, Teitelbaum A. Overall survival advantage for pegylated liposomal doxorubicin compared to topotecan in epithelial ovarian cancer. Eur J Cancer. 2003;12: Abstract S51.

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

a retrospective comparative study of single-agent dosages.

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32. Kudelka AP, Tresukosol D, Edwards CL, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol. 1996;14(5):1552-1557, PMID: 8622071.

33. Hoskins P, Eisenhauer E, Beare S, et al. Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol. 1998;16(6):2233-2237, PMID: 9626225.

34. Sorensen P, Hoyer M, Jakobsen A, et al. Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma. Gynecol Oncol. 2001;81(1):58-62, PMID: 11277650.

35. Burger RA, DiSaia PJ, Roberts JA, et al. Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol. 1999;72(2):148-153, PMID: 10021293.

36. Slayton RE, Creasman WT, Petty W, Bundy B, Blessing JA. Phase II trial of VP-16-213 in the treatment of advanced squamous cell carcinoma of the cervix and adenocarcinoma of the ovary: a Gynecologic Oncology Group study. Cancer Treat Rep. 1979;63(4):2089-2094, PMID: 526942.

37. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16(2):405-410, PMID: 9469322.

38. Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88(2):130-135, PMID: 12586591.

39. Markman M, Zanotti K, Webster K, et al. Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum. Gynecol Oncol. 2003;91(3):573-576, PMID: 14675679.

40. Markman M, Hakes T, Reichman B, et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992;10(2):243-248, PMID: 1732425.

41. Miller DS, Blessing JA, Krasner CN, Mannel RJ. A phase II evaluation of pemetrexed (LY231514, IND#40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecology Oncology Group.

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42. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol.

2007;25(33):5165-5171, PMID: 18024863.

43. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J Clin Oncol.

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44. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180-5186, PMID: 18024865.

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2007;105(1):3-6, PMID: 17383545.

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47. http://www.genengnews.com/news/bnitem.aspx?name=76317022.

Accessed on March 2, 2010.

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17

Indications and Important Safety Information for ALIMTA Indications 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.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

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

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 treatment-related hematologic and GI toxicities.

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

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.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment

ALIMTA® is a registered trademark of Eli Lilly and Company.

PM58001 0709 PRINTED IN USA © 2010, Lilly USA, LLC. ALL RIGHTS RESERVED.

(creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

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 insufficiency should avoid taking NSAIDs with short elimination half-lives 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.

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.

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. 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.

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.

Histology Matters with ALIMTA because

EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy.

For more information, visit www.ALIMTA.com Use in SpeciďŹ c 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 insufďŹ ciency.

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) for NSCLC 1st-line: 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).

Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

ALIMTA姞 (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 1.1

INDICATIONS AND USAGE Nonsquamous Non-Small Cell Lung Cancer—Combination with Cisplatin 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.

1.2 Nonsquamous Non-Small Cell Lung Cancer—Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.3 Nonsquamous Non-Small Cell Lung Cancer—After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, and 14.3)] 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Neurotoxicity Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. 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. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations 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. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleeding a, regardless 50% of previous dose of nadir ANC (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)] ; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation.

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

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.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency 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). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring 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 [see Dosage and Administration (2.4)].

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection)

2.2

Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3

Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4

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5.6

Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Use in Specific Populations (8.1)] 5.7

Third Space Fluid 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.

6

ADVERSE REACTIONS

6.1

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia General Disorders—dehydration Metabolism and Nutrition—increased AST, increased ALT Renal—creatinine clearance decrease, renal failure Special Senses—conjunctivitis Incidence Less than 1% Cardiovascular—arrhythmia General Disorders—chest pain Metabolism and Nutrition—increased GGT Neurology—motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ALIMTA Placebo Reaction b (N=438) (N=218) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Neuropathy-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC)—Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLC a ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin—alopecia, pruritis/itching Gastrointestinal—constipation General Disorders—edema, fever (in the absence of neutropenia) Hematologic—thrombocytopenia Renal—decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses—ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular—supraventricular arrhythmia Dermatology/Skin—erythema multiforme

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection)

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General Disorders—febrile neutropenia, allergic reaction/hypersensitivity Neurology—motor neuropathy Renal—renal failure Non-Small Cell Lung Cancer (NSCLC)—After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive singleagent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 38 2c Alopecia 6 1c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0). c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole —abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin—erythema multiforme Neurology—motor neuropathy, sensory neuropathy Renal—increased creatinine Incidence Less than 1% Cardiovascular—supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin Reaction b (N=168) (N=163) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Table 7 continued in next column.

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Table 7 continued here.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin Reaction b (N=168) (N=163) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic (cont.)

Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropathy-sensory 10 0 10 1 Taste Disturbance 8 0c 6 0c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c 6 0c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia Dermatology/Skin—urticaria General Disorders—chest pain Metabolism and Nutrition—increased AST, increased ALT, increased GGT Renal—renal failure Incidence Less than 1% Cardiovascular—arrhythmia Neurology—motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients a Adverse Event (%) (N=168) (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. 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.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal—colitis General Disorders and Administration Site Conditions—edema ALIMTA姞 (pemetrexed for injection)

PV 5207 AMP

Injury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously received radiotherapy Respiratory—interstitial pneumonitis 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). 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) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives 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 toxicity.

7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established.

8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent-to-treat population.

8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology

(12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-to-treat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent-to-treat population.

8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent-to-treat population.

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen.

If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

PV 5207 AMP

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Literature revised December 1, 2009

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Evolving Treatment Paradigms in

Non-Small Cell Lung Cancer MARGARET E. M. VAN METER, MD Medical Oncology Fellow Division of Cancer Medicine The University of Texas M.D. Anderson Cancer Center Houston, Texas

TIGE STADING, MBA Graduate Student Harvard University Cambridge, Massachusetts

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

L

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

colorectal cancers combined.1 Non-small cell lung cancer (NSCLC) is the most common histologic subtype and accounts for more than 80% of lung cancers.

Although locally resectable NSCLC can be cured with surgical intervention, very few patients present with early-stage disease. Unfortunately, the majority present with advanced (stages IIIB and IV) disease; surgery and radiotherapy are not routinely part of care for these patients. Overall survival (OS) for these groups of patients has improved only modestly over the past few decades through advances in chemotherapy; median OS has improved by approximately 2 months, providing 1-year survival rates of about 30% with chemotherapy compared with 10% with supportive care. More recently, the advent of newer chemotherapy regimens has increased median survival times with standard doublet chemotherapy regimens from 8 to 11 months.2 The addition of biologic agents and efforts to focus their use in specific treatment populations have further

24

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 1 0

increased efficacy, with median survival times in some studies exceeding 12 months.3 Although previous studies of cytotoxic chemotherapy demonstrated no improvement in outcome when regimens were administered for more than 4 to 6 cycles, recent studies in the maintenance setting indicate that more prolonged therapy may be desirable.4 As treatment strategies evolve and chemotherapies and biologic therapies are being increasingly integrated, a more personalized approach should be used to provide the most effective and least toxic treatments to patients with advanced NSCLC.

Conventional Chemotherapy Platinum-based doublet regimens are the mainstay of chemotherapy in patients with advanced NSCLC

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

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

19

Capuzzo et al20 (SATURN)

Treatment Arms

N

PFS, mo

Median OS, mo

GC then immediate docetaxel GC then delayed docetaxel

309

5.7 (P=0.001) 2.7

12.3 (P=0.0853) 9.7

CT then E CT then P

438 451

PFS was significantly prolonged with E versus P in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001)

12 11

Pemetrexed + BSC P + BSC

441 222

Overall/NSQ/SQ 4.3/4.5/2.8 2.6/2.6/2.6

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

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

768

3.7 (P=0.0012) 4.8

NA

Ciuleanu et al4

Miller et al21 (ATLAS)

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

and a good performance status (PS). The survival benefit of cisplatin in the treatment of NSCLC was established in 1995 based on a meta-analysis that included 52 clinical trials with more than 9,000 patients; in the trials involving patients with advanced disease, cisplatinbased chemotherapy showed a 27% reduction in the risk for death at 1 year.5 Thus, in 1997, the American Society of Clinical Oncology (ASCO) issued guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and a good PS. Given the toxicity of cisplatin-based regimens, much effort over the past decade has been directed toward developing better-tolerated, equally efficacious treatments. To this end, trials have evaluated the use of newer agents, either as monotherapy or in combination regimens, as well as the use of carboplatin in lieu of cisplatin in doublet regimens.

In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum agent. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-aventis), paclitaxel, and pemetrexed (Alimta, Lilly). A large trial comparing cisplatin-paclitaxel to 3 other regimensâ&#x20AC;&#x201D;carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabineâ&#x20AC;&#x201D;in 1,155 patients with advanced NSCLC showed no significant difference in OS (median 7.9 months) among the 4 regimens.6 It is notable, however, that patients in the carboplatin-paclitaxel arm had a slightly lower rate of serious toxicities and that the study was limited to patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; initial analysis showed a higher

rate of adverse events in patients with a PS of 2.

The largest Phase III study ever performed in the first-line treatment of advanced NSCLC (N=1,725) compared treatment with cisplatin-pemetrexed with cisplatin-gemcitabine.7 A statistically significant survival advantage was demonstrated for patients with adenocarcinoma or large-cell carcinoma histology treated with cisplatin-pemetrexed, compared with cisplatingemcitabine (median OS, 11.8 and 10.4 months, respectively; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94; P=0.005). In contrast, patients with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed (OS, 9.4 vs 10.8 months; HR, 1.23; 95% CI, 1.00-1.51; P=0.05). This was the first Phase III trial to prospectively show a survival difference based on NSCLC histology.

Newer Targeted Therapies With the advent of new targeted therapies, first-line chemotherapy for advanced NSCLC is changing. Given the limited ability of current chemotherapy regimens to prolong OS, new drug development has focused on improving tolerance, quality of life, and ease of administration, while maintaining at least comparable efficacy to standard first-line therapy.

The Phase III ECOG 4599 trial evaluated first-line platinum doublet therapy with and without the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin, Genentech) in patients with non-predominant squamous cell carcinoma.3 This trial compared carboplatin-paclitaxel versus carboplatin-paclitaxel-bevacizumab in patients with advanced NSCLC. Treatment in the experimental arm included bevacizumab combined with chemotherapy every 3 weeks for 6 cycles,

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

25

Adenocarcinoma or nonsquamous

EGFR mutationpositive

Gefitinib Erlotinib

Squamous

EGFR mutationnegative or unknown

Bevacizumab + chemotherapy doublet a

Chemotherapy doublet with or without cetuximab a

Non-bevacizumab chemotherapy doublet (pemetrexed-based) a

Maintenance therapy • Pemetrexed a • Erlotinib with or without bevacizumab • Docetaxel

Disease progression

• Salvage therapy • Consider clinical trial

Figure. Proposed algorithm for treatment of NSCLC. a

FDA-approved regimens

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

followed by maintenance bevacizumab every 3 weeks until progressive disease or intolerable side effects occurred. Median OS, the primary end point, increased by 2 months (12.3 vs 10.3 months; HR, 0.79; 95% CI, 0.67-0.92; P=0.003) with the addition of bevacizumab.

Statistically significant improvements in response rate (35% vs 15%) and progression-free survival (PFS; 6.2 vs 4.5 months) were seen.

The pivotal FLEX (First-Line Erbitux in Lung Cancer) trial compared the cisplatin-vinorelbine doublet plus the anti-epidermal growth factor (EGFR) antibody cetuximab (Erbitux, Bristol-Myers Squibb) to cisplatin-vinorelbine alone in patients with EGFR-expressing advanced NSCLC.8 Cetuximab was given together with doublet chemotherapy for 6 cycles and continued as maintenance therapy until progressive disease or intolerable side effects developed. For the entire intentionto-treat population, median OS was 11.3 months in the cisplatin-vinorelbine-cetuximab arm, compared with 10.1 months in those treated with cisplatin-vinorelbine alone (HR, 0.871; 95% CI, 0.762-0.996; P=0.044). Prespecified subgroup analysis showed that the survival benefit of treatment including cetuximab persisted across

26

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most subgroups. However, gender, PS, histology, smoking status, and geographic region all had prognostic significance. Specifically, women had longer survival times than men (12.7 vs 9.3 months), Asians had a longer survival than whites (19.5 vs 9.6 months), and patients with a higher PS and those who had never smoked had better prognoses than patients with lower PS and smokers.

Data presented at the ASCO meeting in 2009 expanded on prognostic factors and molecular predictors of OS from the FLEX trial. In one analysis, KRAS mutational status was found not to be predictive for cetuximab efficacy, but patients taking cetuximab who developed an acne-like rash had a longer median OS than those without the rash (15.0 vs 8.8 months; HR, 0.63; 95% CI, 0.52-0.77; P<0.001). 9 Improvements in OS seen with molecular-targeted therapies against VEGF and EGFR in combination with platinum doublets in patients with advanced NSCLC3,8 have led to further investigation of the combined effects. The SWOG (Southwest Oncology Group) 0536 Phase II study combined 4 drugs—cetuximab, bevacizumab, carboplatin, and paclitaxel—for up to 6 cycles, followed by maintenance bevacizumab weekly

until disease progression.10 The primary end point was the frequency and severity of hemorrhagic toxicities that were grade 4 or higher in patients with advancedstage nonsquamous NSCLC. Combining carboplatin, paclitaxel, cetuximab, and bevacizumab resulted in a tolerable safety profile, with a 2% incidence of hemorrhage that was grade 4 or higher (95% CI, 0-7%). An ongoing Phase III trial (SWOG 0819) is comparing the 4-drug regimen used in SWOG 0536 to the 3-drug regimen used in ECOG 4599, carboplatin-paclitaxelbevacizumab.

The studies described above have evaluated biologic targeted agents in combination with cytotoxic chemotherapy. Additional Phase III studies, INTEREST (Iressa NSCLC Trial Evaluating Response and Survival against Taxotere) and IPASS (First-line Iressa versus Carboplatin/ Paclitaxel in Asia), compared single-agent biologic therapy using the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) with traditional chemotherapeutic agents with favorable outcomes.

INTEREST is a randomized Phase III trial comparing gefitinib to docetaxel in patients with advanced NSCLC who had previously received at least 1 platinum-based chemotherapy regimen.11 Patients received either gefitinib daily or docetaxel every 3 weeks until disease progression or unacceptable toxicity. The primary end point was OS, analyzed via noninferiority in the overall population and superiority in patients with a high EGFR copy number. Results for all 1,433 patients confirmed noninferiority of gefitinib compared with docetaxel for OS (7.6 vs 8 months; HR 1.020; 95% CI, 0.905-1.150). However, in the 174 patients with a high number of EGFR gene copies, gefitinib did not show superiority for OS (8.4 vs 7.5 months; HR, 1.09; 95% CI, 0.78-1.51; P=0.62).

Subsequent biomarker analysis of EGFR and KRAS in tumor biopsies from the INTEREST trial showed similar OS in patients treated with gefitinib and docetaxel regardless of biomarker subgroup. However, patients with EGFR mutations had longer PFS and higher objective response rate (ORR), and patients with high EGFR copy number had higher ORR when treated with gefitinib compared with docetaxel.12 Recent data from the IPASS trial have shown that gefitinib is also a valid first-line therapy for a subset of patients.13 This study included patients in East Asia with advanced NSCLC of adenocarcinoma histology who had a World Health Organization PS of 0 to 2 and were never smokers or former light smokers. The primary end point was PFS; median PFS was similar in those treated with gefitinib compared with those treated with carboplatin-paclitaxel (5.7 vs 5.8 months), but the Kaplan-Meier curves crossed at this point and patients treated with gefitinib had a significantly higher rate of PFS at 12 months (24.9% vs 6.7%) with an overall HR of 0.74 (95% CI, 0.65-0.85; P<0.0001).

Preliminary OS (28% maturity with follow-up ongoing) was similar for gefitinib and carboplatin-paclitaxel, but gefitinib demonstrated improved quality-of-life ratings and a more favorable tolerability profile.

In the IPASS trial, EGFR mutational status appeared to be a strong biomarker for gefitinib efficacy.13 Similar analysis has shown that EGFR mutations also are associated with responsiveness to erlotinib (Tarceva, OSI Pharmaceuticals).14 These findings indicate that genetic screening of patients prior to therapy may be warranted to allow clinicians to tailor therapy to individual patients. The study results also highlight a need for a paradigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy.

Maintenance Therapy Debate continues about delayed (second- or thirdline) versus immediate (maintenance) chemotherapy in patients who already have received first-line therapy.

Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in advanced NSCLC (Table).4,15-21 Maintenance chemotherapy could be either continuation of 1 or more of the initial chemotherapy agents or the addition of a new chemotherapeutic or targeted agent.

In one multicenter Phase III trial, patients with advanced NSCLC who did not have evidence of disease progression after first-line treatment with 4 cycles of carboplatin-gemcitabine were randomized to receive docetaxel either immediately or on disease progression.19 Maintenance docetaxel was associated with a statistically significant improvement in PFS (5.7 vs 2.7 months; P=0.0001) and a trend toward improvement in OS (median 12.3 vs 9.7 months; P=0.0853).

Several large Phase III trials of maintenance therapy reported at the 2009 ASCO annual meeting used erlotinib, erlotinib plus bevacizumab, or pemetrexed as maintenance therapy.

The large Phase III SATURN trial tested erlotinib maintenance versus placebo after platinum-based doublet chemotherapy in 1,949 patients with advanced NSCLC. The SATURN trial met its primary end point of PFS, with results showing significantly increased PFS with erlotinib in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001), as well as improved OS (12 vs 11 months).20 In exploratory analysis, an even greater benefit was seen in a subset of patients who had EGFR mutations. Based on this information, in April 2010, the FDA approved erlotinib for maintenance treatment of patients with advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinumbased first-line chemotherapy.

Another Phase III trial evaluated pemetrexed as maintenance therapy. This trial included 663 patients with advanced NSCLC who did not progress on an initial platinum-based doublet and showed that pemetrexed maintenance resulted in significantly better OS than placebo (13.4 vs 10.6 months; HR, 0.79; 95% CI, 0.65-0.95; P=0.012).4 Patients who received pemetrexed maintenance instead of placebo experienced a significant increase in PFS (4.3 vs 2.6 months; HR, 0.50; 95% CI, 0.42-0.61; P<0.0001). Pemetrexedâ&#x20AC;&#x2122;s efficacy, favorable

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

27

tolerability profile, ease of administration, and OS benefit make it appealing as a maintenance drug in advanced NSCLC. In July 2009, the FDA approved pemetrexed for maintenance treatment of patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of platinumbased first-line chemotherapy.

Although most studies discussing maintenance options at the ASCO 2009 annual meeting tested nonâ&#x20AC;&#x201C;cross-resistant regimens, the ATLAS Phase III trial compared bevacizumab therapy with or without erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of advanced NSCLC.21 This study, the first to evaluate combination versus single-agent maintenance therapy options, showed significant improvement in PFS in the group receiving combination therapy (4.8 vs 3.7 months; HR, 0.722; 95% CI, 0.592-0.881; P=0.0012).

Biomarkers and Therapy As discussed above, many of the recent advances in the treatment of NSCLC have involved the integration of targeted therapeutics and more accurately defining the subset of patients who are most likely to benefit from a given treatment. Thus, it is more important now than ever before to explore predictors of efficacy to help direct the best therapy for each individual patient. In clinical practice, factors such as smoking history, histology, gender, or ethnicity may help determine the choice of therapy. Genotypic correlates to response are being actively pursued.

Histology The importance of histology has been highlighted clearly for the use of pemetrexed in the treatment of advanced NSCLC in multiple settings. The large study

by Scagliotti et al. described above found that patients with nonsquamous tumors had a survival advantage when treated first-line with cisplatin-pemetrexed compared with those treated with cisplatin-gemcitabine, while those with squamous cell histology had a shorter median survival when treated with cisplatinpemetrexed.7 This was the first prospective study to show survival differences based on histology. A study

by Hanna et al. comparing pemetrexed and docetaxel in the second-line setting22 was subsequently analyzed retrospectively using subset histology data23; patients with nonsquamous NSCLC had a significant improvement in OS when treated with pemetrexed compared with those treated with docetaxel (9.3 vs 8.0 months; HR, 0.778; P=0.048). When pemetrexed was used as maintenance therapy by Ciuleanu et al., the improvements in PFS and OS were documented primarily in

28

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

patients with nonsquamous histology.4 One possible explanation for the observed differential efficacy of pemetrexed is that baseline thymidylate synthase (TS) levels are higher in squamous cell carcinoma compared with adenocarcinoma.24 Data on TS expression recently have been broadened to include undifferentiated large cell carcinoma. In a study presented at the ASCO meeting in 2009, significantly higher median mRNA and protein TS levels were detected in the large cell and squamous cell carcinoma samples compared with the adenocarcinoma samples (large cell carcinoma: P<0.001 for both mRNA and protein values; squamous cell carcinoma: P=0.002 for mRNA, P<0.001 for protein).25

EGFR, VEGF, and KRAS Somatic mutations in the tyrosine kinase domains of two erbB genesâ&#x20AC;&#x201D;the EGFR and HER-2 (human epidermal growth factor receptor 2) genesâ&#x20AC;&#x201D;have been found in lung adenocarcinomas. EGFR mutations are associated with sensitivity to the TKIs gefitinib26-28 and erlotinib, particularly those in exon 19.29 However, markers of resistance to EGFR inhibitors also have been identified, including the T790M mutation in exon 20.30,31 Approximately 15% to 30% of lung adenocarcinomas contain activating mutations in the KRAS gene and may be associated with unfavorable outcomes.32 Unlike in colon cancer, mutations in KRAS in lung cancer are not associated with a lack of sensitivity to either of the EGFR TKIs.33 Thus, although patients with EGFR mutations had improved PFS when treated with maintenance erlotinib in the SATURN trial, KRAS mutations had no predictive value.20

Broader Genotype Testing As EGFR mutations have emerged as an important target for therapy, strategies for treating patients harboring other mutations that make them refractory to treatment are being tested. EML4-ALK is a novel fusion oncogene in NSCLC.34 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase.

Shaw et al. have shown that the presence of EML4ALK results in a similar clinical profile to that seen in patients with EGFR mutations and is particularly frequent in light or never smokers; however, unlike EGFR mutations, EML4-ALK is found more often in men.35 Patients with EML4-ALK tumors did not benefit from EGFR TKIs; there were no responses in the EML4-ALK cohort. A Phase I trial has begun testing the ALK inhibitor PF-02341066,36 and promising initial data have allowed early development of a Phase III trial of an ALK inhibitor with docetaxel as second-line therapy.

Another active area of research centers on mechanisms of resistance to EGFR TKIs, including amplification of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation. Molecular testing for these abnormalities may eventually play a role in treatment selection. Preclinical studies employing MET inhibitors and next-generation TKIs have shown encouraging results and these agents have been moved into clinical trials.37-38 BIBW 2992 is one new small-molecule EGFR TKI that differs from its predecessors by binding irreversibly to both EGFR and HER-2 and is active against both wild-type and multiple mutant forms of EGFR. Preliminary results from an ongoing Phase II study of patients with NSCLC whose tumors had EGFR-activating mutations and had progressive or recurrent disease following chemotherapy showed a 97% disease control rate when treated with BIBW 2992 alone.39 Additional Phase II/III studies are under way investigating use of BIBW 2992 in NSCLC patients in other treatment settings.

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

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2. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials for patients with advanced non-small-cell lung cancer; sobering results. J Clin Oncol. 2001;19(6):1734-1742, PMID: 11251004.

3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550, PMID: 17167137.

4. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440, PMID: 19767093.

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6. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.

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7. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551, PMID: 18506025.

8. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet.

2009;373(9674):1525-1531, PMID: 19410716.

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J Clin Oncol. 2009;27(15 suppl): Abstract 8083.

10. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD3.5.5. Presented at the 2009 IASLC World Congress on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 11. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized Phase III trial. Lancet. 2008;372(9652):1809-1818, PMID: 19027483.

12. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized Phase III INTEREST trial. J Clin Oncol. 2009;28(5):744-752, PMID 20038723.

13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957, PMID: 19692680.

14. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967, PMID: 19692684.

15. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV nonsmall-cell lung cancer. J Clin Oncol. 2002;20(5):1335-1343, PMID: 11870177.

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

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

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

19. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-598, PMID: 19075278.

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29

20. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol.

2009;27:15(suppl): Abstract 8001.

21. Miller VA, O’Connor P, Soh C, et al. A randomized, doubleblind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27:18(suppl): Abstract LBA8002.

22. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–smallcell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597, PMID: 15117980.

29. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer— molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144, PMID: 16014883.

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

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

32. Rodenhuis S, Slebos RJ. The ras oncogenes in human lung cancer.

Am Rev Respir Dis. 1990;142(6 Pt 2):S27-S30, PMID: 2252272.

33. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.

PLoS Med. 2005;2(1):e17, PMID: 15696205.

23. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): P2-328. J Thorac Oncol. 2007;2(8):S851: Abstract P2-328.

34. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer.

Nature. 2007;448(7153):561-566, PMID: 17625570.

24. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer.

2006;107(7):1589-1596, PMID: 16955506.

36. Kwak EL, Camidge DR, Clark J, et al. Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066. J Clin Oncol. 2009;27:15(suppl): Abstract 3509.

25. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27:15(suppl): Abstract 7521.

26. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139, PMID: 15118073.

27. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science.

2004;304(5676):1497-1500, PMID: 15118125.

28. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311, PMID: 15329413.

30

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

35. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253, PMID: 19667264.

37. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77-88, PMID: 20129249.

38. Regales L, Gong Y, Shen R, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009;119:3000-3010, PMID: 19759520.

39. Yang CH, Shih JY, Su WC, et al. BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor, in chemonaive patients with adenocarcinoma of the lung and activating EGFR mutation (LUX-Lung 2). Presented at: 13th World Conference on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 40. Kim ES, Herbst RS, Lee JJ, et al. Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program. J Clin Oncol. 2009;27(15 suppl): Abstract 8024.

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GC58323 0509 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

Her struggle is fresh, but she can

move on with new confidence.

GLEEVEC® (imatinib mesylate) tablets are indicated for the adjuvant treatment of adult patients following complete gross resection of KIT (CD117)–positive GIST. Important Safety Information ■ GLEEVEC is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.

■ Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

■ Dose adjustments may be necessary due to hematologic adverse reactions, hepatotoxicity, and other nonhematologic adverse reactions.

■ In the adjuvant treatment of GIST trials (GLEEVEC; placebo) severe (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2% to 1%), nausea (2%; 1%), vomiting (2%; 1%), and periorbital edema (1%; 0%) were reported among patients receiving adjuvant treatment of GLEEVEC. ■ Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

■ Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

■ Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment.

■ There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.

■ Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

■ Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients.

■ Consider potential toxicities—specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

■ Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception.

If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.

1 in 2 patients experiences recurrent disease after surgery1

GLEEVEC for adjuvant therapy in KIT+ GIST ■ With a median follow-up of 14 months,

GLEEVEC Significantly Improves RFS vs Placebo2

more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (P<0.0001): GLEEVEC 30/359 = 8.4%, placebo 70/354 = 19.8%.2

Patients with RFS (%)

100

■ Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism.2

80

60 TREATMENT PERIOD

FOLLOW-UP PERIOD

40 GLEEVEC (n=359)

20

Placebo (n=354)

0

■ The most frequently reported common

0

adverse reactions were gastrointestinal disturbances, fatigue, edema, decreased hemoglobin, and rash.2

6

12

18

24

30

36

42

48

54

Time to recurrence (months)

Patients at risk: GLEEVEC

359

258

207

166

105

60

33

23

5

Placebo

354

243

186

138

89

57

34

19

8

1

A Phase III, randomized, double-blind study of adjuvant GLEEVEC versus placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence, or death from any cause.2

■ GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50% and clinical response should be carefully monitored in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)

■ For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common Side Effects of GLEEVEC Tablets ■ In the adjuvant treatment of GIST trials, the majority of both GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (60%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), and abdominal pain (21%; 22%).* ■ In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.* ■ Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.

■ GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

■ Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. *For more detailed study information, please see full Prescribing Information.

References: 1. National Comprehensive Cancer Network. Soft tissue sarcoma. Clinical Practice Guidelines in Oncology—V.1.2009. http://www.nccn.org. Accessed July 20, 2009.

2. GLEEVEC® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2009.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2009 Novartis

Printed in USA

7/09

C-GLI-100051

GLEEVEC (imatinib mesylate) tablets for oral use

(3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages.

Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information.

5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.

1 INDICATIONS AND USAGE 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information].

Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information].

5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Gleevec [see Dosage and Administration (2.10) in the full prescribing information].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression.

Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 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.

6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses â&#x2030;Ľ750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment.

6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients.

Bilirubin elevation was observed in 2.7% of patients.

6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9.

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N=818 Reported or Specified Term

Imatinib 400 mg N=818 Reported or Specified Term

Imatinib 800 mg N=822

All Grades Grades 3/4/5 All Grades Grades 3/4/5 % % % %

Edema Fatigue/lethargy, malaise, asthenia Nausea Abdominal pain/cramping Diarrhea Rash/desquamation Vomiting Myalgia Anemia Anorexia Other GI toxicity Headache Other pain (excluding tumor related pain) Other dermatology/ skin toxicity Leukopenia Other constitutional symptoms Cough Infection (without neutropenia) Pruritus Other neurological toxicity

76.7

9.0

86.1

13.1

69.3 58.1 57.2 56.2 38.1 37.4 32.2 32.0 31.1 25.2 22.0

11.7 9.0 13.8 8.1 7.6 9.2 5.6 4.9 6.6 8.1 5.7

74.9 64.5 55.2 58.2 49.8 40.6 30.2 34.8 35.8 28.1 19.7

12.2 7.8 11.8 8.6 8.9 7.5 3.8 6.4 4.7 6.6 3.6

20.4

5.9

20.8

5.0

17.6 17.0

5.9 0.7

20.1 19.6

5.7 1.6

16.7 16.1

6.4 4.5

15.2 14.5

4.4 3.2

15.5 15.4

6.6 5.4

16.5 18.9

5.6 4.3

15.0

6.4

15.2

4.9 (continued)

All Grades Grades 3/4/5 All Grades Grades 3/4/5 % % % %

Constipation Other renal/ genitourinary toxicity Arthralgia (joint pain) Dyspnea (shortness of breath) Fever in absence of neutropenia (ANC <1.0 x 109/L) Sweating Other hemorrhage Weight gain Alopecia Dyspepsia/heartburn Neutropenia/ granulocytopenia Rigors/chills Dizziness/ lightheadedness Creatinine increase Flatulence Stomatitis/pharyngitis (oral/pharyngeal mucositis) Lymphopenia

14.8

5.1

14.4

4.1

14.2 13.6

6.5 4.8

13.6 12.3

5.2 3.0

13.6

6.8

14.2

5.6

13.2 12.7 12.3 12.0 11.9 11.5

4.9 4.6 6.7 1.0 4.3 0.6

12.9 8.5 13.3 10.6 14.8 10.9

3.4 2.8 6.1 0.6 3.2 0.5

11.5 11.0

3.1 4.6

16.1 10.2

4.1 3.0

11.0 10.8 10.0

4.8 0.4 0.2

10.0 10.1 10.1

2.8 0.6 0.1

9.2 6.0

5.4 0.7

10.0 10.1

4.3 1.9

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials

Imatinib 800 mg N=822

Table 10: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n=73) % CTC Grades1 Hematology Parameters – Anemia – Thrombocytopenia – Neutropenia Biochemistry Parameters – Elevated Creatinine – Reduced Albumin – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT (AST) – Elevated SGPT (ALT)

600 mg (n=74) %

Grade 3

Grade 4

Grade 3

Grade 4

3 0 7

0 0 3

8 1 8

1 0 3

0 3 1

0 0 0

3 4 1

0 0 3

0 4 6

0 0 0

3 3 7

0 3 1

Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L)

1CTC

Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11.

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades

Preferred Term Diarrhea Fatigue Nausea Periorbital Edema Hemoglobin Decreased Peripheral Edema Rash (Exfoliative) Vomiting Abdominal Pain Headache Dyspepsia Anorexia Weight Increased Liver Enzymes (ALT) Increased Muscle Spasms Neutrophil Count Decreased Arthralgia White Blood Cell Count Decreased Constipation Dizziness Liver Enzymes (AST) Increased Myalgia Blood Creatinine Increased Cough Pruritus Weight Decreased Hyperglycemia Insomnia Lacrimation Increased Alopecia Flatulence Rash Abdominal Distension Back Pain Pain in Extremity Hypokalemia Depression Facial Edema Blood Alkaline Phosphatase Increased Dry Skin Dysgeusia Abdominal Pain Upper Neuropathy Peripheral Hypocalcemia Leukopenia Platelet Count Decreased Stomatitis Upper Respiratory Tract Infection Vision Blurred

CTC Grade 3 and above

Gleevec (n=337) %

Placebo (n=345) %

Gleevec (n=337) %

Placebo (n=345) %

59.3 57.0 53.1 47.2

29.3 40.9 27.8 14.5

3.0 2.1 2.4 1.2

1.4 1.2 1.2 0

46.9 26.7 26.1 25.5 21.1 19.3 17.2 16.9 16.9

27.0 14.8 12.8 13.9 22.3 20.3 13.0 8.7 11.6

0.6 0.3 2.7 2.4 3.0 0.6 0.9 0.3 0.3

0 0 0 0.6 1.4 0 0 0 0

16.6 16.3

13.0 3.3

2.7 0

0 0

16.0 15.1

6.1 14.5

3.3 0

0.9 0.3

14.5 12.8 12.5

4.3 17.7 10.7

0.6 0 0

0.3 0.3 0.3

12.2 12.2

7.5 11.6

2.1 0

0 0.3

11.6 11.0 11.0 10.1 9.8 9.8 9.8 9.5 8.9 8.9 7.4 7.4 7.4 7.1 6.8 6.8

5.8 11.3 7.8 5.2 11.3 7.2 3.8 6.7 9.6 5.2 6.4 8.1 7.2 2.0 6.4 1.2

0 0 0.9 0 0.6 0.9 0 0 0 0.9 0.3 0.6 0.3 0.9 0.9 0.3

0.3 0 0 0 1.7 0 0 0 0 0 0.3 0 0 0.6 0.6 0

6.5 6.5 6.5

7.5 5.2 2.9

0 0 0

0 0 0

6.2

6.4

0.3

0

5.9 5.6 5.0

6.4 1.7 2.6

0 0.3 0.3

0 0 0

5.0 5.0

3.5 1.7

0 0.6

0 0

5.0 5.0

3.5 2.3

0 0

0 0

adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

(1)All

6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec.

Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema

Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including

some fatalities

6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec. 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.

Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/ tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysaesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including

some fatalities

In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAEDs decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated.

Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.9) in the full prescribing information].

7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the

cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.

7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits acetaminophen O-glucuronidation (Ki value of 58.5 μM) at therapeutic levels. Systemic exposure to acetaminophen is expected to be increased when co-administered with Gleevec. No specific studies in humans have been performed and caution is recommended.

888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].

Gleevec can cause fetal harm when administered to a pregnant woman.

Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).

There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, 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 Gleevec safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferonalpha therapy. There are no data in children under 2 years of age. Follow-up in children with newly diagnosed Ph+ chronic phase CML is limited.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs. 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years.

No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepaticallyimpaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information].

8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day.

Dose reductions are necessary for patients with moderate and severe renal impairment [see Dose Modification Guidelines (2.9) in the full prescribing information].

Table 13: Renal Function Classification Renal Dysfunction

Renal Function Tests

Mild

CrCL = 40-59 mL/min

Moderate

CrCL = 20-39 mL/min

Severe

CrCL = <20 mL/min

CrCL = Creatinine Clearance

Table 12: Liver Function Classification Liver Function Test

Normal (n=14)

Mild (n=30)

Moderate (n=20)

Severe (n=20)

Total Bilirubin

≤ULN

>1.0-1.5x ULN

>1.5-3x ULN

>3-10x ULN

SGOT

≤ULN

>ULN (can be normal if Total Bilirubin is >ULN)

Any

Any

ULN=upper limit of normal for the institution

T2009-124 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Dilemmas in the Management of Treatment-Na誰ve Patients With

Metastatic Renal Cell Carcinoma SABY GEORGE, MD Medical Oncology Fellow Cancer Therapy & Research Center University of Texas Health Sciences Center at San Antonio San Antonio, Texas

RONALD M. BUKOWSKI, MD Professor Emeritus Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio

O

ver the past couple of decades, biomedical research in renal cell carcinoma (RCC), and enhanced

understanding of the von Hippel-Lindau disease (VHL) gene and how its dysfunction leads to highly vascular tumors, has resulted in the development of 6 new treatment options for patients with metastatic RCC.1-8

The approval of these new treatments happened at an amazing pace, occurring over a span of 4 years between late 2005 and late 2009. The approval of sorafenib (Nexavar, Bayer) was followed by approval of sunitinib (Sutent, Pfizer), temsirolimus (Torisel, Wyeth), bevacizumab (Avastin, Genentech) plus interferon (IFN), everolimus (Afinitor, Novartis), and, most recently, pazopanib (Votrient, GlaxoSmithKline).

Because these agents were approved in such quick succession, there is a lack of data from randomized trials compararing these therapeutic options in the front-line setting, which leads to the current dilemma in choosing the best first-line agent. This article reviews the pertinent data in the front-line setting (Table), and 2 recent metaanalyses, to provide information concerning acceptable front-line therapy in patients with metastatic RCC.9,10

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

First-Line Therapeutic Options SUNITINIB Sunitinib was evaluated in a large, randomized, multicenter Phase III trial in treatment-na誰ve patients with metastatic RCC.6 During the study, 750 patients were randomized to receive either sunitinib or IFN, in a 1-to-1 fashion. Randomization also was stratified based on baseline lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and nephrectomy status. Random permuted blocks of 4 were used to ensure balance between groups. Oral sunitinib was administered as 50 mg daily for 28 days on and 14 days off, in a 6-week cycle. IFN was administered as a subcutaneous injection of 9 million units (MU) 3 times per week. The dosing was initiated at 3 MU in

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 1 0

39

Table. Large RCC Trials Conducted in the Front-Line Setting Treatment Arms (Randomization Ratio)

N

Progression-Free Survival, mo

Response Rate, %

Overall Survival, %

Sunitinib vs IFN6

Sunitinib IFN (1:1)

375 375

11 5.5

47 12

26.4 21.8

AVOREN11

Bevacizumab + IFN Placebo + IFN (1:1)

649

10.2 5.4

31 13

NA

CALGB 902067

Bevacizumab + IFN IFN (1:1)

732

8.5 5.2

25.5 13

NA

Pazopanib Phase III8

Pazopanib Placebo (2:1)

290 145

11.1 2.8

32 4

NA

Temsirolimus vs IFN3

Temsirolimus Temsirolimus + IFN IFN (1:1:1)

626

3.8 3.7 1.9

8.6 4.8 8.1

10.9 7.3 8.4

Clinical Trial

CALGB, Cancer and Leukemia Group B; IFN, interferon

week 1, 6 MU in week 2, and 9 MU from week 3 onward.

The primary end point of this study was progression-free survival (PFS), and the secondary end points included overall survival (OS), response rates, patient-reported outcomes, and safety. More than 90% of the patients accrued to the study belonged to favorable or intermediate Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups. All patients had ECOG PS of 0 or 1.

The median PFS was 11 versus 5 months (P<0.001), favoring sunitinib. The response rate also favored sunitinib (47% vs 12%). Sunitinib was found to be safe and generally well tolerated in this study. The use of sunitinib was associated with more frequent diarrhea, nausea, vomiting, hypertension, stomatitis, cytopenias, and skin changes compared with IFN. The updated report of the survival analysis demonstrated an advantage for all patients treated with sunitinib, irrespective of individual baseline risk factors.

The median OS, which was reported after data maturations, favored sunitinib (26.4 vs 21.8 months; P=0.051).

Although the P value was not significant, this result is clinically meaningful to patients with metastatic RCC. Additionally, an exploratory analysis that censored patients crossing over from IFN to sunitinib showed that the OS significantly favored sunitinib (26.4 vs 20 months; hazard ratio [HR], 0.808; 95% confidence interval [CI], 0.610.987; P=0.036). This large trial of sunitinib showed OS and PFS benefits in patients with metastatic RCC who were treatment-naïve and primarily in favorable- and intermediate-risk categories.

BEVACIZUMAB

AND

IFN

Two trials—AVOREN11 and CALGB (Cancer and Leukemia Group B) 902067—tested the utility of combining bevacizumab and IFN in patients with metastatic RCC. AVOREN was a large randomized, double-blind, Phase III multicenter trial conducted in 18 countries outside the

40

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

United States. The study included 649 treatment-naïve patients with metastatic RCC who had mostly clear cell histology, either radical or partial nephrectomy, Karnofsky performance status (KPS) of 70 or more, no brain metastases, and good organ function. (More than 75% of the patients studied had KPS 90 and 100 and favorable/intermediate MSKCC risk scores.) After blocking and stratification based on the country of residence and MSKCC risk groups, the patients were randomly assigned in a 1-to-1 ratio to receive 9 MU of subcutaneous IFN (initial dose escalation from 3 to 9 MU over 3 weeks, with a maximum of 52 weeks of therapy) and either bevacizumab (10 mg/kg IV every 2 weeks) or placebo. IFN dose reductions were allowed, whereas bevacizumab was continued at the starting dose unless a serious adverse event (AE) occurred. The primary end point of this study was OS; secondary end points included PFS and safety.

The investigators found that 641 patients had at least one dose of treatment in their respective study arms: 325 receiving bevacizumab plus IFN and 316 receiving placebo plus IFN. The overall response rate (ORR) favored the bevacizumab group (31% vs 13%). The median PFS also favored bevacizumab (10.2 vs 5.4 months; HR, 0.63; 95% CI, 0.52-0.75; P=0.0001). Additionally, an ad hoc analysis suggested that IFN dose reductions and/ or delays were not associated with decreased efficacy (reduced dose of IFN: PFS HR, 0.63; P=0.0026; full dose of IFN: HR, 0.69; P=0.0007).4 AEs were reported in 97% of the bevacizumab plus IFN group and 94% of the placebo plus IFN group. Grade 3 or 4 AEs were reported more frequently in the bevacizumab arm and included fatigue, asthenia, proteinuria, neutropenia, hypertension, and bleeding. In addition to the above AEs, gastrointestinal perforations, wound-healing complications, and arterial thromboembolic events were seen at a low frequency in bevacizumab-treated patients. This trial established bevacizumab and IFN as a robust first-line treatment for

patients with metastatic RCC who are in intermediateand favorable-risk groups.

Rini et al reported a similar Phase III trial (CALGB90206).7 This open-label study randomly assigned 732 patients in a 1-to-1 ratio to receive bevacizumab plus IFN or IFN alone. Stratified random block design was used, and stratification was based on the nephrectomy status and number of prognostic factors. The primary end point of this study was OS, and secondary end points included PFS, ORR, and safety. All of the patients had clear cell component in the pathology, 85% of those in both groups had prior nephrectomy, and 90% of those in both groups had an intermediateor favorable-risk classification.

Rini et al found that PFS favored bevacizumab (8.5 vs 5.2 months; P<0.0001). The ORR also favored bevacizumab (25.5% vs 13.1%; P<0.0001). In patients who were assessed for toxicity, 79% in the bevacizumab group and 61% in the IFN-alone group had at least grade 3 AEs. The most common AEs in the bevacizumab group were hypertension, fatigue, anorexia, proteinuria, and weight loss. This trial also demonstrated clinical benefits in the form of superior ORR and PFS in patients who are treatment-naïve and who have intermediate or favorable prognostic factors.

PAZOPANIB Pazopanib is a multi-tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-KIT.8 This drug showed promising results in a Phase II study.12 The double-blind, randomized Phase III trial was conducted in patients with locally advanced and/or metastatic RCC at multiple centers on 5 continents (not North America).8 This study allowed prior cytokine therapy and randomly assigned patients to receive pazopanib at a dosage of 800 mg daily (n=290), or matching placebo (n=145), in a 2-to-1 ratio. The primary end point was PFS, and secondary end points included OS, ORR, and safety.

Response evaluation was conducted every 6 weeks until week 24, and every 8 weeks thereafter. The majority of the patients had intermediate- or favorable-risk status and a prior nephrectomy. All patients had an ECOG PS of either 0 or 1; 53% of the patients in the pazopanib arm (n=155) were previously untreated, whereas 47% (n=135) had received prior cytokine therapy.

In treatment-naïve patients, the ORR was superior in the pazopanib arm at 32% (4% for placebo) and the median PFS was 11.1 months (2.8 months for placebo; HR, 0.40; 95% CI, 0.27-0.60; P<0.0001). The assessment of health-related quality of life (QoL) showed no differences between placebo and pazopanib, meaning no deterioration in the QoL secondary to pazopanib use. AEs were more frequent and severe in the pazopanib arm, with diarrhea (52%), hypertension (40%), hair color changes (38%), nausea (26%), and elevation in liver function tests (≥53%) occurring most frequently. This small Phase III trial showed pazopanib to be effective in patients with treatment-naïve RCC.

TEMSIROLIMUS Temsirolimus was approved for patients with metastatic RCC after proving to be beneficial in a randomized Phase III trial.3 During the trial, 626 patients with metastatic RCC were randomized to receive either temsirolimus alone (25 mg weekly IV injection), temsirolimus (15 mg IV weekly) plus IFN (6 MU subcutaneously 3 times weekly), or IFN alone (3 MU subcutaneously 3 times weekly escalating to 18 MU subcutaneously 3 times weekly). This study included patients with non– clear cell histology (18%), as well as those with protocol-defined poor prognostic features.

Temsirolimus was well tolerated compared with IFN. AEs were more frequent in the IFN and IFN plus temsirolimus groups, with the exception of hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, which were increased in the temsirolimus group. Temsirolimus alone improved OS (10.9 vs 7.3 months) and increased PFS (3.8 vs 1.9 months) compared with IFN alone. ORRs, which were not significantly different, were 8.6% and 4.6% for temsirolimus alone and IFN alone, respectively (P=0.1232).

In the combination arm, the ORR, median PFS, and OS, which were not statistically significant, were 8.1%, 3.7 months, and 8.4 months, respectively. The OS and PFS improvements with temsirolimus alone were noted in previously untreated patients with poor-risk features, including the group with non–clear cell histology.13

SORAFENIB Sorafenib was tested in the treatment-naïve setting of metastatic RCC in a randomized Phase II trial comparing it with IFN.14 In period 1 of this open-label study, 97 patients were assigned to receive sorafenib (400 mg twice daily on a continuous dosing regimen) and 92 to receive IFN (9 MU 3 times weekly). In period 2, patients who progressed on sorafenib were allowed a dose escalation to 600 mg twice daily and those who progressed on IFN were crossed over to receive sorafenib.

The investigators found that for period 1, the median PFS was 5.7 and 5.6 months for sorafenib and IFN, respectively. Although the response rates were similar in both arms, tumor shrinkage rates favored sorafenib (68.2% vs 39%). In period 2, 41.9% of the escalated sorafenib group (n=43) experienced tumor shrinkage, and the median PFS was an additional 3.6 months. In the group that crossed over to sorafenib, 76.2% of patients had a reduction in tumor size (n=50), and the median PFS was 5.3 months. Common grade 3 or higher AEs associated with sorafenib were hand–foot syndrome, diarrhea, and rash/desquamation; those associated with IFN were fatigue, nausea, flu-like syndrome, and anorexia. No increase in the frequency or grade of AEs was reported in the dose-escalation arm.

HIGH-DOSE INTERLEUKIN-2 The T-lymphocyte growth factor interleukin (IL)-2 (aldesleukin, Proleukin, Prometheus) was approved to treat patients with metastatic RCC in 1992. Because of limited efficacy, a high rate of toxicity, and high cost,

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

41

MSKCC Risk Status

Favorable Risk

Intermediate Risk

Poor Risk

Level 1 Evidence

Level 1 Evidence

Level 1 Evidence

• Sunitinib • Bevacizumab plus IFN • Pazopanib

• Sunitinib • Bevacizumab plus IFN • Pazopanib

• Temsirolimus

Level 2 Evidence

Level 2 Evidence

• High-dose IL-2 in selected patients

• High-dose IL-2 in selected patients

Level 2 Evidence • Sunitinib

Figure. Algorithm for front-line treatment of patients with metastatic RCC. IFN, interferon; IL, interleukin; MSKCC, Memorial Sloan-Kettering Cancer Center Based on references 20-22.

IL-2 is restricted to a few centers, but it has a role in a subset of patients with good risk features, even in this age of targeted therapies.15-17 McDermott et al recently reported the results of the Select trial, a nonrandomized study of 123 patients with all types of histology who were in favorable-risk categories.18 The majority of the patients had prior nephrectomy (99%), clear cell histology (96%), and good or intermediate-risk score per MSKCC criteria (94%) or UCLA Survival After Nephrectomy and Immunotherapy (SANI) score19 (93%). Biomarker analysis also was an integral part of the design.

IV IL-2 was administered at a dose of 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19.

The ORR was significant (95% CI, 28%, 20.5%-37.3%; P=0.01695). There were 7 complete responses (6%) and 27 partial responses (22%), 12% had stable disease and 71% had progressive disease. The median PFS was 4.2 months, and the benefit was greater for patients with low SANI scores (P=0.002).

Systematic Reviews of Various First-Line Trials Trials comparing these agents in untreated patients are lacking, and therefore conclusions or recommendations regarding the best treatment alternatives are problematic. A series of randomized trials in progress will provide information on this issue. These trials include COMPARZ (NCT00720941), evaluating sunitinib versus pazopanib; RECORD-2 (REnal Cell cancer treatment with Oral RAD001 given Daily-2; NCT00719264), evaluating bevacizumab plus everolimus versus bevacizumab plus IFN; RECORD-3 (REnal Cell cancer treatment with Oral RAD001 given Daily3; NCT00903175), evaluating sunitinib versus everolimus; and INTORACT (Investigation of Torisel and

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Avastin Combination Therapy; NCT00631371), evaluating bevacizumab plus IFN versus bevacizumab plus temsirolimus.

In the poor-risk patient population, data from the various randomized trials are limited, but level 1 data with temsirolimus indicate that it is a preferred therapy.

Two meta-analyses have examined this question. Both of these reports used PFS data.

In their meta-analysis, Mills et al evaluated 7 trials of bevacizumab (n=3), sorafenib (n=2), sunitinib (n=1), and temsirolimus (n=1) in metastatic RCC.9 Indirect comparisons done using IFN as a common comparator indicate that sunitinib was superior to sorafenib (HR, 0.58; 95% CI, 0.38-0.86; P<0.001) and bevacizumab plus IFN (HR, 0.75; 95% CI, 0.60-0.93; P=0.001) in terms of PFS benefit. They also noted that temsirolimus provided significant PFS benefit for patients with poor prognostic features (HR, 0.69; 95% CI, 0.57-0.85).

Thompson Coon et al conducted an indirect comparison of sunitinib and bevacizumab plus IFN.10 They included 3 randomized, first-line studies in the analysis (Phase III sunitinib vs IFN,6 AVOREN,11 and CALGB 902067). The indirect comparison revealed that both sunitinib and bevacizumab plus IFN prolonged median PFS compared with IFN alone, with sunitinib being superior to bevacizumab plus IFN (HR, 0.796; 95% CI, 0.63-0.1; P=0.0272). The frequency of AEs reported with sunitinib was lower than that reported with IFN, as were grade 3 toxicities (7% vs 12%; P<0.05), but the frequency of grade 3/4 AEs was higher with the combination of bevacizumab plus IFN than with IFN alone (P<0.0001).

Choosing the Best First-Line Option The process of choosing the ideal first-line therapy for

patients with metastatic RCC should incorporate baseline prognostic factors, respective organ function, and background comorbidities such as hypertension, cardiac illnesses, renal dysfunction, and so on. If the patient belongs to favorable- or intermediate-risk strata, sunitinib, bevacizumab plus IFN, or pazopanib are acceptable alternatives. The indirect meta-analyses suggest the possible superiority of sunitinib, and patterns of use suggest it is the option used by the majority of oncologists. In patients with poor-risk features or non–clear cell histology, the best first-line choice would be temsirolimus. High-dose IL-2 is an alternative choice in favorable-risk group patients with small-volume metastatic disease after careful preselection. Various clinical trial options comparing the front-line treatment alternatives should be considered if they are available. Several organizations have developed algorithms for the treatment of metastatic RCC. National Comprehensive Cancer Network, the European Association of Urology, the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology are leaders in this area. The Figure is a modified version of the ASCO guidelines presented by Atkins (2006),20 Bukowski (2007),21 and Rini (2008)22 that incorporates the latest evidence. These guidelines and the algorithm can serve as good resources to follow when any questions arise regarding treatment choices.

Conclusion Patients with metastatic RCC have multiple treatment options in the front-line setting. Making the best therapeutic choice for these patients can be perplexing, and requires consideration of toxicity, efficacy, and survival benefits. Until data comparing the various front-line alternatives are available, it will be challenging to determine which treatment is best for a given patient. All of the recently approved agents produce toxicity that is acceptable but can be problematic, especially in patients receiving long-term or chronic treatment. Careful monitoring, familiarity with the various toxicities produced, and early intervention are the best approaches to maximize benefit. Outside of a clinical trial, the patient’s risk group, prior therapy status, histologic subtype, and underlying comorbidity dictate choice of therapy. In the future, results from ongoing clinical trials will provide data to assist with treatment choices, and the development of biomarkers to characterize patient subsets most likely to benefit will improve clinician’s ability to choose the most appropriate and effective treatments for each patient.

References 1.

Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2): 125-134, PMID: 17215530.

2. George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003;349(5):419-421, PMID: 12890838.

3. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281, PMID: 17538086.

4. Melichar B, Koralewski P, Ravaud A, et al. First-line bevacizumab

combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol.

2008;19(8):1470-1476, PMID: 18408224.

5. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637): 449-456, PMID: 18653228.

6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356(2):115-124, PMID: 17215529.

7. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol.

2008;26(33):5422-5428, PMID: 18936475.

8. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized Phase III trial. J Clin Oncol. 2010;28(6):1061-1068, PMID: 20100962.

9. Mills EJ, Rachlis B, O’Regan C, et al. Metastatic renal cell cancer treatments: an indirect comparison meta-analysis. BMC Cancer.

2009;9:34, PMID: 19173737.

10. Thompson Coon JS, Liu Z, Hoyle M, et al. Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness.

Br J Cancer. 2009;101(2):238-243, PMID: 19568242.

11. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007; 370(9605):2103-2111, PMID: 18156031.

12. Hutson TE, Davis ID, Machiels JP, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma.

J Clin Oncol. 2010;28(3):475-480, PMID: 20008644.

13. Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol.

2009;26(2):202-209, PMID: 19229667.

14. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol.

2009;27(8):1280-1289, PMID: 19171708.

15. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21(16):3127-3132, PMID: 12915604.

16. Dutcher JP, Fisher RI, Weiss G, et al. Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study.

Cancer J Sci Am. 1997;3(3):157-162, PMID: 9161781.

17. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med. 1998;338(18):1272-1278, PMID: 9562581.

18. McDermott D, Ghebremichael M, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) Select trial in patients with metastatic renal cell carcinoma (mRCC): preliminary assessment of clinical benefit.

Presented at: ASCO Genitourinary Cancers Symposium; March 5-7, 2010; San Francisco, CA; Abstract 321.

19. Leibovich BC, Han KR, Bui MH, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;98(12):2566-2575, PMID: 14669275.

20. Atkins MB. Plenary session presentation. Presented at: 42nd Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, GA..

21. Bukowski RM. Plenary session presentation. Presented at: 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, IL. 22. Rini BI. Oral presentation. Presented at: 44th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2008; Chicago, IL.

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Bone Issues in Breast Cancer LARISSA A. KORDE, MD, MPH Assistant Professor of Medicine

JULIE R. GRALOW, MD Professor of Medicine Division of Medical Oncology University of Washington and Seattle Cancer Care Alliance Seattle, Washington

B

reast cancer is the most common malignancy among women in the United States, with approximately 190,000

new cases expected each year.1

It is estimated that there are more than 2.5 million women living in the United States with a past or present diagnosis of breast cancer. Treatments for breast cancer can have significant effects on bone. In premenopausal women, chemotherapy use often leads to premature menopause, accelerating bone loss. In postmenopausal women, hormonal therapy, including aromatase inhibitors (AIs), and ovarian suppression also can decrease bone density. Additionally, up to three-fourths of women with metastatic breast cancer will have disease involvement in the bones, leading to bone pain, increased risk for fracture, and other morbidities.2 Thus, a thorough understanding of factors associated with cancer therapy-induced bone loss, and treatment options are essential to providing quality care to cancer survivors. This review summarizes risk factors, evaluation, and treatment options for cancer therapy-induced bone loss and metastatic bone disease in breast cancer. Emerging data regarding new, targeted therapies and the effect of bone-targeted agents on breast cancer recurrence also are discussed.

Evaluation of Bone Health Bone health generally is evaluated by bone mineral density (BMD) levels, and usually is assessed using dualenergy x-ray absorptiometry scanning of the hip and spine. It commonly is expressed on a relative scale as the difference in standard deviations from the expected BMD for the patient’s age and sex (Z score) or from that of “young normal” adults of the same sex (T score). The

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World Health Organization (WHO) defines a normal BMD as that within 1 standard deviation of a young normal adult value (T score of >–1); a T score of –1 to –2.5 is considered osteopenia; and a T score of less than –2.5 constitutes osteoporosis.3 It is estimated that fracture risk doubles for each standard deviation reduction in BMD; however, many other factors, particularly age, also contribute to fracture risk.4 Recently, the WHO developed a risk assessment tool (FRAX) that combines BMD measures with other risk factors for fracture, including age, to provide estimates of 10-year risk for fracture.5 Medicare guidelines recommend therapeutic intervention if a patient has a 10-year FRAX risk of 3% for hip fractures and more than 20% for all major fractures. Cancer patients with elevated risk for bone loss and fracture should be evaluated periodically to assess the impact of their treatment on bone mass.

Initial strategies for prevention and treatment of bone loss include lifestyle modifications such as performing regular weight-bearing, strength-training, and balance exercises; avoiding tobacco; and limiting alcohol intake.

Additionally, all patients should be counseled regarding fall prevention and adequate intake of calcium (at least 1,200 mg/d) and vitamin D (800-1,000 IU/d).6 Therapeutic intervention should be strongly considered for patients with a T score below –2, particularly those with additional risk factors for fracture. Medications approved by the FDA for prevention and treatment of osteoporosis and/or cancer-related bone disease are listed in the Table. Certain medications used for osteoporosis management in

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noncancer patients, such as estrogen replacement therapy, raloxifene (a selective estrogen receptor modulator), and terapatide (a recombinant form of parathyroid hormone), are generally not recommended for women with a history of breast cancer. The optimal duration of therapy for osteoporosis is unknown.

Effects of Breast Cancer Therapy on Bone Health AI-INDUCED BONE LOSS Multiple breast cancer studies have shown AIs to decrease the risk for recurrence in postmenopausal patients with breast cancer when compared with tamoxifen, and these agents are commonly used as adjuvant therapy for hormone receptor-positive breast cancer.

AIs inhibit peripheral conversion of androgen to estrogen, resulting in a rapid decrease in circulating estrogen levels, and thus accelerated bone loss and increased risk for fracture. In the large adjuvant trials comparing AIs to tamoxifen, a 35% to 55% greater incidence of fracture was observed in AI-treated patients.7-9 Data from the MA-17 trial, in which patients previously treated with 5 years of tamoxifen were subsequently randomized to an additional 5 years of placebo or letrozole, showed no statistical differences.10 This suggests that most of the fracture difference seen in trials of AIs versus tamoxifen may be due to the bone-protective effects of tamoxifen.

In the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial, in which patients were randomized to 5 years of anastrozole (Arimidex, AstraZeneca) or tamoxifen, fracture rates after discontinuation of therapy were similar, suggesting that the increased risk for fracture with AI therapy is not permanent.8 In a prospective substudy of the ATAC trial that assessed BMD changes among 197 randomized women, no patients with normal BMD at baseline developed osteoporosis during the 5 years of therapy, and 5% of patients with osteopenia at baseline became osteoporotic.11 Among AI-treated patients, older age and baseline osteopenia have been identified as risk factors for fracture.

A number of recent studies suggest that both oral and IV bisphosphonates are effective for maintaining BMD in women receiving AI therapy. The SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE) and ARIBON studies assessed the combination of anastrozole with ibandronate (Boniva, Roche) or risedronate in women with osteoporosis or osteopenia. In both trials, the addition of a bisphosphonate resulted in favorable effects on BMD.12-14 The Z-FAST and Zo-FAST (Zometa-Femara Adjuvant Synergy Trials) studies evaluated the efficacy of up-front versus delayed initiation of zoledronic acid (ZA; Zometa, Novartis), a highly potent IV bisphosphonate, given with calcium and vitamin D, in preventing AIassociated bone loss. Fracture rates were similar between the 2 groups, but among those who received up-front ZA, lumbar spine BMD at 12 months was 5.2% higher.15 Oral bisphosphonate use has been associated with pill esophagitis, and therefore should be avoided in patients

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with esophageal emptying disorders and those unable to sit upright.16 IV bisphosphonates are associated with an acute phase reaction in about 30% of patients; this usually occurs with the initial dose of therapy. IV bisphosphonates also can affect renal function, and are not recommended in patients with a creatinine clearance less than 30 mL per minute.17 Calcium intake and vitamin D status should be optimized when starting any bisphosphonate. Osteonecrosis of the jaw (ONJ) has emerged as a rare but serious complication of bisphosphonate treatment. ONJ occurs in 1% to 10% of patients with IV bisphosphonate used at the higher doses for treating metastatic bone disease.18 This complication appears to be rare with bisphosphonate dosing to treat osteoporosis or prevent cancer treatment-induced bone loss.19,20 IV bisphoshonate therapy also has been associated with an increase in risk for atrial fibrillation,21 and a small but significant number of subtrochanteric hip fractures.22,23 Increased bone resorption also occurs in cancer patients as a result of receptor activation of nuclear factor-Îş B ligand (RANKL), which enhances osteoclast production and survival. Denosumab, a humanized monoclonal antibody to RANKL in development by Amgen, was evaluated in a Phase II placebo-controlled study in breast cancer patients receiving AIs. Patients receiving 60 mg of denosumab subcutaneously every 6 months for 2 years had significant (7.6%) increases in lumbar spine BMD; increases also were seen in BMD at the hip and radius.24 Denosumab is under study in breast cancer patients for reduction of skeletal-related events (SREs) due to bone metastases, and for prevention of bone metastases.

TREATMENT-INDUCED OVARIAN FAILURE Premenopausal women with early-stage breast cancer who receive adjuvant chemotherapy generally experience at least temporary amenorrhea, and many experience premature ovarian failure.25-27 In a prospective study by Shapiro et al, 71% of young women undergoing adjuvant chemotherapy experienced ovarian suppression, and in these patients a highly significant loss of bone density was seen in the lumbar spine at 6 months.28 Both oral clodronate and risedronate have been studied in the setting of chemotherapy-induced ovarian failure. When compared with placebo, both agents imparted about a 2% to 3% absolute improvement in BMD.29,30 IV therapy with ZA also is effective. In the CALGB (Cancer and Leukemia Group B) 79809 study, in which premenopausal women beginning adjuvant chemotherapy were randomized to immediate (every 3 months) versus delayed (1 year after chemotherapy) administration of ZA. Patients in the immediate-treatment arm had a 2.6% improvement in BMD at 12 months, whereas those who did not receive ZA experienced a 6.4% loss of BMD.31 The ABSCG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12) study evaluated 1,800 premenopausal women with stage I or II estrogen receptor (ER)-positive breast cancer.

Patients received goserelin (Zoladex, AstraZeneca) with either tamoxifen or anastrozole, and were randomized

Table. Medications Approved by the FDA for Prevention And Treatment of Osteoporosis and/or Cancer-Related Bone Disease Indication

Medication a

Typical Dosage

Route

Prevention

Estrogen ± progesterone

0.625 mg/d

Oral

Prevention (P) and treatment (T)

Alendronate

35 mg/wk (P); 70 mg/wk (T)

Oral

Ibandronate (Boniva, Roche)

150 mg/mo

Oral

Risedronate

35 mg/wk or 150 mg/mo

Oral

Raloxifene (Evista, Lilly)

60 mg daily

Oral

Ibandronate (Boniva, Roche)

3 mg q3mo

IV

Zoledronic acid (Reclast, Zometa, Novartis)

5 mg annuallyb

IV

Calcitonin

200 IU daily

Intranasal

Teriparatide (Forteo, Lilly)

20 mcg/d for up to 2 y

Subcutaneous

Treatment

a

Not routinely recommended for women with a history of breast cancer, particularly those with hormone receptor-positive disease.

b

The dose of zoledronic acid in most studies evaluating its use in breast cancer treatment-related bone loss was 4 mg IV every 6 months; however, the dose that is FDA-approved for treatment of postmenopausal osteoporosis is 5 mg IV annually.

to receive ZA every 6 months or not. In a subprotocol aimed at bone density evaluation (n=400), bone loss was observed in those receiving ovarian suppression with bisphosphonate. Among patients not receiving ZA, bone density loss at the lumbar spine was more severe in those patients on anastrozole compared with those receiving tamoxifen (–7.4% vs –11.6%). In contrast, among women receiving ZA, bone density remained stable, regardless of hormonal therapy administered.

Bone-Targeted Agents And Breast Cancer Recurrence Emerging evidence suggests that bisphosphonates also may have antitumor and antimetastatic properties. Early studies assessing the effect of oral clodronate on risk for breast cancer recurrence in early-stage patients produced promising yet conflicting results.32-34 In the largest randomized placebo-controlled trial to date (N=1,069), breast cancer patients receiving standard systemic therapies were randomized to receive oral clodronate (1,600 mg/d) or placebo for 2 years as adjuvant treatment. Bone metastases were reduced at both 2 and 5 years in the clodronate arm. Survival at 5 years, the preplanned study end point, favored the clodronate group, with a hazard ratio (HR) of uncertain significance due to multiple analyses (for all patients HR, 0.77; P=0.048).34 A second, smaller randomized openlabel study showed similar results,32,35 but a third small trial showed no reduction in bone metastases and an increase in nonskeletal recurrence (visceral and local), although 10-year disease-free survival was significantly lower in the clodronate group and there was a significant

overall survival difference.34,36 Additionally, recent metaanalysis of trials using oral clodronate in the adjuvant setting did not show improvements in overall or recurrence-free survival,37 although marked heterogeneity among the trials and wide confidence intervals make these data difficult to interpret. The ABSCG-12 trial, of ZA in premenopausal patients with ER-positive breast cancer receiving endocrine therapy, examined risk for recurrence as a secondary end point.38 After a median follow-up of 47.8 months, the addition of ZA resulted in a significant reduction of 36% in the risk for disease recurrence compared with endocrine therapy without ZA (HR, 0.64; 95% confidence interval, 0.46-0.91; P=0.01). Subset analyses of sites of recurrence revealed reductions in the incidence of distant recurrences, locoregional recurrences, and contralateral breast cancer, although the overall number of recurrences in both arms is quite small to date.

Time to recurrence also was a secondary end point in the Z-FAST and ZO-FAST studies of ER-positive, postmenopausal women on letrozole and randomized to “up-front” versus “delayed” ZA therapy. A recent combined analysis of these trials showed lower recurrence rates in the group receiving up-front ZA therapy (1.1% vs 2.3%; P=0.04).15 Several other studies are addressing the question of whether bisphosphonates affect disease recurrence, with results expected in the near future. The NSABP (National Surgical Adjuvant Breast and Bowel Project) B34 study, which closed to accrual in 2004, is assessing clodronate versus placebo in 3,300 women with stage I or II breast cancer. The AZURE trial is studying “intensive dosing” ZA

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versus control in women receiving chemotherapy and/ or endocrine therapy for the treatment of stage II or III breast cancer. This study closed to accrual in January 2006 and will likely report results sometime in 2010. The SWOG (Southwest Oncology Group) S0307 trial recently closed to accrual; it is comparing the efficacy of IV ZA with oral clodronate and ibandronate in 6,000 pre- and postmenopausal women with stage I to III breast cancer receiving standard adjuvant systemic therapy.

Bone Metastases Patients with bone metastases are at risk for SREs, which include fracture, the need for radiation to bone, spinal cord compromise, hypercalcemia, and surgery.

Bone metastases can cause significant pain and morbidity and account for a significant proportion of hospitalizations among cancer patients.39 The mainstay of oncologic care for bone metastases is control of tumor burden, which typically involves chemotherapy and/or hormonal therapy. Surgery and radiation also can be used for local control of specific bony lesions. Pamidronate and ZA both have been shown to reduce the frequency of skeletal morbidity in breast cancer patients with bone metastases.40,41 The American Society for Clinical Oncology (ASCO) clinical practice guidelines for breast cancer suggest that patients with radiographic evidence of bone metastases should receive therapy with either ZA or pamidronate at 3- to 4-week intervals.42 The optimal duration and dosing interval for bisphosphonate therapy in the metastatic setting is not well defined. ASCO guidelines recommend continuing bisphosphonate therapy indefinitely or until there is a substantial decline in the patientâ&#x20AC;&#x2122;s performance status.42 Two ongoing clinical trials, OPTIMIZE 2 and CALGB 70604, are evaluating optimal dosing intervals in women with metastatic breast cancer, either up-front or after 1 year of monthly dosing. A third trial, BISMARK, is evaluating the use of bone resorption markers to determine dosing intervals versus standard monthly dosing.

Within the bone microenvironment, RANKL secretion by stromal cells and osteoblasts is stimulated by tumor cells, resulting in increased osteoclast differentiation, function, and survival.43 Results of a Phase III trial comparing monthly treatment with denosumab versus ZA in 2,046 women with metastatic breast cancer to bone were reported in September 2009 at the European Society of Medical Oncology meeting.44 Denosumab significantly delayed the time to first and subsequent on-study SRE (P=0.001). Although overall toxicities were similar in the 2 arms, the incidence of ONJ was numerically but not statistically higher in denosumab-treated patients (2% vs 1.4%).

Although the widespread use of bisphosphonates has resulted in a decrease in the incidence of SREs, complications of bone metastases, including pain, fracture, and decreased mobility, still can have a significant impact on quality of life. Localized therapies, including radiation and surgery, can be used for palliation and for prevention of an impending event. Radiation therapy

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provides response rates in the range of 60% to 70%, and can result in complete pain relief in up to 20% to 30% of patients.45,46 Surgery can be performed to relieve pain, provide stabilization, and prevent impending fracture or cord compression. General criteria for lesions resulting in a high risk for fracture include lytic lesions that are larger than 2.5 cm or encompass more than 50% of the bone diameter, or the presence of lesser trochanter avulsion. Surgery also can be considered for impending fractures that include a lesion in a weight-bearing area and for readily identifiable painful lesions that are refractory to external beam radiation therapy.6

Conclusions Bone health is an increasingly important issue for breast cancer patients and their health care providers.

An understanding of factors associated with cancer therapy-induced bone loss, and its treatment are essential to providing quality care to cancer survivors. Strategies to reduce morbidity include education, lifestyle modification, calcium and vitamin D supplementation, screening for osteoporosis, and, when appropriate, initiation of drug therapy. For patients on bisphosphonate therapy, careful monitoring for side effects is essential.

Emerging data suggest that in addition to effectively treating cancer therapy-induced bone loss, bisphosphonates may impact risk for recurrence in patients with early-stage breast cancer.

The bone is a common site of metastatic disease in breast cancer patients. In patients with documented bone metastases, SREs lead to significant morbidity and adversely affect quality of life. Treatment should employ a multidisciplinary approach, including systemic anticancer therapy, osteoclast-targeted therapy, such as bisphosphonates, pain control, and possibly surgery and radiation for local control. Emerging strategies, including novel bone-targeted agents, are being evaluated and may contribute to the management of patients with metastatic bone disease.

References 1.

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

2. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2) 6243s-6249s, PMID: 17062708.

3. Kanis JA, Melton LJ 3rd, Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9(8):1137-1141, PMID: 7976495.

4. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):1254-1259, PMID: 8634613.

5. World Health Organization. FRAX WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/. Accessed November 9, 2009.

6. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw.

2009;7(suppl 3):S1-S32; quiz S33-S35, PMID: 19555589.

7. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-1092, PMID: 15014181.

8. Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer:

100-month analysis of the ATAC trial. Lancet Oncol. 2008;9(1): 45-53, PMID: 18083636.

9. Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747-2757, PMID: 16382061.

10. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):17931802, PMID: 14551341.

29. Delmas PD, Balena R, Confravreux E, et al. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebocontrolled study. J Clin Oncol. 1997;15(3):955-962, PMID: 9060533.

30. Saarto T, Blomqvist C, Valimaki M, et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol. 1997;15(4):1341-1347, PMID: 9193325.

11. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol.

2008;26(7):1051-1057, PMID: 183009940.

31. Shapiro CL, Halabi S, Gibson G, et al. Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results from CALGB trial 79809. J Clin Oncol. 2008;26 (suppl): Abstract 512.

12. Lester J, Dodwell D, Purohit OP, et al. Use of monthly oral ibandronate to prevent anastrozole-induced bone loss during adjuvant treatment for breast cancer: Two-year results from the ARIBON study. J Clin Oncol. 2008;26(15 suppl): Abstract 554.

32. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339(6):357-363, PMID: 9691101.

13. Van Poznak C, Hannon RA, Mackey JR, et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol. 2010;28(6):967-975, PMID: 20065185.

33. Powles T, Paterson A, McCloskey E, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 2006;8(2):R13, PMID: 16542503.

14. Van Poznak C, Hannon R, Clack G, et al. Managing cancer treatment-induced bone loss: 24-month results from the Study of Anastrozole with the Bisphosphonate RisedronatE (SABRE).

Cancer Res. 2009;69(suppl): Abstract 1137.

15. Brufsky A, Bundred N, Coleman R, et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist. 2008;13(5):503-514, PMID: 18515735.

16. Khan MN, Khan AA. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol. 2008;15(Suppl 1):S30S40, PMID: 18231646.

17. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med. 2003;349(17):1676-1679, PMID: 14573746.

18. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park).

2006;20(9):1053-1062, PMID: 16986349.

19. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479-1491, PMID: 17663640.

20. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144(10):753-761, PMID: 16702591.

21. Black DM, Arden NK, Palermo L, Pearson J, Cummings SR. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res. 1999;14(5):821-828, PMID: 10320531.

22. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89(3):349-353, PMID: 17356148.

23. Kwek EB, Goh SK, Koh JS, et al. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury. 2008;39(2):224-231, PMID: 18222447.

24. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):48754882, PMID: 18725648.

25. Burstein HJ, Winer EP. Primary care for survivors of breast cancer.

N Engl J Med. 2000;343(15):1086-1094, PMID: 11027744.

26. Fornier MN, Modi S, Panageas KS, et al. Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer. 2005;104(8):1575-1579, PMID: 16134178.

27. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol. 2000;18(7):15701593, PMID: 10735906.

28. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 2001;19(14):3306-3311, PMID: 11454877.

34. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 2001;19(1):10-17, PMID: 11134190.

35. Diel IJ, Jaschke A, Solomayer EF, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up.

Ann Oncol. 2008;19(12):2007-2011, PMID: 18664560.

36. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol.

2004;43(7):650-656, PMID: 15545185.

37. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival.

Br J Cancer. 2007;96(12):1796-1801, PMID: 17325699.

38. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7):679-691, PMID: 19213681.

39. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases.

Clin Cancer Res. 2006;12(20 Pt 2):6213s-6216s, PMID: 17062703.

40. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials.

Cancer. 2000;88(5):1082-1090, PMID: 10699899.

41. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, doubleblind, multicenter, comparative trial. Cancer. 2003;98(8):1735-1744, PMID: 14534891.

42. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol.

2003;21(21):4042-4057, PMID: 12963702.

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

44. Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Can Suppl.

2009;7(3): Abstract. 2LBA. 45. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007; 25(11):1423-1436, PMID: 17416863.

46. Wu JS, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases.

Int J Radiat Oncol Biol Phys. 2003;55(3):594-605, PMID: 12573746.

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Identification of patients with lower-risk MDS * and a poor prognosis

Clinical challenge: MDS treatment selection Approximately two-thirds of patients with myelodysplastic syndromes (MDS) have lowerrisk disease, defined as Low- and Intermediate-1–risk per IPSS.* However, existing prognostic tools for MDS do not differentiate those patients with lower-risk disease who have a poor prognosis.1

The International Prognostic Scoring System (IPSS) The IPSS helps to estimate the overall survival of patients with MDS. One limitation of the IPSS is that it does not identify patients with lower-risk MDS and poor prognosis who may be candidates for early therapeutic intervention. Certain patients classified with lower-risk MDS by the IPSS system may benefit from the “wait and watch” approach currently used by many physicians; but some patients with lower-risk MDS have a worse prognosis and may benefit from active therapy.1

A proposed prognostic scoring system for patients with lower-risk MDS This scoring system stratified patients with lower-risk MDS into 3 risk categories and evaluated the characteristics associated with survival.1 Following a multivariate analysis, the parameters below were found to be associated with decreased survival1: • Platelets (<50 x 109/L; 50–200 x 109/L) • Age (≥60 years) • Unfavorable cytogenetics† • Hemoglobin (<10 g/dL-1) • Percent of marrow blasts (≥4%–10%) The authors recommend the validation of this model by confirming the results in another patient population. Until these results are validated, the main use of this model will be to assign patients with poor prognoses to investigational clinical trials.1

Benefit of proposed scoring system This scoring system may help to identify those patients with lower-risk MDS who may benefit from early active therapy. Using this system, the authors determined that of the 673 patients in Risk Categories 2 and 3, 80% had a poor prognosis if untreated. They believed that the need to treat this population was further supported by the number of patients who died (90%) before their disease transformed to acute myelogenous leukemia.1 Results from 856 patients showed 31% of patients with a median survival of 14.2 months (1.2 years) (Risk Category 3), 48% with a median survival of 26.6 months (2.2 years) (Risk Category 2), and 21% with a median survival of 80.3 months (6.7 years) (Risk Category 1).1‡

Estimated Survival of Lower-risk MDS Patients by Risk Category1 Survival Assigned Score‡ Total (%) Dead (No.) Median (mo) 4-yr (%) 0-2 3-4 ≥5

Cumulative Proportion Alive

1.0

182 (21) 408 (48) 265 (31)

43 212 173

80 27 14

65 33 7

0.8 0.6 0.4 0.2 0 0

12

24

36

48

60

72

84

96

Months from Referral Reprinted with permission from Garcia-Manero et al (2008).1

A study indicated that it is possible to identify those lower-risk MDS patients with a poor prognosis (those in Risk Categories 2 and 3) who may benefit from active therapy. The proposed prognostic tool based on the IPSS classification of this specific patient type may have a significant impact on1: • MDS treatment approaches • Benefits of different therapies for lower-risk MDS • Clinical trial development • Targeted interventions

This proposed model may have significant implications for clinical trial design and ultimately for the treatment decision process for patients with lower-risk MDS.1

*MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk per International Prognostic Scoring System. †In this scoring system, only diploid and 5q were considered favorable cytogenetics; all others were considered unfavorable.1 ‡Category scoring based on: Category 1 = score 0-2, Category 2 = score 3-4, Category 3 = ≥5. Assigned score: age (≥60 years) = 2; platelets (<50 x 109/L) = 2, platelets (50–200 x 109/L) = 1; hemoglobin (<10 g/dL-1) = 1; bone marrow blasts (≥4%–10%) = 1; unfavorable cytogenetics = 1.1 Reference: 1. Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia. 2008;22(3):538-543.

©2009 Celgene Corporation

01/09

CELG08070

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Recent Therapeutic Advances in the Management of

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

T

he myelodysplastic syndromes (MDS) are a heterogeneous group of

bone marrow failure disorders.

Patients typically present with peripheral blood cytopenias in the setting of a (typically) hyperplastic bone marrow with dysplastic cellular elements.

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

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

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a prognostic model for patients with MDS.1 Based on a multivariate analysis, 3 clinical factors were included in the International Prognostic Scoring System (IPSS): percentage of bone marrow blasts, bone marrow karyotype, and number of cytopenias. Patients can be divided into 4 prognostic groups with median survival ranging from 5.7 years (low risk) to 0.4 years (high risk). It is important to remember that this model was based on patients who had their type of MDS identified by the French-American-British (FAB) classification system. Patients with treatment-related MDS were excluded from this prognostic model. An alternative prognostic scheme for de novo MDS patients recently has been published based on the World Health Organization (WHO) classification of disease that relies on bone marrow karyotype and transfusion requirements to categorize the type of MDS.2 Karyotypic data was available for 816 patients included in the IMRAW; 62% had a normal karyotype.

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% of Patients

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LEN 5 mg

LEN 10 mg

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60

54 48

50 40

33

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20 10

17.5 6

10.9

8

6.5 0

0 RBC-TI Protocol Defined (≥26 wk)

RBC-TI IWG (≥8 wk)

Complete Responsea

0 Partial Responseb

Figure 1. MDS-004: red blood cell transfusion independence and cytogenetic response IWG, International Working Group; LEN, lenalidomide; RBC-TI, red blood cell transfusion independence a

Defined as absence of chromosome 5q31 abnormality; b Defined as reduction of abnormality by >50%

Based on reference 21.

The most frequently identified specific cytogenetic changes were del(5q), del(20q), loss of Y chromosome, trisomy 8, and abnormalities of chromosome 7. Most of the other specific cytogenetic abnormalities were combined and included in the intermediaterisk group. An analysis of 3,856 MDS patients included in the IMRAW, German-Austrian MDS Registry, and the Spanish and International Cytogenetic Working Groups identified 2,901 adults with primary MDS (defined by the FAB classification) who had received supportive care. Only patients with short courses of oral chemotherapy or hemopoietic growth factors were included.3 Other single cytogenetic abnormalities associated with a more favorable prognosis were identified from this data set including –1/1p–, t(1;7), del(11q), del(12p), –13/13q–, del(16q), and +19. This prognostic information in patients with rare karyotypic abnormalities can be used to help guide therapeutic decisions.

Based on a review of the Surveillance Epidemiology and End Results (SEER) database, there were 14,648 estimated cases of MDS in the United States in 2003, or 3.1 cases per 100,000 Americans.4 It is likely that the SEER database underestimates the true incidence of MDS because the incidence increases with advancing age and older patients may not undergo diagnostic bone marrow examination for evaluation of cytopenias. For example, there were 7.4 cases per 100,000 people between the ages of 60 and 69 compared with 36.3 cases per 100,000 in individuals who were 80 years of age or older. Patient age, along with associated comorbid conditions and performance status, is arguably the most important factor influencing

the choice of therapeutic goal: palliation alone, palliation with prolongation of survival, or curative intent.

Hematopoietic Stem Cell Transplantation Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative therapeutic option for patients with MDS. However, prospective clinical trials have not yet identified the optimal timing of allo-HSCT. The IPSS has been shown to be predictive of outcomes (survival and relapse) for patients who receive allo-HSCT. However, there is significant risk for early treatment-related mortality associated with allo-HSCT. Investigators addressed this problem by performing an analysis examining the optimal timing of bone marrow transplantation for patients younger than age 60 who received sibling donor allo-HSCT with myeloablative conditioning regimens, and comparing these patients with patients who received supportive care alone. The transplantation cohort was composed of patients taken from the International Bone Marrow Transplant Registry (IBMTR) and patients seen at the Fred Hutchinson Cancer Research Center (FHCRC).

Data on the outcome of patients not undergoing transplantation was mined from the IMRAW database.

For low- and intermediate-1–risk MDS, delayed alloHSCT was associated with maximal life expectancy; immediate allo-HSCT for intermediate-2– and highrisk patients was associated with maximal life expectancy. Risk was assessed using the IPSS.5 This retrospective analysis has several important limitations. For example, the median age of patients in the IMRAW was significantly older (49.8 years) than that of

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the patients who received allo-HSCT (IBMTR, 39.4 years and FHCRC, 45.6 years). There likely were other clinical differences between patients in these 2 databases that could affect survival, such as comorbid illnesses and performance status. Patients in the analysis underwent alloHSCT between 1990 and 1999. Since that time, there have been improvements in supportive care offered to patients undergoing HSCT, thus resulting in improved patient outcomes. Likewise, patients with MDS can receive therapy that may affect their survival (see below). Finally, the analysis was limited to patients under the age of 60 and does not include patients receiving reduced-intensity conditioning regimens or alternative donors.

Over the past two decades, clinicians have witnessed important advances in the practice of alloHSCT. Best supportive care (BSC) of patients receiving allo-HSCT has improved with the use of azole antifungal antibiotics, instead of the more toxic amphotericin preparations, and the use of antiviral prophylaxis to prevent recurrence of cytomegalovirus. The pool of donors has increased over time as well. Furthermore, donor selection has improved with the use of molecular human leukocyte antigen (HLA) typing using DNAbased technologies in place of serologic methods.

Many different, reduced-intensity conditioning regimens have been developed, leading to a lower incidence of severe mucositis and less early mortality.

Therefore, it is clear that the prior practice of restricting allo-HSCT to younger patients can no longer be accepted. It is possible for patients in their seventh and even eighth decade of life to undergo allo-HSCT with acceptable morbidity and mortality.

Despite these advances, however, randomized trials comparing allo-HSCT with BSC or alternative therapies have not been performed for older MDS patients. A retrospective analysis has validated the use of allo-HSCT in older MDS patients.6 In this study, 126 patients over the age of 60 years with de novo high-risk MDS who were treated with allo-HSCT between 1995 and 2008 were matched with patients enrolled in an MDS registry receiving BSC alone. Patients were matched by IPSS, FAB class, age, and marrow blast count. The average age for the study participants was 65 years (maximum age 77). Most of the patients had progressed to advanced disease, and the median blast count was 12% prior to allo-HSCT. The conditioning regimens included reduced-intensity regimens, but 38% of patients received intensive conditioning. The overall survival (OS) rate at 5 years was 45% following allo-HSCT and only 25% with BSC (P=0.008).

Although this study showed increased survival with HSCT over BSC, a retrospective analysis with case controls cannot determine which treatment strategy improves survival. Patients who receive BSC likely are very different from patients selected for allo-HSCT. Caseâ&#x20AC;&#x201C;control studies of patients with MDS should match patients based on performance status, comorbid illnesses, and socioeconomic status, all of which can affect survival of older patients with high-grade

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hematologic malignancies. Several recent, prospectively validated clinical assessments of frailty in older patients may help clinicians in the future appropriately select patients for therapy.

In the study, 60% of the 126 transplant patients underwent chemotherapy prior to allo-HSCT. This factor is important for several reasons. The implication is that these transplant patients had chemotherapysensitive disease and likely responded to the pretransplant chemotherapy. These patients also were shown to be able to tolerate chemotherapy as well as comply with follow-up care. Finally, the contribution of the pretransplant chemotherapy to the survival benefit is difficult to discern.

Supportive Care: Erythropoietin-Stimulating Agents The erythropoietin-stimulating agents (ESAs) epoetin alfa (Epogen, Amgen; Procrit, Ortho Biotech) and darbepoetin (Aranesp, Amgen) have been shown to decrease red blood cell (RBC) transfusion requirements in patients with MDS. Patients with lower RBC transfusion requirements, lower endogenous erythropoietin (EPO) levels, and low-grade MDS are more likely to have an erythroid response.7,8 Erythroid responses also are more durable in patients with lowand intermediate-1â&#x20AC;&#x201C;risk disease than in patients with higher-risk disease.9 In fact, superior survival was seen in MDS patients treated with EPO and granulocyte colony-stimulating factor (G-CSF) in Nordic clinical trials compared with MDS patients receiving RBC transfusions without ESAs in Pavia, Italy.10 Therefore, ESAs have been recommended in the supportive care of select MDS patients with anemia.11 However, recent randomized trials have demonstrated increased risk for thromboembolic complications and inferior survival in patients with carcinoma receiving ESAs,12,13 raising concern about the use of ESAs in oncology patients, including those with MDS. The Eastern Cooperative Oncology Group has published a prospective, randomized trial comparing daily EPO with or without G-CSF, to RBC transfusion support alone.14 Between December 1997 and June 2004, 110 MDS patients were enrolled and were evaluable.

Baseline demographics of the study population were as follows: age older than 65 years, 85%; refractory anemia (RA)/refractory anemia with ringed sideroblasts (RARS), 72%; EPO level at least 200 mU/mL, 69%; lowor intermediate-1â&#x20AC;&#x201C;risk, 83%. There was no statistical difference in the patient demographics between the 2 treatment groups. Following 4 months of therapy, the erythroid response rates (based on 2006 International Working Group [IWG] criteria) were 34% with EPO and 6% without (P=0.001). Erythroid responses were less likely in patients with serum EPO levels greater than 200 mU/mL and those with refractory anemia with excess blasts (RAEB), type 1 (ie, 5%-10% marrow blasts). Additional erythroid responses were seen when G-CSF was given and the dose of EPO was

1.0 0.9

Proportion Surviving

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0.6 0.5 0.4 0.3 0.2 P=0.0001

0.1 0 0

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132

95

69

32

14

5

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Figure 2. Comparison of overall survival using azacitidine or conventional care.

Reprinted from reference 23, © 2009, with permission from Elsevier.

increased. OS and time to leukemic transformation of patients randomized to BSC alone versus to EPO/GCSF was not statistically different. There was a single deep venous thrombosis identified among the 53 patients randomized to receive EPO. Therefore, EPO is effective for the treatment of MDS patients—especially those with low-grade MDS, low or intermediate-1–risk disease and low endogenous EPO levels—and it is not associated with increased risk for mortality or leukemic transformation.

Immunosuppressive Therapy Laboratory investigation of bone marrow samples from patients with MDS suggests that immune dysregulation may contribute to the pathogenesis of the cytopenias. In a Phase II National Institutes of Health (NIH) study, 61 patients with MDS were treated with antithymocyte globulin (ATG), 40 mg/kg per day administered for 4 consecutive days.15 The investigators found that 34% of patients became RBC transfusion-independent within 8 months of therapy, with 76% of these responders remaining transfusion-independent at 5 years. Neutrophil and platelet responses also were observed. The factors predictive of response were younger age, RA subtype, and lower platelet counts. Hypercellular marrow and abnormal karyotype were associated with lack of response. Subsequent analyses showed that expression of the HLA-DR15 (a serologic split of DR2) predicts for response to ATG in MDS patients.16 Expression of HLA-DR15, younger age,

and shorter duration of RBC transfusion requirement all predicted for response to ATG in multivariate analysis. The NIH group described a predictive model of response based on these 3 factors.17 The long-term outcome of MDS patients treated with immunosuppressive therapy (IST) recently has been described.18 Patients with de novo MDS (N=129) were treated in 1 of 3 trials with ATG, cyclosporine (CSA), or a combination of both. The majority of patients (n=110) had low- and intermediate-1–risk MDS. Complete or partial responses were observed in 30% of patients: 24% with ATG alone, 45% with ATG plus CSA, and 8% with CSA alone. The response rate was significantly better in intermediate-1–risk patients treated with ATG/CSA versus ATG alone (54% vs 29%; P=0.004).

In multivariate analysis, age as a continuous variable and expression of HLA-DR15 were the most significant variables affecting response. The survival and risk for leukemic transformation of patients treated with IST was compared with the same long-term outcomes in patients included in the IMRAW. OS in intermediate-1– risk MDS patients who were at least 60 years of age was superior for the IST cohort compared with the patients who received BSC alone in IMRAW (median survival >8.1 vs 5.2 years; P=0.001). Likewise, the proportion of patients developing AML was lower in the intermediate-1–risk group treated with IST compared with the IMRAW cohort. Because there was no difference in survival or risk for leukemic transformation between older patients in the IST and IMRAW cohorts,

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lack of response to IST likely does not adversely affect the long-term outcome of MDS patients.

Alemtuzumab (Campath, Berlex) is an anti-CD52 humanized murine monoclonal antibody approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia. This agent has been associated with profound immunosuppression by T-cell depletion. A Phase II study of alemtuzumab 10 mg by IV infusion for 10 consecutive days in MDS patients was reported at the American Society of Hematology (ASH) meeting in December 2009.19 Patients likely to respond to IST were selected based on the criteria in a study by Saunthararajah et al.17 HLA-DR15 expression was identified in 61% of patients; median age was 57 years. Fifteen of 16 (93%) intermediate-1–risk patients and 2 of 5 (40%) intermediate-2–risk patients responded by 3 months.

All responders were transfusion-independent. Five of 7 patients had complete cytogenetic remissions. Median follow-up has been short (11 months), but responses have been durable. The most common adverse events were related to infusion reactions. Viral (EBV) reactivation was observed in 4 of 22 patients.

Lenalidomide Lenalidomide (Revlimid, Celgene) has been approved by the FDA for the treatment of low- and intermediate1–risk MDS patients with del(5q). In 4 different studies (including the pivotal trial MDS 003), 168 MDS patients with del(5q) were treated with lenalidomide.20 The median age of these patients was 71 years, with a female predominance. The majority had previously received EPO (74%) and was receiving 2 or more units of RBC every 4 weeks (71%). It also is important to remember that only a minority of these patients had any degree of neutropenia or thrombocytopenia. Sixty-eight percent of patients became RBC transfusion-independent, with a median time to RBC transfusion independence of 4.7 weeks. Response was not affected by IPPS or karyotype complexity. The median duration of response was 2.2 years. However, responses were longer in patients with low-risk disease and the 5q– syndrome. Lenalidomide appears to be cytotoxic to the 5q– clone, with complete cytogenetic responses observed in 50% of the patients, likely explaining the initial period of treatment-related myelosuppression in responders.

Lenalidomide dose interruptions and reductions due to myelosuppression are very common early in therapy for patients with low- and intermediate-1–risk MDS with del(5q). Some researchers have questioned the approved starting dose of lenalidomide in this population. The MDS 004 study was a Phase III multicenter, randomized, double blind, placebo-controlled trial conducted in Europe and Israel.21 The trial included 205 patients with low- and intermediate-1–risk MDS with del(5q), RBC transfusion dependence, an absolute neutrophil count (ANC) above 500 cells/mcL, and a platelet count above 25,000 cells/mcL. Patients were randomized to receive lenalidomide 5 mg daily for 28 days, 10 mg daily for 21 of 28 days, or placebo. Sixty-seven

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patients were excluded for a variety of reasons including higher risk disease and insufficient data, leaving 138 patients with centrally confirmed eligibility receiving more than one dose of lenalidomide. The rate of RBC transfusion independence was significantly higher with lenalidomide compared with placebo using both protocol-specific response criteria and IWG criteria. There also was a trend for a higher response rate with lenalidomide 10 mg daily than with 5 mg daily (Figure 1).

RBC transfusion independence rate was not affected by age, gender, FAB classification, IPSS classification, time from diagnosis, cytogenetic complexity, baseline platelet counts, and number of cytopenias. Transfusion independence was achieved by a median of one cycle in both treatment groups, and the duration of transfusion independence was similar with both doses. The rates of complete and overall cytogenetic responses were significantly higher in the lenalidomide 10 mg daily group than in the 5 mg daily group, but there was no difference in grade 3/4 toxicities including hematologic toxicities, discontinuations, dose interruptions, and dose reductions between the 2 groups. The authors concluded that lenalidomide 10 mg daily is the appropriate starting dose for patients with low- and intermediate-1– risk MDS with del(5q).

Lenalidomide also is active in patients with lowand intermediate-1–risk MDS without del(5q). However, the rate of RBC transfusion independence is 26% and the median duration of RBC transfusion independence is 41 weeks.22 Again, the prognostic risk group and karyotype were not predictive of response.

Myelosuppression was observed but was not associated with response. Identification of non-del(5q) MDS patients who are more likely to benefit from lenalidomide would avoid the potential toxicities of this agent in the majority of these patients who are unlikely to respond. Recently, Ebert et al identified a gene expression signature predictive of response to lenalidomide in patients with MDS.23 Bone marrow samples of lenalidomide-responders with or without del(5q) tend to underexpress a number of genes involved in normal erythroid differentiation. It is interesting to note that patients with the 5q– syndrome often have bone marrow erythroid hypoplasia. Because the RNA was isolated from whole bone marrow aspirate samples without cell selection, it can be speculated that erythroid hypoplasia also may predict for response. However, an association of erythroid response with marrow erythogenesis has not been reported.

Major erythroid responses also were observed in a few patients with higher risk MDS with del(5q) treated with lenalidomide in the MDS 003 study. Recently, Ades et al reported the results of a Phase II study of lenalidomide in patients with intermediate-2– and high-risk MDS.24 Forty-seven patients were treated with lenalidomide 10 mg daily for 21 days of a 28-day cycle. Although this was a high-risk group of patients, 38% had an ANC below 1,000 cells/mcL and 57% had a platelet count less than 100,000 cells/mcL. The majority (81%) had either

100 AZA 5-2-2

AZA 5-2-5

AZA 5

% of Patients

80

60

40

20

0 Any Hematologic Improvement

Red Blood Cell Transfusion Independence

Grade 3/4 Neutropenia

Figure 3. Comparison of three azacitidine (AZA) regimens.

Based on reference 25.

RAEB-2 or AML by WHO criteria; 40% had high-risk disease and 19% had del(5q) as an isolated cytogenetic abnormality. Of the 47 patients, 13 (28%) had a response, including 7 patients (15%) with a complete remission (CR). Nine patients had a complete cytogenetic remission. However, CR only was seen in the patients with a baseline platelet count above 100,000 cells/mcL and del(5q) alone or with a single other change. There was a trend for a higher CR rate in patients with marrow blast counts less than 20%. Myelosuppression was the major toxicity with many patients requiring hospitalization for treatment of complications.

Although lenalidomide clearly exerts a cytotoxic effect on the del(5q) MDS clone, this agent should be used cautiously in del(5q) MDS patients with intermediate-2â&#x20AC;&#x201C; and high-risk disease. The goal of therapy for patients with intermediate-2â&#x20AC;&#x201C; and high-risk MDS is palliation of symptoms, as well as improvement in expected survival. The Phase II studies of lenalidomide in MDS patients have not shown a survival benefit.

DNA Methyltransferase Inhibitors: Azacitidine and Decitabine Azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Eisai) are both FDA-approved for the treatment of MDS. These agents both cause DNA hypomethylation, which alters global chromatin structure, resulting in reactivation of gene expression. However, it still is not known for certain if responses are solely due to this mechanism of action. Azacitidine was the first drug approved for the treatment of all FAB subtypes of MDS in 2004. Using IWG response criteria, CRs, partial

remissions (PRs), and hematologic responses were observed in 10%, 1%, and 36%, respectively, of MDS patients treated in the CALGB 9221 study.25 Patients receiving azacitidine either at study entry or within 6 months of study entry had a superior OS compared with patients receiving BSC alone during this time.26 Azacitidine is the only agent that has been shown to improve the survival of MDS patients compared with other conventional care regimens, including BSC alone.27 The AZA-001 study randomly assigned patients to azacitidine 75 mg/m2 per day for 7 consecutive days or a conventional care regimen (BSC, low-dose cytarabine, or anthracycline and cytarabine induction chemotherapy). The physician selected the conventional care regimen prior to randomization. Patients assigned to intensive chemotherapy were more likely to be younger than age 65, to have high-risk disease, and to have AML

by WHO criteria. Treatment with azacitidine continued as long as there was no evidence of progression or unacceptable toxicity; the median number of cycles was 9.

Only patients with intermediate-2â&#x20AC;&#x201C; and high-risk disease

by IPSS and with RAEB and RAEB in transformation by FAB criteria were treated in this study. The median survival of patients was significantly longer in the azacitidine-treated group compared with the conventional care regimens (24.5 vs 15 months; P=0.0001; Figure 2). A survival benefit was observed even in patients over age 75, as well as in patients with high-risk disease, poorrisk cytogenetics including monosomy 7 or del(7q), and marrow blast counts between 21% and 30%. CRs and PRs were seen in 29% of azacitidine-treated patients; 49% of patients had hematologic improvement (HI).

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Patients achieving HI with azacitidine had superior survival compared with patients achieving the same response with the conventional care regimens.28 Treatment with 7 consecutive days of azacitidine is inconvenient. A randomized Phase II study investigated 3 different doses and schedules of azacitidine: 75 mg/m2 per day for 7 days with a 2-day weekend break, 50 mg/ m2 per day for 10 days with a 2-day break, and 75 mg/ m2 per day for 5 days (Figure 3).29 The median age of patients in each treatment arm was 73, 76, and 76 years, respectively. The IPSS was not reported, but slightly more than 50% of patients in each arm had low-grade MDS by FAB criteria, and only 4 of the 151 patients had RAEB in transformation. There was no obvious difference in rates of HI (44%-56%) or RBC transfusion independence (50%-64%) between the 3 schedules. Marrow CRs and PRs were not reported because follow-up bone marrow exams were not required in the protocol. However, patients receiving the 5-day schedule were less likely to have treatment-emergent hematologic toxicity. The majority of hematologic responses and transfusion independence occurred within 2 cycles of therapy.

However, it is not certain that this 5-day schedule also would lead to a survival advantage in intermediate-2– and high-risk patients.

Analyzing data from AVIDA, a longitudinal, prospective, multicenter registry of azacitidine use in MDS patients, can shed further light on schedule.30 Of the 331 patients in the registry with MDS or oligoblastic leukemia, 57% received azacitidine by the IV route and 43% by subcutaneous injection. Only 17% of patients received the FDA-approved continuous 7-day dosing schedule; 51% received less than 7 days; 30% received 7 days with breaks; and 2% received more than 7 days.

There was no difference in HI with IV or subcutaneous dosing (24% HI). Patients with higher risk MDS were less likely to receive less than 7 days of azacitidine per cycle. A Spanish registry of 144 MDS patients treated with azacitidine suggested a lower rate of hematologic response in patients receiving less than 7 days of therapy per cycle, despite similar baseline patient characteristics.31 In a Phase I study of oral azacitidine, 45 patients with MDS, AML, and chronic myelogenous leukemia were treated.32 All patients received subcutaneous dosing during the first cycle followed by oral dosing in subsequent cycles in order to facilitate comparison of pharmacokinetic and pharmacodynamic data. The dose-limiting toxicity was diarrhea at 600 mg daily dose for 7 days.

The bioavailability of oral azacitidine was 5% to 35%.

Responses were assessed following 6 cycles; 16 patients without prior exposure to the DNA methyltransferase inhibitors had received 6 cycles by the time the data

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was presented at the ASH 2009 meeting. Nine of the 16 patients (53%) achieved either CR, marrow CR, or HI. DNA hypomethylation could be detected in peripheral blood following both subcutaneous and oral dosing.

Decitabine also was approved for the treatment of MDS patients based on responses seen in a Phase III study.33 Both de novo and secondary MDS patients with intermediate-1–, intermediate-2– and high-risk disease were treated with IV decitabine 15 mg/m2 over 3 hours every 8 hours for 3 consecutive days. The median number of cycles delivered was 3. The rates of CR, PR, and HI were 9%, 8%, and 13%, respectively. However, there was no difference in survival without leukemic transformation between decitabine-treated patients and those receiving BSC alone. The European Organisation for Research and Treatment of Cancer (EORTC) recently reported a Phase III study of the same dose and schedule of decitabine compared with BSC alone in 233 MDS patients over the age of 60 with intermediate- and high-risk disease.34 The median number of cycles was 4, and no patient received more than 8 cycles by study design. Patients who achieved a CR only received 2 additional cycles of therapy. The rates of CR, PR, and HI were 13%, 6%, and 15%, respectively.

Again, there was no difference in OS or survival without leukemic transformation between the 2 treatment arms. The discontinuation of decitabine after at most 8 cycles may have affected the ability to demonstrate a survival advantage over BSC alone.

A lower total dose of decitabine (100 mg/m2 per cycle) was evaluated in a randomized Phase II study conducted at the University of Texas M.D. Anderson Cancer Center in Houston.35 Among the 95 patients, median age was 65 years; 24% of patients had less than 5% blasts and only 6% had 21% to 30% blasts. The patients received 1 of 3 schedules of decitabine. Those receiving IV decitabine 20 mg/m2 per day for 5 consecutive days had a CR rate of 39%. The results of this singlecenter study led to the multicenter ADOPT (Alternative Dosing for Outpatient Treatment) trial,36 in which 99 patients received decitabine 20 mg/m2 per day for 5 days on an outpatient basis. The median number of cycles delivered was 5. The median age of the patients was 72 years; 37% had RA or RARS; 53% had intermediate-1–risk, 46% had intermediate-2– and high-risk disease; 49% had good-risk karyotypes; 42% had less than 5% marrow blasts. The CR rate was 17%, marrow CR was 15%, PR was 0%, and HI was seen in 18%; 33% of RBC transfusion-dependent patients became independent of transfusion. Half of the patients experienced a cytogenetic remission. The response was not affected by IPSS or FAB subtypes.

Decitabine and azacitidine are both clearly effective

therapies for MDS patients. The M.D. Anderson Cancer Center and ADOPT trials have demonstrated activity of decitabine in patients with treatment-related MDS. Decitabine 20 mg/m2 per day for 5 days is a more convenient outpatient-dosing regimen than the higher total dose tested in the 2 Phase III studies of decitabine. However, the population of patients treated in the M.D. Anderson Cancer Center and ADOPT trials appears to be different from the population of patients treated in the EORTC study or the AZA-001 study. The former studies include a higher proportion of patients with lower-grade and lower-risk disease. The studies also differ slightly in the response criteria. Although achievement of marrow CR does demonstrate activity, these patients may not have achieved HI.37 Therefore, it is difficult to determine the effect of marrow CR on the quality of life. Finally, the improvement in survival observed with azacitidine may well be due to maintenance therapy. The median number of cycles of therapy in the single-center and multicenter trials of the 5-day decitabine regimen was less than that of the AZA-001 study.

Conclusions The majority of patients with MDS are older and not candidates for curative therapies. There are now 3 FDA-approved drugs for the treatment of these patients. Azacitidine 75 mg/m2 per day for 7 days is the only treatment that has been shown to improve the survival of intermediate-2– and high-risk MDS patients.

Decitabine and azacitidine appear to be effective in the setting of high-risk clinical features, such as highrisk karyotype and treatment-related disease. Nonetheless, responses only are observed in at most half of the patients treated with the DNA methyltransferase inhibitors, and the responses are not durable even with maintenance therapy. Although maintenance therapy with azacitidine and decitabine is felt to be important, the value of maintenance has not yet been demonstrated in a randomized trial. The degree of crossresistance between azacitidine and decitabine remains uncertain. These and many other unanswered questions remain in the treatment of MDS. It is appropriate to consider therapy on well-designed clinical trials for the majority of MDS patients. Combinations of the DNA methyltransferase inhibitors with other agents, such as the histone deacetylase inhibitors and lenalidomide, are actively being explored to continue to improve the outcome of MDS patients.

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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%.

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.

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.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA V1238 03/10

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Stem Cell Transplantation for

Multiple Myeloma: Do We Still Need It? SHAJI KUMAR, MD Associate Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

H

igh-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) have been an integral part of the treatment algorithm in patients with multiple myeloma (MM) for more than a decade.

This has been based on results of randomized trials demonstrating a survival improvement with ASCT compared with conventional treatment approaches with chemotherapy regimens containing alkylating agents, anthracyclines, or steroids.1,2 Although not all trials confirmed the survival improvement and the clinical trials primarily targeted patients younger than 65 years, ASCT has been used widely in patients up to 75 years old. In fact, MM remains the most common indication for ASCT in North America, and the number of transplants reported to the Center for International Blood and Marrow Transplant Research has steadily increased over the years. Increasing use of ASCT has no doubt contributed to some extent to the improved survival of patients with MM seen in the past few years, particularly that of younger patients.3 However, the introduction of effective therapies such as the IMiDs, for example, lenalidomide (Revlimid, Celgene), and the proteasome inhibitor bortezomib (Velcade, Millennium) has brought up the question as to whether ASCT still has a role in the management of patients with MM.4 To answer this question, we need to first take a look at what the contribution of ASCT had been prior to the introduction of these new drugs. When used in the upfront setting, a short course of induction therapy (3-6 months) followed by stem cell collection and ASCT without maintenance therapy resulted in very good partial response (VGPR) rates of 50% to 60% and complete responses (CR) of 25% to 35%, translating to a median time to progression of around 2 years.1,5,6 The improved outcome seen with ASCT has been widely attributed to

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the higher rates of VGPR or CR with this modality compared with conventional therapies. In fact, in the more recent trials in which the depth of response was comparable between the conventional therapies and ASCT, the survival advantage with ASCT was not so evident.7-9 Recent trials have evaluated the role of tandem or backto-back ASCT or maintenance therapy following ASCT to improve outcomes.5,6,10,11 These trials have suggested improved progression-free survival (PFS) and overall survival (OS) for these approaches, but the benefit appears to be primarily among those patients obtaining less than a VGPR following ASCT. With the introduction of the new drugs, response rates similar to those seen in the context of ASCT have become more common.12-14 Two strategies have been explored in clinical trials, long-term administration of one of the drugs in combination with corticosteroids, and multidrug combinations that incorporate at least 2 of the new drugs. The long-term results of a Phase II trial of lenalidomide and dexamethasone in patients with previously untreated MM yielded a VGPR rate of 67% after a median of 19 cycles of therapy.12 Multidrug regimens combining bortezomib with thalidomide or lenalidomide have similarly led to 100% overall response rates and VGPR rates of more than 60%, all of which compare favorably with historical results seen with ASCT.13-15 Does this mean that we can replace ASCT with one or more of the newer approaches?

The simple answer to this question is no. There are several unanswered questions regarding the role of ASCT in the era of new drugs. Although the responses seen with the new drug approaches rival those of ASCT,

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recent studies also show that these high response rates can be further enhanced when patients receive ASCT following initial therapy with the new drugs. Although these incremental improvements in response have led to improved PFS, data for a favorable impact on the OS are not yet available. Phase II trials have incorporated bortezomib safely into conditioning regimens, with promising response rates and deep responses, so incorporating the new drugs into a treatment approach that includes the ASCT process represents another avenue for improving outcomes.16 Finally, ongoing trials are examining the role of incorporating the new drugs into the post-ASCT period as maintenance or consolidation therapy to further enhance the outcomes seen with ASCT. Early results suggest favorable effects on the time to progression, but conclusive results showing a survival improvement are required for incorporation of these measures into routine clinical practice. The other unknown at this time is the lack of long-term data with the newer drugs, especially with regard to response durability. Long-term follow-up of current trials will provide a better understanding of response durability.

Before the new drugs became available, the common approach was to proceed to an ASCT after initial induction therapy, even though the randomized trials had suggested comparable outcomes with ASCT used up-front or early, or in a delayed fashion at the time of relapse from initial therapy.17 This was primarily due to a better quality of life or time without symptoms and toxicity of therapy associated with the early transplant. Although this question has not been formally assessed in the era of new drugs, retrospective studies suggest a comparable outcome with the 2 strategies today as well.18 However, with the tolerability of newer drugs, one can question whether the quality-of-life advantage of early transplant still exists.

In summary, ASCT still should be considered an important component of MM therapy in patients eligible for the procedure. New drugs can be used in combination with transplantation to improve outcomes or can be used as primary therapy, with the aim of delaying ASCT. In the latter situation, it is important to collect stem cells early, because some of the newer treatments can impede collection of adequate numbers of stem cells.19

References 1.

Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91-97, PMID: 8649495.

2. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.

N Engl J Med. 2003;348(19):1875-1883, PMID: 12736280.

5. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495-2502, PMID: 14695409.

6. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.

Blood. 2006;108(10):3289-3294, PMID: 16873668.

7. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group MyelomeAutogreffe. J Clin Oncol. 2005;23(36):9227-9233, PMID: 16275936.

8. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of Phase III US Intergroup Trial S9321. J Clin Oncol.

2006;24(6):929-936, PMID: 16432076.

9. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: longterm results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755-3759, PMID: 16105975.

10. Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and metaanalysis. J Natl Cancer Inst. 2009;101(2):100-106, PMID: 19141779.

11. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stemcell transplantation procedure. J Clin Oncol. 2009;27(11):1788-1793, PMID: 19273705.

12. Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 2007;82(10):1179-1184, PMID: 17908524.

13. Richardson PG, Lonial S, Jakubowiak AJ, et al. High response rates and encouraging time-to-event data with lenalidomide, bortezomib, and dexamethasone in newly diagnosed multiple myeloma: final results of a Phase I/II Study. Blood. ASH Annual Meeting Abstracts.

2009;114(22): Abstract 1218.

14. Kumar S, Flinn IW, Noga SJ, et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the Phase I/II multicenter EVOLUTION Study.

Blood. ASH Annual Meeting Abstracts. 2008;112(11): Abstract 93.

15. Cavo M, Tacchetti P, Patriarca F, et al. A Phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: superior clinical outcomes with VTD compared to TD. Blood. ASH Annual Meeting Abstracts. 2009;114(22): Abstract 351.

16. Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a Phase 2 study of the Intergroupe Francophone du Myelome (IFM).

Blood. 2010;115(1):32-37, PMID: 19884643.

17. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131-3136, PMID: 9787148.

3. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood.

2008;111(5):2516-2520, PMID: 17975015.

18. Kumar S, Lacy MQ, Dispenzieri A, et al. Novel agents for initial therapy of multiple myeloma: comparable results with continued initial therapy and delayed transplantation at relapse versus early transplantation. Blood. ASH Annual Meeting Abstracts.

2009;114(22): Abstract 956.

4. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84(12):1095-1110, PMID: 19955246.

19. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035-2042, PMID: 17581613.

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ca m w #1 B Vis nc ak rite 0 o o it 04 t er e a pa a 3 h w tie dif is t nt fer h o s. en a ce nd fo r

Image: Colored scanning electron micrograph (SEM) of a lung cancer cell.

One focus: a shared commitment to improve the lives of cancer patients everywhere.

Now the innovative science of a leading American biopharmaceutical company joins the global assets of Takeda, Japan’s largest pharmaceutical company, for a global commitment to oncology.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers.

To make a dramatic impact on cancer therapeutics, we are dedicated to a strong partnership with the oncology community. Stop by Booth #10043 to learn about our commitment and take part in our 1000 Cranes of Hope initiative.

What is your wish?

Visit the 1000 Cranes of Hope initiative at Booth #10043 to help in the advancement of research and patient support.

As each person’s wishes and dreams join ours, Millennium will provide a charitable grant to The ASCO Foundation in support of Patient Advocacy and Education.

To learn more, visit us at millennium.com.

Join us in the morning for a fresh fruit cup and in the afternoon for a Chicago-style ice cream treat. ©2010 Millennium Pharmaceuticals, Inc. All rights reserved. CCO200

®

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With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare.

CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine.

Help and Hope

1-800-813-HOPE (4673) www.cancercare.org

POLICY & MANAGEMENT Electronic Health Records

Opinion: The State of Electronic Health Record Systems HITECH [the Health Information Technology for Economic and Clinical Health Act] is part of that law.

Indeed, it may turn out that the HITECH provisions may be among the most potent aspect of health care reform that the nation will enjoy.

Clinical Oncology News recently spoke with Donald E. Detmer, MD, MA, who has served as president and chief executive officer of the American Medical Informatics Association, on the state of electronic health record (EHR) systems in health care today.

Q

Conventional wisdom states that EHRs will help control costs and improve patient care.

Given the relatively sparse adoption of EHR systems in this country, how strong is the evidence that such benefits are real?

DD: Saving money and improving quality are not guaranteed outcomes of using EHRs. But evidence does show that EHRs can help control waste through avoiding test duplication and improve patient care through both timely access to past record data and decision support; for example, drug–drug interactions and reminders.

Currently, we are paying a price in poorer care and less security in EHR systems due to less adequate authentication of individuals.

Having said this, EHRs vary a great deal and so, too, do users. Plus, care is slowed down for a matter of weeks when EHR systems are implemented, and depending on the EHR system, maintenance costs can be very substantial.

In short, you need to be thoughtful about what you implement and how you use EHR systems. Most users conclude that after learning how to use an EHR, they are delivering better care.

Q

Technology evangelists often speak of the importance of institutional champions. What resources exist for clinicians who want to take on that role?

DD: Those new to EHRs often confuse information technology with informatics. Information and communications technologies (ICTs) are simply technologies, whereas informatics deals with how one uses information, including how one chooses and supports the change management of implementation and improving care with EHRs. The American Medical Informatics Association (AMIA) has 2 successful initiatives to help clinicians learn how to lead these transformations. Their oldest program is known as “10 x 10” and consists of essentially 3-credit graduate-level courses plus some time face-to-face with the instructor and classmates (see https://www.amia.org/10x10). More recently, AMIA has innovated a Chief Medical Information Officer [CMIO] “Boot Camp,” an intensive 3-day course (see https:// www.amia.org/primary-links/cmiobootcamp). Evaluations from both approaches have been quite positive.

Another program, Digital Patient Record Certification, teaches health care providers what they need to know to have access to person-specific health information on a monitor screen (see http://www.dprcertification. com/benefits.html). Finally, AMIA meetings, as well as those of the American Health Information Managers Association, are good vehicles for gaining expertise in medical informatics.

Q

Q

Independent of health care reform legislation, what monies are available now to hospitals and medical practices looking to implement an EHR system? How should they go about trying to obtain that funding?

DD: The American Recovery and Reinvestment Act (ARRA) of 2009 is already the law of the land and

DD: The “meaningful use” payment provision of HITECH within ARRA will be the most available source of supportive funding. Visit the Web sites of the Office

What are the prospects for a significant push for widespread implementation of EHRs in this country?

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POLICY & MANAGEMENT Electronic Health Records

of the National Coordinator for Health Information Technology and the Centers for Medicare & Medicaid Services to get additional information. The AMIA CMIO Boot Camp specifically relates to helping one achieve meaningful-use compliance.

approaches that are better in terms of both privacy and support of legitimate biomedical research.

Today, I’m not optimistic about a more balanced approach at the federal level. As a nation, we are damaging our common sense of community and public altruism for the sake of privacy policies that are not as protective of privacy as they might be, while also costing us a lot in terms of less innovation and discovery that could save lives and unnecessary costs.

Q

You have been a longtime advocate for a “unique identifier” as a means of making patient record keeping and information exchange more efficient. That idea has run up against privacy concerns and other EHR obstacles. Do you think momentum is shifting in its favor?

DD: The issue of unique personal identifiers is rather curious because it has been a part of federal legislation, but due to pressure from the most radical sector of the privacy community, it has not been allowed to be implemented in this nation. Sadly, not having even easy voluntary use allowed at the federal or state levels means that both privacy and safety are compromised because personal authentication is enhanced with a “unique” alphanumeric much like a password.

The idea of using the Internet for e-commerce or e-mail without passwords and identifiers lets you get some idea of the irrationality of the current situation.

There are privacy folks who would rather see hundreds of citizens lose their lives for the privacy exposure of a body scanner in an airport.

Currently, we are paying a price in poorer care and less security in EHR systems due to less adequate authentication of individuals. We’re paying a higher price in terms of lost opportunities through undesired barriers to legitimate research because of some of the policies and regulations in the United States to help protect privacy through HIPAA. Other nations take

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Q

One criticism of EHR systems is that they are private and proprietary. Is there any movement toward an open-source platform, and what would be the key advantages of such a model?

DD: There are some open-source EHRs that are emerging. One excellent example is OpenMRS [medical record system] (see http://openmrs.org). Originally intended for low-resource nations, it is also gaining appeal and interest in high-resource nations. Whether open-source or not, EHRs that are interoperative and connected are an excellent idea; creating such a world is not a goal aggressively supported by private enterprise systems.

If one or more privately developed systems were to become a de facto standard, its developers would deserve to be bought out at a fair price to become part of the public commons. Even then, there would be a need for continuing support since standards still evolve over time.

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Dr. Detmer also is professor emeritus and professor of medical education in the Department of Public Health Sciences at the University of Virginia, in Charlottesville, and senior associate of the Judge Business School, at the University of Cambridge, England.

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Updates in the Diagnosis and Treatment of

Mycosis Fungoides and Sézary Syndrome FREDERICK LANSIGAN, MD Assistant Professor of Medicine Hematology and Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

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

M

ycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) constitute 4% of non-Hodgkin’s

lymphoma cases. They are low-grade cutaneous T-cell lymphomas (CTCL) characterized by skin-homing CD4+ T cells.

MF is highly symptomatic and progressive, with poor prognosis at later stages. When MF is grouped by stage, patients with patch-plaque disease (stages IA, IB, and IIA) have a survival of more than 12 years and those with tumors or erythroderma (stages IIB/III) have a median survival of approximately 4 years; however, those with stage IV, which includes patients with lymph node or visceral involvement, have a median survival of less than 3 years.1 Similarly, patients with SS have a median survival of less than 3 years.2,3 CTCL patients endure years of a disfiguring disease and often avoid being seen in public. Emotionally, many patients feel depleted as they face ongoing therapies. Financially, treatment for MF/SS can be burdensome, requiring expensive oral and topical therapies not fully reimbursed by insurance, home services

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for wound and skin care, and frequent hospitalizations for infections.

Over the past several years, new therapies have been approved for MF and SS, including 2 histone deacetylase (HDAC) inhibitors—vorinostat (Zolinza, Merck) and romidepsin (Istodax, Celgene/Gloucester).

Denileukin diftitox (Ontak, Eisai) continues to be an active agent for the treatment of MF/SS. Novel therapies also are emerging, such as the antifolate pralatrexate (Folotyn, Allos), which targets the reduced folate carrier.

Navigating the panoply of treatment options for MF can be difficult, but the wide range of treatment options allows therapy to be tailored to a patient’s clinical situation. Sequencing of various agents can be attempted to help control the disease. Most of the

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Table 1. Systemic Therapies for the Treatment of MF and SS Systemic Nontraditional Chemotherapy

Systemic Traditional Chemotherapy

Single Agents Denileukin diftitox (Ontak, Eisai) Extracorporeal photopheresis HDAC inhibitors Romidepsin (Istodax, Celgene/Gloucester) Vorinostat (Zolinza, Merck) Interferons IFN-α IFN-γ Methotrexate Retinoids Acitretin (Soriatane, Stiefel) All-trans retinoic acid Bexarotene (Targretin, Eisai) Isotretinoin

Single Agents Bortezomib (Velcade, Millennium) Chlorambucil (Leukeran, GlaxoSmithKline) Cyclophosphamide Etoposide Gemcitabine Liposomal doxorubicin Methotrexate Pentostatin Temozolomide

Combinations Bexarotene + denileukin diftitox Photopheresis + IFN Photopheresis + retinoid Photopheresis + retinoid + IFN Retinoid + IFN

Combinations EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) GND (gemcitabine [Gemzar, Lilly], vinorelbine, liposomal doxorubicin [Doxil, Ortho Biotech]) hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) ICE (etoposide, methylprednisolone, cytarabine, cisplatin)

HDAC, histone deacetylase; IFN, interferon; MF, mycosis fungoides; SS, Sézary syndrome Adapted from reference 5.

agents available for the treatment of MF and SS have about a 30% overall response rate especially after bexarotene (Targretin, Eisai) fails, and it may take up to 3 agents before an active agent is found for a patient (Table 1).

Mycosis Fungoides: A Diagnostic Dilemma The diagnosis of MF remains a challenge. Diagnosis typically takes months to years and the disease often is confused with benign dermatoses, such as eczema or psoriasis. A diagnosis of MF requires the presence of erythematous scaling lesions in sun-protected areas of the body that can wax and wane for years. A skin biopsy in most cases confirms the diagnosis and is often done when skin manifestations persist or worsen after therapeutic interventions.

The diagnostic algorithm for CTCL proposed by Pimpinelli et al4 is included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for MF and SS (Table 2).5 A point scoring system using the clinical history and physical, histopathologic features, molecular identification of clonal T-cell receptors, and characteristic immunophenotyping can help determine a diagnosis of MF. In this regard, a good clinical history and physical examination is as essential as histopathology. The differential diagnosis includes other poorly defined entities, such as pseudolymphomas due to drug-induced skin reactions, skin manifestations associated with connective tissue disorders,

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lymphomatoid dermatitis, and lichen sclerosus. Referrals to centers that have expertise in cutaneous lymphomas often are helpful.

The recently updated NCCN guidelines for the management of CTCL provide useful algorithms to understand the different treatment options,5 but the specific therapies chosen for patients should be tailored to their individual needs. We have reviewed various skin-directed and systemic treatment options in prior issues (See Clinical Oncology News Special Edition. 2009;12[2]:59). In this review, we will focus on the latest developments in the systemic treatment of MF and SS.

Role of Histone Deacetylase Inhibitors Epigenetic modulation has emerged as a novel therapeutic approach for patients with T-cell lymphomas.

HDAC inhibitors prevent the removal of the acetyl modification from lysine residues, leading to a more open chromatin structure and to global alterations in gene expression.6 Vorinostat, an oral pan-HDAC inhibitor, was approved by the FDA in 2006 for the treatment of MF and SS. In a Phase II trial of vorinostat given at different doses and schedules, responses were seen in 30% of the patients; moreover, 42% experienced relief of pruritus.7 A multicenter Phase IIB trial using vorinostat 400 mg daily also showed an objective response rate (ORR) of 30% with one complete response (CR).8 The median time to response was 2 months, and the response duration

Table 2. Proposed Diagnostic Criteria for Mycosis Fungoidesa Criteria

Score

Clinical Basic Persistent and/or progressive patches/thin plaques 2 points for basic + 2 additional criteria Additional 1 point for basic + 1 additional criterion • Non–sun-exposed location • Size/shape variation • Poikilodermab Histopathologic Basic • Superficial lymphoid infiltrate

2 points for basic + 2 additional criteria 1 point for basic + 1 additional criterion

Additional • Epidermotropism without spongiosis • Lymphoid atypiac Molecular Biologic Basic

1 point for clonality

• Clonal T-cell receptor gene rearrangement Immunopathologic • <50% CD2+, CD3+, and/or CD5+ T cells 1 point for 1 or more criteria • <10% CD7+ T cells • Epidermal/dermal discordance of CD2, CD3, CD5, or CD7d a b

Four or more points satisfy criteria for a diagnosis of early mycosis fungoides.

Poikiloderma is defined as the combination of skin atrophy, telangiectasia, and mottled pigmentation.

c

Lymphoid atypia is defined as cells with enlarged, hyperchromatic nuclei and irregular or cerebriform nuclear contours.

d

T-cell antigen deficiency confined to the epidermis.

was 9.8 months or longer. The most common side effects were diarrhea, nausea, fatigue, and anorexia.

Asymptomatic QTc prolongation was observed on serial electrocardiograms in 4% of patients, but it was not clinically significant.

Romidepsin is an HDAC inhibitor that preferentially targets Class I histone deacetylases, HDAC1 and HDAC2.

Romidepsin, which is synthesized from a natural product obtained from the bacterium Chromobacterium violaceum, has been found to have potent cytotoxic activity against several human cancer cell lines, with minimal effect on normal cells.9 Romidepsin was approved by the FDA in November 2009 for the treatment of CTCL in patients who have received at least one previous systemic therapy.

The approval was based on 2 prospective multicenter,

single-arm clinical studies in patients with CTCL. The first study included 96 patients with confirmed CTCL after failure of at least 1 previous systemic therapy.10,11 The second study included 71 patients with a primary diagnosis of CTCL who received at least 2 previous skin-directed therapies or one or more systemic therapies.12 Patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 in a 28-day cycle. In both studies, patients could be treated until disease progression. Objective response was evaluated according to a composite end point that included assessments of skin involvement, lymph node and visceral involvement, and circulating Sézary cells.

The ORRs in these two trials were similar (34%) and CR rates were the same (6%). The median response

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Table 3. Comparison of the FDA-Approved HDAC Inhibitors ORR, %

CR Rate, %

Median TTFR, mo

Median DOR, mo

Median TTP, mo

Vorinostat Study 1 (N=74)8

30

1

2

5.6

5

Vorinostat Study 2 (N=33)13

24

0

3

3.5

7

Romidepsin Study 1 (N=96)10,11

34

6

2

15

Not reported

Romidepsin Study 2 (N=71)12

35

6

2

13.7

15.1

Toxicities

Cause of Death (n)

Thromboembolism, thrombocytopenia, anemia, nausea, vomiting, diarrhea (may require electrolyte replacement), fatigue

None reported

Neutropenia, thrombocytopenia, anemia, nausea, fatigue, T-wave changes, QT prolongation requiring electrolyte monitoring

Cardiopulmonary failure (2) Acute renal failure (1) Infection (4) Cardiac (1) Respiratory distress (1)

CR, complete response; DOR, duration of response; HDAC, histone deacetylase; ORR, objective response rate; TTFR, time to first response; TTP, time to progression

duration was 15 months (range, 1 to >20 months) in the international trial by Kim et al,10 and 11 months (range, 1 to >66 months) in the National Cancer Institute (NCI) study led by Piekarz et al.12 Median time to first response was 2 months (range, 1-6 months) in both studies. Median time to CR was 6 months in the international study and 4 months in the NCI study (range, 2-9 months). The most common adverse reactions in these studies were nausea, fatigue, infections, vomiting and anorexia, electrocardiographic T-wave changes, neutropenia, lymphopenia, and anemia. Due to the risk for QT prolongation with romidepsin, potassium and magnesium values should be within normal ranges before this agent is administered. Hematologic parameters should be monitored during treatment with romidepsin. Most deaths occurring in the studies were due to disease progression, but there were deaths that were attributed to cardiac and cardiopulmonary causes and infection.

Table 3 compares the FDA-approved HDAC inhibitors with regard to response rates and toxicities based on the results of the aforementioned trials.8,11-13 Additionally, 2 studies analyzing subsets of SS

78

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patients treated with vorinostat or romidepsin were reported at the American Society of Hematology (ASH) meeting in December 2009.14,15 Out of 18 evaluable SS patients treated with vorinostat, the composite ORR of skin and blood was 17%.14 Out of 27 evaluable SS patients treated with romidepsin, the composite ORR was 32%.15 It is important to note that vorinostat and romidepsin have not been compared head-tohead, and enrollment criteria differed between these clinical studies.

Emerging Treatments Pralatrexate is a novel, targeted antifolate with a high affinity for the reduced folate carrier. Cancer cells overexpress the reduced folate carrier RFC-1, and thus selectively accumulate the drug. Once inside the cells, pralatrexate effectively interferes with the action of dihydrofolate reductase (DHFR), a key enzyme involved in the synthesis of deoxythymidine and the purine DNA nucleotides, which leads to cell death. Pralatrexate is approved for relapsed or refractory peripheral T-cell lymphoma, including transformed MF.

Updated results from an ongoing multicenter, openlabel, Phase I dose-finding study of pralatrexate in patients with CTCL who failed at least one previous systemic therapy were presented at ASH 2009.16 Eleven of 31 evaluable patients achieved a response (35%), including partial response in 9 patients and CR in 2 patients. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 for 3 out of 4 weeks, the ORR was 56%.

This dose-intensity cohort requires further study. The most common toxicities of pralatrexate include mucositis, stomatitis, and bone marrow suppression. Vitamin B12 supplementation is required when this agent is used.

Treatment Strategies Before systemic traditional chemotherapy is used, treatment with systemic immunomodulatory agents, retinoids, extracorporeal photopheresis, targeted agents, or HDAC inhibitors is recommended. Use of combinations of some of these systemic treatments that have nonoverlapping toxicities often is helpful. Because MF and SS are chronic diseases that are considered incurable, treatment goals usually are focused on finding an agent or agents that can cause a durable response with minimal toxicities. Traditional chemotherapy and chemotherapy combinations can be used to gain control of advanced disease; however, this is not considered curative. Allogeneic stem cell transplantation including reduced-intensity conditioning regimens for MF and SS demonstrates a graft-versus-tumor effect and can induce long-term remissions in selected patients.17

Conclusion The treatment options for MF and SS are expanding, and multiple agents in each therapeutic class have shown efficacy. Therapy should be tailored to the individual patient taking into account their comorbidities, their preference for oral or IV drugs, their preconceived notions regarding certain therapies, and the drug side effects. Enrollment in clinical trials is encouraged to help continue to bring new agents to these patients.

References 1.

Sausville EA, Eddy JL, Makuch RW, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the SĂŠzary syndrome.

Definition of three distinctive prognostic groups. Ann Intern Med. 1988;109(5):372-382, PMID: 3408055.

2. Demierre MF, Kim YH, Zackheim HS. Prognosis, clinical outcomes and quality of life issues in cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 2003;17(6):1485-1507, PMID: 14710899.

3. Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol.

2002;46(1):95-106, PMID: 11756953.

4. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053-1063, PMID: 16310068.

5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkinâ&#x20AC;&#x2122;s Lymphomas, v.1.2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed April 12, 2010.

6. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287-299, PMID: 12120280.

7. Duvic M, Becker JC, Dalle S, et al. Phase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous T-cell lymphoma (CTCL). Blood. ASH Annual Meeting Abstracts.

2008;112: Abstract 1005.

8. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol.

2007;25(21):3109-3115, PMID: 17577020.

9. Ueda H, Manda T, Matsumoto S, et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice.

J Antibiot (Tokyo). 1994;47(3):315-323, PMID: 8175484.

10. Kim Y, Whittaker S, Demierre MF, et al. Clinically significant responses achieved with romidepsin in treatment-refractory cutaneous T-cell lymphoma: final results from a Phase 2b, international, multicenter, registration study. Blood. ASH Annual Meeting Abstracts. 2008;112: Abstract 263.

11. Istodax (romidepsin) package insert. Cambridge, MA: Gloucester Pharmaceuticals; November 2009.

12. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol.

2009;27(32):5410-5417, PMID: 19826128.

13. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31-39, PMID: 16960145.

14. Duvic M, Kim YH, Kuzel TM, et al. The systemic effects of vorinostat in patients (pts) with cutaneous T-cell lymphoma (CTCL): post-hoc analyses in pts with high blood tumor burden. Blood.

ASH Annual Meeting Abstracts. 2009;114: Abstract 1709.

15. Kim YH, Demierre MF, Kim EJ. Clinically significant responses achieved with romidepsin in 37 patients with cutaneous T-cell lymphoma (CTCL) with blood involvement. Blood. ASH Annual Meeting Abstracts. 2009;114: Abstract 2683.

16. Horwitz SM, Duvic M, Kim Y, et al. Pralatrexate is active in cutaneous T-cell lymphoma (CTCL): results of a multicenter, dose-finding trial. Blood. ASH Annual Meeting Abstracts. 2009;114: Abstract 919.

17. Herbert KE, Spencer A, Grigg A, Ryan G, McCormack C, Prince HM. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34(6): 521-525, PMID: 15286686.

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Neulasta® (pegfilgrastim) 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.

Important Safety Information SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED. IF PATIENTS REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN, THEY SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute respiratory distress syndrome (ARDS) has been reported. Evaluate patients who develop fever, lung infiltrates, or respiratory distress for ARDS. If patient is diagnosed with ARDS, discontinue and/or withhold Neulasta® until resolution.

Allergic reactions to Neulasta®, manifesting as anaphylaxis, angioedema, or urticaria have been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment.

Severe sickle cell crises have been associated with the use of Neulasta® in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta® for such patients.

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

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 93% reduction in febrile neutropenia–related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 80% reduction in febrile neutropenia–related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. The use of Neulasta® has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C).

In a placebo-controlled trial, bone pain occurred at a higher incidence in patients treated with Neulasta®, as compared to placebo-treated patients. The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain.

Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia.

© 2010 Amgen. All rights reserved.

MC49047

01-10

www.neulasta.com

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

BRIEF SUMMARY OF PRESCRIBING INFORMATION 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.

CONTRAINDICATIONS Neulasta is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ pegfilgrastim‚ Filgrastim, or any other component of the product.

WARNINGS General The safety and efficacy of Neulasta for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies.

Neulasta should not be used for PBPC mobilization.

Splenic Rupture SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA AND ITS PARENT COMPOUND, FILGRASTIM. PATIENTS RECEIVING NEULASTA WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition.

Allergic Reactions Allergic reactions to Neulasta, including anaphylaxis, skin rash, urticaria, and erythema/flushing have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta should be permanently discontinued in patients with serious allergic reactions.

Sickle Cell Disorders Severe sickle cell crises have been associated with the use of Neulasta in patients with sickle cell disorders. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Neulasta for such patients, and only after careful consideration of the potential risks and benefits.

PRECAUTIONS General Use With Chemotherapy and/or Radiation Therapy Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy.

The use of Neulasta has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C).

The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival.

The use of Neulasta has not been studied in patients receiving radiation therapy.

Potential Effect on Malignant Cells Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts.

If it is determined that a patient or caregiver can safely and effectively administer Neulasta (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the “Information for Patients and Caregivers” insert.

Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal.

A puncture-resistant container for the disposal of used syringes and needles should be available.

Laboratory Monitoring To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended.

Drug Interaction No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils;

patients receiving lithium and Neulasta should have more frequent monitoring of neutrophil counts.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies.

In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted.

When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.

Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day.

Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation.

Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices.

There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised when Neulasta is administered to a nursing woman.

Pediatric Use The safety and pharmacokinetics of Neulasta were studied in 37 pediatric patients with sarcoma. The mean (± Standard Deviation) systemic exposure (AUC 0-inf) of Neulasta after subcutaneous administration at 100 mcg/kg was 22.0 (±13.1) mcg·hr/mL in the 6–11 years age group (n = 10), 29.3 (±23.2) mcg·hr/mL in the 12–21 years age group (n = 13) and 47.9 (±22.5) mcg·hr/mL in the youngest age group (0–5 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.

The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.

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.

ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Acute Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disorders.)

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to Neulasta use and for approximating rates.

The data described below reflect exposure to Neulasta in 932 patients.

Neulasta was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian.

Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.

In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta-treated patients as compared to placebo-treated patients. The incidence of other commonly reported adverse events were similar in the Neulasta- and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those adverse events occurring in at least 10% of patients treated with Neulasta in the placebo-controlled study.

Table 1. Adverse Events Occurring in ≥ 10%a of Patients in the Placebo-Controlled Study Event Alopecia Bone Painb Diarrhea Pyrexia (not including febrile neutropenia) Myalgia Headache Arthralgia Vomiting Asthenia Peripheral Edema Constipation

Neulasta (n = 467) 48% 31% 29%

Placebo (n = 461) 47% 26% 28%

23%

22%

21% 16% 16% 13% 13% 12% 10%

18% 14% 13% 11% 11% 10% 6%

Events occurring in ≥ 10% of Neulasta-treated patients and at a higher incidence as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain”

a

b

In the active controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta, n = 465; Filgrastim, n = 331).

These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever.

Bone Pain The analysis of bone pain described below is based on a composite analysis using multiple, related, adverse event terms.

In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta-treated patients compared to 50% in placebo-treated patients.

Bone pain was generally reported to be of mild-to-moderate severity.

Among patients experiencing bone pain, approximately 37% of Neulasta-and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta- and 9% of placebo-treated patients utilized narcotic analgesics.

In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta-and Filgrastimtreated patients. No patient withdrew from study due to bone pain.

Laboratory Abnormalities In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects.

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 sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Cytopenias resulting from a neutralizing antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia. This has not been observed in clinical studies of Neulasta.

Postmarketing Experience The following adverse reactions have been identified during postapproval 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 relationship to drug exposure.

• splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) • allergic reactions (including anaphylaxis, skin rash, urticaria, erythema/flushing) (see WARNINGS: Allergic Reactions) • sickle cell crisis (see WARNINGS: Sickle Cell Disorders) • injection site pain • Sweet’s syndrome (acute febrile dermatosis) OVERDOSAGE The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS).

The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.

No dosing adjustment is necessary for renal dysfunction.

Neulasta should be visually inspected for discoloration and particulate matter before administration. Neulasta should not be administered if discoloration or particulates are observed.

Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending.

REFERENCE *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia.

Blood. 1997;90:4710-4718. v.10 Issue Date: 11/2008

Manufactured by: Amgen Manufacturing, Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 ©2002–2009 Amgen Inc. All rights reserved.

MC45288

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Maximizing Therapy for Chronic Phase

Chronic Myelogenous Leukemia

MICHAEL R. SAVONA, MD

C

Clinical Assistant Professor of Internal Medicine University of Texas Health Science Center at San Antonio San Antonio, Texas

hronic myelogenous leukemia (CML) is the first clonal disorder recognized to be driven by a dominant acquired genetic mutation.1-4 That mutation, the Philadelphia

chromosome t(9;22)(q34;q11)—the reciprocal translocation and fusion of the Abelson kinase (ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22—encodes for BCR-ABL tyrosine kinase, the molecular machinery behind CML.

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

Imatinib Trials of imatinib showing significant activity in chronicphase (CP) patients who were previously treated with interferon-alpha (IFN-α) and in patients with advanced

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

stages of the disease (eg, accelerated phase [AP] and blast crisis [BC]) led to FDA approval of imatinib for previously treated patients with CML.6-9 The use of imatinib was then explored in newly diagnosed CML patients in IRIS (International Randomized Study of Interferon-alpha plus cytarabine versus ST1571), which compared the drug with the standard of care at the time (IFN-α plus cytarabine). Imatinib markedly increased cytogenetic response rates with an improved toxicity profile, leading to its approval as first-line therapy for CML.10,11 At the time, limited information existed on the durability of the remissions, the impact on survival, and the nature of resistance. A large body of data has since become available, and complete hematologic response (CHR) and complete cytogenetic response (CCyR) are seen in 94% and 87% of newly diagnosed patients

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treated with imatinib, respectively.12 These benchmarks are important because patients who do not develop at least a partial cytogenetic response account for most (more than 70%) of resistant disease, and ultimately the majority of the disease-related mortality.13 Long-term outcome of therapy is not clear; however, before 1990, the median survival of patients with CML was approximately 4 years, so the impact of imatinib on survival is dramatic (Figure 1).14 Overall survival (OS) was reported to be 86% at 8 years, and since IRIS randomization, fewer than 5% of patients have died due to progression of CML.15,16 Early studies of imatinib in advanced disease revealed modest, dose-dependent responses in AP8 and BC CML.9,17,18 Indeed, outcomes are clearly less favorable in the advanced stages of CML, but imatinib may still have a role in combination with cytotoxic agents, and perhaps as part of a strategy that uses several treatment modalities including cytotoxic agents, allogeneic stem cell transplantation (SCT), newer TKIs, and other pathwaytargeted therapies.19 Perhaps the greatest reward with regard to advanced-stage CML is the dramatic reduction of its prevalence with imatinib therapy for chronic phase CML.

Monitoring Therapy and Speed of Response Cytogenetic monitoring was established as a preferred method for following therapy outcomes in CML, when it was demonstrated that patients treated with IFN who achieve CCyR had a lower risk for disease progression and improved survival compared with patients who failed to achieve this response.11 This response is measured via classic karyotyping with a metaphase spread,

or with interphase cytogenetic analysis via fluorescence in situ hybridization (FISH) assays. FISH can be performed on peripheral blood, and can be useful during diagnosis to identify cases of Philadelphia (Ph) chromosomeâ&#x20AC;&#x201C;negative BCR-ABLâ&#x20AC;&#x201C;positive CML, Ph amplification, or other variant chromosomal aberrations.13 The development of real-time quantitative polymerase chain reaction (RQ-PCR) amplification assays, which quantify the ratio of BCR-ABL transcripts and a common gene transcript (typically ABL), has provided a tool to detect and quantify minimal residual disease.20 These assays have been incorporated in the prospective studies of imatinib in CML, and have helped to further characterize the kinetics of treatment response.

Although the majority of CP CML patients who receive TKI therapy will achieve the desired clinical response, it is critical to monitor response to therapy at regular intervals because failure to respond and loss of response are harbingers of poor outcome.12 It has become clear that the time needed to reach cytogenetic response has prognostic significance. For example, at 6 months, event-free survival was less than 60% for patients with no cytogenetic response, and was greater than 90% for patients with CCyR. Similarly, if the CCyR is less than 35% at 12 months, then the chance of achieving a CCyR at 2 years decreases to 20%.12 Likewise, establishing at least a major molecular response (MMR; â&#x2030;Ľ3 fold reduction in BCR-ABL) by 18 months appears to correlate these excellent survival data in patients with early CCyR. After achieving timely cytogenetic and molecular remissions, some patients will have rising protein levels by RQ-PCR during surveillance, but the significance of this is unclear. In a University of Texas

Patients Without Event, %

100 90 80 70 60 50 40

Survival: deaths associated with CML

30

Overall survival

20 10 0 0

12

24

36

48

60

72

Months Since Randomization

Figure 1. Overall survival in IRIS (ITT principle): imatinib arm.

ITT, intent to treat Based on reference 14.

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96

M.D. Anderson Cancer Center cohort of patients who had achieved a CCyR while taking imatinib but had an increase in their minimal molecular disease by RQ-PCR, 13 of 116 (11%) had disease progression.21 It seems likely that there is prognostic value in achieving at least an MMR; however, patients who have CCyR with minimal residual molecular disease, or evidence of a modest increase in molecular disease while retaining a CCyR, may not be relapsing but should be monitored closely.

Various schemes have been used to monitor patients while they are receiving TKI therapy. After initiating therapy, physicians should monitor for hematologic toxicity and measure hematologic response weekly, or more frequently if necessary. Conventional karyotyping (metaphase cytogenetics) of bone marrow should be completed prior to therapy, and every 6 months until a CCyR is achieved. More frequent FISH analysis of peripheral blood can lead to clearer establishment of CCyR and thus lend prognostic utility, but there is a lack of clear guidance from the literature on the continued utility of FISH at short intervals if conventional karyotyping already is performed. Once a CCyR has been achieved, conventional cytogenetics can be conducted annually until an MMR has been attained, and then as clinically indicated. Molecular testing should be performed every 3 months during therapy and should continue for at least 3 to 5 years, even in the setting of complete molecular response (CMR), because a small number of patients

with MMR or CMR lose molecular response and eventually relapse.22 In the presence of CCyR, RQ-PCR is likely to be sufficient, because any significant molecular changes will prompt cytologic evaluation. However, as the significance of late cytogenetic abnormalities which are considered poor prognosis in other disease states (eg, trisomy 8 or monosomy 7 in acute myeloid leukemia or myelodysplastic syndrome, respectively) is not clear in CML, it may be worthwhile to continue occasional cytogenetic monitoring for several years after achieving CCyR.23 An extended interval between follow-ups can be considered for patients with CMR after several years of stable disease control. Mutational analyses should be performed for treatment failure (including patients with a significant rise in BCR-ABL transcript levels) and suboptimal response (Table 1).13,24,25

Mechanisms of Resistance Although most CML patients initially respond to TKI therapy, nearly 4% of newly diagnosed CP patients are resistant to imatinib, and up to 18% lose response or become intolerant of the drug.15,17 Long-term followup reveals a declining rate of resistance over time, with a near-negligible rate of resistance in patients who achieve a timely CCyR.26 Presumably, the greater resistance seen in the first year of therapy is in patients with late CP CML who may have been developing advanced disease at the time of their diagnosis.

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

a

Recommended Follow-up

Failure

Suboptimal Responseb

3

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

No HR

<CHR

6

Monitor for CHRc Bone marrow biopsye RQ-PCRd

<CHR or no CyR

<PCyR (Ph+ >35%)

9

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

<CHR or no CyR

<PCyR (Ph+ >35%)

12

Monitor for CHRc Bone marrow biopsye RQ-PCRd

<PCyR (Ph+ >35%)

<CCyR

18

Monitor for CHRc RQ-PCRd

<CCyR

<MMR

400 mg/d

b

Consider mutational analysis for any suboptimal response or treatment failure.

c

Monitor for CHR every 2 wk until achieved.

d

Monitor every 3 mo during therapy.

e

Every 6 mo until CCyR achieved, then as indicated.

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

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

Dasatinib

Nilotinib

Recommended Second-line Therapy

Q252H

MCyR39

Not tested

Dasatinib or nilotinib

39

49

Y253F

CCyR Sensitive in vitro54

CHR Moderate resistance in vitro54

Dasatinib

T315I

No response54

No response49

Clinical trial or allogeneic stem cell transplantation

F317L

CCyR39 Resistance in vitro54

CHR49 Moderate resistance in vitro54

Dasatinib or nilotinib

F359V

CCyR39 Sensitive in vitro54

MCyR49 Resistance in vitro54

Dasatinib or nilotinib

H396R

CHR39 Sensitive in vitro54

CCyR49 Moderate resistance in vitro54

Dasatinib or nilotinib

E255V

CHR39 Moderate resistance in vitro54

High resistance in vitro54

Dasatinib

E279K

Sensitive in vitro54

CCyR49 Sensitive in vitro54

Dasatinib or nilotinib

V299L

Resistance in vitro54

Sensitive in vitro54

Nilotinib

F486S

Moderate resistance in vitro54

Sensitive in vitro54

Nilotinib

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

Approximately one-half of imatinib resistance is BCRABLâ&#x20AC;&#x201C;dependent or secondary to clones expressing mutant forms of BCR-ABL. Point mutations in the ABL kinase domain decrease imatinibâ&#x20AC;&#x2122;s ability to bind to this region. Other mutations (eg, P-loop, C-helix, activation loop, and C terminal lobe mutations) lead to conformational changes in the kinase. There are more than 100 described mutations of BCR-ABL tyrosine kinase.27-29 Four of them account for more than 70% of all mutations identified (Y253F, E255V, T315I, and M351T).26 While BCR-T315I confers significant resistance to imatinib and second-generation TKIs, all other imatinibresistant clones are susceptible to alterative therapy.

High-Dose Imatinib Although the maximum tolerated dose has not been reached for imatinib, patients with CCyR or MMR have higher trough levels of the drug than those who do not respond to imatinib.30 Additionally, researchers have demonstrated that some BCR-ABL mutations confer only relative resistance and these patients respond to higher doses of imatinib.31 Higher doses of imatinib can lead to greater rates of cytogenetic and molecular responses,32,33 and early use of high-dose imatinib in patients who are TKI-naĂŻve may improve the overall molecular response rate, and reduce the risk for emergence of imatinib-resistant clones. For these reasons,

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higher doses of imatinib could be considered during the first year of therapy, either from treatment initiation or after failure to achieve adequate timely cytogenetic and molecular responses. Some groups are even recommending consideration of high-dose imatinib from treatment onset given evidence of superior PFS, and faster achievement of CCyR and MMR with 600 mg per day or higher doses.34 The advantages of high-dose imatinib therapy, however, also must be considered in the context of increased hematologic and nonhematologic toxicities. Likewise, although dose escalation may saturate the cell and override steric hindrance,31,35 the changes incurred by some BCR-ABL mutants cannot be overcome with a greater concentration of imatinib,36 and thus, increasing the dose of imatinib may not be appropriate for some mutations.18 Guidance on use of higher doses of imatinib may be improved by measuring trough levels during treatment30 or evaluating polymorphisms in the cytochrome P450 liver enzyme (CYP3A4) that is responsible for drug metabolism.18 In the future, the potential of pharmacogenomics may help determine appropriate doses for individual patients, and standardized tests will be readily available to clinicians.

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

Independence from addiction to BCR-ABL

Blast Crisis

Accelerated Phase

Anaplastic threshold

Oncogenic addiction to BCR-ABL

Late Chronic Phase

Genetic instability

Early Chronic Phase

Time

Figure 2. Addiction to BCR-ABL, and avoiding the anaplastic threshold.

The natural history of chronic myelogenous leukemia most commonly includes an indolent progression with disease susceptible to suppression by tyrosine kinase inhibitors (TKIs). During this period, the disease is “addicted” to the oncogenic events stimulated

by BCR-ABL. If the disease is left unchecked, it will progress to a more disorganized state marked by increased genetic instability.

At some point during disease progression, the anaplastic threshold is reached and the disease is sufficiently disorganized and is driven independent of input from BCR-ABL tyrosine kinase. At this point, the disease is no longer addicted to BCR-ABL, and the therapeutic value of BCR-ABL–targeted TKIs is vastly diminished.

Based on reference 25.

the Src family tyrosine kinases, binding to both the active and inactive conformation of the ABL kinase domain.37 This less stringent binding requirement is thought to be responsible for dasatinib’s activity against most imatinib-resistant kinase domain mutations.17 Dasatinib showed early activity in both CP and advanced CML in imatinib-resistant patients, with CHR achieved in 92% of CP patients and major hematologic response in 70% of AP CML.38 Given these findings, a series of trials was initiated to evaluate the efficacy of dasatinib in CP, advanced CML, and Ph-positive acute lymphocytic leukemia. Nearly 200 CP patients with treatment failure or intolerance to imatinib were given 70 mg of dasatinib twice daily, and 53% achieved a CCyR.39 These responses were maintained in 86% of imatinib-resistant patients at 24-month follow-up.

Patients with advanced disease also responded to dasatinib.40-42 Discontinuation of therapy occurred in 9% of patients because of adverse events, most commonly myelosuppression and pleural effusion.39 As mentioned previously, escalating the dose of imatinib (to 800 mg daily) overcomes resistance to imatinib in some cases.29 In a randomized crossover study comparing high-dose imatinib and dasatinib, CCyR was achieved in 40% of the dasatinib group and 16% of the high-dose imatinib group. Further markers of disease response were similarly favorable in the dasatinib group, and notably, failure rates rose among patients who crossed over from the dasatinib to the high-dose

imatinib group and fell among patients who crossed over from the high-dose imatinib to the dasatinib group.18 Given the cytopenias and pleural effusions seen with the early use of dasatinib, alternative dosing has been explored, and dasatinib at a dose of 100 mg once daily seems to have similar efficacy but significantly less toxicity than the 70 mg twice-daily dose.43 Early data appear to indicate that intermittent use of dasatinib does not affect outcome, and thus clinicians can consider this strategy in patients who are intolerant of dasatinib or patients with limited treatment options.44 Nevertheless, the 70 mg twice-daily dosing scheme should be maintained for patients with advanced CML. Interestingly, kinetics observed with BCR-ABL–dependent resistance with imatinib are similar to kinetics seen with dasatinib; recent data show that CCyR at 12 months on dasatinib portends a PFS of 90% at 3 years.45 Dasatinib is ineffective against the T315I mutation, and likely has limited activity against other mutations including Q252H, V299L, and F317L,46 which have variable sensitivities to imatinib and other second-generation kinase inhibitors.

Nilotinib (Tasigna, Novartis) binds to the inactive conformation of the ABL kinase approximately 30-fold more potently than imatinib,47 and also has increased activity with the KIT and PDGF receptor kinases, but unlike dasatinib, nilotinib has no activity against the Src family kinases. Like dasatinib, this drug was shown to have activity in dose-finding experiments in patients

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who were resistant to or intolerant of imatinib.48 These results were confirmed in a follow-up Phase II trial, in which 321 patients with CP CML resistant to, or intolerant of, imatinib were treated with nilotinib at a dose of 400 mg twice daily. At the time, the rate of CHR was 77% and the rate of major cytogenetic response was 57% (with 41% CCyR).49 Patients experienced the same hematologic side effects as with imatinib, but they did not have significant fluid retention or subsequent effects that can lead to imatinib intolerance.50 The ENACT registry data revealed similar trends in responses and side effects.51 Nilotinib has been tested in advanced CML as well, and it appears to have similar efficacy to dasatinib.52 Both dasatinib and nilotinib are being studied in the first-line setting,53 but the roles of these agents in previously untreated CML are not well defined, and they should be reserved for clinical trials for these patients.

In vitro mutational analyses revealed that these second-generation TKIs are ineffective against BCR-ABL T315I but differentially potent against other mutations (Table 2).39,49,54 The mutational analyses from early clinical studies seemed to correlate with these findings, with dasatinib superior to nilotinib for Y253F, F359V, and E255V, and the converse for L248V, V299L, and F486S.18,38,48,55 Given differing side-effect profiles and mutation sensitivities for each drug, one may develop a rational approach for dealing with imatinib failure. Specifically, when imatinib treatment failure occurs, selection of a second agent can be directed by mutational analysis. Alternative TKIs, such as bosutinib (SKI-606), may have a role against specific mutations such as Q252H and L384M.54

The T315I Problem and Investigational Options In the Phase I trials of dasatinib and nilotinib, the T315I mutation prevented response to either agent.38,49 As BCR-ABL T315I represents 10% to 15% of all BCR-ABL mutations in patients who fail imatinib therapy,24 and it likewise fails to respond to second-generation agents, great effort has been invested in the development of agents capable of inhibiting the BCR-ABL T315I mutant kinase. The T315I mutation occurs via the substitution of a threonine residue by isoleucine, placing the bulky isoleucine side chain within the imatinib binding site of the ABL kinase. This resultant steric hindrance is believed to be the basis of resistance to first- and secondgeneration TKIs.56 Aurora/ABL kinase inhibitors (AKIs) are able to overcome the resistance of T315I because they do not bind as deeply to the hydrophobic pocket of the ABL kinase; through this shallow binding, they can avoid the steric hindrance of this isoleucine side chain. There are many AKIs undergoing both preclinical and clinical study, and several including MK-0457 seem to lead to clinical response in patients with the T315I mutation.57 An expanding understanding of intracellular signaling in CML has led to exploration of both tyrosine kinase–specific, and BCR-ABL–independent

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targets for therapy, and this is reviewed elsewhere.19,58 These agents remain investigational but hold promise in the therapy of de novo and resistant CML.

Stem Cell Transplantation Allogeneic stem cell transplantation (SCT) remains a viable option for patients with resistant disease. In a large retrospective review of more than 1,480 CML patients receiving allogeneic SCT, OS was 47% at 8 years, with a relapse rate of 33% at 5 years.59 Mutational analyses were not available for these patients, and many received transplants prior to imatinib; however, reason and early data suggest that the alloimmune effect brought about by hematopoietic SCT may have equivalent potency against the T315I mutation.60 For patients with CML and a T315I mutation, either allogeneic SCT or enrollment in a clinical trial is recommended.

Approaching the Anaplastic Threshold TKI therapy has revolutionized the treatment of CML, but it seems that the influence of TKIs is limited in primitive CML cells. The low replicative indices of these primitive cells define an inherent refractoriness to growth/cell cycle-specific therapy; these cells are not resistant but rather refractory to TKIs. Refractoriness of CML stem cells implies acquisition of the complete characteristics of the stem cell in an affected clone or the insertion of the malignant genotype into a normal hematopoietic stem cell, leading to quiescence and a protected reservoir for the Ph chromosome.25 Primitive refractory CML cells likely exist even in patients in CMR, and may be quiescent over long periods of time in the setting of the proper immune milieu.61 In contrast, BCR-ABL–independent resistance implies acquisition of cellular machinery that enables the progeny cell to exert the leukemic phenotype beyond strict regulation of a refractory CML stem cell. BCR-ABL– independent resistant CML cells are armed with defenses against apoptosis, including increased drug efflux and deactivation, overexpression of other oncogenes (c-Myc, Lyn kinase), amplification of the fusion gene, and activation of epigenetic pathways.62,63 Left uncontrolled (ie, without TKI inhibition), the active progeny of the refractory CML stem cells develop secondary genetic aberrations and progressively more powerful leukemic genotypes64 in the inevitable sequelae of advanced disease. Typically, in CP, when patients are likely to have a response to TKIs, their disease is below the anaplastic threshold (Figure 2). In more advanced disease, it seems that CML progeny cells can acquire the “stem cell–like” feature of self-renewal.65 As the disease progresses and genetic instability increases, progrowth and antiapoptotic cellular functions of the CML cells may surpass signals for senescence, regardless of the contribution of BCR-ABL tyrosine kinase. In this case, above the anaplastic threshold, BCR-ABL is potentially superfluous to progression of the disease, and for this reason, early-generation TKIs are significantly less

effective in advanced disease.25 The complexity and genetic heterogeneity seen in blastic CML and acute leukemias suggest that the best treatment for advanced disease is avoiding it with timely, effective treatment of the disease before the anaplastic threshold is reached.66 To that end, there is mounting evidence of the compounding inertia of the disease, even in CP. In a corollary to the IRIS trial, for example, patients who had previously failed IFN were then treated with imatinib and followed for 6 years. Unlike the previously undiagnosed patients of IRIS, this cohort included patients who were months, and more commonly years, from their original diagnoses. At 6 years of follow-up, 57% of patients maintained a CCyR67 (vs 87% in IRIS),12 implying further progression of CP CML nearer to this anaplastic threshold.

Conclusion The speed of drug development for CML is a testament to the power of laboratory investigation into the molecular mechanism of this disease. However, TKIs are not without toxicities; they are not sufficiently effective in a significant minority of patients; and perhaps most cogently, as of yet they rarely eradicate or cure the disease, demanding lifelong continuation of treatment. As experience grows with the use of this type of therapy, investigation into the pathogenesis of CML and potential strategies for therapy improvement continue to emerge. Soon, molecular fingerprinting of individual tumors including mutational analysis, assays of protein expression related to drug metabolism, and other factors influencing the disease will allow for tailoring of multifaceted therapy to individual patients. Combinations of agents, a rational approach to choosing second-line therapy, and a focus on eradication—not only suppression—of CML by better understanding the CML stem cell should become a focus of the next several years of CML research.

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34. Osborn MP, Branford S, White DL, Maintaining imatinib â&#x2030;Ľ600 mg daily in the first 12 months of chronic phase CML treatment is associated with superior event-free survival at 5 years. Blood. ASH Annual Meeting Abstracts. 2009;114(22): Abstract 1125.

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37. Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood.

2007;110(12):4055-4063, PMID: 17720881.

38. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinibresistant Philadelphia chromosome-positive leukemias.

N Engl J Med. 2006;354(24):2531-2541, PMID: 16775234.

39. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood.

2007;109(6):2303-2309, PMID: 17138817.

40. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200-1206, PMID: 18401416.

41. Rea D, Dombret H, Kim DW, et al. Dasatinib efficacy in patients with imatinib-resistant/-intolerant chronic myeloid leukemia in accelerated phase: 24-month data from START-A. Haematologica.

2008;93(s1):391. Abstract 0982.

42. Saglio G. Dasatinib efficacy in patients with imatinib-resistant/ -intolerant chronic myeloid leukemia in blast phase: 24-month data from the START program. Haematologica. 2008;93(s1):349.

Abstract 0880.

43. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol.

2008;26(19):3204-3212, PMID: 18541900.

44. La Rosee P, Leitner A, Martiat P, et al. Weekend drug holiday of dasatinib in CML patients not tolerating standard dosing regimens.

Reducing toxicity with maintained control. Blood. ASH Annual Meeting Abstracts. 2009;114(22): Abstract 1119.

45. Shah N, Bahceci E, Lambert A, et al. Resistance, outcome and the development of mutations with dasatinib in patients with chronicphase chronic myeloid leukemia. Blood. ASH Annual Meeting Abstracts. 2009;114(22): Abstract 1122.

46. Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of

responses according to preexisting BCR-ABL mutations. Blood.

2009;114(24):4944-4953, PMID: 19779040.

47. Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Crit Rev Oncol Hematol. 2006;57(2):145-164, PMID: 16213151.

48. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542-2551, PMID: 16775235.

49. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia resistant to or intolerant of imatinib.

Clin Cancer Res. 2008;14(17):5325-5331, PMID: 18765523.

50. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540-3546, PMID: 17715389.

51. Powell BL, Khoury HJ, Lipton JH, et al. Nilotinib responses and tolerability confirmed in North American patients with chronic myeloid leukemia from ENACT (Expanding Nilotinib Access in Clinical Trials). Blood. ASH Annual Meeting Abstracts.

2009;114(22): Abstract 3295.

52. le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood.

2008;111(4):1834-1839, PMID: 18048643.

53. Cortes J, Oâ&#x20AC;&#x2122;Brien S, Jabbour E, et al. Efficacy of nilotinib (AMN107) in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood. ASH Annual Meeting Abstracts. 2007;110: Abstract 29.

resistance. Proc Natl Acad. Sci U S A. 2006;103(24):9244-9249, PMID: 16754879.

57. Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood. 2007;109(2):500-502, PMID: 16990603.

58. Quintas-Cardama A, Cortes J. Therapeutic options against BCRABL1 T315I-positive chronic myelogenous leukemia. Clin Cancer Res. 2008;14(14):4392-4399, PMID: 18628453.

59. Gratwohl A, Hermans J, Niederwieser D, et al. Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 1993;12(5):509-516, PMID: 8298562.

60. Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood. 2006;108(4):1421-1423, PMID: 16601247.

61. Mahon FX, Rea D, Guilhot F, et al. Discontinuation of imatinib therapy after achieving a molecular response in chronic myeloid leukemia patients. Blood. ASH Annual Meeting Abstracts.

2009;114(22): Abstract 859.

62. Kantarjian HM, Giles F, Quintas-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13(4):1089-1097, PMID: 17317816.

63. Lee SM, Bae JH, Kim MJ, et al. Bcr-Abl-independent imatinibresistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors.

J Pharmacol Exp Ther. 2007;322(3):1084-1092, PMID: 17569822.

64. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia.

Proc Natl Acad Sci U S A. 2006;103(8):2794-2799, PMID: 16477019.

54. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469-471, PMID: 19075254.

65. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657-667, PMID: 153006667.

55. Soverini S, Gnani A, Colarossi S, et al. Long-term mutation followup of Philadelphia-chromosome positive leukemia patients treated with second-generation tyrosine kinase inhibitors after imatinib failure shows that newly acquired Bcr-Abl kinase domain mutations leading to relapse are mainly detected during the first year.

Blood. ASH Annual Meeting Abstracts. 2008;112: Abstract 2118.

66. Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature.

2008;453(7191):110-114, PMID: 18408710.

56. Azam M, Nardi V, Shakespeare WC, et al. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug

67. Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood.

2008;111(3):1039-1043, PMID: 17932248.

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

MARTHA POLOVICH, PHD, RN, AOCN

Senior Pharmacy Consultant Power Enterprises San Francisco, California

Associate Director Clinical Practice Duke Oncology Network Durham, North Carolina

T

he year 2010 marks 3 decades of concern for health care

workers exposed to cytotoxic

and other hazardous drugs. As a new generation of health care workers joins those already engaged in patient care, it is essential that they understand the occupational risks associated with the handling of hazardous drugs and the need for training in proper techniques for all handling activities to reduce occupational exposure to such drugs.

Continuing research in this area, promoted by the National Institute for Occupational Safety and Health (NIOSH), demonstrates ongoing exposure. Studies conducted at prominent health care facilities show surface contamination in many areas, not just pharmacy. Additionally, biological sampling of exposed staff indicates damage to key chromosomes.

Hazardous drugs, which include antineoplastic agents, antiviral agents, biological modifiers, hormones, and other agents, provide therapeutic benefit to patients but studies have shown that healthy workers exposed to these drugs may experience adverse effects.1-4 Potential health risks for workers who compound and administer these agents include adverse reproductive outcomes and cancer.5 This review emphasizes new information about this well-recognized issue. It focuses on NIOSHâ&#x20AC;&#x2122;s activities as well as the 2008 revision of United States Pharmacopeia (USP)

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Chapter <797>, which mandates compliance with environmental, engineering, and training standards for worker protection.

Routes of Occupational Exposure Many studies have documented both surface and worker contamination from hazardous drugs.6-13 Standard work practices for handling injectable drugs in vials and syringes generate powder and liquid aerosols. These drug residues may contaminate the air and surfaces in the work area.6-8,14,15 It also has been shown that many hazardous drug vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.16 Certain hazardous drugs have been shown to vaporize at room temperature, resulting in drug contamination in the air.17-19 Workers may

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breathe contaminated air or touch contaminated surfaces and absorb hazardous drugs. Drug uptake also may occur through the ingestion of contaminated food or drink that is improperly located in or near drughandling areas. Additionally, the transfer of contaminated residues from hands to mouth may result in the ingestion of hazardous drugs. Needlesticks with hazardous-drug contaminated needles or cuts from glass fragments of vials or ampules also may result in exposure by injection.

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

Continuing Exposure Adverse health effects and chances for exposure have been demonstrated among health care workers for more than 2 decades. Studies of surface and worker contamination conducted in the late 1990s and the early years of the following decade continued to document exposure.6-8,10,14,15 Some possible reasons for the problem include new workers’ lack of awareness of the issue, a lack of vigilance in work practices, poor adherence to the use of personal protective equipment (PPE),29-32 and other potential sources of contamination that have yet to be discovered.33 In 2000, NIOSH convened a working group of interested individuals to examine the issue of occupational exposure of health care workers to hazardous drugs.

The Hazardous Drug Safe Handling Working Group was composed of representatives from government (OSHA, NIOSH, and FDA), industry, pharmaceutical manufacturers, academia, membership organizations (eg, American Nurses Association [ANA], ASHP, and ONS), and union leaders whose members handle hazardous drugs. The Working Group assessed existing information and formulated a plan to increase affected workers’ awareness of the risks and to reduce those risks. In 2004, as a result of the efforts of the Working Group, NIOSH issued “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”34 This NIOSH Alert is similar to the OSHA documents in that it is a guidance document without enforcement authority.

However, OSHA may enforce the recommendations in

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the NIOSH Alert and the OSHA Technical Manuals under the general duty clause of the Occupational Safety and Health (OSH) Act, which sets safety and health standards for US workers. Employers subject to the OSH Act have a general duty to provide work and a workplace free from recognized, serious hazards.35 NIOSH actively continues to increase awareness of this issue by maintaining 2 Safety and Health Topic pages online: “Hazardous Drug Exposures in Health Care”36 and “Occupational Exposure to Antineoplastic Agents.”37 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications.

In 2007, the USP released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.38 This revision of the 2004 standard includes a section specific to the compounding of hazardous drugs and is coordinated with much of the 2004 NIOSH Alert. More importantly, USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of hazardous drugs are compounded, not just hospitals and clinics.

To assess the impact of the 2004 NIOSH Alert on hazardous drugs,34 NIOSH designed a large, multifacility study to provide a comprehensive evaluation of the workplace and the potential sources of exposure. The prepublication results of this study were presented at the Safe Handling of Hazardous Drugs in the Clinical Environment Symposium in Massachusetts in October 2009 and at the ASHP Midyear Clinical Meeting in Las Vegas in December 2009.39,40 The study included surface sampling in pharmacy and nursing areas; self-maintained exposure diaries for health care workers in the study; and urine and blood sampling. Consistent with previous studies, contaminated surfaces were detected in all study sites. The findings of the study included a correlation between the size and spatial design of the compounding area and the amount of surface contamination. Preliminary reports support the USP Chapter <797> design standard that requires an appropriate buffer area around the primary engineering control (PEC).38 The site with a smaller, less delineated compounding area had greater surface contamination.

At the Massachusetts and Las Vegas meetings, members of the Massachusetts General Hospital (MGH) Hazardous Drug Safety Task Force presented the findings of an extensive, longitudinal study designed to assess contamination from receipt of the hazardous drug (loading dock) to hazardous waste transport (loading dock).41,42 The MGH Task Force identified a “chain of custody” for hazardous drugs and found surface contamination in most of the study areas along this chain, including on elevator buttons. According to the MGH investigators, another round of surface wipes will be conducted to assess interventions prior to publication of the study results.

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

ASHP

Carcinogenicity

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

Teratogenicity or developmental toxicity

Teratogenicity in animal studies or in treated patients

Reproductive toxicity

Fertility impairment in animal studies or in treated patients

Organ toxicity at low doses

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

Genotoxicity

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

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

Reprinted with permission. (R1010)

These reports are not surprising but they are alarming.

Additional concern was generated by a substudy within the NIOSH research.43 Investigators at the University of Maryland evaluated chromosomal effects of the hazardous drugs studied to determine specific effects in the health care workers involved in the study. Therapyrelated malignancies (myelodysplastic syndrome [MDS] and acute myeloid leukemia [AML]) are known to be associated with signature lesions in chromosomes 5, 7, and 11 based on fluorescence in situ hybridization. In the prepublication data, the DNA of exposed workers in this study showed a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01). The published conclusions of the researchers will provide additional evidence of valid concerns regarding occupational exposure to hazardous drugs.

Defining Hazardous Drugs A number of drug types that are potent and toxic to patients have the potential to cause adverse effects in persons exposed to them occupationally. Although the cytotoxic potential of the alkylating agents is of primary concern, there are multiple mechanisms by which drugs exhibit hazardous effects. In 1990, ASHP attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”24 for the first time using the term “hazardous drug” in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety concerns and to be compatible with the then newly developed OSHA Hazard

Communication Standard (HCS).44,45 The HCS is intended to ensure that employers and workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken.

The HCS defines a “hazardous chemical” as any chemical that poses a physical or health hazard. It further defines a “health hazard” as any chemical for which statistically significant evidence from at least one study conducted in accordance with established scientific principles is available to indicate that it may cause acute or chronic health effects in exposed employees. The HCS further notes that the term “health hazard” includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects.

ASHP has used similar criteria to define hazardous drugs.23,24 Data on the side effects of a drug are collected during both the premarket investigational phase of the drug and clinical use. These data reasonably may be used to infer “health hazards” in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define hazardous drugs24: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer (IARC); • teratogenicity or fertility impairment in animal studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients.

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ASHP’s criteria for hazardous drugs were revised by NIOSH for the 2004 Hazardous Drug Alert.

USP Chapter <797> has adopted the following definition of hazardous drugs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.38 NIOSH has adopted a mechanism both to review its hazardous drug criteria and to judge newly FDA-approved drugs against these criteria on a regular basis. In 2007, a group of experts met to review the drugs that have been approved by the FDA since 2004 to evaluate which ones should be considered hazardous. Sixty-two drugs from many different therapeutic categories met at least one criterion of the hazardous definition in the preliminary analysis by NIOSH.46 The final list will be published when it is approved by the Office of Management and Budget (T. Connor, personal communication, July 10, 2008). Once published, the complete list may include nearly 200 pharmacologic agents available in the United States that are deemed hazardous to health care workers. The current NIOSH list of drugs that should be considered hazardous can be found in Appendix A of the NIOSH Alert.47 Table 1 compares the 2004 NIOSH and 1990 ASHP definitions of hazardous drugs.

Recommendations Recommendations for the safe handling of hazardous drugs have been available since the early 1980s. As more research has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns; and USP Chapter <797> deals exclusively with sterile compounding.

All guidelines agree that to reduce exposure to hazardous drugs in the occupational setting, a comprehensive safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative controls, environmental and engineering controls, work practice controls, and PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate risks from other occupational exposures.48

ADMINISTRATIVE CONTROLS Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of hazardous drug handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the

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ongoing monitoring of adherence to policies judiciously established.

USP Chapter <797> emphasizes administrative controls for the safe compounding of hazardous drugs by mandating conditions that protect health care workers and other personnel in preparation and storage areas.

Further requirements include extensive training of all personnel who handle hazardous drugs in the storage, handling, and disposal of such drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing specific hazardous drug preparation techniques. Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of hazardous drugs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new hazardous drug that enters the marketplace.

Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposure.

OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2007, NIOSH released “Workplace Solution: Medical Surveillance for Health Care Workers Exposed to Hazardous Drugs,” which provides direction for establishing such a program and the elements that should be included.49 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks associated with handling hazardous drugs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle hazardous drugs along the chain of custody.

ENVIRONMENTAL

AND

ENGINEERING CONTROLS

The recent revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of hazardous drugs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments. Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which hazardous drugs are compounded.

Hazardous drugs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns

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

ASHP

USP Chapter <797>

Storage environment

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

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

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

Compounding

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

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

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

Ventilation

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

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

Storage: area should have exhaust ventilation of at least 12 air changes per hour.

Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.

ASHP, American Society of Health-System Pharmacists; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 23, 34, and 38.

of volatilization at room temperature, storage is preferably within a containment area such as a negativepressure room with sufficient exhaust ventilation and at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants.

An International Organization for Standardization (ISO) class 5 primary engineering control (PEC) is required for hazardous drug compounding to prevent microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of hazardous drug aerosols or residue. Appropriate PECs for compounding sterile hazardous drug preparations include class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) meeting or exceeding the standards set forth in USP Chapter <797>.

Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP hazardous drug guidelines.

The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile hazardous drug preparations (CACIs). To meet the criteria of USP Chapter <797>, an isolator must provide isolation from the room and maintain ISO class 5 air quality within the cabinet

during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during material transfer in and out of the isolator. Recovery time to ISO class 5 air in the main chamber must be documented after material is transferred into and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time.

A CACI meeting all of these conditions, as detailed in USP Chapter <797>, is exempt from the requirement of placing the CACI in an ISO class 7 buffer area. For hazardous drug compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A class II BSC has an open front and depends on an air barrier to prevent hazardous drug contamination from escaping the cabinet.50 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.51 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO class 5 compounding environment within the class II BSC. A class II BSC or CACI not meeting the conditions

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

ASHP

USP Chapter <797>

Primary engineering controls

• Aseptic containment ventilation control class II BSC-type B2 is preferred.

• Class III BSC or CACI.

• Class II BSC-type B2 with outside exhaust is preferred.

• Total exhaust is required if the hazardous drug is known to be volatile.

• Class III BSC or CACI.

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

Ventilation

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

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

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

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; USP, United States Pharmacopeia Based on references 23, 34, and 38.

listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and have air quality of ISO class 7. Optimally, this area should be at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas, thus providing inward airflow to contain airborne drug.

It is also optimal for a PEC used for compounding sterile hazardous drug preparations to be 100% vented to the outside air through high-efficiency particulate air (HEPA) filtration.

All environments in which sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more than 50% of the ACPH in that environment. The ISO class 7 buffer area and ante-area must be supplied with HEPA-filtered air providing a total of at least 30 ACPH. Table 3 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for hazardous drug PECs.

WORK PRACTICE CONTROLS Work practices must be designed to minimize the generation of hazardous drug contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill.

The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of hazardous drugs.52 These techniques, when performed accurately, minimize the escape of drugs from vials and ampules.

Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the

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powder and liquid drug residues that escape from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced to make the compounding process more efficient. One study documents the effectiveness of one of these devices, but the investigators used only a visual inspection process because no sensitive drug assays were available at the time of the study.53 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in an adjunct device, generically named by NIOSH in the 2004 Alert as a “closed-system drug-transfer device” (CSTD). NIOSH defines a CSTD as a drug-transfer device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.34 These systems provide some of the benefits of the earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of IV push and IV infusion doses, which had not been available previously.

Numerous studies using markers for hazardous drugs have demonstrated the effectiveness of a CSTD in reducing hazardous drug contamination in the workplace.6,14,15 At clinical practice sites representing inpatient and outpatient compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.6,14,15 USP Chapter <797> similarly defines CSTDs as “vialtransfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within

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

General handling

NIOSH/OSHA

ASHP

USP Chapter <797>

• Use double gloving for all activities involving hazardous drugs.

• Wear double gloves for all activities involving hazardous drugs.

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

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

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

Receiving and storage

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

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

Compounding

• Wear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs.

• Make sure that gloves are labeled as chemotherapy gloves.

• Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).

• Select disposable gowns of material tested to be protective against the hazardous drugs to be used.

• Coated gowns must not be worn for longer than 3 hours during compounding and must be changed immediately when damaged or contaminated.

• Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area.

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

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

Administration

Sterile compounding: • Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves.

Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; OSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 22, 23, 34, and 38.

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the ISO class 5 environment of a BSC or CACI. In facilities that prepare a low volume of hazardous drugs, the use of 2 tiers of containment (eg, a CSTD within a BSC or a CACI that is located in a nonâ&#x20AC;&#x201C;negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet.

Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of hazardous drugs. Any device marketed as a CSTD should be clinically tested.

PERSONAL PROTECTIVE EQUIPMENT In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and the hazardous drug during episodes of potential contact. This is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness. Glove and gown materials should be able to withstand permeation by a selection of hazardous drugs.54-56 Several hazardous drugs require nonaqueous diluents for patient use and may permeate PPE more readily than others. The American Society for Testing and Materials has developed a standard for testing chemotherapy gloves.57 There is no standard for chemotherapy gowns, but recommendations have been made based on several studies.55,56 See Table 4 for a comparison of PPE recommendations.

During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks), a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves.

Appropriate PPE must be worn when the sterile compounding of hazardous drugs is performed in a BSC or CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile hazardous drugâ&#x20AC;&#x201C;tested gloves.

New Technologies Technological advances include robotic automation that can compound sterile doses of hazardous and nonhazardous drugs. By replacing the human compounder, these robots reduce the occupational exposure of health care workers during the compounding process.

Robotic units provide contained ISO class 5 environments and use techniques to reduce the generation of hazardous drug residues during compounding. Robots

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operate with sophisticated mechanics and software and provide a degree of accuracy and patient safety not available with manual compounding. CytoCare from Health Robotics, and RIVA (Robotic IV Administration) from Intelligent Hospital Systems all provide robotic solutions to the compounding of sterile preparations of hazardous drugs.

Like most technology, these robots are not perfect.

They require human staff to load and clean them. Hazardous drug contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection as well as decontamination of hazardous drug residues. No particular cleaner has been shown to effectively deactivate all known hazardous drugs,11 so routine cleaning and spill control are still challenges to the health care personnel working with these robots. The robots help only with the compounding process, leaving the workers administering hazardous drugs without protection. Spill control and waste handling also remain issues for human workers to address.

Conclusion Despite almost 3 decades of data on the adverse health effects of occupational exposure to hazardous drugs, skepticism about the risks continues, as evidenced by the lack of programmatic controls for reducing exposure. NIOSH has renewed its dedication to this health risk by continuing to promote worker awareness of safety. USP Chapter <797> has elevated many of the NIOSH recommendations to a standard, ensuring both awareness and compliance with at least the compounding segment of safety program controls.

Each new generation of health care workers needs to be educated about the risks of handling hazardous drugs and the importance of training in the proper techniques to reduce their exposure. Employers and employees must implement all aspects of hazardous drug safety programs to reduce occupational exposure and its potential adverse effects.

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5. Martin S. The adverse health effect of occupational exposure to hazardous drugs. Community Oncol. 2005;2(5):397-400, PMID: 10230582.

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Nygren O, Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health.

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9. Sessink PJ, Van de Kerkhof MCA, Anzion RB, Noordhoek J, Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health. 1994;49(3):165169, PMID: 8185386.

guidelines on handling hazardous drugs. Am J Health Syst Pharm.

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24. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049.

25. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals.

Am J Hosp Pharm. 1985;42(1):131-137.

26. Brown KA, Esper P, Kelleher LO, O’Neil JEB, Polovich M, White JM, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 2001.

27. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice.

2nd ed. Pittsburgh, PA: Oncology Nursing Press; 2005.

10. Sessink PJ, Boer KA, Scheefhals AP, Anzion RB, Bos RP. Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-112, PMID: 1399019.

28. Mahon SM, Casperson DS, Yackzan S, et al. Safe handling practices of cytotoxic drugs: the results of a chapter survey. Oncol Nurs Forum.

1994;21(7):1157-1165, PMID: 7971426.

11. Dorr RT, Alberts DS. Topical absorption and inactivation of cytotoxic anticancer agents in vitro. Cancer. 1992;70(4 suppl):983-987, PMID: 1638468.

29. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum.

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12. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health. 1997;70(3):205-208, PMID: 9298404.

30. Nieweg R, de Boer M, Dubbleman R, et al. Safe handling of antineoplastic drugs. Results of a survey. Cancer Nurs. 1994;17(6):501-511, PMID: 7820828.

13. Sessink PJ, Wittenhorst BCJ, Anzion RB, Bos RP. Exposure of pharmacy technicians to antineoplastic agents: reevaluation after additional protective measures. Arch Environ Health.

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14. Vandenbroucke J, Robays H. How to protect environment and employees against cytotoxic agents, the UZ Ghent experience.

J Oncol Pharm Pract. 2001;6(4):146-152.

15. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63(18):1736-1744, PMID: 16960258.

16. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm.

2005;62(5):475-484, PMID: 15745910.

31. Valanis B, McNeil V, Driscoll K. Staff members’ compliance with their facility’s antineoplastic drug handling policy. Oncol Nurs Forum. 1991;18(3):571-576, PMID: 2057401.

32. Valanis B, Vollmer WM, Labuhn K, Glass A, Corelle C. Antineoplastic drug handling protection after OSHA guidelines. Comparison by profession, handling activity, and work site. J Occup Med. 1992;34(2):149-155, PMID: 1597769.

33. Connor TH, Anderson RW, Sessink PJ, Broadfield L, Power LA. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health Syst Pharm. 1999;56(14):1427-1432, PMID: 10428450.

34. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004165. Washington, DC: NIOSH; 2004. http://www.cdc.gov/niosh/ docs/2004-165/. Accessed February 16, 2010.

18. Opiolka S, Schmidt KG, Kiffmeyer TK, Schoppe G. Determination of vapor pressure of cytotoxic drugs and its effects on occupational safety. J Oncol Pharm Pract. 2000;6:15. Abstract.

35. Code of Federal Regulations. Title 29—Labor. Subtitle B—Regulations Relating to Labor. Chapter XVII—Occupational Safety and Health Administration, Department of Labor. Part 1910—Occupational Safety and Health Standards. Subpart A—General.

Article 1910.2—Definitions. Washington, DC: US Government Printing Office; 2004. http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&tpl=/ecfrbrowse/Title29/29cfr1910_main_02.tpl.

Accessed February 16, 2010.

19. Kiffmeyer TK, Kube C, Opiolka S, Schmidt KG, Schoppe G, Sessink PJ. Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety.

Pharm J. 2002;268:331-337, PMID: 10986478.

36. National Institute for Occupational Safety and Health. NIOSH safety and health topic: hazardous drug exposures in health care. http://www.cdc.gov/niosh/topics/hazdrug. Accessed February 16, 2010.

20. Yodaiken RE, Bennett D. OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Occupational Safety and Health Administration. Am J Hosp Pharm.

1986;43(5):1193-1204, PMID: 3717176.

37. National Institute for Occupational Safety and Health. NIOSH safety and health topic: occupational exposure to antineoplastic products. http://www.cdc.gov/niosh/topics/antineoplastic/.

Accessed February 16, 2010.

21. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21.

38. US Pharmacopeial Convention. Chapter <797> Pharmaceutical compounding—sterile preparations. In: The United States Pharmacopeia, 31st rev, and The National Formulary, 26th ed. Rockville, MD: US Pharmacopeial Convention; 2008.

17. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470(1):85-92, PMID: 10986478.

22. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (TED 01-00-015 [TED 1-0.15A] Sec VI Chap 2); 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.

Accessed February 16, 2010.

23. American Society of Health-System Pharmacists. ASHP

39. Connor TH. NIOSH Multi-Center Study of Hazardous Drug Exposure. Presented at: Safe Handling of Hazardous Drugs in the Clinical Environment Symposium; October 23, 2009; Bedford, MA. 40. Connor TH. NIOSH Study of Health Care Workers in Three Sites: Study Design & Results. Presented at: American Society of HealthSystem Pharmacists Midyear Clinical Meeting; December 6-10, 2009; Las Vegas, NV.

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41. Demonaco HJ. Report on the Massachusetts General Hospital Hazardous Drug Study. Presented at: Safe Handling of Hazardous Drugs in the Clinical Environment Symposium; October 23, 2009; Bedford, MA.

49. National Institute for Occupational Safety and Health. Medical surveillance for healthcare workers exposed to hazardous drugs.

NIOSH Publication No. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/. Accessed February 16, 2010.

42. Ahmed S. Massachusetts General Hospital (MGH) study of hazardous drug (HD) work practices: Study design and results.

Presented at: American Society of Health-System Pharmacists Midyear Clinical Meeting; December 6-10, 2009; Las Vegas, NV.

50. NSF International. NSF/ANSI 49-2007: NSF 49 Class II (Laminar Flow) Biosafety Cabinetry. Ann Arbor, MI: NSF International; 2007.

43. McDiarmid MA. NIOSH Study of Healthcare Workers Handling Anti-Cancer Agents: Chromosomal Effects. Presented at: American Society of Health-System Pharmacists Midyear Clinical Meeting; December 6-10, 2009; Las Vegas, NV. 44. Occupational Safety and Health Administration. Hazard Communication-59:6126-6184. http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=federal_register&p_id=13349. Accessed February 16, 2010.

45. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10099.

Accessed February 16, 2010.

46. National Institute for Occupational Safety and Health. Draft document for public review and comment: process for updating the list of hazardous drugs (Appendix A) for the NIOSH Alert on Hazardous Drugs. NIOSH Docket #105. http://www.cdc.gov/niosh/review/ public/105/default.html. Accessed February 16, 2010.

51. Clark RP, Goff MR. The potassium iodide method for determining protection factors in open-fronted microbiological safety cabinets.

J Appl Bacteriol. 1981;51(3):439-460, PMID: 7037724.

52. Wilson JP, Solimando DA Jr. Aseptic technique as a safety precaution in the preparation of antineoplastic agents. Hosp Pharm.

1981;16(11):575-576, 579-581, PMID: 10253180.

53. Hoy RH, Stump LM. Effect of an air venting filter device on aerosol production from vials. Am J Health Syst Pharm. 1984;41(2):324-326, PMID: 6702843.

54. Connor TH. Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs. Am J Health Syst Pharm. 1999;56(23):2450-2453, PMID: 10595805.

55. Harrison BR, Kloos MD. Penetration and splash protection of six disposable gown materials against fifteen antineoplastic drugs.

J Oncol Pharm Pract. 1999;5(2):61-66.

56. Connor TH. An evaluation of the permeability of disposable polypropylene-based protective gowns to a battery of cancer chemotherapy drugs. Appl Occup Environ Hyg. 1993;8:785-789.

57. American Society for Testing and Materials. D 6978-05 standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. West Conshohocken, PA: American Society for Testing and Materials; 2005.

47. National Institute for Occupational Safety and Health. NIOSH Publication No. 2004-165: Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Appendix A. Drugs considered hazardous. http://www.cdc.gov/niosh/docs/2004-165/2004-165d.html#o.

Accessed February 16, 2010.

Suggested Reading

48. US Department of Labor. 1998. OSHA 3143. Informational booklet on industrial hygiene. http://www.osha.gov/Publications/ OSHA3143/OSHA3143.htm. Accessed February 16, 2010.

Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Press; 2009.

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Your Complete Advanced Aseptic Compounding™ Solutions Provider Containment Technologies Group, Inc. encompasses much more than just superior compounding aseptic isolator technology. We have grown to become your one-stop provider for all of your USP<797> needs.

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Chemotherapy-Induced Nausea and Vomiting: Guideline Summary and Clinical Challenges LISA A. THOMPSON, PHARMD Assistant Professor

CINDY L. O’BRYANT, PHARMD, BCOP Associate Professor Department of Clinical Pharmacy School of Pharmacy University of Colorado Denver Aurora, Colorado

C

hemotherapyinduced nausea and vomiting (CINV)

can significantly impact patient care and quality of life (QoL), resulting in potential complications of electrolyte disturbances, decreased functional ability, weight loss, anorexia, esophageal tears, and treatment noncompliance.1

CINV results in higher health care resource utilization, including hospital admissions and outpatient visits.2 Although substantial progress has been made in the treatment and prevention of CINV over the past 2 decades, this patient-focused treatment complication remains an important issue.

In addition to the emetic risk of the chemotherapy regimen, CINV risk factors include patient characteristics such as female gender, high levels of anxiety, age younger than 50 years, and a history of CINV with previous chemotherapy.

The pathogenesis of CINV is multifactorial, involving release of multiple emetic transmitters, such as dopamine, serotonin, and substance P, that stimulate emesis by binding receptors in the gastrointestinal

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tract and central nervous system.3,4 The approved antiemetics work by binding to the receptors of these pro-emetic neurotransmitters, thus preventing the emetic stimulus.

Antiemetic Information Today’s oncology practitioners have many antiemetic agents at their disposal. One of the most frequently used classes of antiemetic drugs is the serotonin (5-HT3) receptor antagonists. Three first-generation agents and 1 second-generation agent are available (Table 1). The class is well tolerated, with constipation and headache as the most common adverse effects. Although the 5-HT3 receptor antagonists have relatively few drug–drug continued on page 107

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STRONG. FROM THE START.

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

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL447 08/09

www.ALOXI.com

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection.

ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice.

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron.

Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

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

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

Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects.

Dosage adjustment is not necessary in patients with any degree of renal impairment.

Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.

OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].

• Patients should be instructed to read the patient insert.

Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

continued from page 104

interactions, it is important to use caution in patients receiving other QTc-interval prolonging agents.

Corticosteroids are among the oldest agents used in prevention of CINV, and they remain a backbone of therapy. They are highly effective at preventing delayed CINV and they increase the effects of other antiemetic agents. Due to ease of dosing and experience with its use, dexamethasone is the preferred corticosteroid for antiemetic regimens. Common adverse effects of shortterm use of dexamethasone include hyperglycemia, hypertension, and agitation (with higher doses); longterm use may result in immunosuppression.

The neurokinin (NK1) antagonists are the newest class of medications for CINV. Aprepitant (Emend, Merck), the first drug in this class, is used with a corticosteroid and a 5-HT3 receptor antagonist to prevent CINV associated with high-risk regimens. Aprepitant a major substrate of cytochrome P450 (CYP) 3A4, has clinically significant drug–drug interactions with strong CYP 3A4 inhibitors, moderate-strong CYP 3A4 inducers, and other substrates of CYP 3A4. Fosaprepitant (Emend, Merck), the IV prodrug of aprepitant, also is used in combination with a corticosteroid and a 5-HT3 receptor antagonist for patients receiving high-risk CINV regimens; fosaprepitant may be given on day 1, followed by oral aprepitant on days 2 and 3. Although this adds another option for route of administration, drug–drug interactions still must be considered and addressed.

Historically, dopamine antagonists were one of the first agents to show benefit in preventing CINV. However, effective prevention requires high doses of these agents and their efficacy is limited by an increased incidence of extrapyramidal reactions associated with these drugs at these doses. The development of 5-HT3 receptor antagonists has shifted the role of dopamine antagonists from primary prevention and treatment to the management of breakthrough or refractory nausea and vomiting.

Guideline Summary There are multiple guidelines for prevention and treatment of CINV. The 4 used most regularly are those of the American Society of Clinical Oncology (ASCO),5 the European Society for Medical Oncology (ESMO),6 the Multinational Association of Supportive Care in Cancer (MASCC),7 and the National Comprehensive Cancer Network (NCCN).1 These clinical practice guidelines are summarized in Table 2. The guidelines classify IV chemotherapy products by potential into high (>90%), moderate (30%-90%), low (10%-30%), and minimal (<10%) risk groups.

ACUTE

AND

DELAYED NAUSEA

AND

VOMITING

Acute and delayed CINV are defined by the onset of nausea and/or vomiting (N/V)—up to 24 hours and more than 24 hours up to 5 days, respectively. Antiemetic regimens for the prevention of acute and delayed CINV should include treatment on day 1 followed by days 2 and

3, if appropriate per the guidelines. An NK1 antagonist, a 5-HT3 receptor antagonist, and a corticosteroid are recommended to prevent acute CINV in patients treated with high-risk chemotherapy regimens, with continued use of the NK1 antagonist and corticosteroid to prevent delayed CINV. A 5-HT3 receptor antagonist and corticosteroid are recommended on day 1 to prevent acute CINV for moderate-risk regimens. A 5-HT3 receptor antagonist, corticosteroid, or NK1 antagonist (with or without a corticosteroid) should be continued on days 2 and 3 of the moderately emetogenic regimen. As noted in the guidelines, an NK1 antagonist is recommended for select moderate-risk regimens (eg, anthracycline plus cyclophosphamide). A corticosteroid on day 1 only is recommended for regimens with a low risk for CINV, and minimal-risk regimens do not require routine prophylaxis.

BREAKTHROUGH NAUSEA

AND

VOMITING

Breakthrough or refractory CINV can occur at any point in a treatment cycle, despite adequate therapy for acute and delayed CINV. Clinical recommendations advise that the emetic risk of the regimen be reevaluated and therapy adjusted through the addition of an agent with a different mechanism of action, such as a dopamine antagonist or an NK1 antagonist (if not already used). Other principles of management include scheduling antiemetics instead of using them on an asneeded basis and assessing the patient for other potential causes of nausea and vomiting.

ANTICIPATORY NAUSEA

AND

VOMITING

Anticipatory N/V can occur hours to days before chemotherapy and are estimated to occur in up to 29% and 11% of patients receiving chemotherapy, respectively.8 As anticipatory N/V is considered a learned response due to classical conditioning (ie, Pavlovian response), the clinical guidelines stress the importance of preventing an initial episode of CINV by using appropriate antiemetic regimens. In this setting, behavioral interventions are effective and are a primary treatment modality. Techniques that may be used include hypnosis, systematic desensitization, relaxation techniques, and distraction. Due to their anxiolytic effects, benzodiazepines such as lorazepam and alprazolam also play a role in the management of anticipatory N/V.

RADIATION-INDUCED NAUSEA

AND

VOMITING

The risk for developing radiation-induced nausea and vomiting (RINV) is primarily dependent on the treatment administered, including both the location of the radiation field and the dose and pattern of fractionation.5,7,9 The clinical practice guidelines for prevention of RINV are summarized in Table 3. A 5-HT3 receptor antagonist and corticosteroid should be administered prior to highly emetogenic radiation therapy. Patients undergoing moderately emetogenic radiation therapy should receive a 5-HT3 receptor antagonist. Routine prophylaxis is not recommended for mildly or minimally emetogenic radiation therapy, although patients should

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Table 1. Characteristics of Commonly Used Antiemetic Agents Place in Therapy

Drug

How Supplied

Dose

Common Adverse Drug Events

Drug–Drug Interactionsa

Other Notes

Neurokinin Antagonists Aprepitant/ Fosaprepitant (Emend, Merck)

High-risk regimens

Casopitant (Rezonic, Glaxo SmithKline)

Pending FDA approval

PO, IV

PO: 125 mg, day 1; 80 mg, days 2-3 IV: 115 mg, day 1, followed by 80 mg PO days 2-3

Fatigue, hiccups, weakness

Strong CYP 3A4 inhibitors, moderatestrong 3A4 inducers, major 3A4 substrates

Caution with severe hepatic impairment (Child-Pugh class C)

Neutropenia, alopecia, fatigue, leukopenia, anemia, constipation

3A4 substrates, inhibitors, inducers

Potentially single-dose regimen

Headache, constipation, diarrhea, fatigue

Not clinically significant

Cross-react with others in class, risk for QTc prolongation with dolasetron, granisetron, and ondansetron (highest with dolasetron); palonosetron is secondgeneration agent

Serotonin Antagonists High- and moderate-risk regimens

PO, IV

PO: 100 mg, day 1; as indicated, days 2-3 IV: 1.8 mg/kg or 100 mg, day 1; as indicated, days 2-3

Granisetron

PO, IV, transdermal

PO: 1 mg, day 1; 1-2 mg as indicated, days 2-3 IV: 0.01 mg/kg (max 1 mg), day 1 Transdermal: patch applied at least 24 h before chemotherapy; remove ≥24 h but ≤7 d after chemotherapy

Not clinically significant

Ondansetron

PO, IV, ODT tablets

PO: 24 mg, day 1; 8 mg bid as indicated, days 2-3 (high-risk) or 8 mg bid, day 1; as indicated, days 2-3 (moderate-risk) IV: 8 mg or 0.15 mg/kg once

Strong 3A4 inducers

Palonosetron (Aloxi, Eisai)

PO, IV

PO: 0.5 mg once IV: 0.25 mg once

Not clinically significant

PO, PO solution, IV

High-risk regimens: 12 mg, day 1; 8 mg, days 2-4 Moderate-risk: 8-12 mg, days 1-3 Low risk: 8 mg PO, day 1

Dolasetron (Anzemet, Sanofi-aventis)

Corticosteroids Dexamethasone

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High-, moderate- and low-risk regimens

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Mood disturbance, hyperglycemia, HTN, immune and adrenal suppression with prolonged use

Moderatestrong 3A4 inhibitors and inducers, 3A4 substrates

If given with aprepitant, administer 12 mg instead of 8 mg

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Table 1. Characteristics of Commonly Used Antiemetic Agents

Drug

Place in Therapy

How Supplied

Common Adverse Drug Events

Dose

Drug–Drug Interactionsa

Other Notes

Dopamine Receptor Antagonists PO, PO solution, IV

PO: 1-2 mg q4-6h PRN

Dystonia, QTc prolongation, drowsiness, confusion

Moderatestrong 2D6 and 3A4 inhibitors and inducers

Metoclopramide High-, moderate- and low-risk regimens

PO, PO solution, IV

PO/IV: 10-40 mg q4-6h PRN

Dystonia, drowsiness, fatigue, restlessness, diarrhea

Not clinically significant

Prochlorperazine

PO, IV, suppository

PO/IV: 10 mg q4-6h PRN (max dose 40 mg/d) PR: 25 mg q12h

Not clinically significant

PO, PO syrup, IV, suppository

PO/IV/PR: 12.5-25 mg q4-6h PRN

Sedation, somnolence, extrapyramidal symptoms, tardive dyskinesia, urinary retention, anticholinergic effects, reports of QTc prolongation

Haloperidol

Adjunctive

Adjunctive

Promethazine

Moderatestrong CYP 2B6 and 2D6 inhibitors and inducers

Decrease dose by 50% for ClCr <40

IV should be given through a free-flowing IV catheter to prevent extravasation and tissue necrosis continued on next page

have breakthrough medications (such as a 5-HT3 receptor antagonist or dopamine antagonist) available.

Clinical Challenges MULTIPLE-DAY REGIMENS Many patients receive multiday treatment regimens for the treatment of their cancer. It is important that these patients receive appropriate CINV prevention and treatment on all days they are receiving chemotherapy. For moderate to highly emetic regimens, a 5-HT3 receptor antagonist and dexamethasone is recommended. Aprepitant or fosaprepitant can be added if significant delayed CINV has been associated with the regimen. Another treatment option would be the granisetron transdermal patch (Sancuso, Strakan), which is approved for use in chemotherapy regimens of up to 5 days in length.

ORAL CHEMOTHERAPY Management of CINV in patients receiving oral chemotherapy is critical to patient adherence. The number of new oral anticancer therapies approved and in development is increasing. Select oral agents, including temozolomide, busulfan (Myleran, GlaxoSmithKline), etoposide, and cyclophosphamide (≥100 mg/m2 per day), require prophylactic therapy for CINV that typically consists of a

5-HT3 receptor antagonist.1,7 Prophylactic therapy should be administered 30 to 60 minutes prior to the oral chemotherapy dose to ensure adequate serum concentrations. Because oral therapies may be continued for many days, it is important to consider the toxicities of antiemetic medications in addition to their efficacy. When oral chemotherapy is being used in addition to parenteral chemotherapy, CINV prophylaxis for the parenteral agent should be given in addition to therapy required for prevention of CINV secondary to the oral agent.

The majority of approved oral chemotherapy agents fall within the low- to minimal-emetic risk categories and do not typically require prophylactic therapy, although the patient should have breakthrough N/V medication available. The NCCN guidelines suggest administering metoclopramide or prochlorperazine prior to the first dose, then as needed thereafter during treatment.1 Adjuvant agents such as proton pump inhibitors, histamine 2-receptor antagonists, and lorazepam should be considered. CINV can significantly affect a patient’s ability to be compliant with oral chemotherapy, so swift action to control CINV should be taken.

Economic Considerations There has been much discussion in the literature regarding the most cost-effective means of preventing

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Table 1. Characteristics of Commonly Used Antiemetic Agents

Drug

Place in Therapy

How Supplied

Adjunctive

PO

Dose

Common Adverse Drug Events

continued

Drugâ&#x20AC;&#x201C;Drug Interactionsa

Other Notes

Cannabinoid Dronabinol

PO: 5-10 mg q3-6h or 5-15 mg/m2 q4-6h

Abnormal thinking, euphoria, paranoia, somnolence, appetite stimulation

Not clinically significant

Anticipatory: 0.5-2 mg PO tid beginning the night before through day of treatment

Sedation, somnolence, impaired cognition, abnormal coordination, depression, irritability, memory impairment, lightheadedness, xerostomia, constipation, appetite changes and weight gain/ loss

Moderatestrong 3A4 inhibitors and inducers

Caution in elderly patients

Benzodiazepines Alprazolam

PO, PO Anticisolution, patory, adjunctive ODT

Lorazepam

PO, IV

PO/IV: 0.5-2 mg q4-6h PRN Anticipatory: give night before and morning of treatment

Adjunctive

PO

PO: 2.5-5 mg bid

Somnolence, extrapyramidal symptoms, insomnia, dizziness, constipation, weight gain, xerostomia, weakness

Moderatestrong 1A2 inhibitors and inducers

Use in elderly patients being treated for dementia associated with increased mortality

Adjunctive

PO, PO elixir, IV

PO/IV: 25-50 mg q4-6h PRN

Anticholinergic effects, sedation, somnolence, blurred vision, disturbed coordination, tachycardia, palpitations, irritability, paradoxical excitement

Major 2D6 substrates

Useful for treatment of dystonic reactions due to dopamine antagonists

Not clinically significant

Atypical Antipsychotic Olanzapine

Antihistamine Diphenhydramine

bid, twice daily; CrCL, creatinine clearance; CYP, cytochrome P450; HTN, hypertension; ODT, orally disintegrating tablets; PO, orally; PRN, as needed; tid, three times a day a

clinically significant CYP-enzyme drugâ&#x20AC;&#x201C;drug interactions.

Based on prescribing information and references 1 and 5.

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Table 2. Guideline Summary: ASCO, ESMO, MASCC, NCCN Emetic Risk Category

Antiemetic Regimen

Higha

Day 1: NK1 antagonist + 5-HT3 receptor antagonist + corticosteroidb Days 2 and 3: NK1 antagonist + corticosteroidb (ASCO, NCCN recommend continuing corticosteroid on day 4)

Moderatea

Day 1: 5-HT3 receptor antagonist + corticosteroidb ± NK1 antagonist Days 2 and 3: 5-HT3 receptor antagonist or corticosteroidb or NK1 antagonistc ± corticosteroidb

Lowa

Day 1: Corticosteroidb or metoclopramided or prochlorperazined Days 2 and 3: No routine prophylaxis

Minimal

No routine prophylaxis

Anticipatory

Use of best initial therapy + behavioral therapy if needed + lorazepam or other benzodiazepines beginning day –1 ± behavioral techniquese

Multiple-day regimens

Day 1: Acute management per above recommendations based on risk category Days 2 and 3: Delayed management per above recommendations based on risk category

Breakthrough • • • •

Re-evaluate emetogenic risk of regimen to ensure appropriate prophylaxis Add 1 agent from a different drug class (see Table 1) to current regimen Use medications around-the-clock, not as needed Consider adjunctive therapies (see Table 1)

ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; H2RA, histamine-2 receptor antagonist; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network; PPI, proton pump inhibitor a

Consider addition of lorazepam ± H2RA or PPI starting on day 1 per NCCN guidelines; bDexamethasone preferred; cFor select patients, eg, anthracycline + cyclophosphamide; dNCCN only; eHypnotherapy, acupuncture, acupressure, etc.

Based on references 5-7.

CINV. As mentioned previously, CINV also can significantly increase health care resource utilization. A recent retrospective review of hospital database information for patients receiving highly and moderately emetogenic chemotherapy noted that delayed CINV was responsible for the majority of health care visits associated with CINV.4 The mean costs of these visits ranged from $900 (emergency department visit) to $5,300 (hospitalization). This represents the potential for significant cost savings and emphasizes the financial impact of developing and initiating appropriate CINV prophylaxis in a patient receiving emetogenic chemotherapy.

New Directions Olanzapine is an atypical antipsychotic that antagonizes multiple neurotransmitters involved in the pathogenesis of CINV. It has an effect on dopamine, serotonin, α-adrenergic, muscarinic, and histamine receptors.10 It has been studied in combination with a 5-HT3 receptor antagonist and dexamethasone in the acute setting and in combination with dexamethasone

or alone in the delayed setting. In a study of 30 patients who received either a highly or moderately emetogenic regimen, the drug demonstrated a 100% and 80% complete response for acute and delayed CINV, respectively.10 In a larger study (N=229) of patients receiving highly or moderately emetogenic regimens, olanzapine resulted in better QoL and less-delayed CINV compared with standard antiemetic therapy, but it did not have an effect on acute CINV.11 Casopitant (Rezonic, GlaxoSmithKline) is an NK1 antagonist in development that is pending approval by the FDA. Like aprepitant, it has been studied in combination with a 5-HT3 receptor antagonist and dexamethasone. The results from Phase II and III studies conducted with casopitant in moderately and highly emetogenic regimens, showed a complete response of 73% to 86% for delayed CINV and no difference in response for acute CINV.12 An improvement in QoL has been observed in patients who received highly emetogenic regimens.12,13 Casopitant differs from aprepitant in that it has the potential for one-time dosing, but the

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Table 3. Treatment Recommendations for RINV Level of Radiation Emetogenicity (Area of Treatment) Recommended Therapy Highly emetogenic (total body irradiation)

5-HT3 receptor antagonist + corticosteroid

Moderately emetogenic irradiation (upper abdomen)

5-HT3 receptor antagonist

Low emetogenic (lower thorax regions, pelvis, cranium-radiosurgery, craniospinal)

Rescue with a 5-HT3 receptor antagonist if patient experiences N/V followed by a 5-HT3 receptor antagonist before future radiation

Minimally emetogenic (head and neck, extremities, cranium, breast)

Rescue with a dopamine antagonist or 5-HT3 receptor antagonist

N/V, nausea and/or vomiting; RINV, radiation-induced nausea and vomiting Based on references 5, 7, and 9.

2 agents are similar with respect to their drug窶電rug interaction profile.

3. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol. 2008;5(1):32-43, PMID: 18097455.

Conclusion

4. Trigg ME, Higa GM. Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice. J Oncol Pharm Pract. 2010 [Epub ahead of print], PMID: 20085961.

Appropriate CINV prophylaxis in patients receiving emetogenic chemotherapy is critical. Effective, cost-conscious prevention of CINV can improve QoL, patient compliance, and treatment outcomes as well as foster appropriate consumption of medical resources.

Newer antiemetics have significantly improved the control of acute N/V but have had less impact in the delayed setting. Continued research and the development of new antiemetics likely will lead to improved outcomes for patients.

The recommendations in the major antiemetic guidelines are comparable and are represented in this review of CINV and RINV. It is important to realize that although these guidelines provide highly supported treatment plans they should be considered general recommendations. An individual risk assessment should be performed, the emetogenicity of a regimen identified, and an individualized treatment plan developed for each patient receiving chemotherapy or radiation therapy to achieve optimal CINV outcomes.

References 1.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis v.1.2010. http://www.nccn. org/professionals/physician_gls/f_guidelines.asp. Accessed April 16, 2010.

2. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer. 2010 [Epub ahead of print], PMID: 20101417.

5. Kris M, Hesketh PJ, Somerfield M, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol. 2006;24(18):2932-2947, PMID: 16717289.

6. Herrstedt J, Roila F, ESMO Guidelines Working Group.

Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol. 2009; 20(suppl 4):156-158, PMID: 19454442.

7. Antiemetic Guidelines. Multinational Association of Supportive Care in Cancer 2008; www.mascc.org. Accessed March 21, 2010.

8. Morrow GR, Roscoe JA, Kirschner JJ, Hynes HE, Rosenbluth RJ. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer. 1998;6(3):244-247, PMID: 9629877.

9. Roila F, Hesketh PJ, Herrstedt J, et al. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol. 2006;17(1):20-28, PMID: 16314401.

10. Navari RM, Einhoarn LH, Loehrer PJ Sr. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer.

2007;15(11):1285-1291, PMID: 17375339.

11. Tan L, Lui J, Lui X, et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting.

J Exp Clin Ca Res. 2009;28:131-137, PMID: 19775450.

12. Ruhlmann C, Herrstedt J. Casopitant: a novel NK1-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manage. 2009;5(2):375-384, PMID: 19536319.

13. Gridelli C, Haiderali AM, Russon MW, et al. Casopitant improves the quality of life in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2009 Oct 31. [Epub ahead of print], PMID: 19882176.

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VISIT BOOTH 10043 AT ASCO FOR A COMPLIMENTARY 3-MONTH SUBSCRIPTION TO EPOCRATES RX PRO®*

VELCADE CRs Resulted in More Durable Responses MEDIAN DURATION OF RESPONSE IN PINNACLE† TRIAL (n=48/155) Complete responders (CR+CRu)

15.4 (95% CI, 13.4-15.4) (n=12)

All responders (CR+CRu+PR)

9.3 (95% CI, 5.4-13.8) (n=48)

0

1

2

3

4

5 6 7 8 Time (Months)

9

10 11 12 13 14 15 16

▼ VELCADE® (bortezomib) is the only FDA-approved therapy for patients with relapsed MCL ▼ VELCADE delivers a 31% overall response rate, with 8% CR (CR+CRu) ▼ Responding patients received a median of 8 cycles of treatment with VELCADE ▼ VELCADE has a well-characterized safety profile

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page.

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. *Subject to federal and state restrictions. EPOCRATES Rx Pro is a registered trademark of Epocrates, Inc. in the United States and other countries. All other trademarks referenced are those of their respective owners. †

PINNACLE, a single-arm, multicenter, phase 2 trial (N=155) evaluating the efficacy and safety of VELCADE in mantle cell lymphoma (MCL) patients who have received at least 1 prior therapy.

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit 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%.

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.

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.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and

are registered trademarks of Millennium Pharmaceuticals, Inc.

Other trademarks are property of their respective owners.

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 Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon Copyright © 2010, Millennium Pharmaceuticals, Inc. 2, or visit www.VELCADE.com.

For Patientof VELCADE. Assistance or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION discontinuation There isInformation limited re-challenge information in these patients.

All rights reserved.

Printed in USA

V1284

03/10

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Guidelines for the Management of

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

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

F

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

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

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

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHING

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

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

C L INIC AL ONCOLOGY NE WS S P E C IAL E DIT ION 2 01 0 • N O. 1

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

Regimen

Bladder

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin)

Breast

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

Esophageal and gastric

Docetaxel-cisplatin-fluorouracil

Melanoma

Dacarbazine-based combinations

Myelodysplastic syndrome

Decitabine

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

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

Ovarian

Topotecan Paclitaxel or docetaxel

Pancreatic

Gemcitabine-docetaxel

Sarcoma

MAID (mesna, doxorubicin, ifosfamide, dacarbazine)

Small cell lung

Topotecan

Testicular

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

a

Does not contain all high-risk regimens.

Based on reference 9.

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

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are the most common gram-positive pathogens6 and E. coli, Klebsiella spp, Enterobacter spp, and P. aeruginosa are the most common gram-negative species.

Fungal infections such as Candida and Aspergillus can occur later in the course of prolonged neutropenia.

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

of individual risk factors also have been conducted to aid in identifying patients at greatest risk.12 Although there is no consensus nomogram for risk assessment, the NCCN has developed a risk categorization for patients based on disease, chemotherapy regimen, patient risk factors, and treatment intent (ie, curative vs palliative).9 This scheme categorizes patients as having either a high (>20%), intermediate (10%-20%), or low (<10%) risk for developing febrile neutropenia. Table 2 lists patient risk factors for experiencing a poor clinical outcome or infection-associated complications, as noted in the 2010 NCCN Myeloid Growth Factor guidelines.9 The identification of patients at low risk who may be treated on an outpatient basis with oral antibiotic therapy is an important consideration in the management of febrile neutropenia. The Multinational Association for Supportive Care in Cancer (MASCC) risk scoring index (Table 3)13 accurately identifies those at low risk for complications associated with febrile neutropenia who may then be treated with a more convenient and cost-effective option. The MASCC index was validated in a prospective, multinational study where a MASCC score of at least 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%.13 In addition, the IDSA and the NCCN have identified various individual factors that favor a low risk for severe infection among patients with neutropenia (Table 4).5,6

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

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

Clinical Presentation

Mild symptoms (5 points)

Febrile neutropenia should be suspected in any patient who has received chemotherapy in the prior 4 to 6 weeks and presents with a fever or a general feeling of malaise.14 An infection may be present in these patients even without fever because a lack of neutrophils may negatively impact the ability to mount a sufficient immune response. A thorough history and physical examination should be completed to identify the site of infection; however, a definitive infection site may never be discovered.14,15 This examination should include the skin, mucous membranes, fundi, sinuses, and the perianal area.15 All peripheral and central catheter sites should be inspected for signs of infection.

The date and the medications involved in the most recent chemotherapy treatment should be obtained.

In addition, any history of prior prophylactic antibiotics should be noted because this therapy could alter the patientâ&#x20AC;&#x2122;s microflora and influence subsequent antibiotic choice.14 Initial laboratory evaluations include a complete blood count with differential, liver function tests, lipase, a complete chemistry panel, and a full set of cultures (ie, sputum, blood, and urine).15 Cultures should be drawn from every peripheral and central access point. Chest radiographs should be obtained even in patients without obvious pulmonary symptoms. If local signs or symptoms exist, consider acquiring additional imaging studies or laboratory tests that may provide more information regarding symptom etiology. Although patients may present with only fever and malaise, signs and symptoms

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

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

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

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

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

NCCN 2009 Guidelines

• Absolute neutrophil count of ≥100 cells/mcL

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

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

IDSA, Infectious Diseases Society of America; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network a

High-risk factors are listed on page FEV-3 of v.2.2009 of the NCCN Practice Guidelines for the Prevention and Treatment of Cancer-Related Infections.

Based on references 5 and 6.

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

Patients at high risk for severe infections should be treated in the hospital with IV antimicrobials, according to the IDSA and NCCN guidelines.5,6 Both guidelines

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

Table 5. Factors Influencing Initial Antimicrobial Selection

Table 6. Empiric Antimicrobial Therapy for Febrile Neutropenia

Infection risk assessment (ie, low vs high risk)

IDSA 2002 Guidelines

NCCN 2009 Guidelines

Antimicrobial susceptibilities of pathogens isolated locally

Monotherapy

Monotherapy

• Imipenem/cilastatin

• Imipenem/cilastatin

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

• Meropenem

• Meropenem

• Cefepime

• Piperacillin/tazobactam

• Ceftazidime

• Cefepime • Ceftazidime (limited utility)

Colonization or previous infection with MRSA Potential site of the infection

Combination therapy

Importance of broad spectrum antimicrobial coverage that includes antipseudomonal coverage

• Aminoglycoside plus antipseudomonal penicillin

Previous antimicrobial use Clinical instability such as organ dysfunction, hypotension

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

Drug allergy

• Ciprofloxacin plus antipseudomonal penicillin

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

antimicrobials should be limited to specific situations involving infections caused by documented vancomycin-resistant organisms or for patients in whom vancomycin is not an option.

Patients with febrile neutropenia who are clinically unstable, such as those with sepsis, should be initiated on combination therapy that includes a broad-spectrum β-lactam (eg, imipenem-cilastatin, meropenem, or piperacillin-tazobactam [Zosyn, Wyeth]) plus an aminoglycoside and vancomycin.6 The addition of antifungal therapy (eg, fluconazole or an echinocandin) also should be considered for patients not receiving antifungal prophylaxis.

Alterations in the initial empiric regimen are needed for patients who are not responding to therapy.5,6 The NCCN guidelines recommend assessing the appropriateness of antimicrobials for isolated pathogens in patients with documented infection who are not responding to empiric therapy.6 In addition, for patients with fever of unknown origin who are unstable, antimicrobials should be broadened to include coverage of anaerobes, resistant gram-negative rods and gram-positive organisms, and Candida. Empiric antifungal therapy is generally initiated after 4 to 7 days in patients who remain febrile.

The NCCN guidelines state that the duration of antimicrobial therapy is determined by several factors such as the underlying site of infection, causative organisms, and the patient’s clinical condition, response to treatment, and time to neutrophil recovery.6 For patients with fever of unknown origin, antimicrobial therapy is generally

Combination therapy

Vancomycin (for select patients)

Vancomycin (for select patients)

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

• Monotherapy or combination therapy

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

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

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

Duration of Therapy

Skin and soft tissue

7-14 d

Blood stream infections Gram-negative Gram-positive

10-14 d 7-14 d

Sinusitis

10-21 d

Bacterial pneumonia

10-21 d

Fungal (mold and yeast) Candida

Minimum of 2 wk after first negative blood culture

Mold (eg, Aspergillus)

Minimum of 12 wk

Viral Herpes simplex/Varicella zoster Influenza

7-10 d 5-10 d

Based on reference 6.

patient is clinically stable.

PROPHYLACTIC ANTIMICROBIALS Both the IDSA and NCCN guidelines comment on the use of antimicrobial prophylaxis for afebrile neutropenic patients.5,6 The IDSA guidelines recommend against the routine use of antimicrobial prophylaxis because of emerging resistance.5 Antimicrobial prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX)

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

PROPHYLACTIC USE

OF

COLONY-STIMULATING FACTORS

Reducing the incidence, severity, and duration of neutropenia is another important treatment strategy used for managing patients with febrile neutropenia.

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

Table 8. Labeled Indications for CSFs CSFs

FDA-Approved Indications

Filgrastim (Neupogen, Amgen)

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

Pegfilgrastim (Neulasta, Amgen)

• Cancer patients receiving myelosuppressive chemotherapy

Sargramostim (Leukine, Genzyme)

• • • •

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

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

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Table 9. ASCO Recommendations on Use of CSFs As primary prophylaxis of febrile neutropenia for patients at high risk based on age, medical history, disease characteristics, and risk for myelotoxicity associated with a chemotherapy regimen.

For patients undergoing nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications due to bone marrow compromise or other comorbidities.

As secondary prophylaxis in patients who have previously experienced an episode of febrile neutropenia (without primary prophylaxis) when a reduction in dose of chemotherapy is not appropriate.

Use can be considered as adjunctive treatment of febrile neutropenia for patients at high-risk for infectious complications.

To allow for a modest to moderate increase in dose-density and dose-intensity of chemotherapy regimens.

As an adjunct to progenitor-cell transplantation.

For reduction of neutropenia in patients with AML with initial or repeat induction chemotherapy or completion of consolidation therapy.

To increase ANC in patients with myelodysplastic syndrome.

Following completion of initial induction therapy or first post-remission course of chemotherapy for ALL. For limited use with refractory or relapsed AML (data suggest only a few shortened days of neutropenia can be expected).

As prophylaxis in patients 65 y and older with diffuse aggressive lymphoma undergoing CHOP or more aggressive regimens.

For patients being treated with lethal doses of total body radiotherapy.

For pediatric patients, CSFs can be used for primary prophylaxis and as secondary prophylaxis or as adjunctive therapy for high-risk patients; the risk for secondary myeloid leukemia or myelodysplastic syndrome should be considered in children with ALL. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ANC, absolute neutrophil count; ASCO, American Society of Clinical Oncology; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CSFs, colony-stimulating factors Based on reference 16.

Pegfilgrastim is given as one dose of 6 mg per treatment cycle. Sargramostim is given at a dose of 250 mcg/m2 per day, also initiated 24 to 72 hours after the completion of chemotherapy, and continued through the post-nadir recovery period.19 The American Society of Clinical Oncology (ASCO) guidelines recommend that use of sargramostim is limited to its labeled indications.16

RECOMMENDATIONS

FOR

USE

OF

CSFS

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

nonmyelosuppressive therapy but who have risk factors for febrile neutropenia or infectious complications.

A summary of ASCOâ&#x20AC;&#x2122;s recommendations is presented in Table 9.16 The CSFs are not recommended for routine treatment of afebrile neutropenia and use should be avoided in patients receiving a combination of chemotherapy and radiation.

The 2010 recommendations from NCCN on the use of CSFs are summarized in Table 10.9 These guidelines, which are similar to the ASCO guidelines, also recommend the prophylactic use of CSFs with chemotherapy regimens that have at least a 20% risk for febrile neutropenia. In addition, patients are considered to be at high risk if they experienced a previous neutropenic complication in the immediate previous cycle with no plan to reduce the dose intensity of the chemotherapy regimen. When deciding if CSFs should be used, clinicians are encouraged to consider the intent of the chemotherapy regimen. For example, is therapy curative or is it being used for symptom control? For patients in the intermediate-risk category (10%-20%), NCCN recommends that if the risk is based on patient-specific

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Table 10. NCCN Recommendations on CSFs for Febrile Neutropenia Risk for Febrile Neutropenia Associated With Chemotherapy Regimen Curative/Adjunctive

Goal of Chemotherapy Regimen Prolong Survival/QoL

Symptom Management/QoL

High (>20%)

CSF

CSF

CSF

Intermediate (10%-20%)

May be considered

May be considered

May be considered

Low (<10%)

No CSFa

No CSF

No CSF

a

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

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

factors, then use of CSFs is reasonable. However, if the intermediate risk is based on the chemotherapy regimen, then use of less myelosuppressive therapies or a dose reduction should be considered.

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

References 1.

Lyman G. Kuderer NM. Epidemiology of febrile neutropenia.

Support Cancer Ther. 2003;1(1):23-35, PMID: 18628128.

2. Viscoli C, Vanier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification.

Clin Infect Dis. 2005;40(suppl 4):S240-S245, PMID: 15768329.

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

4. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis. 2003;36(9):1103-1110, PMID: 12715303.

7. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management.

Cancer. 2004;100(2):228-237, PMID: 14716755.

8. Lyman G. Risks and consequences of chemotherapy-induced neutropenia. Clin Cornerstone. 2006;8(suppl 5):S12-S18, PMID: 17379159.

9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Myeloid growth factors (v.1.2010). http://www. nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf.

Accessed April 19, 2010.

10. Ellis M. Febrile neutropenia. Ann NY Acad Sci. 2008;1138:329-350, PMID: 18837909.

11. Lyman GH. Risk assessment in oncology clinical practice. From risk factors to risk models. Oncology (Williston Park). 2003;17(suppl 11):8-13, PMID: 14682113.

12. Lyman GH, Lyman CH, Agboola O, for the ANC study group. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10(6):427-437, PMID: 15967836.

13. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051, PMID: 10944139.

14. Walji N, Chan AK, Peake DR. Common acute oncological emergencies: diagnosis, investigation, and management. Postgrad Med J. 2008;84(994):418-427, PMID: 18832403.

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

16. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol.

2006;24(19):3187-3205, PMID: 16682719.

17. Neupogen [package insert]. Thousand Oaks, CA: Amgen; 2007.

18. Neulasta [package insert]. Thousand Oaks, CA: Amgen; 2008.

19. Leukine [package insert]. Seattle, WA: Bayer; 2008.

5. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.

Clin Infect Dis. 2002;34(6):730-751, PMID: 11850858.

20. Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;(4):CD003189, PMID: 18843642.

6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related Infections (v.2.2009). http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed April 19, 2010.

21. Sung L, Nathan PC, Alibhai SM, Tomlinson GA, Beyene J. Metaanalysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med. 2007;147(6):400-411, PMID: 17876022.

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EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, has a global commitment to developing new therapeutic options for people living with cancer. We are focused on developing novel cancer therapies that combine approaches targeting the tumor cell, tumor environment and immune system to optimize treatment outcomes.

Antifungal Prophylaxis Educational Review Available EXCLUSIVELY ONLINE GO TO

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and click on Educational Reviews on the left side of the page.

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his article, written by a collaborative team from Memorial Sloan-Kettering Cancer Center, reviews the epidemiology and diagnosis of invasive fungal infections (Candida, Aspergillus, and Zygomycetes) and relevant clinical trials addressing antifungal prophylaxis in high-risk oncology patients.

This comprehensive, extensively referenced review features tables on:

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Copyright Š 2010 by McMahon Publishing, New York, NY 10036. All rights reserved.

Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Application for Periodicals Postage Rate is pending at New York, NY and other mailing offices. www.mcmahonmed.com POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036.

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Cancer Treatment Centers of America National Director, Medical Oncology Services

Cancer Treatment Centers of America holds a unique position in the marketplace in the continuum of care for cancer patients. While many of our patients do present with an early stage diagnosis of cancer, the majority of our patient population present with later-stage cancer. As we continue to meet the demand to provide late-stage treatment options to patients, we never lose sight of our commitment to provide the highest quality clinical care across our organization.

Our current search is for a National Director for Medical Oncology Services, whose primary purpose is to assist the organization in bridging that level of quality care across the regional centers. These centers include our sites in Metro Chicago, Illinois; Philadelphia, Pennsylvania; Tulsa, Oklahoma; and in the West Valley of Phoenix, Arizona. This highly visible leadership position includes responsibilities for: • Ongoing evaluation of the current state of clinical care with creation of appropriate quality initiatives • Ensuring best practices by facilitating ongoing outcome analysis and continuous medical education activities that assist in optimizing patient care • Facilitating utilization of evidence-based best practices/guidelines • Facilitating development and/or implementation of new or established clinical protocols • Chairing committee composed of regional Medical Oncology directors from each center • Utilizing outcome measures to analyze data for presentation and publication • This position combines both a clinical practice with administrative responsibilities • Reports directly to the organizational Chief Medical Officer; this position will be considered a threshold for advanced future leadership positions The ideal candidate must be board-certified in Medical Oncology or Hematology/Oncology with a record of excellence and prior experience as a division chief or chair of an academic department preferred. A record of national publications and presentations is also preferred. In this position, the National Director is expected to provide clinical expertise to our current medical staff, as well as assist in the recruitment of additional oncology personnel. Salary is highly competitive, commensurate with experience, and includes an excellent benefits package. The National Director may choose to work from any of the CTCA hospital sites.

CONSIDER MAKING A DIFFERENCE IN YOUR CAREER, AND IN THE LIVES OF OUR PATIENTS. Interested candidates should send a copy of their curriculum vitae by email to: drexa.unverzagt@ctca-hope.com or send to: Dr. Edgar Staren, MD, PhD, MBA, Senior Vice President and Chief Medical Officer, Cancer Treatment Centers of America, c/o Drexa Unverzagt, RN, MS, National Director of Physician Recruitment, 2610 Sheridan Road, Zion, IL 60099; Phone: 847-746-4384; Fax: 847-746-4380 EOE/M/F/D/V

© 2009 Rising Tide, Kft.

Cancer Treatment Centers of America Medical Oncology

Cancer Treatment Centers of America is currently seeking BE/BC Medical Oncologists to consider joining our hospital-based practices with opportunities at our locations in Philadelphia, PA; Metro Chicago; Tulsa, OK; and suburban Phoenix, AZ. • Our employed physicians typically see 10-15 patients a day • Practicing in a truly integrative model, where the patient is provided a standard of care protocol chemotherapy, with access to a palliative care team, mind-body medicine, strong nutritional support services and spiritual counseling • Access to latest technologies, including on-site IMRT/PET/CT scanner and TomoTherapy • High nurse-patient ratios, and most nurses have ONS certification • Research initiatives include investigator-initiated trials emphasizing biologically based therapies with patient-specific vaccines, activated immune cell-based therapies, and molecular and functional characterization of patient tumor tissue and response; in addition to an extensive portfolio of drug company studies

Cancer Treatment Centers of America: • State-of-the-art traditional medicine with a fully integrative model, our success is measured one patient at time • Electronic Medical Records at all sites • On-site office space, with assigned advanced practice nurse to assist with management of patients

Benefits and compensation: • • • •

Paid medical malpractice Excellent health insurance benefits 401(k) with match CME and vacation

• Compensation based on experience • With beautiful facilities in Chicago metro; Tulsa, OK; Philadelphia, PA; and Phoenix, AZ, you can have the lifestyle that works best for you and your family, be it urban or suburban

Cancer Treatment Centers of America has an expansive name, but our hospitals are small, personal, well-run facilities that have a collegial practice style. Our patients are complex and challenging, but you will have an opportunity to work in a supportive environment that will allow you time to practice patient-focused medicine.

COME VISIT US AT BOOTH 33 IN THE CAREER FAIR. To learn more about our opportunities, contact: Dr. Edgar D. Staren, MD, PhD, MBA, Sr. VP of Clinical Affairs and Chief Medical Officer for CTCA, c/o Drexa Unverzagt, RN, M.S., National Director of Physician Recruitment, Cancer Treatment Centers of America, 2520 Elisha Avenue, Zion, IL 60099; 847-746-4384; Email: drexa.unverzagt@ctca-hope.com

EOE/M/F/D/V

© 2009 Rising Tide, Kft.

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K. Krishnan Unni; Carrie Y. Inwards

The classic text on Mayo Clinic's experience with bone tumors, Dahlin's Bone Tumors presents a succinct, profusely illustrated summary of the largest single collection of well-diagnosed bone tumors anywhere in the world. This updated sixth edition contains a strong blend of archival material and new cases, and incorporates the latest knowledge about the grading and staging of these tumors.

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Atlas of Diagnostic Oncology: Expert Consult—Online and Print

Arthur T. Skarin Atlas of Diagnostic Oncology, Fourth Edition, by Arthur T. Skarin, MD, FACP, FCCP, provides the guidance you need to diagnose a full range of neoplastic conditions with greater accuracy for better patient outcomes. An unrivaled collection of more than 2,500 images and drawings—combined with succinct, clinically focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations. New discussions on modern diagnostic PET imaging of cancer, and expanded coverage on the side effects of chemotherapy, bring you up to date on the issues impacting research and treatment.

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Bethesda Handbook of Clinical Oncology Jame Abraham; Carmen J. Allegra; James Gulley

Written by clinicians from the National Cancer Institute and other leading institutions, this comprehensive, clear and concise oncology handbook is designed specifically for quick bedside consultation. It covers all malignancies and offers busy clinicians practical guidelines on daily patient management. The user-friendly format features tables, charts, bullet points and algorithms. The thoroughly updated second edition includes new chemotherapeutic agents, dosages and treatment regimens and the latest clinical trials data. New chapters focus on targeted therapies and complementary and alternative medicine in oncology. The Bethesda Handbook of Clinical Oncology, Second Edition, also is available for PDAs. See PDA listing for details.

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Hereditary Breast Cancer

6

Manual of Clinical Oncology, Sixth Edition (Spiral Manual Series)

Claudine Isaacs; Timothy R. Rebbeck

This text presents the epidemiological, biological and clinical issues associated with hereditary breast cancer. It offers clear guidance on the application and utilization of cancer risk assessment models, genetic counseling and testing of high-risk patients and screening and prevention options for individuals at risk for hereditary breast cancer.

Dennis A. Casciato; Mary C. Territo Updated for its sixth edition, this pocket manual is a practical, accessible and comprehensive guide to the management of patients with cancer. In an outline format designed for rapid reference, the book provides the essential information needed for fast, effective clinical decision making at the bedside.

7

Ovarian Cancer: Comprehensive and Contemporary Management

K. Chitrathara; Shalini Rajaram; Amita Maheshwari This book presents the latest clinical guidelines for treating ovarian cancer. Written by a stellar team of international experts, this full-color text provides the latest evidence-based treatment guidelines for patients with ovarian cancer.

8

The Elsevier Guide to Oncology Drugs & Regimens

This premier edition gives busy oncology practitioners fast access to the most current information on all commonly prescribed oncology drugs and regimens—plus the supportive therapies needed to manage side effects. Created by oncology experts, this remarkable reference presents accurate, comprehensive, unbiased prescribing data in clear, concise language in a format tailored to meet the need of oncology specialists.

OncSE0510

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration].

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Immediately and permanently discontinue Vectibix infusion in patients experiencing severe (grade 3 or 4) infusion reactions.

Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Preparation and Administration: Do not administer Vectibix as an intravenous push or bolus.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix if discoloration is observed.

• Withdraw the necessary amount of Vectibix for a dose of 6 mg/kg.

• Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake.

Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.

• Vectibix must be administered via infusion pump.

– Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions.

Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.

– Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes.

Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4).

Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain.

One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit.

Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

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

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

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

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions].

Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%).

For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies.

No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing experience: The following adverse reaction has been identified during post-approval use of panitumumab. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Angioedema DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients.

Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17␤-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

Animal Toxicology and/or Pharmacology: Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive and Developmental Toxicology: Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v8, 7/2009 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006-2009 Amgen Inc. All rights reserved.

The case for Vectibix® Convenient Q2W dosing

Only FDA-approved anti-EGFR monoclonal antibody with convenient every-other-week dosing (Q2W) schedule for patients with mCRC1 No loading dose is required

No loading dose

60-min. infusion

Use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1 The recommended dose of Vectibix® is 6 mg/kg administered over 60 minutes (for doses >1000 mg, infuse over 90 minutes) as an intravenous infusion every 14 days1 ~1% severe infusion reactions reported1

Infusion reactions

Please see Important Safety Information, including Boxed WARNINGS for infusion reactions

Vectibix® injection: solution for intravenous infusion INDICATION: Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Product Labeling: Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [See Product Labeling: Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. [See Product Labeling: Dosage and Administration (2.1)].

Withhold Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page.

Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen.

©2010 Amgen Inc. All rights reserved. 3-10 48257