Clinical Oncology News - April 2011 - Digital Edition by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist clinicaloncology.com • April 2011 • Vol. 6, No. 4

I n this month’s column, Maurie Markman, MD, asks who gets to define ‘clinical benefit’?

Bevacizumab fails to show benefit in adjuvant treatment of colon cancer in AVANT study.

W atchful waiting before surgery presented as new strategy for rectal cancer.

C hanges in hormone and HER2 status underscore need for multiple biopsies in breast cancer patients.

Continuous Sunitinib Dosing Regimen Is Not Recommended in RCC Orlando, Fla.—In patients with renal cancer, continuous dosing with 37.5 mg of sunitinib (Sutent, Pfizer) per day is not superior to the standard regimen of 50 mg per day for four weeks with two weeks off (4/2). This news comes from a Phase II trial presented at the Genitourinary Cancers Symposium (abstract LBA308). The results should put an end to the use of an initial 37.5 mg per day continuous dosing schedule for sunitinib in kidney cancer, said lead author Robert Motzer, MD, attending physician at Memorial Sloan-Kettering Cancer Center in New York City, who presented the findings. “The trial was a Phase II and not a Phase III, so it did have some limitations, but see DOSING, page 25 

HematOlogic DISEASE

PET-CT imaging highly prognostic in PRIMA study subanalysis.

I nvestigational JAK1/JAK2 inhibitor shows promise in Phase II trial of myeloproliferative neoplasms. CLINICAL TRIALS

Recently launched Phase II and Phase III clinical trials.

WWW.CMEZONE.COM

Palliative Chemo: When Is Enough Too Much?

etween 15% and 20% of people with cancer receive chemotherapy within 14 days of their death—at a point when the treatment has virtually no chance of extending survival or the quality of their life. It’s referred to as “palliative” chemotherapy, but it frequently “palliates” very little—indeed, it often causes more discomfort and additional burden to the patient and family. True palliative chemotherapy does have a purpose, and not all chemotherapy near the end of life is futile, said Thomas J. Smith, MD, FACP, co-founder of the palliative care program at the Massey Cancer Center at Virginia Commonwealth University, Richmond. see PALLIATIVE, page 18 

In Prostate Cancer Patients With Biochemical Relapse ...

Study Supports Intermittent Adjuvant Hormone Therapy Orlando, Fla.—When levels of prostatespecific antigen (PSA) begin to rise after definitive radiation therapy, most men with prostate cancer do just as well whether they receive intermittent or continuous administration of hormone therapy, according to a large multicenter trial reported at the Genitourinary Cancers Symposium (abstract 3). “Intermittent androgen suppression should be the standard of care for most patients with PSA recurrence after initial treatment with radiation Prostate cancer cells. therapy or radical prostatectomy and subsequent radiation,” said Oliver Sartor, MD, professor of medicine Laurence Klotz, MD, chief of urology at and urology at Tulane University School Sunnybrook Health Sciences Center in of Medicine in New Orleans, who was not see HORMONE, page 8  Toronto, who presented the study.

POLICY & MANAGEMENT

Oncology Medical Home Model Could Increase Reimbursement Found Money: Part 2 of a Four-Part Series

or oncology practices, the discouraging reimbursement landscape may at last have some hopeful glimmers. One bright spot is the emergence of integrated care delivery models such as accountable care organizations (ACOs) and patient-centered medical homes (PCMHs). Both models may be on the verge of reaping financial incentives from Medicare and Medicaid, as well as private insurers, in return for producing measurable quality outcomes and cost

savings. Physician practices and hospitals have been scrambling to align themselves into networks that fit one or another of the new models, particularly ACOs. Prompting the new interest in alternative care models is the 2010 Affordable Care Act (ACA) and its offspring, the Center for Medicare and Medicaid Innovation, which has been charged with “spreading new ways of delivering care and new ways of paying for care.” Commercial health see FOUND MONEY, page 22 

McMahonMedicalBooks.com Hematology: Clinical Principles and Applications: Fourth Edition Bernadette F. Rodak

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SOLID TUMORS

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

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

insideALIMTA.com

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 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. 1.5 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, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous q Non-Small Cell Lungg 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. 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. 2.3 Premedication Regimen Vitamin Supplementation pp 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 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoringg 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 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 bleedinga, 50% of previous dose regardless of nadir ANC (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. 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 and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) 75% of previous dose 75% of previous dose

Dose of Cisplatin (mg/m2) 75% of previous dose 75% of previous dose

Any Grade 3 or 4 toxicities except mucositis Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (seee 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 CTC Grade 0-1 2

Dose of ALIMTA (mg/m2) 100% of previous dose 100% of previous dose

Dose of Cisplatin (mg/m2) 100% of previous dose 50% of previous dose

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. Renallyy Impaired p 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]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 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 pp 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. ALIMTA® (pemetrexed for injection) PV 5208 AMP

Corticosteroid Supplementation pp 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)]. 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 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%) were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lungg Cancer ((NSCLC)) — Combination with Cisplatin p 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 NSCLCa Reactionb

ALIMTA/cisplatin (N=839) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 90 37

Gemcitabine/cisplatin (N=830) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 91 53

All Adverse Reactions Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn 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. Incidence 1% to 5% Body as a Wholee — febrile neutropenia, infection, pyrexia General Disorderss — dehydration Metabolism and Nutritionn — increased AST, increased ALT Renall — creatinine clearance decrease, renal failure Special Sensess — conjunctivitis Incidence Less than 1% Cardiovascularr — arrhythmia General Disorderss — chest pain ALIMTA® (pemetrexed for injection) PV 5208 AMP

Metabolism and Nutritionn — increased GGT Neurologyy — motor neuropathy 6.2

Additional Clinical Trials Experience Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

6.3

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. Gastrointestinall — colitis General Disorders and Administration Site Conditionss — edema Injury, poisoning, and procedural complicationss — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratoryy — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal. 7 DRUG INTERACTIONS 7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen p 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.

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 overthe-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 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

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 Effectss - 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. 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 intentto-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. 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. ALIMTA® (pemetrexed for injection) PV 5208 AMP

Literature revised August 9, 2010

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Clinical Oncology News • April 2011

Clinical Value

Clinical Benefit in Clinical Trials: From Whose Perspective? ADVISORY BOARD EDITORIAL Maurie Markman, MD Vice President of Patient Oncology Services and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

he term “clinical benefit” is widely employed in the oncology arena.1 The question is, from whose perspective should “clinical benefit” be defined and documented: the investigator’s, the health care economist’s or the patient’s? A clinical trial examining the therapeutic potential of a novel antineoplastic agent may define something labeled “clinical benefit” to have occurred when there is a documented objective response of a measurable tumor mass on an imaging study (e.g., RECIST criteria). Increasingly, trials may conclude that a benefit has occurred when cancers have not progressed for a prospectively declared period of time (e.g., two to six months) following the initiation of treatment. This is often called stable disease.1 These days, the proportion of individual

patients achieving these clinical states may be used in the calculation of the cost-effectiveness of a particular treatment paradigm. This is frequently discussed as a method to demonstrate the value of a specific therapeutic approach. Again, in this scenario, “clinical benefit” may be defined by a somewhat arbitrary measure that includes the percentage of patients who exhibit tumor shrinkage, the failure to discover any new visible lesions or the absence of a certain amount of growth on imaging studies for a specified period of time. Alternatively, statistically significant differences in overall survival (e.g., median) between arms of a Phase III randomized trial, certainly a more definitive end point, may be used in this calculation of “benefit.” Unfortunately, it is far from clear what role more patient-centric parameters, such as relief of cancer-related symptoms, development of treatment-related side effects or the impact of the disease or its therapy on activities of daily living and a patient’s emotional well-being, play in either the academic (clinical trials) or economic (cost-effectiveness analysis) assessment of “clinical benefit.” Although it is understandable that clinical investigators and economists

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD

Advisory Board Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

Leonard Saltz, MD

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

Genitourinary Cancer

Community Oncology

Ronald M. Bukowski, MD

Michael J. Fisch, MD, MPH

Gynecologic Cancer

John W. Finnie, MD

Maurie Markman, MD

Hematologic Malignancies

Lung, and Head and Neck Cancers

Jennifer R. Brown, MD, PhD

Edward S. Kim, MD

Richard Stone, MD

Oncology Nursing Betty Ferrell, RN, PhD

Pharmacy Cindy O’Bryant, PharmD Sara S. Kim, PharmD

Policy and Management Mary Lou Bowers, MBA

Lung Cancer, Emesis Richard J. Gralla, MD

Infection Control Susan K. Seo, MD

Breast Cancer

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a one-month period of “stable disease,” with pain and other problematic symptoms being well controlled and with the continued ability to conduct personally gratifying activities of daily living (e.g., being actively engaged with family and friends, enjoying hobbies) to be of meaningful clinical benefit. Of course, an individual’s conclusion that a period of apparent disease stability with an accompanying acceptable quality of life is of value does not mean that, scientifically, the specific treatment regimen in question is actually responsible for this favorable clinical state, which may in reality simply represent the “natural history of the cancer.” An individual’s conclusion also may be independent of whether the antineoplastic therapy in a specific setting falls within the health economist–defined parameter of being cost-effective. However, from the patient’s perspective, there may have been genuine clinical benefit.

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Joseph V. Pergolizzi Jr., MD

Bone Metastases

might use these measurable, even if questionably rather arbitrary, indicators to define therapeutic effectiveness, one must ask if these definitions accurately reflect what individual cancer patients consider to be of greatest value to them. In fact, limited data exploring the goals of patients with advanced cancer and people with other serious medical conditions suggest that many individuals in these very difficult situations may be willing to undergo rather aggressive care and considerable potential risk to attain what reasonably could be considered quite modest measurable outcomes.2-4 In such circumstances, patients might believe that continuing life of acceptable quality for objectively rather short periods of time is of genuine value to them. These individuals may conclude that a particular treatment regimen that appears to permit a three-, two-, or even

Symptom Control and Palliative Care

Barbara Constable, RN, MBA

Solid Tumors

Unfortunately, it is far from clear what role more patient-centric parameters, such as relief of cancer-related symptoms, play in either the academic (clinical trials) or economic assessment (cost-effectiveness) of ‘clinical benefit.’

McMahon Publishing Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

Circulation Coordinator, Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. Fax: (212) 664-1242. If you are not a member of the groups listed above and would like to subscribe, please send a check payable to Clinical Oncology News. Please allow 8-12 weeks for delivery of the first issue. Subscription: $70.00 domestic, $90.00 international. Single copies $7.00 domestic, $10.00 international.

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Clinical Oncology News • April 2011

Clinical Value

There should be no confusion regarding the preceding statements specifically related to who should define “clinical benefit” and the truly stark economic reality of our dysfunctional payment system for the delivery of health-related services. It is absolutely understood that the escalating costs associated with cancer management mandate future changes in the manner in which medical care is both evaluated and financed in this country. And it is certainly quite reasonable in this national debate to carefully consider the value of the care being delivered as an essential component of the discussion. However, as we move forward in what will surely be an extremely complex, emotional and potentially troublesome debate on how to define “value,” let us not forget that the primary focus of all our efforts is (and absolutely should be) the patient. As such, should it not be from the patient’s perspective, rather than—or at least as much as—that of the researcher or economist, that we view any definition of “clinical benefit” in future discussions of the value of cancer care being delivered? Finally, perhaps those who disagree with this conclusion regarding the ultimate foundation for a definition of “clinical benefit” in oncology should be asked to justify their opinion.

References 1. Markman M. “Clinical benefit rate” in Phase II gynecologic cancer trials: implying more than the data support? Gynecol Oncol. 2010;117:348-349, PMID: 20167354. 2. Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses and general public. BMJ. 1990;300:1458-1460, PMID: 2379006. 3. Murphy DJ, Burrows D, Santilli S, et al. The influence of the probability of survival on patient’s preferences regarding cardiopulmonary resuscitation. N Engl J Med. 1994;330:545-549, PMID: 8302322. 4. Everhart MA, Pearlman RA. Stability of patient preferences regarding life-sustaining treatments. Chest. 1990;97:159-164, PMID: 18955642.

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An Investigational Therapeutic Cancer Vaccine for Unresectable Stage III NSCLC START (Stimulating Targeted Antigenic Responses To NSCLC) is a multi-center, Phase III clinical trial assessing the efficacy and safety of BLP25 liposome vaccine, an investigational therapeutic cancer vaccine, in patients with unresectable stage III non-small cell lung cancer (NSCLC), after chemoradiation. Based on experimental models, L-BLP25 may induce an immune response to MUC1, a tumor-associated antigen widely expressed on common cancers, that could potentially harness the body’s natural immune system to target cancer cells directly.1 MAIN INCLUSION CRITERIA Documented stable disease or response within 4 weeks after primary chemoradiotherapy for unresectable stage III disease Receipt of concomitant or sequential chemoradiotherapy: at least two cycles of platinum-based chemotherapy and 50 Gy radiation therapy Completed primary thoracic chemoradiotherapy between 4 and 12 weeks before randomization ECOG PS 0-1 Platelet count 140 x 109/L, WBC 2.5 x 109/L, and hemoglobin 90 g/L

MAIN EXCLUSION CRITERIA Any other lung cancer therapy including surgery Any history of metastatic cancer, malignant pleural effusion, another neoplasm, autoimmune disease, hepatitis B or C, immunodeficiency, or conditions requiring steroid therapy Received investigational systemic drugs (including off-label use of approved products) within 4 weeks prior to randomization

COMMENT

Do you have thoughts or reactions to Dr. Maurie Markman’s editorial? Clinical Oncology News would love to hear them. Send responses to korourke@mcmahonmed.com.

TLY

1. Butts C, Anderson H, Maksymiuk A, et al. Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients with stage III/IV non-small cell lung cancer (NSCLC). ASCO Congress 2009; Abstract No. 3055. BLP25 liposome vaccine is currently under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proven to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the START Trial

Please call 1-800-507-5284 or refer to www.nsclcstudy.com or www.clinicaltrials.gov (NCT00409188)

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Clinical Oncology News • April 2011

Prostate Patients receiving continuous hormone therapy

continued from page 1 

involved with the study, said the findings have potentially huge clinical implications. “This is an important study and reflects what a lot of us have been doing in the clinic with our patients on androgen deprivation therapy,” Dr. Sartor said. “The results provide the proof that intermittent therapy is just as effective as continuous androgen deprivation therapy. The potential savings with regard to medication costs are huge.” Patients randomized to intermittent hormone therapy had a median overall survival (OS) of 8.8 years compared with 9.1 years in patients receiving continuous therapy, a difference that was not statistically significant. Intermittent treatment reduced hormone exposure by 75% compared with continuous treatment. The trial met its predefined primary end point of noninferiority for intermittent versus continuous therapy in terms of OS. This comparability means that the vast majority of patients with localized prostate cancer can begin adjuvant hormone therapy with an intermittent regimen, according to the investigators. The study provides much-needed highlevel data on one of the most controversial issues in the management of prostate cancer: how to respond to a rising PSA level after definitive treatment. No consensus exists about the optimal therapeutic strategy for this clinical situation. The findings came from a randomized clinical trial involving 1,400 men with localized prostate cancer initially treated with curative radiation therapy. Subsequently, all of the patients had PSA recurrence more than a year after curative treatment, defined as a PSA level greater than 3 ng/mL. The patients were randomized to continuous therapy or to an intermittent schedule of eight months on treatment,

Patients receiving intermittent hormone therapy

‘The results provide the proof that intermittent therapy is just as effective as continuous androgen deprivation therapy. The potential savings with regard to medication costs are huge.’

—Oliver Sartor, MD

100

Patients, %

HORMONE

60 40 20

followed by a break until the patient’s PSA level exceeded 10 ng/mL. At that point, patients in the intermittent arm received an additional eight months of hormone therapy, followed by another break in treatment. The median followup was 9.1 years. Patients in both arms continued treatment until progression to castration resistance, defined as a PSA level greater than 10 ng/mL on three consecutive occasions at least one month apart despite hormone therapy. In the intermittent arm, men were switched to continuous therapy if their PSA value exceeded the 10-ng/mL threshold within two months of stopping treatment. The trial ended prematurely when a planned interim analysis showed the results had surpassed the threshold for noninferiority in terms of OS (hazard ratio [HR], 1.25; P=0.009). Patients in the intermittent arm were more likely to die of prostate cancer (122 vs. 97 deaths), whereas the continuous-therapy arm had more deaths from causes unrelated to prostate

cancer (146 vs. 134). “The net effect was that the differences in deaths in the two arms canceled each other out, so that the total number of deaths did not differ significantly between the groups,” Dr. Klotz said. Patients in the intermittent arm received a median of two, eight-month cycles of androgen suppression (range, one to nine). Intermittent therapy was associated with a significant slowing of progression to castration resistance compared with continuous therapy (HR, 0.80; P=0.024). “One of the surprises [in] men in the intermittent arm was the time on therapy,” said Dr. Klotz. “Earlier Phase II studies suggested that men spent about equal amounts of time on and off therapy. Instead, we found that men in the intermittent-therapy arm were on treatment only 27% of the time.” The incidence of hormone-related hot flashes was significantly lower with intermittent therapy than with continuous treatment (90% vs. 93%; P=0.02, Figure). Otherwise, the two treatment groups

‘Earlier Phase II studies suggested that men spent about equal amounts of time on and off therapy. Instead, we found that men in the intermittent-therapy arm were on treatment only 27% of the time.’

Figure. Incidence of hot flashes. were similar with regard to adverse events, including sexual dysfunction, urinary frequency or urgency, fatigue, cardiac events and fractures. Dr. Klotz said the results show that intermittent androgen suppression is a “win—win situation. Not only do we have a therapy that appears to be better tolerated and just as effective [as continuous therapy], but it is also cost-saving.” Although Dr. Sartor agreed that intermittent therapy has advantages, it is not for every patient. Intermittent therapy requires greater compliance with care in terms of keeping clinic visits for serial PSA testing, he said. According to Michael Carducci, MD, AEGON Professor in Prostate Cancer Research at the Johns Hopkins Kimmel Cancer Center, Baltimore, intermittent therapy “also may not be appropriate for the patient with documented metastatic disease.” He said that clinical trial 9346 conducted by the Southwest Oncology Group is investigating intermittent therapy in men with newly diagnosed metastatic prostate cancer, but the data are not yet mature.

—Laurence Klotz, MD

—Charles Bankhead

LETTER TO THE EDITOR

The following was written in response to “Drug Shortages Put Cancer Centers in Crisis,” January 2011, page 2.

Are you having difficulty explaining the current drug shortages to your patients? Order reprints of an article explaining the situation.

To the Editor: “Drug Shortages Put Cancer Centers in Crisis” is a frightening example of our “profitat-all-cost” system reverting against us and biting us in the _ss! If a pharmaceutical company cannot make enough profit from the manufacture of an agent, even if it has been proven to save innumerable lives, then simply slow down or stop the production of the drug! CMS also bears a tremendous burden of responsibility for relentlessly reducing the reimbursement of these drugs to the point where Big Pharma simply says, “No thank you!” What an indefensible moral tragedy! T.F. Tenczynski, MD Houston, Texas

Clinical Oncology News welcomes letters to the editor. E-mail your thoughts to korourke@mcmahonmed.com.

Reprints of Clinical Oncology News articles are available. Call Julianna Dawson at (212) 957-5300 x271. Reprints can be ordered in black & white or 4-color.

SOLID TUMORS

Clinical Oncology News • April 2011

Colon

Bevacizumab Disappoints in AVANT Study San Francisco—Results of the AVANT trial support a body of recent data suggesting that treatments that work in the metastatic setting of colorectal cancer (CRC) do not necessarily work for earlier-stage disease. In that trial, bevacizumab (Avastin, Genentech) added to a standard adjuvant regimen for CRC failed to prevent more relapses or improve overall survival (OS). “Bevacizumab is the third agent, after irinotecan and cetuximab [Erbitux, Bristol-Myers Squibb], with proven efficacy in metastatic colorectal cancer and no observed benefit in the adjuvant treatment of colon cancer,” noted investigator Aimery de Gramont, MD, of Hopital Sainte-Antoine in Paris, presenting the results during the 2011 Gastrointestinal Cancers Symposium (abstract 362).

Rationale for AVANT There is strong rationale for bevacizumab in CRC, given the well-established roles of angiogenesis and vascular endothelial growth factor (VEGF) in these tumors. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-O8, bevacizumab improved disease-free survival (DFS) during the first 15 months of follow-up, although the benefit disappeared over time and patients in the bevacizumab arm eventually showed a trend toward worse outcomes (J Clin Oncol 2011;29:1116, PMID: 20940184). “A significant time and treatment interaction was observed in NSABP C-O8, suggesting that bevacizumab maintenance therapy might sustain the early benefit observed with adjuvant bevacizumab,” Dr. de Gramont said. The AVANT trial was designed to test that hypothesis about maintenance therapy, enrolling 3,451 patients with stage II/III CRC and randomizing them to one of three postoperative therapy arms: FOLFOX (folinic acid, fluorouracil and oxaliplatin) alone, FOLFOX plus bevacizumab followed by six months of bevacizumab maintenance therapy, or XELOX (capecitabine plus oxaliplatin) plus bevacizumab followed by six months of bevacizumab maintenance. The primary end point focused on the 2,867 patients with stage III disease, comparing disease-free survival (DFS) in each experimental arm with FOLFOX chemotherapy alone after a minimum of three years of follow-up. Compared with FOLFOX alone, FOLFOX plus bevacizumab and XELOX plus bevacizumab were associated with hazard ratios for DFS of 1.17 (P=0.0739) and 1.07 (P=0.4433), respectively, Dr. de Gramont reported. The three-year DFS rates were 76% for FOLFOX alone, 73% for FOLFOX plus bevacizumab and 75% for XELOX plus bevacizumab. There was no statistically significant difference between the bevacizumab arms and FOLFOX alone, and none of the analyses performed at six-month intervals

favored bevacizumab. Preliminary analysis of OS in patients with stage III disease showed a nonsignificant trend toward worse survival

in both bevacizumab arms. Patients treated with FOLFOX plus bevacizumab had a 31% excess mortality risk, whereas patients receiving XELOX plus

bevacizumab had a 27% excess risk. These “immature overall survival data suggest a potential detriment [with bevacizumab],” Dr. de Gramont said, noting that “follow-up is ongoing.” Similar to the results seen in the NSABP C-O8 trial, the effects of bevacizumab were not constant over time. A transient favorable effect was seen within one year, which is in line with what was seen in the NSABP trial. However, the treatment see STUDY, page 11 

SOLID TUMORS

Clinical Oncology News • April 2011

Rectal

A New Strategy for Rectal Cancer: Watch and Wait No Immediate Surgery for Neoadjuvant Responders; 65% Respond in Study Neoadjuvant chemoradiation should be considered the preferred initial treatment strategy for locally advanced distal rectal cancer, with no need for immediate radical surgery, according to a team of Brazilian surgeons. The new study was presented at the recent International Rectal Cancer Consensus Conference in Wynnewood, Pa. According to these surgeons, one of the advantages of this treatment strategy is that a significant proportion of these patients experience a considerable decrease in tumor size and there is a trend toward earlier disease stage. “In some patients, tumor regression may be so intense that it leads to complete pathological response,” said Angelita Habr-Gama, MD, professor of surgery, University of Sao Paulo School of Medicine in Brazil. Because radical surgery is associated with morbidity, mortality and urinary and sexual dysfunction, not to mention the requirement for stomas, Brazilian researchers led by Drs. Habr-Gama and Rodrigo Perez, MD, decided to test whether immediate surgery could be skipped in certain patients. Specifically, they examined whether it could be skipped in patients who underwent neoadjuvant chemoradiation, when complete pathological response was suspected based on a complete clinical response assessed by clinical, endoscopic and radiological studies. In those patients who have no residual ulcer, mass or any irregularity of the rectal mucosa at least eight weeks after radiation therapy completion, a strict follow-up program is performed, with no immediate radical surgery. “In patients with any suspicious residual lesion, full-thickness local excision should be performed, primarily as a diagnostic approach—to rule out complete pathological response,” said Dr. Perez. Standard chemoradiation regimens included 45 to 54 Gy of radiation and concomitant fluorouracil (5-FU)-based chemotherapy delivered at the very beginning and end of radiation therapy (two cycles). After this six-week period of treatment, patients usually rested for six to eight weeks before tumor regression was reassessed, followed by radical surgery. Initial results with this regimen showed rates of complete clinical response in up to 27% of patients treated by neoadjuvant chemoradiation (Figure 1). “Several studies have been conducted to understand the role of other chemotherapy agents in the neoadjuvant setting, trying to improve complete tumor regression rates,” said Dr. Perez. “However, most

studies adding new agents to the standard regimen have not observed any significant increase in response rates, at a cost of significant increase in toxicity rates.”

In 2006, Drs. Habr-Gama and Perez initiated a study in Brazil using additional chemotherapy cycles (5-FU-based) delivered not only during radiation (three cycles instead of two), but also during what used to be called the resting period of six to eight weeks (an additional three cycles; Figure 2). “With this new extended regimen,” said Dr. Habr-Gama, “we have observed a

significant increase in complete response rates, leading to no immediate surgery in up to 60% of the patients and sphincter preservation in more than 97% of cases. So far, the increase in tumor regression rates was not followed by an increase in toxicity rates.” “Dr. Habr-Gama has to be credited for several important achievements over the last few years,” said John Monson, MD, professor of surgery and oncology

‘With this new extended regimen, we have observed a significant increase in complete response rates leading to no immediate surgery in up to 60% of the patients and with an overall rate of sphincter preservation in more than 97% of cases.’ —Angelita Habr-Gama, MD

Figure 1. Previous standard regimen for locally advanced distal rectal cancer used by surgeons at the University of Sao Paulo.

Figure 2. The new regimen with the impact on complete clinical response rates. Images courtesy of Angelita Habr-Gama, MD, and Rodrigo Perez, MD.

and chief, Division of Colorectal Surgery, vice chairman, Department of Surgery at University of Rochester Medical Center in Rochester, N.Y. “First, she has demonstrated that it is possible to increase the rates of complete response to therapy to levels that make this a realistic proposition in the future. More and more protocols are now being developed around the world with this aim in mind,” Dr. Monson said. “Almost as important,” he continued, “it should be recognized that Dr. Habr-Gama is asking one of the most important questions that still remains unanswered: Is it safe to watch and wait when the patient appears to have been ‘cured’ by the preoperative therapy? She has had the courage and also the science to ask this question, and her work has the potential to fundamentally change the way we approach rectal cancer in the 21st century.” According to Ed Chu, MD, chief of the Division of Hematology/Oncology and deputy director of the University of Pittsburgh Cancer Institute, what is really needed is a randomized controlled trial. “While there is clinical data suggesting that this approach is now possible in a subset of patients with early-stage rectal cancer, I’m not sure that it is ready for prime time,” Dr. Chu said. “Obviously, it would be ideal to have a randomized study to determine whether there is a need for surgical resection, but I doubt that this will ever happen.” —Colleen Hutchinson

SOLID TUMORS

Clinical Oncology News • April 2011

Colon

STUDY

‘Bevacizumab is the third agent, after irinotecan and cetuximab, with proven efficacy in metastatic colorectal cancer and no observed benefit in the adjuvant treatment of colon cancer.’

continued from page 9 

effect became unfavorable after one year, which was earlier than in NSABP C-O8, Dr. de Gramont pointed out.

—Aimery de Gramont, MD

Possible Explanations Commenting on the findings, Johanna Bendell, MD, director of GI Oncology Research at the Sarah Cannon Research Institute in Nashville, Tenn., said, “We still have a lot to learn about colorectal cancer. The results of AVANT were eagerly anticipated, given the results of NSABP C-O8 … and the study was well designed and well balanced.” Comparing the two key adjuvant trials, Dr. Bendell noted that initial DFS improvements in AVANT were lost much earlier than in C-O8. In C-O8, the hazard ratio appeared to favor bevacizumab throughout the follow-up period (through three years), although the difference versus chemotherapy alone was not statistically significant, whereas in AVANT the difference was lost after one year. “Does the disease-free survival at years 2, 2.5 and 3 [the six-month intervals that showed no benefit for bevacizumab] suggest a rebound effect of bevacizumab?” Dr. Bendell speculated, noting that preclinical studies have suggested that metastases or tumor cell invasion may be increased when VEGF inhibitors are used, especially upon their withdrawal. Robert Kerbel, PhD, the Canada Research Chair in Tumor Biology Angiogenesis and Anti-Angiogenic Therapy at Sunnybrook Health Sciences Centre, in Toronto, considers the concept of “rebound” in the adjuvant setting biologically plausible. He explained that tumors outgrow their blood supply, leaving areas of hypoxia that usually are resistant to chemotherapy and radiotherapy. Antiangiogenic treatment actually increases hypoxia, and tumor rebound, drug resistance and tumor progression might be a consequence of this. He acknowledged that this concept has not been adequately tested in adjuvant models. Dr. de Gramont suggested in his presentation that induction of tumor cell

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dormancy with bevacizumab also might be a possibility. “Arrested angiogenesis is a component of cell dormancy and experimental models have shown that

dormancy can protect tumor cells from chemotherapy,” he noted. Additionally, more patients in the FOLFOX-only arm than in the other two arms received bevacizumab after recurrence: 35% versus 16% and 20%, respectively. This may have influenced OS, Dr.

Bendell pointed out. Considering the body of data indicating a lack of benefit of adjuvant bevacizumab, she suggested that “adjuvant bevacizumab development should stop for now.”

TRIAL CURRENTLY RECRUITING

A Randomized Phase II Trial for Newly Diagnosed Glioblastoma Patients: Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized, multicenter, open-label, controlled, phase II study investigating two cilengitide regimens in combination with standard treatment (TMZ with concomitant RT, followed by TMZ) versus standard therapy alone MAIN INCLUSION CRITERIA Newly diagnosed supratentorial glioblastoma (WHO grade IV) Unmethylated MGMT gene promoter status ECOG PS 0-1 Baseline Gd-MRI Stable or decreasing dose of steroids (for 5 days)

MAIN EXCLUSION CRITERIA Prior anti-angiogenic therapy Investigational agents within 30 days Chemotherapy within 5 years Prior cranial radiotherapy Placement of Gliadel® wafer Significant hepatic or renal impairment Coagulation disorder, myocardial insufficiency, peptic ulcer or another malignancy

MGMT: O6-methylguanine–DNA methyltransferase; RT: radiotherapy; TMZ: temozolomide Cilengitide (EMD 121974) currently is under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proved to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the CORE trial Please call 1-800-507-5284 or refer to ClinicalTrials.gov for more information (http://www.clinicaltrials.gov/ct2/show/NCT00813943) The CORE study is in collaboration with the Canadian Brain Tumour Consortium (CBTC).

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Clinicaloncology.com 101108 - 115024

—Audrey Andrews

SOLID TUMORS

Clinical Oncology News • April 2011

Breast

Everolimus-Tamoxifen Combo Effective For Metastatic Breast Cancer in Phase II Trial San Antonio—Adding everolimus (Afinitor, Novartis) to tamoxifen can improve outcomes compared with tamoxifen monotherapy in some women with metastatic breast cancer (MBC). This finding comes from a Phase II, nonblinded, randomized trial sponsored by everolimus’s manufacturer. Specifically, the therapies were tested in aromatase inhibitor–exposed women with hormone receptor–positive, HER2-negative MBC. Thomas Bachelot, MD, PhD, the principal investigator of the study from the Department of Medical Oncology, National Institute of Health and Medical Research, Lyon, France, presented these results at the 33rd annual San Antonio Breast Cancer Symposium (SABCS; abstract S1-6). Mothaffar Rimawi, MD, medical director of Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, who attended the talk, said that the findings are “interesting and promising” and are consistent with the growing body of evidence that

Clinical Benefit Rate, %

Tamoxifen

100

Tamoxifen + everolimus

80 61.1

60 42.1

40 20 0

Figure. Clinical benefit rate at six months of treatment.

Table. Tolerance of Tamoxifen Versus Combination Therapy for Metastatic Breast Cancer

inhibiting the mammalian target of rapamycin (mTOR) enzyme—the main mechanism of action of everolimus—is efficacious. “However, these findings need to be confirmed in further and larger studies before [it can be determined whether] they impact clinical practice,” Dr. Rimawi told Clinical Oncology News. “It would also be interesting to study tissue from patients and identify those who would benefit most from this combination. In the era of targeted therapy, tissue collection and characterization of molecular changes need to be part of every clinical trial.” Dr. Bachelot noted that these were valid comments. “I totally agree with the first comment: No definitive conclusion can be drawn from this ‘proof of concept’ trial,” he acknowledged. “With respect to the second comment, tissue collection was not mandatory at study entry, but we are currently doing our best to retrieve most of the tumor samples available from the subjects, which we intend to analyze by the second quarter of 2011.” In the study, 54 women with MBC were randomized to receive tamoxifen 20 mg per day plus everolimus 10 mg per day (TAM plus everolimus arm). Another 57 women were randomized to receive tamoxifen 20 mg per day (TAM arm). The subjects in both arms had similar characteristics, and neither the subjects nor the investigators were blinded to treatment. An intentionto-treat (ITT) analysis was used to

Tamoxifen

Tamoxifen Plus Everolimus

Patients with dose reductions due to adverse events

Patients discontinuing treatment due to adverse events

Cases of grade 3/4 fatigue

Cases of grade 3/4 stomatitis

examine the data. The number of subjects and the study design did not allow formal comparison between arms, said Dr. Bachelot. Rather, “the TAM data should be used to afford a degree of reassurance that the results obtained in the TAM plus [everolimus] arm are valid. As a consequence, all P values and confidence intervals that we arrived at are considered exploratory.” The primary end point was clinical benefit rate at six months, which was defined as the combination of the rate of complete response, partial response and stable disease. The clinical benefit rate was 61.1% in the TAM plus everolimus subjects and 42.1% in the TAM-alone arm (P=0.045) (Figure). In a post-hoc subanalysis, the team found that the largest clinical benefit advantage seemed to accrue in women with secondary hormone resistance. They did not calculate hazard ratios or confidence intervals for these differences. Women in the TAM plus everolimus arm had an average time to progression (TTP), one of the secondary end points, of 8.6 months, during a median follow-up of 22.3 months. The average TTP in the

TAM-only arm was 4.5 months, during a median follow-up of 22.6 months. Dr. Bachelot’s team calculated that these data represented a hazard ratio (HR) of 0.53 for TAM plus everolimus versus TAM (95% confidence interval [CI], 0.35-0.81; P=0.0026). In a post-hoc subanalysis, the team found that women with secondary hormone resistance, but not those with primary hormone resistance, had a statistically significant increase in TTP. Another secondary end point was overall survival. This also favored patients receiving everolimus—as of October 2010, the HR was 0.32 (95% CI, 0.15-0.68; P=0.0019). Rates of adverse events (AEs), dose reduction due to AEs, and treatment discontinuation due to AEs differed in some instances between the groups, but the investigators did not perform statistical analyses (Table). Dr. Bachelot said, “There are obvious differences, but we did not statistically test the differences because this was only a secondary end point; it was a small study and there were multiple comparisons.” —Rosemary Frei, MSc

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Expert Reports Potentially Troubling Trends in Breast Cancer

Micromets: Little Bearing in Breast Cancer Survival

Pregnant Women With Cancer May Benefit From Regional Anesthesia

Meta-Analyses Ignore Financial Conflicts in Trials

SOLID TUMORS

Clinical Oncology News • April 2011

Breast

Fickle Breast Tumors Pose Challenge for Clinicians benign tumor or another primary cancer requiring different therapy decisions and patient management,” Dr. Lindström said. Of 1,051 patients in the registry, 459 had known ER status for the primary tumor and at relapse; 437 had known PR status for the primary tumor and at relapse; 118 patients had known HER2 status for the primary tumor and at relapse; and 101 patients had known ER status for multiple relapse sites (up to six aspirates during time course of disease). The study identified changes in ER, PR and HER2 status (Figure). Patients who were ER-positive but became ER-negative at relapse developed liver metastases more frequently than stable ER-positive patients. Patients with ER-negative primary tumors may experience a change to ER-positive tumors over time and may have a tendency to relapse locally in the breast and develop metastasis to the lung and skeleton. “In a multivariate analysis of survival, patients who switched from ER-positive to ER-negative [status] during tumor progression tended to have worse survival,” Dr. Bergh told the audience. He said that other prospective and retrospective studies also have shown that hormone receptor and HER2 status can change during disease progression.

San Antonio—A recent study adds to the growing evidence that estrogen receptor (ER), progesterone receptor (PR), and HER2 status can change over time in patients with breast cancer. Clinicians should be aware that these changes may have important implications for patient management. In the recent study, a retrospective analysis presented at the 33rd annual San Antonio Breast Cancer Symposium (abstract S-35), more than one-third of patients had a hormone receptor (HR) status that changed during progression and 10% had a HER2 status that changed. Patients who were initially ER-positive but became ER-negative during tumor progression were at increased risk for death compared with those whose ER-positive status remained stable during progression. “These data, together with prospective and other retrospective data, demonstrate that morphologic verification of suspected ‘metastatic’ breast cancer lesions will improve the diagnostic precision, and even occasionally excludes the rare patient with no relapse,” said investigator Jonas Bergh, MD, Karolinska Institute, Stockholm, who presented the study for lead author Linda Lindström, MD, PhD, also from the Karolinska Institute. Dr. Bergh contended that tumor biopsy obtained during progression offered the opportunity for improved personalized management of patients with breast cancer. “These data should

challenge present management. This [i.e., repeated biopsy at progression] is a better strategy. It may be cost-effective to retest for HER2/neu at recurrence, because in our study 10% of patients changed HER2 status and we want to be sure to give the optimal treatment based on tumor marker status,” he said. Primary ER, PR and HER2 status, along with clinical status, stage, previous therapies and relapse-free survival, are frequently used to choose treatment strategies not only for primary cancer but also in the relapse and metastatic settings. The retrospective study was based on 1,051 patients with breast cancer drawn from a regional breast cancer registry in Sweden. Cytology was used to verify recurrence for most of these patients, although Dr. Bergh said that core biopsy has some advantages over cytology, including the ability to obtain more tissue for further study and ease of interpretation. ER and PR status was assessed by biochemical, immunohistochemical or immunocytochemical methods. HER2 status was assessed by IHC and/or fluorescence in situ hybridization. “We recommend biopsies be taken to verify relapse, because radiological diagnosis may not be enough to confirm relapse. Suspected relapse on radiographs may, for example, turn out to be a

Patients whose ER status remained stable ER+ patients who became ER– ER– patients who became ER+

6.7%

Understanding the Changes “Over the last few years, it has become clear that there can be discordance between hormone receptor and HER2 status in the primary tumor and the metastases at the time of progression. This has led to the increasing realization that it may be important to re-biopsy patients at progression,” said Steven Isakoff, MD, medical oncologist

Patients whose PR status remained stable PR+ patients who became PR– PR– patients who became PR+

4.8%

26.4%

at Massachusetts General Hospital (MGH) in Boston. “However, we need to better understand the nature of these changes. In some cases, it may be due to technical issues as the tissue was processed; in other cases, [the changes] may be a true change in the receptors; and in some cases, different metastatic sites could have discordant markers. It isn’t clear yet what the treatment implications of these changes are,” he continued. Dr. Isakoff said repeating biopsy at disease progression can help move research along and, in selected patients, may inform treatment decisions. For example, if a primary tumor is HER2-negative and at progression a repeat biopsy shows transformation to HER2 positivity, then the patient might receive trastuzumab. “I also think it makes sense to consider re-biopsy after treatment failure. A change in receptor status could open up new therapeutic options,” he said. To date, no large, prospective, randomized studies have been initiated to evaluate changes in therapy based on discordance in receptor status between the primary tumor and metastatic disease. At MGH and Dana-Farber Cancer Institute, a pilot study is under way using circulating tumor cell technology (i.e., CellSearch) as a surrogate for invasive biopsy to detect a change in HER2-positive breast cancer. Patients who transform from HER2-negative to HER2-positive will receive trastuzumab with vinorelbine. This study will serve as the basis for the design of a randomized prospective trial to evaluate therapy changes based on changes in HER2 status during progression. —Bonnie Gillis

Patients whose HER2 status remained stable HER2– patients who became HER2+ HER2+ patients who became HER2–

6.8% 3.4%

35.9%

66.9%

59.3%

N=459

N=437

89.8%

N=118

Figure. Change in patient ER, PR and HER2 status between primary tumors and tumors at relapse. ER, estrogen receptor; PR, progesterone receptor

In advanced RCC:

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

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

Probability (%)

4.9

1.9

months

Placebo 40

Afinitor 20

Time (months)

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

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

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

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

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

Printed in U.S.A.

10/10

AFI-1002330

AFINITOR

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

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

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

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

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

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

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

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

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

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

Vascular disorders: Hypertension (4%)

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

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

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

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

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

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

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

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

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

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

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

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

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

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

T2010-56

MULTIPLE CANCERS

Clinical Oncology News • April 2011

End-of-life Care

PALLIATIVE continued from page 1 

“Less than 25% of the treatments oncologists give are curative. Palliative chemo is given to extend life, or improve symptoms or quality of life, and hopefully all three together.” And even at the end of life, when drugs may be buying patients little if any more time at all, there may be some benefit. “There is a small body of literature that [says] you may not make people live longer, but you may make them feel better on the chemotherapy,” said David Weissman, MD, a pioneer in hospice and palliative medicine, who until recently served as director of the MCW Palliative Care Center and the Froedtert Hospital Palliative Care Program in Milwaukee. 100

Chemotherapy, %

Last six months of life Last three months of life

Last month of life

60 40

33 23

Figure 1. Percentage of patients given chemotherapy in the last months of life. It’s also true that chemotherapy isn’t always as toxic as it used to be. “The classic perception of losing hair and vomiting incessantly isn’t the case with all treatments,” said Sharon Weinstein, MD, director, pain medicine and palliative care, at the Huntsman Cancer Institute at the University of Utah, Salt Lake City. “Some of this may reflect advances in cancer chemotherapies, not just in effectiveness but in tolerability. In some cases, patients are staying on treatment longer because it is more tolerable, and they may be getting some palliative benefit.” But there comes a time when further chemotherapy not only is useless, it even may be counterproductive. “There’s a very predictable pattern of functional decline in cancer patients in the last two months of life, and when they hit that curve, chemotherapy is largely futile, assuming they’ve never been on it before, and this isn’t a brand-new cancer. If they’ve been through multiple treatments and on treatment they’re still declining, then it’s time to stop,” Dr. Weissman said. The problem is recognizing when that time has come—when the “cure” has become worse than the disease. “Giving chemotherapy to people with poor ECOG [Eastern Cooperative Oncology

Group] performance status [PS] is more likely harmful than beneficial,” Dr. Smith said. “That is, if you are ECOG PS 3—in a bed or chair more than half the time, and the cancer is really interfering with daily living—the NCCN [National Comprehensive Cancer Network] guidelines call for a switch to non–chemo-based palliative care.” But that’s not what’s happening, said Alexi Wright, MD, a gynecologic oncologist and instructor in medicine at Harvard Medical School in Boston, who is researching chemotherapy at the end of life as part of a grant from the National Palliative Care Research Center. “It’s clear that the use of chemotherapy within the last few weeks of life is increasing, even though it’s often painful, burdensome and expensive.” In fact, research into end-of-life care in oncology has found that extensive use of chemotherapy in end-stage cancer can shorten life, rather than extend it. According to Dr. Smith, studies show that patients who use hospice for even a single day live longer than those who have never used hospice. “The best explanation is that—since in the U.S., hospice and chemotherapy are rarely used together—patients who keep getting chemotherapy may be dying earlier due to complications from treatment.” A randomized controlled trial by Temel et al (N Engl J Med 2010;363:733-742, PMID: 20818875) among lung cancer patients at Massachusetts General Hospital supports this theory. Those who were randomized to early palliative care plus usual oncology care lived 2.7 months longer than those who got usual oncology care only (P=0.02). “The palliative care group also had better symptom management and less depression, and the caregivers fared better afterward—maybe because they were prepared, or their loved one died at home rather than in the ICU [intensive care unit], intubated,” Dr. Smith said. These results are consistent with the idea, he noted, that early palliative care and usual oncology care improve medical outcomes, and that continuous chemotherapy worsens them. Chemotherapy usually is incompatible with hospice care, and patients often are forced to choose, Dr. Wright said. “Our research has found that patients who get chemotherapy at the end of life have lower rates of hospice use, and more aggressive care.”

A Cost to Families— And the Health Care System Overly aggressive care at the end of life isn’t just futile and often counterproductive—it’s costly, both to families and to the health care system. (Half of all bankruptcy filings are the result of illness and injury, according to a study in the February 2005 edition of Health Affairs.) Aetna’s Compassionate Care Program, a program that integrates

palliative care services for severely ill cancer patients without giving up any oncology services, “would save about $30 million for every 1,000 Medicare enrollees,” Dr. Smith said. None of this information is particularly new, Dr. Weissman said. “The first study showing the costs of end-of-life chemotherapy to both the patient and the health care system came out more than a decade ago, published by Ezekiel Emanuel [N Engl J Med 1994;330:540-544, PMID: 8302321] when he was at the NIH [National Institutes of Health].” In 2003, an Annals of Internal Medicine article (138:639-643, PMID: 12693886) examined the extent of cancer therapy in Medicare recipients during the latter stages of life. Overall, one-third of patients in the study received chemotherapy in the last six months of life and more than 20% received chemotherapy in the last three months of life (Figure 1). The study did not include any data on the cost or appropriateness of that care. So why has little improved since then? “The forces pushing people to receive treatments are overwhelming. They include everything from the societal view that you can’t ever give up, which is a very big reason people continue on treatments, to family pressure, to the increasing availability of drugs,” Dr. Weissman said. “If there are more drugs available, people feel like there are more options. And then there are financial incentives for oncologists who make more money based on the chemotherapy they [provide]. You have a whole gamut of forces pushing people toward treatment, and there’s very little push in the opposite direction. It’s hard for patients and families to say that it’s time to stop. Oncologists have been very poor at having these discussions.” Indeed, Dr. Wright’s research shows that only about 37% of people with cancer have had such a frank discussion with their oncologist about their options at the end of life (Figure 2). “These are really tough conversations to have,” Dr. Smith acknowledged. “But they need to happen. You’re not telling your patient that you’re giving up, but that it’s time to change goals.”

MD Anderson Pharmacist Describes Gentler Approach At the University of Texas MD Anderson Cancer Center in Houston, patients

who are not yet entirely ready to change goals may find better care in the investigational cancer therapeutics program, launched about five years ago to investigate targeted therapies, with broad Phase I trials aimed at all tumor types. “The patients who come to us have failed all standard-of-care chemotherapies and tried all the Phase II or III research trials [available],” said JoAnn Lim, PharmD, BCOP, clinical pharmacy specialist in the Investigational Cancer Therapeutics, Phase I Department. “They know that we do not expect to cure them but hope to control their disease and prolong their lives, and a lot of the agents we are investigating do not cause the side effects that we see [with] cytotoxic chemotherapies.” For example, the program is now investigating an insulin-like growth factor receptor (IGFR) inhibitor. “The IGFR pathway is implicated in Ewing’s sarcoma, and in our trial of this agent in Ewing’s sarcoma, it’s worked wonderfully. The patients had formerly undergone three to five lines of cytotoxic chemotherapy, and now they have been in remission, some of them for a year or more,” Dr. Lim said. She acknowledged that such impressive results are limited. “We’re more likely to see them in single-point mutations with rare cancers like medullary thyroid carcinoma,” Dr. Lim said. “But we’re also looking hard for targeted agents for other, more prevalent

37%

63%

have discussed

have not discussed

Figure 2. Comparison of patients who have and have not discussed the pros and cons of endof-life chemotherapy.

MULTIPLE CANCERS

Clinical Oncology News • April 2011

End-of-life Care

cancers, and when you come to our department, we’ll run the mutational analyses to fit you into the right investigational drugs for your mutations.” Some patients who come into the Phase I program have accepted their disease and realize that they have progressed despite everything they’ve tried, and are willing to participate in the program knowing that it’s an unknown frontier. Others, Dr. Lim said, “are still in denial. They don’t think they’re end-stage. They think we can cure their cancers. They’re the ones who expect a lot out of trials and may be more disappointed.” Patients do best, she noted, when their initial treating oncologists have had very open communication with them and divulged everything they can. “They let them know step by step what is a second-, third- and fourth-line therapy, and when they are out of options,” Dr. Lin explained. “Then they’re better prepared to make a decision about whether they want to explore an investigational agent or not.”

‘It’s hard for patients and families to say that it’s time to stop. Oncologists have been very poor at having these discussions.’ —David Weissman, MD

when to stop chemotherapy; currently, it is largely consensus-driven. In one positive step, the Huntsman Cancer Institute has initiated a pilot project to examine its data on cancer treatment at the end of life, with the ultimate goal of revising treatment guidelines. “We have preliminary data that we’re reviewing right now to look specifically at what antineoplastic treatments are being given

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Tailoring Therapy in Metastatic Breast Cancer

Where’s the Data? At some point, even investigational therapies have their limits. So how can patients and their doctors recognize when too much is too much? More research and education are needed in this area. Education is key, said Dr. Weissman, who advocates for a change in the way in which oncologists are trained. “People largely practice how they were trained, and our medical education programs are focused on the science at the expense of the art,” he said. “That is changing in some programs. The Medical College of Wisconsin is integrating palliative care into oncology, as are Dana-Farber and the University of California, San Diego. Then there’s the National Cancer Institute’s Oncotalk program for improving communications skills. These are good positive steps, but we’re not nearly where we need to be.” It’s also clear that more research is needed to set appropriate parameters. In an effort to gain further information, the American Society for Clinical Oncology (ASCO) initiated the Quality Oncology Practice Initiative (QOPI), which measures how often people get chemotherapy near the end of their lives. This type of information can help practices make changes. When the University of Michigan began participating in QOPI, they learned that their practice tended to give more end-of-life chemotherapy than community practices in their area. After they got this information, they lowered the percentage of people receiving chemotherapy within two weeks of death dramatically, from 50% to 25%. At this time, experts point out, ASCO’s guidelines do not define a clear minimum benefit for the use of chemotherapy and the NCCN has scant data on

at the end of life and how those decisions are made,” Dr. Weinstein said. “We then want to start establishing decision frameworks, with specific palliative guidelines for the major disease categories, in collaboration with the NCCN.” Having clear guidelines may be just the support that oncologists need when they’re struggling with the decision to stop treatment—and with talking to

their patient about that decision. “I find it gut-wrenching. Stopping therapy in patients who are having progressive disease and really want to continue treatment is a really difficult thing to do,” Dr. Wright said. “You’re looking at an individual patient who has hopes and dreams for the future. It’s hard to stop. But we have to counterbalance that with the research we’ve done showing that physicians, patients and families—with the best intentions in the world—may [bring about] terrible outcomes in the drive to try to treat at all costs.” —Gina Shaw

Novel Clinical Approaches May 21, 2011

Rescheduled

Ballroom • The Rittenhouse Hotel 210 West Rittenhouse Square Philadelphia, PA 9:00 am – 11:30 am Target Audience This activity is designed for oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with breast cancer or metastatic breast cancer. There are no prerequisites for attendees.

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Program Agenda For information about the accreditation of this program, please contact Global at (303) 395-1782 or inquire@globaleducationgroup.com.

This activity is supported by an educational grant from Genentech, Inc.

9:00 am – 10:00 am 10:00 am – 11:20 am 11:20 am – 11:30 am

Registration and Breakfast Educational Session Q&A Session

Continuing Education Credit This activity has been approved for 1.5 AMA PRA Category 1 CreditsTM

Register now for this free 1.5-hour CME breakfast symposium Online: www.mededpre-reg.com/metastaticCME Phone: (866) 408-3732 Fax: (815) 377-2470 Pre-registration is encouraged. Pre-registrant seats will be held until 8:55 am. After this time, available seats wil be filled with on-site registrants. There is no fee to attend this meeting Please print clearly Name

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HEMATOLOGIC DISEASE

Clinical Oncology News • April 2011

Lymphoma

In Follicular Lymphoma ...

PET-CT-negative

PET-CT Is a Powerful Prognostic Tool Orlando, Fla.—Post-treatment assessment of follicular lymphoma (FL) with fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is a far better predictor of progression-free survival (PFS) than conventional assessment, according to a subanalysis of the PRIMA trial presented at the 2010 annual meeting of the American Society of Hematology (ASH). The PRIMA (Primary Rituximab and Maintenance) trial demonstrated that two years of rituximab (Rituxan, Genentech) maintenance therapy after a first-line immunochemotherapy regimen substantially improved PFS in patients with FL who had a high tumor burden. Updated results from PRIMA presented at the ASH 2010 meeting showed that after a median follow-up of 36 months, three-year PFS was 60.3% in the observation arm and 78.6% in the

regimens but were required “hypothesis-generating,” but to have at least a partial the data were impressive response before randomizanonetheless. According to Dr. tion to maintenance therapy Trotman, there was no signifor observation. After a mediicant difference in the hazard an follow-up of 36 months, ratio (HR) for PFS in those the HR for progression in the whose conventional disease Scan for PET-CT maintenance rituximab arm restaging showed a comabstract; instructions was reduced by 45% (HR, plete remission (CR) relative page 7. 0.55; 95% confidence interto those who had a partial remission (PR). If patients were PET- val, 0.44-0.68; P<0.0001). In the subCT negative, they had almost precisely study, the goal was to assess PET-CT as a response-assessment tool. “There has been some skepticism in the past as to the role of PET-CT in FL ‘The inferior survival of post-treatment PET-CT-positive for a variety of reasons,” said Dr. Trotpatients compels us to study a PET response-adapted man. She noted that some researchers approach for follicular lymphoma.’ predicted that heterogeneity in glucose avidity of lesions in this indolent but —Judith Trotman, MBChB, FRACP incurable lymphoma might compromise the ability of PET-CT findings to predict outcomes. Others theorized that the limited capacity of PET-CT to assess the frequent bone marrow involvement in FL also might preclude any capacity to predict disease progression. In 160 patients, 277 PET-CT scans using FDG were obtained at 40 of the centers participating in the PRIMA trial. Of the 120 patients who underwent PET-CT scans at diagnosis, all but one were positive. After treatment, there was a significant correlation between the PET-CT result and conventionrituximab maintenance arm (P<0.0001) the same risk for progression (HR, 1.0; al response assessment, with the pro(abstract 1788). Additionally, the sub- P=0.98). portion of patients with a positive analysis of PRIMA data showed that Despite the impressive ability of PET- PET-CT increasing as the degree of FDG PET-CT is a powerful and inde- CT to predict outcome in this study, the response diminished. For those with pendent prognostic tool (abstract 855). results should not be considered prac- CR, only 8% had a positive PET-CT, but “Patients who are negative on a PET- tice changing because they come from the percentage jumped to 31% in those CT scan can expect a prolonged PFS a substudy, according to John P. Leon- with an unconfirmed CR (CRu), 41% in whether in conventional complete ard, MD, clinical director of the Center those with a PR and 67% in those with remission or partial remission, but for for Lymphoma and Myeloma, Weill Cor- stable disease. those who remain PET-CT positive, FL nell Medical College, New York City. He Regardless of conventional assesscannot be characterized as indolent,” said the results do suggest, however, that ment, PFS at three years was more reported Judith Trotman, MBChB, PET-CT may be useful and prospective than double in patients who were PETFRACP, Department of Hematology, trials should be launched to define how CT negative compared with patients Concord Hospital, University of Syd- PET can be integrated with the prognos- who were PET-CT positive (74% vs. ney, Australia, who presented the sub- tic tools that already have been validat- 32%; P<0.0001). The HR for progresstudy results at ASH. She said that a ed, such as FLIPI. sion in PET-CT positive patients was PET-CT scan was substantially more The PRIMA study, from which the 3.5 (P<0.0001). The median PFS for predictive of progression than either data were drawn, was a multination- those who were PET-CT positive was conventional assessment of remission al Phase III trial designed to compare 19 months, but had not yet been reached or the Follicular Lymphoma Interna- rituximab maintenance (375 mg/m 2 in those who were PET-CT negative every eight weeks) with observation for when investigators assessed the data at tional Prognostic Index (FLIPI). As these data were generated by a two years after any one of three immu- 52 months. substudy in a trial that did not man- nochemotherapy induction regimens. In contrast, the predictive valdate PET-CT in the protocol, Dr. The 1,217 patients who participated ue of conventional assessment indeTrotman characterized them as were not randomized to the induction pendent of PET-CT was limited to

PET-CT-positive

100

P<0.0001

Patients, %

60 40

20 0

Figure. Progressionfree survival at three years.

comparisons between those who did and did not have an objective response. Although the HR for progression was 9.7 (P<0.0001) for stable disease or progressive disease relative to CR or CRu, PR patients had a nonsignificant HR of 1.5 (P=0.33) for progression relative to CR/CRu. “Conventional response assessments can be misleading,” Dr. Trotman reported. “These may lead to false optimism for some PET-positive patients in conventional CR and unwarranted pessimism for many PETnegative patients in PR.” Predictors of a poor PFS on multivariate analysis were PET-CT positivity (HR, 3.1; P<0.0014), use of observation instead of rituximab maintenance (HR, 2.8; P<0.014), or a baseline β2M of 3 or greater (HR, 2.6; P<0.0042). Although the number of deaths on the trial so far has been few, investigators say it is perhaps noteworthy that lymphoma was the cause of all seven of the deaths that occurred in the patients who had a positive PET-CT compared with only one of the three deaths in those who were PET-CT-negative. Importantly, patients in PR as well as CR can be reassured by a PET-CT-negative result. Conversely, Dr. Trotman concluded that “the inferior survival of post-treatment PET-CT-positive patients compels us to study a PET response-adapted approach for follicular lymphoma.” According to Dr. Leonard, more study is needed before the findings are implemented into practice. “This report was based on a subset of patients who underwent PET-CT scanning at the discretion of the treating physician, based on clinical judgment, rather than in a prospectively defined fashion for all patients,” Dr. Leonard said. Therefore, “this study does not currently change the reality that PET-CT is not appropriate for routine clinical use in most situations for follicular lymphoma.” He suggested that a prospective study in which review of PET scans is performed in a uniform fashion according to defined criteria is needed to evaluate whether practice should be changed. —Ted Bosworth

Clinical Oncology News • April 2011

HEMATOLOGIC DISEASE Myeloproliferative Neoplasms

JAK1/JAK2 Inhibitor Ruxolitinib Is a Rising Star Orlando, Fla.—The investigational selective JAK1/JAK2 inhibitor ruxolitinib provided durable clinical benefits in patients with myeloproliferative neoplasms, resolving splenomegaly and obviating the need for phlebotomy, during a recent Phase II study.

(29%) were the most common AEs, with grade 3 thrombocytopenia reported among 6% of patients. Eight treatment-emergent serious AEs were found in five patients, with two patients Scan for JAK discontinuing for AEs that inhibitor abstract; In a presentation at the American achieved at least a 50% reduc- instructions page 7. possibly were related to Society of Hematology annual meeting tion or a reduction to less than treatment (renal tumor, atrial (abstract 313), investigator Srdan Ver- 600,000 as of their last follow-up vis- flutter). Most of the PV patients (82%) stovsek, MD, PhD, reported the results it. Also, 13 of 14 patients with baseline continued on the study after the mediof the study of ruxolitinib (also known platelet counts greater than 1 million an follow-up. Among six patients disas INCB 18424; in development by achieved more than a 50% reduction. continuing treatment, one discontinued Incyte) in patients with advanced poly- Additionally, 65% to 83% of patients because of lack of response and anothcythemia (PV) and essential thrombo- achieved 50% or greater reductions in er was because of disease progression. cythemia (ET). other symptoms (peripheral numbness, Although a downward trend was Patients included in the study had pruritus, bone pain and night sweats). observed in the JAK2V617F allele buran intolerance of or a contraindication The two most common adverse den in PV patients (all patients had to the standard therapy, hydroxyurea, events (AEs) seen in the ET popula- JAK2V617 mutation; four patients expeaccording to Dr. Verstovsek, associate tion were anemia (74%) and weight rienced a >50% decrease in allele burden), clinical response did not correlate with the change in JAK2V617F allele burden. Allele burden for ET patients ‘It’s clear that INCB 18424 has activity, not only in [mycosis was 16% at baseline. The investigators did not report a change in allele burden fungoides], but also in PV and ET. This is quite encouraging for ET patients, but they noted that the and bears further investigation.’ —Harry Erba, MD presence of the JAK2V617 mutation did not correlate with outcomes. “What is important to highlight is that we now know that in these myeloprolifprofessor in the Department of Leu- increase (23%). Dr. Verstovsek noted erative diseases there is more than one kemia at the University of Texas M.D. that in many cases, doses were adjust- mutation that makes the JAK2-STAT Anderson Cancer Center in Houston. ed because of anemia. The only grade pathway hyperactive,” noted Dr. VerPatients with ET (n=39), which is char- 3 event was leukopenia (5%), and no stovsek in a follow-up interview. “Furacterized by clonal proliferation of ery- treatment-related grade 4 AEs were thermore, the JAK2-STAT pathway throid, myeloid and megakaryocyte reported. Hematologic AEs general- is dysregulated in every patient with cell lineages, had platelets greater than ly were reversible, managed with dose a myeloproliferative disorder, regard650 × 109/L unless they were already reduction or temporary interruption. less of the presence of a known mutabeing treated; patients with PV (n=34), Among five reported serious AEs, one tion. So it really doesn’t matter which, which is characterized by megakaryo- was considered possibly related to if any, gene is mutated or how high the cyte hyperplasia and persistent throm- treatment (renal failure) and led to dis- JAK2V617F allele burden is. All patients bocytosis, had hematocrits greater than continuation of therapy. Among the benefit from JAK2-STAT pathway inhi45% or phlebotomy twice in the last 11 patients who discontinued thera- bition,” he said. six months, with at least one phlebot- py (28%), five discontinued because Dr. Verstovsek concluded, “Duraomy in the last three months. The pri- of lack of response and six because of ble clinical benefits have been demonmary treatment goal for patients with other medical reasons (fatigue, weight strated for INCB 18424 in advanced ET ET was platelet count normalization; gain, gastrointestinal disorder, renal and PV patients.” He suggested that the for those with PV, it was normaliza- insufficiency and foot pain). results support further development tion of hematocrit. The majority of ET of this agent in the ET and PV patient patients (65%) and all PV patients were Results for PV Patients populations, and he noted that a Phase In the PV population, at the same III trial in PV—RESPONSE (Randompositive for the dominant gain-of-function V617F mutation in the JH2 kinase- 21-month median follow-up, CRs were ized, Open Label, Multicenter Phase like domain of JAK2. The dose for most reported in 50% of patients and PRs in III Study of Efficacy and Safety in Polyof the ET patients (90%) was 5 to 25 mg 47% (97% OR). Ninety-seven percent of cythemia Vera Subjects Who Are Resistwice daily, whereas the dose for most patients achieved a hematocrit of 45% tant to or Intolerant of Hydroxyurea: of the PV patients (66%) was 5 to 10 mg or less without the use of phlebotomy. JAK Inhibitor INC424 Tablets Versus Most patients with palpable splenomeg- Best Available Care)—is under way. twice daily. aly (68%) achieved complete resolution, Commenting on the findings in an Results for ET Patients and 80% achieved at least a 50% reduc- interview, Harry Erba, MD, associIn the ET population, at a median fol- tion. Reductions in white blood counts ate professor of medicine at Univerlow-up of 21 months, 26% of patients were rapid and durable, and thrombo- sity of Michigan Medical School in achieved complete responses (CRs) cytosis (>600 × 109/L) resolved in 69% Ann Arbor, said, “It’s clear that INCB and 64% achieved partial respons- of patients as of the last follow-up vis- 18424 has activity, not only in [myeloes (PRs), for a 90% overall response it. Pruritus, bone pain and night sweats fibrosis], but also in PV and ET. This (OR) (Figure). Nearly half (49%) of the reported at baseline resolved rapidly is quite encouraging and bears further ET patients achieved normalization of and durably with treatment. investigation.” Anemia (74%) and thrombocytopenia their platelet counts; 79% of patients Dr. Erba further noted that “patients

Complete response rate Partial response rate No response rate

Essential thrombocythemia 90% Overall response rate

64%

26%

10% Advanced polycythemia 97% Overall response rate

50%

47%

3% Figure. Response rates of patients on ruxolitinib at a median of 21 months follow-up.

intolerant of hydroxyurea are often those who develop cytopenias related to therapy. This may be due to progression to a more fibrotic stage of the disease, especially when they have significant amounts of splenomegaly. I’d like to know if the amount of fibrosis, or pretreatment cytokine levels, impacted response to therapy in PV and ET.” In a follow-up response, Dr. Verstovsek said the investigators have not analyzed whether or not cytokine levels correlated with outcome, but they did find that the degree of splenomegaly did not correlate with outcomes. He noted that all patients in the study had high blood cell counts with no cytopenias at study entry and a low degree of fibrosis in the bone. —Walter Alexander

POLICY & MANAGEMENT

Clinical Oncology News • April 2011

Finance

FOUND MONEY continued from page 1 

insurers from Blue Cross Blue Shield to United Healthcare also are getting into the game with the launch of pilot projects designed to test whether monetary incentives for delivering coordinated, quality care can spur a reduction in emergency department (ED) visits and hospitalizations as well as in the overall growth of medical costs. Over the next two issues, as part of its ongoing series on economic survival strategies, Clinical Oncology News will examine the potential benefit of these new models for oncology practices and community cancer centers. This issue focuses on the PCMH, an older concept with a heightened emphasis on quality, cost-effective care delivery that has burst into recent prominence.

A Bargaining Chip in Negotiating Payer Contracts Although PCMHs are primarily the domain of primary care, there is nothing to prevent oncology practices from becoming the core of a provider network overseeing the comprehensive health needs of a patient with cancer. In fact, it makes eminent sense. “The bottom line,” said Ted Okon, MBA, executive director of the Washington, D.C.–based Community Oncology Alliance (COA), “is that cancer is the focus for that patient. Oncology is the gatekeeper and the oncology practice becomes the medical home.” However, oncology groups seeking to achieve the status of a medical home likely will have to put significant effort, time and money into doing so. In Pennsylvania’s suburban Delaware County, for example, a nine-physician group called Consultants in Medical Oncology and Hematology spent years and invested large sums in reengineering its practice and upgrading information technology systems to bring it to the point last year when the National Committee for Quality Assurance (NCQA) recognized it as a level III PCMH—the highest tier. The NCQA recognition has given the practice, which has four locations and an active register of more than 6,000 patients, a strong point of differentiation as it negotiates payer contracts. What also has helped is evidence showing a steady decline in ED visits and hospital admissions among the practice’s patients. From 2004 to 2010, for example, the number of ED evaluations performed at Delaware County Memorial per chemotherapy patient per year for the Drexel Hill office population decreased from 2.6 to less than 1 (Commun Oncol 2010;7:565-572) (Figure). John D. Sprandio, MD, a medical oncologist who is the practice’s lead physician, told Clinical Oncology News that, although progress in contract

talks had been slow, breakthroughs with several national insurers seemed imminent. And, in fact, the practice has landed one medical home–related contract with a Pennsylvania Medicaid HMO. “There is a lot of interest from payers,” Dr. Sprandio said.

Demonstration Projects Dr. Sprandio also is deeply involved in an effort by COA to win support from the Medicare and Medicaid Center for Innovation for a multipractice demonstration pilot project modeled partly on what the Pennsylvania oncology group has been able to achieve as a PCMH. In late February, COA’s board of directors voted unanimously to take a two-pronged approach to creating PCMH-based demonstration projects. One would involve a more focused project for up to a dozen practices that are already well advanced in terms of achieving PCMH standards, according to Mr. Okon. “The second demonstration project would be open to a much wider group of practices at varying levels of sophistication,” he said. “This project would provide a roadmap for them to move to the highest PCMH level. “We’re looking to take the bull by the horns rather than have some policy wonk say this is how you should define what you do in oncology,” said Mr. Okon. “Let the people in actual practice develop the measures and take the lead.” To this end, he said, Dr. Sprandio has been “a real pathfinder in terms of his practice being the first and still only oncology practice to achieve level III recognition from NCQA.” Mr. Okon added that it was “important to understand” that the provision of quality and value is “nothing new for oncology practices. The whole nature of community oncology is built around a quality-efficiency model. We’ve got pretty good outcomes to prove it, including the survival rates of the United States system of [oncology] care versus anywhere else.” But he noted that it is also necessary “to provide a scorecard” showing that “we can increase quality even more, and at

Average ER Evaluations Per Patient Per Year

3 2.60 2.07

2 1.27 0.97

2004

2006

2008

2010

Figure. Average number of emergency room evaluations.a a

Per chemotherapy patient per year at Delaware County Memorial Hospital for the Drexel Hill office population.

‘The Oncology Patient-Centered Medical Home (OPCMH) model of cancer care may potentially serve as a practice framework for oncologists. The OPCMH model attempts to promote a value-based agenda that facilitates physician accountability, encourages clinical integration between like-minded medical oncology groups, enhances communication and coordination of care with primary care PCMH models, and collaborates with payers while maintaining a focus on patient needs and evidence-based care.’ —John D. Sprandio, MD (Commun Oncol 2010;7:565-572) other specialists and we conthe same time provide very tinually measured our perforefficient care.” mance at the physician and Allison Cuff Shimooka, practice level. We made a sciMBA, managing director of the ence out of our performance,” Oncology Roundtable, a unit of Dr. Sprandio said. the Advisory Board Company, Standardization was said that the PCMH developed by Dr. Sprandio’s practice For the first article also a key, he added. “We in the Found Money shows how it is possible series, scan here; standardized the way we to achieve value in cancer instructions page 7. approached things such as delayed chemotherapycare. “Obviously,” she said, oncologists “can’t operate in a vacuum. induced nausea and vomiting. We They need to work closely not only with standardized the way we followed our primary care but also other oncology effectiveness in palliating symptoms as practices to deliver this value from the well as our patients’ performance status point of diagnosis through survivorship. results and utilized these data to form In cancer care, this can be tough, as it the basis for our treatment decisions as is often so fragmented, but the medical well as end-of-life care discussions.” About a year and a half ago, he said, home can serve as a platform to achieve the care coordination we’ve been working “we realized that we met or exceeded all of the requirements for NCQA toward for decades.” recognition,” and six months after Transforming Into a PCMH submitting an application, “we became Dr. Sprandio said the move toward the first hematology/oncology practice PCMH recognition began about seven in the nation to be recognized.” years ago when the practice “made a Dr. Sprandio said that this was not just conscious effort to standardize and a model of care achievable for one unique streamline our processes of care, make practice. “We knew we needed to create our patients and their families the a model that could be replicated and central focus and fix accountability at the extended to other hematology/oncology patient–physician locus. We also made practices,” he said. “We believe that a conscious effort to make clinically we’ve shown that it can be. We are in the relevant, as much as possible, everything process of successfully extending our … that physicians touch, taking away a oncology PCMH-related infrastructure, lot of the tedious stuff—the regulatory processes of care, software systems and precertification issues, a lot of the and data support to similar-sized, likeinteractions with insurance companies.” minded medical oncology practices in At the same time, as the practice began our region.” reengineering its processes of care, At this point, Dr. Sprandio noted, it converted to an electronic medical oncology practices all get paid the same record system, Dr. Sprandio continued, rates, despite the quality level and any “and once we found the deficiencies in cost savings generated. He said it is the system that came out of the box, we going to be important for payers to added software to better manage data encourage the progressive changes that and to streamline physician and patient practices like his are making in the way responsibilities.” care is delivered. “Our … model,” he Dr. Sprandio’s own patient popula- said, “cannot be sustained or effectively tion acted as the laboratory for evaluat- disseminated to other community ing new practice methods, “and as we oncology practices without appropriate saw improvements, we extended [the changes in the existing payment new methods] to the rest of the prac- methodologies.” tice. We focused on enhancing communication, coordination and patient access —Bruce Buckley to care. We assumed case management responsibilities, improved patient education, engaged patients more actively Found Money is a four-part series. and appropriately in their care, produced The third article in the series will run in May ways to track patient compliance in terms and will discuss the promise of accountable of keeping appointments for tests or with care organizations.

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Bernadette F. Rodak Featuring hundreds of full-color photomicrographs, Hematology: Clinical Principles and Applications prepares you for a job in the clinical lab by exploring the essential aspects of hematology. It shows how to accurately identify cells, simplifies hemostasis and thrombosis concepts and covers normal hematopoiesis through diseases of erythroid, myeloid, lymphoid and megakaryocytic origins.

The Md Anderson Manual of Medical Oncology, Second edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller A hands-on desk reference for the practicing oncologist from the leader in the field of cancer management.This manual details the personalized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.

Thalassemia: An issue of Hematology/Oncology Clinics of north America

Bernard G. Forget Topics discussed include the population genetics and dynamimcs of thalassemia, alpha thalassemia, HbE/beta thalassemia, management of iron overload in thalassemia syndromes, allogeneic cellular gene therapy for hemoglobinopathies, cord blood transplantation for beta thalassemia major and gene therapy for hemoglobin disorders.

The Bethesda Handbook of Clinical Oncology

WHO Classification of Tumours of the digestive System (iArC WHO Classification of Tumours)

Jame Abraham; James L. Gulley; Carmen J. Allegra

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The International Agency for Research on Cancer; F. T. Bosman; F. Carneiro; R. H. Hruban; N. D. Theise This authoritative, concise reference book provides an international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design of studies monitoring response to therapy and clinical outcome.

Williams Hematology: eighth edition

Kenneth Kaushansky; Uri Seligsohn; Marshall Lichtman; Thomas Kipps; Josef Prchal This reference guides readers through the origins, pathophysiologic mechanisms and management of benign and malignant disorders of blood cells and coagulation proteins. The book begins with the evaluation of the patient and progresses to the molecular and cellular underpinnings of normal and pathological hematology. Subsequent sections present topics such as disorders of the erythrocyte, granulocytes and monocytes, lymphocytes and plasma cells, among others. CO0411

CLINICAL TRIALS

Clinical Oncology News • April 2011

New Phase II and III Clinical Trials

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to March 15, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Hematologic

Protocol Type

Age

Protocol ID

Trial Sites

Regorafenib Plus FOLFIRI Versus Placebo Plus FOLFIRI as Second-Line Therapy in K-RAS/BRAF Mutant Metastatic Colorectal Cancer, Phase II

18 and over

LCCC 1029

Monoclonal Antibody to OX40, Cyclophosphamide and Radiation in Patients With Progressive Metastatic Prostate Cancer, Phase I/II

18 and over

PH&S IRB 10-088

Panitumumab and Gemcitabine in Relapsed Ovarian Cancer, Phase II

18 and over

WIH 20050782

Trial of Adjuvant FANG Vaccine for High Risk Stage IIIc Ovarian Cancer, Phase II

18 and over

CL-PTL 105

Study Of Oral PHA-848125AC In Patients With Malignant Thymoma Previously Treated With Multiple Lines Of Chemotherapy, Phase II

18 and over

CDKO125a-007

A Safety and Efficacy Study of Patients With Metastatic or Locally Advanced (Unresectable) Chondrosarcoma, Phase II

18 and over

IPI-926-04

Gemcitabine, Oxaliplatin and Panitumumab in Kras/B-raf Wild-Type Biliary Track and Gallbladder Cancer, Phase II

18 and over

UGIH09067

MA, NY

A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With Gastrointestinal Stromal Tumor, Phase II

18 and over

AT13387/0002

A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma, Phase II

18 and over

AV-951-10-202

STEREOtactic Radiation and Chemotherapy in Lung Cancer (STEREO), Phase II

18 and over

BCC-LUN10-STEREO

Maximum Tolerated Dose Study of Belinostat (PXD-101) in Combination With Paclitaxel Plus Carboplatin in Chemotherapy-Naive Patients With Stage IV Non-Small-Cell Lung Cancer (NSCLC), Phase I/II

18 and over

SPI-1014-Bel

Study of Romidepsin and Erlotinib Hydrochloride in Patients With Stage IIIB or IV NSCLC, Phase I/II

18 and over

SCCC-12508

Molecular Profiling and Targeted Therapy for Advanced NSCLC, Small Cell Lung Cancer, and Thymic Malignancies, Phase II

18 and over

110096

MD, OR

Randomized Study of Multipeptide Vaccination Comprising Recombinant MAGE-3.1 Antigen, MART-1 Antigen, gp100 Antigen, and NA17-A2 Peptide Vaccines Emulsified With Montanide ISA-51 With Versus Without Recombinant Interleukin-12 Followed by Daclizumab in Patients With Metastatic Melanoma, Phase II

18 and over

UCCRC-10324-B

Sorafenib and TRC105 in Hepatocellular Cancer, Phase I/II

18 and over

110102

Effects of High Dose Calcitriol in Breast Cancer Patients, Phase II

18 to 88

25741

Carboplatin and Bevacizumab for Recurrent Ependymoma, Phase II

18 and over

CERN09-02

Altered Chemotherapy Sequencing During Neoadjuvant Therapy for Patients With Stage II or III Rectal Adenocarcinoma, Phase I/II

18 and over

STU 082010-335

Prospective Evaluation of a New Covered Metal Stent for Malignant Lesions of the Esophagus, Phase II

18 and over

14989

Panitumumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Advanced Esophageal or Gastroesophageal Junction Cancer, Phase II

19 and over

221-09

Clinical Study of Vorinostat in Combination With Etoposide in Pediatric Patients <21 Years at Diagnosis With Refractory Solid Tumors

4 to 21

10-096

Study of EZN-2208 Pediatric Patients With Solid Tumors, Phase I/II

1 to 21

EZN-2208-05

CO, MA

Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN, Phase II

18 and over

20080645

Amgen 386 for Recurrent Glioblastoma, Phase II

18 and over

00021773

Endoscopic Bipolar Radiofrequency Probe (ENDOHPB) in the Management of Unresectable Bile Duct and Pancreatic Cancer, Phase I/II

18 and over

14865

ABT-888 With Cyclophosphamide in Refractory BRCA-Positive Ovarian, Primary Peritoneal or Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, Triple-Negative Breast Cancer, and Low-Grade Non-Hodgkin’s Lymphoma, Phase II

18 and over

110080

CA, FL, IL, MD, MN, NE, NY, OH, TX

Allo Transplant Followed by Lenalidomide and Sirolimus Maintenance in High-Risk Multiple Myeloma, Phase I/II

18 to 70

1012-24; IUCRO-0307

A Trial of TBL-12 Sea Cucumber Extract in Patients With Untreated Asymptomatic Myeloma, Phase II

18 and over

NYU# 10-02181

AKT Kinase Inhibitor MK-2206 With Relapsed Refractory Acute Myelogenous Leukemia, Phase II

18 and over

2010-0243

Safety and Efficacy Study of CAL-101 in Patients With Previously Untreated Low-grade Lymphoma

18 and over

101-10

SOLID TUMORS

Clinical Oncology News • April 2011

Kidney

DOSING continued from page 1 

Supportive Care

there was a strong trend that suggested that continuous dosing was inferior,” Dr. Motzer said. “That surprised me; I thought they’d look about the same.” The Renal EFFECT trial, a randomized, multicenter study, found no statistically significant differences between the two regimens in terms of time to progression (TTP) (9.9 months for 4/2 vs. 7.1 continuous; P=0.090), overall response rate (32.2% vs. 28.1%; P=0.444) and overall survival (23.1 vs. 23.5 months; P=0.615). There was, however, a nonstatistically significant trend toward inferior TTP and progression-free survival with the continuous dosing regimen; additionally, on a composite score for time to deterioration, the standard 4/2 regimen was statistically superior (4 vs. 2.9 months; P=0.034). “Based on these results, I could not at all recommend continuous dosing over the FDA-approved 4/2 schedule,” said Toni K. Choueiri, MD, director of the Kidney Cancer Program at the DanaFarber Cancer Institute in Boston. Continuous dosing was initially designed and investigated because of concerns about cancer returning during the “two-weeks-off” period of the standard 4/2 schedule. “There had been case reports of tumor rebound in the two weeks off, so the theory was that

‘Based on these results, I could not at all recommend continuous dosing over the FDA-approved 4/2 schedule.’ —Toni K. Choueiri, MD

by maintaining everything quiet with a continuous dosage, you’d have better tumor control long-term,” Dr. Choueiri said. “And it was thought that perhaps you’d have less side effects with at least the same efficacy with a continuous dose at 37.5 mg, because the overall dose is less. Both practically and biologically, these were reasonable thoughts, but now we’ve seen that this is not true.” Bruce Redman, DO, professor of medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said he never thought that tumor rebound was an issue. “Because of the half-life of the drug, you’re really not off treatment for two weeks, pharmacokinetically speaking,” he said. “Yes, if you check for sunitinib and its metabolites a full two weeks after you go off the drug, they’re gone. But for a number of days after going off, they’re still there. “Starting at 37.5 mg continuously is not

the thing to do,” Dr. Redman agreed, but he noted that a number of other schedules for sunitinib are now being studied. “For example, does a schedule of two weeks on, one week off [which is now being studied in at least one Asian trial] have merit? And the question also comes up—after you’ve achieved an initial steady response, what’s the risk of continuing the drug versus letting the patient have a drug-free holiday, following them for evidence of growth, then reinstating therapy at that time?” Anecdotally, Dr. Redman said, he has had patients achieve a major response to sunitinib and then go off therapy for six to eight months before reinstituting the drug. “Nobody is quite sure of the exact way to administer these targeted agents for maximum clinical benefit, which of course includes the toxicity of the agent itself,” Dr. Redman said. “[The] 4/2 [schedule] was chosen

‘There was a strong trend that suggested that continuous dosing was inferior.’

—Robert Motzer, MD

because that’s the way the drug was developed. Trials looking at other comparative dosing regimens may be of some interest. On the other hand, I’d For a renal cell say it’s of more interest to get patients on cancer educational review, scan here. other investigational Instructions page 7. regimens to see what those do.” Dr. Redman still has some patients taking sunitinib who participated in the original trials six years ago. “I don’t think I have anyone beyond a year who’s still on 50 mg 4/2, although some are on 37.5 4/2. I have one patient who’s out more than five years who’s now receiving 37.5 mg on a three-weeks-on, threeweeks-off schedule, and he’s maintaining clinical benefit—although this is a rare case,” he said. “It’s clear that the 4/2 dosing schedule at 50 mg is the one to start with, but it takes a lot of clinical judgment on the part of the physician to figure out what to do after that.” The EFFECT results send an important message, Dr. Motzer said. “Not all dosing schedules are the same. You’re taking a risk if you deviate from a standard, approved schedule, unless you carefully investigate and compare the new strategies in a controlled trial.” —Gina Shaw

Protocol Type

Age

Protocol ID

Trial Sites

Cognitive Behavioral Therapy +/- Armodafinil for Insomnia and Fatigue Following Chemotherapy, Phase II

21 to 75

UCCS07090

NY, PA

Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis, Phase III

18 and over

9766-CL-0104

NY, OH

Isavuconazole in the Treatment of Renally Impaired Aspergillosis and Rare Fungi, Phase III

18 and over

9766-CL-0103

Study of orBec With Prednisone Therapy in the Treatment of Patients With Graft Versus Host Disease, Phase III

18 and over

BDP-GVHD-03

NC, NY, WA

Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease, Phase I/II

18 and over

MCC 15618

Addition of Etanercept and Extracorporeal Photopheresis to Standard Graft-Versus-Host Disease Prophylaxis In Stem Cell Transplant, Phase II

Not specified

umcc 2008.003

The Use of Etanercept Enbrel as Sole Treatment for Grade I Acute Graft Versus Host Disease, Phase III

Any age

UMCC 2007.139

Topical Dexamethasone and Tacrolimus for the Treatment of Oral Chronic Graft-Versus-Host Disease, Phase II

4 to 120

08-027

Alefacept in Subjects With Steroid-Refractory Chronic Graft-versus-Host Disease, Phase II

18 and over

10-10-230230

Maraviroc in Patients Undergoing Non-Myeloablative Allogeneic Stem-Cell Transplantation, Phase I/II

18 and over

UPCC 04708

Bortezomib for the Treatment of Refractory Chronic Graft-vs-Host Disease, Phase II

18 and over

010-037

Cytotoxic T-Lymphocytes for the Prophylaxis of Cytomegalovirus After Allogeneic Stem Cell Transplant, Phase I/II

Not specified

12683-VICTA

NP2 Enkephalin For Treatment of Intractable Cancer Pain, Phase II

18 and over

NP2/P2/10/2

CA, CO, FL, MT, NC, OH

If you have missed any recent issues of Clinical Oncology News, please visit

www.clinicaloncology.com.

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

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

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

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

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

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

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

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

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

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

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

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

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

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

An ALZA STEALTH® Technology Product

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

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

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

INDICATIONS

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

IMPORTANT SAFETY INFORMATION

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

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

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

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

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