Clinical Oncology News - August 2010 - Digital Edition by McMahon Group

A SC H EN O LI TI McMahon Publishing G ON H TS H

Advances in Cancer Care CLINICALONCOLOGY.COM • August 2010 • Vol. 5, No. 8

9 14

Ed Chu, MD, and Ronald Bukowski, MD, highlight colon, kidney, and prostate cancer news from ASCO meeting.

Maurie Markman, MD, weighs in on ovarian cancer news. Maura Dickler, MD, discusses metastatic breast cancer news. FDA NEWS

FDA Advisory Committee votes to remove bevacizumab’s breast cancer indication. New formulation of odansetron available. PRN

Physicians coping with addiction face long road back.

HEMATOLOGIC DISEASE

Nanoparticle vincristine improves outcomes in ALL.

EDUCATIONAL REVIEW

PlatinumSensitive Recurrent Ovarian Cancer After page 16.

WWW.CMEZONE.COM

In Multiple Myeloma ...

Maintenance Therapy After Transplant Improves PFS Chicago—Maintenance therapy with lenalidomide (Revlimid, Celgene) greatly improves progression-free survival (PFS) in patients with multiple myeloma (MM) after autologous stem cell transplantation (ASCT), according to two large, multicenter Phase III trials. The similarity of the outcomes, which are considered to have immediate relevance to clinical practice, was remarkable. In one study, investigators identified a 54% reduction in the risk for PFS (hazard ratio [HR], 0.46; P<0.00000001). The other found a 58% reduction in time to progression (TTP; HR, 0.42; P<0.0001). “We have just heard two of the most practice-changing presentations that see MAINTENANCE, page 26

Drug Combination Improves Survival in Pancreatic Cancer Chicago—Clinicians have a new regimen to consider for the first-line treatment of certain ain patients with metastatic pancreateatic cancer. First-line therapy with ith FOLFIRINOX, a combination of older chemotherapeutic drugs, s, improved median overall survival (OS) of certain patients with pancreatic cancer by four months (11.1 vs. 6.8 months) com-pared with gemcitabine (Gemzar, zar, Eli Lilly). The dramatic news comes mes from a study by French researchers ers presented at the annual meetingg of the American Society of Clinical cal Oncology (abstract 4010). “It has been vanishingly rare for an abstract in pancreas cancer to be practice-changing. This one probably is,” commented Leonard ard Saltz, MD, professor of medicine at see DRUG COMBO, page 18

Studies Challenge Value of Breast Cancer Procedures

Colored scanning electron micrograph of a pancreatic cancer cell. The blebs (nodules) on the cells surface are typical of cancer cells.

POLICY & MANAGEMENT

Chicago—The indications for immunohistochemistry and axillary lymph node dissections in clinically node-negative breast cancer have been narrowed considerably by a series of large studies presented consecutively at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO). These procedures do not appear to be helpful in several populations, if judged by the criterion that interventions are appropriate only if they change outcomes. The studies that generated the data were sufficiently large and well designed that all three were considered to provide practice-changing see CHALLENGED, page 17

Courtesy of CMSP.

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Tool Improves Patient Access to Oncology Drugs in Development Chicago—Oncologists have access to a new tool to help them provide investigational drugs to patients outside of a clinical trial. Designed by the American Society of Clinical Oncology (ASCO) in collaboration with the FDA, three educational modules seek to make regulations more transparent. The aim is to make it easier for physicians to successfully complete an investigational new drug (IND) application intended for treatment rather than for research.

“This is not so much a change in our policies regarding the use of experimental drugs as it is an effort to help physicians understand the requirements and the processes for gaining access to these agents,” explained Richard M. Klein, Office of Health Affairs, FDA, in Silver Spring, Md.

Navigating the Maze The educational modules walk physicians through the step-by-step process of see IND, page 24

McMahonMedicalBooks.com An Update on Pediatric Oncology and Hematology: An Issue of Hematology/ Oncology Clinics of North America Take 5 minutes to take our survey. See page 14

Max J. Coppes; Russell E. Ware; Jeffrey S. Dome

For more information, see page 29

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

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

Important Safety Information for Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities. Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufﬁciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to ALIMTA® is a registered trademark of Eli Lilly and Company. PM61943 0610 PRINTED IN USA © 2010, Lilly USA, LLC. ALL RIGHTS RESERVED.

moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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.

ALIMTA姞 (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, and 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 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 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 Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA 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 regardless of nadir ANC 75% of previous dose (pemetrexed and cisplatin) 50% of previous dose Nadir platelets <50,000/mm3 with bleeding a, 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 Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA and Cisplatin—Neurotoxicity Dose of ALIMTA Dose of Cisplatin (mg/m2) CTC Grade (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% 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. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)]. ALIMTA姞 (pemetrexed for injection)

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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 included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC)—Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropathy-sensory 9 0 12 1 9 0c Taste disturbance 8 0c Dermatology/Skin 21 1c Alopecia 12 0c 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 Whole—febrile neutropenia, infection, pyrexia General Disorders—dehydration Metabolism and Nutrition—increased AST, increased ALT Renal—creatinine clearance decrease, renal failure Special Senses—conjunctivitis Incidence Less than 1% Cardiovascular—arrhythmia General Disorders—chest pain Metabolism and Nutrition—increased GGT Neurology—motor neuropathy ALIMTA姞 (pemetrexed for injection)

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6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal—colitis General Disorders and Administration Site Conditions—edema Injury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously received radiotherapy Respiratory—interstitial pneumonitis 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established. 8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10), and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population. 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姞 (pemetrexed for injection)

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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 B 12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)]. 17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur. 17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. 17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

Literature revised December 1, 2009

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CLINICAL ONCOLOGY NEWS • AUGUST 2010

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Experts Highlight ‘Need-to-Know’ ASCO Meeting News What information do community oncologists need to incorporate into their practice from the recent annual meeting of the American Society of Clinical Oncology (ASCO)? In this column, several Clinical Oncology News advisory board members offer their picks on practice-changing and crucial news regarding breast, colon, prostate, kidney and ovarian cancers. Ed Chu, MD, Discusses Colon Cancer Advances Cetuximab Comes Up Short Cetuximab (Erbitux, Bristol-Myers Squibb) does not improve outcomes

when used in the adjuvant treatment of patients with stage III colon cancer, according to results from the U.S. Intergroup NO147 study (abstract CRA3507). This trial investigated the effect of combining the anti-epidermal growth factor

receptor (EGFR) antibody cetuximab with infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified [m] FOLFOX-6) chemotherapy in the treatment of stage III colon cancer. Based on this study, it is clear that cetuximab

Ed Chu, MD Chief, Section of Medical Oncology Professor of Medicine and Pharmacology Deputy Director of Clinical Research Yale Cancer Center Yale University New Haven, Conn.

cannot be used as adjuvant therapy outside the context of a clinical trial. Researchers initially set out to randomize 2,300 patients to receive mFOLFOX6 or the combination of mFOLFOX6 plus cetuximab. When it became clear, however, that the efficacy of anti-EGFR antibody therapy was closely linked to KRAS status, the study was amended to enroll only patients with wild-type KRAS with a new target enrollment of more than 3,700 patients. The primary end point of the study was disease-free survival (DFS) with the secondary end points being overall survival (OS) and safety profile.

Based on this study, it is clear that cetuximab cannot be used as adjuvant therapy outside the context of a clinical trial.

(Stimulating Targeted Antigenic Responses To NSCLC) In terms of DFS, patients did not benefit from the addition of cetuximab to mFOLFOX6 chemotherapy. Of note, three-year DFS was significantly worse in patients older than 70 years of age who received the combination of mFOLFOX6 plus cetuximab. Although it is still early in follow-up, no significant difference in threeyear OS rates was identified. This study is disappointing, as it showed no benefit of adding cetuximab to FOLFOX chemotherapy in patients with resected stage III KRAS-wild type colon cancer. The PETACC-8 (PanEuropean Trials in Alimentary Tract Cancer) trial is similar in design to the NO147 study except that the FOLFOX4 regimen was used instead of mFOLFOX6. This study has completed enrollment, and the clinical efficacy results are eagerly awaited.

Maintenance With Single-Agent Bevacizumab Shows Promise Clinicians can consider using maintenance therapy with single-agent bevacizumab (Bev; Avastin, Genentech) following induction therapy with XELOX (capecitabine [CAP; Xeloda, Roche] plus oxaliplatin [Eloxatine, Sanofiaventis])/Bev in patients with metastatic colorectal cancer (mCRC), according to a new study.

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

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Figure 1. Comparison of treatment-related grade 3/4 adverse events.

Over the past five years, significant efforts have focused on identifying the optimal treatment approach for patients with mCRC. A key issue has centered on whether patients should be treated continuously or with a stop-and-go strategy and/or whether an optimal maintenance therapy exists. Tabernero and colleagues from the Spanish Cooperative Group for the Treatment of Digestive Disease addressed the maintenance issue in their randomized Phase III trial of first-line XELOX plus Bev for six cycles followed by XELOX/Bev or single-agent Bev as maintenance therapy in patients with previously untreated mCRC (abstract 3501). The primary end point of this study was progression-free survival (PFS), with OS, overall response rate (ORR), time to tumor response and safety as secondary end points. The study had a noninferiority design. Not surprisingly, the use of XELOX/Bev as maintenance therapy was associated with a higher incidence of grade 3/4 toxicities when compared with single-agent Bev (Figure 1). Of note, no unexpected side effects were observed with maintenance Bev. In terms of clinical efficacy, median PFS was 10.4 months for patients randomized to XELOX/Bev and 9.7 months for those receiving single-agent Bev, but this difference was not statistically significant (hazard ratio [HR], 1.11). The median OS also was similar between the two arms (23.4 months for XELOX/ Bev and 21.7 months for Bev alone; HR, 104). Again, the difference was not statistically significant. This study is interesting because it suggests that maintenance therapy with single-agent Bev may be a reasonable treatment option following induction with XELOX/Bev in patients with mCRC. Clearly, further studies are warranted to confirm these results. Moreover, it will be important to determine the true role of Bev as maintenance therapy when compared with other approaches. Alternate approaches include single-agent CAP or 5-FU and leucovorin (5-FU/ LV) plus or minus Bev as well as the

combination of Bev and erlotinib (Tarceva, OSI/Genentech) and other regimens that incorporate only targeted agents with no cytotoxic agents. Further work also is needed to identify the particular subset of patients who can truly benefit from the incorporation of maintenance therapy, as it is unclear as to whether all patients with mCRC need to be treated with such an approach.

Regimens Tested in Elderly A study presented at ASCO adds to the growing body of evidence that elderly patients can indeed derive clinical benefit from combination chemotherapy in

The findings from the NO16968 study are in sharp contrast to those of the MOSAIC trial and the ACCENT analysis, as they clearly document the benefits of XELOX adjuvant chemotherapy in the elderly population.

the adjuvant setting. The study revealed that some patients may benefit from

XELOX in this setting. With more older patients being diagnosed with colon cancer, much attention in recent years has focused on whether this population derives clinical benefit from adjuvant chemotherapy in the treatment of early-stage disease or chemotherapy in the treatment of advanced, metastatic disease. In 2001, Sargent et al conducted a pooled analysis that showed that older patients derived clinical benefit from adjuvant 5-FU/LV when compared with surgery alone. The X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) trial showed that older see ASCO NEWS, page 8

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

Colon

ASCO NEWS

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patients, defined as patients 70 years or older, benefited from CAP when compared with 5-FU/LV therapy. At the 2009 ASCO meeting, however, McCleary et al presented the results of the ACCENT (Adjuvant Colon Cancer Endpoints) database analysis that suggested that the significant benefits seen in younger patients from the newer adjuvant regimens with oxaliplatin-based chemotherapy compared with 5-FU/LV monotherapy were not seen in patients 70 years or older. One of the unfortunate conclusions drawn from this analysis was that elderly patients should not receive adjuvant chemotherapy. With this in mind, Haller and colleagues (abstract 3521) performed a subgroup analysis of the NO16968 XELOXA randomized Phase III trial with a specific look at efficacy outcomes according to age. This study randomized patients

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Figure 2. Disease-free survival at five years in patients with stage III colon cancer.

with stage III colon cancer to receive adjuvant therapy with bolus 5-FU/LV, as administered by either the Mayo Clinic or the Roswell Park regimen, or XELOX.

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Figure 3. Comparison of adverse events in patients receiving XELOX.

As was initially reported by Haller et al at the 2009 joint Congress of the European Cancer Organisation and Congress of the European Society for Medical Oncology meeting, this was a positive study, in that treatment with XELOX resulted in a significant improvement in DFS and relapse-free survival when compared

with 5-FU/LV with a trend toward superior OS. The DFS at five years was 66.1% in the XELOX arm compared with 59.8% in the 5-FU/LV arm (P=0.0045; Figure 2). Based on this study, the XELOX regimen was approved in Europe in March 2010 as a standard adjuvant therapy for stage III colon cancer and also has been

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

Colon\Ovarian

New Agent on the Horizon A novel agent, perifosine (Keryx), is showing promise as a potential treatment for mCRC. The drug, an oral alkylphospholipid small molecule, has been shown to accumulate selectively in tumor cells when compared with normal cells and inhibits multiple key signaling pathways, including AKT and nuclear factor (NF)-ÎşB. It also has been shown to activate various apoptotic pathways, such as that mediated by c-Jun N-terminal kinases. Additional preclinical data has revealed that perifosine can reverse fluoropyrimidine resistance mediated by the NF-ÎşB signaling pathway. At ASCO, Richards et al (abstract 3531) presented the final results of a randomized Phase II study of perifosine in combination with capecitabine (P-CAP) compared with placebo plus CAP in patients with second- or third-line mCRC. Overall, nearly 90% of patients enrolled in this study had been heavily pretreated, receiving three or more prior lines of therapy. In terms of safety profile, the P-CAP was well tolerated and no significant differences in toxicity were observed between the two arms of the study except for a higher incidence of handâ&#x20AC;&#x201C;foot syndrome and anemia in patients receiving P-CAP combination versus CAP alone. There was nearly a twofold increase in ORR in patients randomized to receive P-CAP when compared with CAP alone. The

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Figure 4. Comparison of overall survival in mCRC.

combination also resulted in a significant improvement in time to progression (28 vs. 11 weeks; P=0.0012; HR, 0.28) and OS (17.7 vs. 10.9 months; P=0.016; HR, 0.41) (Figure 4). This study shows that P-CAP is a safe and active combination regimen in patients with 5-FUâ&#x20AC;&#x201C;refractory disease. Based on the results of this study, the X-PECT (Xeloda + Perifosine Evaluation in Colorectal cancer Treatment) randomized Phase III trial recently has been opened comparing P-CAP with CAP in patients with refractory mCRC. A total of 430 patients are targeted for enrollment, and the primary end point is OS with secondary end points of PFS, ORR, and safety.

Data Supports XELIRI Plus Bev as a Standard Treatment The combination of XELIRI (CAP plus irinotecan [Camptosar, Pfizer]) and Bev is a safe and effective regimen that should be viewed as a standard treatment option in the first-line therapy of mCRC, according to results from two clinical trials conducted in Greece. The studies add to the growing evidence supporting this approach. The two randomized Phase III studies investigated the efficacy and safety of Bev in combination with FOLFIRI (5-FU, folinic acid and irinotecan) or XELIRI chemotherapy in patients with mCRC. Of note, the study by Pectasides et al (abstract 3541), which was conducted under the auspices of the Hellenic Cooperative Oncology Group (HeCOG), used a dose of irinotecan at 240 mg/m2, whereas the study conducted by Ziras et al (abstract 3542) used a dose of 250 mg/ m2. This latter dose of 250 mg/m2 was the same used in the BICC-C (Bolus, Infusional, or Capecitabine with CamptosarCelecoxib) and EORTC (European Organization for Research and Treatment of Cancer) 40015 studies. Significant grade 3/4 toxicities were observed with XELIRI in these two studies. In general, both combination regimens were well tolerated with manageable

safety profiles. Specifically, the incidence of grade 3/4 toxicities was comparable between the FOLFIRI/Bev and XELIRI/Bev arms of both studies. In the HeCOG study, the clinical efficacy of XELIRI plus Bev and FOLFIRI plus Bev were nearly identical in terms of ORR (38% and 40%) and median PFS (14.6 and 15.8 months). Although there was a difference in OS, 20 and 26.2 months for XELIRI and FOLFIRI, respectively, this was not statistically significant. In the study by Ziras et al, ORRs (40.7% [XELIRI] and 40.4%), PFS (10.1 [XELIRI] and 10.5 months), and OS (29.9 [XELERI] and 27.9 months) were nearly identical between the two arms and did not reach statistical significance. It must be emphasized that both studies were not sufficiently powered to look for differences in survival, nor were the subsequent chemotherapy regimens that were used in patients stated in the analysis. These two studies provide further evidence supporting the clinical efficacy of the XELIRI/Bev regimen as front-line treatment of mCRC. Although the safety profiles were manageable at even the higher dose of 250 mg/m2 of irinotecan, one needs to carefully consider the dose and schedule of CAP and irinotecan when using the XELIRI regimen.

Maurie Markman, MD, Weighs in on Ovarian Cancer News From ASCO Maurie Markman, MD Vice President for Clinical Research University of Texas M.D. Anderson Cancer Center Houston, Texas

Bevacizumab Improves PFS The preliminary results of the Phase III randomized trial of 1,873 women evaluating the addition of bevacizumab to primary treatment of advanced ovarian cancer are important and likely will lead many oncologists and patients to consider the use of this agent in the clinical setting. The drug appeared to be reasonably safe when initiated during the second cycle of chemotherapy, and the use of maintenance bevacizumab resulted in patients with a statistically significant improvement in median PFS compared with patients who received chemotherapy alone, 10.3 versus 14.1 months (HR, 0.717; P<0.0001; Figure 5). Data regarding the potential impact of this strategy on overall survival will be of considerable interest, but will not be available for some time. Patients receiving chemotherapy alone received IV carboplatin with an area

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incorporated into the National Comprehensive Cancer Network guidelines. In the analysis presented by Haller et al at this yearâ&#x20AC;&#x2122;s ASCO meeting, investigators assessed the safety profile according to age as well as the treatment effects of XELOX versus 5-FU/LV in patients 65 years and older and patients 70 years and older. They observed that patients older than 70 years of age experienced a higher incidence of grade 3/4 toxicities, but did not identify an appreciable difference between the XELOX and 5-FU/ LV arms (Figure 3). With respect to DFS, the efficacy of XELOX was maintained in patients 65 years or older as well as 70 years or older. Efficacy in the elderly subgroups was achieved despite decreased treatment duration and dose intensity. The findings from the NO16968 study are in sharp contrast to those of the MOSAIC (Multi-center International Study of Oxaliplatin/5-fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer) trial and the ACCENT analysis, as they clearly document the benefits of XELOX adjuvant chemotherapy in the elderly population. Although age certainly is an important factor that must be taken into account when a particular treatment is being considered, age within the context of overall performance status and presence of comorbid illnesses is probably the more critical issue to consider.

Figure 5. Comparison of median PFS in patients with ovarian cancer. PFS, progression-free survival

under the curve of 6 and paclitaxel at 175 mg/m2 plus concurrent placebo and placebo maintenance therapy. Patients who had a PFS of 14.1 months received standard chemotherapy plus concurrent bevacizumab at 15 mg/kg, followed by maintenance with bevacizumab 15 mg/kg. No statistically significant difference in PFS was found between patients who received standard chemotherapy and patients who received standard chemotherapy and concurrent bevacizumab with placebo maintenance therapy. (For a more detailed analysis of this study, please see the July issue of Clinical Oncology News, page 10.)

Standard of Care Remains Carboplatin Plus Paclitaxel It is difficult to draw any definitive conclusions from the Phase III trial comparing paclitaxel/carboplatin (TC) to gemcitabine (Gemzar, Eli Lilly)/carboplatin (GC) in patients with advanced ovarian cancer other than to state the standard of care remains TC (abstract LBA 5008). The GC regimen offered no advantage. PFS was 20 months for GC and 22.2 months for TC, but this was not statistically significant (P=0.199). The study also tested the effect of elective maintenance paclitaxel, and although the data are of interest, this was not a randomized component of the trial. Subset analysis suggested that OS may be improved for patients receiving consolidation with paclitaxel after achieving a complete response (CR); median OS was 65.6 months with consolidation compared with 48.4 months without (P=0.041). The data suggest the potential relevance of paclitaxel maintenance and emphasize the importance of the completion of the ongoing GOG212 (Gynecologic Oncology Group) study. GOG212 specifically examines the impact of maintenance taxanes in women with advanced ovarian cancer who see ASCO NEWS, page 10

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

Kidney\Prostate

continued from page 9

achieve a clinical CR, following primary platinum-taxane based chemotherapy. In the study presented at the ASCO meeting, patients were randomized to gemcitabine 1,000 mg/m2 on days 1 and 8, plus carboplatin (area under the curve [AUC]=5) on day 1 or to paclitaxel 175 mg/m2 plus carboplatin (AUC=6) on day 1 for a total of six 21-day cycles. Patients with a CR could receive consolidation with paclitaxel 135 mg/m2 every 28 days for 12 cycles. Patients who did not achieve a CR received single-agent crossover therapy (crossover with paclitaxel 175 mg/m2 on day 1 or crossover with gemcitabine 1,000 mg/ m2 on days 1 and 8) every 21 days until CR or progressive disease. Responses to induction therapy were similar between treatments, and response rates were similar among crossover patients.

Ronald Bukowski, MD, Discusses Kidney and Prostate Cancer News Ronald M. Bukowski, MD Director of Experimental Therapeutics Program Taussig Cancer Center Cleveland Clinic Foundation Cleveland, Ohio

Markers, Markers Everywhere

For the first time in five years, there were no Phase III trial results present- SELECT and Kidney Cancer ed at the annual ASCO meeting demonFinally, McDermott and colleagues strating the effectiveness of a new agent summarized the results of the multior regimen in patients with metastatic institutional SELECT trial in which 120 renal cell carcinoma (RCC). The reports patients with metastatic RCC were of interest this year analyzed mark- treated with high-dose IL-2 (abstract ers that are associated with outcome 4514). The patients treated were eligiand thus help advance personalized ble for high-dose IL-2, had predomiapproaches to RCC patient therapy. nantly clear cell histology (96%) and Rini and colleagues reported a poten- Memorial Sloanâ&#x20AC;&#x201C;Kettering Cancer Centially important analysis of prognostic ter intermediate risk disease (71%) and genomic markers in 942 patients with prior nephrectomy (99%). The ORR was stage I to III clear cell carcinoma fol- 28%, with a 6% CR rate and median PFS lowing nephrectomy (abstract 4501). of 4.4 months. They extracted RNA from paraffin secThe interesting portion of this tions of tumor, quantified presentation was the inRNA expression for 732 vestigation of immunoGenes genes using reverse transtaining for carbonic anhyassociated scription-polymerase chain drase IX (CAIX) expression with RCC reaction and correlated the in tumors and its relation results with recurrenceto response. It was previrecurrence free interval (RFI) using a ously reported that high KDR Cox proportional hazards CAIX staining (>85%) model. They selected 72 was associated with an EMNC genes for further analysis, improved outcome and CD8A and 20 genes were associathigher response rate. CX3CL 1 ed with RFI. These includHowever, in this trial, in CXCL 10 ed gene groups involved in the group with high CAIX angiogenesis, the immune staining (>85%), the ORR

was 23%, and in the low CAIX staining group (â&#x2030;¤85%), it was 338%. In summary, this prospective trial failed to validate previous retrospective studies suggesting ret high CAIX expression in tumor hi cells identifies patients more likely to respond to IL-2.

Treatment Approaches in Prostate Cancer Tested In the ASCO meeting sessions dealing with prostate cancer, noteworthy presentations included data from two recently completed Phase III trials investigating systemic therapy approaches for metastatic castrationresistant prostate cancer (mCRPC). De Bono and colleagues reported the results of the TROPIC trial in which 755 patients with mCRPC who developed progressive disease following docetaxel therapy were randomized to either cabazitaxel (Jevtana, Sanofi-aventis; 25 mg/m2 IV every three weeks) or mitoxantrone (12 mg/ m2 IV every three weeks), with prednisone (10 mg per day; abstract 4508)

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response, cell adhesion and the cell cycle. Based on this, the authors then proposed a scheme of molecular stratification in which a low risk for recurrence is associated with increased expression of angiogenesis genes (KDR, EMNC) and genes associated with a cellmediated cytotoxic response (CD8A, CX3CL 1, CXCL 10), whereas a high risk for recurrence is associated with increased expression of genes involved with immune response (interleukin [IL]6, IL-8), the cell cycle (TPX2, BUB1) and invasion (MMP14, LAMB1). These data now will be validated on independent patient cohorts and used to develop a multigene algorithm to predict risk for recurrence. In the future, this type of approach can be used to identify patients who could benefit from targeted therapy for metastatic disease. In a second study, Ball and colleagues investigated the association of germ-line genetic markers for IL-8, HIF1A, vascular endothelial growth factor (VEGF) A and VEGFR2 with treatment response to pazopanib (Votrient, GlaxoSmithKline; abstract 4520). The investigators evaluated 40 polymorphisms in 20 candidate genes in 370 patients treated with pazopanib in recently reported Phase II and III clinical trials. They identified several polymorphisms associated with either decreased PFS (IL-8 +2767 TT), decreased response rate (HIF1A +1790AG) or increased blood pressure (VEGFR2, VEGFA). The authors suggest these associations are exploratory and require confirmation in an independent data set.

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In patients who developed progressive disease following docetaxel therapy

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This prospective trial failed to validate previous retrospective studies suggesting high CAIX expression in tumor cells identifies patients more likely to respond to IL-2.

(Figure 6). Patients receiving cabazitaxel and prednisone had significantly longer median survival (15.1 vs 12.7 months; HR, 0.72; 95% confidence interval, 0.61-0.84; P<0.0001), as well as significant improvement in PFS, time to progression, and investigatorassessed response rates (14.4% vs 4.4%; P=0.0005). The most frequent toxicity associated with cabazitaxel therapy was grade 3 or higher neutropenia (81.7%), with a 7.5% rate of febrile neutropenia. These results show cabazitaxel to be a novel taxoid compound that represents a new alternative for mCRPC patients who progress after docetaxel therapy. Based on these results, the FDA approved the drug for second-line treatment of mCRPC in men who have already been treated with docetaxel. In contrast to these results, Scher and colleagues reported negative survival results from the ASCENT-2 (Androgen-independent prostate cancer Study of Calcitriol ENhancing Taxotere) trial (abstract 4509). Previous Phase II studies had suggested that high-dose calcitriol plus docetaxel may increase survival in mCRPC patients compared with chemotherapy alone (J Clin Oncol 2007;25:669-674, PMID: 17308271). ASCENT-2 was designed to test this hypothesis. The Phase III trial randomized 953 chemotherapy-naĂŻve men with mCRPC to docetaxel (36 mg/m2 IV on days 2, 8 and 15), calcitriol (45 mcg, days 1, 7 and 14) and dexamethasone (24 mg weekly for three of four weeks), or docetaxel (75 mg/m2 IV every three weeks), prednisone (10 mg per day) and dexamethasone (24 mg every three weeks). The group receiving weekly docetaxel plus calcitriol had a median survival of 16.8 months compared with 19.9 months for the docetaxel plus prednisone group (Figure 7; P=0.002). The authors suggest the inferior survival in the group receiving calcitriol in part may be secondary to the use of weekly docetaxel regimen in this group, rather than the every 3 weeks regimen.

Predicting Prostate Cancer Outcomes The other prostate cancer studies that were noteworthy focused on see ASCO NEWS, page 14

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

To reach beyond convention…

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

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

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www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. 1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

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In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Speciﬁc Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Speciﬁc Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with and resolved without medical intervention. Grade 1 or 2 hemorrhagic gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy following a venous thromboembolic event. Among these patients, an additional The overall incidence of Grade 3–4 venous thromboembolic events in following Grade 3–4 venous thromboembolic events was higher in intra-abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving presented in Table 1.

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

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

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

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

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

2% 1%

7% 6%

4% 1%

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

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%). Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2). Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all

ODAC Votes To Remove Avastin’s Breast Indication

AVASTIN® (bevacizumab)

patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3. Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

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

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

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

24%

19%

25%

14%

18% 1%

27% 16%

75%

84%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving α) plus Avastin compared to 304 patients receiving α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving α α plus placebo arm are presented in Table 4. Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 α α + Placebo) Preferred term* Gastrointestinal disorders Diarrhea General disorders and administration site conditions

α (n = 304) 16%

α + Avastin (n = 337)

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of speciﬁc gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

21%

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

reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia

31%

36%

14% 6%

19% 12%

16%

24%

20%

4% 0%

27% 5%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the α α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients. Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Manufactured by: Genentech, Inc. 94080-4990

evacizumab (Avastin, Genentech) is likely to lose its breast cancer indication if the FDA follows the advice of its Oncologic Drugs Advisory Committee (ODAC). In late July, the ODAC voted 12 to 1 to remove bevacizumab’s indication as a first-line treatment for metastatic breast cancer (MBC). Committee members argued that although the drug has been shown to increase progression-free survival (PFS), it has not been shown to increase overall survival (OS) in this patient population and is associated with increased toxicity. The FDA is not required to follow advisory committee recommendations, although it does so more often than not.

In February 2008, bevacizumab was granted accelerated marketing approval in combination with paclitaxel chemotherapy for patients who have not received chemotherapy for HER2-negative MBC. The FDA approved the drug on the basis of a trial that showed that adding bevacizumab to paclitaxel increased PFS by roughly five months. Since then, clinical trials such as AVADO and RIBBON-1 have shown that adding bevacizumab to chemotherapy in the first-line treatment of MBC provides statistically significant improvement in PFS, but not OS. “I am a bit perplexed by the ODAC recommendation, and suspect that ‘the elephant in the kitchen’—an important and especially relevant one in today’s health care environment— is COST and cost-effectiveness, rather than the purported balance of efficacy and toxicity of bevacizumab when added to chemotherapy,” said Andrew D. Seidman, MD, a breast cancer expert and advisory board member of Clinical Oncology News. “Consistent benefits in prolonging TTP in the first- and secondline setting, especially in the setting of generally well-tolerated regimens such as weekly paclitaxel or capecitabine, means progress and clinical benefit for patients with metastatic breast cancer, to this clinician.”

New Formulation of Odansetron

he FDA has approved an oral soluble film formulation of odansetron (Zuplenz, Strativa) for the prevention of postoperative nausea and vomiting caused by highly and moderately emetogenic cancer chemotherapy and radiotherapy. According to Strativa, this is the first oral soluble film approved by the FDA as a prescription medication. Approval was granted based on clinical study data comparing the bioequivalence of 8 mg of Zuplenz with 8 mg of Zofran ODT (orally dissolving tablet). The pharmacokinetic results of these studies demonstrated that a single dose of Zuplenz, taken with or without water and under fed and fasting conditions, was comparable with Zofran ODT.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

Prostate\Breast

ASCO NEWS continued from page 10

potential approaches for developing patient-specific approaches to predict outcomes. A series of studies investigating various molecular or genetic markers that may predict outcomes for prostate cancer patients were presented. Ayala et al used immunostaining of tissue microarrays in 640 prostate cancer specimens for a variety of biomarkers (abstract 4500). The results suggest the tumor microenvironment may be â&#x20AC;&#x153;pro-tumorigenicâ&#x20AC;? and potentially represent genetic variability in the host. Markers that were independent predictors of prostate cancer-specific death included reactive stroma grading, perineural invasion diameter, and proteasomes reactivator REGÎł in non-neoplastic tissues. The results suggest the host response may be a critical determinant of outcome.

A second study reported by Gallagher and colleagues examined the association between 29 single-nucleotide polymorphisms (SNPs) and prostate cancer-specific survival in 798 men of Ashkenazi Jewish ancestry treated for localized prostate cancer (abstract 4503). Several prostate cancer susceptibility SNPs (KLK2, KLK3, 7JAZF1) were associated with survival and/or biochemical recurrence. Both groups note that additional studies are now required but suggest that refinement of prognostic models incorporating genetic or molecular biomarkers may be possible.

Maura Dickler, MD, Highlights Metastatic Breast Cancer News Maura Dickler, MD Attending Physician Breast Cancer Medicine Service Memorial SloanKettering Cancer Center New York, N.Y.

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Eribulin Improves Survival The randomized, Phase III EMBRACE trial establishes eribulin mesylate (Eisai) as a new and effective treatment for women with heavily pretreated, metastatic breast cancer (MBC; abstract CRA1004). Twelves et al reported this trial, which compared outcomes in patients receiving eribulin mesylate with a control arm in which patients received a physicianâ&#x20AC;&#x2122;s choice of monotherapy, either chemotherapy, endocrine therapy, biologic therapy or supportive care. Eribulin mesylate is a synthetic analogue of Halichondrin B, derived from a sea sponge identified off the coast of Japan. This antineoplastic agent targets microtubules at a different site than the taxanes and inhibits the lengthening of the microtubule assembly. The study randomized 762 women with heavily pretreated, locally advanced breast cancer or MBC after progression on at least two and up to five prior chemotherapy regimens (including an anthracycline or taxane). The median number of prior chemotherapies was four. The majority of patients in the control arm received chemotherapy (96%). In this heavily pretreated population of patients, eribulin improved the primary end point of OS from 10.65 to 13.12 months (P=0.041). Eribulin also increased PFS (2.2 to 3.7 months), however this difference was not statistically significant. Eribulin was well tolerated,

Figure 8. Comparison of overall survival in metastatic breast cancer. with a slight increase in neutropenia, neutropenic fever and neuropathy over the control arm. This is the first study to show an OS advantage in a heavily pretreated population of patients with MBC. The investigators should be applauded for their daring but â&#x20AC;&#x153;real-worldâ&#x20AC;? design with physician choice of treatment in the control arm. We anxiously await more data and future studies with this agent. [For additional reporting on this story, please see the July issue of Clinical Oncology News, page 8.]

Sunitinib Fails To Improve Outcomes This year, two presentations of randomized trials evaluating chemotherapy with or without sunitinib (Sutent, Pfizer) for advanced-stage disease revealed that the drug did not improve outcomes. The data adds to the growing body of negative studies for the chemotherapy plus sunitinib combination in advanced-stage breast cancer. This regimen should not be offered as treatment in this setting. Sunitinib is a multitargeted tyrosine kinase inhibitor that previously has demonstrated modest single-agent

Take five minutes to fill out our short reader survey online at www.clinicaloncology.com and be entered into a drawing to win a $300 gift card from American Express. The survey can also be found in the back of the ovarian cancer educational review in this issue, see page 16. We appreciate your feedback, and you will also be helping us improve Clinical Oncology News.

activity in one Phase II trial in heavily pretreated patients with MBC. Bergh et al (LBA1010) reported a multicenter randomized study of docetaxel (Taxotere, Sanofi-aventis) with or without sunitinib in the first-line setting, and despite an increased response rate in the docetaxel plus sunitinib arm, there was no improvement in PFS (primary end point) or OS. Crown et al. (LBA1011) reported a randomized study of capecitabine (Xeloda, Roche) with or without sunitinib in a large multicenter study after progression on one to two prior regimens. Unfortunately, the capecitabine plus sunitinib combination was no better than capecitabine alone, with similar PFS and OS. In both studies, patients receiving combination therapy had more grade 3/4 toxicities.

Bevacizumab Disappoints A meta-analysis of prior first-line trials of bevacizumab plus chemotherapy in patients with MBC shows that adding bevacizumab provides a benefit in PFS, but not OS. Oâ&#x20AC;&#x2122;Shaughnessy et al. (abstract 1006) reported a meta-analysis of three first-line randomized studies of chemotherapy with or without bevacizumab in patients with MBC. In all three studies (E2100, AVADO and RIBBON-1) and in this pooled analysis, a statistically significant improvement in PFS was identified. In the pooled analysis, however, there was no benefit in OS, making an improvement in OS unlikely in any future analysis of first-line bevacizumab-containing studies. The validity of PFS as a surrogate for OS is still hotly debated, and it is disappointing that bevacizumab has not been shown to improve OS. Given the cost of this agent and associated toxicity (hypertension, headache etc), the lack of improvement in OS is likely to affect the use of this agent. The need for biomarkers that are predictive of response to antivascular endothelial growth factor therapy is of paramount importance to identify those patients who are most likely to benefit from these therapies.

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work

FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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500,000 PATIENT YEARS

UNIQUE METABOLISM

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Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a signiÀcant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical proÀle EfÀcacy comparable to tamoxifen in head to head trials Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor ﬂare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2004. Data on ﬁle, GTx, Inc.

Please see full prescribing information on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

and the molecular formula is C26H28 H O . The molecular weight of toremifene citrate is 598.10. 6 8 7 The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h. Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin. Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied. Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed. CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 1 2 14+33 11+30 7+25 3+28 19+48 19+56 CR + PR RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of

22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

signiﬁcant age-related differences in FARESTON effectiveness or safety were noted. Race: Fourteen percent of patients in the North American Study were non-Caucasian. No signiﬁcant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reﬂects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug. WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis). Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/ day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly. There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended. Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum. Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice. Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses. Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks. Pregnancy: Pregnancy Category D: (see WARNINGS). Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS). Pediatric use: There is no indication for use of FARESTON in pediatric patients. Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below. Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/ dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from heat and light.

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Chemotherapy Options in the Management of

Platinum-Sensitive Recurrent Ovarian Cancer MARCELA G. DEL CARMEN, MD, MPH Associate Professor of OB-GYN and Reproductive Biology Harvard Medical School Gillette Center for Gynecologic Oncology Massachusetts General Hospital Boston, Massachusetts

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

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

Women with low-volume residual stage III or IV disease (all lesions <2 cm) have a 60% to 70% risk for recurrence following primary surgery. The presence of large-volume residual disease increases that percentage to 80% to 85%.2 Such recurrences are incurable, so the goals of therapy should be palliation of cancerrelated symptoms, prolongation of life, and maintenance of quality of life. Response to first-line therapy influences the choice of therapy for women with recurrent ovarian cancer and predicts how a tumor will respond to treatment in the recurrent setting. Recurrent ovarian cancer has been dichotomized as being either platinum-sensitive (progression-free interval [PFI] >6 months) or platinum-resistant (PFI ≤6 months).3,4 A patient’s PFI predicts response rate (RR) and duration of response.5 This review will focus on the medical treatment, specifically chemotherapy options, available for women with platinum-sensitive disease. The management strategy for women with platinum-

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

resistant disease was formally discussed in a previous issue (Clinical Oncology News Special Edition 2009;12[2]:39-43).

The Importance of Treatment Timing Recurrent disease may be heralded by the onset of new symptoms, radiological evidence of recurrence in an asymptomatic patient, or rising CA-125 levels predating radiological detection or symptoms by several months.6,7 Although formal definitions of ovarian cancer recurrence and progression have been described, based on both clinical and CA-125 criteria, many women present with either an asymptomatic, radiological recurrence or an asymptomatic rise in CA-125 without a radiographic correlate.7,8 Given that recurrent disease is incurable, the goals of therapy outlined earlier should guide decisions about initiation of second-line therapy.9 In patients with symptomatic recurrence, immediate institution of treatment may be justified and warranted to palliate cancer-related

C LIN IC A L ON CO LO GY N EWS • AU G UST 2 010

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

Response Rate, %

Pathologic Complete Response, %

5-12

13-24

>24

symptoms. For women with asymptomatic recurrences (eg, those with no symptoms but with rising CA-125), the timing of therapy is much more controversial. Researchers who advocate immediate treatment argue that patients with small-volume disease are more likely to achieve a complete response if they are treated early.10-12 Advocates for delaying treatment argue that because the increases in complete responses have not been translated into improved survival,13 the goal is still palliation and therapy should be deferred until symptom onset. The controversy over the appropriate time to start therapy was addressed in Rustin et al’s recent prospective study of 1,442 women with ovarian cancer.14 The trial was conducted among patients in complete clinical remission from their cancer, with a normal CA-125 level following completion of primary surgical and platinum-based systemic therapy. Both the investigators and patients were blinded. Serum CA-125 levels were checked every 3 months. Women whose CA-125 rose to a level twice above the upper limit of normal but who remained asymptomatic (n=527) were randomly assigned to receive immediate treatment or treatment upon clinical or symptomatic recurrence. Women randomized to immediate therapy initiated chemotherapy a median of 5 months earlier than those treated upon recurrence. Survival and remission duration were comparable between the 2 arms at 57-month follow-up. However, quality of life was worse for the women undergoing immediate treatment. The investigators concluded that early institution of second-line therapy did not benefit patients and advocated for treatment to be delayed until symptoms develop or patients have signs of recurrent disease.

Importance of Platinum-Free Disease Interval Table 1 summarizes the importance that the length of the treatment-free interval plays in predicting response to platinum therapy in the recurrent setting.11 In general, platinum-sensitive recurrent ovarian cancer is treated with a platinum agent, alone or in combination with another agent. The process of determining whether to use single-agent therapy or combination therapy should

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consider patients’ performance status, other comorbidities, and previous toxicities with other therapies. If combination therapy is elected, the specific combination regimen should be chosen to optimize outcome and minimize overlapping toxicities.

Treatment Regimen Selection A Phase II trial randomly assigning patients with platinum-sensitive recurrences to either single-agent paclitaxel or combination therapy with cisplatin, doxorubicin, and cyclophosphamide documented similar overall response rates between the 2 regimens (45% vs 55%) but showed that the platinum-containing combination was associated with significant increases in response duration (16 vs 9 months) and median survival (35 vs 26 months; hazard ratio [HR], 0.58; 95% confidence interval, 0.34-0.98; P=0.043).10 These results illustrate the importance of platinum agents in the management of women with platinum-sensitive recurrent disease. The choice of whether to use a single platinum agent or a platinum-containing combination is somewhat controversial. Combination regimens are associated with a longer response rate and PFI.15-19 The paclitaxel-carboplatin combination has been shown to lead to a longer overall survival (OS) compared with platinum alone. However, combination therapy is more toxic.15 Selection of single-agent platinum versus combination platinum-containing regimens also should take into account patients’ performance status and previously encountered chemotherapy toxicities.

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

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

Number Of Patients

RR, %

PFS, mo

OS, mo

Toxicity

Reference 16

Carboplatin Carboplatin + gemcitabine

356

31 47

5.8 8.6

17.3 18

Combination associated with higher hematologic toxicity

Carboplatin Carboplatin + PLD

61a

32 67

8 12

18 26

17 Combination associated with higher hematologic toxicity, constipation, and handâ&#x20AC;&#x201C;foot syndrome

Carboplatin + PLD Carboplatin + paclitaxel

976

11.3 9.4

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

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

Single-Agent Chemotherapy Beyond Second Line Numerous single-agent therapeutic options exist for patients with ovarian cancer who have had progression of disease on platinum-based second-line therapy. Table 3 lists some chemotherapeutic options and their documented response rates. The higher response rates are for patients with platinum-sensitive disease.20-41 Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody that targets vascular endothelial growth factor. Results of GOG (Gynecologic Oncology

Group) 218, a placebo-controlled randomized Phase III clinical trial involving the addition of bevacizumab to standard chemotherapy treatment in women with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer recently were reported at the 2010 meeting of the American Society of Clinical Oncology (ASCO). The study included 3 treatment arms: 1) standard IV paclitaxel and carboplatin; 2) IV paclitaxel and carboplatin in conjunction with bevacizumab; and 3) IV paclitaxel, carboplatin, and bevacizumab, with continuation of bevacizumab as a single agent for an

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

ORR, %

Toxicity (Grades 3 and 4)

Reference

Paclitaxel

21-53

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

20-23

Gemcitabine (Gemzar, Lilly)

14-22

Neutropenia, anemia, thrombocytopenia, nausea/vomiting, fatigue

24-26

PLD (Doxil, Centocor/Ortho Biotech)

11-28

Handâ&#x20AC;&#x201C;foot syndrome, stomatitis

27-31

Topotecan (Hycamtin, GlaxoSmithKline)

15-32

Neutropenia, anemia, thrombocytopenia

27, 28, 32, 33

Vinorelbine

3-29

Neutropenia, anemia, worsening paresthesia

34, 35

Etoposide (oral)

18-27

Neutropenia, leukopenia, anemia, thrombocytopenia

36, 37

Docetaxel

7-28

Neutropenia, leukopenia

38, 39

Ifosfamide

Myelosuppression, nephrotoxicity, central nervous system toxicity

Pemetrexed (Alimta, Lilly)

Myelosuppression

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

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Table 4. Bevacizumab Trials in Ovarian Cancer Reference 43 (N=63)

Reference 44 (N=29)

Reference 45 (N=44)

Study treatment

Single-agent bevacizumab 15 mg/kg q3wk

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

Single-agent bevacizumab 15 mg/kg q3wk

Prior treatment setting

Relapsed after platinum therapy; up to 2 prior regimens

Relapsed after platinum therapy, with post-platinum maximum of 2 regimens

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

Efficacy 6-mo PFS, % ORR, %

39 18

57 28

27.4 16

Gastrointestinal perforation, N (%)

2 (3%)

5 (11%)

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

additional 10 months (maintenance therapy). A significant improvement in PFS was observed when bevacizumab was added to upfront IV chemotherapy and continued as a maintenance regimen after chemotherapy. This improvement in PFS was 3.8 months (10.3 months for standard chemotherapy, 14.1 months for the maintenance regimen). Long-term survival data are not yet available.42 Bevacizumab also has been studied in several Phase II studies, alone and in combination with cytotoxic chemotherapy, in which it has been shown to be an active agent in patients with recurrent ovarian cancer (Table 4).43-45 However, studies indicate that there is a risk for gastrointestinal complications with this agent; specifically, the incidence of perforations has been estimated to be 5% to 7%.43-46 Some have suggested that bevacizumab should be used only in patients without clinical symptoms of bowel obstruction, computed tomography scan evidence of bowel involvement, or evidence of rectosigmoid involvement on pelvic examination.47 Bevacizumabâ&#x20AC;&#x2122;s role has yet to be determined. Singleagent bevacizumab may be an appropriate third-, fourth-, and even fifth-line treatment in carefully selected patients. Combination regimens using bevacizumab remain investigational until more data on their efficacy and safety are available. Experience with another anti-angiogenic agent was reported at the 2010 ASCO meeting. AMG 386 is a peptide-Fc fusion protein that inhibits angiogenesis. In a Phase II study evaluating AMG in combination with paclitaxel in patients with recurrent ovarian cancer, the anti-angiogenic agent combined with weekly paclitaxel was noted to have a manageable toxicity profile distinct from that of VEGF inhibitors, with promising antitumor activity warranting further investigation.48 The role of monoclonal antibodies in the treatment

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of recurrent ovarian cancer is also emerging. Results of a Phase II study of farletuzumab (MORAb-003) were also presented at the 2010 ASCO meeting. Farletuzumab is a humanized monoclonal antibody to folate receptor alpha, which is over-expressed in epithelial ovarian cancer. Preliminary results from this trial show that combination of farletuzumab and carboplatin/paclitaxel chemotherapy in patients with platinumsensitive disease is well tolerated, and associated with higher response rates than those seen in historical controls.49 Phase III data also presented at the 2010 ASCO meeting showed that abagovomab, a murine monoclonal anti-idiotypic antibody against CA-125, is safe and induces a measurable immune response as maintenance therapy in patients with stage III/IV ovarian cancer in complete remission, following platinum-taxane first-line, adjuvant chemotherapy.50

Conclusions Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrences treated with a platinumbased agent. Platinum-containing combination regimens are associated with higher response rates and PFI. Paclitaxel in combination with carboplatin has been reported to have an improved OS compared with carboplatin alone. The choice of single-agent versus combination therapy should take into account the patientsâ&#x20AC;&#x2122; performance status, other comorbidities and previous toxicities with other therapies. If combination therapy is selected, the specific combination regimen chosen should also take into consideration these factors to optimize outcome and minimize overlapping toxicities. For patients whose cancer progresses after platinum

retreatment, numerous other agents have been shown to be effective in palliating cancer-related symptoms and extending life. The future may include the use of non-platinum combinations, as well as targeted therapies such as bevacizumab in combination with cytotoxic agents.

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16. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24(29): 4699-4707, PMID: 16966687. 17. Alberts DS, Liu PY, Wilczynski SP, et al. Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group Protocol S0200). Gynecol Oncol. 2008;108(1):90-94, PMID: 17949799. 18. Pujade-Lauraine E, Mahner S, Kaem J, et al. A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC). CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). J Clin Oncol. 2009;27:(18 suppl): Abstract LBA5509. 19. Monk BJ, Herzog T, Kaye S, et al. A randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD in relapsed, recurrent ovarian cancer. In: Proceeding of the 33rd annual European Society of Medical Oncology (ESMO) Congress; Stockholm, Sweden; 2008: Abstract LBA4. 20. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian adenocarcinoma. Ann Intern Med. 1989;111(4):273-279, PMID: 2569287. 21. Einzig AI, Wiernik PH, Sasloff J, Runowicz CD, Goldberg GL. Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol. 1992;10(11):1748-1753, PMID: 1357110. 22. Thigpen JT, Blessing JA, Ball H, Hummel SJ, Barrett RJ. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol. 1994;12(9):1748-1753, PMID: 7916038. 23. Kohn EC, Sarosy G, Bicher A, et al. Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst. 1994;86(1):18-24, PMID: 7505830. 24. Lund B, Hansen OP, Theilade K, et al. Phase II study of gemcitabine (2’,2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst. 1994;86(2):1530-1533, PMID: 7932808.

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

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

10. Cantu MG, Buda A, Parma G, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol. 2002;20(5):1232-1237, PMID: 11870165.

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

11. Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389-393, PMID: 1999708. 12. Ferrandina G, Ludovisi M, De Vicenzo R, et al. Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study. Ann Oncol. 2007;18(8):1348-1353, PMID: 17470449. 13. Canistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24): 2519-2529, PMID: 15590954. 14. Rustin GJ, van der Burg ME, et al. A randomized trial in ovarian cancer (OC) or early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials). J Clin Oncol. 2009;27(18 suppl): Abstract 1. 15. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinumbased chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2-2 trial. Lancet. 2003;361(9375): 2099-2106, PMID: 12826431.

27. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322, PMID: 11454878. 28. Gordon AN, Teitelbaum A. Overall survival advantage for pegylated liposomal doxorubicin compared to topotecan in epithelial ovarian cancer. Eur J Cancer. 2003;12: Abstract S51. 29. O’Byrne KJ, Bliss P, Graham JD, et al. A phase III study of Doxil/ Caelyx versus paclitaxel in platinum-treated, taxane-naïve relapsed ovarian cancer. Proc Am Soc Clin Oncol. 2002;21: Abstract 808. 30. Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol. 1997;15(3):987-993, PMID: 9060537. 31. Rose PG, Maxson JH, Fusco N, Mossbruger K, Rodriguez M. Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol. 2001;82(2):323-328, PMID: 11531287.

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32. Kudelka AP, Tresukosol D, Edwards CL, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol. 1996;14(5):1552-1557, PMID: 8622071. 33. Hoskins P, Eisenhauer E, Beare S, et al. Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol. 1998;16(6):2233-2237, PMID: 9626225. 34. Sorensen P, Hoyer M, Jakobsen A, et al. Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma. Gynecol Oncol. 2001;81(1):58-62, PMID: 11277650. 35. Burger RA, DiSaia PJ, Roberts JA, et al. Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol. 1999;72(2):148-153, PMID: 10021293. 36. Slayton RE, Creasman WT, Petty W, Bundy B, Blessing JA. Phase II trial of VP-16-213 in the treatment of advanced squamous cell carcinoma of the cervix and adenocarcinoma of the ovary: a Gynecologic Oncology Group study. Cancer Treat Rep. 1979;63(4):2089-2094, PMID: 526942. 37. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16(2):405-410, PMID: 9469322. 38. Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88(2):130-135, PMID: 12586591. 39. Markman M, Zanotti K, Webster K, et al. Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum. Gynecol Oncol. 2003;91(3):573-576, PMID: 14675679. 40. Markman M, Hakes T, Reichman B, et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992;10(2):243-248, PMID: 1732425. 41. Miller DS, Blessing JA, Krasner CN, Mannel RJ. A phase II evaluation of pemetrexed (LY231514, IND#40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecology Oncology Group. J Clin Oncol. 2008;26(suppl): Abstract 5524.

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42. Burger RA, Brady, MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a Gynecologic Oncology Group study. J Clin Oncol. 2010;28(18 suppl): Abstract LBA1. 43. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165-5171, PMID: 18024863. 44. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J Clin Oncol. 2008;26(1):76-82, PMID: 18165643. 45. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180-5186, PMID: 18024865. 46. Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3-6, PMID: 17383545. 47. Simpkins F, Belinson JL, Rose PG. Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening. Gynecol Oncol. 2007;107(1):118-123, PMID: 17658587. 48. Karlan BY, Oza AM, Hansen VL, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients (pts) with recurrent ovarian carcinoma. J Clin Oncol. 2010;28(15 suppl): Abstract 5000. 49. White JA, Coleman RL, Armstrong DK, et al. Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: final data from a multicenter Phase II study. J Clin Oncol. 2010;28(15 suppl): Abstract 5001. 50. Sabbatini P, Berek JS, Casado A, et al. Abagovomab maintenance therapy in patients with epithelial ovarian cancer after complete response (CR) post first-line chemotherapy (FLCT): preliminary results of the randomized, double-blind, placebo-controlled, multicenter MIMOSA trial. J Clin Oncol. 2010; 28(15 suppl): Abstract 5036.

The Society of Gynecologic Oncologists What is the SGO? The Society of Gynecologic Oncologists, based in Chicago, Illinois, is a national medical specialty organization of physicians, surgeons and healthcare professionals who are trained in the comprehensive management of women with malignancies of the reproductive tract.

Current President Daniel Clarke-Pearson, MD, Professor and Chairman, Obstetrics and Gynecology, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC.

Mission The purpose of the SGO is to improve the care of women with gynecologic cancers by encouraging research and disseminating knowledge to raise the standards of practice in the prevention and treatment of gynecologic malignancies, in cooperation with other organizations interested in women’s health care, oncology and related fields. This is reflected in the Society’s Mission statement to “promote and ensure the highest quality of comprehensive clinical care through excellence in education and research in gynecologic cancers.”

Vision As medical professionals with special interest and expertise in gynecologic cancers, SGO members dedicate their work to helping women conquer the cancers unique to them. The SGO upholds the highest standard of quality care and through research hopes to forge new and innovative ways to improve the treatment and care of women with gynecologic cancers. The SGO advocates and contributes to a comprehensive approach to prevention, screening, diagnosis and treatment and empowers women with knowledge that provides answers, support and hope. The Society’s ultimate goal and vision is to “eradicate gynecologic cancers.”

Membership SGO is a national medical specialty society for physicians trained in the comprehensive management of women’s cancers. The Society’s membership, totaling more than 1,300, is comprised of gynecologic oncologists -obstetrician/gynecologists with three-four years of additional, intensive training in the specific study of gynecologic cancers – as well as women’s cancer healthcare professionals including medical oncologists, radiologic oncologists, nurses, social workers and pathologists.

Gynecologic Oncology: Evolution of a Subspecialty The Society of Gynecologic Oncologists was organized in the late 1960s and officially incorporated in the state of Florida in 1970. The SGO included 56 founding members. Today the Society has more than 1,230 members, including gynecologic oncologists and other related medical specialists, such as medical oncologists, radiation oncologists and pathologists. The American Board of Medical Specialists first approved subspecialty certification in Gynecologic Oncology in 1972. The first written and oral examinations for certification for Special Competence in Gynecologic Oncology were given in 1974.

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Breast

CHALLENGED continued from page 1

information, according to William C. Wood, MD, Division of Surgical Oncology, Emory University, Atlanta. As the expert invited by ASCO to put these data into perspective, Dr. Wood indicated that some of these data reflect the changing nature of breast cancer, which is being detected earlier. The value of sentinel lymph node (SLN) histology, SLN immunohistochemistry (IHC) analyses and IHC assessment of bilateral iliac crest bone marrow aspiration was evaluated in a collaborative study from the American College of Surgeons Oncology Group (ACOSOG), called Z0010 (abstract CRA504). The impact of these procedures on five-year overall survival (OS) was assessed in 5,539 women with clinical T1 or T2 disease and clinically nodenegative breast cancer. Although those with a positive SLN were significantly less likely to be alive at five years than those with negative SLN (92.8% vs. 95.6%; P=0.0002), investigators found no difference in five-year survival when patients were stratified by positive or negative SLN IHC status (95.1% vs. 95.8%; P=0.53). This led Kelly K. Hunt, MD, chief, Surgical Breast Section, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, who presented the data, to conclude “routine examination of sentinel lymph nodes by IHC is not supported in this patient population by this study.” Investigators identified a significant survival difference in patients with a positive bone marrow IHC status when compared with negative status (90.2% vs. 95.1%; P=0.015), but Dr. Wood was not convinced that this information would change clinical decisions in the context of other prognostic factors that might identify the same patients. He observed that if negative SLN patients who might not receive cytotoxic therapy were evaluated separately, the bone marrow IHC did not produce a significant influence on five-year survival (P=0.16). Overall, he estimated that 33 iliac bone marrow aspirations would need to be conducted to identify one positive result in this group, and that this “lacks clinical utility.” In another study, NSABP B-32, 5,611 women with clinically node-negative invasive breast cancer were randomized to SLN resection plus axillary lymph node dissection (ALND) or to SLN resection alone (abstract LBA505). Presented by David N. Krag, MD, professor of surgery, University of Vermont, Burlington, the five-year survival was 96.5% in those with both surgeries compared with 95% in those with SLN resection alone (P=0.13). Other outcomes, such as disease-free survival, also failed to show a

‘The Z-0011 trial is not overly reassuring to me to make this uniformly practice-changing. It’s accrual was less than 50% of planned, and as such, it is a result that begs confirmation.’ —Andrew D. Seidman, MD

Blue stained sentinel lymph node.

‘Routine examination of sentinel lymph nodes by IHC is not supported in this patient population by this study.’ —Kelly K. Hunt, MD

significant difference. Dr. Krag concluded that SLN resection without ALND is a safe and effective method of regional node treatment in women with SLNnegative breast cancer. Dr. Wood agreed. “The B-32 study provides definitive evidence that axillary node dissection does not add benefit to sentinel lymph node biopsy alone in clinically node-negative patients,” Dr. Wood said. In a third trial, ACOSOG Z0011, 891 clinically node-negative patients who underwent SLN biopsy and had one or two positive nodes detected were randomized to SLN biopsy alone or SLN biopsy plus ALND (abstract CRA506). After five years of follow-up, in-breast recurrence was

observed in 3.7% of those who received ALND compared with 2.1% (P=0.16) of those who received SLN biopsy alone. Five-year nodal recurrences also were similar (0.6% vs. 1.3%; P=0.44). Five-year OS rates were 91.9% and 92.5% (P=0.24). Investigators did not find any significant difference in disease-free survival. “In this prospective randomized study, sentinel lymph node biopsy alone in clinically node-negative women with one or two positive sentinel nodes provides excellent locoregional control and survival comparable to [adding] axillary node dissection,” said Armando E. Giuliano, MD, chief of science and medicine, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica,

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Calif. “This study does not support the routine use of axillary node dissection in early nodal metastatic breast cancer.” Again, Dr. Wood concurred, calling this study, like the other two studies “practice-changing.” Not everyone, however, agrees. One of the potential limitations of the ACOSOG Z10011 study was an early termination due to slow accrual. The 891 patients represented only about half of the planned study size. Dr. Giulano maintains that “the local and regional recurrence rates were so low and the confidence intervals such that it is highly unlikely that survival would be affected in this population by axillary dissection.” But during the discussion after the presentation, some oncologists voiced concern about how the low accrual could have affected the confidence intervals and the strength of the conclusion that patients eligible for the study could expect the same result when foregoing axillary dissection. Asked for a comment, Andrew D. Seidman, MD, an attending physician in the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York City, was among those who introduced some caution in interpreting the results. “While it is quite attractive to hope to abandon the morbid procedure of complete axillary lymph node dissection in a subgroup of patients with cancerous sentinel nodes, the Z-0011 trial is not overly reassuring to me to make this uniformly practice-changing,” Dr. Seidman said. “Its accrual was less than 50% of planned, and as such, it is a result that begs confirmation.” When Dr. Wood was asked by Clinical Oncology News if he had any reservations about altering practice on the basis of ACOSOG Z0011, he responded, “although the numbers were not those originally sought, the trend was for the patients NOT having axillary dissection to do better than those who did. If the total number desired had been accrued, even if the additional patients exhibited a bit of benefit from the dissection, it would have been offset by those patients accrued. If the results had been identical between the two arms that were accrued, the possibility would exist that another subset of patients would have revealed an overall detriment to avoiding dissection. So, I find the results convincing and practice-changing.” Although there appears to be general agreement that the first two studies proved their hypothesis and have immediate relevance to current practice, the conclusion about ACOSOG Z0011 is expected to remain controversial. In talking about this latter study, one expert said that “we are struggling with what to do with this data,” while another questioned whether using SLN biopsy alone would “leave some cancer behind.” —Ted Bosworth

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2010

Pancreatic

DRUG COMBO

no data <1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 > 11

continued from page 1

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Figure 1. Comparison of survival between different regimens.

Age-standardized death rates from pancreatic cancer by country (per 100,000 inhabitants). Note. Based on World Health Organization Data for 2004

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â&#x20AC;&#x2DC;It has been vanishingly rare for an abstract in pancreas cancer to be practice-changing. This one probably is.â&#x20AC;&#x2122;

3<936?6;<E

â&#x20AC;&#x201D;Leonard Saltz, MD

were randomized to standard treatment with gemcitabine or FOLFIRINOX (F), which is a combination of 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin. Patients were required to have adequate organ function, a PS of 0 or 1, bilirubin less than 1.5 upper limit of normal and no prior chemotherapy or radiotherapy. Patients were not included if they had non-ductal pancreatic cancer; adenocarcinoma of the ampulla of Vater; unresectable, locally advanced pancreatic cancer without distant metastases; central nervous system metastases; chronic diarrhea; or other previous or concomitant malignant disease. Patients aged 18 to 75 years (median, 60 years) were stratified by center, PS and primary tumor location. Specifically, patients in the FOLFIRFIRINOX arm received oxaliplalatin (85 mg/m2 over two hours), s), leucovorin (400 mg/m2 over ver two hours), irinotecan (180 mg/ m2 over 90 minutes), and 5-FU FU (400 mg/m2 bolus then 2,400 0 mg/m2 over 46 hours), all on day 1, and then repeated every two weeks. Patients in the control arm received gemcitabine (1,000 mg/m m2 IV over 30 minutes weekly for seven of eight weeks, one week ek rest, and then weekly for three ee of four weeks). The two study dy arms were well balanced for baseline characteristics. At the planned interim im analysis, the Independent nt Data Monitoring Committee ee

recommended that the study be halted when it was determined that the median OS was significantly increased (P<0.0001) and that the findings were unlikely to change with additional patients. At the final analysis, the median OS was 6.8 months for gemcitabine compared with 11.1 months in the FOLFIRINOX arm (hazard ratio [HR], 0.57; P<0.0001) (Figure 1). Median progression-free survival was 6.4 months in the FOLFIRINOX arm and 3.3 months in patients receiving gemcitabine (HR, 0.47; 95% confidence interval [CI], 0.370.59; P<0.0001). A greater percentage of patients receiving FOLFIRINOX had a complete response, partial response or stable disease (70.2% vs. 50.8%; P=0.0003); the response rate

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Memorial Sloan-Kettering Cancer Center, in New York City. â&#x20AC;&#x153;The outcome in the experimental arm was superior compared to the gemcitabine control arm; however, it was at a considerable price in terms of toxicity. This is not a new standard of careâ&#x20AC;&#x201D;it is a new standard option. It is a reasonable consideration only in patients with excellent performance status [PS)]â&#x20AC;&#x201D;Eastern Cooperative Oncology Group status 0 or 1â&#x20AC;&#x201D;and within that population, the benefits versus toxicities need to be carefully discussed with each individual patient. It will be right for some, and not for others.â&#x20AC;? The studyâ&#x20AC;&#x2122;s lead researcher agreed that the regimen was only for certain patients. â&#x20AC;&#x153;This is the first time in a randomized Phase III study that we have achieved an 11-month median overall survival [OS] in pancreatic cancer,â&#x20AC;? said Thierry Conroy, MD, the Centre Alexis Vautrin and Nancy University, in Vandoeuvre-lĂ¨s-Nancy, France. â&#x20AC;&#x153;We recommend FOLFIRINOX as the new international standard of care for patients with metastatic pancreatic cancer, but only in patients with normal or [near] normal level of bilirubin and performance status 0 or 1.â&#x20AC;? He said that the regimen delayed deterioration of quality of life. â&#x20AC;&#x153;FOLFIRINOX is more toxic, but overall has very manageable toxicities,â&#x20AC;? Dr. Conroy said. Ed Chu, chief of the Section of Medical Oncology and deputy director of clinical research at Yale Cancer Center, Yale University, in New Haven, Conn, speculated whether the regimen could be used in another setting. â&#x20AC;&#x153;Perhaps another setting to use this regimen would be locally advanced pancreatic cancer, where tumor reduction could lead to better surgical outcomes,â&#x20AC;? Dr. Chu said. â&#x20AC;&#x153;It is probably similar in concept to using FOLFOXIRI in the treatment of [metastatic colorectal cancer].â&#x20AC;? In the French trial, 342 patients with metastatic pancreatic adenocarcinoma

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Figure 2. Comparison of selected adverse events. was higher in the FOLFIRINOX group (31.6% vs. 9.4%; P=0.0001). Several grade 3/4 hematologic toxicities were more common in patients receiving FOLFIRINOX including neutropenia (45.7% vs. 18.7%), febrile neutropenia (5.4% vs. 0.6%) and thrombocytopenia (9.1% vs. 2.4%) (Figthr ure ur 2). One toxicity-related death occurred in each arm. Several nonheoc matologic grade 3/4 adverse events m also al were more frequent in patients receiving FOLFIRINOX, including rec peripheral neuropathy (9% vs. 0), vompe iting (14.5% vs. 4.7%), fatigue (23.2% itin vs. 14.2%), diarrhea (12.7% vs. 1.2%) aand grade 2 alopecia (11.4% vs. 0.6%). In contrast, alanine aminotransferase elevations were more common in patients receiving gemcitaabine (18.6% vs. 7.3%). â&#x20AC;&#x153;â&#x20AC;&#x153;FOLFIRINOX treatment results in higher frequency of grade 3/4 febrile ah neutropenia,â&#x20AC;? Dr. Conroy said. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s ne clear that we should select patients and cle explain the risk of febrile neutropenia.â&#x20AC;? exp â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke

New Indication TASIGNA IS NOW APPROVED FOR THE TREATMENT OF NEWLY DIAGNOSED CHRONIC-PHASE Ph+ CML PATIENTS 300-MG BID DOSING NOW AVAILABLE

TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome. TASIGNA is indicated for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Please see brief summary of Prescribing Information, including Boxed WARNING, on the following pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

ÂŠ2010 Novartis

Printed in USA

6/10

C-AM7-100024

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments (5.2, 5.3, 5.6, 5.12). 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2) in the full prescribing information]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with resistant or intolerant Ph+ CML receiving nilotinib (n=867; 0.6%). A similar incidence was also reported in the expanded access program for patients with resistance or intolerant Ph+ CML. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)]. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2) in the full prescribing information, Drug Interactions (7.2)]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Boxed Warning, Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.10 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.11 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.13 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 18.6 months. The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities in the full prescribing information. Discontinuation for adverse events regardless of causality was observed in 7% of patients. Resistant or Intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 438 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=318; CML-AP=120) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145-1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1-163). In CML-CP patients, the most commonly reported adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the most commonly reported adverse drug reactions (>10%) were rash, pruritus and constipation. The common serious adverse drug reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF >60 msec from baseline was observed in 2.1% of the patients and QTcF of >500 msec was observed in 3 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation for drug-related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients. 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), uncommon (0.1%-1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations,” very common events (≥10%), which were not included in Tables 5 and 6 (in the full prescribing information), are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis), pneumonia, urinary tract infection, gastroenteritis. Unknown frequency: sepsis, bronchitis, herpes virus infection, candidiasis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocytosis, leukocytosis. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism. Unknown frequency: hypothyroidism, hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: dehydration, decreased appetite, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia. Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, hypoaesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, peripheral neuropathy, lethargy, dysaesthesia. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival hyperaemia, ocular hyperaemia, ocular surface disease, scleral hyperaemia.

Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing. Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity of teeth, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling face. Unknown frequency: erythema nodosum, skin ulcer, palmar-plantar erythrodysasthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy.

Nilotinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively, during organogenesis. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 times the AUC in patients at the dose of 400 mg twice daily) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses ≥30 mg/kg/day (approximately 2 times the AUC in patients at the dose of 400 mg twice daily) resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic. When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 360 mg/m2 (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 120 mg/m2 (approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups. 8.3 Nursing Mothers It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tasigna, 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 of Tasigna in pediatric patients have not been established.

Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

8.5 Geriatric Use In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 or over.

Renal and Urinary Disorders: Common: pollakuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

• Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged <65 years and those ≥65 years. • Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged <65 years and those ≥65 years. • Patients with resistant or intolerant CML-AP: The major hematologic response rate was 31% in patients <65 years of age and 15% in patients ≥65 years.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain, pain (including neck pain and back pain), chest discomfort. Uncommon: face edema, gravitational edema, influenza-like illness, chills, malaise. Unknown frequency: feeling hot, localized edema.

No major differences were observed for safety in patients ≥65 years of age as compared to patients <65 years.

Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, very low density lipoprotein increased, blood parathyroid hormone increased, blood pressure increased.

8.6 Cardiac Disorders In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia were excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, Warnings and Precautions (5.2)].

6.3 Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Tasigna. 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.

8.7 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to severe hepatic impairment following a single dose administration of 200 mg of Tasigna, the mean AUC values were increased on average of 35%, 35% and 56% in subjects with mild (Child-Pugh class A, score 5-6), moderate (Child-Pugh class B, score 7-9) and severe hepatic impairment (Child-Pugh class C, score 10-15), respectively, compared to a control group of subjects with normal hepatic function.

Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in majority of these cases. 7 DRUG INTERACTIONS 7.1 Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna to induce metabolism has not been determined in vivo. Exercise caution when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Nilotinib inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised.

8.8 Renal Impairment Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range. Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. 16 STORAGE Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Tasigna with agents that are strong CYP3A4 inhibitors should be avoided [see Boxed Warning, Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.2, 5.7)]. Concomitant use of Tasigna with medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected. Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%. 7.3 Drugs that Affect Gastric pH Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, co-administration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna when co-administered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with Tasigna should be used with caution. If a H2 blocker or an antacid is necessary, the doses between the H2 blocker and Tasigna or the doses between the antacid and Tasigna should be separated at least by several hours. However, no clinical study has been conducted to evaluate the effect of H2 blockers or antacids on nilotinib pharmacokinetics. 7.4 Drugs that Inhibit Drug Transport Systems Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised. 7.5 Drugs that May Prolong the QT Interval The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided [see Boxed Warning, Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.2, 5.7)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.13)] Based on its mechanism of action and findings in animals, Tasigna may cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies with Tasigna in pregnant women. Women should be advised to avoid becoming pregnant while on Tasigna. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

T2010-34 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

PRN

CLINICAL ONCOLOGY NEWS • AUGUST 2010

Physician Well-Being

Physicians Coping With Addiction Face Long Road The number of physicians in the United States who are being treated for prescription drug addiction—in many cases pain drugs such as opioids—has been estimated at 8,000, while the total proportion of physicians with substance abuse problems may be as high as 15%. It has become a serious problem that needs to be better addressed, according to the chief medical officer of Hazelden, the famed substance abuse treatment center in Minnesota. “[Misuse and abuse of prescription medications] is increasing, actually rather dramatically, in the population as a whole,” said Marv Seppala, MD, himself a recovering addict who is one of the first physicians in the country to be certified by the American Board of Addiction Medicine. “Abuse of prescribed medications, specifically opioids, is now second to marijuana in terms of abuse. There also is a remarkable increase in cases involving health care professionals.” One of the problems in gauging physician abuse is, of course, the secretive nature of the problem. “We think it’s around 10% to 15% [of U.S. doctors], but it is hard to figure out,” said Dr. Seppala, who co-authored a study on chemical dependency and the physician that appeared in the Mayo Clinic Proceedings (2009;84:625-631), along with Keith H. Berge, MD, assistant professor of anesthesiology in the Department of Anesthesiology at Mayo Clinic in Rochester, Minn., and Agnes M. Schipper, a staff attorney at the Mayo Foundation. “It’s not like you can send out a survey and ask.”

Personal, Societal Costs Although the cost to the health care system resulting from physician abuse is difficult to measure, according to Dr. Seppala, one of the greatest wasted expenses is the money used to train physicians. “Their educations are, of course, usually through private institutions, but there are many highly trained physicians who have cost state governments hundreds of thousands of dollars to get training, and then they are unable to maintain practices. That’s most likely a huge cost to the government, so if [the rates of physician prescription abuse] really are 10% to 15%, we’re talking a remarkable amount of money.” Stress can be a factor leading physician’s to develop an addiction, but Dr. Seppala said the problem also is often one of access. Thus, some specialties in which opioids and other scheduled drugs are used more often are linked to higher rates of abuse. A five-year study of U.S. physicians treated for substance use disorders found that anesthesiologists,

abuse intervention. Even given increased scrutiny, however, it is not easy to find addicted physicians. “The intellect that physicians rely on to learn their craft allows them to develop exceptional rationalization, denial and resistance techniques,” wrote the authors

unique to the health care workplace.” The good news, according to Dr. Seppala, is that addiction treatment often is very successful among physicians, with abstinence rates of 74% to 90% (J Stud Alcohol 1980;41:1217-1220, PMID: 7278264; J Med Assoc Ga 1984;73;755-758). One study, however, puts the one-time relapse rate for substance-abusing physicians at 25% (JAMA 2005;293:1513-1515, PMID: 15784877).

‘We think it [the rate of addicted physicians] is around 10% to 15%, but it is hard to figure out. It’s not like you can send out a survey and ask.’ —Marv Seppala, MD

‘I often use the analogy that you wouldn’t treat an alcoholic bartender and then send him or her back to a neighborhood bar for their recovery. Yet, many physicians in recovery are sent back to their medical practice in a hospital or clinic—these are the places where they obtained their drugs in the first place.’ —Marv Seppala, MD

emergency medicine physicians and psychiatrists had the highest rates of addiction among physicians (BMJ 2008;337:a2038, PMID: 18984632). A review of PubMed did not turn up the incidence of substance abuse in oncologists, but opioids are used more often in oncology so it is likely that oncologists are high on the list. Although opioids historically are the most abused medications by doctors, Dr. Seppala said Hazelden has seen a shift in terms of drugs preferred by physicians. “We’ve seen a lot more propofol-abusing physicians over the last few years,” he continued. “I think initially it wasn’t really noted as something to be considered as addicting, but now that we know it is, we clearly see increased numbers and definitely among physicians. I have a colleague at Mayo who told me recently he is seeing it as well.” The problem of physician drug addiction is becoming more recognized in the medical community, said Dr. Seppala, who cited Mayo Clinic as having a very active program for physician substance

of the Mayo Clinic Proceedings article. “Thus, recognition of their disease is difficult.” “Not just physicians, but any person abusing a substance, will put in all sorts of safeguards to make sure they don’t get caught,” Dr. Seppala said. “Every other aspect of a physician’s life—marriage, family—is usually in shambles before the problem is detected at work. It is very important for them to protect their jobs because, most likely, that’s their supply.”

The Road to Recovery When physicians do seek help for their addiction, in the overwhelming majority of cases (95%), it is through a 12-step program on an inpatient basis (78%; BMJ 2008;337:a2038). Drs. Berge and Seppala and Ms. Schipper recommend addiction treatment programs that focus on the addicted physician and that include group therapy providing “the opportunity for physicians to recognize their own maladaptive behaviors reflected in their peers,” allowing them to “discuss those issues

Dr. Seppala and his co-authors believe that treatment, rather than prosecution, is the best way to solve the problem of addicted physicians. “Society and the individual’s investment in physician training, as well as the high abstinence rates for addicted physicians who complete an appropriate treatment program, support a rehabilitation model, not a punitive stance,” they wrote. The authors of the Mayo Clinic Proceedings piece stress that physicians involved in strict addiction recovery programs and properly monitored (including random and “for cause” drug screens) often can return to work. Dr. Seppala is quick to point out, however, that it is not as simple as the recovering physician simply returning to his or her old job. Nonclinical roles often are necessary, and in some cases, prescribing limitations (e.g., opioids and other scheduled drugs) must be placed on recovering doctors. Still, physicians’ jobs are protected for 12 weeks under state and federal law if they enter a substance abuse program, and the Americans with Disabilities Act and state civil rights laws guarantee “reasonable accommodations” upon their return, of which Dr. Seppala and his colleagues cite a modified work schedule as one example. Still, some physicians do end up back where they left their demons. “I often use the analogy that you wouldn’t treat an alcoholic bartender and then send him or her back to a neighborhood bar for their recovery,” he said. “Yet, many physicians in recovery are sent back to their medical practice in a hospital or clinic—these are the places where they obtained their drugs in the first place.” —Donald M. Pizzi

The case for Vectibix® Q2W dosing schedule1 – The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1 – Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1 – The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the ﬁrst or subsequent episodes of infusional toxicity is unknown

No loading dose1 – No loading dose is required

1% severe infusion reactions reported1 – Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION:

Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations. Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)]. In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or lifethreatening dermatologic toxicity and monitor for inflammatory or infectious sequelae. Terminate the infusion for severe infusion reactions.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed. Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women. Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCICTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Please see brief summary of Prescribing Information on next page. Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); Reference: 1. Vectibix® (panitumumab) dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia prescribing information, Amgen. (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®. ©2010 Amgen Inc. All rights reserved. 07-10 48257-A

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • AUGUST 2010

Access to Drugs

IND continued from page 1

gaining access to investigational drugs. One module provides an overview of expanded access, including the goals and general parameters for which patients may qualify. Another explains the process of completing individual patient IND applications. The third outlines sponsorinvestigator responsibilities, including the critical importance of obtaining and documenting informed consent. The modules are available to all physicians free of charge, online at www.

The modules are available to all physicians free of charge, online at www.university.asco.org/ExpandedAccess. university.asco.org/ExpandedAccess. They include links to templates that can be used to complete the process. Steps described in the module are relevant for gaining treatment access to any experimental drug for a serious or life-threatening illness or condition, not just anticancer therapies. Although most investigational agents will still be offered to patients within the context of a clinical trial, the

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

program should help increase the supply of experimental drugs to patients who have no other options and are likely to benefit from them, but do not qualify for a clinical trial. The new initiative was described at a press conference at the 2010 annual meeting of ASCO. “We were pleased that the FDA offered us the opportunity to develop comprehensive educational materials to assist all doctors, not just oncologists, to

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

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCICTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing experience: The following adverse reaction has been identified during post-approval use of panitumumab. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Angioedema [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Anaphylaxis [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations]. Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v9, 5/2010 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. MC46026-D © 2006-2009 Amgen Inc. All rights reserved.

understand this process,” said George W. Sledge Jr., MD, who is the new president of ASCO and spoke about the collaboration. A professor in the Division of Hematology/Oncology at the Melvin and Bren Simon Cancer Center, Indiana University, in Indianapolis, Dr. Sledge indicated that access to experimental medicines may now be much more feasible outside of academic centers for physicians willing to complete the IND process.

A Matter of Hours In setting off on the path to obtaining an investigational drug, the first step is agreement by the patient and physician that an experimental agent may be appropriate based on the absence of other treatment options, that the patient is not eligible to participate in a clinical trial testing the drug and that there is reasonable evidence that the experimental therapy may be beneficial. The next steps include contacting the pharmaceutical company to confirm that the company is able and willing to provide the drug on an expanded-access basis and then completing the IND application. When the IND is submitted, the FDA then grants or denies the application based on formal criteria of likely benefit and potential for harm. “Once we receive the application, we act quickly. The review may sometimes

Where do you go ... ... if you recall reading an educational supplement, but no longer have a hard copy? ... if you heard about an interesting article from a colleague, and would like to obtain a copy?

CLINICALONCOLOGY.COM

Correction An article in the July issue of Clinical Oncology News, “Battle of Second-Generation TKIs Declared in CML” should have stated that the major molecular response rates of patients on nilotinib (Tasigna, Novartis) at 24 months was based on 145 patients, not 125 patients. In Figure 2, the major molecular response rate in patients on imatinib at 18 months should have been reported as 36%, not 39%. ClinOnc regrets the errors.

The WAITING ROOM be completed in a matter of hours,” Mr. Klein reported. He reiterated that “the FDA is very open to improving access to investigational therapies” but cautioned that this access must be “reasonable” based on the estimated benefit-to-risk ratio for the patient. “INDs for treatment access have often been geared toward large groups of patients, but a clarification of the requirements and the process should provide greater access for the individual patient who is not eligible for a clinical trial,” Mr. Klein said. The treatment-use IND applications are not intended to be a strategy to circumvent the rigorous system of drug development, which is designed to ensure an optimal balance of benefit to risk for drugs widely distributed. Instead, the applications allow controlled access to specific agents before general availability when there are no other treatment options, particularly when a potential for a survival benefit exists.

FDA Takes Step To Streamline In recent years, the FDA has worked to consolidate information about requirements for treatment access in their regulations and to minimize documentation and record-keeping requirements. During the more than 30 years that the FDA has permitted experimental agents to be used under an IND for the purpose of treatment rather than research, the rules had become hard to interpret. Clinicians found it a real challenge to submit applications that would be successful. To remedy this, the FDA, independently of ASCO, completed an effort last year to consolidate and clarify these rules. The result was new regulations, including one that outlined rules for charging for investigational drugs, which were published in late 2009. Representatives of the FDA emphasize that the process of seeking an IND has been redefined, but not necessarily relaxed. The FDA will continue to require substantial documentation of the potential for benefit and evidence that the risks have been fully considered. —Ted Bosworth

by Joan Chiverton

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy). Take five minutes to fill out our short reader survey online at www.clinicaloncology.com and be entered into a drawing to win a $300 gift card from American Express. We appreciate you helping us to improve Clinical Oncology News.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • AUGUST 2010

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2010

Multiple Myeloma

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have happened in myeloma in the last couple of years,” said Sergio Giralt, MD, chief, Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York City. Speaking at the 2010 meeting of the American Society of Clinical Oncology (ASCO), where these data had just been presented, Dr. Giralt emphasized that the benefit of maintenance therapy with lenalidomide after ASCT was observed regardless of β2 microglobulins, cytogenetics, type of induction or response to the initial therapy. The two studies had similar designs and asked the same question. Can a maintenance therapy after ASCT reduce or delay the high rates of relapse that are presumably due to residual disease? Lenalidomide, an oral therapy, was an attractive choice because it is reasonably well tolerated and has demonstrated substantial activity in MM in the past. There were a few design differences between the two studies, one conducted by the International Myeloma Foundation (IMF 2005-02) and the other by Cancer and Leukemia Group B (CALGB 100104), but the consistency of the outcomes were mutually reinforcing. The expert invited by ASCO to discuss the studies, Dr. Giralt, concurred with the authors that the results support maintenance lenalidomide as a new standard after ASCT. In the IMF 2005-02 trial, 614 MM patients younger than age 65 years who had received ASCT within the previous six months and had nonprogressive disease were randomized to lenalidomide or placebo (abstract 8018). Those in the lenalidomide arm received a two-month consolidation course at 25 mg per day for 21 days for each of the two induction months followed by 10 to 15 mg per day of maintenance lenalidomide until

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Figure 1. Comparison of progression-free survival in IMF2005-02 trial. progression. In CALGB 100104, 568 MM patients younger than age 70 years were randomized to placebo or 10 mg per day of maintenance lenalidomide for three months, at which time the dose was escalated to 15 mg per day. At the end of 24 months of follow-up in the IMF trial, 68% of patients receiving lenalidomide maintenance had not progressed compared with 35% of those on placebo, generating the 54% relative improvement. The overall survival estimated at three years was 88% in patients receiving lenalidomide maintenance compared with 80% for those given placebo, a relative 12% improvement that approached statistical significance (HR, 0.88; P=0.08). Compared with previous rates of PFS after ASCT, these outcomes were characterized as “unprecedented” by the senior author of the IMF 200502 trial, Michel Attal, MD, Department of Hematology and Biostatistics, Hôpital Purpan, Toulouse, France. However, he emphasized that the results were preliminary, that the survival figures are not meaningful with this amount of follow-up and a much more complete analysis will be presented at the American Society of Hematology meeting at the end of this year.

In the CALGB 100104 study (abstract 8017), the median TTP was 25.5 months in patients receiving placebo but had not yet been reached in those randomized to receive lenalidomide. This outcome, recorded after a median of 12 months of follow-up, generated the reported 58% risk reduction. There was no difference in overall survival between the arms, but the lead investigator, Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, New York, explained that placebo patients were permitted to switch to lenalidomide at progression, diluting the ability to show a survival advantage. Lenalidomide was well tolerated in both studies. The major difference was the higher rate of hematologic toxicities, which were generally asymptomatic. In IMF 2005-02, grade 3 or 4 neutropenia was recorded in 7% of lenalidomide patients and 1% of patients randomized to placebo (P<0.001). There were no significant differences in any other grade 3 or 4 hematologic outcomes. In CALGB 100104, grade 3 or higher neutropenia was observed in 42% of lenalidomide patients and 7% of those on placebo (P<0.0001), whereas anemia (6% vs. 1%; P=0.0028) and thrombocytopenia (12% vs. 3%; P=0.01) also were significantly higher on lenalidomide. Grade 3 or 4 nonhematologic side effects, including neuropathy, were uncommon and relatively few patients dropped out of either study for adverse events. In his review of this data, Dr. Giralt expressed concern about the potential risks for significant hematologic toxicities among patients, indicating that some routine form of monitoring may

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Figure 2. Comparison of grade 3 or higher neutropenia in CALGB 100104 Trial. be appropriate. Although he advocated lenalidomide maintenance, he said there is a new set of questions to answer, including how long patients should be maintained on treatment and whether a single ASCT before lenalidomide maintenance is the best approach. These questions may be answered by a 750-patient trial called CTN 0702. In this study, described by Dr. Giralt, patients completing melphalan induction and ASCT will be randomized to a second round of the same therapy, lenalidomide maintenance alone, or four cycles of the combination of bortezomib, dexamethasone, and lenalidomide. All will be followed by three years of lenalidomide maintenance. Although he commented that “today, we leave knowing that lenalidomide does prolong PFS,” Dr. Giralt called for a better dissection of what it means to achieve or preserve a complete response (CR) with induction or maintenance therapies. In particular, he expects future work to look at specific definitions of CR as established by polymerase chain reaction or flow cytometry, to determine the relationship of the quality of the CR to prolongation of remission. —Ted Bosworth

ALL

Novel Vincristine Formulation Improves Outcomes in ALL A liposomal formulation of vincristine (Marqibo, Hana Biosciences) is active in adult patients with refractory or relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL), according to a Phase II trial presented at the recent American Society of Clinical Oncology meeting (abstract 6507). Twenty percent of patients in the study achieved complete remission (CR) or CR with incomplete blood count recovery (CRi). Another 9% had a partial remission and 6% had bone marrow that normalized but without full recovery of blood counts.

“We have a significant response rate of 35% in a very heavily pretreated population of patients with ALL—poor performance status in 23%, almost 50% receiving four lines or greater of therapy, and all of whom had prior vincristine,” said Susan O’Brien, MD, who presented the study. “The CR/CRi rate of 20% compares favorably to historical experience of 4% CR with single agents. There were no unexpected toxicities.” Dr. O’Brien is a professor, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston.

Patients were included in the open-label trial if they were in their second relapse or had progressed after two or more prior lines of treatment. Data was available for 56 patients who received liposomal vincristine sulfate injection at 2.25 mg/ m2 with no dose cap, IV weekly over one hour. The median age of patients was 32 years; 48% had received a prior stem cell transplant; 20% had extramedullary disease; 100% had prior vincristine exposure; and 82% had a history of neuropathy. The most common related adverse events of grade 3 or higher were neuropathy (22%), febrile neutropenia (32%),

constipation (2%) and diarrhea (5%). Dr. O’Brien said the liposomal formulation allows higher doses of vincristine to be delivered and prolongs the type of exposure. Additional trials are planned. According to Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, Boston, the agent merits further study. “Packaging the old ‘standby’ vincristine in a liposomal matrix administered as a single agent yielded a better-than-expected 20% CR/CRi rate in a very poor prognosis group of [ALL] patients.” —Kate O’Rourke

PRN

CLINICAL ONCOLOGY NEWS • AUGUST 2010

People

Around the Water Cooler Wasif Saif, MD, has accepted a position as professor of medicine at Columbia University College of Physicians and Surgeons, and director of the Clinical Division of Gastrointestinal Cancers at the Herbert Irving Comprehensive Cancer Center, both in New York City. In addition, he will serve as medical director for the Pancreas Center at NewYorkPresbyterian Hospital. Previously, Dr. Saif was an associate professor and co-director of the Gastrointestinal Cancers Program at Yale Cancer Center, Yale University School of Medicine, in New Haven, Conn. He started his new responsibilities on Aug. 1, 2010. Ed Chu, MD, has accepted a position as chief of the Division of Hematology/ Oncology and deputy director of the University of Pittsburgh Cancer Institute, at the University of Pittsburgh. Previously, Dr. Chu was chief of the Section of Medical Oncology, professor of medicine and pharmacology, and deputy director of clinical research at Yale Cancer Center, Yale University, in New Haven, Conn. Dr. Chu serves as an advisory board member of Clinical Oncology News. He will start his new position on Sept. 1, 2010. Robert Figlin, MD, has joined CedarsSinai Medical Center’s Samuel Oschin Comprehensive Cancer Institute as director of the Division of Hematology/Oncology and as associate director of the institute’s Academic Development Program, in Los Angeles. Dr. Figlin will help manage the institute’s growing clinical trials program, and as leader of the Hematology/Oncology Division, he will oversee breast, prostate, lung, blood and bone cancer programs. Before joining CedarsSinai, Dr. Figlin was chair of the Department of Medical Oncology & Therapeutic Research at City of Hope Comprehensive Cancer Center, in Duarte, Calif. Previously,

If you have news to share (a new job, an award, a cancer center closure or expansion, etc.), please send information to korourke@ mcmahonmed.com.

Dr. Figlin was with the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, for more than 20 years, where he held a number of leadership positions in the areas of urologic cancer and hematology/oncology. A new $1 billion cancer center is being added to the Ohio State University Comprehensive Cancer Center– Arthur G. James Cancer Hospital and Richard J. Solove Research Institution, in Columbus. This is in addition to a new

freestanding Women’s Breast Center that will open in January 2011 just minutes away from the James Cancer Hospital. The new cancer hospital will include

276 beds and a critical care building, providing integrated spaces for groundbreaking cancer research, education and patient care.

NCCN 2010 Patient Safety Summit

The NCCN 2010 Patient Safety Summit will provide an opportunnityy for clinicall, administrative, and indusstryy professiiona als to discusss best pracctices in oncology patient safety as well as to disseminate advances in oncology patient safety systems and processes.

K Keynote address by Pete PPe terr J. PPro rono novo vost st, MD MD, Ph PhD, D, ScD D, Jo ohns Hopkins Medicine Th T h ﬁ 100 id i willl rece wil w receive ive a sig gned copy of Dr. Prono P ovos vo t’s book: book:

Safee Patients, Saf S P Smart rt Hospit p als

Visit NCCN.org for o the compllete agenda d an and d to ssec ecur ure ur e a se seat at a att th this is educ ed ucat atio iona nal ev e en e t.. C-NN 0952-0810

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • AUGUST 2010

New Phase II and III Clinical Trials

Hematologic

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to July 17, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive Care

Protocol Type

Age

Protocol ID

Trial Sites

Randomized Study of Adjuvant FOLFOX Chemotherapy Comprising Oxaliplatin, Leucovorin Calcium, and Fluorouracil With Versus Without Celecoxib in Patients With Resected Stage III Colon Cancer, Phase III

18 and over

CALGB-80702

DC, MS, NC, NY, PA

A Study of a Replication Competent Retrovirus Administered to Subjects With Recurrent Glioblastoma, Phase II

18 to 75

Tg 511-08-01

Randomized Study of Veliparib With Versus Without Carboplatin in Patients With Stage III or IV BRCA-Associated Breast Cancer, Phase II

18 and over

CHNMC-PHII-96

CA, IL, MN, NY, PA, TX

Trial of Exemestane With or Without MM-121 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor-Positive and/or Progesterone Receptor Positive HER2-Negative Breast Cancer, Phase II

18 and over

MM-121-02-02-03

Acolbifene for Breast Cancer Chemoprevention, Phase II

30 to 55

10588

Intensity-Modulated Radiation Therapy for Patients With Rectal Cancer, Phase II

18 and over

09-157

SBRT and Chemo for Unresectable Cholangiocarcinoma Followed by Liver Transplantation, Phase II

18 and over

SU-11122009-4380

Paclitaxel, Carboplatin and Cetuximab Versus Cetuximab, Docetaxel, Cisplatin and Fluorouracil in Previously Untreated Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma, Phase II

18 and over

2009-0885

MA, TX

Pazopanib Hydrochloride Before Surgery in Treating Patients With Kidney Cancer, Phase II

18 and over

CASE4809

Celecoxib and Recombinant Interferon Alfa-2b in Treating Patients With Metastatic Kidney Cancer Who Have Undergone Surgery, Phase II

18 and over

CASE8805

Immune Response Following Treatment of Resectable Renal Cell Carcinoma at Intermediate Risk for Recurrence, Phase II

18 and over

C-100-38

NY, TX

Study of Aldesleukin (IL-2) Following the Administration of Zanolimumab (Anti-CD4mAb) in Metastatic Melanoma and Metastatic Renal Cancer, Phase II

18 and over

100145

Study of IMC-A12 in Patients With Mesothelioma Who Have Been Previously Treated With Chemotherapy, Phase II

18 and over

100146

Study of Paclitaxel/Carboplatin With or Without Bavituximab in Previously Untreated Non-Small Cell Lung Cancer, Phase II

18 and over

PPHM 1001

PET Acetate for Castrate-Resistant Prostate Cancer on Chemotherapy, Phase II

18 and over

PET ACE 01

Randomized Study of Pre-Operative Androgen-Ablation Therapy With Versus Without Hedgehog Antagonist GDC-0449 Followed by Radical Prostatectomy in Patients With Locally Advanced Adenocarcinoma of the Prostate, Phase I/II

18 and over

MDA-2009-0473

MI, NC, TX

Pilot Study of Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers, Thymic Neoplasms, and Malignant Pleural Mesotheliomas, Phase I/II

18 and over

100138

Partially Randomized Study of Hedgehog Antagonist GDC-0449 in Combination With Gamma-Secretase Inhibitor RO4929097 in Patients With Advanced or Metastatic Sarcoma, Phase I/II

18 and over

MSKCC-10049

Trivalent Ganglioside Vaccine With Immunological Adjuvant or Immunological Adjuvant Alone in Metastatic Sarcoma Patients Who Are Rendered Disease Free, Phase II

16 and over

MV-0109DP001

CA, NY, OR

Gemcitabine Plus Fractionated Stereotactic Radiotherapy for Unresectable Pancreatic Adenocarcinoma, Phase II

18 and over

SU-02012010-4843

Study of the Safety and Efficacy of TH-302 in Combination With Gemcitabine Compared With Gemcitabine Alone in Previously Untreated Patients With Pancreatic Adenocarcinoma, Phase II

18 and over

TH-CR-404

Neoadjuvant for Ovarian Cancer, Phase II

18 and over

AAAD8429

NY, PA, TX, VA

Study of Elacytarabine Versus Investigator’s Choice in Patients With Late-Stage Acute Myeloid Leukemia, Phase III

18 and over

CP4055-306

Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma, Phase I/II

18 and over

CASE1A09

A Study of Pegylated Liposomal Doxorubicin, Bortezomib, Dexamethasone and Lenalidomide for Patients With Relapsed/ Refractory Multiple Myeloma, Phase II

18 and over

RV-MM-PI-0533

Study of Bafetinib as Treatment for Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia, Phase II

18 and over

BAFETINIB-P2-CLL-01 TX

Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Phase II

18 and over

100141

Study of Canfosfamide in Refractory or Relapsed Mantle Cell, Diffuse Large B-Cell Lymphoma and Multiple Myeloma, Phase II

18 and over

TLK286.2030

Safety and Efficacy Study for Solid Tumor Patients Treated With Eltrombopag, Phase II

18 and over

112765

A Study to Accelerate Immune System Recovery Following Stem Cell Transplantation, Phase II

16 and over

01.0082

Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801), Phase II/III

Not specified

609

CA, FL, GA, IN, IA, MI, OK, WA

Acute Graft-versus-Host Disease Treatment (BMT CTN 0802), Phase III

Any age

669

CO, GA, IL, IA, MD, MI, SD, TX

Low-Dose or Standard-Dose Glucocorticoids in Treating Patients With Newly Diagnosed Acute Graft-Versus-Host Disease, Phase III

Not specified

CDR0000647225

Treatment of Blood Clots in Children With Cancer

0 to 18

FRAG-A001-201

AK, CA, DC, FL, GA, IL, IN, KY, NM, OR, TN, TX

Randomized Controlled Trial of Group Psychotherapy Interventions for Cancer Patients, Phase III

21 and over

07-094

Sleep Management in Cancer Survivors, Phase II

18 and over

33669

Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation, Phase III

18 and over

465

FL, IN, MD, MA, MI, MN, NC, NY, OR, PA, TX, WA

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An Update on Pediatric Oncology and Hematology, An Issue of Hematology/Oncology Clinics of North America

Max J. Coppes; Russell E. Ware; Jeffrey S. Dome This issue highlights some of the exciting new developments in pediatric oncology and hematology. Three articles are devoted to pediatric leukemia, which remains the most common form of pediatric cancer. Specifically, articles address ALL, AML, leukemia in patients with Down syndrome, CNS tumors and neuroblastoma and advances in cancer immunotherapy. The hematology articles cover aspects that most clinicians see on a regular basis—sickle cell disease, thalassemia, hemophilia and ITP.

2 ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, e-mail your request with billing information to RMcMahon@ McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@ McMahonMed.com.

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Breast Cancer Michael J. Michell

In this volume, key current issues relating to screening, diagnosis and treatment of breast disease are discussed by recognized international experts. The development of new technology enabling more accurate screening and diagnosis is described including complex drug therapy and risk factors for breast cancer.

Cancer: Principles and Practice of Oncology— Advances in Oncology

Vincent T. DeVita The first volume of a new series will focus on the most significant changes in oncologic research and practice that have taken place during the preceding year. Each volume identifies scientific and clinical areas in oncology that are rapidly changing and show a high potential for affecting the management of cancer patients in the future.

The Economics of Cancer Care Nicholas Bosanquet; Karol Sikora

This book analyses tensions between those paying for cancer care, those providing care and those marketing drugs and devices. Written by a leading health economist and oncologist, this is the first comprehensive book on the economics of cancer care and is essential reading for health professionals and policymakers alike.

For Doctors Only: A Guide to Working Less & Building More

Christopher R. Jarvis, MBA; David B. Mandell, JD, MBA; Jason M. O’Dell, CWP; Claudio A. DeVellis, JD, CPA

For Doctors Only teaches doctors how to perform efficiently so they can get more out of a medical practice. More specifically, For Doctors Only will help doctors protect their personal and practice assets from lawsuits, taxes and bad investments while showing them the secrets to building wealth through the leverage of people, assets and effort.

Leibel and Phillips Textbook of Radiation Oncology: Expert Consult - Online and Print

Theodore L. Phillips; Richard M.D .Hoppe Stay on top of the latest scientific and therapeutic advances with the new edition of Leibel and Phillips Textbook of Radiation Oncology. Dr. Theodore L. Phillips offers a multidisciplinary look at the presentation of uniform treatment philosophies for cancer patients emphasizing the "treat for cure" philosophy. You can also explore the implementation of new imaging techniques to locate and treat tumors, new molecularly targeted therapies and new types of treatment delivery.

Medical Practice Management in the 21st Century: The Handbook

Marjorie A. Satinsky, MBA; Randall T. Curnow Jr., MD, MBA This book will help physicians understand the breadth of practice management, learn the essentials about start-up, organization and management, managing finances, recruiting and managing staff and outside resources, improving health care delivery and clinical outcomes and ensuring compliance.

Mosby's Assessment Memory NoteCards

The Physics of Radiation Therapy

Wintrobe's Atlas of Clinical Hematology

JoAnn Zerwekh; Tom Gaglione

This colorful and illustrated collection of spiral-bound cards covers important assessment procedures and tips using humor, cartoons, and mnemonics. Designed to aid in reviewing and studying throughout nursing school and for the NCLEX® examination, Mosby's Assessment Memory NoteCards encourage retention and understanding of assessment skills and tips by using a variety of proven learning techniques.

Faiz M. Khan

This leading reference source devoted to radiation therapy physics is clinically oriented and presents practical aspects as well as underlying theory to clarify basic concepts. The format begins with underlying physics, then progresses to treatment planning and ends with radiation. It contains an expanded focus with seven new chapters on special procedures. Remaining chapters have been revised to detail any new developments in the field.

Douglas C. Tkachuk; Jan V. Hirschmann

With more than 400 high-resolution diagnostic digital photomicrographs and concise text, this new full-color atlas is a comprehensive guide to diagnostic hematology. It enables physicians to see and readily comprehend diseased tissues and understand the complex assays routinely used in the care of patients with hematologic diseases. CO0810

CLASSIFIED

ONCOLOGY—BISMARCK, NORTH DAKOTA

Forbes and Fortune Small Business Magazine rank Billings, MT - the Best! Practice medicine in a city ranked as one of the Best Small Places for Business and Careers (Forbes, 2009) and the Best Small City in which to start a business (Fortune Small Business Magazine, November 2009). Award winning St. Vincent Healthcare and St. Vincent Children’s Healthcare in Billings, MT, seeks well-trained, compassionate physician to build our Pediatric Oncology program. Possible academic appointment available Access to clinical trials 22 bed dedicated pediatric floor and 7 bed PICU supported by Board Certified Pediatric Intensivists who are available 24 hours a day/7 days a week Pediatric specialty clinics which serve patients from Montana and Wyoming Pediatric rehabilitation including physical therapy, speech therapy, and occupational therapy Thriving medical community in a family-oriented suburban location Excellent School System Abundant recreational activities year round – hiking, skiing, fishing, biking and camping Excellent Benefits and Competitive Salary Structure, based on MGMA Sign-on Incentives, Moving Allowances, and CME reimbursement. Will consider loan forgiveness. SVH is staffed for 250 beds and is a regional destination hospital which serves a four-state area and more than 900,000 people each year Known for providing superb patient care Maternal Fetal Medicine Physician and 4 Neonatologists on Medical Staff Pediatric specialists on Medical Staff include: Neurology, Cardiology, Behavioral and Developmental, Urology, GI and Orthopedics Pediatric Specialty Clinics include: Cleft/Craniofacial; Cystic Fibrosis; Endocrine; Gastrointestinal; Genetic High Risk Infant Follow-up; Hematology; Metabolic; Nephrology Neural Tube Defect; Neurology and Rehabilitation AASM accredited sleep center; Level II Trauma Center; HELP Helicopter and Fixed Wing air transport program with specialty transport teams; and CARF Accredited Inpatient Rehabilitation Program SVH invests in the latest technology: Allura Xper FD20/10 interventional angiographic X-ray lab, Toshiba Aquilion ONE dynamic volume 320-slice CT system and Da Vinci Robotics SVH is ranked Best for Heart Attack Care and #15 for Quality in the nation

Find out more, visit www.svh-mt.org/physicians Contact: Colleen Martin 406-237-4003 Collen.Martin@svh-mt.org Therese Harris (406) 237-4017 Therese.Harris@svh-mt.org

Opportunity

edcenter One in Bismarck, North Dakota is seeking an Oncologist to join a very busy practice with two Oncologists, two Radiation Oncologists, two Research Oncology Nurses, Pharmacist and mid-level providers. Call will be 1:3 with a fourth physician joining the practice summer of 2011. The Cancer Program has a strong presence in the region and state market. The minimum requirements for this position requires MD or equivalent; possess or eligible for a North Dakota license. • 19-bed dedicated Oncology unit with a 12-chair infusion center (staffed with oncology and chemo certified nurses and pharmacist) • Research & Clinical Trials performed at Medcenter One, with 7-10% of the patient population currently on research. Includes NCCTG & CTSU trials with Mayo Clinic • Tumor Boards are conducted bi-weekly at Medcenter One • Immunotherapy, Target Directed Therapy and Radio Immunotherapy • Currently working on breast care Center of Excellence

Organization Medcenter One http://www.medcenterone.com is a not-for-profit, fully integrated, multi-specialty clinic and a Level II Trauma Center, with 237 JCAHO accredited licensed beds and teaching hospital. The health system consists of six primary care clinics covering western and central North Dakota, a hospital, a home health agency, three kidney dialysis centers, four long-term care facilities, one independent living center and a college of nursing. The Medcenter One Q&R Clinic was founded in 1902 and was the second multi-specialty clinic in the nation, second only to Mayo Clinic in Rochester, MN. Employs over 150 physicians and 320 credentialed providers.

Community Bismarck is the state capital of North Dakota, located in the south central part of the state in the Missouri River valley, surrounded by high hills, green forests, and charming farm country. Population of Bismarck/Mandan is approximately 100,000, and is one of the only states in the union with a budget surplus, and has one of the nation’s lowest unemployment rates. ND almost always ranks at the top of the FBI’s Safest Places to Live and Raise a Family in the Country. The community offers a variety of cultural attractions, such as a good variety symphony, choir and arts. The area is noted for its excellent private and public schools with great choices of colleges, plus abundant outdoor activities, such as fishing, hunting, boating, golfing, and a ski resort just outside of Bismarck. The UND School of Medicine has a Family Practice residency program in Bismarck, which allows the residents to work in several Bismarck practices.

Benefits & Compensation Employment agreement with guaranteed yearly salary including WRVU incentive. Signing bonus and relocation allowance provided. Excellent health insurance benefits, retirement programs, CME allowance, paid vacation and paid medical malpractice.

Contact information: Connie Long, Manager of Physician Recruitment, clong@mohs.org Office: (877) 323-5417 or (701) 323-5417 • Cell: (701) 516-4000

METRO SOUTH CAROLINA Hospital employed Medical Oncology position joining Hem/Onc and Hematologist in desirable South Carolina metro area nestled in Blue Ridge Mountain and two hours to Charlotte and Atlanta associated with growing 450-bed health system with Bone Marrow Transplant Unit and new Cancer Center affiliated with MD Anderson. 1-3 call. Excellent salary, bonus and benefits. DONOHUE AND ASSOCIATES (800) 831-5475 F: (314) 984-8246 Email: donohueandassoc@aol.com.

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