June 2011 Clinical Oncology Digital Edition

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

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Steven Vogl discusses the approval of ipilimumab.

L arge study shows dietary soy safe for breast cancer survivors.

S tudy dissects gastrointestinal adverse events of Avastin in patients at high risk.

HematOlogic DISEASE

10

T he real costs of defining heterogeneity in AML.

POLICY & MANAGEMENT

16

W hat makes for a successful community cancer center?

ClinOnc gains insight from ProHealth Care Regional Cancer Center.

SUPPORTIVE CARE

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Systematic review backs efficacy of opioid agents.

Image centers in community cancer centers cater to survivors.

Web Exclusives Are Available At

clinicaloncology.com

WWW.CMEZONE.COM

They Will Survive: Building a Cancer Survivorship Program

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s of 2007—the latest year for which the Centers for Disease Control and Prevention has numbers—there were 11.7 million cancer survivors living in the United States. That’s 2 million more than there were just six years earlier. And with 67% of adults with cancer surviving at least five years (pediatric cancers have an even higher five-year survival rate), those numbers are expected to grow exponentially over the next decade.

According to the National Action Plan for Cancer Survivorship, fully one-third of survivors say they experience ongoing physical, psychological or financial consequences of their cancer diagnosis and treatment. To address these see SURVIVAL, page 18 

EDITORIAL BOARD COMMENTARY

Phase III Data: Merely The Start of Patient Management Plans

P

erhaps the word “merely” in the title of this commentary is a bit harsh. Surely, the results of a welldesigned and well-conducted, evidence-based clinical trial is critically relevant, and without quesMaurie tion, should be seriously considered by patients and Markman, MD their physicians in the initial design and modification of patient management discussions.

However, some individuals apparently believe that results of Phase III randomized clinical trials (RCTs) should trump all other considerations in both see MANAGEMENT, page 17 

Maintenance Lenalidomide Improves Survival in Myeloma Paris—Building on previous studies showing that maintenance therapy with lenalidomide improves end points such as progression-free survival (PFS) in patients with multiple myeloma, a study presented at the International Myeloma Workshop shows that this therapy also improves overall survival (OS).

Even though some researchers believe lenalidomide (Revlimid, Celgene) maintenance should become the standard of care, others are urging caution because the therapy appears to be associated with A cluster of neoplastic plasma cells from touch imprints of a bone marrow a higher rate of core biopsy stained with Wright-Giemsa (x1,000 magnification). second cancers.

In the National Cancer Institute–spon- and autologous stem cell transplantation sored double-blind, randomized Phase III with melphalan were randomized at day study, newly diagnosed multiple myeloma 100 post transplant in a 1-to-1 fashion to see MAINTENANCE, page 12  patients who received induction therapy

POLICY & MANAGEMENT

When the Going Gets Tough, The Tough Get … Lean Found Money: Part 4 of a Four-Part Series

C

ommunity oncology practices know what it means to get lean, at least those that have been able to endure the long siege of rising costs and shrinking reimbursements.

Through smart information technology (IT) investments, better staff deployment and more astute coding and billing practices, the survivors are managing to carry on with little or no compromise in patient care.

“You have to make your practice as efficient as you can. There is no other option for that—and it’s tough,” said Barbara McAneny, MD, chief executive officer of New Mexico Oncology Hematology Consultants Ltd., in Albuquerque.

During the past decade or so, Dr. McAneny’s group of eight medical oncologists and two radiation oncologists (a see FOUND MONEY, page 22 

FDA News

Afinitor and Sutent approved for pancreatic neuroendocrine tumors. See page 12.

Credit: Dr. George Deeb, Roswell Park Cancer Institute

SOLID TUMORS

KNOW YOUR PATIENTS’ HISTOLOGY AND 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.

ALIMTA is available in 100 mg and 500 mg vials.

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).

PM70198

0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

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

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

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

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)— 1st-line NSCLC 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.

PM_HCP_ISI_NSCLC1_04052011

insideALIMTA.com

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

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

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

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous 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.

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

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

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

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities 75% of previous dose (pemetrexed and Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin).

50% of previous dose (pemetrexed and Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. 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 (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% 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].

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

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

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

5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation 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)].

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

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

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

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

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

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

Incidence 1% to 5% Body as a 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 Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Gastrointestinal — colitis General Disorders and Administration Site Conditions — edema

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

a

NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

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

PV 5209 AMP

5.2

PV 5209 AMP

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal.

7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen 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 Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

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

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

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

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

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)].

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

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

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

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

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

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

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

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

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

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

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay).

Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

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

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

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

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

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

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

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

PV 5209 AMP

Literature revised March 17, 2011

Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 2004, 2011, Eli Lilly and Company. All rights reserved.

PM_HCP_BS_NSCLC1_04052011 PV 5209 AMP

PRINTED IN USA PV 5209 AMP

6

SOLID TUMORS

Clinical Oncology News • June 2011

Melanoma

Vogl, New York ...

Ipilimumab for Melanoma: More Evidence Needed EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

O

n March 5, Bristol-Myers Squibb, the maker of ipilimumab (Yervoy), published a news release indicating that its representatives will present a positive trial (called CA184-024) at the meeting of the American Society of Clinical Oncology in June 2011, showing longer survival among patients with metastatic melanoma treated with a combination of ipilimumab with dacarbazine compared with dacarbazine alone. I was doubly pleased to read about this news, and eagerly await presentation of the results to find out if the trial was well designed, conducted, and analyzed. On the one hand, the double pleasure has to do with the dearth of effective treatments for metastatic melanoma, and on the other hand, with grave reservations I have about the design and analysis of the study

on which FDA approval of ipilimumab rests (N Eng J Med 2010;363:711-723, PMID: 20525992).

Briefly, 676 patients with worsening unresectable melanoma after prior chemotherapy or interleukin (IL)-2 were assigned to 1 of 3 arms: 4 infusions of ipilimumab (n=137), 8 injections (in a series of 2 each) of 2 modified HLA-restricted peptides with incomplete Freund’s adjuvant called glycoprotein (gp) 100 vaccine (n=136), or both (n=403), in a double-blind study. Objective responses occurred in 11% receiving ipilimumab, 1.5% given gp100 vaccine, and 5.7% treated with both. Median overall survival (OS) of patients, measured in months, was 10.1 for ipilimumab, 6.4 for gp100 vaccine, and 10.0 for both.

The biggest defect in the study design is the absence of an interpretable control group. Was ipilimumab good or was gp100 just bad? If the survival difference is from deleterious effects of gp100 vaccine plus Freund’s adjuvant, then we should spare our patients the toxicity of ipilimumab.

Second, the question the investigators aimed to answer changed several times from when the time the study was designed and conducted, to when it was analyzed and published, to when it

was presented to the FDA. The analysis is flawed by the change in primary end point from response to survival after all the patients had already been treated, presumably with some knowledge of the results.

The analysis also failed to correct the P values for the multiple comparisons that were explicitly made, or that we can assume would have been made, had the results turned out differently.

Is the Control Group Appropriate?

We should not dismiss the possibility that the gp100 vaccine plus Freund’s adjuvant shortened survival compared with no therapy. The paper cites 2 adjuvant vaccine studies in melanoma, 1 investigating BCG plus allogeneic vaccine (J Clin Oncol 2007;25:474s. abstract) and the other examining ganglioside plus KLH (J Clin Oncol 2008;26:484s. abstract), in which vaccination shortened survival compared with no treatment. In addition, consider the Eastern Cooperative Oncology Group

Pictured on left is a graphic of T-cell activation.

Ipilimumab potentiates T-cell activation.

E1694 adjuvant melanoma trial that compared high-dose interferon with a GM2 ganglioside vaccine and adjuvants (J Clin Oncol 2001;19:23702380, PMID: 11331315).

Although this study is often cited to support the efficacy of highdose interferon, I think it is more likely that the vaccine made survival worse compared with high-dose interferon.

Analysis of E1684 at a median followup of 12.6 years showed no significant survival benefit from high-dose interferon over observation, suggesting that the interferon was a toxic placebo in the E1694 trial and that the vaccine impaired survival (Clin Cancer Res 2004;10:16701677, PMID: 15014018).

While the survival curves in the 2010 study for ipilimumab alone and ipilimumab with gp100 do not appear different, we are not given an analysis with the goal of proving noninferiority of the combination. Noninferiority comparisons generally need large sample sizes of 700 to 1,000 subjects per arm, far

EDITORIAL BOARD Solid Tumors

Lung, and Head and Neck Cancers

Bone Metastases

Edward S. Kim, MD

Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University, Hershey, PA

University of Texas, M.D. Anderson Cancer Center, Houston, TX

Lung Cancer, Emesis

Breast Cancer

Richard J. Gralla, MD

Andrew Seidman, MD

Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center, Lake Success, NY

Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, NY

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, NY

Prostate Cancer

Gastrointestinal Cancer

Johns Hopkins Kimmel Cancer Center, Baltimore, MD

Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA

Cathy Eng, MD

Michael Carducci, MD

Editorial Philosophy The Editorial Advisory Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Steven Vogl, MD New York, NY

Hematologic Malignancies

Symptom Control and Palliative Care

Jennifer R. Brown, MD, PhD

William S. Breitbart, MD

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center, Duarte, CA

Pharmacy

Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA

Memorial Sloan-Kettering Cancer Center, New York, NY

Harry Erba, MD, PhD

Steven D. Passik, PhD

University of Colorado Cancer Center, Denver, CO

University of Michigan, Ann Arbor, MI

Vanderbilt University Medical Center, Nashville, TN

Sara S. Kim, PharmD

Gastrointestinal Cancer and Sarcoma

Mayo Clinic, Rochester, MN

Joseph V. Pergolizzi Jr., MD

Richard Stone, MD

Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, NY

Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA

Johns Hopkins University School of Medicine, Baltimore, MD

Bioethics

Ephraim Casper, MD

University of Texas, MD Anderson Cancer Center, Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College, New York, NY

Genitourinary Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH

Gynecologic Cancer Maurie Markman, MD Cancer Treatment Centers of America, Philadelphia, PA

Shaji, Kumar, MD

Community Oncology Michael J. Fisch, MD, MPH University of Texas MD Anderson Cancer Center, Houston, TX

John W. Finnie, MD David C. Pratt Cancer Center, St. John’s Mercy Medical Center, St. Louis, MO

Cindy O’Bryant, PharmD

The Mount Sinai Medical Center, New York, NY

Joseph P. DeMarco, PhD Cleveland State University, Cleveland, OH

Russell K. Portenoy, MD

Paul J. Ford, PhD

Beth Israel Medical Center, New York, NY

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Charles F. von Gunten, MD University of California, San Diego, CA

Policy and Management

Infection Control

Mary Lou Bowers, MBA

Susan K. Seo, MD

The Pritchard Group, Rockville, MD

Memorial Sloan-Kettering Cancer Center, New York, NY

Rhonda M. Gold, RN, MSN The Pritchard Group, Rockville, MD

SOLID TUMORS

Clinical Oncology News • June 2011

Melanoma

676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma with progressive disease

Ipilimumab alone (n=137)

Ipilimumab plus gp100 (n=403)

gp100 alone (n=136)

Figure. Design of study that resulted in ipilimumab approval.

beyond the 137 patients on the ipilimumab-alone arm. Further, it appears that the gp100 vaccine plus ipilimumab had fewer objective responses (5.7%) than ipilimumab alone (11%). As Patrick Hwu, MD, pointed out in the editorial that accompanied the study (N Engl J Med 2010;363:779-781, PMID: 20818880), “The true importance of this drug (ipilimumab) lies in the long-term benefit seen in a subgroup of patients.” Nine of 15 ipilimumab responders (6.5% of treated patients) were still in remission 2 years later, compared with just 4 of 23 responders who received ipilimumab with gp100 (1% of treated patients). By this end point, gp100 vaccine seemed to blunt the efficacy of ipilimumab in this study. It remains plausible that the survival difference observed was due to the deleterious effect of gp100 vaccine—not a benefit from ipilimumab.

Previous experience with gp100 is limited—a Phase II study of gp100 alone or with IL-2 (Nature Med 1998;4:321327, PMID: 9500606) and a Phase III randomized trial of 185 patients given high-dose IL-2 alone or with gp100 vaccine in which response rate rose from 9.7% to 22.1%, progression-free survival (PFS) increased from 1.6 to 2.9 months, and median survival improved from 1.8 to 17.6 months (P=0.09) (J Clin Oncol 2009;18s; 2009 [suppl; abstract CRA9011]). Thus, there are no Phase III data on the survival effects of gp100 vaccine and Freund’s adjuvant without high-dose IL-2, or in the broader population of melanoma patients whose general condition makes high-dose IL-2 dangerous to use.

What Question Was Being Asked?

From looking at the schema and the weighted treatment assignment, it seems the study was designed to show that a combination of ipilimumab and the gp100 vaccine was better than either agent alone. Whoever designed the protocol was hoping to develop a large experience with the combination—I suspect this resulted from the hope that 2 immunologic therapies would work better than 1. The paper states that response rate was the initial

primary measure. Five months after the study closed to accrual, when disappointing response rate data were complete or nearly so, the primary end point was changed to a comparison of OS of the 2 agents versus gp100 vaccine alone. Finally, in the conclusions of the paper, the use of ipilimumab monotherapy is favored, and the company sought and received approval for the drug used as monotherapy. Thus, we moved from “Do 2 drugs produce more responses than 1?” to “Do 2 drugs make patients live longer than gp100?” to “Does ipilimumab improve survival in previously treated metastatic melanoma patients compared with no treatment?” But, there was no “no treatment” arm.

Is The Study Population Representative of All Metastatic Melanoma Patients?

No—patients with advanced melanoma who are still ambulatory after firstline therapy must be a favorable subset enriched with those who have more indolent disease and those with disease outside the brain and liver. Further, patients who are fit for secondline therapy may be immunologically different from the larger population presenting for first-line therapy. This is a minor point, but is relevant if one considers the question to be “Is ipilimumab an effective therapy for metastatic melanoma?” It is conceivable that metastatic melanoma patients who survive a first round of systemic treatment and can be considered for secondline therapy are a distinct subset of the initial population and have a higher rate of long-term responses on ipilimumab than would be seen in first-line therapy of all comers. I, for one, will be listening very carefully to the presentation of the CA184-024 trial at ASCO 2011 for the number of long remissions on ipilimumab plus dacarbazine.

Are the Statistics Really Convincing?

In preparing this column, I asked an eminent statistician if there are too many possible comparisons to support a firm conclusion favoring survival benefit for ipilimumab. He replied that the

P values of less than 0.001 for 2 drugs versus gp100 vaccine and 0.003 for ipilimumab versus gp100 are so robust that they overcome my concern.

How many comparisons are possible?: each single arm with each other single arm (3 comparisons) or each single arm with the other 2 arms combined (3 more comparisons). Further, these 6 comparisons can be made for response rate, PFS and OS—this makes 18 comparisons, and does not take into account multiple looks at the data as the study progressed or in the follow-up period. If each end point was looked at 3 times during the study, that makes 54 comparisons. The study would probably have been reported as positive for some benefit if any of these comparisons revealed a P value of less than 0.05.

analysis are even more important because ipilimumab has substantial toxicity: 15% rate of severe immune– related events i n c l u d i n g d i a r- Scan for The New England Journal of rhea lasting more Medicine study than 2 weeks and requiring systemic corticosteroids.

The FDA mandated a special risk mitigation strategy to ensure that physicians are aware of the occasionally terrible and somewhat unusual toxicities of the drug. There were 14 deaths that were considered drug-related reported in the paper, but it was not specified to which drug they were related. I suspect all were ipilimumab related.

It remains plausible that the survival difference observed was due to the deleterious effect of gp100 vaccine—not a benefit from ipilimumab.

Is it totally fair to hold the investigators and Bristol-Myers Squibb responsible for comparisons they never made?

It probably is not. But if the gp100 vaccine had improved median survival by 4 months compared with the other 2 study arms, is it really conceivable that a statistical test would not have been done because this was not the primary study question?

I remain troubled, and my discomfort really will be relieved only by a wellconducted trial of ipilimumab against observation or placebo. In view of the high stakes in terms of career advancement for the investigators and profit for the pharmaceutical company, I suspect any difference observed in this study would lead to a call for approval of either gp100 vaccine or ipilimumab, or both. In my more cynical moments I wonder if Bristol-Myers Squibb would have dared to double the current $120,000 per course price for ipilimumab if the course included both ipilimumab and gp100 vaccine. Regardless, the stakes are high and positive results are rewarded.

Ipilimumab Is Quite Toxic My concerns about study design and

It is the duty of those of us who care for the sick to demand, as physicians, that studies be well done and well analyzed. For a treatment as toxic as ipilimumab, the data presented at ASCO 2010 and published in The New England Journal of Medicine on Aug. 19, 2010, are insufficient to recommend the treatment outside clinical trials.

I am as impressed as Dr. Hwu with the few long remissions among ipilimumab-treated patients, and I hope, as he does, that the observation will prove reproducible, and that we will be able to identify patients most likely to benefit from the drug with pretreatment immune or tumor studies.

I hope that the presentation of the results of the CA184-024 at ASCO 2011 will demonstrate a survival advantage from adding ipilimumab to dacarbazine as first-line therapy for metastatic melanoma, and that I will have no concerns as to study design, conduct or analysis.

I will be even happier if the data show that toxicity is predictable and generally manageable, with no treatmentrelated deaths.

Disclosures: Dr. Vogl reports that he owns stock in Bristol-Myers Squibb.

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SOLID TUMORS

Clinical Oncology News • June 2011

Breast

Dietary Soy Found Safe for Breast Cancer Survivors Breast cancer survivors can enjoy their tofu, soy milk and edamame without fear that soy consumption may cause disease recurrence, according to a comprehensive study that included more than 18,000 women in the United States and China.

Presented at the recent annual meeting of the American Association for Cancer Research, the study found that dietary soy did not increase the risk for cancer recurrence or death in the participants, who ranged from 20 to 83 years old and had diagnoses of primary invasive breast cancer (abstract 4665). In fact, although the findings were not statistically significant, high soy intake appeared to be associated with a reduced risk for mortality and recurrence compared with the lowest levels of soy intake.

Because of the known estrogen-like and anti-estrogen effects of soy isoflavones, there have been concerns that soy foods may not be safe for breast cancer survivors, and that they could either provoke recurrence by increasing hormonal activity or compromise the effectiveness of tamoxifen because both tamoxifen and isoflavones bind to estrogen receptors.

Neither possibility appeared to be true in this study, one of the largest to

examine the effects of soy. It used data from a multi-institution collaborative study, the After Breast Cancer Pooling Project, which combines the resources of four National Cancer Institute–funded studies: the Shanghai Breast Cancer Survival Study, the Life After Cancer Epidemiology Study, the Women’s Healthy Eating and Living Study and the Nurses’ Health Study.

“This fits with what we’ve been telling our patients: Dietary soy should be safe and it’s hard to avoid, as it’s in a lot of processed foods,” said Jennifer Griggs, MD, MPH, director of the breast cancer survivorship program at the University of Michigan’s Comprehensive Cancer Center, in Ann Arbor. “Since a lot of our patients are vegetarians and soy is a good source of protein, this has been a big concern for many of them. We can reassure people, based not only on this intriguing and well-done study but a wealth of other evidence, that it’s not unsafe to eat soy after having had breast cancer.”

Johanna Lampe, PhD, RD, a full member at the Fred Hutchinson Cancer Research Center, in Seattle, who

has studied the effect of soy consumption on primary breast cancer risk, commented, “I wouldn’t say it’s definitive because epidemiology is always challenging, but given the size and the number of pooled cohorts, this study provides clear reassurance that there is no major concern for breast cancer survivors consuming soy. Since it can be hard for older women to get sufficient amounts of high-quality protein in their diets, this is a definite plus.”

(The body of evidence on dietary soy and primary breast cancer in humans points to a similar conclusion, Dr. Lampe said, that there is no increased risk for developing primary breast cancer associated with high levels of soy consumption.)

Dr. Griggs noted that combining the Shanghai study with U.S. findings may confound the results somewhat because lifestyles are so markedly different. “In a country like China there is much less meat consumption, and, until recently, people rode bikes everywhere. There is a host of factors associated with economic vegetarianism that may be protective in the Shanghai study.”

The average daily intake of soy isoflavones was 3.2 mg among U.S. women. In the Shanghai group, the amount was significantly higher, at 45.9 mg. Dr. Lampe noted that there is evidence that women who start consuming soy at a young age and consume it all their lives—as many women do in China—have a decreased risk for breast cancer as opposed to those

who start consuming more soy later in life.

So that, they say, may explain the nonstatistically significant finding of a small protective effect against recurrence from soy consumption—in other words, it may all be from the Shanghai cohort.

What about supplemental soy, in powder or capsule form? The study does not address that topic, and Dr. Griggs continues to advise her patients to stay away from pharmacologic soy. “I would like to avoid increasing soy to a large blood level through pharmacologic doses of isoflavones because of the concern about blocking the action of tamoxifen,” she said. “I don’t have any proof that this would happen, but I don’t want to take the risk in my patients.”

What’s more, very little is known about how the many isoflavone supplements on the market might affect recurrence risk, Dr. Lampe said. “There’s virtually no data to say what happens if you’re consuming soy or other isoflavones at much higher doses in a pill.”

But when it comes to their tofu sloppy joes or the edamame at the local sushi restaurant, community oncologists can feel comfortable telling their breast cancer patients to stop worrying and enjoy. “It’s hard enough these days to find foods that people like that are also healthy for them, and this issue has, on occasion, really stressed out vegetarians,” said Dr. Griggs.

“I think we can be comfortable now telling them not to worry.”

—Gina Shaw

Ovarian

Study Dissects GI Risk of Bevacizumab Treating ovarian cancer patients with bevacizumab doubles the risk for gastrointestinal (GI) adverse events, but patients at risk for major GI events because of an underlying condition do not face additional risk from the drug, beyond the condition itself, according to a large clinical trial.

In the trial of patients who received chemotherapy or chemotherapy plus bevacizumab, those who had a history of treatment for inflammatory bowel disease or who had large-bowel resection at primary surgery were at a significantly increased risk for grade 2 or higher GI adverse events (AEs). However, bevacizumab (Avastin, Genentech), which carries a known risk for GI perforation, did not add to that risk, according to the study presented at a meeting of the Society of Gynecologic Oncologists (abstract 7). The study was supported by the Gynecologic Oncology Group, the National Cancer Institute and Genentech.

“Bevacizumab does not magnify the risk of grade 2 or higher GI adverse

events already associated with inflammatory bowel disease (IBD) or bowel resection,” said Robert A. Burger, MD, an oncologist at Fox Chase Cancer Center, in Philadelphia. He said he had no relevant disclosures.

Consistent with existing data on bevacizumab, the analysis showed that, overall, patients treated with chemotherapy plus the angiogenesis inhibitor had a twofold increase in grade 2 or higher GI AEs compared with patients who received chemotherapy alone (3.4% vs. 1.7%). Before this study, risk factors for major GI AEs after bevacizumab therapy had been examined only retrospectively in patients with ovarian cancer. Gynecologic Oncology

Group (GOG) 0218 included a prospective evaluation of grade 2 or higher GI AEs, including perforation, anastomotic leak, fistula, necrosis and hemorrhage.

The findings came from a new analysis of the GOG 0218 trial that showed chemotherapy plus bevacizumab followed by bevacizumab maintenance significantly slowed the progression of advanced ovarian cancer compared with chemotherapy alone. GOG 0218 involved patients with previously untreated stage III to IV epithelial ovarian, primary peritoneal or fallopian tube cancers. In the multicenter international trial, 1,800 patients were randomized to one of three regimens: carboplatin-paclitaxel plus bevacizumab, followed by

‘Bevacizumab does not magnify the risk of grade 2 or higher GI adverse events already associated with inflammatory bowel disease (IBD) or bowel resection.’

—Robert A. Burger, MD

bevacizumab maintenance therapy; the same chemotherapy plus concomitant bevacizumab and placebo maintenance; or chemotherapy plus placebo and maintenance placebo.

Patients who received bevacizumab maintenance had a median progression-free survival of 14.1 months compared with 10.3 months among women treated with chemotherapy alone.

The difference translated into a statistically significant 28% reduction in the hazard for progression (P<0.0001).

Chemotherapy plus bevacizumab without maintenance therapy did not

SOLID TUMORS

Clinical Oncology News • June 2011

Ovarian

significantly slow cancer progression compared with chemotherapy alone.

The treatment groups did not differ significantly with respect to baseline characteristics.

Patients who received chemotherapy and placebo had a 1.7% rate of grade 2 or higher AEs, consisting of four fistulae, one case of necrosis, two perforations and three bleeding incidents. The group that received bevacizumab with primary therapy and placebo maintenance had a 3.4% rate of grade 2 or higher GI AEs: four fistulae, 11 perforations, and five bleeding episodes. Patients who received bevacizumab maintenance also had a 3.4% rate of grade 2 or higher GI AEs: four fistulae, three GI leaks, seven perforations and six bleeding incidents.

The risk for GI AEs was not significantly related to age, stage of disease or residual disease after surgical debulking, or time from surgery to initial chemotherapy.

Aspects of medical history associated TM

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with increased risk for grade 2 or higher GI events were diagnosis/treatment of IBD, small bowel resection with anastomosis or at primary surgery, and large bowel resection with anastomosis or at primary surgery.

Logistic regression analysis revealed three independent predictors of grade 2 or higher GI AEs: bevacizumab treatment (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.05-4.40), treatment for IBD (OR, 13.4; 95% CI, 3.44-52.3) and large bowel resection at primary surgery (OR, 2.05; 95% CI, 1.09-3.88).

An assessment of the data on GI AEs

in GOG 0218 should take into account two factors that provide context, said invited discussant David M. O’Malley, MD, of the Ohio State University, in Columbus, Dr. O’Malley, who disclosed that he had received research support from Genentech.

Patients who received bevacizumab with chemotherapy but not maintenance had less than a one-month improvement in PFS compared with chemotherapy alone (11.2 vs. 10.3 months). Additionally, grade 2 or higher GI AEs occurred infrequently—a total of 53—and three of those patients

had incomplete data.

Dr. O’Malley said, “It’s only three events, but that’s 6% of the total.” This year, Genentech plans to file for FDA approval of bevacizumab for treatment of ovarian cancer. Some researchers have raised concerns about the price of the drug. A recent article in the Journal of Clinical Oncology concluded that adding bevacizumab to standard chemotherapy for ovarian cancer is not cost-effective (J Clin Oncol 2011; 29:1247-1251 [Epub 2011 March 7], PMID: 21383297).

—Charles Bankhead

9

HEMATOLOGIC DISEASE

Clinical Oncology News • June 2011

Acute Myelogenous Leukemia

The Real Costs of Defining Heterogeneity in AML Myriad candidate molecular and cytogenetic abnormalities in acute myelogenous leukemia (AML) have been suggested as having influence on the pace of disease, response to therapy, and perhaps even survival.1-3 Three years ago, the World Health Organization classification of myeloid neoplasms was updated to include new molecular and cytogenetic abnormalities, with prognostic relevance in AML.4 Development of new laboratory techniques and targeted therapeutics continues at breakneck speed, outpacing classifications and the writing of guidelines for this disease.5 Additionally, advances in targeted therapy will continue. The precedent of imatinib mesylate and other rationally designed therapies have provided an incentive for drug development to keep pace.6,7 For this reason, this is an exciting time in the history of oncology for physicians, scientists, and patients, but as information and access to information expand, expectations are high. Rationally designed compounds often have just one opportunity in the standard clinical trial mechanism, and then are discarded if not proven to be superior over the standard of care. Highlighting the potential power of rationally designed agents against cancer, the selective HER-2/ neu antagonist trastuzumab (Herceptin, Genentech) was found to improve median survival by 50% in breast cancer patients with HER-2/neu gene amplification.8 Conversely, the epidermal growth factor receptor inhibitor gefitinib (Iressa, AstraZeneca) was removed from general circulation and provided with limited access in the United States after a randomized controlled trial (RCT) failed to show statistically significant improvement in survival among lung cancer patients treated with the agent despite clear benefit in subsets of treated patients.9 In retrospect, this may be blamed on study design; however, the provisional approval had been granted with a condition of survival benefit in Phase III, and this condition was not met.10 In a similar fashion, the most recent casualty appears to be gemtuzumabozogamicin (GO; Mylotarg, Wyeth), which was discontinued in the United States in summer 2010 based on the preliminary results of a Phase III study that showed no survival benefit in patients treated with this agent.11 GO is an antibody to CD33 conjugated to calicheamicin, a cytotoxic antibiotic. Given the high concentration of CD33 in cells of myeloid origin, it was hypothesized that targeting this antigen could lead to death of these myeloid leukemia cells.12-14 Indeed, because GO

showed promise in early Phase I and II clinical trials,15,16 the FDA granted provisional approval for GO. Two large Phase III randomized trials incorporating GO into standard therapy for AML patients quickly followed. The preliminary results of the Southwest Oncology Cooperative Group (SWOG) S0106 trial were first presented at the American Society of Hematology annual meeting in 2009.

This trial randomly assigned newly diagnosed AML patients, aged 18 to 60 years, to either standard cytarabine and daunorubicin (60 mg/m2) or standard cytarabine and lower-dose daunorubicin (45 mg/m2) plus GO (6 mg/m2). There was no improvement in complete response, disease-free survival, or overall survival (OS) in S0106, and the fatal induction rate was higher in the GO arm (5.8% vs 0.8%).11 For these reasons, the FDA recommended withdrawal of GO, and the new drug application was withdrawn in late 2010.17 After the withdrawal of GO from the US market, Burnett et al published the results of the MRC-AML 15 study in February 2011.18 In MRC-AML 15, 1,113 newly diagnosed patients with AML (not acute promyelocytic leukemia [APL]), who were mostly younger than 60 years of age and suitable for curative intent

therapy, were randomized to 1 of 3 standard AML induction regimens—cytarabine plus daunorubicin (50 mg/m2); cytarabine plus daunorubicin (50 mg/ m2) plus etoposide; or cytarabine, fludarabine, granulocyte colony-stimulating factor, and idarubicin (10 mg/m2)—and then further randomized to receive or not receive GO (3 mg/m2). The investigators then randomized 948 patients in remission to consolidation therapy with 1 of 3 consolidation regimens—cytarabine (3 g/m2); cytarabine (1.5 g/m2); or amsacrine, cytarabine, and etoposide— with or without GO. As in S0106, MRCAML 15 revealed no response or OS benefit with the addition of GO. Predefined analysis by cytogenetic risk, however, revealed a sizable benefit in response and survival among patients with favorable cytogenetic risk and a trend toward benefit for those with intermediate cytogenetic risk (Figure). With poor-risk patients excepted, MRC AML15 showed a 10% 5-year survival benefit for 70% of these relatively young AML patients.

As the authors of the MRC-AML 15 trial noted, the induction death rates reported in S0106 represent an outlier, because AML therapy induction death rates historically approximate 5% to 20% in clinical trials (the induction death rate for the MRC-AML 15 trial is unpublished).19-21 Furthermore, GO was given together with what is likely inferior cytotoxic chemotherapy combination of cytarabine and daunorubicin (45 mg/m2) in S0106, raising the question of whether

Our challenge is in properly designing clinical trials with outcome measures that keep us from discarding therapy useful for specific subsets of leukemia, while simultaneously fulfilling the threshold of rigor necessary to gain regulatory approval.

100

75

Survival, %

10

79%

50

51%

No GO GO 25

No GO GO

Arm 65 72

Number of events, obs 30 13

Number of events, exp 18.2 24.8 P=0.0003

0 0

1

2

3

4

5

Years from entry

Figure. Overall survival for favorable cytogenetic risk in MRC-AML 15 trial.

AML, acute myelogenous lekeumia; GO, gemtuzumab ozogamacin; Reprinted with permission from J Clin Oncol. 2011;29(4):Supplemental data.

GUEST EDITORIAL Michael R. Savona, MD Associate Director, Hematologic Malignancies Sarah Cannon Research Institute Sarah Cannon Center for Blood Cancers Nashville, Tennessee

the failure to achieve survival benefit in S0106 was simply the result of lower doses of anthracycline.22 Despite these misgivings, the FDA recommended removal of GO based on the predetermined condition that the study must show superiority for final approval of the drug.

Personalized medicine has become a moniker for this new age of cancer therapy, and with good reason. The molecular heterogeneity within previously defined leukemia subgroups may be nearly as diverse as the individuals with the disease. This is an extremely challenging scenario for the development of new therapies, yet the pace of discovery of new prognostic markers in AML suggests that this extent of heterogeneity may be part of the future. Whether or not there are true fingerprints of clonality, and whether it is even relevant to precisely define minute differences between leukemias remain unclear. The question is whether or not some subgroups of patients are similar enough to derive benefit from a given therapy. In the case of GO, it seems so. Although it is not always clear why, many AML subsets (eg, core binding factor leukemia with or without c-kit gene mutation, APL, AML in the elderly) do benefit from GO in initial and salvage therapy,18,23,24 regardless of the inability to show survival benefit for all composite AML.11,18 We need to consider how to use this drug, and other castoffs, most efficiently for specific subgroups of leukemia patients. Our challenge is in properly designing clinical trials with outcome measures that keep us from discarding therapy useful for specific subsets of leukemia, while simultaneously fulfilling the threshold of rigor necessary to gain regulatory approval. Multicenter cooperation will remain essential, but the Phase III RCT, as we now know it, cannot continue to be the litmus test for diseases such as AML with rapidly growing defined heterogeneity and consequent shrinking incidence of various subtypes.

Scan for Burnett study; instructions page 7.

HEMATOLOGIC DISEASE

Clinical Oncology News • June 2011

11

Acute Myelogenous Leukemia

References 1. Schlenk RF, Dohner K, Krauter J, et al.

Mutations and treatment outcomes in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918, PMID: 18450602.

2. Santamaría CM, Chillón MC, García-Sanz R, et al. Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood. 2009;114(1):148152, PMID: 19398719.

3. Hokland P, Ommen HB. Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood. 2011;117(9):25772584, PMID: 21097673.

4. Vardiman JW, Thiele J, Arber DA, et al.

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5): 937-951, PMID: 19357394.

of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood. 2003;102(13):4277-4283, PMID: 12933575.

16. Larson RA, Boogaerts M, Estey E, et al.

Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002;16:1627-1636, PMID: 12933575.

17. FDA statement on gemtuzumab ozogamicin. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm216790.htm. Accessed May 3, 2011.

18. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of

gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2010;29(4):369377, PMID: 21172891.

19. Wiernik P, Banks PLC, Case DC, et al. Cytarabine plus idarubicin or daunorubin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79(2):313-319, PMID: 1730080..

22. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009:361(13);12491259, PMID: 19776406.

20. Lowenberg B, Pabst T, Vellenga E, et al.

Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027-1036, PMID: 21410371.

23. Borthakur G, Faderl S, Verstovsek S. Molecular response in core binding factor acute myelogenous leukemia with fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin. Blood. 2008;112: Abstract 1937.

21. Lowenberg B, Beck J, Graux C, et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood.

2010;115(13):2586-2591, PMID: 20103782.

24. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol.

2009;27(4):504-510, PMID: 19075265.

PHA

SE I

5. NCCN Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. Version 2.2011.

Fort Washington, PA: National Comprehensive Cancer Network. http://www.nccn.org/ professionals/physician_gls/pdf/aml.pdf.

Accessed May 3, 2011.

Dr. Savona reports no relevant conflicts of interest.

II TR

IAL

6. Kwak, E, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703, PMID: 20979469.

7. Aggarwal S. Targeted cancer therapies.

Nature Rev Drug Discov. 2010;9(6):427-428, PMID: 20514063.

8. Slamon DJ, Leyland-Jones B, Shak S, et al.

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11);783-792, PMID: 11248153.

9. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527-1537, PMID: 16257339.

10. Comis RL. The current situation: erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer. Oncologist. 2005;10(7):467470, PMID: 16079313.

11. Petersdorf S, Kopecky K, Stuart RK, et al.

Preliminary results of Southwest Oncology Group Study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood. 2009;114(22): Abstract 790.

12. van Der Velden VH, te Marvelde JG, Hoogeveen PG, et al. Targeting of the CD33calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood. 2001;97(10):3197-3204, PMID: 11342449.

13. Caron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity.

Blood. 1994;83(7):1760-1768, PMID: 8142644.

14. Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood.

1999;93(11):3678-3684, PMID: 10339474.

CUR

REN

TLY

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

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

1. Butts C, Anderson H, Maksymiuk A, et al. Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients with stage III/IV non-small cell lung cancer (NSCLC). ASCO Congress 2009; Abstract No. 3055.

BLP25 liposome vaccine is currently under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proven to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the START Trial

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

15. Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of simultaneous administration 101108 - 115622

REC

RUIT

ING

12

HEMATOLOGIC DISEASE Multiple Myeloma

MAINTENANCE continued from page 1 

receive maintenance therapy with either lenalidomide or placebo until disease progression. Investigator Philip McCarthy, MD, who presented the study for a network of researchers led by the Cancer and Leukemia Group B (CALGB 100104), reported that at a median follow-up of 28 months from transplantation, patients who received lenalidomide maintenance had an OS rate of 90% compared with 83% for patients randomized to placebo (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.26-1.014; P=0.018). The results in the 460-patient study are deemed even more impressive because nearly 80% of the patients who were randomized to receive placebo had crossed over to receive lenalidomide maintenance.

At a median follow-up of 28 months from transplantation, the median time to progression (TTP) was 48 months in the lenalidomide arm and 30.9 in the placebo arm (HR, 0.44; 95% CI, 0.32-0.60; P<0.0001), noted Dr. McCarthy, director of the Blood and Marrow Transplant Program in the Department of Medicine at Roswell Park Cancer Institute, in Buffalo, N.Y. The TTP was longest in patients who had received lenalidomide during both induction and maintenance therapy.

Patients aged 70 years or younger were included in the study if they had Durie-Salmon stage I to III disease, were diagnosed within a year of study entry, had at least two months of induction therapy and had stable disease or better. Patients were stratified by β2-microglobulin level and prior thalidomide or lenalidomide therapy.

Several grade 3/5 adverse events were more common in patients receiving lenalidomide maintenance than in patients receiving placebo: neutropenia (43% vs. 9%), thrombocytopenia (13% vs. 4%), febrile neutropenia (6% vs.

2%) and other infections (16% vs. 5%).

In the study, second malignancies were more common in patients receiving lenalidomide maintenance; 29 patients developed second cancers and seven of

Clinical Oncology News • June 2011

Table 1. Second Cancers in the CALGB 100104 Study After Randomization Treatment Arm

Hematologic Malignancies (n)

Lenalidomide

Breast (2), Gastrointestinal Acute myelogenous leukemia (2), Gynecologic (2), (5), Acute lymphocytic leukemia (1), Hodgkin’s lymphoma (1), CNS (1), Prostate (1), Thyroid (1), Melanoma (1) Myelodysplastic syndrome (1)

Placebo

Solid Tumors (n)

None

Carcinoid (1), Sarcoma (1), Melanoma (2)

CALGB, Cancer and Leukemia Group B

these occurred before randomization (Table 1).

Kenneth Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and director, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, in Boston, who was the principal investigator of the study, considers the results “a tremendous advance, since it prolongs both progression-free and overall survival. As an oral agent, it is very well tolerated. It’s a really historic moment, since it will change the paradigm of how we treat patients with multiple myeloma.”

However, Shaji Kumar, MD, associate professor of medicine in the Hematology Division at Mayo Clinic, Rochester, Minn., expressed reservations about changing practice based on these results.

Acknowledging that “the [CALGB] study demonstrates an improvement in overall survival in a group of patients randomized to receive lenalidomide maintenance after a single autotransplantation … for the first time,” he pointed to another study presented at the meeting “which had not allowed any early crossover [and] still does not show any difference in overall survival.” In that study, presented by the Intergroupe Francophone du Myelome (IFM 05-02), patients receiving maintenance lenalidomide (n=307) following autologous stem cell transplantation and two cycles of lenalidomide consolidation achieved a median PFS of 41 months compared with 24 months for patients receiving placebo (n=307) (P<0.0001). Investigators identified a trend toward improved OS at four years following randomization, with 79% of patients receiving lenalidomide maintenance still alive compared with

73% of patients receiving placebo, but this difference was not statistically significant (P=0.8). Dr. Kumar also stressed that both trials (Table 2) show an increased risk for second cancers in the patients receiving lenalidomide maintenance. “Given these two pieces of information, it appears that routine maintenance still should not be the universal practice but certainly something to be considered in patients with high-risk myeloma,” Dr. Kumar said.

Dr. McCarthy pointed out that none of the patients in the IFM-0502 trial were treated with lenalidomide as part of induction and that this could play a role in the lack of OS benefit identified.

Others think the benefits of the therapy offset the risks for more malignancies.

Speaking from the workshop, Ola Landgren, MD, chief of the Multiple Myeloma Section of the National Cancer Institute, in Bethesda, Md., said, “the benefits currently outweigh the risks of second malignancies. There is consensus that the next step is to carefully categorize those patients who have developed second malignancies and try to understand and better molecularly define the underlying mechanisms of these developments.

Ideally, if you are able to identify risk factors or mechanisms of developing secondary malignancies, we could use that in the clinical context.”

—Kate O’Rourke Disclosures: Dr. McCarthy reports having received consulting honoraria from Celgene and Onyx. Dr. Kumar has received consultant fees from Celgene and grant support related to research activities from Celgene, Millennium, and Merck. Drs. Landgren and Anderson report no relevant current conflicts of interest.

Table 2. Differences Between IFM 05-02 and CALGB 100104 IFM 05-02

CALGB 100104

• Induction therapy: more VAD (~52%) and bortezomib\dexamathesone (~44%) • Minimal thalidomide or lenalidomide exposure prior to transplant

Induction therapy: more thalidomide and lenalidomide exposure (~74%)

• DCEP consolidation (~50%) • Two-month lenalidomide consolidation ~3 months post-ASCT before randomization

No consolidation pre- or post-transplant

~20% received two transplants with melphalan 200 mg/m2

Single transplant with melphalan 200 mg/m2

Placebo group has not crossed over

Cross over from placebo to lenalidomide at unblinding in 12/2009

Maintenance therapy stopped at 2 years with a median of 3.1 years treatment

Maintenance therapy has not stopped as of May 2011, shortest time on maintenance is ~15 months

Follow-up of ~36 months

Follow-up of ~28 months

ASCT, autlogous stem cell transplant; CALGB, Cancer and Leukemia Group B; DCEP, dexamethasone, cyclophosphamide, etoposide and cisplatin; VAD, vincristine, doxorubicin and dexamethasone; IFM, Intergroupe Francophone du Myelome

FDA NEWS Sutent and Afinitor Approved For Advanced Pancreatic Neuroendocrine Tumors

T

he FDA has approved everolimus (Afinitor, Novartis) and sunitinib (Sutent, Pfizer) for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNETs) in patients with unresectable, locally advanced or metastatic disease.

The safety and effectiveness of everolimus was established in the Phase III RADIANT-3 (RAD001 in Advanced

Neuroendocrine Tumors) trial of 410 patients with metastatic or locally advanced disease who were randomized to receive everolimus or placebo.

Patients who were given placebo were able to receive everolimus if their disease worsened.

Progression-free survival (PFS), the primary study end point, was 11 months in patients who received everolimus compared with 4.6 months in patients who received placebo. The drug reduced the risk for cancer progression by 65% when

compared with placebo (hazard ratio, 0.35; 95% confidence interval, 0.27-0.45; P<0.001). A consistent improvement in PFS was seen in all patient subgroups.

The most commonly reported side effects of the drug in this trial were stomatitis,

rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever and headache.

The safety and effectiveness of sunitinib was established in the SUN 1111 pivotal Phase III trial study of 171 patients with metastatic or locally advanced disease who received sunitinib or a placebo. The study demonstrated that sunitinib improved progression-free survival (PFS) compared with placebo (10.2 vs.

5.4 months; P=0.000146).

The most commonly reported side see APPROVALS, page 22 

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

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

INDICATIONS

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

IMPORTANT SAFETY INFORMATION

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

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

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

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

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

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

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

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

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

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

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

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

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

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

11 10

2 0

0 0

9 6

2 1

0 0

12

0

0

4

0

0

19

2

0

14

<1

0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

18

0

0

12

0

0

22 19

1 6

0 0

18 <1

1 0

0 0

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

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.

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

5% of Patients

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

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

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

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

TM

An ALZA STEALTH® Technology Product

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

16

POLICY & MANAGEMENT

Clinical Oncology News • June 2011

Cancer Center Management

Spotlight on Community Cancer Centers

Wisconsin Cancer Center Offers State-of-the-Art Treatment, Home-Town Care ProHealth Care Regional Cancer Center, headquartered at Waukesha Memorial Hospital in Waukesha, Wis., sums up its approach to fighting cancer in just five words—”World class, close to home.” The center strives to provide patients with sophisticated diagnostic and cancer treatment technologies that are comparable to those of major academic research centers, yet with the up-close, personal care of a community hospital.

“That’s our goal,” said Michael Thompson, MD, PhD, medical director of cancer research at the center. “Cancer patients can become highly stressed outside of their local support system and environment. We provide coordinated cancer care to people who want to stay in the community.”

By staying on the cutting edge of technology, employing a multidisciplinary approach to treatment and conducting high-quality research, ProHealth Care has earned a reputation for excellence. In 2007 and 2010, it received the American College of Surgeons Commission on Cancer Outstanding Achievement Award, and in 2009, the Wisconsin Cancer Council’s Community Service Award.

In addition to an outpatient clinic and dedicated inpatient unit at Waukesha Memorial Hospital, ProHealth Care operates two more outpatient clinics in Oconomowoc and Mukwonago, Wis. Its clinics treat most cancers—brain, breast, colorectal, lung, prostate and skin cancers, as well as leukemias and lymphomas. Within these clinic sites, specialty sites, such as the Center for Blood Cancer and Disorders, Gynecologic Oncology Service, Brain Tumor Treatment and Research Center and Center for Breast Cancer, allow clinicians to focus on particular tumor types.

ProHealth Care takes a multidisciplinary approach to treatment because all cancers are not the same. “There are important differences between any two cancers, even if they are from the same organ,” said medical director Peter Johnson, MD. “Each tumor type may require a special set of resources and support. We recognize that.”

The center’s multidisciplinary team includes five hematology/oncology physicians, a neuro-oncologist, a hematologist, surgeons, pathologists, radiologists, care coordinators and nurses.

The team reviews all cases at interdisciplinary conferences, developing comprehensive cancer care plans for patients.

“By having everybody in the same room at the same time we can look at films, have pathologists interpret biopsies and more,” said Dr. Johnson. “The benefit for the patient is that he or she can come in, see the people they need to

separate cancer support group that offers a variety of individual and familybased support, including access to complementary therapies, such as acupuncture and meditation.

The center also has a partnership with the Internet site, CaringBridge, which allows patients to create their own Web page while undergoing treatment. Through the Web page (www. caringbridge.org/), patients can update family and friends on their progress and family and friends can post messages of support and encouragement.

“We found a lot of our patients were looking for a way to keep in touch with family and friends,” said patient support navigator Colette La Francis. “In CaringBridge, we found a very easy and accessible support system for them.

These kinds of programs demonstrate how much we care for patients, and they set us apart from many other centers,” she added.

Technology for Better Outcomes Members of the ProHealth Care Regional Cancer Center Multidisciplinary Team discuss care plans for breast and GI patients. Left to right are Dr. Michael Thompson, medical director of cancer research; Dr. Wingate Clapper, medical director of radiation oncology; Dr. Peter Johnson, Regional Cancer Center medical director and Dr. James Jones, radiologist.

‘Our investment in technology puts us on par with academic research centers such as Stanford University, Cleveland Clinic and Georgetown University.’

—Wingate Clapper, MD

see and get a plan everyone agrees on.

They get more cohesive care.”

Another benefit for patients, according to Dr. Johnson, “is our great nurses. Anyone in a hospital knows you need really good nurses, and we have exceptional nurses, many who are oncology certified, and who have been here a long time.

Patients are not objects here. They are treated like family members. It’s something that we’re good at.” This “keeps our patients coming back,” he added.

Making Cancer Care Manageable Because a cancer diagnosis and resulting treatment can be a frightening and grueling experience for most people, ProHealth Care works hard to make the ordeal as manageable as possible, with the best outcomes and the least stress for patients.

A key to achieving that is its four

patient navigators—one for patients with breast cancer, one for patients with prostate cancer and two for patients who are underinsured. “They are instrumental in guiding patients through treatment and helping them access resources, such as nursing assistance at home or hospice care if needed,” said Dr. Johnson.

ProHealth offers a cancer genetic risk assessment program for people whose cancer might have a hereditary component, and a cancer second opinion program, in which patients with breast, lung, prostate, brain or hematologic cancers can have ProHealth’s experts review their case and ensure they have been diagnosed correctly and have been provided with the best treatment options available, based on the most current evidence and research.

ProHealth works with the Stillwater Cancer Support Group, an affiliated,

According to Wingate Clapper, MD, ProHealth Care’s medical director of radiation oncology, the center believes its investment in the most advanced, high-tech cancer diagnostic and treatment technologies provide patients with the best chance of beating their disease. “Radiation oncology is all about technology,” he said.

For example, the center is one of only 200 clinics worldwide using the CyberKnife System. CyberKnife delivers precise doses of radiation to tumors, while sparing surrounding healthy tissue. It can be used to treat a broad range of tumors, including prostate, lung, brain, spine, liver, pancreas and kidney tumors.” With CyberKnife, explained Dr. Clapper, “we localize a tumor on a six-dimensional grid, almost like a GPS grid. Then, we target the coordinates, and if there is any movement from the patient or the tumor, the machine moves with it.”

That’s critical in such cancers as lung cancer, where a patient’s breathing during treatment can cause tumor movement. “Because CyberKnife is more accurate and precise, we can deliver a greater dose of radiation, and we’re getting control and survival rates in earlystage lung cancer that are comparable to surgery,” Dr. Clapper said.

Besides CyberKnife, ProHealth makes use of robotic surgery technologies, such as the da Vinci Surgical System, and it is the first cancer clinic in Wisconsin to employ super-dimensional

POLICY & MANAGEMENT

Clinical Oncology News • June 2011

Cancer Center Management

bronchoscopy to locate, test, diagnose and treat early-stage lung lesions.

“Our investment in technology puts us on par with academic research centers such as Stanford University, Cleveland Clinic and Georgetown University,” Dr. Clapper said. “We have a history of support from the administration to stay on the leading edge of technology, be it conventional radiation, such as linear accelerators, MRI [magnetic resonance imaging], and PET [positron emission tomography] scan technology, or cutting-edge technology, like CyberKnife. We take a very aggressive approach to go after it.”

Funding for such technology comes from ProHealth’s general budget, capital improvements and foundation-directed gifts, according to Dr. Thompson.

Clinical Research Equals Top-Level Care For ProHealth Care, clinical research is a core value, and it is very active in enrolling patients in clinical and prevention trials. “Without clinical research, you’re not a player in the cancer game,” explained Dr. Thompson.

“You must have it, if you want to deliver top-level care.” The center is involved in a number of studies involving breast,

gastrointestinal, neurologic, thoracic, hematologic, gynecologic and genitourinary cancers.

“There are multiple reasons for excellent research programs,” said Dr. Thompson. “First is access to new drugs, which provides our patients with the most advanced, clinically approved treatments available. Second is to give our physicians a better understanding of the latest technology and treatments.

And, it also helps us attract and retain good people.”

A typical study ProHealth has been involved in is the Eastern Cooperative Oncology Group’s E3A05 study, which collected bone marrow samples to help understand multiple myeloma and related diseases. “We accrued the most

patients for that study,” Dr. Thompson said. “We’ve also collaborated on a Duke University study identifying types of microRNA and their relationship to lymphoma, and with a company called Tgen, where we looked at biomarkers for lung cancer.”

Recently, ProHealth Regional Cancer Center was among 14 hospitals nationwide to receive a $2.7 million grant from the National Cancer Institute to expand research programs, supportive care services and state-of-the-art cancer care to underserved populations. “The grant is designed to bridge the gap between cancer care at academic research centers and cancer care in the community,” said Timothy Wassenaar, MD, medical director for quality. “We are using the monies to hire and train bilingual patient navigators to reach our Hispanic population, sponsor screening events, conduct and better track more clinical trials and establish a palliative care program.”

Dr. Wassenaar pointed out that a big reason ProHealth attracts such funding is that it is a national leader in measuring outcomes. It tracks everything it does— surgical and treatment outcomes, treatment benchmarks, surgical standards, presurgery diagnostic evaluations, the

availability of data from a Phase I trial that such a combination does not produce excessive toxicity), or administering 1 (or both) agents in the adjuvant or neoadjuvant setting?3 The next question to be asked in the current era of “guidelines” is whether an individual patient, following a thorough discussion with his or her physicians(s) about the evidence-based data and the potential risks and benefits associated with alternative options, will be permitted to make the decision regarding his or her management. And if not, who will make the decision and through what process?

Before leaving this topic, it is important to formally acknowledge an important additional limitation of even the most outstanding, evidence-based clinical research. It is a factual statement that such studies define outcomes, both good and bad, for populations and not individuals. What about the patient who would not have been eligible for the definitive Phase III study because of a specific trial-defined unacceptable comorbidity, or because he or she had received several prior therapies and was therefore not permitted entry into the study? How should such very real-world patients be managed? What dose and schedule should be employed if they receive the new regimen?

These questions get to the heart of the issue being addressed in this commentary.

Optimal individual patient management is not determined by study-defined “P values” and “hazard ratios.” Such data (if available) are surely an essential starting point in a discussion with a patient, regarding both risks and benefits of the specific program, and the “knowns” versus the far more common “unknowns” associated with how an individual will respond (positive or negative) to a given drug or regimen. This includes both the impact of treatment on the cancer (efficacy) and normal organ function (toxicity). Data from well-designed and conducted clinical trials help frame relevant questions regarding treatment, but they should not be considered the final authority on individual patient management.

The most eloquent words written by Sherwin Nuland in “The Uncertain Art: Thoughts on a Life in Medicine” provide a succinct and thoughtful perspective on the fundamental relationship between study data and the care of the individual cancer patient:4 “Though the advent of correctives such as the randomized controlled clinical trial and the newly popular notion of evidence-based medicine may have lessened the uncertainty inherent in general principles of therapy, they are unlikely … to usefully affect the care of an individual man, women, or child to the degree claimed or predicted by their most adamant advocates. Given the spectrum of illness presentations, we will be left with what we have always had and always

‘Without clinical research, you’re not a player in the cancer game. You must have it, if you want to deliver top-level care.’

—Michael Thompson, MD, PhD

levels of multidisciplinary care it provides, tumor incidences and more— through its cancer registry, which has a full-time staff. “We track data so diligently because we want to be sure we are providing quality care,” he said. “To have the ability to look at our outcomes, compared to those nationally, is tremendously helpful. It not only helps us care for patients, but also promotes a continuous learning process. We also seek transparency,” he added. “More and more patients and insurance companies require this kind of information.”

People Count In the end, ProHealth Care Regional Cancer Center’s success comes down to treating the whole patient—his or her physical, psychological, emotional, nutritional, social and spiritual needs— and not just the tumor. “We have a core group of professionals who are passionate about and dedicated to taking care of cancer patients,” Dr. Johnson said. “One of our competitive advantages derives from our culture of compassion, and patients get a clear and consistent sense that we care about them.”

—Tom McDonough

PRN

MANAGEMENT continued from page 1 

the selection of, and payment for oncologic care delivered to an individual cancer patient. This should be vigorously challenged.

Consider, for a moment, the following rather simple situation (and dilemma). In a recent issue of The New England Journal of Medicine, there were 2 reports discussing results from 2 Phase III RCTs that examined different “targeted antineoplastic” strategies in the management of pancreatic neuroendocrine tumors.1,2 Both studies revealed objectively impressive improvements in outcome for the investigative regimen (single-agent sunitinib [Sutent, Pfizer] and single-agent everolimus [Afinitor, Novartis]) compared with a best supportive care plus placebo control arm.

Faced with 2 new therapeutic options, how are practicing oncologists who are attempting to do what is best for their patients going to decide what to recommend? Perhaps it is reasonable to try regimen A followed by regimen B after documented progression, or maybe the reverse is most appropriate. How about sequencing regimen A (2 or 3 cycles) with regimen B (2 or 3 cycles) prior to evidence of progression? And what about the possibility of delivering the 2 drugs during the same treatment cycle (assuming, of course, the

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Vice President of Patient Oncology Services and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

will have—the acceptance of the longestablished principle that the practice of medicine is characterized by uncertainty and will always require judgment in order to be effective. That is its very nature.”

References 1. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:514-523, PMID: 21306238.

2. Raymond E, Dahan L, Raoul J-L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:501-513, PMID: 21306237.

3. Jensen RT, Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors. N Engl J Med 2011; 364:564-565, PMID: 21306243.

4. Nuland S. The Uncertain Act: Thoughts on a Life in Medicine. New York. Random House, Inc. 2008.

Have a response to this editorial?

Clinical Oncology News welcomes letters to the editor. Please send your comments to korourke@mcmahonmed.com or maurie.markman@ctca-hope.com.

17

18

Supportive Care

Clinical Oncology News • JUNE 2011

Survivorship

Report Spurs Survivorship Programs

SURVIVAL continued from page 1 

long-term needs, more and more institutions providing cancer care are racing to establish survivorship programs designed to address the unique concerns of this patient population. Where is your cancer center in this race?

Whereas pediatric oncology has long understood the need for dedicated survivorship care, the concept is much newer to adult oncology. In 2005, the American Society for Clinical Oncology (ASCO) and the Institute of Medicine (IOM) published a report from a joint meeting on survivorship that concluded that follow-up care of survivors is lacking (see box). “It’s only with advances in cancer therapy that we have cured patients with a high enough frequency to have the luxury of being able to consider the longterm effects of those treatments and the myriad of other problems that survivors face. We now recognize that we need to address those issues,” said Louis “Sandy” Constine, MD, professor of radiation oncology at the James P. Wilmot Cancer Center at the University of Rochester, in Rochester, N.Y., who is in the process of establishing a survivorship program there.

Possibly the first survivorship program to include survivors of adult cancers was created in 2001 at the University of Pennsylvania with $500,000 in seed money from the Lance Armstrong Foundation (LAF). The Living Well After Cancer program at Penn is now one of eight Survivorship Centers of Excellence designated by the LAF to lead the effort in building a nationwide network of survivorship care.

But although a big grant certainly helps, cancer centers and hospitals don’t need to be LAF-designated Centers of Excellence to implement a survivorship program. Even smaller institutions—like the St. Elizabeth Regional Medical Center in Lincoln, Neb., and Martin Memorial Health Systems in Stuart, Fla.—have begun developing survivorship initiatives. Centers also are not behind the curve if they haven’t started building a survivorship program. Many major cancer centers, like the Roswell Park Cancer Institute in Buffalo, N.Y., are just formalizing theirs.

Kevin Oeffinger, MD, who directs the Adult Long-term Follow-up Program at Memorial Sloan-Kettering Cancer Center in New York City, often sums it up this way when he speaks with hospitals considering a survivorship program: “Start small. But start.”

Survivorship Basics What are the key elements of a good survivorship program? These will vary with the size of the institution and the scope of its practice, said Dr. Constine. “There’s

not a single model that will be ideal, but instead a variety of models that will need to be entertained for a successful program. But I don’t think there’s an institution out there in the country that doesn’t have a critical mass of cancer patients to warrant a survivorship program.”

The Cancer Treatment Centers of America (CTCA) began developing its survivorship program in 2004, shortly before the ASCO/IOM report was released. “What we discovered, in talking to our patients, was that their primary care physicians didn’t always make the leap between a symptom and a possible relationship to cancer care,” said Tom Lay, director of the program. “Or there were comments like, ‘Gee, your oncologist should be taking care of this.’ Smoothing through those connections is helpful.”

That’s why, at a minimum, a survivorship program needs to have a means of providing what Dr. Constine called a “passport to care.” That is a comprehensive patient history and description of diagnosis, treatment and anticipated possible long-term effects that can be easily made available to anyone participating in the care of that patient.

In 2005, the American Society for Clinical Oncology (ASCO) and the Institute of Medicine (IOM) issued “From Cancer Patient to Cancer Survivor: Lost in Transition, a report from a joint meeting on survivorship.” The study concluded, “Cancer survivors are often lost to systematic follow-up within our health care system and opportunities to effectively intervene are missed. Many people finish their primary treatment for cancer unaware of their heightened health risks and are ill prepared to manage their future health care needs. Furthermore, recommended follow-up care is often not delivered and the psychosocial needs of cancer patients are often not addressed.”

• financial and economic issues, including problems with insurance and employment; and • family concerns.

Larger institutions may be able to address all of these issues in-house, with access to a staff of specialists and subspecialists, advanced practice nurses, social workers, psychologists and psychiatrists, nutritionists, physiatrists, physical therapists and other key personnel. Smaller facilities may need to “outsource,” developing a referral network of trusted experts who can meet the needs of men and women as they move from being “cancer patients” to “cancer survivors.” “You can partner and form coalitions with other groups in the community,” said Mary McCabe, RN, who directs

‘Survivorship care should have a major component of medical interventions that help survivors to heal optimally. This is legitimate medical treatment that is reimbursed.’

—Julie Silver, MD

The National Comprehensive Cancer Network’s 2009 guidelines for survivorship care recommend that such information include • a summary of all treatment received; • the possible clinical course, including timing of expected long-term treatment consequences; • surveillance recommendations; • appropriate timing of transfer of care; and • specific responsibilities of the oncologist and the primary care physician.

What the passport actually looks like may vary: Some patients may be more comfortable with a paper file that they can carry with them, whereas others prefer a Zip drive or thumb drive that holds their comprehensive history and perhaps other documents such as imaging files.

There are a variety of long-term patient needs that every survivorship program should address. They include the following: • ongoing and late side effects of treatment, ranging from neuropathy and chronic pain to fatigue, sexual side effects and infertility; • rehabilitation; • health, wellness and prevention; • screening for recurrence and new primary cancers; • emotional and psychosocial issues such as anxiety and fear of recurrence;

Memorial Sloan-Kettering’s survivorship program. “You don’t have to build it and own it all yourself.”

A key point of all of these services— whether you offer them in-house or refer for them elsewhere—is empowerment of the patient. Julia Stepenske, RN, CPON, oncology quality nurse at Children’s Memorial Hospital in Chicago, knows a little more about that than most oncology nurses. She’s a 22-year survivor of non-Hodgkin’s lymphoma who, three years ago, experienced a late recurrence as an adult.

“It’s a lifelong job to take care of yourself as a cancer survivor, and programs need to empower survivors to be active in their care and navigate the system, so that they are in control of their survivorship journey,” Ms. Stepenske said.

“No survivor is the same as another. I have minimal side effects from my cancer compared to a lot of survivors I’ve worked with, who had everything but the kitchen sink thrown at them.”

Roswell Park Cancer Institute went to the experts when it began building the survivorship program it has christened “Support for Life,” which started as a pilot program for prostate cancer survivors and is now expanding to serve patients with any diagnosis. They consulted with pioneers in survivorship such as Memorial Sloan-Kettering, City of Hope and Johns

Hopkins—but perhaps more importantly, they also held focus groups with a motivated population of patients and their spouses/caregivers.

“Our directors of psychology and social work asked them what were the unexpected, late or long-term effects of their disease or treatment that were most frequent and most distressing,” said Marcia Gruber, RN, vice president of Therapeutic Services and Patient Access. “What they told us helped to focus our efforts on developing services that are meaningful to the survivors and their families.”

Staffing How should a cancer survivorship program be staffed? That, too, will vary widely by institution. But every program needs what Julie Silver, MD, assistant professor in the Department of Physical Medicine and Rehabilitation (PM&R) at Harvard Medical School, in Boston, called a “front door.” Dr. Silver, a survivor herself who has authored several books on oncology rehabilitation and cancer survivorship, noted that just as many cancer centers are establishing “patient navigators” for new patients; survivorship programs require their own skilled navigators as well. The person could be an advanced practice nurse or social worker or just a very well-trained nonmedical staff member, but he or she should be able to field inquiries and triage patients’ needs appropriately.

Ms. Stepenske suggested that there be a triad of staff members that forms the basic structure of a good survivorship program: “A physician dedicated to this population, a nurse practitioner with survivorship experience, and a social worker or psychologist, all dedicated to the late effects and the psychosocial impact of surviving cancer and going back to life afterward.”

A survivorship program could be headed by an oncologist, advanced practice nurse, a physician’s assistant, physiatrist, psychologist or social worker—the person’s title matters less than his or her passion. “It must be led by someone who’s passionate about survivorship and doing it as their primary focus, not as a sideline,” said Karen Kinahan, MS, RN, APN, a clinical nurse specialist who directs the STAR (Survivors Taking Action and Responsibility) program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Evanston, Ill. see SURVIVAL, page 20 

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20

SUPPORTIVE CARE

Clinical Oncology News • June 2011

Survivorship

SURVIVAL continued from page 18 

“It has to be their full-time job, or close to it. If your job is 60% acute care and 40% survivorship, acute care is always going to win out.”

“Our social worker is probably the most important member of our survivorship staff,” said Melissa Hudson, MD, who directs the cancer survivorship division at St. Jude’s Research Hospital in Memphis, Tenn., and chairs ASCO’s newly established survivorship committee. “We see over 5,000 survivors in our program, and they often need help with day-to-day issues like getting their medications, getting screening covered if insurance is denying payment, finding ways to pay for their medical needs, getting access to rehabilitation, coping with fatigue and infertility—all issues that social workers can help to address through their network of resources.”

At Memorial Sloan-Kettering, survivorship program patients are usually seen for their regular annual visit by a nurse practitioner, but Ms. McCabe said that such visits could also be conducted by an oncologist or an internist, depending on the model the program has developed. “It also may vary based on where the patient is, physically and emotionally. Are they having new symptoms? Do they need resources for support groups? Psychological interventions? Do they need resources closer to home? Rehab? The visit always includes being a bit of a resource to make sure that patients get hooked up to all the services they might need.”

Sustainability All these efforts, however, cost money.

How are centers supposed to pay?

Survivorship care isn’t a moneymaker.

“Many services in survivor care aren’t reimbursable by third-party payers,” noted Dr. Hudson. “That’s because a lot of it is time. Time spent talking to the patient or talking to their primary care doctor to help them understand how to take better care of the patient and how

to access resources.”

But the wise administrator will think beyond direct revenue and expense calculations, said Mr. Lay. “What are patient satisfaction, loyalty and relationships with primary care worth to you? When patients tell us the things they value, providing these survivorship services clearly does have a payback. It’s easy to justify when you look at it from that point of view.”

The program costs about $150,000 a year, Mr. Lay reported, but yields about the same figure in Evaluation and Management reimbursements. He also calculated that indirect reimbursement from imaging services, pathology, nutrition, physical therapy and same-day surgeries, along with the income from community physician referrals to CTCA generated by the survivorship program, yields millions more in annual income.

But that may not be the case at smaller institutions, and it certainly won’t be the case if the directors of a survivorship program don’t think strategically about making it sustainable. “I know of places that got an initial grant, implemented services that weren’t reimbursable and then applied for another grant that didn’t get funded,” said Dr. Silver. “Now, their survivorship programs are shrinking or even disbanding.”

To get at least some third-party reimbursement for survivorship services, she suggested that all such programs include a cancer rehabilitation component—which is an important component of survivorship care in any case.

“Services such as medical appointments with physiatrists, physical therapy and occupational therapy are generally covered,” Dr. Silver said. “In some instances, other therapies, like nutrition and dietary therapy and certain kinds of integrative medicine and vocational rehab, can be covered too, if they are provided by health care professionals who have specific training in that field. Survivorship care should have a major component of medical interventions that help survivors to heal optimally. This is legitimate medical treatment that is reimbursed.”

It’s Better To Look Good and Feel Good

T

he first question most people ask when they’re diagnosed with cancer is “Am I going to die?” One of the next questions is often, “Am I going to lose my hair?”

One of the most maddening things about cancer is that the treatment itself can feel worse than the disease, leaving a person exhausted, sore, nauseous, pale, puffy and bald with eyebrows and eyelashes also gone.

Part of coping with cancer is coping with the hit that a person’s self-image takes from all of this, which is why many cancer programs are establishing image programs for their patients and survivors. For years, the American Cancer Society has offered free makeup and lessons to people with cancer as part of its “Look Good, Feel Better” program, but these days, at many institutions, that’s just the beginning.

Dozens of cancer centers and hospitals nationwide have contracted with Image Recovery Centers, a nationwide program that provides appearance counseling, rehabilitation and education—which means everything from wigs and wig fittings, turbans and hats, skin care and camouflage makeup, and cosmetic solutions for lash and eyebrow loss, to mastectomy and lymphedema products.

The Nebraska Medical Center in Omaha is developing its own such facility, called a Life Renewal Center, at its new cancer center. “We heard clearly from patient focus groups that they would like something like this, particularly because our freestanding cancer center is in a separate facility away from our primary main campus hospital,” said Ann Yager, director of the cancer center. “One room will be solely dedicated to massage; another is a salon, with a sink and a stylist’s chair. We made that room extra large, with puffy chairs and a table, so you can bring your girlfriends with you for your wig fitting.”

The space also includes a large fitting room for prosthetics, with three-way mirrors, and classroom space that will host “Look Good, Feel Better” sessions along with yoga, exercise classes and support groups.

The Cancer Treatment Centers of America (CTCA) also offer their own aesthetics programs. “We have certified mastectomy fitters, as well as all different kinds of clothing, not just for mastectomy and lumpectomy patients, but for ostomy patients and others,” said Tom Lay, who directs CTCA’s survivorship program. “There’s no bounds for where we’ll look to find something that’s going to help a patient feel better and get on with living their life.”

The Central Indiana Cancer Center has been running an image program for years. “It’s open to anyone, male or female,” said Thomas Whitaker, MD, medical oncologist and physician partner. “We run it with a local beautician, and there is makeup care, wig and toupee work. We also have a boutique with mastectomy products and prostheses, run by a survivor who has researched all of them— which one feels natural, which one is lightest, which one doesn’t fall out when you are bending over to weed the garden. I’ve been doing this for 20 years, and I never realized at the start how important all of that was. We are really trying to boost the self-image of each individual patient.”

—Gina Shaw

Dr. Silver encouraged colleagues to consider “a social entrepreneurial model with a double bottom line that measures advances in survivorship care as well as fiscal health with reimbursable services.”

Philanthropy provides much of the support for the new survivorship program at Martin Memorial Health System in Stuart, Fla., which will launch in November. “Half of all women, and onethird of all men, will get cancer in their lifetime,” said Deb Lewandowski, RN,

director of oncology. “Everyone knows someone. This is very personal for a lot of people, and I haven’t found it difficult to generate support.”

“You’re missing out if you don’t have a program,” said Ms. Stepenske. “Even if survivorship doesn’t make money for your institution, the profit is in improving the quality of life of the people who have survived, and you can’t put a dollar value on that.”

—Gina Shaw

SUPPORTIVE CARE Pain Management

Review of Opioid Studies Backs Agents’ Efficacy A recent systematic review has revealed that opioid therapy effectively reduces cancer pain (Pain Physician 2011; 14:E85-E102, PMID: 21412384).

Based on seven observational studies, investigators at the West Virginia University Hospitals in Morgantown gave a strong recommendation (1C) for using opioids to treat cancer pain, and said the studies included represent evidence

on par with that from randomized controlled trials (RCTs).

“For practicing oncologists (whether medical, radiation, surgical, gynecologic or pediatric), hospitalists who take care of their inpatients, and primary care

doctors, the take-home message is opioids work for pain management,” said Charles F. von Gunten, MD, PhD, provost of the Institute for Palliative Medicine at San Diego Hospice, and clinical professor of medicine at the University of California, San Diego. “Assess and apply the pain management guidelines as part of standard oncology [practice]. It’s a national embarrassment that 50% of patients with cancer and pain

don’t get adequate management.”

According to Scan for Web Paul Glare, MD, exclusive on chief of Pain and smoking and pain, Palliative Care Ser- instructions page 7 vices at Memorial Sloan-Kettering Cancer Center, New York City, it is unusual to treat evidence from observational studies as equal to data from randomized trials. “Any observational trial is

SUPPORTIVE CARE

Clinical Oncology News • June 2011

Pain Management

going to be more biased than a randomized trial; a randomized trial that compares one pain medicine with another will be free of bias,” he said. “We need more head-to-head randomized trials of opioids. The problem is that most randomized trials are short and not always feasible, and thus there is a place for long-term observational studies. But the reality is the evidence is never as valid with this design.”

In response to Dr. Glare’s comments, James Colson, MD, assistant professor of anesthesiology at West Virginia University Hospitals, who led the study, defended observational studies. “I do not believe that RCT head-to-head comparisons of opioids alone are going to contribute much to the treatment knowledge base, because we already know that not all opioids are equally efficacious in all clinical situations,” said Dr. Colson.

“I feel that study emphasis should be placed on novel opioid delivery systems, such as the transdermal buprenorphine formulation or on multimodal opioid combination therapies. Within this context, both RCTs and observational studies can provide credible safety and efficacy information.”

To perform the review, Dr. Colson and colleagues searched PubMed, EMBASE, Cochrane Reviews and clinicaltrials. gov, as well as reviews and cross references between 1996 and June 2010 for studies of adults treated for cancerrelated pain for any duration with any opioid. Other selection criteria were minimum follow-up of three months, studies with at least 50 subjects and primary outcomes involving effective pain relief and treatment safety.

The investigators determined the quality and validity of each study using the Agency for Healthcare Research and Quality criteria for observational studies.

Grading was based on Guyatt et al.’s recommendations, which contain six levels: three in the strong category and three in the weak category (Chest 2006;129:174181, PMID: 16424429).

The seven studies that met the criteria ranged from a Phase III, open-label, single–treatment arm study (BMC Palliat Care 2009;8:14-27, PMID: 19754935) to a long-term, open-label safety study (Cancer 2009;115:2571-2579, PMID: 19373888). Overall, the researchers determined that the evidence for opioid therapy in cancer pain was Level II-3 for quality, defined as “evidence obtained from multiple time series with or without the intervention.” The investigators also noted that the findings from these studies are supported and validated by many other observational studies that fell short of the inclusion criteria.

The authors concluded that the seven observational studies provided strong evidence for the use of opioids to treat cancer pain, although they acknowledged that this recommendation could

‘Although every clinician would be delighted to have evidence-based guidelines that reflect clinically relevant data from well-designed randomized controlled trials, the reality is that no such guideline is now possible.’

—Russell Portenoy, MD

change pending future evidence.

Russell Portenoy, MD, chairman of the Department of Pain Medicine and Palliative Care at the Beth Israel Medical Center in New York City, agreed.

“Although every clinician would be delighted to have evidence-based

guidelines that reflect clinically relevant data from well-designed randomized controlled trials, the reality is that no such guideline is now possible in pain medicine or palliative care, and patients cannot wait for it to appear,” Dr. Portenoy said. “In medicine, our

goal must be to define practices that can be highly recommended, on the basis of the best evidence we have integrated with the experience and wisdom of knowledgeable experts. This does exist for cancer pain. The care of patients can be improved today if oncologists and others followed guidelines, such as those developed by the National Comprehensive Cancer Network, that reflect the high-quality observational data described by Colson et al filtered through decades of clinical experience.”

TRIAL CURRENTLY RECRUITING

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

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

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

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

101108 - 115024

—Rosemary Frei, MSc

21

22

POLICY & MANAGEMENT

Clinical Oncology News • June 2011

Cost Savings

FOUND MONEY continued from page 1 

third will join the practice this summer) has implemented an assortment of IT, staffing and office management strategies designed to increase productivity while enhancing patient care and patient experiences.

The group’s latest efficiency-improvement tool is a password-protected Web site portal that will give patients direct and secure access to information about their test results and disease progression. It also will allow them to input information about their condition and schedule or reschedule office visits. The innovation aims to reduce the time spent by oncology nurses trying to reach patients by telephone to report results and set up new appointments.

“It can take four or five phone calls to track a patient down. That’s very inefficient,” Dr. McAneny said. Now nurses will be able to leave patients a telephone message or send an email telling them to log on to the portal to learn the results of their latest computed tomography scan, for example, or to schedule a new visit.

The portal is designed not only to increase efficiency but also to advance clinical goals. “I just want my nurses to do more patient-centered work that only face-to-face encounters can accomplish,” Dr. McAneny said. Additionally, the interactive nature of the portal will help ensure that patients “won’t just vanish when they leave the office,” she said.

“For example, if I give you platinum chemotherapy and you’re likely to have some nausea and vomiting, we’ll have you flagged as a patient who needs extra watching,” she said. In such cases, patients will be asked to indicate how much they’re drinking and how they’re feeling the next day, so that our nurses can scan the site and say, ‘These six patients are doing fine. We’ll just leave them alone. These patients, I’m going to call and check on. These over here are sick, but they’re coming in today.’”

The WAITING ROOM

The new portal will be linked to patients’ electronic health records (EHRs). “Any note that we leave the patient has to be part of the EHR, the permanent record, because it’s a legal document,” Dr. McAneny said. “So it has to be an integrated portal.”

To increase efficiency, Dr. McAneny also has introduced a system designed to speed the flow of patients through their office visits. “We give patients not a schedule but an itinerary,” she said.

The itinerary is meant to guide patient visits in tightly scheduled time segments, from the point they arrive to fill out paperwork through laboratory testing and physicians’ evaluation and management, to chemotherapy, imaging or whatever else is required. “Mostly we’re

figure out ways to work smarter.”

Dr. McAneny said the group has tried to be smart about bringing in new physicians. For example, she decided to hire an internist-hospitalist for supportive care issues not related to cancer decision making, such as managing pulmonary emboli, nausea, vomiting and diarrhea. She said she wants her oncologists to see patients only for oncology-specific care.

Another way oncology practices often lose money is through lax coding and billing procedures. To address this problem, Dr. McAneny said her group

The group’s latest efficiency-improvement tool is a passwordprotected Web site portal that will give patients direct and secure access to information about their test results and disease progression.

able to follow that,” she said, adding, “I think that has been a key because that is an area where you can really create some economies, but it also enhances rather than hurts patient care.”

The practice has tried to economize as much as possible on front office staff but not at the cost of care and patient experiences, noted Dr. McAneny. “If you have fewer office staff people and patients can’t get into the examination room in a timely matter, you’ll irritate more people than it’s worth for the small salary that a receptionist gets,” she said.

And even though times are tough, the group has tried to avoid layoffs. When employees leave, however, “we are trying very hard not to replace them,” she said. “We have a commitment to the people who work here that when we do well, we will share that in terms of raises and bonuses. But when times are tough—as they are right now—we expect everybody to pull together and

by Joan Chiverton

tightened up its billing practices more than a year ago. Before then, she said, coding levels often failed to match the complex decision making that her oncologists provided. The process has been automated and linked to the EHR system, she said, “and we are able to capture a lot more of the reimbursement that we are genuinely entitled to.”

Dr. McAneny’s group has long focused on technology as a way to improve patient care and efficiency. “We shredded our patient charts in 2002,” after converting to an EHR system, she said.

The group has received federal incentive payments for adopting electronic prescribing.

Part of that money, she noted, went to install an in-house, closed-door pharmacy for practice patients. “We were spending a huge amount of time on prior authorizations and in convincing patients’ local chain pharmacies that they really needed to have these

[chemotherapy agents] on hand for our patients,” she said. Opening the pharmacy has eliminated those time wasters.

Patients now pick up their prescriptions before they leave the office. Pharmacy technicians remind them when the therapy is supposed to start and end and ask them to call back if any questions come to mind after they arrive home.

Besides increasing efficiency, Dr. McAneny said, distributing medications at the point of care with specific instructions has meant fewer patient complications, “which can get very expensive for the overall health system but also expensive in terms of wear and tear and burnout for oncologists.”

—Bruce Buckley FDA NEWS

APPROVALS continued from page 12 

effects of sunitinib in this patient population included diarrhea, nausea, vomiting, fatigue, anorexia, high blood pressure, asthenia, abdominal pain, changes in hair color, stomatitis and neutropenia.

Treatment with sunitinib also yielded a statistically significant improvement in tumor response, with an objective response rate of 9.3% (95% CI, 3.215.4; P=0.0066). No objective responses were observed with placebo.

PNETs are slow growing and rare; clinicians estimate that there are fewer than 1,000 new cases in the United States each year. The drug is the first new treatment for PNETs in nearly 30 years, according to Novartis. Approximately 60% of patients with PNETs are diagnosed with advanced disease, and the five-year survival rate for these patients is 27%.

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