July 2011 Clinical Oncology Digital Edition by McMahon Group

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Independent News for the Oncologist and Hematologist/Oncologist clinicaloncology.com • July 2011 • Vol. 6, No. 7

PRN

Maurie Markman, MD, discusses the difficulties of communicating about cancer.

HematOlogic DISEASE

Revised methotrexate dosing strategy improves outcomes in pediatric and young adults with acute lymphoblastic leukemia.

High oral chemotherapy agent copays lead patients to abandon therapy. SOLID TUMORS

13 14

New standard proposed for breast cancer patients.

OCEANS trial sheds light on bevacizumab use in recurrent, platinum-sensitive ovarian cancer.

Clinicians suggest new standard for locally advanced rectal cancer. CLINICAL TRIALS

Actively recruiting Phase II/III trials started in the last 30 days.

EDUCATIONAL REVIEW

Systemic Therapy for Patients With Well-Differentiated Neuroendocrine Tumors After page 12

WWW.CMEZONE.COM

New Gold Standard Proposed for Patients With High-Risk GIST

Oncologists Discuss How To Use New Melanoma Drugs

Chicago—A three-year course of therapy with imatinib (Gleevec, Novartis) after surgery soon may become the new standard of care for patients with resected gastrointestinal stromal tumors (GIST) who are at high risk for relapse. In this patient population, the three-year course of therapy improved the five-year overall survival rate by roughly 10% compared with patients who received imatinib for one year, which is the current standard treatment. “I think that three years of imatinib will become the standard of care for adjuvant treatment of high-risk GIST for patients at risk for relapse,” said Heikki Joensuu, MD, professor of oncology at Helsinki University Central

Chicago—One year ago, the monoclonal antibody ipilimumab generated big news as an agent that could provide a survival benefit in second-line therapy for metastatic melanoma. At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), two Phase III latebreaker trials (LBA4 and LBA5) demonstrated that ipilimumab and a new agent, vemurafenib, improved survival in advanced melanoma, this time in first-line treatment. Vemurafenib, an inhibitor of BRAF kinase, is effective when advanced metastatic melanoma is positive for the V600EBRAF mutation. Ipilimumab (Yervoy, Bristol-Myers Squibb) received regulatory approval in March 2011. If vemurafenib (Roche) receives Above, melanoma cells and tumors. regulatory approval, clinicians will have two highly active therapies from which to choose, at least for those advanced melanomas with the V600EBRAF mutation, a mutation present in about half of these cancers. This is an

see THREE YEARS, page 10 

EDITORIAL BOARD COMMENTARY

see NEW OPTIONS, page 16 

Vogl, New York …

Is It Good To Prevent Breast Cancer With Exemestane?

recent editorial by Nancy Davidson and Thomas Kensler in The New England Journal of Medicine (NEJM)1 chides Steven Vogl, MD the medical establishment for not having used tamoxifen to prevent breast cancer and exhorts us to now use exemestane, an agent with significantly lower acute toxicity, to prevent breast cancer in women at risk. This editorial accompanies the NEJM article by Goss et al2 reporting the efficacy of exemestane given for 5 years in preventing breast cancer. see PREVENT, page 12 

POLICY & MANAGEMENT

Shifting Payment Landscape Spurs Innovative Oncology Partnerships

or 16 years, Patrick Cobb, MD, a medical oncologist in Billings, Mont., had practiced medicine following a time-tested model for community oncology clinics: providing office-based chemotherapy and related services. From the standpoint of patient care and satisfaction, and as a business model, it worked. With a series of changes in health care payment structures, most prominent among them the 2003 Medicare Modernization Act (MMA), the status

quo began to unravel. The MMA drastically cut the amounts paid for chemotherapy drugs; it raised somewhat, and later slashed, payments for chemotherapy administration. At the same time, the costs of chemotherapy drugs were well along a steep upward trajectory, and the prospect of new models of reimbursement and health care delivery, such as episodic care, bundled payments and accountable care organizations see Landscape, page 20 

McMahonMedicalBooks.com Cancer Metastasis: Biologic Basis and Therapeutics

FDA News

David Lyden (Editor), Danny R. Welch (Editor), Bethan Psaila (Editor)

Istodax (Celgene) approved for peripheral T-cell lymphoma.

For more information, see page 17.

See page 5.

In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval,

and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. Hemorrhagic Events: Fatal hemorrhagic events have been reported (all grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. Hypertension: Hypertension has been observed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided signiﬁcant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 2,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 2,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 2,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines Category 1 recommendation4 • First-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology

Proven safety proﬁle1,2 • Most common adverse events observed with VOTRIENT (>20%) were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

Once-daily oral dosing1 • The recommended dosage of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal) • Dose modiﬁcations, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events • Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced VOTRIENT is a multitargeted tyrosine kinase inhibitor that is indicated for the treatment of patients with advanced RCC.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2010. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on ﬁle, GlaxoSmithKline. 4. Referenced with permission from ©National Comprehensive Cancer Network, Inc 2010. All Rights Reserved. NCCN Guidelines™: Kidney Cancer, V.1.2011. NCCN. org Accessed January 12, 2011. NCCN® and NCCN GUIDELINES™ are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • July 2011

Sales Staff Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Editorial Staff Kate O’Rourke, Managing Editor korourke@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com Nancy Parker, Executive Manager/Classified Advertising, nparker@mcmahonmed.com

James Prudden, Group Editorial Director

Art and Production Staff

David Bronstein, Editorial Director, Hospital Group

Michele McMahon Velle, Creative Director, MAX Graphics

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations

Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

McMahon Publishing Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

BRIEF SUMMARY VOTRIENT™ (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension: Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced.

FDA NEWS

Clinical Oncology News • July 2011

Istodax Approved for PTCL

he FDA has granted accelerated approval for romidepsin for injection (Istodax, Celgene) for the treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication has been granted based on response rate; clinical benefit, such as improved overall survival, has not been demonstrated. The approval is based on results from two studies. One of the studies was a Phase II, multicenter, international, open-label study of romidepsin in progressive or relapsed PTCL following

prior systemic therapy. In the study, patients with histopathologically confirmed PTCL who failed or were refractory to prior systemic therapy received 14 mg/m2 of romidepsin as a four-hour infusion on days 1, 8 and 15 of a 28-day cycle for up to six cycles. Treatment could be

Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290) Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension

extended for response or stable disease. Of 130 patients with histopathologically confirmed PTCL in the study, the overall response rate (ORR) was 26%, as assessed by an Independent Review Committee (IRC). Thirteen percent of patients achieved a complete response (CR), the primary end point of the study, and another 13% achieved a partial response (PR). The median duration of response for all patients who responded was 12 months. The median duration of response for patients who achieved a CR has not been reached (median duration of follow-up: 8.2 months), and 82% of

were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.2).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.3).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.5).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any postbaseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.7).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/ kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was

patients with a CR had not progressed as of the data cutoff for the IRC evaluation. In the study, 96.2% of patients evaluable for safety experienced at least one treatment-emergent adverse event (AE), with the most common grade 3 or higher AEs reported as thrombocytopenia (24%), neutropenia (20%), infections (17%) and anemia (10%). In a second Phase II study, 47 patients with PTCL of various subtypes were enrolled. All patients had received prior therapy with a median of three previous treatments (range, one to 11); 38% see FDA NEWS, page 10 

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Clinical Oncology News • July 2011

Patient Discussions

Words and Their Unique Meanings in Oncology Although both the specific use and choice of words are relevant issues in all of medicine, from communication between health care professionals to physician interactions with patients and the public, words often have a very special and particularly powerful meaning in oncology. This was eloquently discussed by Susan Sontag in her groundbreaking masterpiece, “Illness as Metaphor.”1 For example, consider the word “advanced” in the context of describing an individual patient’s cancer. What

exactly does this mean? As used in a recently published outstanding overview of the need for oncologists to honestly discuss realistic goals for disease management of “advanced incurable” cancer, the word “advanced” implies

reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/ day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for

(although it does not definitively state) the existence of limited available therapeutic options and an anticipated relatively short survival.2 Although a cancer specialist or someone with a clear understanding of

26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. • yellowing of the skin or the whites of the eyes (jaundice), • unusual darkening of the urine, • unusual tiredness, • right upper stomach area pain. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

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

this multidimensional and potentially highly emotional topic will (or at least should) appreciate the intent of this term and need for discussion, it is reasonable that individuals without knowledge of the complexity of oncologic management may expand the definition beyond this intentionally specific and narrow meaning. In fact, the term “advanced” has long been used as a component of a standard description of the anatomic stage of cancer at diagnosis. So, a patient with a “stage III ovarian cancer” is said to have an “advanced-stage cancer.” Yet, in this specific clinical setting, more than 70% of patients are expected to achieve major objective responses (eg, decrease in the size of measurable tumor masses, disappearance of ascites) and subjective responses (eg, decrease in pain and improved appetite and overall quality of life) to primary therapy (surgery plus chemotherapy), with an anticipated median overall survival currently exceeding 3 to 5 years. This is based on the reported extent of residual disease following initial surgical cytoreduction.3 Surely, in this context the use of the words “advanced cancer” to explain the extent of disease at the time of an ovarian cancer diagnosis is meant to convey a different meaning from the identical term employed to suggest the appropriate need for end-of-life discussions. Furthermore, similar concerns can be raised about the second powerful word noted above, “incurable.” Again, this term (like that previously noted for “advanced”) may be used appropriately to denote a situation where options and anticipated survival unfortunately are quite limited. But on objective reflection of the current status associated with the management of a number of malignant diseases, it is relevant to acknowledge that even some unquestionably “incurable cancers” are becoming chronic disease processes. In this increasingly common scenario, death will likely ultimately result from progression of the neoplasm (if it does not occur earlier from an unrelated cause). However, extended survival of more than 2 to 3 years may be a very realistic possibility with careful and judicious application of a wide range of therapeutic options—chemotherapy, radiotherapy,

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Clinical Oncology News • July 2011

Patient Discussions

surgery, and supportive and palliative care. In this specific setting, the term “incurable” may have a very different meaning to patients and their families. Of course, the converse of the argument noted here is that words routinely used by specialists to describe a particular clinical state actually may provide a somewhat overly optimistic assessment of the possible outcome, if considered by a patient who doesn’t have knowledge of the underlying intent of the use of such terminology. For example, in the management of epithelial ovarian cancer, the expression “platinum-sensitive,” recurrent disease is used frequently to describe the course of a patient whose disease recurs more than 6 to 12 months following the completion of a primary platinum-based chemotherapy regimen. Use of this expression by oncologists is meant to suggest that a particular patient has a reasonable possibility (eg, >20%-30%) of responding a second time to reintroduction of a platinum-containing regimen and not that it is actually known that her cancer remains sensitive to this class of antineoplastic agents. But consider the patient and her family in this clinical setting who may be reading these words in a scientific or lay description of the treatment of ovarian cancer, or perhaps on a consent form for a clinical trial. Without further explanation, these words very easily could be interpreted to mean “the doctor says my cancer remains sensitive to platinum.”

descriptive terms in

regarding prognosis, it is highly relevant to both understand and anticipate differing meanings for the identical (or nearly identical) terms. As a result, great care is advised when selecting specific words to be used in complex oncologic settings. Doctors should be as realistically certain as possible that the meaning one intends or hopes to convey is the actual meaning that is being conveyed.

oncology, based on

—Maurie Markman, MD

The point of this commentary is to emphasize the reasonable conclusion that there is the potential for quite different interpretations of

specific clinical

Have a response to this editorial? Please send your comments to maurie.markman@ctca-hope.com or korourke@mcmahonmed.com.

settings and the unique perspectives of individuals.

References 1. Sontag S. Illness as Metaphor. New York, NY: Farrar, Straus and Giroux; 1978. 2. Peppercorn JM, Smith TJ, Helft PR. American Society of Clinical Oncology statement: Toward individualized care for patients with advanced cancer. J Clin Oncol. 2011;29:755-760, PMID: 21263086. 3. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. 2009;374:1371-1382, PMID: 19793610.

What are your thoughts?

The point of this commentary is to emphasize the reasonable conclusion that there is the potential for quite different interpretations of descriptive terms in oncology, based on specific clinical settings and the unique perspectives of individuals.

For those writing or speaking about topics where such expressions are likely to be employed, whether involving a large audience who will potentially read these words or, at the other extreme, where there will be a discussion with an individual patient and her or his family

Clinical Oncology News encourages letters to the editor. Do you have thoughts on Dr. Markman’s commentary? Please send comments to

korourke@mcmahonmed.com.

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

HEMATOLOGIC DISEASE

Clinical Oncology News • July 2011

Leukemia

In Pediatric and Young Adults With ALL ...

Revised MTX Dosing Strategy Improves Outcomes Chicago—Oncologists have a new standard of care for the treatment of high-risk acute lymphoblastic leukemia (ALL) in children and young adults, according to a new study. The clear superiority of the investigational arm of the Phase III trial was so striking that the trial was stopped early. Presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3), the trial compared a high-dose regimen of methotrexate (MTX) with the standard Capizzi regimen, which employs escalating doses, in patients aged 1 to 30 years. At five years, the event-free survival (EFS) rates were 82% and 75.4%, respectively (P=0.006). Outlining “the numerous strengths of this trial” and praising the investigators for a “tenacity that was amply rewarded by a major advance in the field,” Martin Tallman, MD, chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, New York City, characterized the high-dose MTX regimen as “the new standard of care for treatment of highrisk ALL.” Dr. Tallman, the ASCO-designated discussant for the study, praised the inclusion of patients up to 30 years of age into the study. Even though patients between the ages of 20 and 30 represented only 2% of the study population, data suggesting that the benefit extends to young adults are helpful for the small but substantial number of patients who fall in this age range. Of the more than 3,000 patients initially planned for inclusion in the study, known as AALL 0232, data on 2,104 were available for the interim analysis. The study randomized patients with newly diagnosed high-risk B-precursor ALL into a 2 x 2 factorial design. This included an initial randomization to prednisone or dexamethasone at induction, which was followed by a second

Presenting these data on behalf of the Children’s Oncology Group (COG), Dr. Larsen noted that the design of the study was initiated approximately 10 years ago, when it became apparent that the improvement in outcomes in high-risk ALL pediatric patients, particularly those with central nervous system (CNS) disease, were not keeping pace with those with lower risk. He explained that there were no promising experimental therapies available, so the decision was to try to intensify the

trended toward greater rates of EFS at five years in the rapid early responders (86.6% vs. 82.7%; P=0.09), the greatest advantage at the end of the study was observed in those with slow early responses (79.5% vs. 65.4%; P=0.04). Based on these results, the high-dose MTX regimen will be regarded as the standard against which new strategies will be compared in future COG studies, according to Dr. Larsen. Although it is impressive that a widely used drug that has been around for more than 50 years

‘The protocol was closed early when a planned interim analysis demonstrated that the highdose MTX treatment was clearly superior to the standard Capizzi regimen.’ —Eric C. Larsen, MD Acute lymphoblastic leukemia.

randomization to a high- or standarddose MTX regimen. The focus of the results of the trial was on the second randomization. In this second randomization, patients in the experimental arm received 5 g/m2 of MTX on days 1, 15, 29 and 43 with leucovorin rescue along with 6-mercaptopurine, intrathecal MTX and vincristine. The standard Capizzi regimen involved escalating doses of MTX on days 1, 11, 21, 31 and 41. Patients in this group did not receive leucovorin rescue but did receive pegylated asparaginase along with intrathecal MTX and vincristine. “The protocol was closed early when a planned interim analysis demonstrated that the high-dose MTX treatment was clearly superior to the standard Capizzi regimen,” reported Eric C. Larsen, MD, medical director of the Maine Children’s Cancer Program, Maine Medical Center, Portland.

therapy that had already demonstrated activity in ALL. Despite the fact that the newer regimen was more intensive, the incidence of many of the major adverse events was actually lower in the experimental arm. In particular, febrile neutropenia occurred in 5.2% of those on highdose MTX compared with 8.2% of those on the standard regimen (P=0.005). No significant differences were identified between the study arms in terms of mucositis, acute neurotoxicity (e.g., seizures) or osteonecrosis. Dr. Larsen speculated that the leucovorin rescue may have accounted for the greater overall tolerability of the high-dose regimen. In addition to the more favorable EFS rate after five years, there were also fewer treatment failures, including fewer marrow and CNS relapses, in the high-dose arm. Although the high-dose regimen

could be employed in a different strategy to provide a significant improvement in outcome, Dr. Larsen indicated that the next advances are likely to be drawn from therapies with molecular targets. Although the improvement in outcomes among children with a variety of cancers has been a major success story over the past 40 years, B-cell precursor ALL has been challenging, particularly in individuals with a high white cell count and abnormal cytogenetics. ALL, which has its peak incidence between the ages of 2 and 5, is the most common pediatric malignancy, representing about one-third of all pediatric cancers. Dr. Larsen indicated that the results of this study represent an important and needed incremental advance in the treatment of high-risk patients. Drs. Larsen and Tallman had no relevant disclosures. —Ted Bosworth

MULTIPLE CANCERS

Patients Abandon Oral Chemotherapies Due to High Copays Chicago—One-tenth of new oral chemotherapy prescriptions are not filled by patients, according to a study based on national pharmaceutical claims data. Presented at the American Society of Clinical Oncology annual meeting (abstract 6036) and also published recently in both the Journal of Oncology Practice (2011;7:46s-51s) and the American Journal of Managed Care (2011;17:SP38-SP44), the results “highlight the importance of identifying strategies to minimize the

impact of high cost-sharing requirements in prescription drug plans so that they do not pose a barrier to access to newer oral therapies,” noted the authors from The West Clinic in Memphis, Tenn., and health care consultancy Avalere Health, in Washington, D.C. Using claims data from the Wolters

Kluwer Dynamic Claims Database, the investigators found 10,508 patients who met inclusion criteria for the study and had at least one pharmacy claim for one of the study drugs between January 2007 and June 2009. The drugs included were the oral chemotherapeutic agents that were widely available at the time of the study—capecitabine (Xeloda, Roche), erlotinib (Tarceva, Genentech), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), lenalidomide (Revlimid, Celgene), sorafenib (Nexavar,

Bayer), sunitinib (Sutent, Pfizer) and temozolomide (Temodar, Merck). For these patients, 67% of the claims were adjudicated and paid for and 33% were reversed. Although 24% of those who reversed their initial claims did follow up with therapy, there may have been unnecessary delays in treatment. The investigators found several factors associated with medication abandonment. For example, the rate of prescription abandonment increased with copayment required. Claims for which

MULTIPLE CANCERS

Clinical Oncology News • July 2011

patients were required to pay $500 or more had the highest rate of abandonment (25%), and those for which patients had copays of $100 or less had a significantly lower rate of abandonment (6%; P<0.05). Another factor associated with an increased likelihood of an abandoned therapy was multiple concurrent prescriptions. Patients with more than five concurrent prescriptions during the previous month had an abandonment rate of 12%, and those with no claims during the previous month had an abandonment rate of 9% (P<0.05). Lower annual household income also was associated with higher rates of medication abandonment, although this association was

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Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, solicit article ideas and authors, listen to your concerns, meet your staff and patients and observe the physical site of your practice. You can help us improve Clinical Oncology News and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Kate O’Rourke, editor, at (212) 957-5300 ext. 265 or via e-mail at korourke@ mcmahonmed.com.

not statistically significant. Patients with incomes less than $40,000 were 20% more likely than those with incomes greater than $75,000 to abandon their prescription (P=0.058). The authors acknowledged that the study had some limitations. They noted that they did not have full access to IV chemotherapy claims data, so some of the patients who were counted as abandoning therapy altogether may have switched to IV chemotherapy or may have received the originally prescribed oral agent through a manufacturer patient assistance program.

Based on the findings, the authors suggested that “as the structure of Medicare Part D and commercial plans are modified and health reform initiatives evolve, policymakers and stakeholders should be aware of the impact of benefit structure on adherence and access to vital oncology therapy.” Steven Vogl, MD, a community oncologist practicing in New York City, shares the authors’ concerns about the problems associated with the cost of some of the oral agents. Calling the price of oral cancer drugs “a huge problem,” he recounted the story of an elderly patient

with myeloma for whom he prescribed lenalidomide. The patient was unable to pay the $7,000 yearly out-of-pocket cost for the drug and was not a candidate for alternative agents. The patient ended up dying as a consequence of this treatable myeloma. Dr. Vogl added that “the prices of new drugs are outrageous. We need to move to a system in which buyers (read insurance companies, Medicare and Medicaid) negotiate prices with drug companies. This would be simplest in a single-payer system, which would have many other advantages.” —Sarah Tilyou

SOLID TUMORS

Clinical Oncology News • July 2011

GIST Three years of imatinib One year of imatinib

THREE YEARS Hospital in Helsinki, at the recent American Society of Clinical Oncology (ASCO) annual meeting (abstract LBA1). Previous trials have shown that one year of adjuvant imatinib reduces the risk of GIST recurrence compared with placebo but have not yet demonstrated an improvement in survival. Approximately 85% of patients who have advanced GIST respond to imatinib, with partial remission or stable disease lasting a median of two years. High-risk GISTs, which are defined by clinical factors including size (>5 cm), high cell proliferation rate and/ or location, are associated with at least a 50% five-year risk for recurrence after surgery, said Dr. Joensuu. At the ASCO meeting, Dr. Joensuu presented results from a prospective, openlabel, randomized Phase III study carried out in Finland, Germany, Norway and Sweden. The study randomly assigned 400 high-risk GIST patients to one year of imatinib (200 patients, median age 62 years) or three years of imatinib (200 patients, median age 60 years). All patients received imatinib 400 mg daily. After a median follow-up of 54 months in the intention-to-treat population, the results showed a significantly higher five-year recurrence-free survival in patients treated for three years compared with one year (65.6% vs. 47.9%; P<0.0001) (Figure 1). Similarly, the five-year overall survival rate was significantly higher for patients receiving imatinib for three years (92% vs. 81.7%; P=0.019) (Figure 2). “The longer treatment prevented recurrence of GIST in 54% of patients, and there were 55% fewer deaths in the

Recurrence-free Survival Rate, %

continued from page 1 

100 80 65.6

60 47.9

40 20 0

Figure 1. Five-year recurrence-free survival in GIST.

Three years of imatinib One year of imatinib

100

Overall Survival Rate, %

92 81.7

60 40 20 0

Figure 2. Five-year overall survival in GIST.

three-year versus the one-year group,” Dr. Joensuu said. “Historically, 50% of GIST patients had died within five years. With imatinib, we are making substantial improvements.” The treatment was well tolerated, with the most frequent side effects including anemia, eyelid swelling, fatigue, nausea and muscle cramps, which were usually

mild. There were slightly more treatment discontinuations due to adverse events in the three-year group (14% vs. 8%) and slightly more grade 3/4 adverse events in the three-year group (33% vs. 20%). As in previous studies, few patients developed resistance to adjuvant imatinib. Only 2% of patients in the one-year group and 6.1% of those in the three-year group stopped treatment because of GIST recurrence while receiving imatinib. “Compared to one year of adjuvant imatinib, three years of imatinib improves recurrence-free survival and overall survival as treatment of GIST patients who have a high estimated risk for recurrence after surgery,” Dr. Joensuu said. He noted that there are no data that these patients might survive longer if they received five years of adjuvant imatinib, but that studies analyzing GIST risk factors and addressing longer treatment times with adjuvant imatinib are currently under way. Clinicians need to follow these patients carefully to detect early recurrence, he said. “There is evidence that patients with small tumors will respond longer to imatinib than patients with bulky tumors,” said Dr. Joensuu. “If we can detect the tumor when tumor volume is small, there is less likelihood the patient will develop resistance to imatinib.” Charles Blanke, MD, chief of medical oncology at University of British Columbia, Vancouver, was asked to discuss the study at ASCO. “Three years of postoperative imatinib treatment represent the new gold standard for patients with resected, high-risk GIST,” Dr. Blanke said. “The overall survival advantage demonstrated means we cannot try to ‘catch up’ later in the advanced disease setting.” Dr. Blanke pointed out that imatinib is not a cure for advanced GIST. “Even patients in complete remission at five

Endoscopic image of GIST in fundus of stomach, seen on retroflexion.

years are not cured and need to stay on imatinib,” he said. “We also still don’t know how long to administer imatinib for GIST in the postoperative setting.” Dr. Blanke asked, “Should we treat longer than three years? Should we treat forever? There are many reasons to think that giving imatinib for a longer period would be better. For now, if I were a patient with resected GIST, I would request more. As a compliant oncologist, I personally will offer imatinib indefinitely. I reserve the right to change my mind, pending the longer-term overall survival results from SSG [Scandinavian Sarcoma Group] XVIII and the findings from the recently completed PERSIST-5 trial. But I don’t think GISTs are curable (with imatinib) even in the adjuvant setting.” At the moment, Dr. Blanke said, “Given the possibility that we need to treat for a very long term, coupled with the difficulty in patients taking long durations of the drug, I will recommend adjuvant imatinib to patients who have a 50% chance of recurrence following surgery.” He believes the number used to predict recurrence and then treat will be lower in the community. Drs. Joensuu and Blanke disclosed that they serve in a consultant or advisory role for Novartis. Dr. Joensuu has also received honoraria from the company. —Mark Furst

FDA NEWS continued from page 5 

had undergone stem cell transplant. All patients were evaluated for toxicity; two patients discovered to be ineligible were excluded from response assessment. Common AEs were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. CRs were observed in eight and PRs in nine of 45 patients, for an ORR of 38%. The median duration of overall response was 8.9 months (range, two to 74). Responses were observed in various subtypes, with six responses among the 18 patients with prior stem cell transplant. Romidepsin also is approved for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy.

New Formulation of Lupron Depot

he FDA has approved a new 45-mg six-month administration formulation of leuprolide acetate

for depot suspension (Lupron Depot, Abbott), an injectable medication used for the palliative treatment of advanced prostate cancer. The three current formulations of Lupron Depot have allowed patients to receive treatment every one, three or four months. The newly approved sixmonth formulation will provide additional dosing flexibility for patients with advanced prostate cancer. Approval was supported by a 48-week, open-label study involving 151 patients with prostate cancer. Patients received two injections, 24 weeks apart, and were followed for nearly 12 months to evaluate testosterone suppression and safety. Overall, testosterone suppression with the new 45-mg six-month formulation was sustained in patients throughout the treatment period. The onset of testosterone suppression was consistent with other currently available formulations of the drug. The most common side

effects were flushing, injection site pain, respiratory infection and fatigue.

FDA Clears New PET/MRI Scanning System

Clearance was based on bench tests that compared the device with a predicate PET/CT device. The Biograph mMR system is indicated for a patient who needs diagnostic PET or MRI imaging. People with pacemakers, defibrillators or other implanted electronic devices, however, should not be scanned with the Biograph mMR system unless those devices are specifically indicated for use in the MRI environment.

FDA Clears New HER2 Test

he FDA has cleared the Siemens Biograph mMR system, the first device to simultaneously perform a positron emission tomography (PET) scan and a magnetic resonance imaging (MRI) scan. The system reduces radiation dose and increases soft tissue contrast.

he FDA has approved a new test to determine HER2 positivity. Inform Dual ISH (Ventana Medical Systems) allows laboratory personnel, using a stain, to count the number of copies of HER2 genes on chromosome 17 in a small sample of the breast tumor. Copies of the HER2 gene appear black and copies of chromosome 17 appear red, and these changes can be seen with see FDA NEWS, page 14 

SOLID TUMORS

Clinical Oncology News • July 2011

Breast

More Vigilance Urged for DCIS Patients Receiving Radiation Washington—Radiation after surgery significantly reduces the likelihood that breast cancer will recur, but a recent study suggests that if cancer does come back in women treated with breast-conserving surgery and radiotherapy for ductal carcinoma in situ (DCIS), it may be more advanced and should be followed carefully for an extended period of time. “Over the last 10 years there has been a trend toward doing less-invasive procedures in patients with DCIS, and in 2003 the [National Cancer Comprehensive Network] guidelines accepted lumpectomy alone as an option,” said Janie Weng Grumley, MD, a fellow in breast oncology at the University of Southern California Keck School of Medicine, Los Angeles, who presented the findings at the annual meeting of the American Society of Breast Surgeons. “As more patients opt for no radiation, our goal was to see what the difference in patterns of recurrence is when they do get radiation and when they don’t.”

28% of patients who received radiation experienced recurrence in a different quadrant—indicating new cancers—compared with 10% of those in the excision-alone group.

however, those who received radiation had a much higher rate of invasive cancers. Additionally, 28% of the patients who received radiation experienced recurrence in a different quadrant—indicating new cancers—compared with 10%

of those in the excision-alone group. Time to overall recurrence was longer in the radiation group than in the surgery-alone group (about eight vs. four years, respectively). Breast cancer–specific survival was slightly, but

statistically significantly lower, in the radiation group at 98.3%, compared with the excision group at 99.7%. There was, however, a small but significant diseasespecific survival in those patients who did not get radiation. Dr. Grumley hypothesized that radiotherapy may have a blunting effect on recurrences that makes them difficult to detect in early stages. “Radiation may change DCIS so that it doesn’t produce

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

Dr. Grumley’s team looked at patients from a prospective database and found 1,014 people who had undergone treatment for DCIS; 651 had surgery alone and 363 had surgery plus radiation. The researchers evaluated these patients for types of local recurrence, time to recurrence, location of recurrence and breast cancer–specific survival. The investigators found that patients who received radiation had a significantly lower rate of recurrence at 10 years than patients who underwent excision alone, at 18% and 30%, respectively. “The finding was very much consistent with all the collaborative studies in the past; when you get radiation your recurrence rate is approximately half,” Dr. Grumley said. “Achieving this result was important to us because this isn’t a randomized trial; this is just a cohort of patients that was followed over time.” Of the patients who had recurrences,

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

see RECURRENCE, page 21 

SOLID TUMORS

Clinical Oncology News • July 2011

Breast

PREVENT continued from page 1 

I have a lot of difficulty with this recommendation, as I have had with recommendations in the past 14 years to push tamoxifen and raloxifene on healthy women to prevent breast cancer. The short statement of my argument is that before you put every woman in the developed world on 5 years of medicines that will make many of them miserable with joint pains, may give many premature osteoporosis, and may have longterm deleterious consequences we cannot even imagine, we need to be pretty sure that either the quality or the duration of their lives (and preferably both) will improve substantially. The data we have in hand come nowhere close to showing either, so we should not recommend breast cancer prevention with exemestane (Aromasin, Pfizer). I argue here that it is quite plausible that 5 years of exemestane will substantially impair quality of life (QoL) for these women and may not substantially prevent breast cancer deaths. The paper by Goss et al is very well written, thought-out, and referenced, and includes just about all the data that I mention in this editorial. I differ substantially, however, in my weighting of the concerns and in my conclusions. It was no surprise that the NSABP P1 trial demonstrated that tamoxifen prevents breast cancer, nor is it a surprise that the MAP.3 trial shows that exemestane prevents breast cancer. Reduction in new breast cancers clearly was demonstrated in the substantial reduction in the risk for contralateral breast cancer in women who already had one breast cancer and were given either agent—the suppression of contralateral new primaries was seen quite early. The prevention trials were almost guaranteed to be positive for a reduction in breast cancer incidence. In that sense, they are a waste of money and effort. Positive trials that get published in prestigious journals are good for careers, and lead to grant renewals and professional awards. The studies are helpful to some extent because they quantify the benefit in various risk populations. However, the real question, which remains to be answered, is do these agents benefit the population of women exposed to them and how much do they benefit? Is it good to prevent breast cancer in principle? Of course—breast cancer kills approximately 40,000 women annually in the United States, causes suffering, and leads to treatment that is expensive, sickening, deforming, upsetting, and produces early menopause and its attendant ills. Breast cancer has spawned a huge industry aimed at early detection that produces many negative biopsies, painful procedures, and repeated testing

EDITORIAL BOARD COMMENTARY

We need to recognize that the way the studies were designed, nearly every female in the world will be eligible for cancer prevention—this is nearly equivalent to putting tamoxifen or exemestane in the drinking water.

that causes lots of anxiety and loss of time. One surgeon tells me that many of her patients would rather have bilateral mastectomies than undergo a second magnetic resonance imaging-guided biopsy. If we could really prevent breast cancer efficiently, then we could stop screening for early cases! Is it good to prevent breast cancer with a specific agent, like exemestane, tamoxifen, or raloxifene? This is a much more relevant question and has not been answered to my satisfaction for any agent. None of the breast cancer prevention studies have come close to demonstrating improvement in QoL, causespecific mortality, or all-cause mortality. None of the published trials have even tried to address these end points, and only an Italian tamoxifen trial lists breast cancer mortality as its primary end point.3 Mortality was a secondary end point in the International Breast Cancer Intervention Study trial in England.4 Fisher et al, in their final report on the P1 trial, clearly state why these end

points have not been addressed.4 The numbers required are too large, the follow-up too long, and the likelihood of a positive result uncertain, especially in the lifetime of the investigators. Unstated, but implicit, is the expense of a longterm study of a large number of patients, especially in a mobile society. For an agency like the National Surgical Adjuvant Breast and Bowel Project, which depends on annual US government grant funding and is under review every few years, beginning a 30-year study is particularly problematic. Due to the difficulty in completing a study with the important end points, should we then just give in and treat women to prevent breast cancer, even though we do not know if it makes them live longer or live better? I would not, unless the woman is so anxious about this particular issue that she insists despite the lack of appropriate data. How can it be that preventing breast cancer can fail to be good? Perhaps an extreme example would help. Suppose I

What is the price of breast cancer prevention with tamoxifen, raloxifene, or exemestane? We know some of the early toxicities, but we do not really know the long-term benefits or the long-term toxicities.

Steven Vogl, MD Medical Oncologist, New York City

offered an intervention that caused no pain; had no risk for second Scan for malignancy; caused no exemestane study. hot flashes, joint pain, Instructions, see page 20. or increase in cardiovascular risk; and guaranteed that the patient would never develop or die of breast cancer. Sounds great: However, a bullet to the head has all these attributes. “Oh, this is silly,” the prevention advocate replies, but concedes the point that breast cancer prevention is good, but not at any price. So what is the price of breast cancer prevention with tamoxifen, raloxifene, or exemestane? We know some of the early toxicities, but we do not really know the long-term benefits or the long-term toxicities. Indeed, the first of these trials ended its follow-up at 7 years (I assume as part of its funding negotiations), so no effort will ever be made to measure outcomes over the long term. At approximately 14,000 women in the 2 arms, the study was much too small to look at all-cause mortality, and was not designed to do so. A number of issues come to mind in preventing breast cancer with these hormonal agents: The populations at risk are crudely defined, there is a great deal of acute toxicity during therapy, compliance is spotty and hard to measure, and the long-term toxicities are unknown. Additionally, the agents prevent the less-aggressive cancers only, and these are the ones for which hormonal therapy works well and prevents death very effectively.4 The acute toxicities of exemestane are clearly less severe than those of tamoxifen (ie, no thrombosis or uterine cancer or uterine sarcoma), but hot flashes and especially joint pain can be very troublesome, and can severely limit compliance in patients whose lives are at risk from cancer. Compliance would likely be even worse in women taking exemestane in the hope of a benefit at a remote time. Goss et al’s paper suggests the subjective toxicity is not so bad. Perhaps Canadian women are more stoic than the New Yorkers I see, but I know a lot of women who were miserable on aromatase inhibitors (AIs), many of whom refused to take any of them even though, to some extent, their lives depended on the issue. I suspect the QoL instruments Goss et al employed were too crude to measure the misery and discomfort.

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Systemic Therapy for Patients With

Well-Differentiated Neuroendocrine Tumors DIANE REIDY-LAGUNES, MD, MS Assistant Attending Physician hysician Memorial Sloan-Kettering Cancer Center cine Instructor of Medicine Weill Cornell Medical College ge New York, New York rk

EDWARD WYLUDA, DO O Research Intern Memorial Sloan-Kettering Cancer Centerr New York, New York k

LEONARD B. SALTZ, MD D Attending Physician cian Memorial Sloan-Kettering Cancer Center Professor of Medicine edicine Weill Cornell Medical al College New York, rk, New York

lthough unresectable metastatic neuroendocrine tumors (NETs) are incurable, the hallmark of well-differentiated NETs is that they have a relatively indolent course compared with most other cancers.

For this reason, immediate intervention at the time of diagnosis of an asymptomatic, hormonally nonfunctional NET patient is rarely indicated. Instead, careful evaluation of each patient, with an initial interval of observation and assessment, can help define who needs treatment sooner and who is likely to do well without treatment for a more extended period (Figure). It is not a matter of treat or don’t treat; it is a matter of treatment now or treatment later. It is important to remember that all therapies and interventions carry risks and side effects. Even mild to moderate side effects can seriously impact a patient’s sense of well-being and quality of life. If a patient is asymptomatic, then a treatment—be it a drug therapy or a mechanical therapy—does not have the potential to make that patient feel better but certainly has the potential to make him or her feel worse. Premature

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

initiation of chemotherapy or other treatments may subject a patient to months or years of unnecessary side effects for essentially no overall benefit and may exhaust some treatment options too soon. Some newer treatment options are becoming available for patients with pancreatic NETs, and this review will discuss some of these options. However, the basic principles of management of well-differentiated NETs remain the same: Don’t overreact to the initial diagnosis; don’t embark on an overly extensive workup of esoteric tests; and don’t overtreat.

One Size Does Not Fit All Well-differentiated NETs can be subdivided into carcinoid and pancreatic NETs (pNETs). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive

C L I N I C A L O N C O L O G Y N E W S • J U LY 2 0 1 1

to therapeutic agents than pNETs, and recent advances that have been approved by the FDA for pNETs have not been submitted for use in patients with carcinoid NETs.

Initial Evaluation and Workup NETs can be stratified by certain histopathologic features, including cytologic grade (low, intermediate, and high) and proliferative index (as assessed by mitotic index and/or Ki-67).1-3 Well-differentiated NETs typically are relatively refractory to standard chemotherapy agents, although, as will be discussed, a number of newer agents are showing modest activity. In contrast, tumors with higher grade, a mitotic count greater than 20 per 10 high power field, or a Ki-67 of more than 20% represent aggressive malignancies; observation is not an appropriate first approach for these patients. They require urgent and aggressive intervention and typically are treated with small cell lung cancer regimens. Our initial course of action in most patients with welldifferentiated NETs, be they carcinoid tumors or pNETs, is watchful waiting and serial monitoring at an interval of approximately 12 weeks, with triple-phase computed tomography scanning or magnetic resonance imaging to establish that individual’s natural disease growth pattern. Fluorodeoxyglucose positron emission tomography and octreotide scans have not been found to be useful for surveillance or staging in NET patients.4 We typically obtain a baseline octreotide scan only to assess in vivo whether or not the patient’s tumor has receptors for octreotide for therapeutic purposes.

LABORATORY WORKUP A nondirected hormonal workup usually is not indicated in a patient without hormonal symptoms and is at least as likely to produce a false-positive as a true-positive result. One exception to this is that patients with carcinoid tumors of other than rectal origin may have asymptomatic elevations of serotonin, which is best assessed by a 24-hour urine collection for the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA). Note that the urine must be collected in an acidified container for accurate results. Patients with clinically elevated 5-HIAA levels may be at risk for increased carcinoid heart disease and may be candidates for early initiation of octreotide therapy. Symptom-specific hormone levels should be drawn as clinically indicated. Because we base our decisions on the patient’s clinical condition and scans, the rise or fall of a non–symptom-producing hormone is of no proven clinical relevance. For this reason, we do not follow these markers routinely. If the scan at 3 months shows no tumor growth, or very minimal growth, then further watchful waiting and repeat scans at 3- to 4-month intervals are warranted. Indications for treatment would be symptoms due to tumor or tumor bulk, symptoms due to hormone production, or clinically significant growth under observation. Once intervention is being considered, carcinoid tumors and pNETs must be considered separately because a number of therapeutic options that are showing or have

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shown efficacy in pNETs are of little or no use in carcinoid tumors.

Treatment OCTREOTIDE Although it is well documented that the somatostatin analog octreotide is highly useful for treatment of hormone-related symptoms in patients with hormonally functional NETs, it has long been assumed that octreotide has moderate antiproliferative effects on tumor growth as well. The first randomized data to support this hypothesis were provided by the PROMID study. In this trial, 85 patients with newly diagnosed asymptomatic midgut carcinoid tumors were randomly assigned to receive octreotide LAR 30 mg intramuscularly once per month or placebo. The median time to tumor progression was 14.3 months in the octreotide arm compared with 6 months in the placebo group.5 As expected in this small trial, there was no difference in overall survival (OS) between treatment groups. Interpretation of the clinical implications of this trial varies. The trial design placed all patients—95% of whom had Ki-67 less than 2% and 75% of whom had liver tumor burden of 10% or lower—on octreotide at the time of diagnosis. Some have chosen to interpret this as an obligation to place all patients with asymptomatic carcinoid tumors on octreotide at the time of diagnosis. Others (including ourselves) do not agree with this interpretation. As noted, given the variable and often indolent disease course of patients with carcinoid tumors, committing a patient to lifelong injections of octreotide in the absence of symptoms or clinically meaningful disease volume or progression should be questioned. As the median survival reported in the trial exceeded the median progression-free survival (PFS) benefit by more than 5 years, the argument that early initiation of octreotide is needed to achieve benefit is difficult to justify.

MAMMALIAN TARGET

RAPAMYCIN INHIBITORS

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that mediates downstream signaling from a number of signaling pathways that have been implicated as critical in NET growth. The Phase III RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) study evaluated the mTOR inhibitor everolimus (Afinitor, Novartis) 10 mg per day (n=207) versus best supportive care (n=203) in patients with metastatic pNETs.6 Median PFS was improved in the treatment arm (11.0 vs 4.6 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27-0.45; P<0.001). The adverse events (AEs) associated with everolimus most commonly were stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), and infections, predominantly of the upper respiratory tract (23%). Information regarding the duration of each of these toxicities has not been reported, and this information would be clinically relevant. The most common grade 3 or 4 drug-related AEs were stomatitis (7%), anemia (6%), and hyperglycemia (5%). Everolimus is now FDA approved for patients with progressive pNETs.

The benefit of mTOR inhibitors was substantially more limited in carcinoid NETs than in pNETs. RADIANT-2 was a randomized trial evaluating everolimus 10 mg daily versus placebo in 429 patients with metastatic carcinoid tumors. Median PFS was 16.4 months with everolimus versus 11.3 months with placebo; however, the increase was not statistically significant.

VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS

Figure. A nonfunctional pNET in a patient with extensive liver disease and pain who

NETs are highly vascularized and required early therapy for palliation of symptoms (left); a nonfunctional pNET in extensively express vascular enedo- a patient who was followed with no intervention since diagnosis 18 months before thelial growth factor (VEGF).7,8 Bevaci- (right). zumab (Avastin, Genentech) was testis, however, some evidence of activity in the treatment ed in a Phase II trial in which 44 patients with advanced of pNETs. or metastatic carcinoid tumors were randomly assigned An early study randomized 105 patients to streptoto receive either bevacizumab (15 mg/kg every 3 weeks) zocin plus doxorubicin, streptozocin plus fluorouraor pegylated interferon (IFN)-α2β. There was an 18% partial response rate in the bevacizumab group (4 of 22) cil, or chlorozotocin alone in patients with pNETs. This compared with none in the IFN-α2β group.9 A Phase III study reported a 69% response rate for the streptozotrial of bevacizumab plus octreotide versus IFN plus cin and doxorubicin combination, but response assessoctreotide is ongoing. ment in many of the patients was limited to either physSunitinib (Sutent, Pfizer) also was tested in the Phase ical examination (no scan) or hormonal measurements 10 II setting, with activity limited to pNETs. In a recent alone. More recent studies using more objective critestudy, 171 pNET patients were randomly assigned to plaria failed to produce similar results, with retrospective cebo or sunitinib 37.5 mg per day. Accrual was stopped reviews suggesting a 16% to 39% overall response rate prematurely, when more events were noted in the place(ORR) by Response Evaluation Criteria in Solid Tumors bo arm. The median PFS at the time the trial was halt(RECIST).18,19 The regimen likely has some activity, but its use has been limited by the toxicity of the drug. ed was 11.4 months for sunitinib versus 5.5 months for 11 Dacarbazine and the sister oral compound temozoloplacebo. Hand–foot syndrome (23%) and hypertension (26%) were the most common AEs. The most common mide (Temodar, Schering-Plough) are alkylating agents grade 3 or 4 AEs included neutropenia (12%) and hyperthat may be active in a subset of patients with pNETs. In tension (10%). Sunitinib also has been FDA approved for an Eastern Cooperative Oncology Group (ECOG) Phase progressive pNETs. II study of dacarbazine, 14 of the 42 patients with pNETs (33%) were reported to have had a partial or complete RADIOLABELED SOMATOSTATIN ANALOG THERAPY response; again however, response criteria do not meet In single-center trials, radionuclide somatostamodern standards.20 tin analog therapy for patients with advanced, indiRecently, the combination of temozolomide and um octreotide-positive NETs has been reported to capecitabine (Xeloda, Genentech) was studied. The have some efficacy, with manageable toxicity. SeverORR was 70% (21 of 30 patients) and median PFS was al radioisotopes linked to a somatostatin analog have 18 months, with 12% of patients having grade 3 or 4 been used, including indium-111 (111In), yttrium-90 (90Y), toxicity.21 The activity of single-agent temozolomide 177 90 and lutetium-177 ( Lu). Studies of the Y-labeled remains to be elucidated. somatostatin analog, a high-energy β-particle emitter, The dependence of temozolomide responsiveness on 12-15 An analysis reported response rates of up to 27%. deficient methylguanine methyltransferase (MGMT) gene of 504 patients with metastatic NET receiving 177Luexpression may explain the lack of benefit from this drug octreotate also was reported, with a response rate in some NETs and in carcinoids in particular. A retrospecof 30%.16,17 Serious toxicity was seen in 3% of patients tive review of 76 patients showed a response in approxiwho developed myelodysplastic syndrome and leukemately 33% (11) of 35 patients with pNETs but in none of mia, and temporary nonfatal liver toxicity was seen in 2 the 38 patients with carcinoid tumors (P<0.001). Compatients. Radiolabeled somatostatin analogs may hold plete absence of MGMT expression seemed to define promise, but they remain investigational. patients with pNETs who achieve significant benefit from temozolomide (5 of 8 pNET and 0 of 13 carcinoid CONVENTIONAL CHEMOTHERAPY tumors).22 The exception may be bronchial carcinoids. In No clearly defined role exists for conventional chea small retrospective study, 31% (4) of 13 patients had a motherapy in the treatment of carcinoid tumors. There partial response by RECIST criteria.23

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The role of streptozocin plus either 5-fluorouracil or cyclophosphamide was analyzed in an ECOG study of 118 carcinoid patients with metastatic carcinoid tumors. Response rates for the 2 arms were similar—33% and 26%, respectively, with no difference in OS. However, significant toxicity occurred that was felt to be prohibitive.24 Other trials also failed to convincingly demonstrate a meaningful benefit of combination therapy over single-agent therapy in the treatment of carcinoid tumors, and, in the authors’ opinion, it should not be routinely offered for patients with carcinoid tumors.25,26

Conclusions The clinical course of well-differentiated NETs is variable. An initial watch-and-wait period, typically in the range of 3 months for newly diagnosed asymptomatic NETs, permits an assessment of the biology of the tumor and its degree of aggressiveness or lack thereof, and helps define which patients are appropriate for earlier rather than later initiation of therapy. In symptomatic patients or in patients with clinically significant progressive disease, intervention is warranted. Everolimus and sunitinib have demonstrated modest activity in pNETs but are not substantially active in carcinoid tumors. Cytotoxic therapy also is somewhat more effective in pNETs and should be reserved for patients who have heavy tumor burden requiring tumor response. Treatment for progressive carcinoid tumors remains extremely limited.

References 1.

Ferrone C, Tang L, Tomplinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol. 2007;25(35): 5609-5615, PMID: 18065733.

tumors. J Clin Oncol. 2006;24(18 suppl): Abstract 4044. 10. Kulke M, Lenz H, Meropol N, et al. Activity of sunitinib in patients with advanced neuroendocrine tumours. J Clin Oncol. 2008;26(20):3403-3410, PMID 18612155. 11. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513, PMID: 21306237. 12. Waldherr C, Pless M, Maecke H, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-dPhe-Tyr-octreotide in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12(7):941-945, PMID: 11521799. 13. Waldherr C, Pless M, Maecke H, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med. 2002;43(5):610-616, PMID: 11994522. 14. Virgolini I, Britton K, Buscombe J, et al. 111In- and 90Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. J Nucl Med. 2002;32(2):148-155, PMID: 11965610. 15. Valkema R, Pauwels S, Kvols L, et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3] octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2006;36(2):147-156, PMID: 16517236. 16. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124-2130, PMID: 18445841. 17. Kwekkeboom DJ, Teunissen J, Bakker WH, et al. Radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23(12):2754-2762, PMID: 15837990. 18. Cheng P, Saltz L. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999;86(6): 944-948, PMID: 10491519. 19. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22(23):4762-4771, PMID: 15570077.

2. Van Eeden S, Quadvlieg P, Babs G, Offerhaus GJ, Lamers CB, Van Velthuysen ML. Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol. 2002;33(11): 1126-1132, PMID: 12454818.

20. Ramanathan R, Cnaan A, Hahn R, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol. 2001;12(8):1139-1143, PMID: 11583197.

3. Rindi G, D’Adda T, Froio E, Fellegara G, Bordi C. Prognostic factors in gastrointestinal endocrine tumors. Endocr Pathol. 2007;18(3): 145-149, PMID: 18058263.

21. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117(2):268-275, PMID: 20824724.

4. Reidy-Lagunes, DL, Gollub M, Saltz L. Addition of octreotide functional imaging to cross-sectional computed tomography or magnetic resonance imaging for the detection of neuroendocrine tumors: added value or an anachronism? J Clin Oncol. 2010;32:8559 (Correspondence). 5. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663, PMID: 19704057. 6. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523, PMID: 21306238. 7. Terris B, Scoazec J, Rubbia L, et al. Expression of vascular endothelial growth factor in digestive tumours. Histopathology. 1998;32(2):133-138, PMID: 9543669. 8. Phan A, Wang L, Xie K, et al. Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma. J Clin Oncol. 2006;24(18 suppl): Abstract 409. 9. Kulke M, Stuart K, Earle C, et al. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine

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

22. Kulke M, Frauenhoffer C, Hooshmand D, et al. Prediction of response to temozolomide (TMZ)-based therapy by loss of MGMT expression in patients with advanced neuroendocrine tumors (NET). J Clin Oncol. 2007;25(18 suppl). Abstract 4505. 23. Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13(10):2986-2991, PMID: 17505000. 24. Moertel C, Hanley J. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials. 1979;2(4):327-334, PMID: 93982. 25. Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984;2(11):1255-1259, PMID: 6238136. 26. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23(22):4897-4904, PMID: 16051944.

The authors report no relevant financial disclosures.

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Clinical Oncology News • July 2011

Breast

In Breast Cancer Patients ...

Study Establishes New Radiation Standard Chicago—Node-positive women who receive additional radiation to the internal mammary, supraclavicular and high axillary lymph nodes after breast-conserving surgery have a reduced risk for locoregional and distant recurrence, and significantly greater disease-free survival (DFS) rates, than women who receive only whole breast irradiation (WBI). This news comes from the results of the NCIC-CTG MA.20 clinical trial presented at the recent annual meeting of the American Society for Clinical Oncology (ASCO; LBA1003). The intergroup trial of regional nodal irradiation in early breast cancer randomized 1,832 women to receive either WBI alone or WBI plus regional nodal irradiation (RNI) after breast-conserving surgery and adjuvant chemotherapy and/or endocrine therapy. The vast majority of study subjects (85%) had between one and three positive nodes; 10% were node-negative and 5% had four or more positive nodes. After five years of follow-up, patients who had received the additional RNI Even if the number needed to treat turns out to be the optimistic 26 suggested in the recent NEJM paper, that means 26 women will get 5 years of treatment and toxicity to prevent one breast cancer, which probably would not kill the patient anyway. Long-term QoL also is problematic to some extent with AIs. The longterm toxicity scenario that sometimes awakens me at night is that AIs produce an epidemic of premature osteoporosis (with some premature fractures), for which well-meaning physicians prescribe denosumab (Prolia, Amgen) or bisphosphonates. This produces an epidemic of osteonecrosis of the jaw that produces discomfort for decades in otherwise healthy women. There may be other toxicities or drug interactions that I have not considered even in my nightmares. When dealing with treatment for millions of healthy women with years of good life ahead of them, we need to be very sure of the risks as well as the benefits. The eligibility of women younger than age 60 for the MAP.3 trial, as well as the P1 trial, is based on epidemiologic models based on population data collected in the 1980s using crude information to estimate risk. The model does not include known causes of hereditary breast cancer, since the BRCA-1 and BRCA-2 genes had not been identified in the 1980s. It does include number of breast biopsies even if the findings were completely benign on histologic exam, a puzzling risk factor that presumably is a surrogate for some other that was not measured. I suggest that more sophisticated measures of

had significantly improved rates of locoregional DFS (96.8% vs. 94.5%; P=0.02), distant DFS (92.4% and 87%; P=0.002) and overall DFS (89.7% vs. 84%; P=0.004). Overall survival (OS) also was improved for this group, although the trend did not reach statistical significance (92.3% vs. 90.7%; P=0.07). Discussant Thomas Buchholz, MD, chair of the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston, said that MA.20 has major clinical implications. “It addresses a simple, but relevant and important clinical question that affects literally thousands of patients throughout the world,”

he noted. And although the OS findings did not yet reach statistical significance, he predicted that they would with longer follow-up. “The curves are already separating,” he said. Reshma Jagsi, MD, assistant professor of radiation oncology at the University of Michigan Comprehensive Cancer Center, Ann Arbor, who served on the scientific program committee that evaluated the study for ASCO, agreed. “Such a strong trend toward improved overall survival after only five years is striking,” she said. “You wouldn’t necessarily expect a trial evaluating a treatment for microscopic locoregional disease in breast cancer to meet statistical significance for

The agents prevent the less-aggressive cancers only, and these are the ones for which hormonal therapy works well and prevents death very effectively.

breast cancer risk, especially in younger populations, are needed for populations of patients that exclude BRCA-1 and BRCA-2 mutation carriers. Finally, it is not clear that preventing breast cancers with these agents will save many lives. All these agents prevent only estrogen receptor (ER)-positive cancers (the hint that exemestane may prevent HER2-positive cancers is exciting, but HER2-positive cancers no longer have a worse prognosis, now that we can give adjuvant trastuzumab). The prognosis of ER-positive cancers keeps getting better, even if axillary nodes are involved. A major recent advance was the reporting of a 72% reduction in events when letrozole (Femara, Novartis) is given after 5 years of tamoxifen to women premenopausal at diagnosis who experienced a subsequent menopause. Absolute 5-year survivals greater than 90% are common in trials of endocrine therapy with or without chemotherapy. So exemestane, tamoxifen, and raloxifene prevent cancers that will kill only a small minority of women who develop them. Furthermore, the availability of tests, for which Oncotype DX is the prototype, may allow us to avoid giving chemotherapy to large numbers of women with ER-positive breast cancers, thus improving their QoL after diagnosis. Any benefit we project for prevention

now assumes no progress in the treatment of breast cancer in the future— when the cancers will occur if they are not prevented. There is every reason to believe that in 10 years we will have better and less-toxic targeted therapies, and will be better able to define who needs what therapy. Thus, even if a survival benefit now exists, it may not apply when the cancers develop. Finally, we need to recognize that the way the studies were designed, nearly every female in the world will be eligible for cancer prevention—this is nearly equivalent to putting tamoxifen or exemestane in the drinking water. The eligibility for the MAP.3 and P1 trials was open to women at least 60 years old or younger women with other identified risk factors putting their 5-year risk of invasive breast cancer at 1.66%, equivalent to that of the population of 60-yearold women. The only women who would be spared exemestane therapy, if all eligible women get it, would be those who develop a first cancer before they are considered for breast cancer prevention. Every other woman would be eligible for exemestane therapy when she reaches the age of 60. Before putting every woman in the developed world on 5 years of a pill (although probably half will not complete the 5 years), I think we should

the overall survival end point with such a short duration of follow-up. It usually takes longer to see an impact.” Although the choice of whether to use WBI alone or WBI plus RNI might seem like a narrow technical question of interest only to radiation oncologists, the study results illustrate its essential importance, Dr. Jagsi said. “For quite some time, many of us have believed that there may be isolated reservoirs of disease in the regional nodes that may not lead to clinically detected locoregional recurrence, but nevertheless serve as the source of subsequent distant metastases. Eradicating those reservoirs with radiation could, therefore, reduce the risk for distant metastases, and that idea seems to be supported by these results,” she explained. Retrospective studies might understate the impact of RNI, because they show relatively low rates of recurrence see IRRADIATION, page 19 

insist on long-term data on QoL and reduction in all-cause mortality (or perhaps breast cancer mortality with expert review of records of all deaths with the reviewers blinded to treatment assignment in the trial). These trials would take huge numbers of patients, massive funding, and decades of effort. Without these data, however, I cannot justify telling a healthy woman to take annoying pills for 5 years.

References 1. Davidson NE, Kensler TW. “MAPping” the course of chemoprevention in breast cancer. N Engl J Med. 2011; 364: 2463-2464, PMID: 21639807. 2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011; 364: 2381-2391, PMID: 21639806. 3. Bianco AR, De Placido S, Gallo C, et al. Adjuvant therapy with tamoxifen in operable breast cancer. 10-year results of the Naples (GUN) study. Lancet. 1988;2(8620):1095-1099, PMID: 2903322. 4. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-1662, PMID: 16288118.

What are your thoughts? Clinical Oncology News encourages letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to

korourke@mcmahonmed.com.

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Clinical Oncology News • July 2011

Ovarian

New Option for Recurrent Ovarian Cancer Patients Chicago—Adding bevacizumab to conventional cytotoxic agents in patients with recurrent ovarian cancer improved median progression-free survival (PFS) by four months, according to a recent study. The data comes from a latebreaker Phase III trial presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO; LBA7). The trial, called OCEANS, also demonstrated that patients on bevacizumab (Avastin, Genentech) had a greater objective response rate and a greater duration of response. There was a trend toward an overall survival (OS) benefit, even though the median follow-up of 24 months suggests that OS data are not yet mature. “This regimen should be considered a new option for recurrent platinum-sensitive ovarian cancer,” reported Carol Aghajanian, MD, chief of gynecologic medical oncology at Memorial Sloan-Kettering Cancer Center, New York City. Presenting these data on behalf of a multicenter collaboration, Dr. Aghajanian acknowledged that there were more discontinuations in the bevacizumab arm (23% vs. 5%), but a substantial proportion were for essentially asymptomatic adverse events, such as hypertension or proteinuria. Overall, the tolerability and safety of bevacizumab in recurrent ovarian cancer was comparable to that observed with other clinical applications. The study involved 484 patients; most had recurrent platinum-sensitive epithelial ovarian cancer, but patients with primary peritoneal or fallopian tube cancer also were permitted to enroll in the study. A performance status of no greater than 1 was Scan for LBA7. an eligibility criterion. Instructions, see page 20. All patients received a

conventional cytotoxic regimen of carboplatin and gemcitabine (carboplatin on day 1 and gemcitabine on days 1 and 8 of a 21-day cycle). Then patients were randomized to bevacizumab or placebo given every 21 days. Patients were treated with the chemotherapy for six cycles or until disease progression, although treatment responders could continue for up to 10 cycles. Bevacizumab or placebo was given until disease progression or unacceptable toxicity.

greater in the bevacizumab arm (Table). The median OS was 35.5 compared with 29.9 months, an almost 25% improvement (HR, 0.751; 95% CI, 0.537-1.052; P=0.094), a difference that trended toward significance. The proportion of patients in the bevacizumab group withdrawn from the protocol due to disease progression also was substantially lower (41% vs. 65%). The benefit from bevacizumab was consistent across all of the preplanned stratifications, including the length of the platinum-free interval, whether or not cytoreductive surgery had been performed and patient age. Although the side effects typically associated with bevacizumab, particularly rash, were frequent in the experi-

Table. Comparison of Responses Bevacizumab Arm

Placebo Arm

P Value

Objective response rate

78.5%

57.4%

<0.0001

Duration of response

10.4 months

7.4 months

<0.0001

The primary end point was PFS as defined by investigator-assessed RECIST (Response Evaluation Criteria in Solid Tumors) study, but the study is pursuing OS as a secondary end point, and tolerability also is being followed closely. Investigators performed several stratifications of the study population, including those for platinum-free interval before recurrence (>12 vs. <12 months) and previous cytoreductive surgery. After a median of 24 months of followup, the median PFS was 12.4 months in those receiving bevacizumab compared with 8.4 months in the control arm. This translated into a 52% improvement in PFS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.39-0.60; P<0.0001). The objective response rate and duration of response were also significantly

mental arm of the study, the treatment was generally well tolerated. The incidences of neutropenia and febrile neutropenia were almost identical in the two study arms. There were no gastrointestinal perforations. Anil Sood, MD, affiliated with both the Departments of Gynecologic Oncology and Cancer Biology at the University of Texas MD Anderson Cancer Center in Houston, was the expert invited to discuss this and several other studies evaluating targeted therapies in ovarian cancer. He said that the strength of the OCEANS study is that it is built on an existing and proven backbone of therapy in this cancer type. He suggested, however, that it also might be helpful to know what this chemotherapy regimen or any other chemotherapy agents add

FDA NEWS

‘This regimen should be considered a new option for recurrent platinum-sensitive ovarian cancer.’ —Carol Aghajanian, MD

to bevacizumab monotherapy in this patient population. Could bevacizumab monotherapy be an option? “Perhaps not all chemotherapy agents are equal when you combine them with anti-angiogenic drugs,” said Dr. Sood. He was not criticizing the design of the OCEANS trial, but simply pointed out that there are still important questions to ask regarding how optimally to apply anti-angiogenesis treatments in this setting. He also suggested that the duration of anti-angiogenesis treatments in ovarian cancer may be a concerning issue. “One of the things that amazes me in the upfront bevacizumab studies so far is that there is indeed a collapse of the curves following the stopping of bevacizumab in the maintenance phase,” commented Dr. Sood, speaking about several published studies, not OCEANS specifically. Although Dr. Sood did not disagree with the conclusion that the OCEANS results make bevacizumab a reasonable addition to carboplatin and gemcitabine in recurrent ovarian cancer, it is not yet clear that anti-angiogenesis agents are being employed optimally. Dr. Aghajanian’s study was sponsored by Genentech and she consults for and receives research funding from the company. Dr. Sood had no relevant disclosures. —Ted Bosworth

Scan for Web Exclusives

continued from page 10 

standard microscopy. This feature allows lab personnel to see and count copies of chromosome 17 and HER2 genes on the same slide, similar to HER2 amplification measurements that traditionally have only been available using fluorescence microscopes. The FDA based its approval of the Inform Dual ISH on a study involving tumor samples from 510 patients with breast cancer. The study showed that the test was effective in confirming that a patient’s tumor sample contained more than the normal number of copies of the HER2 gene in 96% of the HER2-positive samples. The study also showed that the test was effective in excluding the possibility that more than the normal number of copies of the HER2 gene was present in 92.3% of the HER2-negative tumor samples.

Instructions, see page 20.

Blood Transfusions Speed Recurrence of Ovarian Cancer

Changes in Proteins After Surgery May Spur Angiogenesis

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Clinical Oncology News • July 2011

Melanoma

NEW OPTIONS continued from page 1 

impressive leap forward, but the ASCOinvited discussant of these two studies, Kim Allyson Margolin, MD, Division of Medical Oncology, University of Washington, Seattle, cautioned that the clinical choice between these two agents is not yet straightforward. The decision for those with a V600E BRAF-positive melanoma is between “starting with a drug that has a rapid onset and very early evidence of antitumor activity but potentially limited duration of control, versus starting with an agent that has a slower mechanismdependent onset but may provide a plateau of long-term disease control in a substantial proportion of patients,” explained Dr. Margolin, referring to ipilimumab and vemurafenib, respectively. “Unfortunately, we cannot yet, in either case, further subset the patients to pre-identify those with a therapeutic index that would be superior to the overall pooled results for each drug that we heard about today.”

‘The biggest influence [of Yervoy] is not at the median, but in some long responders. I would love to see some work done on identifying who will be a long responder before the drug is given.’ —Steven Vogl, MD

Steven Vogl, MD, an oncologist who practices in White Plains and Bronx, New York, previously raised concerns about ipilimumab in the June issue of Clinical Oncology News (see page 6 of June issue). He said the

Crystallographic structure of BRAF.

and a 63% improvement in PFS (HR, 0.37; 95% CI, 0.26-0.55; P<0.0001). In the evaluable patients, the response rates also have been profoundly higher in the vemurafenib arm (48.4% vs. 5.5%). The estimated six-month survival rates were 84% for vemurafenib compared with 64% for DTIC. Benefits were seen across all of the subgroups evaluated. The interim data led the independent Data and Safety Monitoring Committee to halt the control arm. “Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib,” reported Paul B. Chapman, MD, an MSKCC attending physician. Presenting these data on behalf of a consortium of 104 participating centers around the world, Dr. Chapman

Ipilimumab Data In the Phase III study of ipilimumab, which binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), 502 patients with metastatic melanoma previously untreated for advanced disease were randomized to 10 mg/kg ipilimumab or placebo. Both groups received 850 mg/m2 dacarbazine (DTIC). The therapies were administered at weeks 1, 4, 7 and 10 and then DTIC was given every three weeks through week 22. This was followed by maintenance ipilimumab at the same dose or placebo administered every 12 weeks. With up to four years of follow-up, investigators identified a 28% improvement in overall survival (OS) (hazard ratio [HR], 0.72; P=0.0009) among those randomized to the ipilimumab arm. The rates of survival were superior at year 1 (47.3% vs. 36.3%), year 2 (28.5% vs. 17.9%) and year 3 (20.8% vs. 12.2%). The median progression-free survival (PFS) was increased modestly (2.8 vs. 2.6 months), but it was highly statistically significant (HR, 0.76; P=0.006), and median PFS “may not tell the most important part of the story,” said Jedd D. Wolchok, MD, PhD, associate director, Ludwig Center for Cancer Immunology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. He presented the results on behalf of participating centers in 24 countries. Dr. Wolchok noted that objective response rates were not only higher in the ipilimumab arm but that durability of these responses, reflecting the biologic activity of the drug, was far longer (19 vs. eight months). Responses have now been observed in a small number of patients out to four years.

‘Experience in recognizing and managing the side effects and toxicities of both of these novel agents is required as well as a strong commitment to compliance.’ —Kim Allyson Margolin, MD

new data presented at ASCO has convinced him that the drug has activity. “The biggest influence is not at the median, but in some long responders who live a long time, presumably doing well. I would love to see some work done on identifying, before the first dose, those likely to have long responses compared to the rest,” said Dr. Vogl. Such a study will save society a lot of money and spare toxicity for patients who will not derive benefit from the drug. “For a two- to four-year remission of metastatic melanoma, a lot of severe toxicity becomes quite acceptable,” Dr. Vogl said. “It beats dying.”

Vemurafenib Data In the Phase III trial of the oral agent vemurafenib, 675 patients with previously untreated unresectable stage IIIC or IV melanoma positive for V600EBRAF were randomized to 960 mg twice daily of vemurafenib or 1,000 mg/m2 DTIC given every three weeks. OS and PFS were co-primary end points. The randomization of patients was stratified by stage, geographic region and lactate dehydrogenase, a marker of poor prognosis. At the preplanned interim analysis, there was a 74% improvement in OS (HR, 0.26; 95% CI, 0.20-0.33; P<0.0001)

indicated that the activity of the agent suggests it will be a major addition to options for control of advanced melanoma, a disease for which options have been extremely limited.

Adverse Events Adverse events (AEs) were not insignificant with either ipilimumab or vemurafenib. Ipilimumab, which has been given a black box warning by the FDA for severe and potentially fatal immune reactions, produced twice as many grade 3 or 4 AEs in combination with DTIC than DTIC with placebo (56.3% vs. 27.5%). The most common AEs were elevations in alanine aminotransferase (21.9% vs. 0.8%) and aspartate aminotransferase (18.2% vs. 1.2%). For vemurafenib, greater rates of arthralgia, rash, and diarrhea were observed in the experimental arm, but the most significant concern may be the greater rate of cutaneous tumors, particularly squamous cell carcinomas, observed in patients on vemurafenib relative to DTIC. These were excised when they occurred and may not pose a longterm risk, but caution is needed. “Experience in recognizing and managing the side effects and toxicities of both of these novel agents is required as well as a strong commitment to

compliance, particularly in regard to reporting and managing of symptoms on the part of both the Scan for LBA4. patient and the famInstructions, see ily,” suggested Dr. page 20. Margolin. According to data from the ipilimumab trial, it is not clear that the addition of DTIC added any therapeutic benefit, she said, but it did appear to increase the rate of hepatoScan for LBA5. toxicity. In particular, it was associated with an increased rate of grade 3 or greater liver enzyme elevations. However, rates of high-grade colitis, diarrhea and endocrinopathy were all lower Scan for Steven than expected based Vogl’s June on prior ipilimumcommentary on ab monotherapy stud- Yervoy. Instructions, see page 20. ies. The relative clinical efficacy of ipilimumab in the absence of DTIC is unknown, but Dr. Margolin suggested that it is possible that higher doses provided as a monotherapy may increase response rates, but further study is needed. Dr. Vogl said clinicians need “some quickly done studies looking at dose of ipilimumab, combination with DTIC, rules for stopping and continuing the drug, and biomarkers to identify those likely to have long remissions.” He also voiced concern with the recommendation of continuing ipilimumab in the face of progressive disease. “I would like to know how many patients benefitted even if they had early progression, and if there was anything special about them,” he said. Overall, the introduction of two agents with activity against late-stage metastatic melanoma may make sequencing of agents “trickier,” according to Dr. Margolin. Although it might be reasonable to employ vemurafenib as a second-line agent in patients with the V600EBRAF mutation who have progressed on firstline ipilimumab, this has not been tested. Both agents may provide a basis on which to explore combinations in order to further extend OS. While Roche seeks approval of vemurafenib, the drug is available through a global Expanded Access Programme. Dr. Wolchok disclosed he is a consultant to BMS and his study was sponsored by BMS. Dr. Chapman disclosed his study was sponsored by Roche and that he is a consultant to and has received research funding from Roche. Dr. Margolin had no relevant disclosures. Dr. Vogl owns stock in BMS. —Ted Bosworth

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Online and in print, Cancer of the Skin is your complete, multimedia guide to early diagnosis and effective medical and surgical treatment of melanoma and other skin cancers. Thoroughly updated with 11 new chapters, this broad-based, comprehensive reference provides you with the latest information on clinical genetics and genomics of skin cancer, targeted therapy for melanoma, the vitamin D debate concerning the risks and benefits of sun exposure and other timely topics.

Care at the Close of Life: Evidence and Experience

Stephen McPhee; Margaret A. Winker; Michael W. Rabow; Steven Z. Pantilat; Amy J. Markowitz A new addition to the JAMA evidence series, this book offers evidencebased and clinical expert guidance on caring for patients with life-limiting illness, incorporating the words and perspectives of affected patients, their families and treating clinicians.

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

Christopher R. Jarvis; David B. Mandell; Jason M. O’Dell This volume helps physicians move beyond theory and into practice by outlining how to find quality advisors and construct a collaborative, multidisciplinary planning team.

Handbook of Cancer Chemotherapy

MD Anderson Manual of Medical Oncology, Second Edition

Roland T. Skeel

This pocket reference is a practical, disease-focused guide to the best current medical practice in cancer chemotherapy. The book provides complete coverage of the principles of rational chemotherapy, the chemotherapeutic and biotherapeutic agents available, the treatment of specific cancers and selected aspects of supportive care. Emphasis is on the indications, dosage/schedule, potential toxicities and safe administration of the drugs and their use in treating specific malignancies.

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

Ophthalmic Oncology

The Elsevier Guide to Oncology Drugs & Regimens

Bita Esmaeli

This book highlights the unique aspects of oncologic ophthalmology as a medical and surgical discipline practiced at a comprehensive cancer center. Multidisciplinary management of ocular, orbital and adnexal cancers are highlighted using simple and tried-and-true algorithms. In addition, ocular problems caused as a direct result of cancer treatment are reviewed using illustrative photographs and case presentations.

Elsevier

This premier edition gives busy oncology practitioners fast access to the most current information on all commonly prescribed oncology drugs and regimens—plus the supportive therapies needed to manage side effects. Created by oncology experts, this remarkable reference presents accurate, comprehensive, unbiased prescribing data in clear, concise language in a format tailored to meet oncology specialists’ needs. CO0711

SOLID TUMORS

Clinical Oncology News • July 2011

Rectal

New Standard Suggested for Rectal Cancer Therapy 5-FU and Capecitabine Face Off In two randomized Phase III trials, capecitabine appeared to be at least as effective in the treatment of locally advanced rectal cancer as the current standard perioperative radiochemotherapy agent, 5-fluorouracil (5-FU). The studies, presented at the recent American Society for Clinical Oncology (ASCO) annual meeting, could lead to capecitabine replacing 5-FU in the perioperative treatment of locally advanced rectal cancer. The first study, a non-inferiority trial investigating neoadjuvant and adjuvant chemoradiotherapy with capecitabine (Xeloda, Roche) or with 5-FU, randomized a total of 401 patients, of whom 392 were evaluable at a median follow-up of 52 months (abstract 3504). For the primary end point of five-year overall survival (OS), capecitabine was clearly noninferior to 5-FU (capecitabine, 75.7% vs. 5-FU, 66.6%; P=0.0004) (Figure). By some measures there was a trend toward superiority for capecitabine compared with 5-FU. The local recurrence rate was similar for both agents (capecitabine, 6% vs. 5-FU, 7%; P=0.665), whereas significantly fewer patients developed distant metastases in the capecitabine arm (18.8% vs. 27.7%; P=0.037). Capecitabine also demonstrated significantly better three-year disease-free survival (DFS) (75.2% vs. 66.6%; P=0.034). “The curves start to separate after about 18 months,” noted lead author Ralf-Dieter Hofheinz, MD, of the Oncology Center of University Hospital Mannheim, University of Heidelberg, in Germany. Patients receiving capecitabine also had fewer lymph node–positive tumors (P=0.09), improved T-downstaging (P=0.07) and more pathologic complete response (pCR) (P=0.16), although these findings were not statistically significant. Both treatments were relatively well tolerated, although their toxicity profiles varied. Patients receiving capecitabine

had more hand-foot-skin reactions, an effect that also appeared to be a predictor of clinical response, because patients with this side effect had significantly better three-year DFS and five-year OS rates than any of the other patients. Patients receiving capecitabine also had more fatigue and proctitis, whereas leukopenia was more frequent in patients receiving 5-FU. “These findings indicate that capecitabine is non-inferior to 5-FU in this setting,” said Dr. Hofheinz, who pointed out that there was a trend toward improved downstaging and a higher rate of pCR. “We believe that it may replace 5-FU in the perioperative treatment of locally advanced rectal cancer.” Reported at the same ASCO oral abstract session was NSABP R-04, a collaborative National Cancer Institute protocol that involved five major clinical trial cooperative groups (abstract 3503). Oral capecitabine with or without oxaliplatin was compared with 5-FU continuous infusion with or without oxaliplatin in 1,608 patients with clinical stage II or III rectal cancer, undergoing preoperative radiotherapy. Although definitive analysis of local tumor control will not be available until late 2013, initial results were similar to the findings of the German trial. No significant differences were seen in the rates of pCR, sphincter-sparing surgery or surgical downstaging between the 5-FU and capecitabine regimens, with or without oxaliplatin. The findings regarding oxaliplatin itself were clearly disappointing; the agent resulted in a great deal of gastrointestinal distress. “The distant relapse rate [after radiochemotherapy with current standard

5-FU] is quite significant—between 24% and 30%,” said Mark S. Roh, MD, chairman of surgery at the University of Texas MD Anderson Cancer Center Orlando, in Houston, who presented the trial findings. “The compliance to adjuvant therapy postoperatively is not as good as we would all like. The hope is that giving more effective systemic therapy up front could decrease the high distant relapse rate.” But the addition of oxaliplatin yielded no benefit with regard to surgical downstaging, rate of sphincter-sparing surgery, node positivity, or pCR to therapy. “[Gastrointestinal] toxicity, unfortunately, was the one time when oxaliplatin did make a difference, leading to a significant increase in grade 3/4 diarrhea,” Dr. Roh noted. “The addition of oxaliplatin did not improve outcomes and added significant toxicity.” “This pretty much confirms findings reported at the 2010 ASCO meeting from the STAR-1 trial, that adding oxaliplatin to improve local control in these patients doesn’t really pay off,” said Tomislav Dragovich, MD, PhD, associate professor of medicine and director of the Clinical GI Cancer Program at the Arizona Cancer Center of the University of Arizona, in Tucson. But the findings on capecitabine are encouraging, Dr. Dragovich said, calling the studies very important. “Rectal cancer is a very complex disease and requires multidisciplinary team expertise with chemotherapy, radiation and surgery. Each component of treatment is very important and it’s not easy to conduct these trials.” Currently, Dr. Dragovich is not about to put all his patients with locally advanced rectal cancer on capecitabine. “Until we

Perioperative 5-FU Perioperative capecitabine

100

P=0.034

Patients, %

75.7 66.6

60 40 20 0

Figure. Five-year overall survival in locally advanced rectal cancer.

‘The curves start to separate after about 18 months.’ —Ralf-Dieter Hofheinz, MD

have more robust survival end points, I would still consider that the standard is continuous-infusion 5-FU with radiation, but in some patients it could be capecitabine with radiation,” he said. “There is the caveat that sometimes it’s a little more difficult to dose capecitabine, especially in the U.S. population, and the side effects are different. For example, capecitabine would be preferable for younger patients and those who refuse to have [a portable catheter] and carry an infusion pump for six weeks.” For elderly patients and those with kidney insufficiency who might not be able to tolerate capecitabine well, Dr. Dragovich suggested that 5-FU would continue to be the first choice. —Gina Shaw

If you have missed any recent issues of Clinical Oncology News, please visit www.clinicaloncology.com.

SOLID TUMORS

Clinical Oncology News • July 2011

Breast

IRRADIATION continued from page 13 

in those regions. Dr. Buchholz noted that his own retrospective studies on the subject at MD Anderson had not been sufficiently powered to detect the surprisingly high improvement in rates of distant metastases associated with RNI. “Quite honestly, we don’t tend to look for recurrence in the internal mammary region,” noted Dr. Jagsi. “And it’s possible that the disease left behind there is the only disease remaining for a certain period of time, before it serves as the source of distant metastases.” The results of MA.20 support that theory, given that distant metastases were reduced even more significantly than locoregional metastases in the RNI group—a finding that surprised many. Lead investigator Timothy Whelan, MD, Canada Research Chair in Health Services Research in Cancer at Toronto’s McMaster University, who presented the results, noted that some additional toxicities were associated with the addition of RNI, including increases in lymphedema (7.3% and 4.1%, respectively; P=0.004) and grade 2 or greater pneumonitis (1.3% and 0.2%, respectively; P=0.01). “Not shown [in the ASCO presentation] are cardiac events and second cancers, which we did evaluate and saw no increase,” he said. “Over time, the impression of fair or poor cosmetic outcome also increased in both groups, but increased more in patients who had additional regional nodal irradiation. The significance of this finding was unclear at five-year follow-up.” The significantly improved outcomes, particularly for distant metastases, should justify the additional treatment for most patients, Dr. Jagsi said. “Patients similar to those enrolled in this study—keeping in mind that until we’ve all seen the final manuscript, we won’t have important details about the exact characteristics of study participants—should be strongly advised to consider regional nodal irradiation. I think the presumption for the radiation oncologist in these patients would be to radiate the regional nodes, unless the patient turns it down.” Such an approach would be significantly different from current practice. In a study published in 2004 in the International Journal of Radiation Oncology Biology Physics, Dr. Jagsi, then at Massachusetts General Hospital in Boston, found that 50% or more of U.S. radiation oncologists might not radiate the supraclavicular fossa in patients with one to three nodes after lumpectomy, and that the vast majority did not radiate the internal mammary nodes. “It’s been about a decade, but my sense is that practice patterns for regional nodal radiation haven’t changed that much,” she said. Dr. Buchholz agreed that the data

would change his practice. “I’m going to offer regional nodal irradiation to my patients who have one to three positive nodes.” However, he suggested that for those with very small-volume disease in a single sentinel node, more data are needed. The findings have practice-changing implications not only for patients who have undergone breast-conserving surgery, but for postmastectomy patients as well, said Dr. Jagsi. “This adds to the evidence that women who undergo mastectomy who have one to three nodes involved should also receive radiation.

The lymph nodes don’t know what procedure you’ve done on the breast.” At present, the National Comprehensive Cancer Network guidelines suggest that radiation should be strongly considered in such cases, but in practice, it appears that only about half of women with one to three nodes involved receive radiation after a mastectomy. The study is not a “one-size-fits-all” mandate, and requires a discussion with each patient about the known increased risks associated with RNI. But it seems clear that most patients similar to those in the study should be receiving the

PHA

SE I

additional radiation. “Some may say all of the benefit or risk came from the supraclavicular fossa field and not the internal mammary nodal field, or vice versa,” Dr. Jagsi said. “But I think that when you have a large, well-designed, well-conducted Phase III trial that showed a benefit from radiating both fields, it is prudent to do what they did, unless more mature results or another study that’s just as good give you a reason to do it differently.” No relevant financial disclosures were reported by clinicians cited in this article. —Gina Shaw

II TR

IAL

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)

101108 - 115622

REC

RUIT

ING

POLICY & MANAGEMENT

Clinical Oncology News • July 2011

Partnerships to Survive What are your thoughts?

Landscape continued from page 1 

(not to mention the uncertainties surrounding the 2010 health care act) presaged further financial pressures. “All of a sudden, most medical oncology practices stopped making money from chemotherapy,” said Dr. Cobb. Among oncology-related specialties, medical oncology has been particularly hard hit by the shifting health care landscape, said Ted Okon, executive director of the Community Oncology Alliance (COA). According to the COA, at least 199 community oncology clinics have closed since 2008, and many more report that they are struggling financially. When Dr. Cobb and his partners realized that their business model was no longer sustainable, they joined forces with other specialists—one of several survival strategies that their colleagues across the country have considered. The Frontier Cancer Center in Billings, which opened in September 2010, is a multidisciplinary operation with five medical oncologists and two radiation oncologists. Frontier also opened facilities in Butte, Mont., and Cody, Wyo. In addition to traditional infusion oncology, Frontier offers diagnostic imaging and radiation oncology. “Everything can be done in one setting, and, because of that, we think we can be sustainable, at least for now,” said Dr. Cobb. There have been a few rough patches associated with merging two diverse medical cultures, but overall the arrangement has worked, and patients like the convenience of a centralized and easily accessible facility. Multidisciplinary oncology practices are nothing new, but they seem to be springing up with increasing frequency beyond the confines of academic medical centers or large, specialized cancer treatment facilities. “The healthiest practices out there are looking at strategic relationships with other practices and are taking very proactive stances,” Mr. Okon said. Some have added a twist to more conventional interspecialty alliances. The Genitourinary Cancer Program at the Maine Medical Center Cancer Institute in Portland, opened in April

According to the Community Oncology Alliance, at least 199 community oncology clinics have closed since 2008, and many more report that they are struggling financially.

2009. Moritz Hansen, MD, a urologist and medical director of the program, calls it a “virtual” cancer clinic, because the specialists continue to work from their own offices. All of the practices are within a few minutes’ drive of one another, yet they function as a multidisciplinary unit. The model has been particularly successful for the coordination of prostate cancer care, for which patients often see multiple providers offering a variety of management options, according to Dr. Hansen.

rapidly from specialist to specialist. In contrast, this virtual model allows for some breathing room between appointments, so patients can consider more fully what they’ve been told. The glue that holds everything together is the inviolable policy that every patient with prostate cancer, regardless of where he enters the system, is assigned to a patient navigator who guides him through the course of care, coordinates appointments and provides decision and information sup-

The Genitourinary Cancer Program at the Maine Medical Center Cancer Institute in Portland, operates a “virtual” cancer clinic, because the specialists continue to work from their own offices.

Housing all of the specialists under one roof wasn’t practical, he explained. “Our model allows us to bring together all of the positive aspects of a centrally located cancer center, such as the ability to see multiple specialists in a short time. [Patients] come away feeling that their care is being expedited and well coordinated, and also that they’re being seen in totality, not just from the perspective of one specialist.” He observed that at a centrally located clinic, patients can feel bombarded with a tremendous amount of information as they move

2-D Bar Codes in ClinOnc 1. Get the FREE Microsoft Tag Reader application through your smartphone browser by going to http://gettag.mobi and follow the steps to download. (There may be a charge from your wireless provider for the data services.) 2. Open the Tag Reader and find the ClinOnc bar-code image in this publication. 3. Let the Tag Reader focus on the bar-code image to instantly access related materials and/or Web sites.

port. “The navigator is the key,” said Dr. Hansen. “If some patients get linked to one and some don’t, the whole system falls apart.” Determining what impact the clinic has had on costs has been difficult, because overall costs for prostate cancer care have risen across the board. However, since the clinic opened, the percentage of patients at low risk for prostate cancer opting for active surveillance rather than radiation therapy or surgery has risen from about 5% to 15%. Those numbers reflect national trends, but Dr. Hansen also attributes the increase within the clinic to patients’ sense of comfort with care coordination, and the single point of contact provided by patient navigation. “People are much more comfortable when they feel that their care is holistic, and the comfort level that a navigator can create makes them more willing to consider a conservative approach to their disease,” he said. “So there’s cost savings in that sense.” The Prostate and Genitourinary

Does your oncology practice use novel strategies to succeed? Clinical Oncology News would love to hear them. Please contact Kate O’Rourke, managing editor, at korourke@mcmahonmed. com to share your thoughts. Your practice could be featured in our newsmagazine or on our Web site.

Multidisciplinary Oncology Clinic at the Presbyterian Cancer Center in Charlotte, N.C., offers another model for multidisciplinary care. What distinguishes this center from other “one-stop shops” for men with prostate, bladder and kidney cancers is that its physicians—two urologists, two radiation oncologists and six medical oncologists—all practice independently and rotate through the clinic for half a day each week. Presbyterian Hospital pays them for their clinic time, but patients pay nothing for clinic services. Clinic patients— about 80 new cases per year—are seen by a team that includes a urologist, a radiation oncologist, a medical oncologist, a dietitian, a nurse navigator, a social worker and a research staff that coordinates the clinic’s clinical trials. The cancer center also supports a breast clinic, a thoracic clinic, a melanoma clinic and a GI cancer clinic. The hospital views the clinics as “loss leaders,” a strategy it admits is not feasible for many community cancer centers. But the hospital ends up earning substantial income from subsequent services provided at the hospital, such as radiation therapy, diagnostic imaging and laboratory studies. Daniel L. Watson, MD, a urologist and director of the center, reports that the specialists have avoided the combativeness that often besets urologists and radiation oncologists who work together. “In most places, there’s a fair amount of friction between urology and radiation oncology because of turf battles and access to patients,” he said. “I’ve been to too many meetings where I’ve watched people expend a lot of energy about the best way to treat prostate cancer, and I think it’s a waste of time. Both approaches to treatment are good, so I don’t think you’re mistreating the patient by recommending one therapy over another, and we usually agree on the best way to manage patients.” According to Dr. Watson, participation has another benefit: allowing him and his colleagues to make sure they maintain a voice at the table along with hospitals while delivery models move in the direction of accountable care organizations. “As specialists, we don’t want to be left out of the negotiations or the process.” —Steve Frandzel

CLINICAL TRIALS

Clinical Oncology News • July 2011

New Phase II and III Clinical Trials

Support

Hematologic Malignancies

Solid Tumors

The studies listed below are actively recruiting trials that were added to the National Cancer Institute’s list of U.S. clinical trials in the 30 days before June 14, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials/search, and enter the protocol ID.

Protocol Type

Age

Protocol ID

Trial Sites

EMD525797 in Subjects With Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer, Phase II/III

18 and over

EMR 62242-006

Assessing the Potential for Reduced Toxicity Using Focal Brachytherapy in Low-Risk Prostate Cancer, Phase II

21 and over

11-056

STA-9090 in Castration-Resistant Prostate Cancer With Assessment of Androgen Receptor Pathway Signaling, Phase II

18 and over

10-333

Trial of Outpatient Intravenous Interleukin-2 in Malignant Melanoma and Metastatic Kidney Cancer, Phase II

18 and over

LLU1101

A Double-blind Study Evaluating IPI-504 and Docetaxel in Patients With Non-Small Cell Lung Cancer, Phase II

18 and over

IPI 504-14

Open-Label Study of Amuvatinib in Combination With Platinum-Etoposide Chemotherapy in Small Cell Lung Cancer, Phase II

18 and over

SGI-0470-07

Gemcitabine and ON 01910.Na in Previously Untreated Metastatic Pancreatic Cancer, Phase II/III

18 and over

04-22

Trial of Radiation Therapy “Sandwiched” Between Chemotherapy to Treat Uterine Carcinosarcoma, Phase II

18 and over

11-02-064

Complete Neoadjuvant Treatment for Rectal Cancer (CONTRE), Phase II

18 and over

BrUOG 224

Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma, Phase II

18 and over

GIPI

Pilot Study of Cytokine-Induced Gene Expression in Patients With Cancer or in Healthy Participants (Breast Cancer, Colon Cancer, Melanoma, Prostate Cancer, Renal carcinoma, Melanoma), Phase I/II

18 and over

CASE-CCF-3164

Use of IL-15 After Chemotherapy and Lymphocyte Transfer in Metastatic Melanoma, Phase I/II

18 and over

110170

Tolerability Study of Xerecept in Pediatric Patients, Phase I/II

1 to 18

CPDS 1001

IL, MA

A Study of Aminolevulinic Acid Used to Enhance Visualization and Surgical Removal of Brain Tumors, Phase I/II

18 and over ALA 11.07

Proton Radiation Therapy for Low Grade Gliomas, Phase II

18 and over

10-439

AE7777 in Combination With CHOP Compared With CHOP Alone for the First-Line Treatment of Peripheral T-cell Lymphoma, Phase III

18 and over

E7777-G000-301

PRO#1278: Fludarabin and Busulfan vs. Fludarabine, Busulfan and Total Body Irradiation (In Patients Receiving Allogeneic Hematopoietic Stem Cell Transplant), Phase III

18 to <70

PRO#1278: Flu-Bu-TBI

Pilot Study of Cytokine-Induced Gene Expression in Patients With Cancer or in Healthy Participants (Acute or Chronic Leukemia, Lymphoma, Myeloma), Phase I/II

18 and over

CASE-CCF-3164

Study of Carfilzomib for Multiple Myeloma Patients Who Are Relapsed/Refractory to Bortezomib-containing Treatments, Phase I/II

18 and over

IST-CAR-516

Redirected Auto T Cells for Advanced Myeloma, Phase II

18 to 80

UPCC 01411

MD, PA

Infusional Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma, Phase II

18 and over

10-228

A Single Center Randomized Controlled Trial Assessing Pain and Quality of Life Following Surgery, Phase III

18 and over

11-034

Improving Continence and Quality of Life in Prostate Cancer Patients, Phase III

21 and over

1R01CA12749301A2

Extended Self-Help for Smoking Cessation, Phase II

18 and over

MCC-15724

SOLID TUMORS Breast

RECURRENCE continued from page 11 

calcifications. If it doesn’t make calcifications, we can’t pick it up with screening mammography,” she said. “By the time we pick it up, seven or eight years later, it’s already a mass, it’s already invasive. But this is just a hypothesis. There is no way we can prove that from the data we have. It would be interesting to do further studies to tease that data out.” A limitation of the study is that follow-up time for the two groups of patients was significantly different. Due

to shifting trends in the acceptability of lumpectomy alone as a treatment for DCIS, the surgery-plus-radiation group was followed for more than nine years, compared with about six years for the surgery-alone group. “Of course the survival is going to be different, it just stands to follow,” said Pond Kelemen, MD, FACS, clinical associate professor of surgery at New York Medical College, Ashikari Breast Center, Dobbs Ferry. “There are studies out there already, the B17 trial, for example, showing that if you compare radiation and no radiation, there is a significant decrease in recurrence

and the radiation group actually has fewer invasive cancers,” Dr. Kelemen said. Dr. Kelemen also pointed to an EORTC [European Organisation for Research and Treatment of Cancer] study that looked at 1,000 patients randomized to lumpectomy alone or lumpectomy with surgery, and found that if you give radiation, you get less-invasive recurrences. Dr. Grumley acknowledges the findings might look different over time. “We did a Kaplan-Meier plot to evaluate the probability of recurrence, which showed the same sort of 10-year recurrence as in the large collaborative group,” she said. “If we were to follow the patients out another 10

to 15 years, that might change.” Dr. Grumley stressed that she is not advocating against radiation therapy. “That’s not the point of the study,” she said. “We’re not saying that radiation is bad for patients. It does reduce recurrence. We want to focus on the fact that since we are seeing this different pattern of recurrence, we can’t say to patients who receive radiation that five years later, ‘you’re free of disease, you can forget about your cancer.’” Dr. Grumley stressed that the decision to have radiation therapy is one to be made between physician and patient. —Monica Smith

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

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

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

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

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

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

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

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

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

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

5% of Patients

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

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

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

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

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

An ALZA STEALTH® Technology Product

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

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

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

INDICATIONS

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

IMPORTANT SAFETY INFORMATION

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

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

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

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

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