TAP Vol 1 Issue 7

Lung screening benefit 3

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Contralateral prophylactic mastectomy 17

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VOLUME 1, ISSUE 7

ESA guideline update 44

DECEMBER 2010 ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

Lymphoma: Many Questions, Too Few Answers

35th ESMO Congress

Studies Show Progress in Treatment of Triple-negative Breast Cancer

By Caroline Helwick

F

or the treatment of triple-negative breast cancer, the PARP inhibitor iniparib improved overall survival, and cetuximab (Erbitux) showed benefit as well, in two randomized phase II studies presented at the 35th ESMO Congress in Milan, Italy.

Use your smartphone to view the original abstracts as presented at the 35th ESMO Congress.

See page 51 for more information about using 2D barcodes

Eagerly Awaited Data The data on overall survival with iniparib (BSI201) have been eagerly awaited after encouraging results were presented at the 2009 ASCO Annual Meeting in Chicago.1 Joyce O’Shaughnessy, MD, of US Oncology and Baylor Sammons Cancer Center, Houston, reported the final results of the multicenter phase II open-label study of 123 patients at ESMO, showing that iniparib (5.6 mg/kg) plus gemcitabine (1,000 mg/m2)and Joyce O’Shaughnessy, MD carboplatin (AUC 2) every

3 weeks produced not only a longer time to disease progression but also a longer survival time, compared with a regimen of gemcitabine/carboplatin only.2 “Overall survival was not a prespecified endpoint in the protocol, but is reported as a clinically relevant endpoint,” Dr. O’Shaughnessy said. A survival benefit was shown in spite of a 30% rate of crossovers from the control to the experimental arm, although the activity of iniparib appeared limited in this setting, she added.

Median overall survival time was 12.2 months with the combination, compared with 7.7 months with chemotherapy, amounting to a 43% reduction in risk (P = .014). Median progression-free survival (PFS) continued on page 9

Health-care Industry

McKesson Buys US Oncology: Assessing the Impact on Oncology Community and Future Practice

By Caroline Helwick

T

he recent announcement that McKesson Corporation, the biggest U.S. drug distributor, will purchase US Oncology was met with some measure of surprise and a large amount of interest within the oncology community. McKesson will pay cash for the deal, valued at $2.16 billion, to merge US Oncology into its Specialty Care Solutions unit. The deal will expand McKesson’s current cadre of oncologists from 1,000 to nearly 3,000. In the words of a Wall Street blogger, the merger gives McKesson “a big customer plugged in as a subsidiary.” The ASCO Post asked a variety of interested parties what this arrangement will mean to the specialty.

‘Bolt Out of the Blue’ The news was a “bolt out of the blue” to Allen Lichter, MD, CEO of ASCO. He maintained that from the point of view of US Oncology, “this is potentially a very good move.”

The merger will relieve US Oncology from its debt,

allow it to free up capital to invest back into its network, and help advance its emerging information technology (IT) system. “It aligns US Oncology with a powerful and successful corporation,” he said. “There are uncertainties as to what the health-care environment will look like in 3 years, and stabilizing your company through a business arrangement such as this is, at least on the surface, something that makes sense.”

Strengths and Weaknesses It certainly makes sense to US Oncology, according to the company’s Medical Director Roy A. Beveridge, MD, who told The ASCO Post, “The entire organization is very excited about this. It allows US Oncology to complement our weaknesses with McKesson’s strengths, and vice versa, which is a situation that doesn’t often happen.”

According to Dr. Beveridge, one of the chief benefits to physicians and patients is the strength of McKes-

By George P. Canellos, MD

T

he successful treatment of malignant lymphoma has been one of the great achievements in medical oncology, but certainly more work is needed to define key biologic targets as well as molecular markers for a more accurate definition of prognosis following therapy. In day-to-day practice, unanswered questions arise in the management of these diseases. Nevertheless, a profusion of new agents is emerging from the biotechnology industry, requiring clinical assessment for safety and efficacy. Meanwhile, we encounter clinical situations for which there are still no answers.

Clinical Trials Needed I am prompted to enumerate situations where appropriate clinical (preferably prospective randomized) trials could have or should have been done to facilitate clinical decisions. To mention just a few issues that have arisen recently: A form of extranodal lymphoma called mediastinal large cell lymphoma, which occurs in younger patients, has biologic and clinical similarities to Hodgkin lymphoma. As with localized Hodgkin lymphoma, there is a propensity to add mediastinal radiation therapy following chemotherapy. continued on page 2

Dr. Canellos is William Rosenberg Professor of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute, Boston.

MORE IN THIS ISSUE Oncology Meetings Coverage

52nd ASTRO Annual Meeting ���������������� 16 2010 Breast Ca Symposium �������������17, 18 35th ESMO Congress �������������� 22, 27, 30 Direct from ASCO ������������������������������������ 33 ESMO/ASCO Joint Symposium ������������� 54 Telehealth/Telemedicine ������������������������� 74

continued on page 8

A Harborside Press Publication

The ASCO Post | DECEMBER 2010

PAGE 2

Opinion

Lymphoma Questions continued from page 1

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University William T. McGivney, PhD, National Comprehensive Cancer Network James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Larry Rosenberg, PhD, Matthew Stenger

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations Financial disclosure information available at ASCOPost.com.

Also as in Hodgkin lymphoma, however, it is unclear whether the addition of radiation adds anything for a patient achieving an excellent response to chemotherapy including a negative PET status.

The rarity of the disease would require a broad multigroup, multi-institutional effort to assess the need for radiation therapy in a randomized trial. These generally young patients would be at risk for the well-recorded, long-term complications of radiation therapy already known to occur in Hodgkin lymphoma survivors. Further, the optimal chemotherapy is unknown. Well-published Italian studies advocated MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, plus bleomycin) given over 3 months.1 With the addition of rituximab (Rituxan) to our armamentarium, it would appear that CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, plus rituximab) may be as effective.2 This uncertainty could be solved by an appropriate clinical trial.

Other Unanswered Questions Another issue arises in elderly patients with lymphoma requiring systemic therapy. Because of age and/or cardiac problems, there is a concern that anthracyclines pose a threat of cardiac toxicity. Liposomal encapsulated doxorubicin (Doxil) has not been shown to penetrate cardiac muscle. Whether this anthracycline, in reality, allows for chemotherapy with a CHOP-R–type regimen in older patients is unknown. A prospective trial could compare CHOP-R to CHOP-R (liposomal) in elderly patients with large cell lymphoma, but surprisingly this has never been done. As a result, patients might receive increasingly reduced doses or alternative regimens that might be inferior.

Oral chemotherapeutic agents have potential appeal for patient convenience in avoiding hospital infusion visits. Oral fludarabine (Oforta) has FDA approval and is used widely in Britain and Canada but has had minimal exposure in the United States. In the emerging era of costsaving in cancer care, this issue will come to the fore if oral drug pricing is realistic and less than infusional therapy.

The daily practice of lymphoma medicine is often determined by phase II trials conducted by single institutions. However, the data in such trials may reflect selection bias of investigators and unique referral patterns to institutions. A number of “standard” regimens such as CHOP or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) had their position

solidified by prospective, randomized trials.3,4 One has only to recall the impact of the SWOG trial that randomized CHOP against three more complicated regimens generated by single institutions.5 It has been noted that an increasing number of phase III randomized trials are being conducted outside the United States, given existing and emerging impediments to U.S.-based clinical trials. Although American geography and lack of centralized cancer care are significant factors, NCI must seek solutions to improve the system.

Conclusions A larger list of unanswered questions in daily practice abuts the issues of cost and lack of scientific evidence—for example, what is the overall survival value of rituximab maintenance for follicular lymphoma, and does CNS prophylaxis in large cell lymphoma significantly decrease the incidence of CNS relapse? Clinical trials have done a great deal to formulate the practice of lymphoma oncology. With the introduction of new agents and new targets, the clinical trials process needs to be expanded and supported by NCI and other independent funding mechanisms.

The cancer clinical trials system has been described as a “chronic but curable crisis.”6 The Institute of Medicine’s recommendations for changes in the system need timely implementation.7

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References 1. Zinzani PL, Martelli M, Bertini M, et al: Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis. Haematologica 87:1258-1264, 2002.

2. Savage KJ, Al-Rajhi N, Voss N, et al: Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution. Ann Oncol 17:123-130, 2006.

3. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992.

4. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease. J Clin Oncol 21:607-614, 2003.

5. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

6. Young RC: Cancer clinical trials— a chronic but curable crisis. N Engl J Med 363:306-309, 2010.

7. Nass SJ, Moses HL, Mendelsohn J (eds): A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Institute of Medicine. Washington, DC, National Academies Press, 2010.

ASCOPost.com | DECEMBER 2010

PAGE 3

News Lung Cancer

NCI Announces Initial Results from the National Lung Screening Trial Data show significant mortality benefit with low-dose spiral CT vs chest x-ray

I

nitial results from a large-scale randomized study of screening methods to reduce deaths from lung cancer by detecting cancers at relatively early stages indicate a significant mortality benefit for low-dose CT. Results of the National Lung Screening Trial (NLST) were announced in a teleconference on November 4 by NCI Director Harold Varmus, MD. Dr. Varmus reported that NLST researchers found 20% fewer lung cancer deaths among trial participants screened with low-dose helical CT relative to chest x-ray. This finding was statistically significant.

Harold Varmus, MD

Involving more than 53,000 current and former heavy smokers aged 55 to 74, the NLST was sponsored by NCI, and conducted by the American College of Radiology Imaging Network (ACRIN) and the Lung Screening Study group. A paper describing the design and protocol of the NLST was published last month in the journal Radiology.1 A fuller analysis, with more detailed results, will be prepared for publication in a peer-reviewed journal early next year.

“This large and well-designed study used rigorous scientific methods to test ways to prevent death from lung cancer by screening patients at

Reimbursement Reimbursement for screening CT scans is currently not provided by most insurance carriers. The current estimated Medicare reimbursement rate for a noncontrast helical diagnostic CT of the lung is $300, but varies by geographic location.

especially high risk,” said Dr. Varmus.

“A validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease.”

National Lung Screening Trial The NLST enrolled about 53,500 men and women at 33 trial sites nationwide over a 20-month period beginning in August 2002. Participants were required to have a smoking history of at least 30 pack-years and were either current or former smokers without signs, symptoms, or history of lung cancer. They were randomly assigned to receive three annual screens with either low-dose helical CT or standard chest x-ray.

The trial participants received their screening tests at enrollment and at the end of their first and second years on the trial. The participants were then followed for up to another 5 years; all deaths were documented, with special attention given to the verification of lung cancer as a cause of death.

Results Are Statistically Significant The NCI’s decision to announce the initial findings from the NLST was made after the trial’s independent Data and Safety Monitoring Board (DSMB) notified the NCI Director that the accumulated data provide a statistically significant answer to the study’s primary question. The DSMB held its final meeting on October 20, 2010, at which time a total of 354 deaths from lung cancer had occurred among participants in the CT arm of the study, compared with a significantly larger 442 lung cancer deaths in the chest x-ray group.

The DSMB concluded that this 20.3% reduction in lung cancer mortality met the standard for statistical significance and recommended ending the study.

“This is the first time that we have seen clear evidence of a significant reduction in lung cancer mortality with a screening test in a randomized controlled trial. The fact that low-dose helical CT provides See page 51 a decided benefit is

Expert Point of View

By Jo Cavallo

T

he findings from the National Cancer Institute’s National Lung Screening Trial (NLST) were especially welcome news to Claudia Henschke, MD, PhD, Professor of Radiology at Mount Sinai School of Medicine in New York and Principal Investigator of the International Early Lung Cancer Action Program (IELCAP). The NLST findings showing that annual CT screenings in heavy smokers could reduce their risk of dying from lung cancer by 20% support earlier results from the I-ELCAP study published in 2006.

Claudia Henschke, MD, PhD “I’m thrilled, of course, that the NLST results confirm the initial results we had, but it’s the fact that lives can be saved now through early screening that’s really the exciting part,” Dr. Henschke said in an interview with The ASCO Post.

Since launching in 1993, I-ELCAP has enrolled more than 53,000 people throughout the United States and in eight other countries at high risk for developing lung cancer, including smokers aged 40 and older and never-smokers exposed to occupational carcinogens or secondhand smoke. Because each study center is allowed to determine the age and smoking background criteria of its participants, data are emerging that may provide smokers of varying ages and smoking history with a tool to calculate their individual risk factors for developing lung cancer.

Individualizing Risk “Our study includes participants with a broad spectrum of ages and smoking history, so we know what the lung cancer rate is among 40 year olds or 50 year olds,” said Dr. Henschke. “And ideally we want lung cancer screenings to be able to individualize risk. One of the articles we’re working on is to show how CT See page 51 screenings can provide the probability of diagnosing lung cancer based on a series of risk factors, including the age a person started smoking, length of time the person smoked, when the person quit, whether the person has a family history of lung cancer, and other relevant information. Then people would have actual data on which to base their decision of whether to undergo lung cancer screening.”

While the NLST study looked at mortality rates from lung cancer, the I-ELCAP study is focused on lung cancer cure rates. In 2006, I-ELCAP researchers reported in The New England Journal of Medicine that patients diagnosed with lung cancer at any stage—early or late—and regardless of the type of treatment given, have a 10year cure rate of about 80%. When the cancer is found at stage I and immediately removed with surgery, the cure rate is 92%.

“Those results have consistently held up, so having lung cancer isn’t a death sentence. It’s something you have to watch out for, find early, and do something about,” said Dr. Henschke.

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a result that will have implications for the screening and management of lung cancer for many years to come,” said Christine Berg, MD, NLST Project Officer for the study at NCI. The investigation also showed that all-cause mortality was 7% lower in those screened with low-dose helical CT than in those screened with chest x-ray. Approximately 25% of deaths in the NLST were due to lung cancer, while other deaths were due to factors such as cardiovascular disease.

‘Potential to Save Thousands of Lives’ The NCI and its partners conducted this trial to obtain reliable results about

the potential benefits of lung cancer screening. Others will begin to use the extensive data from this trial to conduct further analyses and to propose clinical guidelines and policy recommendations for lung cancer screening.

“The results of this trial provide objective evidence of the benefits of lowdose helical CT screening in an older, high-risk population and suggest that if low-dose helical CT screening is implemented responsibly, and individuals with abnormalities are judiciously followed, we have the potential to save thousands of lives,” said Denise Aberle, MD, NLST National Principal Investigator for ACRIN. “Howevcontinued on page 10

BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

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

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

Important Safety Information for Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

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

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

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

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

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatmentrelated hematologic and GI toxicities.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal

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

PM66377 0810 PRINTED IN USA © 2010, Lilly USA, LLC. ALL RIGHTS RESERVED.

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

ALIMTA (pemetrexed for injection) Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

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

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence): The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

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

insideALIMTA.com

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

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

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

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous q Non-Small Cell Lungg Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information.

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

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

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

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

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

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

Table 2: Dose Reduction for ALIMTA and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (seee Table 3).

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

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renallyy Impaired p Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

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

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

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

Corticosteroid Supplementation pp Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials.

Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

ALIMTA T ® (pemetrexed for injection) PV 5208 AMP

5.2

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

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

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

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman.

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

5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA T administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) were fatigue, nausea, and anorexia.

Additional common adverse reactions (incidence ≥20%) included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

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

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

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

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

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

Incidence 1% to 5% Body as a Wholee — febrile neutropenia, infection, pyrexia General Disorderss — dehydration Metabolism and Nutritionn — increased AST, increased ALT Renall — creatinine clearance decrease, renal failure Special Sensess — conjunctivitis Incidence Less than 1% Cardiovascularr — arrhythmia General Disorderss — chest pain Metabolism and Nutritionn — increased GGT Neurologyy — motor neuropathy 6.2 Additional Clinical Trials Experience Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

6.3 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these ALIMTA® (pemetrexed for injection) PV 5208 AMP

reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinall — colitis General Disorders and Administration Site Conditionss — edema Injury, poisoning, and procedural complicationss — Radiation recall has been reported in patients who have previously received radiotherapy.

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

7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen p Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

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

7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion.

Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effectss - Pregnancy Category D [see Warnings and Precautions (5.6)].

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman.

There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

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

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

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

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

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

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

8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females.

For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

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

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

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

The ability of ALIMTA to be dialyzed is unknown.

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

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

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

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

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

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

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

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

ALIMTA T ® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

PV 5208 AMP

Literature revised August 9, 2010

Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 2004, 2010, Eli Lilly and Company. All rights reserved.

PV 5208 AMP

PRINTED IN USA PV 5208 AMP

The ASCO Post | DECEMBER 2010

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News

continued from page 1

About US Oncology

son’s IT platform. “This is not just a sophisticated practice management system,” he said, but a comprehensive system that is the future of health-care delivery. “For example, the patient portal will allow the patient to obtain information (including laboratory results), make her own appointments, and manage survivorship issues. The more integrated the systems are, the better it is for the patient. It also facilitates our clinical research efforts, which is a core mission of US Oncology.”

S Oncology, Inc. is the nation’s leading integrated oncology company. By uniting the largest community-based cancer treatment and research network in America, US Oncology expands patient access to high-quality care and advances the science of cancer care. Headquartered in The Woodlands, Texas, US Oncology is affiliated with more than 1,300 community-based oncologists, and works with patients, hospitals, payors, and the medical industry across all phases of the cancer research and delivery continuum.

By promoting the use of innovative technology, clinical research, evidence-based medicine and shared best practices, US Oncology improves patient outcomes and offers a better patient experience. For more information, visit www.usoncology.com.

McKesson Buys US Oncology

Roy A. Beveridge, MD

US Oncology had already crafted a vision that includes “empowering patients” in this manner, but it was expected to take 3 to 5 years to achieve. “With McKesson, we can accomplish these things in 1 to 2 years,” he said.

US Oncology will continue to pursue their own programs but will incorporate McKesson’s, he said. “Their IT ability is second to none, and that is exciting to us. When we merge these things, we will have the best of the breed in bringing efficiency and quality care to patients. That’s the synergy we will see,” Dr. Beveridge told The ASCO Post.

Part of a Trend?

John H. Hammergren, Chairman and CEO of McKesson, agreed that the merger will help move health IT forward and thus enhance patient care, but added that oncologists will see many additional benefits. “Community oncology practices need strategic support that offers not only technology and distribution solutions, but also value-added clinical and reimbursement management services that enable them to provide the highest-quality, most efficient care to their patients,” he said. “With this acquisition, McKesson will offer a compelling suite of services and solutions to community oncologists and other partners in the rapidly evolving specialty business.”

Patrick Cobb, MD, of Frontier Cancer in Billings, Montana, who is Past

U Patrick Cobb, MD

President of the Community Oncology Alliance (COA), noted that receiving assistance with practice management, which has become such a burden, is a dream of many oncologists. “We moved cancer care from a hospital setting to the community oncology centers, and this has been where care is given efficiently and cost-effectively. That is changing, however,” he noted. “More practices are closing or at least closing satellite offices, and hospital acquisitions are happening. Things are definitely not getting simpler. The death of small oncology practices is a real concern.”

Along the same lines, David Eagle, MD, President of COA, believes that US Oncology’s sale to McKesson may be “a reaction to and emblematic of the deep and growing problems in oncology reimbursement.”

David Eagle, MD

“Because of declining payments for the delivery of high-quality cancer care, even large, well-run oncology organizations such as US Oncology are facing difficulty managing as independent organizations,” he noted.

“The United States has the best cancer survival statistics in the world. However, inappropriate reductions in reimbursement are now causing failures across the full spectrum of practice models. Government and private payers need to accurately recognize and pay for the true resources required to provide quality cancer care. Our organization, the Community Oncology Alliance, will continue to seek policy and payment solutions so that cancer clinics are able to continue to deliver the world’s best care to patients in their local communities.”

About McKesson McKesson Corporation, currently ranked 14th on the FORTUNE 500, is a health-care services and information technology company dedicated to helping its customers deliver high-quality health care by reducing costs, streamlining processes, and improving the quality and safety of patient care. Over the course of its 177-year history, McKesson has grown by providing pharmaceutical and medical-surgical supply management across the spectrum of care; health-care information technology for hospitals, physicians, home care and payors; hospital and retail pharmacy automation; and services for manufacturers and payors designed to improve outcomes for patients. For more information, visit www.mckesson.com.

■

In other words, business deals such as this one may be the way of the future as industry seeks to expand its reach within the specialty pharmaceutical market and as oncology practices struggle to survive. “We are beginning to see deals like this, where McKesson acquires US Oncology and where Cardinal Health acquired P4 Healthcare and P4 Pathways. All the major drug distributors are realizing that oncology is integral to what they want to do,” said Joseph Bailes, MD, ASCO’s immediate past Chair of Government Relations.

Joseph Bailes, MD

Dr. Lichter agreed that the die has been cast. “We are seeing more and more consolidation, practices moving into hospitals or associating with other groups and networks. Now we see that the largest single oncology entity

in the country, which treats 17% of all U.S. cancer patients, is partnering with a huge company. These are interesting signals and we will need to watch them play out.”

Uncertainties Remain “We do get concerned when we see big corporations controlling a quarter of the country’s cancer care,” Dr. Cobb said. “We have to wonder if corporate ownership of oncology practices is the best solution.”

But McKesson has indicated that US Oncology will retain its independence, according to Dr. Lichter. While he said he will take the company’s word on this, he added, “We know that when you bring the cultures of two organizations together there can be risks…Check back with me in 3 years.”

A chief concern is the potential for conflict of interest. “Having a large company that is in the business of distributing cancer pharmaceuticals also control the organization that is determining which drugs to use and how often—ie, developing guidelines and pathways— does create an interesting scenario,” Dr. Lichter acknowledged.

The maintenance of independence with regard to pathways, in fact, was a continued on page 9

ASCOPost.com | DECEMBER 2010

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Triple-negative Breast Cancer continued from page 1

was 5.9 vs 3.6 months (P = .012), overall response rate was 52.5% vs 32.3% (P = .023), and clinical benefit rate was 55.7% vs 33.9% (P = .015).

Approximately 60% of the patients had received no prior treatment in the metastatic setting. Most had three sites of metastases.

There were no significant differences in adverse events between chemotherapy alone or in combination with iniparib. Grade 3-4 adverse events, mainly hematologic toxicity, were seen in 81% vs 86%, respectively, and serious events in 29% and 28%. Treatment discontinuation due to toxicity occurred in 27% with chemotherapy alone and in 14% when iniparib was added.

Cetuximab Doubles Response Rate In a second presentation, Jose Baselga, MD, reported that targeting the epidermal growth factor receptor (EGFR) may be beneficial in triplenegative disease, because about half the tumors of this aggressive subtype express EGFR.3 “This is the first randomized trial assessing this target in breast cancer, and we are excited by these results,” said Dr. Baselga, who is now Associate Director of the Massachusetts General Hospital Cancer Institute, Boston. “Although EGFR had been considered a potential target for therapy in breast cancer, this

is the first proof that this is the case.”

The phase III BALI-1 trial, conducted in six countries, included 173 women with triple-negative metastatic disease who were randomized to cetuximab (400 mg/m2 as the initial dose, then 250 mg/m2 weekly), plus up to six 3-weekly cycles of cisplatin, or to cisplatin alone.

Responses were observed in 20% of the cetuximab/cisplatin arm, which was twice as high as the rate with cisplatin alone 10.3% (P = .11), although the difference was not statistically significant. Adding cetuximab to cisplatin more than doubled the median PFS, from 1.5 to 3.7 months, which was a statistically significant 33% reduction in risk for this secondary endpoint (P = .03), Dr. Baselga reported.

However, the study just failed to meet its primary endpoint, which mandated that a response rate of more than 20% be achieved with the combination.

“Despite the doubling of response, the study did not meet the prespecified assumptions,” he said.

Dr. Baselga acknowledged that cisplatin might not be the best control arm. “This is a tough group to treat, and I am concerned about how poorly these patients responded to cisplatin.

We are wondering if perhaps we should move forward with a more robust control group, such as gemcitabine/carboplatin,” he said.

Nevertheless, Dr. Baselga sees the findings as quite positive, he empha-

Emerging Treatments for Triple-negative Breast Cancer

I

n an open-label randomized phase II trial, the PARP inhibitor iniparib (BSI201) improved overall survival by 4.5 months, and delayed progression by 2.3 months, compared with gemcitabine/carboplatin, with no increase in toxicity Targeting the EGFR pathway may be beneficial in triple-negative disease.

While the BALI-1 study did not meeting its primary endpoint (> 20% increase in PFS), cetuximab plus cisplatin led to a doubling in response rates, vs cisplatin alone, and essentially validated the concept of EGFR targeting in this tumor.

■

PARP = poly (ADP-ribose) polymerase

McKesson Buys US Oncology continued from page 8

factor underlying ASCO’s development of the Quality Oncology Practice Initiative (QOPI),” he pointed out. “ASCO feels that physicians themselves are not only capable of producing guidelines and monitoring quality of care—and have a professional responsibility to do so—but we don’t have conflicts. We are simply looking for the best pathways,

unencumbered by outside influences,” he said.

Dr. Beveridge offered assurances, however, that conflicts of interest will not be a problem. “[US Oncology’s] pathways process is absolutely and completely firewalled from the business portion. There is no commercial influence at all,” he said. “It has been that way for almost 6 years and will continue to be. That’s a promise.”

■

Expert Point of View

R

ichard Bell, MD, Director of Cancer Services at Geelong Hospital in Australia, commented that the targeting of triple-negative breast cancer will involve multiple pathways and processes, two of which—genomic instability and dependence on EGFR—are addressed by agents evaluated in these studies. In particular, he said, the strategy of combining iniparib with gemcitabine and carboplatin “seems to have worked.” A phase III trial has promptly accrued, and confirmation of the phase II data may come soon, he said.

Currently, some 95 registered trials are evaluating not only PARP inhibitors and EGFR-targeted therapies but also angiogenesis, DNA-damaging chemotherapy and other potential targets in triple-negative disease. “If we are to unravel this biologic puzzle and develop effective therapies, we must define the targets and develop clinically useful predictive tests,” as well as conduct robust biologic and translational studies to maximize gains, ensure optimal resource use, and avoid futile therapy, Dr. Bell added.

‘Subtypes Are Here to Stay’ Eric P. Winer, MD, Chief of the Division of Women’s Cancer at Dana-Farber Cancer Institute, Boston, noted that cetuximab increased response rates and PFS “to a modest extent,” though the differences did not meet statistical significance.” The study did not meet its primary endpoint, but the results are consistent with prior studies suggesting limited activity of cetuximab in these tumors, he pointed out.

Eric P. Winer, MD “This is not ready for use outside of a trial,” Dr. Winer maintained, but added that targeting EGFR in triple-negative disease is “worthy of pursuit,” perhaps pairing cetuximab with different chemotherapy. “Intensive translational studies that identify patients most likely to respond,” he said, “will be important if this approach is to move forward. Breast cancer subtypes are here to stay. The era of non– subtype-specific studies is coming to a close.”

■

sized in a press briefing. “We see a doubling in response and a hazard ratio for progression of 0.67. In my mind, the study is vastly positive,” he said. “I am convinced that an anti-EGFR agent has a role in triple-negative breast cancer, without question. We just have to design the appropriate trial.”

■

References 1. O’Shaughnessy J, Osborne C, Pippen J, et al: Efficacy of BSI-201, a poly(ADPribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with triple-negative breast cancer: Results of a randomized phase II

trial. 2009 ASCO Annual Meeting. Abstract 3. Presented May 30, 2009.

2. O’Shaughnessy J, Osborne C, Pippen J, et al: Final efficacy and safety results of a randomized phase II study of the PARP inhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple negative breast cancer. 35th ESMO Congress. Abstract LBA11. Presented October 10, 2010.

3. Baselga J, Gomez P, Awada A, et al: The addition of cetuximab to cisplatin increases overall response rate and progression-free survival in metastatic triple-negative breast cancer: Results of a randomized phase II study. 35th ESMO Congress. Abstract 2740. Presented October 11, 2010.

Details of the Deal

■■ Valuation: $2.16 billion, including the assumption of US Oncology’s outstanding debt.

■■ Targeted Close: By December 31, 2010, subject to customary conditions, including all necessary regulatory clearances.

■■ Leadership: McKesson Specialty Care Solutions business will be led by Bruce Broussard, Chairman and Chief Executive O fficer of US Oncology

■■ Operations: McKesson Specialty Care Solutions business will be headquartered in The Woodlands, Texas

The ASCO Post | DECEMBER 2010

PAGE 10

News Lung Cancer

National Lung Screening Trial continued from page 3

er, given the high association between lung cancer and cigarette smoking,” she added, “the trial investigators reemphasize that the single best way to prevent lung cancer deaths is to never start smoking, and if already smoking, to quit permanently.”

Dr. Varmus also cautioned that “these findings should in no way distract us from continued efforts to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases.”

in patients who prove not to have lung cancer but who need additional testing to make that determination; and risks from additional diagnostic workup for findings unrelated to potential lung cancer, such as liver or kidney disease. In addition, the screening process itself can generate suspicious findings that turn out not

to be cancer in the vast majority of cases, producing significant anxiety and expense. These problems must, of course, be weighed against the advantage of a significant reduction in lung cancer mortality.

Lung cancer is the leading cause of cancer mortality in the United States and throughout the world.

■

Reference 1. National Lung Screening Trial Research Team: The National Lung Screening Trial: Overview and study design.

Radiology. November 2, 2010 (published online ahead of print). Available at http://radiology.rsna.org/cgi/content/ abstract/radiol.10091808. Accessed November 4, 2010.

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Disadvantages of Helical CT

Select ERBITUX + RT

The possible disadvantages of helical CT include the cumulative effects of radiation from multiple CT scans; surgical and medical complications

How do Results of the NLST Compare with the I-ELCAP Trial?

T

he International Early Lung Cancer Action Program (IELCAP) was a nonrandomized trial that used CT screening to detect early lung cancer. Its results, which were reported in 2006,1 suggested that CT screening might be beneficial. However, the combination of I-ELCAP not being a randomized trial and not using the endpoint of lung cancer mortality led many clinical investigators to recommend waiting until the NLST results were available so that they could determine definitively the utility of this screening approach. Another nonrandomized study of CT screening, which was published in 2007,2 failed to demonstrate the benefits inferred from the IELCAP trial.

■

References 1. The International Early Lung Cancer Action Program Investigators: Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 355:1763-1771, 2006.

2. Bach PB, Jett JR, Pastorino U, et al: Computed tomography screening and lung cancer outcomes. JAMA 297:953-961, 2007.

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

ASCOPost.com | DECEMBER 2010

PAGE 11

FDA Update

Oncology Drug News Trastuzumab Approved for HER2-positive Metastatic Gastric or GE Cancer The FDA has granted approval for a new indication for trastuzumab (Herceptin), in combination with cisplatin and a fluoropyrimidine (capecitabine

[Xeloda] or fluorouracil), for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. The approval is based on a significant improvement in

median overall survival of 2.5 months with trastuzumab plus chemotherapy treatment compared to chemotherapy alone, demonstrated in a single, international, multicenter, open-label, randomized clinical trial, BO18255 (ToGA trial).

for Increased OVERALL SURVIVAL ERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT Survival in Combination With RT*1,2 ERBITUX + RT (n=211)

vs

RT alone (n=213)

Median overall survival 49.0 months

vs

29.3 months

vs

45%

19.7

month improvement

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confidence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

New Safety Information In other labeling changes for trastuzumab, new safety information regarding fatal fetal pulmonary hypoplasia was added to the Boxed Warning, Warnings, and Use in Specontinued on page 12

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FDA Update

Oncology Drug News continued from page 11

cific Populations sections of the prescribing information. Based on postmarketing adverse event reports, cases of oligohydramnios manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported in the offspring of

mothers exposed to trastuzumab during pregnancy.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interaction, and contraindications, is available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2010/103792s5256lbl.pdf.

FDA Approves New Indication for Everolimus The FDA approved everolimus (Afinitor) to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis, a rare genetic disorder. This approval was for treatments of SEGA that cannot be treated with surgery.

The result of genetic mutations, tuberous sclerosis causes benign tumors to grow in the brain and in other parts of the body. SEGAs are considered a major diagnostic feature of tuberous sclerosis and manifest as slow-growing tumors, seen in 6% to 9% of patients.

The disease can be fatal for patients who develop complications with tu-

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms.

Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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FDA Update

mor growth on the brain.

The drug was approved under the FDA’s accelerated approval program, based on a single study of 28 patients. At 6 months into the study, nine patients (32%) had a greater than 50% reduction in volume of their largest SEGA lesion.

The duration of response ranged from

3 months to 2½ years, with a median of 266 days. Seven of these patients retained the greater than 50% reduction in space the tumor occupied at time of last follow-up.

Patients participating in the study did not develop any new tumors. However, no tumor resolved completely. Four of the patients

had previous surgery, but their tumor grew back. After receiving everolimus, three of these patients had greater than 50% reduction in tumor volume.

Additional Indication for Dasatinib Granted The FDA approved a new indication for dasatinib (Sprycel) for the

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

© 2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US10AB02404

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treatment of Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (Ph+ CP-CML), when it is first diagnosed. The FDA granted the drug a priority review for Ph+ CP-CML. In June 2006, the FDA granted accelerated approval for dasatinib to continued on page 14

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FDA Update

Oncology Drug News continued from page 13

treat adults with CP-CML with resistant disease or who were intolerant to prior therapy, including imatinib. The agency converted dasatinib to a regular approval in May 2009. This is the third drug approved for Ph+ CP-CML under accelerated approval, after ima-

tinib, approved in May 2001, and nilotinib (Tasigna), approved in October 2007.

FDA Working to Prevent Radiation Overdoses during CT Scans The FDA has been investigating reports that patients undergoing CT

brain perfusion scans were accidently exposed to excess radiation. The agency found that when properly used, the CT scanners did not malfunction. Instead, it is likely that the improper use of the scanners resulted in these overdoses. However, the FDA has identified a series of steps to enhance the safety of these procedures.

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONs None.

WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

The FDA has sent a letter to the Medical Imaging and Technology Alliance, the major professional industry organization for manufacturers of CT scanners and other radiologic imaging devices, reporting on the results of the investigation and discussing possible CT equipment enhancements that could improve patient safety. The

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

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 data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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agency will hold follow-up discussions with manufacturers.

Recommended changes include a console notification to alert the operator of a high radiation dose; providing particular information and training on brain-perfusion protocols to all facilities that receiving base CT equipment; clarification of parameters affecting

dose, along with clear instructions on how to appropriately set those parameters; and organization of all dose-related information into one section of each user manual, in a dedicated dose manual, or indexed comprehensively in a concordance covering all manuals.

While unnecessary radiation exposure should be avoided, a medically

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades 2 Preferred Term Grades 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 Infusion Reactions3 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 11 0 4 0 Mouth Dryness Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 1 2 3

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

needed CT scan has benefits that outweigh the radiation risks, the FDA notes.

Denosumab (Xgeva) Approved for the Prevention of Skeletal-Related Events The FDA has approved denosumab (Xgeva) for the prevention of skeletal-related events in patients with bone metas-

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A7

ER-B0001A-09-10

Rev September 2010

tases from solid tumors. Denosumab was approved following a 6-month priority review by the FDA. Denosumab is a RANK ligand inhibitor. The RANK ligand pathway is believed to play a central role in cancerinduced bone destruction, regardless of cancer type. Denosumab is a fully human monoclonal antibody that binds to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts. Denosumab prevents RANK ligand from activating its receptor, RANK on the surface of osteoclasts, thereby decreasing bone destruction.

The FDA approval of denosumab is based on the results of three pivotal, phase III head-to-head trials that evaluated denosumab delivered every 4 weeks as a 120 mg subcutaneous injection vs zolendronate (zoledronic acid; Zometa) delivered every 4 weeks via a 15-minute intravenous infusion.

In the Phase III trials, denosumab demonstrated a clinically meaningful improvement in preventing skeletal-related events compared to zolendronate. Specifically, in patients with breast or prostate cancer and bone metastases, denosumab was superior to zolendronate in reducing the risk of skeletal-related events.

Overall rates of adverse events and serious adverse events were generally similar between dennosumab and zolendronate. (See related news on page 22.)

■

2010 FDA Approvals ■■

Cabazitaxel (Jevtana), for metastatic hormone-refractory prostate cancer

■■

Dasatinib (Sprycel), for newly diagnosed adult patients with Philadelphia chromosome–positive CML

■■

Denosumab (Xgeva), for prevention of skeletal-related events

■■

Eribulin mesylate (Halaven), for previously treated metastatic breast cancer

■■

Erlotinib (Tarceva), tablets for locally advanced or metastatic non–small cell lung cancer

■■

Everolimus (Afinitor), accelerated approval for subependymal giant cell astrocytoma (SEGA)

■■

Lapatinib (Tykerb), accelerated approval for hormone receptor–positive metastatic breast cancer

■■

Nilotinib (Tasigna), accelerated approval for newly diagnosed Philadelphia chromosome–positive CML

■■

Rituximab (Rituxan), for chronic lymphocytic leukemia

■■

Trastuzumab (Herceptin), for metastatic gastric or gastroesophageal junction adenocarcinoma

For more information, visit http://www. fda.gov/ See page 65 for more FDA updates.

The ASCO Post | DECEMBER 2010

PAGE 16

52nd ASTRO Annual Meeting Preoperative Radiation Therapy Reduces Pelvic Recurrence Rates in Patients with Rectal Cancer

By Barbara Boughton

R

ectal cancer patients who receive 1 week of radiotherapy prior to total mesorectal excision have a 50% reduction in the chance for local pelvic recurrence, according to a large randomized study presented at the plenary session of the 52nd Annual Meeting of the American Society for Radiation Oncology (ASTRO), held October 31–November 4 in San Diego. The Dutch trial, which followed more than 1,800 patients for a median of 11 years after treatment, found that the benefit of additional radiotherapy was most pronounced for patients with tumors in the middle rectum and those with stage III rectal cancer.

See page 51

Key Data “During the 1980s, local recurrence rates from rectal cancer ranged from 25% to 45%,” commented Corrie Marijnen, MD, one of the lead authors of the study and a radiation oncologist at the Leiden University Medical Center in Leiden, Netherlands. “That has changed with total mesorectal excision. So the question became: Do we still need radiotherapy when surgery is performing so well?”

To answer that question, the Dutch researchers enrolled 1,861 patients with rectal cancer whose disease had spread outside of its original location but not to other parts of the body and randomly assigned them to total mesorectal excision alone or the surgery plus radiotherapy.

Radiotherapy was given preoperatively at a dose of 5 × 5 Gy over 5 to 7 days.

After a median follow-up of 11 years, the local recurrence rate among those who underwent radiotherapy and surgery was 5.1%, compared with 11.1% for those who received total mesorectal excision alone (P < .001). Although radiotherapy significantly affected the chance of local recurrence, there was no

difference in overall survival between the two groups.

Subgroup Analyses The researchers performed a number of subgroup analyses, and found that patients diagnosed with stage III cancer derived the most benefit from radiotherapy compared to patients with stage I/II disease. Among patients with stage III disease, 19.2% experienced local recurrence after just total mesorectal excision, compared to 8.9% who experienced recurrence after radiotherapy plus total mesorectal excision (P < .001). However, patients with stage II disease also showed a trend toward reduced local recurrence rates after radiotherapy and total mesorectal excision vs surgery alone.

In the subgroup analyses, patients who had tumors with a height greater than 5 cm also benefitted more from additional radiotherapy than those with tumors less than 5 cm. The local recurrence rate in patients with tumors of 5 to 10 cm was 3.6% among those who received additional radiotherapy vs 13.8% among those who received surgery alone (P < .001). Among those with tumors between 10 and 15 cm, the local recurrence rate was 3.1% for the surgery-plus-radiotherapy group and 7.1% among those who received surgery alone (P = .04).

To the researchers’ surprise, additional radiotherapy had a greater effect on patients with a negative circumferential resection margin (CRM) after surgery than those with positive margins. Local recurrence in CRMnegative patients who received additional radiotherapy was 3% vs 8.7% among those who received total mesorectal excision alone. Cancer-specific death was also significantly reduced in patients with a negative CRM who underwent radiotherapy and total mesorectal excision vs those who had surgery alone (16.9% vs 21.5%, P = .04)

Total Mesorectal Excision for Rectal Cancer ■■ In a large randomized Dutch trial of total mesorectal excision plus

radiotherapy vs the surgery alone for rectal cancer, the local recurrence rate at 11 years’ median follow-up was 5.1% vs 11.1%, respectively (P < .001).

■■ No difference was seen in overall survival.

■■ In subgroup analysis, radiotherapy reduced local recurrence among

patients with a negative circumferential resection margin, positive lymph nodes, or a tumor more than 5 cm from the anal verge.

Expert Point of View

T

he randomized Dutch total mesorectal excision study is notable for a variety of reasons, including the large number of patients enrolled and the long-term follow-up, said Anthony Zietman, MD, Past President of ASTRO and Professor of Radiation Oncology at Massachusetts General Hospital, Boston. The study also helped answer a question that had plagued oncologists since the advent of total mesorectal excision: How necessary is radiation in Anthony Zietman, MD an era of improved surgery for rectal cancer?

“The trial shows us that there are groups that don’t need radiation anymore, although some still do. And it defines what the benefit is of additional radiotherapy for patients who undergo total mesorectal excision,” Dr. Zietman said. “The benefit to patients of having radiotherapy is not a lot, but there is some benefit. So patients with rectal cancer can now make an informed decision about whether to undergo radiation. Some people may choose radiotherapy because any reduction in risk is important to them, while others might say: ‘I’ll do without the radiation,’” Dr. Zietman added.

‘Mopping Up’ After Surgery?

Before the advent of total mesorectal excision, a number of randomized controlled trials had shown that adding radiotherapy to surgery for rectal cancer improved cure rates. But after total mesorectal excision became the standard of care, control rates improved enough that oncologists began to wonder whether radiation was really necessary, “especially if previous to total mesorectal excision, radiation had just been mopping up when surgery was inadequate,” Dr. Zietman said.

Although the Dutch trial showed no difference in overall survival with radiotherapy, the improved local control seen in patients who received both radiation and total mesorectal excision is crucial, he added. “If cancer comes back in the pelvis, it’s a disaster. Although patients don’t die from it, they suffer from local recurrence. Most rectal cancer patients die from metastasis, but cancer recurrence in the pelvis causes bowel obstruction and affects the nerves in the pelvis, causing terrible intractable pain,” Dr. Zietman said.

The U.S. protocol for radiotherapy in rectal cancer is different from the one used in the Dutch trial, Dr. Zietman noted. American patients are more likely to get radiation after surgery and for a more protracted course than in the Dutch trial.

“This study encourages us to look at shorter courses of radiation, similar to that used in Europe,” Dr. Zietman said. “It’s more convenient, and patients would certainly like it more, although it does carry a higher risk of late rectal dysfunction.”

■

The researchers concluded that although additional radiotherapy conferred no overall survival benefit, it did significantly reduce the chance of local recurrence—an effect likely to be crucial in maintaining patients’ quality of life.

They recommended that patients with stage II/III rectal cancer should receive preoperative radiotherapy before total mesorectal excision, and also advised mandatory preoperative imaging with MRI. Although there is a need to reduce overtreatment in patients with rectal cancer, 1 week of preoperative radiation is safe and effective—and convenient for patients, Dr. Marijnen commented.

■

Reference 1. Marijnen CA, van Gijn W, Nagtegaal ID, et al: The TME trial after a median follow-up of 11 years. 52nd Annual ASTRO Meeting.

Abstract 1. Presented November 1, 2010.

2 1 ASTR

gathering EVIDENCE proving VALUE

See next month’s issue of The ASCO Post for more news from ASTRO

ASCOPost.com | DECEMBER 2010

PAGE 17

2010 Breast Cancer Symposium Breast Cancer

Studies Justify the Trend for Contralateral Prophylactic Mastectomy

By Caroline Helwick o reduce the risk of a second breast cancer, contralateral prophylactic mastectomy has become an increasingly acceptable option, with rates doubling over the past decade.1,2 Papers and discussions at the 2010 Breast Cancer Symposium, held recently in National Harbor, Maryland, supported this trend.

Elisa Port, MD, Chief of Breast Surgery and Co-Director of the Dubin Breast Center at Mount Sinai Medical Center, New York, was the invited discussant of these studies. She noted that, ironically, “despite 30 years of progress toward minimizing breast surgery—using breast-conserving approaches vs mastectomy and sentinel node biopsy vs axillary nodal dissection—we increasingly see, even with sporadic breast cancer, that many women are choosing more aggressive procedures.”

There may be a variety of different reasons for this, she pointed out. Greater use of screening and evaluation with MRI reveals more lesions that require mastectomy, improved reconstructive techniques may make prophylactic mastectomy more palatable, and genetic testing clarifies one’s risk of cancer or recurrence and identifies a group of women at highest risk for whom risk-reducing mastectomies are a reasonable approach.

Findings presented at the meeting suggest that the decision to undergo contralateral prophylactic mastectomy might be lifesaving for some women, and for society, more cost-effective than surveillance.

ing unilateral mastectomy and no contralateral mastectomy, matched according to age at diagnosis, year of diagnosis, tumor stage, and nodal status.

At a median follow-up of 17.3 years, two patients (0.5%) in the contralat-

eral prophylactic mastectomy cohort developed contralateral breast cancer, compared with 31 patients (8.1%) in the unilateral mastectomy cohort. This amounted to a 95% decrease in the risk of contralateral breast cancer (P < .0001),

Imetelstat

(GRN163L) Telomerase Inhibitor

3C

Dr. Boughey reported.

“The result remained strongly significant after adjusting for age, stage, nodal status, and first-degree family history,” she noted.

lin

continued on page 18

ica

lT

ria

• A phase 2 trial to evaluate the activity of imetelstat in patients with essential thrombocythemia Key Inclusion Criteria • Patients with ET requiring cytoreduction who have failed or are intolerant to at least one prior therapy or who refuse standard therapy Patients with ET requiring therapy

Stratify by JAK2 and MPL mutations

Imetelstat

ls

Re

cru

iti

ng

Primary Endpoint • Normalization or reduction in platelet counts

Secondary Endpoints • Duration of hematologic response • Rate of molecular response in patients with a molecular mutation (JAK2 or MPL) at baseline

• A randomized phase 2 study of imetelstat in combination with paclitaxel (with or without bevacizumab) in patients with locally recurrent or metastatic breast cancer Key Inclusion Criteria • Up to one non-taxane based chemotherapy regimen in the metastatic setting (no limit on prior hormonal therapies) • Non-measurable disease allowed

Primary Endpoint

• Progression free survival

Locally recurrent or metastatic breast cancer

Randomize 1:1

T

Imetelstat + paclitaxel +/– bevacizumab Paclitaxel +/– bevacizumab

• A randomized phase 2 study of imetelstat as maintenance therapy after

initial induction chemotherapy for advanced non-small cell lung cancer

Judy C. Boughey, MD, of the Mayo Clinic, Rochester, noted that while prophylactic mastectomy is known to decrease the occurrence of contralateral breast cancer by 90% to 95%, its effect on overall survival has been debated.

She and her colleagues evaluated 385 patients at high risk based on family history.3 All underwent mastectomy for stage I or II breast cancer and prophylactic mastectomy in the opposite breast between 1971 and 1993. They were compared with 385 women hav-

Stage IV NSCLC eligible for platinum-based doublet therapy

Platinum-based doublet therapy +/– bevacizumab x 4 - 6 cycles

Randomize 2:1

Improved Survival

Key Inclusion Criteria • Completed four to six cycles of platinum-based chemotherapy doublet for first line, with no evidence of disease progression according to RECIST

no PD

Judy C. Boughey, MD

Primary Endpoint • Progression free survival

Imetelstat + standard therapy (bevacizumab or observation) Standard therapy (bevacizumab or observation)

Optional cross over to imetelstat

Imetelstat (GRN163L) currently is under clinical investigation and has not yet 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 or effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

• For more information, refer to ClinicalTrials.gov or email info@geron.com Geron Ad ASCO Post 2010-Dec.indd 1

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The ASCO Post | DECEMBER 2010

PAGE 18

2010 Breast Cancer Symposium Prophylactic Mastectomy continued from page 17

At 10 years, estimated overall survival was 83% with contralateral prophylactic mastectomy and 74% with unilateral mastectomy, which in the multivariate analysis amounted to a 23% reduction in risk of death (P = .03). The disease-free survival difference reflected a 33% risk reduction due to contralateral prophylactic mastectomy (P = .0005), she reported.

“In one of the longest follow-ups we have seen, there is clearly a survival benefit for women undergoing contralateral prophylactic mastectomy,” Dr. Port commented. “Interestingly, there were still many locoregional recurrences in the contralateral mastectomy group. This is a point to make with patients: that they still have a risk of recurrence with mastectomy.”

tectomy to routine surveillance, the contralateral procedure provided “good value for select patient groups,” reported Dr. Boughey and Benjamin Zendejas, MD, also of the Mayo Clinic, Rochester.5 A Markov model was used to simulate the management of patients with breast cancer from initial treatment (mastectomy) to death. Investigators focused on the average-risk breast cancer patient who started treatment at age 45 and compared contralateral prophylactic mastectomy to routine surveillance and clinical breast examination every 6 months.

Who Opts for the Procedure?

From the Mayo Clinic in Scottsdale, Arizona, Chee-Chee H. Stucky, MD, and colleagues questioned whether certain women were more likely to opt for contralateral prophylactic mastectomy.4 “The decision to undergo contralateral prophylactic mastectomy for unilateral breast cancer is a complex interplay between patient- and tumor-specific factors, as well as socioeconomic variables,” Dr. Stucky suggested.

From the Surveillance, Epidemiology and End-Results (SEER) database, they identified 97,815 patients with breast cancer who had unilateral/segmental mastectomy or contralateral prophylactic mastectomy. Rates for the contralateral procedure increased from 2.5% in 2004 to 3.6% in 2007.

The study found that patients choosing contralateral prophylactic mastectomy were more likely to have the following characteristics: white race, age < 55 years, T2 or T3 stage, estrogen receptor–negative tumors, high tumor grade, nodal positivity, higher rate of high school education, and lower rate of unemployment.

Dr. Port commented that the findings were not surprising. “Being white and younger than 55 may be a surrogate for BRCA positivity, which influences the decision to have contralateral prophylactic mastectomy. And contralateral mastectomy, particularly in the non–BRCAmutation setting, is often a patient-driven decision, so women who are more educated and employed are probably more likely to seek out information.”

Cost-effectiveness In a cost-effectiveness analysis comparing contralateral prophylactic mas-

Benjamin Zendejas, MD

As expected, the rate of new contralateral breast cancers was significantly lower for the contralateral mastectomy group—101/10,000 vs 2,127/10,000 for the surveillance group—though survival was not different. To prevent one contralateral breast cancer, only five women needed to undergo contralateral mastectomy, he said.

Contralateral prophylactic mastectomy proved cost-effective for younger average-risk patients. Mean total breast cancer–related costs for women aged 45 were comparable: $30,222 for the contralateral mastectomy strategy and $29,076 for the surveillance strategy. But the contralateral mastectomy strategy provided 22.53 mean quality-adjusted life years (QALYs; ie, years in perfect health) compared to 22.44 for the surveillance strategy, resulting in an incremental cost-effectiveness ratio (ICER) of $12,733 per QALY gained. For the general population of patients with breast cancer aged 65 and older, mastectomy lost its cost-effectiveness.

For patients with BRCA-positive breast cancer, the contralateral prophylaxis strategy was clearly cost-effective and provided more QALYs at all ages.

“Contralateral prophylactic mastectomy was slightly more expensive up front than surveillance, but it represented an improvement in QALYs and clearly in contralateral breast cancer rates,” Dr. Port commented. “For BRCA-positive patients, because they have such a high rate of contralateral breast cancers, reductions in cost were sustained for the

Recent Findings on Contralateral Prophylactic Mastectomy ■■ In women with breast cancer deemed at high risk, followed for 17 years, contralateral prophylactic mastectomy reduced the risk of developing contralateral breast cancer by 95% and reduced mortality risk by 23%.

■■ White race, younger age, and higher levels of education and employment are associated with the decision to have contralateral mastectomy.

■■ Contralateral prophylactic mastectomy is a cost-effective strategy when compared with routine surveillance in younger patients and in those with BRCA mutations. However, it is less cost-effective for the general population of patients with breast cancer aged 65 and older.

■■ Surveillance that combines mammography and MRI can be considered a reasonable alternative in BRCA mutation carriers; interval cancers occur in 2%, and 97% of incident cancers are noninvasive or stage I. However, systemic therapy is often needed.

duration of their lives.”

She noted that while costs for contralateral mastectomy are reimbursed now, “in the current economic and health-care climate, all interventions will be scrutinized from a financial standpoint. This adds valuable data to support the validity of this option.”

How Good Is Surveillance for BRCA Mutation Carriers?

BRCA mutation carriers choosing surveillance should be aware, however, that mammography alone is not an effective means of detection, regardless of age, with sensitivity of about 20% whether women are over or under the age of 50, Canadian investigators determined.6

Kavitha Passaperuma, MD

On the other hand, when mammography is combined with MRI annually and clinical breast exams semiannually, surveillance is “a very reasonable alternative to risk-reducing mastectomy,” said Kavitha Passaperuma, MD, of the University of Toronto, who presented the results of a prospective surveillance study of 496 BRCA mutation–positive women aged 25 to 65.

At a median follow-up of 6.3 years, the interval cancer rate was only 2% overall and the predicted long-term systemic recurrence rate was less than 10%, particularly for incident cancers, 97% of which were ductal carcinoma

in situ or stage I tumors.

“However,” Dr. Port pointed out, “even the mutation carriers with earlystage cancers underwent chemotherapy to a large extent—30% of those with incident cancers and 60% with prevalent cancers—despite early detection. So, yes, surveillance is a reasonable alternative to contralateral prophylactic mastectomy, but with the understanding that early detection is a goal, not a guarantee, and even with early detection, systemic treatment is often needed.”

■

References 1. Tuttle TM, Habermann EB, Grund EH, et al: ������������������������������������������ Increasing use of contralateral prophylactic mastectomy for breast cancer patients: At trend toward more aggressive surgical treatment. J Clin Oncol 25:5203-5209, 2007.

2. Tuttle TM, Jarosek S, Haberman EB, et al: Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol 27:1362-1367, 2009.

3. Boughey JC, Hoskin TL, Degnim AC, et al: Association of contralateral prophylactic mastectomy with survival in high-risk women with a personal history of breast cancer. 2010 Breast Cancer Symposium. Abstract 164. Presented October 2, 2010.

4. Stucky CH, Pockaj BA, Gray RJ, et al: The interplay of tumor, patient, and socioeconomic variables in the rising incidence of contralateral prophylactic mastectomy across the United States. 2010 Breast Cancer Symposium. Abstract 104. Presented October 2, 2010.

5. Zendejas B, Moriarty JP, O’Byrne TJ, et al: Cost-effectiveness of contralateral prophylactic mastectomy versus routine surveillance for patients with breast cancer. 2010 Breast Cancer Symposium. Abstract 163. Presented October 2, 2010.

6. Passaperuma K, Warner E, Hill K, et al: Long-term results of the Toronto MRI breast surveillance study of women with BRCA mutations. 2010 Breast Cancer Symposium. Abstract 5. Presented October 2, 2010.

For patients with advanced RCC...

prognostic risk

Identifying is an important consideration.

Can you determine prognostic risk status based on MSKCC criteria listed below for a 65-year-old female?

LDH

450 IU/L

Time from diagnosis

9 months

Hb KPS Corrected calcium

14 g/dL 80 12 mg/dL

For the answer, see the following page.

RCC=renal cell carcinoma.

MSKCC=Memorial Sloan-Kettering Cancer Center.

LDH=lactate dehydrogenase.

Hb=hemoglobin.

KPS=Karnofsky Performance Status.

The patient’s prognostic risk is poor because at least 3 of the 5 values for the MSKCC criteria listed below indicate elevated prognostic risk.1

LDH: 450 IU/L Time from diagnosis: 9 months

Every patient

Hb: 14 g/dL KPS: 80

with advanced

Corrected calcium: 12 mg/dL

Poor

Prognostic risk is widely varied at diagnosis and significantly reflects survival1,2 Percentage of patients in each prognostic risk group in RCC clinical trials1,2 Prognostic Category

MSKCC

Modified MSKCC*

Poor Risk

20%

28%

Intermediate Risk

62%

35%

Favorable Risk

18%

37%

Evidence shows that prognostic risk is one of a number of important factors to consider when managing advanced RCC3 • NCCN treatment guidelines list prognostic risk stratification as an important consideration when developing a management approach3 * MSKCC criteria + prior radiotherapy and additional sites of metastases. The following number of risk factors were required for each prognostic risk group: MSKCC: 0=Favorable Risk, 1 - 2=Intermediate Risk, ≥3=Poor Risk; Modified MSKCC: 0 - 1=Favorable Risk, 2=Intermediate Risk, ≥3=Poor Risk.

RCC is

unique.

Easily calculate prognostic risk status per published MSKCC prognostic criteria or Modified MSKCC criteria with the FREE Advanced RCC Prognostic Calculator app To take advantage of this FREE tool on your iPhone® or iPod touch®, visit www.itunes.com/app/advancedrccprognosticcalculator for download.

www.PfizerOncology.com iPhone, iPod touch, and iTunes are trademarks of Apple Inc., registered in the U.S. and other countries. iTunes is for legal or rightholder-authorized copying only. Don’t steal music.

NCCN=National Comprehensive Cancer Network.

References: 1. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296. 2. Mekhail TM, Abou-Jawde RM, BouMerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23:832-841. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

TRS00119C

© 2010 Pfizer Inc.

All rights reserved.

November 2010

The ASCO Post | DECEMBER 2010

PAGE 22

35th ESMO Congress Supportive Care

Denosumab Prolongs Time to Skeletal-related Events and Their Incidence in Patients with Bone Metastases

By Alice Goodman

D

enosumab (Xgeva) was superior to zolendronate (zoledronic acid; Zometa) in patients with advanced cancer and bone metastases in preventing or delaying time to first skeletal-related events, as well as reducing the incidence of these events, in a pooled analysis of three pivotal trials presented at the 35th ESMO Congress.1 This effect was consistent regardless of the type of skeletalrelated event. Overall survival and progression-free survival were similar between the two treatment arms. The overall rates of adverse events, including osteonecrosis of the jaw, were similar as well, with the exception of an increased incidence of hypocalcemia with denosumab.

“The take-home message of this analysis is that the newer drug, denosumab, is statistically better than zoledronic acid in delaying [skeletalrelated events] in cancer patients with bone metastases,” said lead author Allan Lipton, MD, of Hershey Medical Center, Hershey, Pennsylvania.

“Denosumab is easier to administer [it is given subcutaneously, whereas zoledronic acid is given intravenously] and does not require renal monitoring.

The incidence of severe adverse events was similar between both groups.”

Key Data Taken together, the three studies (all sponsored by Amgen) included 2,862 patients randomly assigned to denosumab and 2,861 patients randomly assigned to zolendronate. Mean age was 63 years, and about 40% had had a previous skeletal-related event at baseline.

The main findings favoring denosumab were as follows: ■■ A 17% delay in time to first onstudy skeletal-related events (P < .001), with a median time to first event of 27.7 months for denosumab and 19.5 months for zolendronate ■■ An 18% delay in time to first and subsequent on-study skeletal-related events (multiple-event analysis, P < .001) ■■ Longer time to first on-study skeletalrelated events in those with previous skeletal complications (P < .01) and in those who had not experienced such effects previously (P = .0006)

The curves for both treatment arms were superimposable for progression-free and overall survival.

Osteonecrosis of the jaw after 2 years of treatment was reported in 1.8% of the denosumab group and 1.3% of zolendronate recipients (P = .13). Hypocalcemia occurred in 9.6% and 5%, respectively.

Denosumab is approved for treatment of osteoporosis and to help skeletal-related events in patients with metastatic cancer (see page 15). Both denosumab and zolendronate are being studied for the potential treatment of bone metastases and prevention of new bone metastases, and results of large randomized trials in breast and prostate cancer should be available soon.

“We are waiting for results of these studies. If positive, they may move up bone-targeting therapy to the adjuvant setting,” Dr. Lipton said. “In metastatic disease, denosumab looks more effective than zoledronic acid.”

High Health Resource Utilization An international observational study in patients with bone metastases, also sponsored by Amgen, showed that skeletal-related events entailed high consumption of health resource utilization in a cohort of 206 U.S. patients.2 In this cohort, each of the four types of skeletal-related event—pathologic fracture, radiation to the bone, spinal cord compression, and surgery to the bone—consumed a significant amount of health resource utilization in terms of outpatient visits, emergency room visits, inpatient stays, mean length of inpatient stay, and procedures.

The patterns of health resource utilization reflected the underlying type of skeletal-related event, according to lead author James Lee, MD, Hematology Oncology Associates of South Jersey, Mt. Holly, New Jersey, and colleagues.

Radiation to the bone occurred in 70% of skeletal-related events, making it the most common such effect.

Surgery to the bone and spinal cord compression required inpatient stays most frequently of the four event types, with more than 50% of patients continued on page 25

Balloon Kyphoplasty Relieves Painful Spinal Compression Fractures

B

alloon kyphoplasty offers relief of painful compression fractures in patients with cancer, according to the first randomized trial of this minimally invasive procedure in this setting.1 Patients who underwent balloon kyphoplasty had reduced pain scores, experienced fewer days limited by back pain, and used less pain medication compared with those managed nonsurgically.

“The evidence for balloon kyphoplasty is growing, but these are the first results in metastatic cancer,” said Leonard Bastian, MD, Klinikum Leverkusen, Leverkusen, Germany. “Balloon kyphoplasty offers quick pain relief, restores patient activity and mobility, and improves quality of life. It may be the right treatment option for vertebral compression fractures if conventional pain medication is ineffective or has too many side effects.”

The procedure costs an estimated 6,000 Euros in Germany and is reimbursed by the health-care system in that country. The procedure is done only to improve quality of life—it is not curative, he said. Also, balloon kyphoplasty cannot be performed if the bone is completely eroded, Dr. Bastian noted. In this study, all patients had a life expectancy beyond 3 months.

Balloon kyphoplasty is performed under fluoroscopy. Balloons filled with fluid are inserted through a 1-cm incision into the fractured vertebra to increase the height and restore the shape of the vertebra; the balloon is deflated and removed, and bone cement is injected into the cavity to stabilize the bone.

International Trial Results The international, controlled Cancer Patient Fracture Evaluation (CAFÉ) Study randomly assigned 134 patients with at least one painful spinal compression fracture to either balloon kyphoplasty or nonsurgical management. At 1 month, patients could cross over to the balloon kyphoplasty arm, and 38 (of 61) patients in the nonsurgical arm did so.

Patients treated with balloon kyphoplasty had an improvement in status quantified as –8.3 points on the Roland-Morris Disability Questionnaire (RMDQ) score—a widely used measure for low back pain—whereas no change in RMDQ score was observed for the nonsurgical group (P < .0001). Balloon kyphoplasty patients reported significant improvement in back pain at 1 month postsurgery, while no improvement was seen in the control group (P < .0001). Balloon kyphoplasty remained superior at 1 year, he said, and results were just as good in crossover patients as in those initially randomized to balloon kyphoplasty.

Two treatment-related adverse events were reported in balloon kyphoplasty patients: one myocardial infarction and one adjacent fracture probably related to cement flowing out of the surgically treated vertebral body.

Formal discussant of the trial, Fausto Roila, MD, Medical Oncology, Santa Maria Hospital, Terni, Italy, said that the main limitation of this study was the lack of a true sham procedure as control. He also noted that the procedure is not risk-free. Nevertheless, kyphoplasty appears to be superior to no surgical intervention for painful vertebral compression fractures in this no-blind study. Double-blind studies will be needed to determine the true effects of the procedure on symptoms.

■

Fausto Roila, MD

Reference 1. Bastian L, Pflugmacher R, Berenson JR, et al: First randomized trial comparing balloon kyphoplasty (BKP) to non-surgical management among cancer patients with vertebral compression fractures. 35th ESMO Congress, Abstract 1181O. Presented October 9, 2010.

ASCOPost.com | DECEMBER 2010

PAGE 23

JCO Spotlight Breast Cancer

Higher-dose Fulvestrant Improves Benefit–Risk Ratio in Postmenopausal Women with ER-positive Advanced Breast Cancer

By Barbara Boughton he results of the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) doubleblind phase III trial, first published in the Journal of Clinical Oncology (JCO) online and subsequently in the journal’s print edition,1 show that a 500‑mg regimen of fulvestrant (Faslodex) produces a significantly longer progression-free survival in postmenopausal women with estrogen receptor–positive (ER+) advanced breast cancer than a 250‑mg regimen of the same drug—without any additional toxicity.

The study provides a new standard for fulvestrant dosing, and a new alternative for treating postmenopausal women with ER+ advanced breast cancer, according to the CONFIRM study authors. The study also raises the tantalizing question of whether the higher dose of fulvestrant might be superior to currently used aromatase inhibitors, such as anastrozole, according to an accompanying editorial published in the same issue of JCO.2

FDA Approval Based on the CONFIRM trial, the FDA approved the 500‑mg dose of fulvestrant intramuscular (IM) injection for the treatment of ER+ metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy.

“Fulvestrant was already routinely used in the treatment of breast cancer. But the CONFIRM trial shows us that the 500‑mg dose allows longer disease control as well as a longer duration of clinical benefit,” said one of the CONFIRM trial authors, Guy Jerusalem, MD, PhD, of the CHU Liege Domaine Universitaire du Sart Tilman in Belgium. “This allows

patients to avoid much more toxic chemotherapy. And more importantly, the higher dose has similar side effects to the previous standard dose of 250 mg,” Dr. Jerusalem told The ASCO Post.

In the CONFIRM trial, 736 postmenopausal women with locally advanced or metastatic ER+ breast cancer, previously treated with an antiestrogen or aromatase inhibitor therapy, from 128 medical centers in 17 countries were randomly assigned to receive a fulvestrant 500‑mg IM regimen or a 250‑mg dose of fulvestrant every 28 days. The 500‑mg fulvestrant regimen consisted of a loading dose of 500 mg IM at baseline and 500 mg on days 14 and 28 and every 28 days thereafter.

Key Findings Results indicated that progressionfree survival was significantly longer for women who received the 500‑mg regimen than for those who were given 250‑mg dosing (HR = 0.80, P = .006), translating to a 20% reduced risk of progression with the higher dosage (Fig. 1).

The median progression-free survival was 6.5 months in the 500‑mg group and 5.5 months in the 250-mg group. At 12 months, 34% in the 500‑mg group remained alive and were progression-free, compared with 25% in the 250‑mg group who survived without progression.

Although objective response rates were similar in both arms, the duration of clinical benefit for those who received 500 mg of fulvestrant was significantly more prolonged than for those who received the lower dose (16.6 vs 13.9 months). There was also a trend

Fulvestrant in Estrogen Receptor–positive Breast Cancer ■■ Fulvestrant is a synthetic estrogen receptor antagonist administered

by intramuscular injection. The drug is unlike tamoxifen (which has partial agonist effects) and the aromatase inhibitors (which reduce the estrogen available to tumor cells) in that it binds competitively to estrogen receptors in breast cancer cells, resulting in estrogen receptor deformation and decreased estrogen binding.

■■ Among postmenopausal women with advanced ER+ breast cancer, progression-free survival was significantly longer with a 500‑mg fulvestrant regimen than with 250‑mg dosing (HR = 0.80, P = .006), translating to a 20% reduced risk of disease progression.

■■ Median progression-free survival was 6.5 months in the 500‑mg group and 5.5 months in the 250-mg group.

■■ A nonsignificant trend toward improved overall survival was seen in the 500‑mg arm; a final survival analysis is expected in 2012.

1.0

Proportion of patients progression-free

T

Fulvestrant 500 mg Fulvestrant 250 mg Hazard ratio (95% CI): 0.80 (0.68 to 0.94) P = .006

0.8 0.6 0.4 0.2 0

0

4

8

12

16

20

24

28

32

36

40

44

48

12 4

7 3

3 1

2 1

0 0

Time (months) No. of patients at risk Fulvestrant 500 mg 362 Fulvestrant 250 mg 374

216 199

163 144

113 85

90 60

54 35

37 25

19 12

Fig. 1: Progression-free survival by treatment arm in the COMMIT trial. Reprinted with permission from Di Leo et al.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

toward improved overall survival in the 500‑mg fulvestrant arm compared to the 250‑mg arm (25.1 vs 22.8 months, HR = 0.84, P = .091). The final survival analysis will be performed when 75% of patients have experienced an event, which is expected to occur in 2012.

The safety of the 500‑mg dose of fulvestrant was also equivalent to the 250‑mg dose. There was no significant difference in either the incidence or severity of adverse events between the two groups in the CONFIRM trial. Serious adverse events affecting 2 or more patients included 2 cases of bronchitis, 2 cases of dyspnea, and 3 cases of vomiting in the 500‑mg group compared to no serious adverse events affecting 2 or more patients in the 250‑mg group. Quality of life as assessed by a FACT-B questionnaire administered to 145 patients in the CONFIRM study showed no significant difference between patients who received 250 mg of fulvestrant and those who receive the 500‑mg dosing regimen.

“We now have three classes of drugs with major activity and a different mode of action in endocrine-responsive breast cancer—aromatase inhibitors, fulvestrant, and tamoxifen,” Dr. Jerusalem said.

“It may be that we can improve the cure rate for women with postmenopausal ER+ breast cancer by sequential administration of these agents.”

Fulvestrant Role Reconsidered In an editorial that accompanied publication of the CONFIRM trial in JCO,2 Anthony Howell, MD, and Jonas

Bergh, MD, PhD, suggested that the CONFIRM data, along with data from the phase II Fulvestrant First-line Study Comparing Endocrine Treatments, or FIRST trial,3 indicate an increased duration of response with the higher dose of fulvestrant. The FIRST trial compared an anastrozole dosage of 1 mg/d with a 500‑mg fulvestrant regimen in just over 200 patients with advanced breast cancer.

“These prolongations are potentially important for patients with advanced endocrineSee page 51 responsive disease; they indicate a need to reassess the place of fulvestrant in the endocrine treatment hierarchy,” the authors wrote. In the openlabel phase II FIRST trial, 500‑mg fulvestrant resulted in significantly improved time to progression compared to anastrozole.

“Both of these trials show a time-toprogression advantage (for 500‑mg fulvestrant) and I think it is likely that they will (eventually) both show a survival advantage,” Dr. Howell said during an interview with The ASCO Post. “If this is the case, then the standard 500‑mg dose of fulvestrant may well become the treatment of first choice for women with ER+ breast cancer.” Dr. Howell is Professor of Medical Oncology and Director of the Manchester Breakthrough Breast Cancer Research Unit at the Paterson Institute for Cancer Research in England.

Until now, fulvestrant has been hamcontinued on page 24

The ASCO Post | DECEMBER 2010

PAGE 24

JCO Spotlight

Higher-dose Fulvestrant continued from page 23

pered by its expense and the fact that it is given by injection, Dr. Howell noted. “Yet with the new data, I think there might be more of a tendency to use it first-line,” he said.

Dr. Jerusalem has reported research funding and honoraria from AstraZeneca,

and Dr. Howell has disclosed a consultant role with honoraria from AstraZeneca.

■

References 1. Di Leo A, Jerusalem G, Petruzelka L, et al: Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast

cancer. J Clin Oncol 28:4594-4600, 2010.

2. Howell A, Bergh J: Insights into the place of fulvestrant for the treatment of advanced endocrine responsive breast cancer. J Clin Oncol 28:4548-4550, 2010.

3. Robertson JF, Llombart-Cussac A, Rolski J, et al: Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: Results from the FIRST study. J Clin Oncol 27:4530-4535, 2009.

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Expert Point of View

T

he results of the CONFIRM trial are significant because they validate what had been suggested in previous studies—that the 500‑mg dose of fulvestrant is superior to the previous standard dose, commented John Glaspy, MD, MPH, Professor of Medicine at the University of California-Los Angeles Jonsson Comprehensive Cancer Center.

When fulvestrant first became available at the 250‑mg dose, scientists were hopeful that the drug might prove to be a powerful addition to hormonally targeted agents in breast cancer, he said. “It was clear that it had a novel mechanism of action. But the 250‑mg dose turned out to be equal to the aromatase inhibitors in terms of the length of time it worked and the proportion of patients it benefitted. And like other hormonal agents, it didn’t work as long as we would have liked,” Dr. Glaspy said.

Dr. Glaspy noted that the CONFIRM trial allows clinicians to be certain that the 500‑mg dose of fulvestrant is a better approach to treatment than the lower-dose regimen.

“It will also raise the question of whether the more effective Faslodex therapy is superior to the aromatase inhibitors. We’re going to have to go back and address that question in clinical trials now,” he said.

Dr. Glaspy noted that the CONFIRM data might cause clinicians to use fulvestrant sooner in the sequential treatment of ER+ advanced breast cancer.

However, he cautioned that since fulvestrant is an intramuscular injection, it requires office time and expertise as compared to aromatase inhibitors, which can be given orally. “Because of the injection needle pain with fulvestrant, many doctors will continue to think about the aromatase inhibitors as the front-line therapy,” he said. However, that may change when there is evidence showing which treatment may be superior, he added.

Dr. Glaspy has reported receiving honoraria from AstraZeneca.

■

Copyright © 2010 US Oncology, Inc. All rights reserved.

ASCOPost.com | DECEMBER 2010

PAGE 25

Global Perspective Reporter at Large

European Oncologists Offer Snapshots of Clinical Practice ‘Over There’

By Caroline Helwick How are the challenges faced by medical oncologists in Europe different from issues facing their colleagues in the United States? At the 35th ESMO Congress, held October 8-12 in Milan, Italy, The ASCO Post asked a few attendees to comment on the practice of oncology in their country.

ample, I can’t prescribe ipilimumab or the BRAF inhibitor in melanoma yet, but my patients are asking about it. Still, we have universal health coverage, and some patients have additional insurance, so most patients are getting the care they need.”

—Lore Decoster, MD Brussels, Belgium

“In Belgium, many or most oncology drugs are paid for by the government, though not for all the same indications as in the United States. For instance, bevacizumab (Avastin) is reimbursed in colorectal cancer but not in lung cancer, where the benefit is so small. But we must wait longer for drug approval. For ex-

“We have a high approval rate for new oncology drugs, so I can’t complain about patient access.

But my fear is that, since the global economic crisis is also affecting our health-care budget, the future could be more problematic. Currently, oncology drugs get priority fast-track approval, but I don’t know if this status will be maintained. I worry that the avail-

ability of drugs may become a problem, especially for patients who do not have additional insurance to supplement the care that the government provides.”

—Tim Van Den Wyngaert, MD Antwerp, Belgium

the regulatory burdens for investigator-led studies are becoming more difficult.”

—Richard Baird, PhD Sutton, UK

“Many UK oncologists are concerned about access to new cancer drugs.

We would like to be able to give all our patients the best evidence-based treatments, and there is tension between this and the public health side of things because money is limited. We have some patients treated within the National Health System, and we have a subset with additional insurance. The treatment for the same problem might be different for these two populations within one physician’s practice, and there is also some geographic variability. Furthermore, I’m involved in phase I trials, and I find that

“My main concern is how to implement all the new oncology drugs: how to select the right patients for them and when to use them. While reimbursement is good, and ultimately The Netherlands gets every new drug, it takes longer than in the United States. Fast-track approval in the U.S. is about 6 months, but it is at least twice that long in The Netherlands, and that is frustrating. Similar to the situation in the U.S., oncologists in The Netherlands are not completely satisfied with how they are paid. We receive a fee per diagnosis, not per treatment [ie, bundling], and we have found that the government is losing money with this system. We need to rethink this.”

—Winald Gerritsen, MD, PhD Amsterdam, The Netherlands We have access to most oncology drugs, and I believe in many ways our health-care system is better than in the United States. Our medical oncologists are as good as those anywhere, but our physical conditions are not as good. For example, we need better facilities, and we need hospice. Some hospitals are quite good, but others are not.

—Tariq Salman, Izmir, Turkey

The 35th ESMO Congress was held in Milan, Italy. Photo courtesy of ESMO. Copyright 2010, ESMO.

Denosumab for Bone Metastases continued from page 22

Denosumab vs Zolendronate in Patients with Bone Metastases ■■ Denosumab was superior to zolendronate in preventing skeletal-related events in a pooled analysis of three pivotal trials.

■■ Ongoing studies will determine the role of these two bone-targeted therapies in treating and preventing bone metastases.

■■ Skeletal-related events in patients with bone metastases consume a considerable amount of health resources, including inpatient stays, outpatient and emergency room visits, radiation to the bone, and other procedures.

in these groups hospitalized. However, all four types of skeletal-related events required related inpatient stays, and the average duration of inpatient stay was 11 days. Each type of skeletal-related event was associated with an average of 10 procedures. All four types were associated with outpatient visits as well. Emergency room visits were more common with spinal cord compression.

These preliminary results require confirmation, the authors noted. The final analysis will show results according to tumor type.

■

References 1. Lipton A, Siena S, Rader M, et al: Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials.

35th ESMO Congress. Abstract 1249P. Presented October 10, 2010.

2. Lee J, Suenaert P, Atchison C, et al: Health resource utilization associated with skeletal-related events in patients with bone metastases—US interim analysis results from a multinational observational study. 35th ESMO Congress. Abstract 1101P. Presented October 9, 2010.

ASCOPost.com | DECEMBER 2010

PAGE 27

35th ESMO Congress Melanoma

Two Drugs Show Promising Activity in Melanoma with CNS Metastases

By Alice Goodman

T

he future appears a bit brighter for patients with advanced melanoma and brain metastases, according to two studies presented at the 35th ESMO Congress, held October 8–12 in Milan, Italy. A subgroup analysis of a larger trial showed encouraging activity for ipilimumab in patients with a history of brain metastases,1 and a second preliminary study showed dramatic shrinkage of brain metastases with an investigational BRAF inhibitor called GSK2118436.2

‘Exciting Beginning’ Ipilimumab is active in patients with advanced melanoma and a history of brain metastases, according to a subgroup analysis1 of a large phase III trial originally presented at the 2010 ASCO Annual Meeting. MDX010-20 was the first randomized phase III trial to demonstrate a survival improvement for any drug in advanced melanoma, and this was considered a major advance in the field. In the subgroup analysis, ipilimumab had comparable safety in patients with and without a history of brain metastases.

umab, and the survival benefit was consistent across all subgroups of patients, regardless of gender, age, melanoma stage at study entry, baseline LDH level, previous use of interleukin-2 (Proleukin), and history of central nervous system (CNS) metastasis.

The subpopulation of 77 patients with a history of brain metastases (ie, not active at time of trial enrollment) had improved overall survival when treated with ipilimumab, although the magnitude of improvement was smaller than in the 338 patients with no history of brain metastases.

‘Benefit Comes with a Price’ “The benefit of ipilimumab comes with a price,” said Dr. Lebbé.

In the overall trial, the major adverse event was immune-related toxicity (eg, enterocolitis, dermatitis), which was manageable with vigilant follow-up and early steroids. The rate of grade 3/4 toxicity was 17% and 23% for ipilimumab given with and without a vaccine, respectively, compared to 11% for the vaccine alone. Grade 3/4 immune-related toxicity in the three

Novel Agents for Melanoma with Brain Metastases ■■ Ipilimumab has activity in advanced melanoma with a history of brain

metastases and has comparable safety in patients with and without brain metastases.

■■ An investigational BRAF inhibitor, GSK2118436, showed dramatic activity in a small study of melanoma patients with active brain metastases, achieving tumor shrinkage of up to 80%.

“This is a beginning [in patients with brain metastases], but it is a very exciting beginning. An ongoing phase II study is currently investigating ipilimumab activity in patients with active brain metastasis to get a more complete story,” said Céleste Lebbé, MD, Hôpital St. Louis, Paris, France.

Ipilimumab is a monocolonal antibody that blocks CTLA-4 downregulation of T cells. The effect of the monoclonal antibody is to potentiate T cells.

In the overall trial, ipilimumab achieved a significant survival benefit in 676 previously treated patients with advanced melanoma, when administered with the gp100 vaccine (P = .0004) and without the vaccine (P = .0026) vs the vaccine alone. The 1- and 2-year survival rates were nearly doubled in both groups treated with ipilim-

arms was 10%, 15%, and 0.8%, respectively. Treatment-related deaths occurred in 2.1%, 3.1%, and 2%, respectively; and immune-related deaths occurred in 1.3%, 1.5%, and 0%.

In the subgroup analysis, safety was consistent between the groups with and without a history of brain metastases. No new neurologic concerns were evident in those with brain metastases.

Formal discussant of the subgroup analysis, Cornelis J. A. Punt, MD, of Nijmegen Medical Center in the Netherlands, said the good news is that there is finally an active drug in advanced melanoma, but the bad news is that it is given only after other drugs fail.

“We have no good drugs for firstline treatment of melanoma,” he said.

“The other bad news is that the new drug has toxicity,” he added.

Issues for Further Study Dr. Punt raised several important issues for further study. In the MDX010-20 trial, HLA-A2 matching was required for use of the Gp100 vaccine, which was the control arm of the trial and included in one experimental arm combined with ipilimumab. It is not clear whether the activity of ipilimumab is restricted to patients with the HLA-A2 subtype, and more data are needed. It is also not clear whether gp100 was the optimal control arm, he continued.

The 23% rate of grade 3/4 toxicity and the 3.1% rate of toxic deaths in the ipilimumab-alone arm suggest that the optimal dose of ipilimumab remains to be determined.

Regarding the subgroup analysis, Dr. Punt commented, “These authors are to be commended for including patients who are usually excluded from clinical trials. The favorable effect of ipilimumab in patients with a history of brain metastases is promising.”

Potentially ‘Miraculous’ Results A small phase I/II study of 10 patients with advanced melanoma and active brain metastases treated with a new oral drug called GSK2118436 produced “miraculous” preliminary results,2 according to Caroline Robert, MD, PhD, formal discussant of this late-breaking abstract at the ESMO meeting.

The investigational compound, known as GSK2118436, is an inhibitor of BRAF, a gene that is mutated in 50% of melanomas. The drug binds to the active BRAF protein on melanoma cells and inhibits proliferation, explained lead author Georgina Long, MD, Melanoma Institute Australia and Westmead Hospital in Sydney, Australia.

“The compound is only active in patients with BRAF mutations, and this drug is showing robust clinical activity,” she emphasized.

All 10 patients had untreated brain metastases at study entry, and 9 patients experienced tumor shrinkage ranging from 20% to 100%. Responses were seen in those with multiple metastases; in fact, one of the responding patients had over 10 metastases, she said. Prior to treatment, all brain metastases were 3 mm or greater in diameter.

Dr. Long said a similar effect of the BRAF inhibitor was seen in a separate phase I/II study of patients with melanoma and extra-CNS metastases (ie, breast, pelvis, axillae, liver, and spleen), with a response rate of 77% at last update at the Society of Melanoma Research Conference 2010, in Sydney, Australia.

The most frequent side effects of the new drug are fatigue, pyrexia, and dehydration.

Other Surprising Findings Dr. Robert, of the Institut Gustave Roussy, Villejuif, France, called these preliminary results “astonishing.”

“Median overall survival for melanoma patients with brain metastases is under 4 months, and there are no good treatments. Chemotherapy, surgery, and radiotherapy don’t work,” she told listeners. “Ongoing studies are looking at ipilimumab. The results with this new oral compound are surprising, in that there is a parallel response in the brain and in extra-CNS sites.”

Areas for further study include the durability of response, impact on survival, efficacy for larger brain metastases, and See page 51 efficacy in the adjuvant setting, she continued.

“We are confronted here with extremely promising results. Only the future will tell us if these miraculous results hold up,” she concluded.

■

References 1. Lebbé C, McDermott DF, Robert C, et al: Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: Subgroup analysis from a phase III trial. 35th ESMO Congress. Abstract 13240. Presented October 10, 2010.

2. Long GV, Kefford RF, Carr PJA, et al: Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (mut) BRAF kinase: Evidence of activity in melanoma brain metastases (mets). 35th ESMO Congress. Abstract LBA27. Presented October 10, 2010.

For more news from ESMO, see pages 1, 22, 30

Clinical challenge: Treatment selection for patients with lower-risk MDS* Supportive care: The most common initial MDS treatment 90% of patients with newly diagnosed myelodysplastic syndromes (MDS) present with anemia, and most patients eventually become red blood cell (RBC) transfusion dependent.1 For years, MDS was treated with best supportive care—RBC or platelet transfusions and antibiotics.2 With the advent of hematopoietic growth factor therapy, supportive care expanded to include erythropoiesis-stimulating agents (ESAs), with or without G-CSF,† which were used to reduce the need for transfusions.3,4

Survival decreases with increasing transfusion requirements5 Therefore, it is critical to achieve transfusion independence in patients with transfusiondependent MDS. While ESAs can effectively relieve the symptoms of anemia, they may not be sufficient to provide RBC transfusion independence in all MDS patients.6-9 Some of your patients with lower-risk MDS may need treatment other than growth factors (GFs).

Use baseline serum erythropoietin (sEPO) levels to guide treatment decisions Because the response to ESAs declines with increasing baseline sEPO levels, it is critical to measure endogenous levels of erythropoietin before initiating treatment with ESAs. As many as 85% of patients with MDS have elevated baseline sEPO levels,10 making them less likely to respond to growth factors. Patients with high sEPO levels (>500 U/L) and high transfusion needs (≥2 RBC units/month) have a low chance of response to erythropoietin.3 Current treatment guidelines recommend that the determination of baseline sEPO levels should be a required part of the initial evaluation of patients with cytopenias.11 *MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk MDS per International Prognostic Scoring System (IPSS). † G-CSF, granulocyte colony-stimulating factor. Growth factor therapy includes ESA ± G-CSF or granulocyte/macrophage (GM)-CSF.3

©2010 Celgene Corporation

07/10

CELG10174T

Two variables can be used to help predict response to growth factor therapy: Baseline sEPO levels and RBC transfusion burden 9

GOOD Transfusion Requirement sEPO Level

Chance of responding to ESAs‡

INTERMEDIATE

POOR

Low (<2 units/month)

High (≥2 units/month)

Low (<2 units/month)

High (≥2 units/month)

Low (≤500 U/L)

Low (≤500 U/L)

High (>500 U/L)

High (>500 U/L)

74%

23%

7%

Adapted from Hellström-Lindberg et al (2003).9

Consider baseline sEPO levels and transfusion burden when determining treatment options for your RBC transfusion-dependent patients with lower-risk MDS. It is also important to continually evaluate these patients.

If your patients have a predicted intermediate or poor response to ESAs, it may be appropriate to consider non-growth factor therapies.3

‡

The Hellström-Lindberg study defined complete erythroid response as an increase in hemoglobin (HgB) to ≥11.5 g/dL. Partial response was defined as an increase in HgB of ≥1.5 g/dL in patients with anemia who are not transfusion dependent, and for RBC transfusion-dependent patients, a stable HgB level for ≥4 weeks and transfusion independence.9

References: 1. Italian Cooperative Study Group For rHuEpo in Myelodysplastic Syndromes. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998;103:1070-1074. 2. Nimer SD. ASH 50th anniversary review: Myelodysplastic syndromes. Blood.

2008;111(10):4841-4851. 3. Sekeres MA, Fu AZ, Maciejewski JP, Golshayan A-R, Kalaycio ME, Kattan MW. A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer. 2007;109(6):1125-1132. 4. Fenaux P, Kelaidi C. Treatment of the 5q- syndrome. American Society of Hematology Education Program–Myelodysplastic Syndromes. Hematology. 2006;192-198. 5. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica.

2006;91(12):1588-1590. 6. Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106(3):803-811. 7. Miller KB, Kim HT, Greenberg P, et al. Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone in the treatment of myelodysplastic syndromes (MDS): results of the ECOG-CLSG trial (E1996). Blood. 2004;104(11):24a. Abstract 70. 8. Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2004;128(2):204-209. 9. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al.

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life.

Br J Haematol. 2003;120(6):1037-1046. 10. Hofmann W-K, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16. 11. National Comprehensive Cancer Network®.

Myelodysplastic Syndromes. V.2.2010. NCCN Clinical Practice Guidelines in Oncology ™.

The ASCO Post | DECEMBER 2010

PAGE 30

35th ESMO Congress Colorectal Cancer

Outlook Dramatically Improved for Patients with Metastatic Colorectal Cancer and Liver Metastases

By Alice Goodman

S

tage IV colorectal cancer with metastases confined to the liver no longer carries as dire a prognosis as it once did for a sizeable proportion of patients. With modern chemotherapy and specialized liver surgery, 10year survival has improved dramatically over the past decade, according to presentations at the 35th ESMO Congress, held October 8-12 in Milan, Italy. Recent studies show 5‑year survival rates of almost 40% and 10year survival rates of 24%.

Graeme Poston, MD

“Ten years ago the criteria for liver resection were much more restrictive than they are today. Less than 10% of patients with liver disease were considered eligible for surgery, and only 1 in 3 were cured. Ten-year survival was 3% a decade ago; now it is 24% for stage IV disease and liver metastases only,” said Graeme Poston, MD, liver surgeon at University Hospital Aintree, NHS Trust, Liverpool, UK, and winner of the prestigious Stanford Cade Medal in 2010 for his work in liver cancer. “The chance of curing a patient is small, but we can reset that clock by resecting liver metastases,” he told listeners at the ESMO/ ESTRO/ESSO Joint Symposium on multidisciplinary management of colorectal cancer.1 Current criteria for liver surgery include disease confined to the liver, resectable with adequate margins (“according to the surgeon, not the textbook,” said Dr. Poston), adequate

future liver remnant of 25% to 30%, and preservation of liver anatomy.

About 20% of patients with liver metastases are now resectable, and chemotherapy brings another 10% to 30% to resection.

Dr. Poston emphasized the need for multidisciplinary management and specialized services for this patient group. “Patients need to be evaluated and treated by a liver surgeon.

Currently too many patients are being managed by a general surgeon. The surgeon’s experience is important,” he said. Regarding multidisciplinary management, he commented, “We cannot work in isolation.”

He was optimistic about this being a potentially curative disease. “In the year 2020, we might have 50% 5-year overall survival,” he told listeners.

Much of Dr. Poston’s presentation was based on data from the LiverMetSurvey (www.livermetsurvey.org), a European registry developed at six specialized cancer centers in Europe including 11,887 patients. These data show that resection benefits subgroups not traditionally thought to be candidates: patients with metachronous metastases, up to 10 metastatic sites in the liver, or larger tumors.

“At 10 years, we have good results. If you can remove it, do it,” he recommended.

Related Meta-analysis A separate poster presentation of a meta-analysis based on 116 studies of patients with colorectal cancer and resected liver metastases showed a 5-year overall survival rate of 39%, an increase of 5% to 9% from 2001, said lead author Aliki Taylor, MD, Epidemiology Department, Amgen Ltd, Uxbridge, UK.2 Dr. Poston was senior author of this poster.

“We wanted to tease out which groups had the best survival, and we found that those with solitary liver

Colorectal Cancer and Liver Metastases ■■ Data from the LiverMetSurvey and a poster presentation at ESMO show that 5‑year survival approaches 40% for patients with colorectal cancer and hepatic metastases.

■■ This impressively improved outcome depends on skilled liver surgeons and a multidisciplinary approach.

Aliki Taylor, MD

metastases had a 5-year overall survival rate of up to 70%,” Dr. Taylor said.

Overall survival ranged from 16% to 71% in the studies included in the meta-analysis Patients with extrahepatic metastases had a median survival of 2.5 years, whereas those with metastases confined to the liver had a median survival of 3.6 years.

Postoperative mortality was low, ranging from 0% to 4%, which is an important point, she said. The most frequent morbidity was wound infection, reported in 4.8% of cases.

Prognostic factors correlated with shorter survival included more than one liver metastasis, node-positive primary tumor, positive resection margins, extrahepatic disease, poor differentiation of primary tumor, tumor size greater than 5 cm in diameter, and carcinoembryonic antigen (CEA) level.

Dr. Taylor said that these factors might be useful in determining optimal treatment for patients with colorectal cancer and liver metastases.

Fortunato Ciardiello, MD

Need for Multidisciplinary Approach Fortunato Ciardiello, MD, a member of ESMO’s Steering Committee and Professor of Medical Oncology at the Second University of Naples, Italy, fully agreed with Dr. Poston’s statement about the need for a multidisciplinary approach. “Pa-

tients with metastatic disease should see a colorectal surgeon, a liver surgeon, and a medical oncologist to define optimal therapy.”

This is even more important for liver metastases that are initially unresectable due to the number of metastases or location. “A complex approach is needed to decide the optimal time for surgery, and a very skilled liver surgeon is needed to define anatomy.”

Medical oncologists should use the most active therapy for the shortest time, he said, to achieve tumor shrinkage without harming the normal liver.

“European surgeons have pursued this approach most aggressively. The paradigm has changed the way we consider liver disease. Up to 30% of patients with stage IV colorectal cancer and liver-only metastasis can undergo successful resection. Some of them can have a resection upfront, and many of those with unresectable disease can be converted to resection,” Dr. Ciardiello See page 51 commented.

References 1. Poston GJ: It’s resectable, but is it curable? ESMO/ESTRO/ESSO Joint Symposium. Surgery, radiotherapy and ablation of metastatic disease and chemotherapy for localized disease: Changing roles in multidisciplinary management of colorectal cancer. 35th ESMO Congress. Abstract 59IN. Presented October 9, 2010.

2. Taylor A, Kanas G, Langeberg WJ, et al: Survival after surgical resection of hepatic metastases from colorectal cancer: A systematic review and meta-analysis. 35th ESMO Congress. Abstract 632P. Presented October 10, 2010.

Coming in future issues of

The ASCO Post

Coverage of these important meetings: 52nd American Society of Hematology Annual Meeting 33rd Annual San Antonio Breast Cancer Symposium

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

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

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

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

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

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

References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page.

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

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

C

COOH

CH2COOH

and the molecular formula is C26H28CINO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growthstimulating effects of estrogen in the tumor.

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours.

Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.

Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied.

Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 14+33 11+30 7+25 3+28 19+48 19+56 CR1 + PR2 RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.)

5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.)

33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median

survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

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

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

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% 4% Vaginal Bleeding 2%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known.

Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/ kg/day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly.

There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended.

Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum.

Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes.

Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma.

The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice.

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses.

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS).

Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS).

Pediatric use: There is no indication for use of FARESTON in pediatric patients.

Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.

Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.

FARESTON Tablets are identified with TO 60 embossed on one side.

FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from heat and light.

Distributed by GTx, Inc. Memphis, TN 38163, USA Product covered by Orion Product Patents and related patent numbers. © 2004 GTx, Inc. All rights reserved.

1E Rev. 12/2004

ASCOPost.com | DECEMBER 2010

PAGE 33

Direct from ASCO

Call for Abstracts: 2011 ASCO Annual Meeting Deadline: February 2, 2011, 11:59 PM EST

the partnering of the right treatments with the right patients All abstracts must be sponsored by an ASCO member. The privilege of submitting an abstract is only one of many exclusive ASCO membership benefits, including an average savings of 50% off the Annual Meeting nonmember registration rates. To join ASCO, visit benefits.asco.org.

A

SCO is now accepting abstracts to be considered for presentation or publication at the 2011 Annual Meeting in Chicago. The submission deadline is 11:59 PM on February 2, 2011.

ASCO encourages abstracts of studies on all types of cancer as well as investigations focusing on the following areas: Patients: addressing the care delivered to patients with cancer, how more patients are becoming cancer survivors, and the resultant survivorship and quality-of-life concerns Pathways: highlighting the biologic pathways that help drive dis-

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

Submit an abstract at Chicago2011.asco.org/ CallForAbstracts.

ease, as well as the understanding of these pathways that is defining new clinical treatments and leading to improved patient care

Progress: discussing how discoveries made at the lab bench are translated into ongoing progress against cancer, lower cancer mortality, and

Topic categories and submission guidelines are available online.

ASCO Grants to State Affiliates Pay Off Hawaii and Washington Projects Benefit Patients, Practices

A

SCO’s State Affiliate Grant Program helps jump-start exciting local projects undertaken by state oncology societies. Established in 2005, the program has so far awarded 38 grants to its state affiliates for projects ranging from creating a statewide clinical trial network to providing career planning seminars for oncology fellows.

Projects recently completed by the Hawaii Society of Clinical Oncology (HSCO) and the Washington State Medical Oncology Society (WSMOS) offer excellent examples of the kinds of initiatives supported by the program.

Hawaii Addresses Patient Language Barriers Many immigrant and first-generation Filipinos in Hawaii are not fluent or literate in English. “We struggle to talk meaningfully about the diagnosis, prognosis, treatment options, side effects of therapy, and goals of treatment,” says Past HSCO President William S. Loui, MD. After learning from community focus groups that a DVD would be a useful medium for patient education,

HSCO applied for and received a $10,000 grant from ASCO to help develop a DVD for use with patients.

“We are beta-testing the DVD now and doing a survey to assess its effectiveness,” Dr. Loui says. He has had gratifying responses from patients. “Last month, I was struggling in a consultation with an elderly Filipina, and a gap in comprehension was evident. I brought her and her adult grandson into my office to watch the DVD on the computer.

After 15 minutes, we could tell that she had better insight into the proposed chemotherapy. Her grandson was also appreciative because he had been struggling to translate the medical terms.”

Dr. Loui says that the most powerful part of the DVD is the first section, in which cancer survivors who are fluent in Tagalog, the official language in the Philippines, or Ilocano, the Philippine dialect most common in Hawaii, relate their own feelings and experiences. Other segments of the DVD provide information about chemotherapy, radiation therapy, surgery, and clinical trials.

HSCO hopes to produce hun-

dreds of the DVDs to distribute to patients, doctors, clinics, and cancer programs. “We’re looking for funding to have a copy for everyone who asks,” Dr. Loui comments.

Washington Aim: Boost Supply of Midlevel Providers With an eye to increasing the use of midlevel providers in oncology practice, WSMOS used an ASCO grant to conduct two surveys to profile oncology practices and training programs in the state and to create a resource for enhanced interaction.

Both surveys had a 51% response rate.

WSMOS found that 68% of the responding practices employed either nurse practitioners (NPs) or physician assistants (PAs) who perform all of the functions of physicians.

“We were somewhat surprised—and pleased—by the widespread use of midlevel providers in oncology practices,” says Jonathan C. Britell, MD, Past President of WSMOS. The second survey polled training programs about annual numbers of graduating students, clinical externships offered, and interest in devel-

oping an externship in oncology. The 17 responding programs reported that they graduate 10 NPs annually; PAs are not trained in these programs. The programs did not express interest in collaborating in oncology training.

“They are really focused on filling a primary care need,” comments WSMOS President Jeffery C. Ward, MD. He thinks additional flow of NPs into oncology will require either on-the-job training after graduation or significant oncology experience by an individual before beginning NP training.

WSMOS has published the survey results and profiles of both training programs and oncology practices, with contact information, in a brochure posted on the WSMOS website and mailed to all members.

“The WSMOS initiative to create a directory and profile the professional roles of NPs and PAs is our first effort to help alleviate the anticipated workforce shortage,” Dr. Britell comments.

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

The ASCO Post | DECEMBER 2010

PAGE 34

Direct from ASCO

Coding Questions? You Ask . . . ASCO Answers Free Service Solves Coding Conundrums

C

an I bill for a port flush if I am also billing for drug administration?”

That’s a typical question received

by ASCO’s Coding & Reimbursement Service, the online assistance service offered free to members and their staff.

It’s User-Friendly Unlike those unhappy online experiences you may have had using the website of your phone company, bank, or Internet provider, the Coding & Reimbursement Service does not send you to a series of new Web pages so that you can answer your own question. Nor does it present a menu of questions and ask you to choose the one closest to your own.

And it definitely does not surprise you with a service fee after you click on “submit.”

Au contraire! On the Coding & Reimbursement site, you can ask your entire question in a free-text box. Within 3 to 5 days, the answer—supplied by a real person, not a computer database—will arrive in your e-mail inbox.

“We want to ease the burden for our members,” says Julia E. Tomkins, Program Manager in the Cancer Policy and Clinical Affairs Department at ASCO. “It’s so difficult for physicians to keep abreast of all the clinical, business, and Medicare changes—we are trying to be the shortcut for them,” Tomkins says. Now there’s a customer-service attitude.

Knowledgeable Answers The ASCO staff continually monitor Medicare changes. In addition to reading Medicare rules and published updates, Tomkins attends the annual meeting of the AMA’s CPT Editorial Panel. She is the designated staff for oncology for the AMA’s CPT Advisory Committee, a group of physicians appointed by major specialty societies to serve as a resource to the CPT Editorial Panel, which is responsible for any revisions, deletions, and additions to the CPT code set.

“I learn a lot about

More Reimbursement Help from ASCO ■■ Practical Tips for the Oncology Practice: Over 500 pages covering Medicare, Medicaid, coding, insurance coverage for clinical trials, Medicare audits, billing for nonphysician services, and more.

Available at www.store.asco.org

■■ Adapting to Changes in Medicare—annual audio conference:

Presents what’s new for the coming year with Medicare, physician fee schedules, coding, and the Physician Quality Reporting Initiative. ASCO will offer the Adapting to Changes in Medicare for 2011 audio conference in January. Register at www.asco.org/ janaudiocall.

■■ Practical Tips Online: Three interactive modules available through ASCO University at www.university.asco.org/PracticalTips:

Billing and Coding Primer: Basics of billing for oncology services, with an overview of Medicare coverage and reimbursement policies.

Medicare Cases: Case scenarios with commentary and selfassessment questions to facilitate understanding of situations that commonly cause confusion.

Billing and Coding Cases: Case scenarios with self-assessment questions to test the user’s knowledge of certain billing and coding concepts for oncology-related services.

Medicare coverage rules, guidelines, and initiatives,” she says. “In addition, the CPT meetings give me insight into answering questions people have.”

People using the Coding & Reimbursement Service receive more than just the answer to their coding or coverage question. Typically ASCO also provides the Medicare documentation that explains and supports it.

Once in a while the staff can’t answer a question, Tomkins says. “In those cases, we try to give people everything we can to help. Usually we

will provide a resource or refer them to their local Medicare contractor to find the answer.”

Still wondering if you can bill for a port flush if you are also billing for drug administration? The answer is no, Tomkins says. Naturally, she refers to language from the CPT manual and explains: “Flush at the conclusion of an infusion is considered part of the infusion or injection service and therefore is not reported as an individual service itself.”

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

Clinical Cancer Advances 2010: ASCO’s Annual Report on Progress against Cancer

E

very year significant progress is made in the fight against cancer.

Although hundreds of cancer clinical trials are completed each year, identifying the most notable advances in cancer research in any given year can be challenging. Six years ago, ASCO stepped in to fill this information gap and undertook the compilation and publishing of Clinical Cancer Advances (CCA).

About the CCA Report In keeping with ASCO’s mission to improve the treatment and care of people living with cancer, the advances featured in the annual Clinical Cancer Advances report document the most significant progress being made on the front lines of clinical cancer research and highlight emerging trends in the field. The report is intended for anyone with an interest in cancer care,

including oncologists, the oncology care team, people living with cancer, caregivers, policymakers, and patient advocates, among others.

The information in the report is categorized by cancer type, which in 2010 includes blood and lymphatic, breast, gastrointestinal, genitourinary, gynecologic, lung, and pediatric cancers, and melanoma. Research considered for the CCA also covers

a wide range of clinical cancer issues, including epidemiology, prevention, screening, early detection, traditional treatment (surgery, chemotherapy, radiation), targeted therapies, immunotherapy, genetic research, personalized medicine, access to care, quality of life, and end-of-life care.

Developed under the direction of an editorial board comprising prominent oncologists, only stud-

ASCOPost.com | DECEMBER 2010

PAGE 35

Direct from ASCO

ies that significantly altered the way a cancer is understood or had an immediate impact on patient care were included. The editors, who included a specialty editor for each of the disease- and issue-specific sections and two co-executive editors, reviewed research presented at major scientific meetings and studies published in peer-reviewed scientific journals from October 2009 to September 2010, for this year’s report.

Major Advances in Care The 2010 CCA features a total of 53 advances in clinical oncology over the past year. Of the 53 studies, 12 are noted as “major” advances, meaning they are likely to have a significant impact on survival and care for people with cancer. The major advances include: ■■ NCI released initial results from the National Lung Screening Trial, which found 20% fewer lung cancer deaths among trial participants screened with low-dose chest CT than those screened with chest x-ray.

■■ New options for hard-to-treat cancers, such as the use of a pair of drugs for elderly patients with advanced lung cancer, a combination of drugs for metastatic pancreatic cancer, and the addition of the drug bevacizumab (Avastin) to standard chemotherapy for advanced ovarian cancer ■■ A new strategy of using a shorter 3-week course of higher-dose radiation in breast cancer patients that was shown to prevent recurrence in early-stage disease ■■ Progress in personalized medicine and targeted therapies, such as an antibody, ipilimumab, which produces a survival benefit in advanced melanoma, and a novel ALK gene inhibitor, crizotinib, which causes tumor shrinkage in patients with advanced lung cancer ■■ A study showing that the addition of palliative care to chemotherapy improves survival in patients with lung cancer ■■ Research that found that insomnia and other sleep disorders are common among patients receiving

chemotherapy ■■ Two new treatments approved this year for hormone-refractory prostate cancer—sipuleucel-T (Provenge), a therapeutic vaccine, and cabazitaxel ( Jevtana), a chemotherapy agent

Cancer Policy Priorities Another highlight of the Clinical Cancer Advances report is ASCO’s annual policy recommendations for accelerating progress against cancer and improving cancer care overall. This year, ASCO puts forth two major recommendations related to the Institute of Medicine report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the National Cancer Institute Cooperative Group Program.” The report itself focuses on improving the speed, efficiency, and flexibility of cooperative group clinical trials, while maximizing the involvement of patients and physicians.

ASCO specifically recommends the following: ■■ The NCI should double funding for cooperative group trials in the

academic and community settings from the current level of $250 million to $500 million by 2015.

Funding for cooperative group research has been virtually flat since 2002, forcing the NCI cooperative groups to limit patient enrollment in clinical trials.

■■ Stakeholders affected by the Institute of Medicine report should work together to implement the outlined recommendations.

ASCO is working with the Institute of Medicine to convene a meeting of stakeholders to discuss implementing the IOM recommendations in early 2011.

■■ Clinical Cancer Advances 2010: ASCO’s Annual Report on Progress Against Cancer was published online in the Journal of Clinical Oncology (www.jco.org).

The full-color report and additional resources are available at www.cancer.net/clinicalcancer advances.

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

What’s Hot in JCO

Top 10 most-accessed articles recently published in Journal of Clinical Oncology 1. EGFR Antibodies in Colorectal Cancer: Where Do They Belong?

Axel Grothey 28(31):4668 Vol 28, No 20

July 10, 2010

J OURNAL OF C LINICAL O NCOLOGY Comments and Controversies: Research on Early-Stage Carcinogenesis: Are We Approaching Paradigm Instability? S.G. Baker et al Editorial: Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: A Mismatch? K. Ng et al Editorial: Defective Mismatch Repair in Colon Cancer: A Prognostic or Predictive Biomarker? D.J. Kerr et al Editorial: Wrestling With the High Price of Cancer Care: Should We Control Costs by Individuals’ Ability to Pay or Society’s Willingness to Pay? J.L. Malin Confirmation of Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of FU-Based Adjuvant Therapy in Colon Cancer. D.J. Sargent et al Comparison of Anticancer Drug Coverage Decisions in the United States and United Kingdom. A. Mason et al Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane. J.A. Sparano et al EGFR Inhibitor Gefitinib Added to Chemoradiotherapy in Locally Advanced Head and Neck Cancer. E.E.W. Cohen et al Review Article: Emerging Targeted Therapies for Breast Cancer R.H. Alvarez et al Biology Of Neoplasia: Clinical Relevance of Microsatellite Instability in Colorectal Cancer. A. de la Chapelle et al ASCO Special Article: American Society of Clinical Oncology 2009 Clinical Practice Guideline on Uses of Serum Tumor Markers in Adults With Germ Cell Tumors. T. Gilligan et al Official Journal of the American Society of Clinical Oncology

www.jco.org

2. New Pharmacogenomic Paradigm in Breast Cancer Treatment Kenneth Offit, et al 28(31):4665 3. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study Jean-Yves Douillard, et al 28(31):4697 4. Personalized Medicine in Non–Small-Cell Lung Cancer: Is KRAS a Useful Marker in Selecting Patients for Epidermal Growth Factor Receptor–Targeted Therapy?

Patrick J. Roberts, et al 28(31):4769 5. Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors James N. Ingle, et al 28(31):4674

6. Living in the Moment David N. Korones 28(31):4778 7. Urinary Obstructive Problems Exposed But Hormonal Health-Related Quality-of-Life Concerns Eschewed in Prostate Cancer Quality-of-Life Study Martin G. Sanda 28(31):4667 8. Randomized Phase III Study of Panitumumab With Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal Cancer Marc Peeters, et al 28(31):4706 9. Randomized Phase II Trials: Misleading and Unreliable David J. Stewart 28(31):e649 10. Cancer Vaccines in Glioma: How to Balance the Challenges of Small Trials, Efficiency, and Potential Adverse Events Pedro R. Lowenstein 28(31):4670

The ASCO Post | DECEMBER 2010

PAGE 36

Direct from ASCO

2010 ASCO Cancer Foundation® Merit Awards

A

t the opening session of ASCO’s 46th Annual Meeting, held in Chicago this past June, The ASCO Cancer Foundation® announced the recipients of the 2010 Brigid Leventhal Merit Award and the 2010 Bradley Stu-

art Beller Merit Award. These ASCO Cancer Foundation Merit Awards are designed to promote clinical research performed by young scientists and to provide fellows with an opportunity to present their research and interact

with other clinical cancer investigators at ASCO scientific meetings.

Brigid Leventhal Merit Award The Brigid Leventhal Merit Award, which is granted to the author of the

(Stimulating Targeted Antigenic Responses To NSCLC)

highest-ranked abstract submitted in the field of pediatric cancer research, is named in honor of Brigid Leventhal, MD, a pioneer in children’s oncology at Johns Hopkins University who dedicated her career to helping young patients with cancer.

The 2010 Brigid Leventhal Merit Award was presented to Laura E. Hogan, MD, a fellow in pediatric hematology/oncology at the New York University Medical School, for research focused on creating an integrated genomic profile by using highthroughput RNA sequencing to detect mutations, insertions, deletions, and fusion transcripts in relapsed acute lymphoblastic leukemia (ALL).

Dr. Hogan displayed the findings of her research during the Annual Meeting’s Pediatric Cancer Poster Discussion Session.1 As of the Annual Meeting, Dr. Hogan and her team had performed RNA sequencing on matched-diagnosis/relapse bone marrow samples from pediatric patients with relapsed ALL by looking for novel mutations that might explain the chemoresistance found at recurrence. Dr. Hogan has worked to sequence four pediatric matched-diagnosis/relapse pairs (ie, eight marrow samples) from patients with B-precursor ALL. The team found 232 variants that were relapsespecific and that were shared among all four patients. They identified 2,454 variants that were relapse-specific and shared among three of the four patients and 16,100 relapse-specific variants shared by two of the four patients.

These findings are significant because RNA sequencing in relapsed pediatric ALL reveals many novel relapse-specific variants shared among patients. Although further analysis of these variants will be necessary to determine their functional significance and therapeutic relevance, Dr. Hogan believes they hold the potential to identify new pathways to target with therapy. She added that validation of a subset of these variants in a larger group of patients is underway.

Bradley Stuart Beller Merit Award EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

Whereas the Brigid Leventhal Merit Award was granted Dr. Hogan as the author of the highest-ranked

ASCOPost.com | DECEMBER 2010

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Direct from ASCO

abstract submitted to the ASCO Annual Meeting in the field of pediatric cancer research, the Bradley Stuart Beller Merit Award is awarded to the fellow with the overall highestranked abstract, as determined by the Scientific Program Committee.

The award—created by Ronald E. Beller, PhD, former ASCO Vice President and CEO, and his wife, Judith Beller (along with The ASCO Cancer Foundation Board of Directors), in honor of their son, Bradley Stuart Beller—was presented to Kristin A. Higgins, MD, of Duke University Medical Center, for her research, “Characterizing the clinical relevance of epithelial-mesenchymal transition (EMT) in human tumors.”2 Dr. Higgins explains EMT as a biologic process with a substantial role in normal embryologic development. Later in life, EMT can also lead to adverse cellular events, including the ability of a tumor cell to transform into a motile, mesenchymal cell that can then invade and metastasize.

In this particular study, Dr. Higgins and her colleagues studied EMT in breast, lung, and prostate cancer. “We basically created an in vitro model of EMT in cancer cells, analyzed genomic changes occurring in these cells, and developed a genomic signature predictive of EMT,” she explained.

“This signature predicts for clinical outcomes including metastasis-free

and disease-free survival in [patients with] breast cancer, prostate cancer, and lung cancer.”

Dr. Higgins plans to use an EMT genomic signature in hopes of identifying patients at high-risk for development of metastatic disease, and in turn, developing a treatment aimed at preventing this process. “This award validates our hard work thus far and speaks to the importance of translational research,” said Dr. Higgins. “I feel honored to have been selected amongst a group of such outstanding people.”

What’s Hot in

JOP Online Top 5 most-accessed articles recently published in Journal of Oncology Practice Journal of Oncology Practice

American Society of Clinical Oncology

■

THE AUTHORITATIVE RESOURCE

References 1. Hogan LE, Mason C, Meyer J, et al: High throughput transcriptome sequencing of pediatric relapsed acute lymphoblastic leukemia (ALL). Abstract 9521. J Clin Oncol 28(15 suppl):683s, 2010.

2. Higgins KA, Walters KS, Potti A, et al: Characterizing the clinical relevance of epithelial-mesenchymal transition (EMT) in human tumors. Abstract 10507. J Clin Oncol 28(15 suppl):724s, 2010.

Selected portions reprinted from ASCO Daily News. © American Society of Clinical Oncology. (From “Pediatric Oncology Fellow Receives Top Merit Award for Genomic Research on Relapsed ALL.” ASCO Daily News Vol. 13, No. 2, 2010:10C; and from “Dr. Kristin Higgins Receives 2010 Bradley Stuart Beller Merit Award.” ASCO Daily News Vol. 13, No. 1, 2010:28C.) All rights reserved.

Save the Date January 20-22, 2011 San Francisco Gastrointestinal Cancers Symposium www.gicasymposium.org

VOLUME 6

ISSUE 1

FOR

ONCOLOGY PRACTICES

JANUARY 2010

Filling the Gap: Development of the Oncology Nurse Practitioner Workforce “Developing new strategies for oncology care delivery by increasing the numbers and expanding the roles of nonphysician practitioners, such as nurse practitioners (NPs) and physician assistants (PAs), is critically important to meet the current and potential cancer care needs of the US population.”

By Brenda Nevidjon, MSN, RN, FAAN, et al

Ensuring Quality Cancer Care Through the Oncology Workforce

“There is a crisis in the oncology workforce. Health professionals . . . are experiencing significant workforce shortages . . . because of the rapidly growing population of Americans requiring cancer care, an aging oncology workforce, and inadequate numbers of newly trained workers. This mismatch between supply and demand for cancer care could threaten patient care, safety, and quality.”

Role of Advanced Nurse Practitioners and Physician Assistants in Washington State

By Jonathan C. Britell, MD

Practical Model for Psychosocial Care

By Susan S. Hendrick, PhD, et al

Physician Assistant Perspective on the ASCO Workforce Study Regarding the Use of Physician Assistants and Nurse Practitioners

By Maura Polansky, MS, PA-C, et al

Georgia Society of Clinical Oncology Forms a Patient Navigator Affiliate Basic Steps to Building a Research Program

By Allison Baer, RN, BSN, et al

By Laura Levit, JD, et al

http://jop.ascopubs.org

jop.ascopubs.org 1. National Practice Benchmark: 2010 Report on 2009 Data Elaine L. Towle, et al 6(5):228 2. Commentary: When It Comes to Chemotherapy, Location Matters Michael N. Neuss, et al 6(5):235 3. American Society of Clinical Oncology Clinical Practice Guideline Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer Harold J. Burstein, et al 6(5):243 4. Impact of Shifting From Office- to Hospital-Based Treatment Facilities on the Administration of Intraperitoneal Chemotherapy for Ovarian Cancer William R. Robinson, et al 6(5):232 5. Coverage Policy Development for Personalized Medicine: Private Payer Perspectives on Developing Policy for the 21-Gene Assay Julia R. Trosman, et al 6(5):238

Provide Your Patients with Advice for Navigating the Holiday and Flu Seasons

T

he holidays can be a busy time with unique challenges for people and families coping with cancer.

Direct your patients to Cancer.Net (www.cancer.net), ASCO’s patient information website, where they will find an article (“Cancer and the

Holidays”) that provides tips for managing responsibilities and relationships during this season. Meanwhile, another article outlines what cancer patients need to know about the flu (“Flu Facts for People with Cancer”).

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

With the first and only IV mTOR inhibitor indicated for advanced renal cell carcinoma (RCC)1...

Change

expectations

for overall survival

Important portant Safety Information • TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN. • Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. • Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.

• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.

• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. • Due to abnormal wound healing, use TORISEL with caution in the perioperative period.

• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

TORISEL—Significant overall survival benefit as first-line therapy1 Kaplan-Meier curves for overall survival (OS)*—TORISEL vs IFN 1

Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

• Studied first-line in patients with ≥3 of 6 preselected prognostic risk factors1

The advanced RCC pivotal study included patients with2 • Clear-cell or non–clear-cell tumor histologyII • Any nephrectomy status

mTOR=mammalian target of rapamycin.

IFN =interferon alpha.

CI=confidence interval. * Time from randomization to death.1 † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1 ‡ Based on log-rank test stratified by prior nephrectomy and region.1 § Based on Cox proportional hazard model stratified by prior nephrectomy and region.1 II 82% and 82.5% of patients had known clear-cell histology for TORISEL and IFN , respectively.2 ¶ NCCN Category 1 recommendations are based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.3 # TORISEL was approved by the FDA in 2007.1

• Category 1 NCCN recommendation— first-line for poor-prognosis patients3¶ • >3 years experience since FDA approval#

Median duration of treatment was 17 weeks (range 1-126 weeks) for the TORISEL arm and 8 weeks (range 1-124 weeks) for the IFN arm.1

• Live vaccinations and close contact with those who received live vaccines should be avoided.

• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.

• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).

• In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks.

Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion.

• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).

• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.

• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the brief summary of the full Prescribing Information on the next page.

References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. Data on file, Pfizer Inc. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

Change expectations

The ASCO Post | DECEMBER 2010

PAGE 42

Expert’s Corner Hematology

A Conversation with Jasmine Zain, MD The Evolving Role of Stem Cell Transplantation in the Treatment of Blood Cancers

By Jo Cavallo

S

tem cell transplantation has long played a key role in the management—and cure—of various forms of leukemia, lymphoma, and multiple myeloma. With the advent of novel agents, including rituximab (Rituxan) in the treatment of some types of nonHodgkin lymphoma and bortezomib (Velcade) and lenalidomide (Revlimid) in the treatment of multiple myeloma, that role may be increasing as less toxic agents enable more patients to have successful transplant outcomes. The availability of better therapies to control nausea and infections are making transplants safer. For patients with multiple myeloma, growing evidence suggests that the use of ongoing maintenance therapy following transplantation can help patients stay in remission longer.

Jasmine Zain, MD

The ASCO Post talked with Jasmine Zain, MD, Director of the Bone Marrow Transplant Program and Assistant Professor, Division of Hematologic Malignancies and Medical Oncology at NYU Cancer Institute and NYU Langone Medical Center in New York, about how stem cell transplantation is being used both as a front-line treatment in these cancers and as a treatment for relapsed disease.

Novel Agents and Transplants How has the use of novel agents in the treatment of some types of leukemia, lymphoma, and multiple myeloma changed the role of stem cell transplantation as a therapy for these diseases?

Dr. Zain: You can’t approach all these diseases with the same paradigm. When you talk about stem cell transplantation (SCT) for lymphoma, you’re usually considering an autologous stem cell transplant as a curative option for certain types of relapsed lymphoma. Allogeneic stem cell transplantation for lymphoma is reserved for cases of patients who fail

an autologous stem cell transplant or where a graft-vs-lymphoma effect has been shown to be an effective therapeutic option—for example, in some indolent lymphomas. The use of reduced-intensity stem cell transplants is increasingly being explored in the treatment of certain types of lymphomas such as T-cell lymphomas, follicular lymphomas, and other indolent lymphomas to minimize toxicity while preserving the graft-vs-lymphoma effect. In the treatment of lymphomas, front-line stem cell therapy is being offered in the treatment of mantle cell lymphomas, T-cell lymphomas, and very rare aggressive lymphomas where an allogeneic stem cell transplant is offered for long-term disease control.

The use of SCT for multiple myeloma is not curative, but nonetheless remains important in the management of these patients. It is considered to be a therapeutic tool that can provide good disease control for a period of time, freeing the patient from ongoing therapy and its associated side effects. The use of post-transplant maintenance therapy and multiple transplants are among the approaches employed to provide longterm disease control in these patients.

Advantages of Targeted Therapy An abundance of novel targeted therapies are being evaluated for the treatment of various hematologic malignancies. For physicians, this is exciting news because it allows patients with chemoresistant disease (or those in whom standard therapy has failed) to achieve a good enough remission to allow them to undergo stem cell transplantation. In almost all scenarios, the outcome of any kind of transplant correlates with the state of remission of the disease. In other words, if a patient has active disease, the likelihood of a transplant working is less than if the transplant is done when the patient is in remission. Hence, the use of novel targeted agents even on a clinical trial can make more patients eligible to undergo the curative therapy of SCT if they can achieve adequate disease control.

Another advantage of using targeted agents is that they are generally associated with fewer side effects and are better tolerated by patients with recurrent or refractory diseases. From a biologic per-

spective, the novel targeted agents attack and kill cancer cells using pathways that are different than the cell-kill associated with conventional chemotherapy. In cells that have developed chemoresistance, this provides a “breather” during which some of the pathways of cell death can recover so that these cells can regain their sensitivity to conventional

chemotherapy and stem cell rescue performed as an autologous stem cell transplant is a very important treatment option for these patients because it provides a means of delivering fairly intensive chemotherapy for its antimyeloma effect, allowing freedom from disease and the ability to undergo ongoing treatment for some period of time. Although

Novel therapies allow patients to recover from the effects of their therapy before they get to transplant. chemotherapy. Although it has not been proven, giving a chemotherapy break before transplant may allow high-dose chemotherapy, radiation, and stem cell rescue to be more effective.

Another way to look at novel therapies is to consider them to be chemotherapy-sparing agents that allow patients to recover from the effects of their therapy before they get to transplant. For example, a patient with relapsed lymphoma may be offered several rounds of combination chemotherapy with associated side effects, particularly those on bone marrow function and immune status. If the patient has developed chemoresistant refractory disease, he is likely to experience all the toxic side effects with no real antitumor effect. However, if you administer a novel agent like an oral histone deacetylase (HDAC) inhibitor or some other targeted agent that is nontoxic to the marrow and doesn’t affect blood counts but provides adequate disease control, the patient will be in a better position to undergo a transplant and recover from it successfully.

The same is true in the management of acute leukemias. Allogeneic transplants for acute (high-risk) leukemia are considered curative in the upfront setting and in cases of relapsed disease.

Once chemotherapy has failed, the therapeutic choices are limited. Administering salvage therapy with a novel agent either on a clinical trial or otherwise can make the patient eligible for transplant with the real possibility of a cure.

Multiple myeloma is a slightly different model because it is not considered a curable disease, but rather, a chronic disease that needs to be managed throughout the lifetime of the patient. High-dose

a transplant is not curative, it is an important tool in the management of multiple myeloma along with other agents.

The use of novel agents, including bortezomib and lenalidomide, in the treatment of multiple myeloma has increased the percentage of patients who can attain clinical remission upfront and has allowed the possibility of overcoming some of the molecular and genetic adverse factors associated with a poor outcome in multiple myeloma.

These drugs have also extended therapeutic options so that many patients can be treated without conventional chemotherapy for a long time. This spares the bone marrow from the toxic effects of cytotoxic agents, allowing a more robust collection of stem cells at the time of harvesting. The stem cells can then be cryopreserved and used when and if there is a need to treat the patient with high-dose chemotherapy, usually to complete or consolidate a very good partial remission.

Patient Age Considerations How has the use of novel agents improved age limitations for transplants?

Dr. Zain: The age range for transplants has definitely increased. Autologous transplants are being performed in patients well over age 70 in cases of lymphoma and multiple myeloma.

Again, patients who are spared aggressive chemotherapy in the pretransplant period are better able to tolerate the toxicity of SCT, and this allows older, frail patients to undergo such treatment. The use of less toxic reducedintensity conditioning regimens with better supportive care has increased the age of patients receiving allogeneic

ASCOPost.com | DECEMBER 2010

PAGE 43

Expert’s Corner

transplants from 45 to 50 to over 70 years of age, with excellent outcomes.

Safety and Remission Rates Overall, the safety rates in both types of transplants have increased?

Dr. Zain: Yes, we now have better supportive care, better antiemetics to control nausea, and better drugs for fighting infections, particularly fungal and other opportunistic infections.

The concept of reduced-intensity conditioning has definitely made a difference in terms of reducing the upfront mortality from the transplant, although graft-vs-host disease continues to be a problem and remains a major cause of mortality and morbidity associated with an allogeneic stem cell transplant. In terms of the autologous transplant, the mortality rate is now less than 1% in experienced centers.

How has the continued use of maintenance therapy after transplantation in myeloma patients improved remission rates?

Dr. Zain: A good deal of data support the use of maintenance therapy after transplantation, particularly for myeloma patients. Studies have shown that remission can be prolonged if agents such as thalidomide (Thalomid), lenalidomide, bortezomib, and even dexamethasone are used for maintenance after SCT. The benefits of using maintenance therapy in other diseases like leukemia and lymphoma after transplant are unclear, but the question is being addressed in clinical trials.

Patient Selection and Potential for Cure When is a stem cell transplant not appropriate for a blood cancer patient?

Dr. Zain: A transplant is not appropriate for patients with severe underlying medical problems like uncontrolled infections, severe heart or lung

disease, and liver or kidney impairment, or for patients with progressive and refractory disease.

When is a stem cell transplant curative?

Dr. Zain: SCT is considered curative for most cases of Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia but not for multiple myeloma. It also

depends on the type of transplant— autologous vs allogeneic. For relapsed Hodgkin disease and certain types of aggressive lymphomas such as diffuse large B-cell lymphoma, the curative therapy is autologous SCT. Allogeneic transplants are considered curative for acute and chronic leukemias, follicular lymphoma, mantle cell lymphoma, and T-cell lym-

phoma. But the type of transplant needs to be individualized for each patient.

The last thing I would say is that SCT outcomes are getting better, and supportive care is better. If a transplant needs to be considered, patients should be encouraged to discuss the issues involved with their health-care team, and then go to a good transplant center.

■

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY INCLUSION CRITERIA* PRIMARY ENDPOINT • Advanced NSCLC

• Overall survival

• Receiving 1st-line chemotherapy

SECONDARY ENDPOINTS

• Hemoglobin (Hb) ≤ 11 g/dL

• Progression-free survival • Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

2:1 Randomization

Darbepoetin alfa 500 mcg Q3W

(darbepoetin alfa: placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Call for Papers The ASCO Post invites readers to share their thoughts and opinions on matters of interest to the oncology community (500 words recommended). All submissions will be acknowledged and considered for publication.

Write to: Editor@ASCOPost.com for more information or to submit your commentary.

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria can be found in the protocol.

For more information, please visit www.782study.com or call 1-866-965-0782 (US and Canada only).

© 2010 Amgen. All rights reserved.

MC45038-D-6

04-10

The ASCO Post | DECEMBER 2010

PAGE 44

News Supportive Care

Updated ESA Guideline from ASCO/ASH Provides Stronger Basis for Patient Discussions on Risk vs Benefit

By Alice Goodman

U

pdated guideline recommendations for use of the erythropoiesis-stimulating agents (ESAs) epoetin (Epogen, Procrit) and darbepoetin (Aranesp) will help clinicians sharpen their decision-making regarding use of these agents and give them a springboard for discussing risks and benefits with patients. The updated guideline, published jointly by ASCO and ASH online,1 incorporates the most recent evidence since the 2007 guideline was issued.2

J. Douglas Rizzo, MD

“The difference between these new guideline recommendations and the 2007 guideline recommendations is that now we have better evidence about the risks and benefits posed by ESAs. It is important to frame the usefulness of these drugs in the context of randomized controlled trials that are up to date in 2010,” said lead author J. Douglas Rizzo, MD, Professor of Medicine at the Medical College of Wisconsin in Milwaukee.

New Data Considered The updated guideline incorporates new individual patient data metaanalysis, four literature-based metaanalyses, two other systematic reviews (without pooled data analysis), and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.

These data show that ESAs increase the risk of venous thromboembolism and/or survival in patients with cancer. Recent trials focused on patients with certain malignancies also showed increased risks of tumor progression.

“The key [in undertaking this revision] is to understand the risks and benefits of ESAs. The data show that they work well to avoid transfusion and that should be their principal use.

We have better data on associated mortality, although we don’t understand

the mechanism for increased mortality so we can’t refine which patients are most likely to be at risk,” Dr. Rizzo told The ASCO Post.

Very Specific Indications According to the updated guideline, ESAs should only be initiated to avoid transfusion, not for other purposes such as improving fatigue or quality of life. Also, the starting hemoglobin level is different from the 2007 guideline; the updated guideline recommends that ESAs only be initiated when the hemoglobin level is below 10 g/dL. “Use of ESAs for hemoglobin [levels] between 10 and 12 g/dL is open to clinical judgment. The optimal level at which to initiate ESA therapy in patients with anemia and hemoglobin between 10 and 12 g/dL cannot be definitively determined from the available evidence, and the decision should be informed by avoiding known risks,” Dr. Rizzo commented.

“Patients with cancer who are not on chemotherapy appear to be the ones at greatest risk,” he stated. According to the recommendations, ESAs should not be used to treat anemia associated with malignancy in patients with cancer who are not receiving concurrent myelosuppressive chemotherapy. Use of ESAs in lower-risk myelodysplastic syndrome to avoid transfusion is an exception.

The first rule of thumb when treating anemic patients with nonmyeloid hematologic malignancies is to treat the underlying condition first, not the anemia. Some cancers—for example, myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia— are associated with anemia. These (and other) malignancies should be

treated first with chemotherapy, and the anemia would generally be expected to improve, he continued. If an increase in hemoglobin is not observed after chemotherapy, that may signal chemotherapy-induced anemia, and treatment with an ESA should be considered according to the recommendations set forth in the recent publication.

Initial and modified doses of ESAs should be in strict accordance with FDA guidelines. ESAs should be discontinued when chemotherapy is finished. Hemoglobin can be increased to the lowest concentration needed to avoid transfusions, which varies according to individual patients and conditions. To avoid excessive ESA exposure, the dose of ESA should be modified when the hemoglobin reaches a level sufficient to avoid transfusion or the increase exceeds 1 g/dL in any 2-week period.

Perspective on the Updated Guideline The updated guideline recommendations are based on an excellent reevaluation of data, especially publications of meta-analyses since the 2007 version of the guideline was published, said Sam Silver, MD, Professor of Medicine at the University of Michigan Medical School.

“The updated version places a greater emphasis on risk of harm from ESAs in cancer patients, particularly thromboembolism and death,” Dr. Silver commented. “To me, the most important issue raised by the updated version is the need for discussion with patients who are undergoing chemotherapy and have anemia about the relative risks of the three available choices: transfusion, no transfusion, or

ASCO/ASH Guideline on ESA Use in Cancer Patients ■■ Updated guideline recommendations based on new evidence since 2007 provide a sharper picture of risks of ESA therapy.

■■ The guideline recommendations emphasize that the only indication

for ESA therapy is to avoid transfusion in patients with anemia who are undergoing chemotherapy.

■■ ESA therapy should be initiated only when the hemoglobin level is below 10 g/dL. Dosing should strictly follow FDA guidelines

■■ An abridged version of the guideline is published in JCO, while the full version, data supplements, and clinical tools are available online at www.asco.org/guidelines/esa.

ESAs,” he continued.

In his view, another key issue is related to FDA’s decision to limit the indication for ESA therapy to patients un-

Sam Silver, MD

dergoing chemotherapy with palliative intent. There is no published literature evaluating ESA therapy in subpopulations of patients treated with chemotherapy for palliative vs curative intent.

The definition of palliative is not codified by FDA. In fact, the distinction between palliative and curative intent can be “a slippery slope,” Dr. Silver said. For example, a patient with low-grade lymphoma treated with palliative intent can live for another 20 years.

“With better understanding of the potential risks of ESAs, FDA’s decision to limit ESA therapy for patients receiving chemotherapy with palliative intent is reasonSee page 51 able. But you can be faced in the clinic with a patient treated with curative intent who is anemic and has congestive heart failure. This patient may not be a candidate for transfusion due to risk of morbidity from fluid overload. In such cases, it may be reasonable to have a discussion with patients about the risks and benefits of ESA therapy,” he explained.

■

References 1. Rizzo JD, Brouwers M, Hurley P, et al: American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. October 25, 2010 (early release online).

2. Rizzo JD, Somerfield MR, Hagerty KL, et al: Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 26:132149, 2008.

ASCOPost.com | DECEMBER 2010

PAGE 45

News Lymphoma

Cancer Support Community Launches Patient Education Campaign

T

he Cancer Support Community (CSC), uniting The Wellness Community and Gilda’s Club Worldwide, announced the launch of Framing Life with Lymphoma, a new educational program designed to enhance lymphoma patient and physician communication.

This research-based program, led by the CSC with support from Cephalon, Inc, provides lymphoma patients with tip sheets outlining ways to approach each conversation with their health-care team across the course of their cancer, from diagnosis through treatment.

believe that receiving support from nonphysician health-care professionals such as a social worker or nurse or a caregiver such as a friend or family member could help them have more effective conversations with their physician.

“Non-Hodgkin lymphoma is the

seventh most common cancer in the United States. Yet the majority of people who are diagnosed have very little information on the disease and how it may impact their lives. This survey shows that it is critical that patients have resources to help them understand their

condition and treatment options so they can communicate more effectively with their physicians,” said David Henry, MD, Hematologist/Oncologist, Clinical Professor of Medicine, Pennsylvania Hospital, and the physician advisor for Framing Life With Lymphoma.

■

There are thousands of ways to show you care: working to improve health is one of them.

David Henry, MD

The patient tip sheets and other campaign information were created through input from an expert Steering Committee and a national survey fielded by Harris Interactive of 150 hematologists/ oncologists and 133 patients with indolent lymphoma, which found that almost all physicians (96%) and most patients (86%) felt their communication could be more efficient with some form of aid or assistance as a guide. The patient tip sheets, survey results, and other program information can be found at www.FramingLifeWithLymphoma.org.

Sanofi-aventis U.S. is the U.S. affiliate of sanofi-aventis, a leading global pharmaceutical company that discovers, develops and distributes therapeutic solutions to help improve the lives of patients and their families.

Effective Patient-Physician Communication The national survey showed that nearly all indolent non-Hodgkin lymphoma (NHL) patients (97%) and physicians who treat them (94%) agree that being an informed lymphoma patient is very important in ensuring effective patient-physician communication. Despite the value of this communication, indolent NHL patients and treating physicians overwhelmingly agree (79% and 90%, respectively) that patients need guidance in learning how to communicate with their health-care providers.

The survey also found that nearly four out of five physicians and patients believed physician support had a major impact on a positive indolent NHL treatment experience (patients: 79%; physicians: 78%). In addition, 23% of patients

To find out more about our research, please visit www.sanofi-aventisoncology.com

© sanofi-aventis 174, Avenue de France 75635 Paris, France sanofi-aventis U.S. www.sanofi-aventis.us US.XON.10.04.049

The ASCO Post | DECEMBER 2010

PAGE 46

News Myeloma

Lenalidomide-based Induction and Maintenance Therapies Prove Safe and Effective in Multiple Myeloma

By Larry Rosenberg, PhD

T

hree phase III trials addressing the use of lenalidomide (Revlimid) for either induction or maintenance therapy in multiple myeloma suggest that the drug is safe and effective in both settings.

These findings were Paul G. Richardson, MD presented at the Best of ASCO Meeting in Boston by Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Center for Multiple Myeloma at Dana-Farber Cancer Institute (DFCI) and Associate Professor of Medicine at Harvard Medical School.1-3

CALGB 10014 Results of the intergroup trial ­ ALGB 100104 showed that mainteC nance therapy with lenalidomide following induction therapy and autologous stem cell transplantation (ASCT) in pa-

tients with multiple myeloma can significantly delay disease progression compared to placebo. This benefit appears to be independent of β2-microglobulin level or prior thalidomide (Thalomid) or lenalidomide therapy.1 These data were first presented at the 2010 ASCO Annual Meeting by Philip L. McCarthy, Jr, MD, of the Roswell Park Cancer Institute, on behalf of the Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group (ECOG), and Blood and Marrow Transplant Clinical Trials Network (BMTCTN). The prospective randomized trial compared a continuous dosing schedule of lenalidomide with placebo in patients with multiple myeloma following ASCT. The ASCT regimen consisted of melphalan, 200 mg/m2. At days 100 through 110 post-transplant, patients were randomly assigned to placebo or lenalidomide, 10 mg/d, which could be escalated to 15 mg/d or decreased to 5 mg/d after 3 months, depending on tolerance. The study enrolled 568 patients. An interim analysis involving 418 randomly assigned patients was

Expert Point of View

A

ccording to S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota, “One of the most important questions patients have right now is, in the era of novel drugs, do we still need to do transplants?” The Italian/Israeli study by Palumbo et al addresses this question in some regard and shows that such approaches are feasible, but the follow-up of 12 months is much too short to determine if either approach is superior. “This is a S. Vincent Rajkumar, MD good trial but is best viewed as a feasibility study; long-term follow-up may answer this question,” emphasized Dr. Rajkumar.

Median time to progression with such regimens ranges from 30 to 35 months in this population, so another 2 to 3 years of follow-up are required to detect significant differences in progression-free survival, Dr. Rajkumar explained. And since median overall survival can be as long as 7 years, survival differences, if present, will take much longer before they can be detected.

Studies like the present phase III trial of MPR vs MEL 200 would have been very difficult to perform in the United States, where patients often have more autonomy in selecting their own therapy rather than choosing to be randomly assigned to transplantation or not, Dr. Rajkumar said. However, other similar studies are ongoing to determine the role of transplantation given the availability of modern agents. For example, the trial conducted by the French group and the Dana-Farber Cancer Institute team is comparing the combination of lenalidomide/bortezomib/dexamethasone vs transplantation, and this key U.S./European study will hopefully provide important information on this agent in the future.

■

Induction and Maintenance Approaches to Multiple Myeloma ■■ Following autologous stem cell transplantation (ASCT), lenalidomide

maintenance therapy significantly prolonged progression-free survival compared to placebo, with higher response rates.

■■ Melphalan/prednisone/lenalidomide (MPR) and ASCT (MEL200) appear

to be equally effective as consolidation therapy, producing identical progression-free and overall survival. However, MPR was associated with less toxicity.

■■ Lenalidomide/dexamethasone as an induction regimen appears to be safe and effective. Recent trials have demonstrated that this regimen, in combination with bortezomib, is highly effective with overall response rates of 100%.

conducted after 28% of events (disease progression or death) had occurred.

Results demonstrated that 29 events occurred among 210 lenalidomidetreated patients compared with 58 of 208 patients on placebo (P < .0001).

The estimated hazard ratio was 0.42, translating into a 58% reduction in risk of disease progression for patients on lenalidomide maintenance therapy.

Median time to progression was 25.5 months in the placebo arm and had not been reached in the lenalidomide arm at the time of this analysis. Lenalidomide maintenance therapy was well tolerated.

According to Dr. Richardson, “This study conveyed strikingly the importance of maintenance therapy posttransplant as a strategy to significantly reduce the risk of early progression, with a trend suggesting survival benefit.”

With 1 year of follow-up, no significant difference in overall survival could be detected as yet (11 deaths with lenalidomide vs 17 with placebo; P < .2).

The study was unblinded in December 2009 to allow for crossover of eligible placebo patients from placebo to lenalidomide, which occurred in 77 of 89 patients.

“Because progression-free survival has always been a consistent surrogate for overall survival in multiple myeloma,” said Dr. Richardson, “I would expect that within the next 1 to 2 years, a survival difference will become apparent.”

IFM 2005-02 A similar randomized, placebo-controlled French study, IFM 2005-02, also found that lenalidomide maintenance therapy is effective in patients with multiple myeloma following ASCT, significantly increasing both the response rate and progression-free survival compared to placebo. The drug was found to be ef-

fective in all stratified subgroups examined and was generally well tolerated, Dr. Richardson reported.2 Data from the first interim analysis of this trial were previously presented at the Annual Meeting

by Michel Attal, MD, of the Centre Hospitalier de Purpan in Toulouse, France, on behalf of the Intergroupe Francophone du Myelome (IFM).

Patients with nonprogressive disease ≤ 6 months following initial ASCT were randomly assigned to consolidation therapy with lenalidomide (25 mg/d, 21 days per month, over a 2-month period), which was followed by either maintenance lenalidomide at 10 to 15 mg/d until relapse (arm B) or placebo (arm A). Randomly assigned patients were stratified according to β2-microglobulin level, deletion of the long arm of chromosome 13 (associated with poor response to chemotherapy in multiple myeloma), and very good partial response status.

A total of 614 patients were enrolled at 78 centers between July 2006 and August 2008, with 307 patients randomly assigned to each arm. A preplanned interim analysis was conducted, with a median follow-up of 24 months. The proportion of patients achieving at least a very good partial response following maintenance therapy was greater with lenalidomide compared to placebo (77% vs 70%; P = .08). Death or progression occurred in 77 patients (25%) in arm B vs 143 (47%) in arm A. Median progression-free survival (the primary endpoint) was 24 months in arm A and has not yet been reached in arm B. At 3 years post-randomization, the progressionfree survival rate was significantly superior with lenalidomide (68% vs 34%, Fig. 1), with a hazard ratio of 0.46 (P < 10‑7); however, overall survival was no

ASCOPost.com | DECEMBER 2010

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News

different (88% vs 80%; HR = 1; P = .88).

Lenalidomide was generally well tolerated in both this study and the CALGB trial; toxicities included myelosuppression, rare thrombosis, and occasional rash.

In Dr. Richardson’s opinion, “Maintenance lenalidomide, by virtue of these two large randomized trials, should be considered as an important new treatment option for patients post-transplant.”

Novel Induction Regimen Early data from a phase III Italian/ Israeli study suggest that use of a novel lenalidomide-based induction therapy is safe and as effective as an initial therapy prior to either high-dose therapy with stem-cell support or conservative treatment with melphalan, prednisone, and lenalidomide in patients with newly diagnosed multiple myeloma. Although further follow-up is needed, this approach may allow ASCT to be delayed in some patients.

This randomized trial compared the combination of melphalan, prednisone, and lenalidomide (MPR) to tandem ASCT plus melphalan (MEL200), following lenalidomide induction therapy.

According to Dr. Richardson, these See page 51 results are quite striking because, to date, the response and early progression-free survival data are identical in both arms. This suggests that the efficacy of the MPR regimen after lenalidomide and dexamethasone induction was identical to that of tandem transplantation. Results of this trial were initially presented at the Annual Meeting by Antonio Palumbo, MD, of the University of Torino, Italy.

All patients received an induction

regimen consisting of four 28-day cycles of lenalidomide (25 mg on days 1–21) and low-dose dexamethasone (40 mg on days 1, 8, 15, 22). This was followed by stem-cell mobilization using cyclophosphamide and granulocyte colony-stimulating factor. For consolidation therapy, patients (N = 202) were randomly assigned to MPR (six 28-day cycles of melphalan at 0.18 mg/kg on days 1–4), prednisone (2 mg/kg on days 1–4), and lenalidomide (10 mg on days 1–21); or to MEL200 (tandem melphalan at 200 mg/m2 plus stem-cell support). A subsequent randomization allocated patients to either no therapy or maintenance lenalidomide (10 mg/d on days 1–21 every 28 days).

A total of 402 patients from 62 centers were randomly assigned in a 1:1 ratio. Best response following induction with lenalidomide and dexamethasone was a partial response in 49% of patients, very good partial response in 31%, and complete response in 6%.

One month after induction, the minimum stem cell yield (> 2 × 106 CD34+ cells/kg) could be collected from 91% of patients, with a median yield of 8.85 × 106 CD34+ cells/kg.

With a median follow-up of 14 months, progression-free survival was equivalent in both arms (86%; P = .49), as was overall survival (96% MPR, 98% MEL200; P = .13). However, compared with MPR, consolidation with MEL200 was associated with a significantly higher incidence of grade 3/4 neutropenia (86% vs 45%) and thrombocytopenia (87% vs 8%).

Dr. Richardson emphasized that while the findings are provocative, these results should be interpreted with caution because the data are early.

“Results from this trial stress that, usPlacebo

Percentage of patients

100%

Lenalidomide

75%

Lenalidomide P < 10-7

50% 25%

Placebo

0% 0

6

12

18

24

30

36

Months from randomization Fig. 1: Progression-free survival in IFM 2005-02. Adapted from Attal et al.2 Courtesy of Michel Attal, MD.

Expert Point of View

S

haji Kumar, MD, said that although the lenalidomide maintenance data are encouraging, he does not believe such therapy should be adopted yet for all patients with multiple myeloma. Dr. Kumar, who is Associate Professor of Medicine in the Hematology Division at Mayo Clinic, Rochester, Minnesota, presented the CALGB 100104 and IFM 2005-02 study results at the Best of ASCO Meeting in San Francisco.

The hurdle in terms of widespread acceptance of Shaji Kumar, MD lenalidomide maintenance therapy at this point is the lack of overall survival data, noted Dr. Kumar. “I think we should not be using lenalidomide as maintenance therapy for everyone post-transplant until we have data showing a difference in overall survival,” he said. Lenalidomide may be more appropriate in high-risk patients, who generally have a very short duration of response post-transplant. For these patients there is a stronger rationale for a more proactive approach to treatment that could include maintenance therapy with lenalidomide.

Upfront use of lenalidomide also could have implications for selection of therapy when patients subsequently experience disease progression or become resistant to treatment. According to Dr. Kumar, “Patients who are on maintenance lenalidomide therapy may have disease relapse at some point in the future, and then would have one less drug available for treatment compared with patients who had not received lenalidomide.”

In the absence of a clear overall survival benefit, Dr. Kumar suggested discussing these results with patients and clearly presenting the advantages and disadvantages of lenalidomide maintenance therapy. Unfortunately, for multiple myeloma patients who have not received lenalidomide before transplantation or have received it in combination with another drug such as bortezomib, there is no reliable way to determine if their myeloma is responsive to lenalidomide. Identification of a predictive marker would clearly aid in patient selection and help avoid unnecessary toxicity in those not likely to respond, Dr. Kumar said.

■

ing novel induction regimens, the ability to delay transplant in some patients and thus keep it in reserve does appear to be a reasonable strategy.”

Dr. Richardson’s group reported that the lenalidomide and dexamethasone regimen is also highly effective when used in combination with bortezomib (Velcade) as induction therapy for newly diagnosed multiple myeloma as part of the so-called RVD regimen (lenalidomide, bortezomib, and dexamethasone).4 This regimen achieved an unprecedented 100% partial response rate or better in 66 patients as part of a multicenter phase I/II trial. Remarkably, a very good partial response rate of 74% and a near-complete/complete response rate of 52% were seen in the phase II portion of study, with favorable tolerability reported and no treatmentrelated mortality.

A large randomized trial (IFM/ DFCI) starting in the fall will evaluate the combination of RVD with early or late ASCT in newly diagnosed patients with multiple myeloma.

■

References 1. McCarthy PL, Owzar K, Anderson KC, et al: Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. Best of ASCO Meeting Boston. Abstract 8017. Presented July 23, 2010, by Paul G. Richardson, MD. 2. Attal M, Cristini C, Marit G, et al: Lenalidomide maintenance after transplantation for myeloma. Best of ASCO Boston.

Abstract 8018. Presented July 23, 2010, by Paul G. Richardson, MD. 3. Palumbo AP, Cavallo F, Di Raimondo F, et al: A ������������������������������������ phase III trial of melphalan/prednisone/lenalidomide (MPR) versus melphalan (200 mg/m2) and autologous transplantation (MEL200) in newly diagnosed myeloma patients. Best of ASCO Boston.

Abstract 8015. Presented July 23, 2010, by Paul G. Richardson, MD. 4. Anderson KC, Weller E, Lonial S, et al: Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma (MM): Final results of a multicenter phase I/II study. 2010 ASCO Annual Meeting. Abstract 8016. Presented June 6, 2010, by Paul G. Richardson.

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

Š 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

Oncogenic BRAF: A new potential therapeutic target1,2 The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2: ~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6 In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell.

2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul.

2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

The ASCO Post | DECEMBER 2010

PAGE 50

News Leukemia

Hyper-CVAD/Imatinib Proves Superior to Hyper-CVAD Alone in Philadelphia Chromosome–positive ALL

By Barbara Boughton

A

study from The University of Texas MD Anderson Cancer Center that evaluated long-term outcomes in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) found that the combination treatment of a hyperCVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and imatinib has more benefits than hyper-CVAD alone, accord-

Deborah Thomas, MD

ing to results presented at the 2010 ASCO Annual Meeting by Deborah Thomas, MD, Associate Professor in the Department of Leukemia at M. D. Anderson. In the study of 54 de novo or minimally treated patients with Ph+ ALL, the 3-year rate of complete response duration for those receiving hyper-CVAD plus imatinib was 68%, compared with 24% for a historical cohort treated with hyper-CVAD alone (P < .001). The combination regimen also resulted in significantly improved overall survival of 54% at 3 years, compared with 15% for hyperCVAD. “Ph+ ALL has historically been very difficult to treat, although 90% of patients achieve an initial complete response even with traditional chemotherapy regimens—but long-term survival is only in the region of 10% to 20%,” said Farhad Ravandi, MD,

Associate Professor in the Department of Leukemia at MD Anderson.

Dr. Ravandi presented the data at the Best of ASCO meeting in San Francisco.1 “The regimen of hyper-CVAD plus imatinib is very effective and does improve outcomes, especially for patients who do not go on to a stem cell transplant,” he added.

Of 35 patients in the study who received imatinib and did not proceed to an allogeneic stem cell transplant (aSCT) after complete response, 10 are still in complete remission, he said. Yet Dr. Ravandi noted that the study’s long-term data suggest that aSCT remains important for those who receive hyper-CVAD plus imatinib, particularly for patients under age 40.

Study Design The study included de novo and primary refractory imatinib-naive Ph+ ALL patients as well as those who achieved a complete response after one cycle of an alternative induction therapy without imatinib. The regimen consisted of eight cycles of alternating hyper-CVAD with methotrexate/cytarabine as well as 600 mg of imatinib on days 1 to 14 of induction and continuously during courses 2 through 8. Patients received 800 mg of imatinib (or best tolerated dose) during 24 months of maintenance therapy with monthly vincristine/ prednisone interrupted by two intensifications of hyper-CVAD plus imatinib, and then imatinib indefinitely.

Results were compared to a historical cohort of 50 patients treated with hyper-CVAD without imatinib, also at MD Anderson.

Initial results after induction in-

Hyper-CVAD/Imatinib in Ph+ ALL ■■ A study of long-term outcomes in Ph+ ALL patients found that treatment with hyper-CVAD and imatinib produced more durable complete remissions and significantly superior overall survival rates compared to a historical cohort treated with hyper-CVAD alone.

■■ Patients who went on to receive allogeneic stem cell transplant after

experiencing complete remission with hyper-CVAD and imatinib fared better than those who received chemotherapy and imatinib, particularly if they were under age 40.

■■ Older patients (especially those over age 60) were more likely to experience treatment failure.

Expert Point of View

O

latoyosi Odenike, MD, of The University of Chicago, said the findings of the hyperCVAD plus imatinib study were striking, given the wide difference in overall survival between the hyper-CVAD plus imatinib group and the historical cohort who received chemotherapy alone. “Although the CR rates were virtually identical (over 90%) between the two cohorts, the responses were more durable in the hyper-CVAD plus imaOlatoyosi Odenike, MD, tinib cohort. The 3-year CR duration rate was almost 70% in the imatinib cohort compared with 24% in the chemotherapy-alone arm. Patients were able to stay in remission for a longer time, and this translated into an improvement in overall survival,” said Dr. Odenike, Assistant Professor in the Department of Medicine in the Section of Hematology and Oncology at The University of Chicago.

Dr. Odenike presented the study results at the Best of ASCO Meeting in Boston.

Although the addition of imatinib to chemotherapy has now become a standard approach for treating Ph+ ALL, the M. D. Anderson study did provide important information with regard to long-term outcomes for this approach. It adds to data by other research groups confirming the longterm survival benefits of combining chemotherapy with a tyrosine kinase inhibitor (TKI) for Ph+ ALL, Dr. Odenike said. She noted that although a limitation of this study was the use of a historical cohort for comparison, a randomized study of chemotherapy with or without imatinib in Ph+ ALL would not be ethical, given the obvious benefits of TKIs in this disease.

Continued Role of Stem Cell Transplant The findings of the MD Anderson study also suggest that allogeneic stem cell transplants cannot be dispensed with for Ph+ ALL patients, particularly younger patients—even in an era when imatinib has significantly extended the durability of complete remission, Dr. Odenike said. Whether the addition of second- or third-generation TKIs to chemotherapy in lieu of imatinib would further improve outcomes compared to chemotherapy plus imatinib remains an open question, she added.

“We know that it’s feasible to add a second-generation TKI such as dasatinib to chemotherapy and to get good outcomes in Ph+ ALL,” she said. “A randomized study would be required to determine whether dasatinib would be superior to imatinib in Ph+ALL. Dasatinib does have the potential additional advantage of crossing the blood-brain barrier.”

■

dicated that 36 (92%) of 39 de novo patients achieved a complete response as well as 100% of 6 patients with primary refractory disease. Also, more patients achieved a complete response after just one cycle of the imatinib regimen (85%) compared to those who received hyper-CVAD (70%).

Subgroup Results Although initial study data did not indicate a benefit for aSCT in those who received imatinib, continued follow-up revealed that patients who

went on to stem cell transplants experienced superior outcomes. When the investigators looked at use of aSCT in de novo patients younger than age 60 who received hyperCVAD plus imatinib vs those in the same treatment group who did not go on to aSCT, the trend favored stem cell transplant—although the difference had not yet reached significance.

The 3-year overall survival rates for these patients were 77% with aSCT vs 57% without aSCT (P = .1) When the researchers compared patients on chemotherapy alone who went on to

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News

aSCT vs those who did not, however, they found that patients in the hyper-CVAD historical cohort derived more survival benefits from stem cell transplant (P = .02).

Dr. Ravandi pointed out that the use of aSCT was particularly beneficial for de novo patients under age 40 in first complete remission after chemotherapy and imatinib. In this group, patients treated with imatinib had a 3-year overall survival rate of 90% with aSCT vs 33% without aSCT (P = .05).

“It’s very significant that only 1 out of the 10 who got a transplant has died, as opposed to 4 out of 6 patients who did not receive a transplant,” he said.

Patients over age 60 who received imatinib fared worse than younger subjects because of the intensity of the regimen, Dr. Ravandi said. Among 16 de novo patients under age 40, treat-

Farhad Ravandi, MD

ment failed in 5, for instance, whereas among 13 patients over age 60, treatment failed in 10. The investigators did not find that persistence of BCR-ABL transcripts by quantitative polymerase chain reaction (PCR) testing was predictive of relapse.

Other TKIs Dr. Thomas noted that second- or later-generation tyrosine kinase inhibi-

Using 2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the Application

tors used with hyper-CVAD might further improve treatment outcomes for patients with Ph+ ALL. In fact, researchers at MD Anderson are now studying the use of dasatinib (Sprycel) combined with hyper-CVAD in patients with Ph+ ALL. In a recent phase II study of 35 previously untreated patients with Ph+ ALL, published in Blood,2 Dr. Ravandi and fellow researchers found that the dasatinib/chemotherapy regimen achieved a 94% initial complete response rate. The median disease-free survival and overall survival had not been reached after 14 months, but the estimated 2-year survival rate was 64%. Although the dasatinib regimen does not appear to produce improved survival over one containing imatinib, Dr. Ravandi noted that 10% of patients in the dasatinib study went on to aSCT in first remission, compared with 20% of

patients in the imatinib study reported at the Annual Meeting.

“One could argue hypothetically that dasatinib may negate the need for transplant in a subset of this population,” Dr. Ravandi said.

■

References 1. Thomas DA, O’Brien SM, Faderl S, et al: Long-term outcome after hyperCVAD and imatinib for de novo or minimally treated Philadelphia chromosomepositive acute lymphoblastic leukemia.

Best of ASCO Annual Meeting San Francisco. Abstract 6506. Presented July 17, 2010, by Farhad Ravandi, MD. 2. Ravandi F, O’Brien S, Thomas D, et al: First report of phase II study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Blood. May 13, 2010 (epub ahead of print).

Inside The ASCO Post – Don't miss these important perspectives: Page 1 Dr. George Canellos shares his perspective on the many questions remaining to be answered by prospective randomized clinical trials concerning the management of hematologic diseases. He calls for the expansion of the clinical trials process and the support of NCI and other independent funding mechanisms to find solutions.

There are three ways to download the ScanLife application:

1

2

3

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

Scanning 2D codes When you see a code that you would like to scan, start the ScanLife application.

The screen will look similar to camera mode.

Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically.

A short audio chime will indicate a successful scan and the phone will contact the server for further instructions.

This may take up to a minute depending on data speeds and phone type.

Page 74 Dr. Richard Boxer discusses the role of telehealth, also referred to as telemedicine, as the access point to medicine for millions of Americans, and he believes its use will continue to increase every year. Health professionals need to be at the forefront of telemedicine’s introduction to ensure that it is used ethically, with the patient at the center of the process.

Plus: Page 3 Results from the National Lung Screening Trial (NLST) show significant mortality benefit with low-dose spiral CT vs chest x-ray. Dr. Claudia Henschke of the International Early Lung Cancer Action Program (I-ELCAP) shares her thoughts about these important new data indicating that lives can be saved now through early screening Page 16 Data presented at the 52nd Annual Meeting of the American Society for Radiation Oncology show that preoperative radiation therapy reduces pelvic recurrence rates in patients with rectal cancer.

Page 17 Is contralaterial prophylactic mastectomy an acceptable option to reduce the risk of second breast cancer? Find out what data reviewed at the 2010 Breast Cancer Symposium indicate.

Page 22 Denosumab prolongs time to skeletal-related events and their incidence in patient with bone metastases, according to data reported at the 35th European Society of Medical Oncology Congress.

Visit The ASCO Post online at www.ASCOPost.com

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ASCOPost.com | DECEMBER 2010

PAGE 53

Global Perspective

UICC: Toward the Globalization of Cancer Control

By Caroline Helwick

O

ncologists and other cancer professionals in the United States may not have heard of this cancer organization based in Geneva, Switzerland, but a Canadian oncologist is now President-Elect of the Union for International Cancer Control (www.uicc.org) and wants her American colleagues to take notice.

Mary Gospodarowicz, MD

The UICC is the leading nongovernmental organization dedicated exclusively to global cancer control. President-Elect Mary Gospodarowicz, MD, Professor and Chair of Radiation Oncology at the University of Toronto, Medical Director at Princess Margaret Hospital, and Regional Vice President of Cancer Care Ontario, described the UICC for The ASCO Post and called on ASCO members to partner with UICC by signing the World Cancer Declaration (see sidebar).

Organization and Operation What is the UICC? Dr. Gospodarowicz: The UICC is a nonpolitical, nonsectarian global organization based in Geneva, Switzerland.

Since it was founded in 1933, the UICC has grown to embrace organizations engaged in all aspects of cancer prevention and control: research and treatment centers, public health authorities, cancer societies, patient support networks, advocacy groups, governmental cancer agencies, and ministries of health. It now has 389 member organizations (one of which is ASCO) in 120 countries.

I hope that more individual U.S. cancer centers and professional organizations that deal with cancer join the UICC as members. It is the broad range of membership that gives the UICC a voice.

UICC also offers corporate partners a unique opportunity to demonstrate social responsibility on a global scale.

How is UICC governed and how does it accomplish its goals?

Dr. Gospodarowicz: The UICC is governed by its member organizations and a board of 17 directors, which acts

as the executive body. The UICC meets in a general assembly every 2 years, held in conjunction with the World Cancer Congress. About 3,000 people attended our August meeting in Shenzhen, China. In 2011 we will meet in Montreal.

In the past, the UICC Congress was dedicated almost entirely to medical research and treatment of cancer, but in recent years it has transformed into an event that follows the UICC agenda and is more and more directed toward the issues surrounding cancer systems and population-based cancer control.

The UICC is essentially rebranding itself as a “cancer control congress” where its members and cancer professionals can exchange information on research and implementation of the most effective cancer control systems. These issues are of enormous importance all over the world. There is a paucity of available information regarding the science and cost-effective implementation of optimal cancer prevention, screening, treatment, and supportive care interventions.

Objectives and Themes What are the aims and strategies of the UICC? Dr. Gospodarowicz: The UICC mission is to connect, mobilize, and support organizations, cancer experts, key stakeholders, and volunteers in a global community working together to eliminate cancer for future generations.

We now know that about one-third of all cancers can be prevented and a further third can be cured, but for many countries this is still not a reality. And though it’s hard to believe, we still need to raise awareness about the burden of cancer. For instance, cancer is still not on the World Health Organization’s global agenda.

■■ To accomplish our goals, the UICC strategy is quite broad and includes the following items and more: ■■ promoting the World Cancer Declaration (see sidebar) ■■ organizing the World Cancer Congress ■■ raising awareness through the World Cancer Campaign ■■ coordinating World Cancer Day annually, on February 4 ■■ exchanging information on effective cancer control programs ■■ changing inaccurate cancer-related beliefs and ineffective behaviors through information and education ■■ creating special initiatives in preven-

■■ ■■ ■■ ■■

tion, early detection, access to treatment, and supportive care awarding international cancer fellowships publishing and disseminating the TNM cancer staging classification of malignant tumors publishing the International Journal of Cancer The challenge now is to fine-tune the agenda in a way that will satisfy the diverse segments of the cancer community.

The UICC Cancer Congress is intensifying its focus on particular aspects of cancer, is it not?

Dr. Gospodarowicz: Yes, the Congress has “themes” that will help us focus our effects in certain critical areas.

One is tobacco control, which is an extremely important issue in prevention. At the recent Congress we heard data suggesting that if we don’t improve tobacco control, in this century 1 billion people will die of tobacco-related diseases. That’s a staggering number of lives that could potentially be saved.

Another theme is that of cancer prevention and screening—what we should be doing about infection-related cancers such as HPV, as well as ways in which we should be encouraging lifestyle changes. Other themes include capacity

building for cancer advocacy, supportive and palliative care, advances in cancer treatment and prognosis, and more.

Partners and Plans What are some of the outside organizations that partner with UICC? Dr. Gospodarowicz: UICC works closely with the World Health Organization, the International Agency for Research on Cancer, and the International Atomic Energy Agency Programme of Action for Cancer Therapy. It also has consultative status with the United Nations Economic and Social Council.

How can ASCO members contribute to the UICC efforts?

Dr. Gospodarowicz: The United Nations has always emphasized the control of infectious diseases, especially in the developing world. Next September the UN will hold a high-level summit on noncommunicable disease, and we view this as a prime opportunity to move the UICC agenda forward. Specifically, we are pushing to have the UN make the control of cancer (and other noncommunicable diseases) an official Millennium Development Goal. As part of this effort, we must put cancer on the UN agenda. We will be promoting the World Cancer Declaration, which I hope every ASCO member will sign!

■

Click Here for Cancer Control

T

he World Cancer Declaration is a tool to help cancer advocates bring the growing cancer crisis to the attention of health policymakers at national, regional, and global levels. It represents a consensus among foundations, national and international nongovernmental and governmental organizations, professional bodies, the private sector, academia, and civil societies from all continents that are committed to the vision of eliminating cancer.

Through a simple click of the mouse, ASCO members can join the more than 1,000 organizations and 127,000 other individuals who have already signed the proposal to reduce the global cancer burden through specific strategies.

“The World Cancer Declaration has 11 targets that adSee page 51 dress not only cancer treatment but also prevention, access, education, public attitudes, and other factors in cancer,” said Dr. Gospodarowicz. The declaration includes targets to be achieved by 2020 and a list of priority actions with regard to health policy, cancer prevention and early detection, and cancer treatment. For more details, go to http://www.uicc.org/node/80.

“The UICC wants every cancer professional to sign the declaration, and of course this includes the ASCO membership. While over 100,000 persons have signed, we want 1 million signatures to present to the UN summit next year.”

■

The ASCO Post | DECEMBER 2010

PAGE 54

35th ESMO Congress Targeted Therapy

Making Sense of Antiangiogenesis in the Adjuvant Setting: What Now? ESMO/ASCO Joint Symposium

By Caroline Helwick

R

ecent data from adjuvant trials of antiangiogenic therapy have left many in the field scratching their heads. For an approach seemingly

brimming with promise, what went wrong? Is there a place for antiangiogenic therapy in early-stage tumors?

The topic is “hot” enough that it

was debated before a filled auditorium by leaders in the field at the ESMO/ ASCO Joint Symposium, presented October 11 at the 35th ESMO Con-

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

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gress in Milan, Italy. ASCO President George Sledge, MD, and ESMO President David Kerr, MD, emphasized the importance of the issue.

“This is a fantastic opportunity to discuss an issue that is very topical, incredibly timely, and of huge interest to clinicians,” Dr. Kerr said in an interview.

“We have proof of concept that antiangiogenesis therapy is beneficial for patients with a wide spectrum of cancers,” Dr. Sledge added. Clinical success has been shown in renal cell and hepatocellular cancers, non–small cell lung cancer (NSCLC), colorectal cancer, breast cancer, and gliomas. “But there are challenges.”

Although in the metastatic setting studies of bevacizumab (Avastin), usually when combined with chemotherapy, have been positive, findings from adjuvant trials have been clearly negative. The unanticipated findings have “led to clinical and financial turmoil,” he said. “After a decade in the clinic, we have a number of questions” (Table 1).

Lee M. Ellis, MD

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A Look at the Clinical Scenario

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

ing

Lee M. Ellis, MD, of the Departments of Cancer Biology and Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston, said it was a predictable next step to take bevacizumab into the adjuvant setting. “It’s just what we do in oncology,” he said. “We take a drug that is efficacious on the metastastic setting and test it in adjuvant studies.”

But two phase III adjuvant trials in colorectal cancer—NSABP C-O8 and AVANT—found no additional benefit for bevacizumab (plus maintenance) vs chemotherapy alone, nixing the notion that what is good for metastatic disease is also good for early-stage cancer.

“These are examples that more is not better, and there is no reason to think that tweaking the regimen will provide

ASCOPost.com | DECEMBER 2010

PAGE 55

35th ESMO Congress any benefit,” Dr. Ellis suggested.

Dr. Sledge commented, “The old paradigm that what works in metastasis will work in the adjuvant setting is no longer necessarily the case, and not just for bevacizumab. These findings tell us that we have to totally revisit how we look at adjuvant therapy in cancer.”

Furthermore, Dr. Ellis noted that the additional risk of toxicities with bevacizumab is important “when 65% to 70% of patients will be cured by surgery alone.”

Meanwhile, based on C-O8 and AVANT, the future of the ongoing adjuvant trials is uncertain. This includes Eastern Cooperative Oncology Group (ECOG) 5202, which has been suspended after enrolling 3,125 patients, and QUASAR-2, with 2,240 patients. ECOG 5202 was designed to study patients with stage II colorectal cancer stratified by risk; high-risk patients were randomly assigned to modified FOLFOX6 (oxaliplatin, leucovorin, fluorouracil [5-FU]) with or without bevacizumab, and low-risk patients were observed. In QUASAR-2, patients receive capecitabine with or

without bevacizumab for 6 months, plus 6 months of bevacizumab.

Dr. Kerr, the principal investigator of QUASAR-2, told The ASCO Post, “Of course we have concerns and are having ongoing discussions. Our Data Safety and Monitoring Committee will advise us as to whether we should stop bevacizumab.”

Other adjuvant trials with vascular endothelial growth factor (VEGF)-targeted agents include two in renal cell carcinoma, one in NSCLC, and three in breast cancer.

Table 1: Antiangiogenic Therapy: Unanswered Questions 1. Resistance is common; why does it occur? Are compensatory pathways induced by VEGF blockade?

2. Is the micrometastatic setting different than the overt metastatic setting?

3. How do we choose the right partners (chemotherapeutic and/or biologic)?

4. Why do consistent improvements in progression-free survival not translate into improved overall survival?

5. Can we dissociate anti-VEGF toxicity from anti-VEGF efficacy?

6. What is the impact of shorter-term treatment on established vs microscopic metastases?

7. What are the most promising combination approaches?

Is Further Study Warranted?

VEGF = vascular endothelial growth factor.

Meanwhile, is there a way to improve upon the FOLFOX/bevacizumab–based regimen in the adjuvant setting? “This is doubtful,” Dr. Ellis said. “Adding a monoclonal antibody to the epidermal growth factor receptor (EGFR) was detrimental in two trials in the metastatic setting.”

Nor is longer duration of bevacizumab treatment the answer. Since most responses in patients with metastatic colorectal cancer occurred

within the first 4 months, “there is no reason to believe that longer-term combination therapy or single-agent bevacizumab will lead to more cures,” he maintained. “After 12 months of bevacizumab, including 6 months of chemotherapy, I think we can declare tumor cells resistant. Also, giving bevacizumab ‘forever,’ as a cytostatic agent, is simply not feasible.”

Dr. Ellis called for interim analyses of all ongoing studies in the various

tumor types, noting that some cancers may respond differently to the drugs.

“As I stated at the plenary session at the 2009 ASCO Annual Meeting, if AVANT is not ‘outright positive,’ no further study of long-term adjuvant anti-VEGF treatment in colorectal cancer is warranted. Lacking a biomarker, we should not administer a potent drug like bevacizumab forever in a population where up to 95% of patients will not benefit.”

■

Do Antiangiogenic Agents Make Tumors More Aggressive?

C

ould therapies that inhibit VEGF be rendering tumors more aggressive? A limited number of preclinical studies have suggested the drugs may in some cases accelerate metastases or enhance tumor cell invasion; this may also occur upon withdrawal, creating a “rebound” effect.

According to Dr. Ellis, the metastatic trials yield “no evidence that bevacizumab leads to a paradoxical increase in metastasis.” In C-O8, the percentage Robert Kerbel, PhD of patients recurring in multiple sites was equivalent between the arms (18%).

According to Robert Kerbel, PhD, the Canada Research Chair in Tumor Biology Angiogenesis and Antiangiogenic Therapy at Sunnybrook Health Sciences Centre, Toronto, the exception may be glioblastoma; several bevacizumab therapy–related studies have indicated increased rates and extent of invasive disease at relapse. However, in metastatic colorectal cancer studies thus far, no worsening has been observed when bevacizumab was discontinued, and, in fact, continuing the drug beyond disease progression has been shown to improve survival.

Biologically Plausible Concept The concept of “rebound” is not new or unexpected, not restricted to antiangiogenic agents, and does not necessarily herald a worse survival outcome. “It may be more of an issue with tyrosine kinase inhibitors, which have short halflives, than with antibodies, and more of a problem in the adjuvant (and possibly neoadjuvant) setting,” he suggested.

With respect to antiangiogenic drugs, the rebound idea is biologically plausible, Dr. Kerbel said. For example, tumors may outgrow their blood supply, and have poorly perfusing vessels, leaving areas of hypoxia that are usually resistant to chemotherapy and radiotherapy. Antiangiogenic treatments usually increase hypoxia, triggering adaptive upregulation of proangiogenic, invasion-related, and metastasis-related genes.

In addition, Dr. Kerbel reported preclinical results showing that some antiangiogenic tyrosine kinase inhibiting drugs can cause upregulation of multiple proangiogenic cytokines and growth factors in a tumor-independent fashion. “Tumor rebound,” drug resistance, and tumor progression might be consequences of this host-dependent multi-cytokine “surge” induced by antiangiogenic tyrosine kinase inhibitors, similar to the hypoxia-related changes within tumors, he said.

His group has begun to study this possibility and reported results showing that short-term adjuvant treatment with some antiangiogenic tyrosine kinase inhibitors could actually promote the growth of microscopic metastases, whereas in other experiments the growth of established and vascularized tumors was inhibited by exactly the same treatments.

“Preclinical studies carefully assessing antitumor drug activity in either adjuvant or advanced metastatic settings are uncommon,” said Dr. Kerbel. Greater efforts, he said, should be made to undertake more such studies before embarking on clinical trials, especially enormously expensive long-term adjuvant trials; this applies not only to antiangiogenic drugs, he said, but to other types of agents, especially many of the new targeted therapies.

Where to Go Next?

Current agents target VEGF for “vessel pruning,” but this may not be the best antiangiogenic approach, as it creates a hostile microenvironment from which tumors attempt to escape. In addition, Dr. Kerbel reported results showing that some antiangiogenic tyrosine kinase–inhibiting drugs can cause upregulation of multiple proangiogenic cytokines and growth factors in a tumor-independent fashion.

A promising alternative, described by Peter Carmeliet, MD, PhD, of the Catholic University of Leuven, Belgium, is to aim for vessel normalization. This might correct the impairment in perfusion that results in hypoxia and the leakiness that results in intravasation—both fueling metastasis. Drugs that address the imbalance of angiogenic stimulators and inhibitors causing abnormalization are in development. In addition, chronic daily metronomic dosing of antiangiogenic drugs has been shown to improve survival in mice and is being tested in clinical trials.

■

ASCOPost.com | DECEMBER 2010

PAGE 59

News Breast Cancer

Breast Cancer and Sexuality: Issues and Answers

By Caroline Helwick

T

he majority of breast cancer survivors report some alteration—often profound—in sexual drive or pleasure. Less is known about the optimal treatment approach to restore sexual health to these women. In fact, sexual health concerns are rarely even addressed, in either the primary care or oncology settings, leading patients to find their own solutions.

Michael L. Krychman, MD

One expert in this area is Michael L. Krychman, MD, Executive Director of the Southern California Center for Sexual Health and Survivorship Medicine and Medical Director of Sexual Medicine at Hoag Memorial Presbyterian Hospital in Newport Beach, California. Dr. Krychman answered questions on this topic for The ASCO Post.

Scope of the Problem, Definitions, and Findings How big is the problem of sexual dysfunction in breast cancer survivors?

Dr. Krychman: If you are not seeing sexual health issues in your oncology practice, you are not asking the right questions, because 50% to 90% of breast cancer survivors report concerns about sexual health. Even 20 years after diagnosis, nearly one-third still report problems they attribute to breast cancer. We hear things like, “I’m thankful to be alive, but I am dead down there!” and “breast cancer contributed to the deterioration of my marriage.”

Medical and surgical oncologists as well as all health-care professionals who treat these women should be familiar with simple interventions.

Discussing sexuality concerns will not bottleneck your office or open a Pandora’s box, and your patients will be grateful.

How do you define female sexual dysfunction?

Dr. Krychman: Female sexual dys-

function is a (1) persistent or recurrent problem, (2) causing “marked distress” or “interpersonal difficulty,” and (3) not accounted for by another axis I disorder (eg, clinical disorder, including depression and anxiety), or exclusively caused by the direct physiologic effects of a substance (eg, medication) or general medical condition. For patients with cancer, sexual problems often overlap, including sexual desire disorders, sexual arousal disorders, pain syndromes including dyspareunia and vaginismus, and orgasmic disorder. Usually, you have to tease out the main issue. For instance, patients may report lack of desire, but you discover they have severe vulvar and vaginal atrophy, which may be associated with aromatase inhibitor use, so naturally they aren’t interested in sex.

What are the main physical findings you observe in breast cancer survivors who report sexual health issues?

Dr. Krychman: Many problems are the result of lowered estrogen levels, which can produce urogenital and vulvovaginal changes such as vaginal dryness and irritation, increased malodorous discharge, and vulvar discomfort. Vaginal atrophy can lead to dyspareunia and distress, during intercourse and even during the annual pelvic examination. Decreased vaginal length, lubrication, and secretions can cause problems with intercourse. Loss of vaginal mucosal tone can also lead to genitourinary complaints. Menopausal syndrome including hot flashes can interfere with sexual health. Negative body perceptions, and changes in sexual self-esteem caused by surgery, radiotherapy, chemotherapy, or adjunctive treatment can all affect many women. This is a huge quality-of-life issue, and it’s not just about sex.

Therapeutic Options Once you’ve broached the topic and have an understanding of the problem, what is your next step?

Dr. Krychman: First, you help the patient focus on “the new norm”: pleasure, intimacy, and sexual togetherness, without a huge emphasis on “goal-oriented sex” (ie, penetration, with orgasm and sexual release as the objective). In the field of sexual health, we instruct couples to focus on pleasure and sexual satisfaction rather than performance. Vaginal atrophy can

sometimes be effectively treated with vaginal moisturizers, such as Replens or vaginally applied vitamin E, and the use of vaginal dilators. In selected cases where risk-benefit is discussed with both the patient and the provider, minimally absorbed local vaginal estrogen may be a viable option for treating vaginal atrophy. Plans need to be individualized.

Interestingly, mindfulness-based sex therapy has been shown to significantly improve several domains of response and to reduce sexual distress.

Acupuncture is emerging as a means of treating hot flashes. Bupropion may help women with coexisting mood disorder and sexual dysfunction. For sexual dysfunction associated with antidepressants, sildenafil has been shown in small studies to be an effective antidote. And some women like over-the-counter nonhormonal Zestra Sensual Arousal Fluid, which is a blend of botanical oils and extracts that is topically applied to the genital area to enhance sensitivity. I usually suggest that patients try these conservative nonhormonal approaches first, and if necessary, progress to more aggressive therapies later on. Bibliotherapy, including reading about sexuality issues and topics related to couples therapy, can also be helpful.

Useful Products Patients generally accept the use of lubricants and moisturizers. In your opinion, what are the best products?

Dr. Krychman: I prefer the more natural products because they have fewer additives, such as parabens and propylene glycol. For lubricants, I usually recommend Good Clean Love and Hydra-Smooth, which can be ordered online. Paraben- and glycinefree Astroglide and K-Y Jelly are also helpful. For moisturizers, Feminease and Moist Again are good choices.

Replens is backed by clinical trial data, but patients need to understand that it should be used twice weekly and can take up to 2 months to work. Colors, warming gels, flavors, bactericides, and spermicides should be avoided, as they can be irritative to the already sensitive vaginal mucosa.

Can breast cancer survivors safely use the low-estrogen products?

Dr. Krychman: We tend to avoid minimally absorbed local vaginal es-

trogen as much as possible. These products are not FDA-approved for those with hormonally sensitive tumors. However, if conservative approaches are not enough, patients often try the minimally absorbed local vaginal estrogen products such as the estradiol vaginal ring (Estring), conjugated equine estrogen cream (Premarin), estradiol cream (Estrace), and the new ultra-low-dose 10-µg tablet (Vagifem), which used to be 25 µg of 17beta estradiol but is now available only in the lower dose.

However, patients must be made aware that all forms of estrogen are minimally absorbed to some extent.

All estrogens carry a black box warning for estrogen-sensitive tumors. Even local vaginal treatments may increase serum estradiol levels to some extent, and their effects may not be limited to the vagina. The clinical importance of this increase remains to be elucidated.

In a recent study of women who used Vagifem or Premarin cream for 7 days, serum estradiol increased fivefold within 24 hours of application, as assessed by mass spectrometry.1 Patients should discuss the issues of local estrogen with their health-care teams.

Some patients may need a combination of products—one external and one intravaginal—for relief. The new trend is to individualize care, with a personalized care plan for those who are presently suffering in silence.

Are there newer products or more innovative treatments ahead that may be more helpful and less potentially harmful?

Dr. Krychman: Yes! I am really excited about new data on the daily use of intravaginal dehydroepiandrosterone (DHEA) ovules (prasterone), which is in phase III trials. It provides stimulation over several vaginal layers and thus improves atrophy. Preliminary data demonstrate relatively potent beneficial effects on sexual function, but the hormone does not appear to increase serum sex steroid levels.2-4

Concluding Thoughts Do you have some final advice for managing patients with breast cancer who have sexual health issues?

Dr. Krychman: Personalize the patient’s treatment, and try an “aggressive continued on page 60

The ASCO Post | DECEMBER 2010

PAGE 60

News

Breast Cancer and Sexuality continued from page 59

conservative” nonhormonal approach first. If this is not enough, analyze risk and then consider off-label treatment, documenting your discussion and getting informed consent. Treat the patient and her symptoms. Do not neglect sexuality and sexual health

concerns in your patients who are suffering in silence.

Finally, I would stress that the best care is multidisciplinary, using a biopsychosocial model, because there is a complex interplay of factors. For patients, I recommend that they talk to their medical oncologists about their individual situations and sexual con-

cerns, and for health-care professionals, I recommend that they get educated about these problems.

In fact, there is a Cancer Survivorship and Sexual Health Symposium sponsored by the International Society of Sexual Medicine coming to Washington, DC, in June 2011, which will help break the silence!

■

JOIN THE CONVERSATION at ASCOconnection.org

ASCOconnection.org is ASCO’s newly launched social networking site The premier online meeting place for the worldwide oncology community, ASCOconnection.org gives you a platform to: • share ideas and opinions with other ASCO members • expand your network of contacts across the oncology community • interact directly with ASCO leadership ASCOconnection.org is your online home for exchanging oncology-related information, news, and experiences with colleagues around the world.

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References 1. Labrie F, Cusan L, Gomez JL, et al: Effect of one-week treatment with vaginal estrogen preparations on serum estrogen levels in postmenopausal women. Menopause 16:30-36, 2009.

2. Labrie F, Archer D, Bouchard C, et al: Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration.

Menopause16:897-906, 2009.

3. Labrie F, Archer D, Bouchard C, et al: Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause 16:907-922, 2009.

4. Labrie F, Archer D, Bouchard C, et al: ������������������������������������ Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause 16:923-931, 2009.

Dr. Krychman is author of 100 Questions and Answers About Life after Breast Cancer: Sensuality, Sexuality, Intimacy, and 100 Questions and Answers for Women Living with Cancer: A Practical Guide for Female Survivorship.

For more information, please visit http:// www.thesexualhealthcenter.com.

Contact The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief email: Editor@ASCOPost.com Cara H. Glynn, Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash, Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

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PAGE 61

In the News JOP Spotlight

Benchmark Survey Indicates Efficiency Gains in Oncology Practices

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ASCOPost.com

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COGPF

Fig. 1: Three-year trend in total revenue, total practice expense, and cost of goods paid for (COGPF).

Percentages represent change from one year to the next. Reprinted with permission from Towle and Barr.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

5,000,000 4,500,000 4,000,000 3,500,000 3,000,000 2,500,000 2,000,000 1,500,000 1,000,000 500,000 0

Total Medical Revenue Total Operating Costs Medical and Sugical Supplies

9 19 1 9 19 2 9 19 3 9 19 4 9 19 5 9 19 6 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 0 20 5 0 20 6 0 20 7 0 20 8 0 20 9 10

in the same reporting period.

Total practice expense, defined as all cash expenses (including all physician and other salaries) rose by 13.4% in 2008 and then decreased slightly by 0.5% in 2009. “We believe this indicates an overall lowering of the cost of practice operations even as the cost of drugs continues to rise, consistent with the slight increase in the number of new patients per FTE HemOnc,” the authors wrote. “These three measures indicate an overall increase in service delivery efficiency.” (See Fig. 1.) The efficiency gains were accomplished with roughly the same number of nonphysician staff members.

The average number of new patients per FTE HemOnc rose from 378 in 2008 to 389 in 2009, which the authors deemed to be “up slightly.” In their concluding remarks, however, the authors noted that when they introduced the concept of a Elaine L. Towle, CMPE Thomas R. Barr, MBA “Standard HemOnc” several years ago and defined it as The “National Practice Benchmark: “a medical oncology or hematology/ 2010 Report on 2009 Data,” published oncology physician who sees 350 new in the Journal of Oncology Practice,1 patients per year,” many people considpresented results from 189 oncology ered that to be an extremely high numpractices in 44 states responding to the ber. “In this survey that standard has survey (out of approximately 2,000 pracrisen to 389, quite a remarkable gain in tices nationwide invited to participate). productivity,” the authors commented.

Demographic, operational, and finanThe difference between total medical cial data compiled from the practices for revenue and total practice expense “is an 2009 were compared with previously approximation of the amount of money collected data for 2007 and 2008. that is generated to pay both for physician labor and as a return on the risk of Total Revenue Rose business ownership by the physician Looking at total revenue per full-time owner/operator,” the authors explained. equivalent (FTE) hematology/oncol“After years of steady and predictable ogy physician (HemOnc), the survey performance, this gap began to expand in found that total revenue—defined as 2001 and continued to do so until 2007. all collected revenue (both medical and However, from that time on, the gap has nonmedical)—rose 5.6% from 2008 been narrowing.” (See Fig. 2.) to 2009. The rise in revenue occurred New Line of Business despite a 16.1% increase in the cost of A new benchmarking category added goods paid for (COGPF), defined as the to the survey for 2009 was closed-door total of all money paid for drugs minus pharmacy, defined as “a pharmacy that rebates or other cash reductions received

19

“shift toward efficiency” in oncology practices is lowering overall practice expenses even as the cost of drugs continues to rise, according to results of a national survey of community oncology practices. “That efficiency increase can take the form of the hematology/oncology physician doing more clinical work, thus more efficiently utilizing the most valuable and expensive resource of the practice: physician time,” reported Elaine L. Towle, CMPE, and Thomas R. Barr, MBA, of Oncology Metrics, Los Altos, California, where the survey was developed and conducted.

Amount ($)

A

Amount ($)

By Charlotte Bath

Fig. 2: Oncology business trends per full-time equivalent physician. Data from 1991–2003 compiled

by Medical Group Management Association (Englewood, Colorado); data from 2004–2009 compiled

by Oncology Metrics, a division of Altos Solutions (Los Altos, California). Reprinted with permission from Towle and Barr.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

provides services to patients and employees of the practice but is not available to the public at large.” Only 50 of the practices responding to the survey reported operating a closed-door pharmacy, and only 17 provided financial data. “In this small data set, it appears that practices are able to add some revenue to the practice bottom line through this new line of business,” the authors wrote.

The survey requested that practices report drug inventory levels for the beginning and ending of the 12-month period. Data from 51 practices reporting showed that they have been successful in efforts to decrease drug inventory levels. “This frees up capital that was formerly invested in pharmacy inventory and demonstrates an increase in the efficient use of capital rather than an increase in productive capacity. Only if the freed up capital were reinvested to reduce debt or add

capacity in the practice would the financial strength of the practice have remained the same. The financial strength of the See page 51 practice would have been reduced if the cash were not retained,” the authors stated.

“We believe the data presented here indicate that the business operation of oncology practice is becoming more mature, efficient, and self-aware,” the authors concluded. They also contend that the number of survey participants and the quality of data shared indicate “a broader understanding of the use and importance of peer-to-peer benchmarking.”

■

Reference 1. Towle EL, Barr TR: National practice benchmark: 2010 report on 2009 data.

J Oncol Pract 6:228-231, 2010.

The ASCO Post | DECEMBER 2010

PAGE 62

Expert’s Corner Translational Research

A Conversation with Dana-Farber Researcher David Frank, MD, PhD

By Jo Cavallo

S

ince the early 1990s, David Frank, MD, PhD, Associate Professor of Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School in Boston, has focused his research on the regulation of signaling pathways that control gene expression and how these pathways become inappropriately activated in a cancer cell.

In particular, his work led him to the study of STAT transcription factors, which control the expression of genes that regulate cellular proliferation and survival. In normal cells, STATs turn genes on and off within minutes, but in cancer cells, STAT proteins become inappropriately activated, locking the gene in the “on” position, thereby driving the malignant behavior of a cancer cell.

in humans as a way to expedite initial proof-of-concept clinical trials, which is how we identified pyrimethamine as a STAT3 inhibitor. The primary goal of the study is to determine the safety and efficacy of pyrimethamine in pa-

tients with CLL whose disease has progressed on other therapies. However, an important additional goal is to recover cells from these patients after they have been treated to see if we are effectively blocking STAT3 in the can-

cer cells and to determine how we can optimize this type of targeted therapy in subsequent studies.

Do you think pyrimethamine and other drugs you’re investigating in the labo-

When First-line Irinotecan Treatment Fails in EGFR-Expressing Metastatic Colorectal Cancer...

Select ERBITUX + Irinotecan For

David Frank, MD, PhD

Recently, Dr. Frank, and coinvestigator Jennifer Brown, MD, PhD, launched a phase I/II clinical trial for a STAT inhibitor they’ve identified called pyrimethamine (Daraprim) for patients with chronic lymphocytic leukemia (CLL). He hopes to soon open clinical trials for STAT inhibitors to fight other forms of blood cancers and solid tumors as well. The ASCO Post asked Dr. Frank about his research into STAT proteins.

Role of STAT Proteins Would you discuss how STAT proteins affect CLL cells?

Dr. Frank: We have found that one member of the STAT family, STAT3, was activated inappropriately in CLL, as well as in many other types of cancer. Thus, one of our key goals was to try to discover drugs that could block STAT3 function, to form the cornerstone of more effective and less toxic regimens. In addition to screening large chemical libraries, we also examined drugs already known to be safe

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNING ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions

ASCOPost.com | DECEMBER 2010

PAGE 63

Expert’s Corner

ratory will have applications in blood cancers other than CLL and in some solid tumor cancers?

Dr. Frank: Yes, many other forms of cancer are also associated with an overactivation of STATs. These include blood cancers like multiple myeloma and acute forms of leukemia, as well as many other solid tumors

like breast, prostate, lung, pancreatic, and ovarian cancers. So we would really like to extend our work to include these other patients as well. Our overall goal is to identify specific abnormalities in cancer cells that can be effectively targeted in patients. STATs are appealing molecular targets because cancer cells are dependent on

their continuous activation. Normal cells, by contrast, tolerate inhibition of STAT function with little apparent consequence.

Research Challenges What is the biggest obstacle to translational research today?

Dr. Frank: One major concern is

Improved Objective RESPONSE RATE ERBITUX Is the Only Anti-EGFR MAb With Evidence to Suggest That It Restores Chemosensitivity to Irinotecan After Progression on Irinotecan ■ ERBITUX + irinotecan is more effective than ERBITUX alone2,3

Objective Response Rates in Second-line Treatment and Beyond, All Patients (N=329)*2,3 23% ERBITUX + irinotecan (n=218)

vs

11% ERBITUX alone (n=111)

95% CI: 18-29% P=0.007

95% CI: 6-18%

Median duration of response: 5.7 months Median time to progression†: 4.1 months

Median duration of response: 4.2 months Median time to progression†: 1.5 months

2x

increase in response rate

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; CI=confidence interval. *A multicenter, randomized (2:1), controlled clinical trial was conducted with ERBITUX + irinotecan vs ERBITUX alone. 2 † Difference between groups (hazard ratio: 0.54 [95% CI: 0.42-0.71]; P<0.001). 1

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients2

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/ malaise (16%), and acneform rash (14%) Please see Important Safety Information including Boxed WARNINGS on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

that we need greater funding to support research focused on translating laboratory advances into clinical trials for patients. The basic research journals are filled with interesting new findings, and we have to make more of an effort to determine which of these discoveries will really continued on page 64

The ASCO Post | DECEMBER 2010

PAGE 64

Expert’s Corner

Conversation with Dr. Frank continued from page 63

be important to improving the care of our patients.

In addition, there is an erroneous perception among some individuals that new therapies can only come from industry. I think that a lot of innovative translational work

is coming from academic laboratories, and it would be beneficial if there were stronger support for academic investigators to directly test these discoveries.

Would you like to share any closing thoughts about clinical research?

With 1,500 people dying of can-

cer each day in the United States, we need to do whatever we can to accelerate the introduction of novel therapeutic strategies. In the case of pyrimethamine, we were fortunate to have received funding from a private foundation, the Lymphoma Research Foundation, to accelerate this research.

I’ve been an oncologist for 20 years, and I’m somewhat disappointed at the relative lack of progress we have made in that time. We desperately need better treatments for our patients with cancer and I feel that we in the oncology community need to take more of a leadership role to make this occur.

■

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 —Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

ASCOPost.com | DECEMBER 2010

PAGE 65

FDA Update

FDA Approves New Treatment for Late-stage Breast Cancer The FDA has approved eribulin mesylate (Halaven, marketed by Eisai) to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for latestage disease.

Eribulin is a synthetic form of a che-

motherapeutically active compound derived from the sea sponge Halichondria okadai. This injectable therapy is a microtubule inhibitor, believed to work by inhibiting cancer cell growth.

Before receiving eribulin, patients should have received prior anthracycline- and taxane-based chemotherapy for early or late-stage breast cancer.

Eribulin’s safety and effectiveness were established in a single study in 762 women with metastatic breast cancer who had received at least two prior chemotherapy regimens for late-stage disease. Patients were randomly assigned to receive either eribulin or a different single-agent therapy chosen by their oncologist. The median overall survival for pa-

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX (cetuximab) and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/ malaise (16%), and acneform rash (14%) References: 1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345. 2. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 3. US Food and Drug Administration, Center for Drug Evaluation and Research. Medical review of ERBITUX (cetuximab) BLA. http://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/ 125084_ERBITUX_MEDR_P2.pdf. Accessed January 7, 2010.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

© 2010 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014and Bristol-Myers Squibb, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US09AB24413

10/10

tients receiving eribulin was 13.1 months compared with 10.6 months for those who received a single-agent therapy.

“Halaven shows a clear survival benefit and is an important new option for women,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

■

The ASCO Post | DECEMBER 2010

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Appointments

Michael L. Steinberg, MD, Named President-Elect of ASTRO Michael L. Steinberg, MD, FASTRO, UCLA Center for Health Sciences, Los Angeles, has been named President-elect of the American Society for Radiation Oncology (ASTRO).

Dr. Steinberg’s term became effective

at ASTRO’s 52nd Annual Meeting held recently in San Diego.

Other newly elected members to ASTRO’s Board of Directors included: Secretary/Treasurer-elect, Phillip M. Devlin, MD, Brigham and Women’s Hospital, Boston; Education Council Vice-chairman Laura A. Dawson, MD, Princess Margaret Hospital, To-

ronto, Ontario, Canada; and Government Relations Council Vice-chairman Bharat Mittal, MD, FASTRO, Northwestern Memorial Hospital, Chicago.

“Strong leaders are essential to the success of an organization like ASTRO, and I am honored to announce the new officers that our mem-

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONs None.

WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

bers have elected,” Tim R. Williams, MD, ASTRO chairman, said. “I am confident these dedicated individuals will bring the same level of expertise and commitment to the Society that our members and the patients they serve have come to expect. I offer my sincere congratulations to each of the new officers.”

■

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

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 data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 16 0 5 0 Chills1 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 38 1 24 1 Aspartate Transaminase, high3 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 skin/Appendages 4 87 17 10 1 Acneform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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Appointments

Four US Oncology Oncologists Elected by Peers as ‘Best Doctors’ Four oncologists from Wilshire Oncology Medical Group, Inc. (WOMGI), an affiliate of the United Network of US Oncology, have been elected by their peers for inclusion in the Best Doctors in America 2010-2012.

Linda D. Bosserman, MD, FACP

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 11 0 4 0 Mouth Dryness Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

Ben Ebrahimi, MD

Frank D. Howard, IV, MD, PhD, FACP

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Physicians are included in this database based on the results of an extensive, confidential peer-review process. Linda D. Bosserman, MD, Cary A. Presant, MD FACP has been included in the database since 2005. Ben Ebrahimi, MD and Frank D. Howard, IV, MD, PhD, FACP, have been elected since 2007.

Cary A. Presant, MD, FACP has received this recognition since 1994.

“It is a huge honor for Wilshire Oncology Medical Group to have four of its doctors recognized year-after-year for doing what they are passionate about, caring for their patients,” said Dr. Bosserman, practice president, WOMGI. “To be chosen by medical professionals, our own peers and colleagues, makes it special for us as well.”

Best Doctors® harnesses the knowledge of the 47,000 physicians included in the database to provide a unique combination of medical experience, skill and insight that patients can access to help them confidently manage complex medical problems. Today, Best Doctors serves more than 10 million people in 30 countries and has worldwide acclaim for successfully connecting patients to the best medical care – in the process, saving time, anguish and in some cases, lives.

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Lung screening benefit 3

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Contralateral prophylactic mastectomy 17

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DECEMBER 2010 ASCOPost.com

Lymphoma: Many Questions, Too Few Answers

35th ESMO Congress

Studies Show Progress in Treatment of Triple-negative Breast Cancer

By Caroline Helwick

F

or the treatment of triple-negative breast cancer, the poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor iniparib improved overall survival, and cetuximab (Erbitux) showed benefit as well, in two randomized phase II studies presented at the 35th ESMO Congress in Milan, Italy.

Eagerly Awaited Data The data on overall survival with iniparib (BSI201) have been eagerly awaited after encouraging results were presented at the 2009 ASCO Annual Meeting in Chicago.1 Joyce O’Shaughnessy, MD, of US Oncology and Baylor Sammons Cancer Center, Houston, reported the final results of the multicenter phase II open-label study of 123 patients at ESMO, showing that iniparib (5.6 mg/kg) plus gemJoyce O’Shaughnessy, MD citabine (1,000 mg/m2) and

Use your smartphone to view the original abstracts as presented at the 35th ESMO Congress.

See page 51 for more information about using 2D barcodes

carboplatin (AUC 2) every 3 weeks produced not only a longer time to disease progression but also a longer survival time, compared with a regimen of gemcitabine/carboplatin only.2 “Overall survival was not a prespecified endpoint in the protocol, but is reported as a clinically relevant endpoint,” Dr. O’Shaughnessy said. A survival benefit was shown in spite of a 30% rate of crossovers from the control to the experimental arm, although the activity of iniparib appeared limited in this setting, she added.

Median overall survival time was 12.2 months with the combination, compared with 7.7 months with chemotherapy, amounting to a 43% reduction in risk (P = .014). Median progression-free survival (PFS) continued on page 9

Health-care Industry

McKesson Buys US Oncology: Assessing the Impact on Oncology Community and Future Practice

By Caroline Helwick

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

VOLUME 1, ISSUE 7

ESA guidelines update 44

Editor-in-Chief, James O. Armitage, MD

T

he recent announcement that McKesson Corporation, the biggest U.S. drug distributor, will purchase US Oncology was met with some measure of surprise and a large amount of interest within the oncology community. McKesson will pay cash for the deal, valued at $2.16 billion, to merge US Oncology into its Specialty Care Solutions unit. The deal will expand McKesson’s current cadre of oncologists from 1,000 to nearly 3,000. In the words of a Wall Street blogger, the merger gives McKesson “a big customer plugged in as a subsidiary.” The ASCO Post asked a variety of interested parties what this arrangement will mean to the specialty.

‘Bolt Out of the Blue’ The news was a “bolt out of the blue” to Allen Lichter, MD, CEO of ASCO. He maintained that from the point of view of US Oncology, “this is potentially a very good move.”

The merger will relieve US Oncology from its debt,

allow it to free up capital to invest back into its network, and help advance its emerging information technology (IT) system. “It aligns US Oncology with a powerful and successful corporation,” he said. “There are uncertainties as to what the health-care environment will look like in 3 years, and stabilizing your company through a business arrangement such as this is, at least on the surface, something that makes sense.”

Strengths and Weaknesses It certainly makes sense to US Oncology, according to the company’s Medical Director Roy A. Beveridge, MD, who told The ASCO Post, “The entire organization is very excited about this. It allows US Oncology to complement our weaknesses with McKesson’s strengths, and vice versa, which is a situation that doesn’t often happen.”

According to Dr. Beveridge, one of the chief benefits to physicians and patients is the strength of McKes-

By George P. Canellos, MD

T

he successful treatment of malignant lymphoma has been one of the great achievements in medical oncology, but certainly more work is needed to define key biologic targets as well as molecular markers for a more accurate definition of prognosis following therapy. In day-to-day practice, unanswered questions arise in the management of these diseases. Nevertheless, a profusion of new agents is emerging from the biotechnology industry, requiring clinical assessment for safety and efficacy. Meanwhile, we encounter clinical situations for which there are still no answers.

Clinical Trials Needed I am prompted to enumerate situations where appropriate clinical (preferably prospective randomized) trials could have or should have been done to facilitate clinical decisions. To mention just a few issues that have arisen recently: A form of extranodal lymphoma called mediastinal large cell lymphoma, which occurs in younger patients, has biologic and clinical similarities to Hodgkin lymphoma. As with localized Hodgkin lymphoma, there is a propensity to add mediastinal radiation therapy following chemotherapy. continued on page 2

Dr. Canellos is William Rosenberg Professor of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute, Boston.

MORE IN THIS ISSUE Oncology Meetings Coverage

52nd ASTRO Annual Meeting................ 16 2010 Breast Ca Symposium.............17, 18 35th ESMO Congress.............. 22, 27, 30

Direct from ASCO.................................... 33 ESMO/ASCO Joint Symposium............. 54 Telehealth/Telemedicine ......................... 74

continued on page 8

A Harborside Press Publication

Copyright © 2004–2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

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Rev September 2010

Send Us Your News Send your news of new appointments, awards, or significant events to The ASCO Post. Write to editor@ASCOPost.com. All submissions will be considered for publication.

The ASCO Post | DECEMBER 2010

PAGE 68

In the News Screening

Is ‘Autopilot’ Screening Subjecting Patients with Advanced Cancer to Meaningless Tests?

By Charlotte Bath In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

W

hy would patients with advanced cancer continue to undergo mammograms or colonoscopies when their limited life expectancies make it unlikely the screening will provide any benefit and could cause harm or at least discomfort? In many cases, suggests a recent article in the Journal of the American Medical Association,1 the screening continues out of habit and is an example of the “culture of screening on ‘autopilot.’”

Barnett S. Kramer, MD

“A sizeable proportion of patients with advanced cancer continue to undergo cancer screening tests that do not have a meaningful likelihood of providing benefit,” the authors concluded. That proportion included 8.9% of women with a diagnosis of advanced cancer who received at least one screening mammogram and 5.8% who received at least one Pap test; 15% of men with a diagnosis of advanced cancer who received a prostate-specific antigen (PSA) test; and 1.7% of all patients with a diagnosis of advanced cancer who received a lower GI endoscopy. The study used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry to evaluate use of cancer screening among 87,736 Medicare patients aged 65 or older who were diagnosed with advanced lung, colorectal, pancreatic, gastroesophageal, or breast cancer, and 87,307 matched controls. For all screening tests studied (mammogra-

phy, Pap test, PSA, and lower GI endoscopy), use was higher among the controls.

What’s Driving the Screening?

The strongest predictor of patients with advanced cancer receiving screening was a personal history of screening. “The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits,” the study authors commented. “Patients and their health-care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risks from advanced cancer.”

Barnett S. Kramer, MD, MPH, Associate Director for Disease Prevention at the National Institutes of Health, agreed that habit is one of the factors driving screening. “People who have been screened regularly in the past basically feel that it is part of their health program and that they may therefore continue screening,” he said.

Another reason he cited for continued screening is “the difficulty in talking about things like shortened life expectancy. Physicians often overestimate the prognosis in someone who has advanced cancer. Patients don’t like to think that their cancer is going to shorten their life so much, and they may be optimistic or feel like they are going to beat the odds, and therefore screening remains a good strategy for them. But, on average, the overwhelming majority of people are not going to beat the odds. The odds are that their life expectancy is far shorter than it would take for a benefit from screening to emerge,” Dr. Kramer continued.

“I think that any medical intervention should only be proposed when there is an anticipated benefit, because there are harms,” Dr. Kramer added. “Whenever the issue of screening comes up, the underlying health of the patient should be taken into account. As a medical oncologist, I’ve been involved in that discussion many times, and it is very difficult for both patient and physician. Neither party to the discussion looks forward to the facts. So it is easy to set it aside and go onto autopilot,” as stated in the study.

Expect (and Encourage) Questions

W

hen patients using denial as a coping strategy meet physicians reluctant to discuss poor prognoses, the result can be a “communication deficit,” according to the recent JAMA study on cancer screening of patients with advanced cancer. Coverage of the study by the medical and popular media, including the Boston Globe and National Public Radio’s Health Blog, may prompt questions from patients and facilitate communication among physicians. The study serves as “one more reminder for good communication between primary care doctors and oncologists,” noted Deborah Schrag, MD, MPH, one of the study’s authors.

What should patients be encouraged to do?

“If patients with advanced cancer get reminders to have their colonoscopy, or mammogram, or PSA, they should discuss with their oncologist whether continuing screening makes sense for them in the context of their particular illness. That’s a very clear message,” Dr. Schrag added.

What can primary care physicians do?

Patients with advanced cancer who are used to getting screening tests and doing what their doctors tell them to do may worry if they receive a reminder about a screening test and feel that they should follow their doctor’s orders to get the test, even when dealing with the effects of advanced cancer. Dr. Schrag suggested that one way to counteract “autopilot” screening reminders would be to put a “tickler” in a patient’s medical record, so that physicians would double-check before going ahead with a screening test for a patient with advanced cancer. For example, the tickler might read: “You just ordered a mammogram on this patient who also has metastatic lung cancer. Are you sure? If the benefit of mammography in patients with stage IV lung cancer is uncertain, are you sure you want to proceed?”

What can oncologists do?

Oncologists can explain to patients with advanced cancer who ask about screening reminders they received that the patients are unlikely to benefit from the screening test and might choose to spend their time doing something more enjoyable. “When someone has advanced cancer,” Dr. Schrag said, “we need to be respectful of the patient’s time and energy.”

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Putting It in Perspective “High-quality care means getting the right care to the right patient at the right time,” one of the study’s authors, Deborah Schrag, MD, MPH, explained in an interview with The ASCO Post. “The major problem in this country concerns people for whom screening is the right care, but they are not getting it,” she said. “A more minor problem that our paper shone a spotlight on is that some patients are getting the right care at the wrong time in their lives. It is not helpful for them. It is not respectful.” Dr. Schrag is a medical oncologist and clinical investigator, Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School.

“There is always a balance of risks

and benefits, and even a beneficial screening test for the general healthy population may have a reversed ratio of benefit to harm if the person has a serious life-threatening comorbid condition. Certainly very few would question that advanced cancer is one of those conditions,” Dr. Kramer said.

“Any intervention that has both benefits and harms should be individualized. That is the nature of personalized medicine, and this is a clear setting in which personalized medicine would have a benefit,” he commented.

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Reference 1. Sima CS, Panageas KS, Schrag D: Cancer screening among patients with advanced cancer. JAMA 304:1584-1591, 2010.

ASCOPost.com | DECEMBER 2010

PAGE 69

In the Literature

Emerging Clinical Data on Cancer Diagnosis and Management BREAST CANCER Hormone Therapy Linked to Increased Incidence of Breast Cancer, Node-positive Disease, and Risk of Death Use of estrogen plus progestin among postmenopausal women was associated with an increased incidence of breast cancers, and these cancers are more likely to be node-positive, according to followup of participants in the Women’s Health Initiative (WHI). For the first time, information was reported on breast cancer mortality related to combined hormone therapy use in the WHI trial, and the data showed a higher risk of deaths attributable to breast cancer. The results of the follow-up were reported in The Journal of the American Medical Association.

The WHI trial compared estrogen plus progestin to placebo in 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy. The women were initially randomized in 1993 to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo. The study intervention phase was stopped in 2002, when combined hormone therapy was associated with an increased risk of invasive breast cancers and delayed breast cancer diagnosis, leading to more advanced cancers. Participants were then instructed to stop taking their assigned study medication, but clinical visits and follow-up continued until the planned trial completion date at the end of March 2005.

Reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.

Key Results Mean follow-up in the intervention and postintervention phases was 11 years. In the latest follow-up, the researchers found that in intention-to-treat analyses, including all randomized participants and censoring those not consenting to additional follow-up, estrogen plus progestin increased the incidence of invasive breast cancer compared with placebo. There were 385 cases (0.42% per year) in the estrogen-plus-progestin group vs 293 cases (0.34% per year) in the placebo group. A significantly larger fraction of women receiving the combined hormone therapy (81 women, or 23.7%) had breast cancers with positive lymph nodes, compared with women

given placebo (43 women, or 16.2%).

“More women died of breast cancer in the combined hormone therapy group compared with the placebo group,” the authors state. There were 25 deaths (0.03% per year) in the hormone group vs 12 deaths (0.01% per year). This represents 2.6 vs 1.3 deaths per 10,000 women per year in the hormone therapy vs placebo groups.

“Consideration of all-cause mortality after breast cancer diagnosis provided similar results,” the authors continued.

There were 51 deaths (0.05% per year) in the hormone therapy group, compared with 31 deaths (0.03% per year) among women in the placebo group, representing 5.3 vs 3.4 deaths per 10,000 women per year, respectively.

“With some exceptions, the preponderance of observational studies have associated combined hormone therapy use with an increase in breast cancers that have favorable characteristics, lower stage, and longer survival compared with breast cancers diagnosed in nonusers of hormone therapy,” the authors commented. In the WHI trial, however, “combined hormone therapy increased breast cancer risk and interfered with breast cancer detection, leading to cancers being diagnosed at more advanced stages.” The longer follow-up results now available reveal a cumulative, statistically significant increase in breast cancers in the combined hormone therapy group, and these cancers more commonly involved the lymph nodes.

“The observed adverse influence on breast cancer mortality of combined hormone therapy can reasonably be explained by the influence on breast cancer incidence and stage,” the authors added.

risk-benefit tradeoffs in pursuit of an informed patient decision—may seem at first blush to be a reasonable approach given this lack of evidence.

But the reality is that informed patient decisions are not valid when the information underlying the decision is itself speculative.” He added that additional randomized trials are needed to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk.

Chlebowski RT, et al: JAMA 304:16841692, 2010.

Bach PB: JAMA 304:1719-1720, 2010.

SUPPORTIVE CARE Integrating Management of Hypogonadism into Oncology Practice The prevalence of symptomatic hypogonadism is higher among men with cancer and because of the impact of hypogonadism on quality of life (QOL), “the diagnosis and management of hypogonadism should be integrated into oncology practice,” according to a study reported in the Journal of Clinical Oncology. “As greater numbers of patients with cancer become long-term survivors, conditions associated with low serum testosterone levels, such as osteopenia, altered cognitive function, increased risk of metabolic syndrome and atherosclerosis, and alterations in QOL, assume greater importance,” the study authors stated.

Investigators collected blood and medical histories from 428 male patients with non–testosterone-related

cancers. Patients with prostate, testicular, or male breast cancer were excluded, as were men with known hypogonadism and HIV. The study measured crude prevalence of hypogonadism on the basis of serum testosterone levels.

Although the study excluded prostate cancer, the Functional Assessment of Cancer Therapy–Prostate (FACT-P) QOL questionnaire was used to target areas of assessment in the study population, measuring physical, social, emotional, and functional domains, as well as sexual function.

Study Details Among the 407 evaluable patients, the mean age was 62; 88% had received chemotherapy, and 40% had received radiotherapy. Nearly half of the patients (48%, n = 196) were hypogonadal (total testosterone [TT] < 300 ng/dL). The median TT level for hypogonadal patients was 185 ng/dL; for eugonadal patients, it was 438 ng/ dL. Significant differences were found for other measures of testosterone, including free testosterone, bioavailable testosterone, and sex hormone–binding globulin.

Hypogonadal patients were more likely than eugonadal patients to be white (73% vs 59%), obese (26% vs 17%), diabetic (21% vs 14%), present with pain ≥ 2 on a 5-point scale (34% vs 25%), and be treated with opioids (29% vs 18%). Hypogonadal patients had decreased overall QOL scores on the FACT-P and decreased scores for physical well-being, functional wellbeing, and sexual function.

Expert Perspective In an accompanying editorial, Peter B. Bach, MD, of Memorial Sloan-Kettering Cancer Center in New York noted that the “available data dictate caution in the current approach to use of hormone therapy, particularly because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health.

Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude.”

Dr. Bach continued, “One option—discussing with patients the

© Harry Bliss/The New Yorker Collection/www.cartoonbank.com

continued on page 70

The ASCO Post | DECEMBER 2010

PAGE 70

In the Literature

Emerging Clinical Data continued from page 69

“The most important predictors of hypogonadism in our cancer population were obesity, opioid use, and white ethnicity. The higher prevalence is partly explained by these factors, but an effect of cancer and related therapy is suspected, although

the exact contribution can only be postulated,” the investigators stated.

“Because of long-term consequences and alterations in QOL, the diagnosis and management of hypogonadism should be integrated into oncology practice.”

Fleishman SB, et al: J Clin Oncol October 25, 2010 (early release online).

LUNG CANCER Crizotinib Produces ‘Impressive’ Response Rate in Patients with Advanced NSCLC and ALK Rearrangement Crizotinib (PF-02341066), an oral selective inhibitor of the anaplas-

w ww w w. w. a ap po os s -- s so oc c ii e e tt y. y. o or rg g // a ap po os s2 20 0 11 11

The American Psychosocial Oncology Society (APOS) invites you to join us at the The American Psychosocial Oncology Society (APOS) invites you to join us at the APOS 8th Annual Conference in Anaheim, CA, USA, 17 - 19 February 2011.

APOS 8th Annual Conference in Anaheim, CA, USA, 17 - 19 February 2011.

Quality Quality Cancer Cancer Care Care Across Across the the Lifespan: Lifespan:

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tic lymphoma kinase (ALK) tyrosine kinase, resulted in tumor shrinkage or stable disease in most patients with advanced non–small cell lung cancer (NSLC) with ALK rearrangement enrolled in a phase I study. The overall response rate at a mean treatment duration of 6.4 months was 57%, with 46 of the 82 patients enrolled in the study having confirmed partial responses and 1 having a confirmed complete response). In addition, 27 patients (33%) had stable disease. Of the 82 patients, 63 (77%) continued to receive crizotinib after the data cutoff for the study, and the estimated probability of 6-month progressionfree survival was 72%, with no median for the study reached at the time of publication.

Potential of Prospective Genotyping “The response rate is impressive, as compared with the approximate 10% response rate in such cancers that were treated with second-line chemotherapy,” the investigators reported in The New England Journal of Medicine. “The rate and speed of clinical response were similar to those shown

by EGFR tyrosine kinase inhibitors in EGFR-mutant non–small cell lung cancers,” the authors continued, “which suggests that ALK-positive tumors constitute a second genetically defined subgroup of oncogene-driven lung cancer that is highly susceptible to targeted therapy.”

Most of the 82 patients in this study had received previous treatment. “Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas,” the researchers reported. Patients were enrolled in this expanded cohort study after a phase I dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. The most commonly reported side effects were grade 1 nausea and diarrhea.

The investigators noted that prospective genotyping was crucial in being able to identify patients with ALK rearrangement. They point out that prospective genotyping “has the potential to streamline drug development” and “may also more effectively direct patients to the trials that are most likely to provide benefit.”

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Kwak E L, et al: N Eng J Med 363:16931703, 2010.

ASCOPost.com | DECEMBER 2010

PAGE 71

News Gastrointestinal Cancer

New Treatments for GI Cancers Desperately Needed, but Thoughtfulness and Economy Are Necessary

By Margot J. Fromer

D

espite the quantity and diversity of research that will improve the future for people with gastrointestinal (GI) cancers, the present is not a happy place for them, said John L. Marshall, MD, Chief, Division of Hematology and Oncology and Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Lombardi Comprehensive Cancer Center.

He moderated the symposium, “Molecular Diagnostics Drive Personalized Medicine: State of the Art 2010,” which was held at Lombardi in early November.

John L. Marshall, MD

“There is no continuum of treatment for the 275,720 people newly diagnosed with GI cancers last year (and the more than 135,300 deaths), and development of blockbuster drugs has just about stopped,” he said. Not only are there upwards of 50 genetic mutations, we have barely begun to figure out their patterns. “Moreover, NCCN guidelines are no longer just guidelines; they have become ‘the law of the land.’ We give 97% of all patients the same treatment regimen (about 3% are in clinical trials), and 80% of them die regardless. The standard of care is less than adequate—far less.”

With that gloomy preamble, Dr. Marshall introduced speakers who discussed the impact of personalized medicine on the health-care system.

They approached the issues from different perspectives, but their messages were similar: Although new treatments for GI cancers are desperately needed, the endeavor must be approached thoughtfully, with attention paid to ethical ramifications and the ultimate value to patients of this very costly research.

Medicare Wants Treatments that Work Louis Jacques, MD, Director of

the Centers for Medicare & Medicaid Services (CMS) Coverage and Analysis Group, explained that cancer policy includes treatment with both curative and palliative intent, supportive care for complications and adverse events, and use of biomarkers for drug and/or biologic discovery and development.

When reviewing clinical evidence, CMS asks if the patient is better, if there is an increased chance of survival, and whether he or she can continue to function reasonably normally.

Dr. Jacques described some of CMS’s challenges in molecular testing and biomarker development: standards and techniques that are not FDA approved (“home brews”), tests that may be used during drug development but that are not commercially available for clinical practice, and the problems posed by molecular testing when there is no simple way to recognize an erroneous or misleading test result.

How do these factors affect outcome? Is the patient better or worse off?

To evaluate these issues, or at least determine which questions are appropriate, CMS and other agencies use a process developed by the Centers for Disease Control and Prevention (CDC) for evaluating genetic tests. It’s called ACCE and consists of: ■■ Analytic validity: how accurately and reliably a test measures a genotype.

■■ Clinical validity: how consistently and accurately a test detects or predicts intermediate or final outcomes.

■■ Clinical utility: how likely the test is to significantly improve patient outcomes.

■■ Ethical, legal, and social issues that arise in the context of using a test.

Bioethical Implications In September 2007, when personalized medicine became the acknowledged wave of the future in cancer treatment, then Secretary of the U.S. Department of Health and Human Services (HHS) Michael Levitt coined a motto for it: The right treatment for the right person at the right time. (Andrew C. von Eschenbach, MD, former NCI Director and FDA Commis-

Expert Point of View

W

e need to change the way we research and treat cancer,” said John L. Marshall, MD, Chief, Division of Hematology and Oncology and Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Lombardi Comprehensive Cancer Center.

“About 40 of my 50 current patients with GI cancers are going to die no matter what I do, and that is simply not acceptable. We have to figure out how to give patients longer and better lives.”

Dr. Marshall was referring not only to individuals but also to the entire research endeavor. “And to the American public.”

Imperfect, Expensive Drugs People want value for their money, and the current crop of extraordinarily expensive cancer agents don’t work as well or as long as first thought.

He cited two dramatic examples: sipuleucel T (Provenge) and bevacizumab (Avastin).

The vaccine sipuleucel T was approved in April for advanced prostate cancer, and now CMS is running a “national coverage analysis” to determine if it will reimburse the $93,000 per-patient cost—for an average 4 months of survival.

Bevacizumab for metastatic breast cancer is even more expensive, and postmarketing studies showed that it did not extend survival at all. The FDA Oncologic Drugs Advisory Committee overwhelmingly recommended withdrawal of bevacizumab’s approval for that indication. FDA says it will decide by mid-December.

And gemtuzumab (Mylotarg) for acute myeloid leukemia has already been withdrawn after postmarketing studies cast doubt on the agent’s effectiveness and a shadow over its safety.

Giant Disconnect “Rethinking cancer treatment means that we cannot count on finding ‘one-size-fits-all’ blockbuster drugs; rather we have to discover treatments that not only improve survival and quality of life but provide good value for the investment,” Dr. Marshall said. “Right now, there’s a giant disconnect between the cost of cancer care and clinical benefit. We’re not getting what we pay for.”

Moreover, he added, there is little evidence to support the treatments we are providing, and because so few patients participate in clinical trials, we have no way of tracking their outcomes, and we learn almost nothing from them.

“There has to be public dialogue about these problems, and we have to solve them. We can’t wait.”

■

sioner, would add: for the right reason and the right outcome.)

What does this mean? asked Kevin T. FitzGerald, SJ, PhD, Research Associate Professor and David Lauler Chair for Catholic Health Ethics, Georgetown University. “Who, after all, wants the wrong treatment—at any time?”

Public airing of Secretary Levitt’s somewhat indistinct goal highlighted its elementary status and inherent challenges: ■■ Health-care disparities are wide-

spread in the United States, especially with regard to genetic endowment. This results in significant variance in response to drugs and biologicals.

■■ Issues of race, sociology, and biogeographics also affect the way people respond to treatment—and whether they receive treatment at all.

■■ All problems regarding privacy, informed consent, and liability were not resolved by GINA (Gecontinued on page 72

The ASCO Post | DECEMBER 2010

PAGE 72

News

New Treatments for GI Cancers Needed

Health-care Reform and Cancer Treatment

continued from page 71

The Lombardi seminar took place 2 days after House Democrats received a shellacking at the polls, and Dr. von Eschenbach, now Senior Director for Strategic Initiatives at the Center for Health Transformation, Washington, DC, wondered aloud about implica-

netic Information Nondiscrimination Act). “People see these issues very differently, and they have widely varying views about benefit, risk, and harm,” said Dr. FitzGerald.

tions of the election for health-care reform. “The Democrats who lost are conservatives, but the Republicans who took their places are even more so.”

He thinks that at least for the next 2 years, the country will focus on the economy and jobs, as well as an effort to repeal the health-care reform law.

call For PaPers

He said that 54% of Americans are in favor of getting rid of the law, and there probably won’t be much discussion about which parts of it should be saved and which can be ditched. “The emphasis is on repeal, repeal, repeal—rather than on the challenges of implementation and on the economics of change.

President Obama is going to be hard put to save his signature legislation.”

Payer/Provider relationshiPs in oncology: A Joint call for Papers for a Special Issue from The American Journal of Managed Care & Journal of Oncology Practice

To help facilitate cooperation between the often divergent groups of payers and providers in oncology, American Journal of Managed Care and Journal of Oncology Practice are collaborating on a special issue that addresses topics relevant to the payer/provider relationship in the field of oncology. This special issue will present clinical, pharmacoeconomic, and regulatory information that will help inform decisions — at the provider, plan, and policy levels — to help manage costs and improve outcomes in cancer care. The Editors seek original research papers and informed commentary on the following topics: • Comparative effectiveness research and methodologies • Measuring outcomes and quality of care • New innovations for diagnosing and treatment • Cost of new therapeutic agents and their impact on patients/providers • Understanding reimbursement for approved and non-approved indications • Effects of healthcare reform on cancer care • Impact of plan design on patient access to appropriate therapies • Examples of integrating evidence-based guidelines into practice • Methodologies for provider and payers accountability • Innovative partnerships between payers and providers All papers will undergo each Journal’s customary peer-review process. Final decisions regarding inclusion in this special issue rest solely with the Editors. Please submit your manuscript by January 15, 2011 to http://mc.manuscriptcentral.com/ajmc. Limit text to 2,500 words excluding references.

Andrew C. von Eschenbach, MD

Dr. von Eschenbach believes that all decisions about health-care reform will have serious economic consequences for cancer research and cancer care, especially the pressure to lower costs. Finding new funds is just about impossible now. “We’re broke,” he said flatly.

Therefore, ensuring that all Americans have access to the health care they need requires what he calls the three As: ■■ Availability. “If care doesn’t exist, it obviously isn’t available; therefore, innovation is imperative.”

■■ Affordability. “We need to be more disciplined stewards of our resources.”

■■ Appropriateness. “No one likes change, but we must create value for the research dollars we spend, and we have to generate jobs in the process.” Moreover, the mass migration of innovation out of the United States and into China, India, and the rest of the world is having catastrophic effects on our economy.

“We must foster innovation and development, and we must decrease cost and improve quality. This will engender profound and complex change over the next few years, but it’s not just necessary, it’s a matter of life and death.”

■

For more on GI cancers, see pages

For more information, visit www.jop.ascopubs.org or www.ajmc.com.

ASC 101271 JOP AJMC Call for Papers Ad V2.indd 1

10/14/10 4:59:56 PM

11, 16, and 30.

ASCOPost.com | DECEMBER 2010

PAGE 73

News Prevention

HHS Announces New Tobacco Strategy and Proposed New Warnings and Graphics for Cigarette Packs and Advertisements

T

he U.S. Department of Health and Human Services recently unveiled a new comprehensive tobacco control strategy that includes proposed new bolder health warnings on cigarette packages and advertisements. Once final, these health warnings on cigarettes and in cigarette advertisements will be the most significant change in more than 25 years. These actions are part of a broader strategy that will help tobacco users quit and prevent children from starting.

The strategy includes a proposal issued by the Food and Drug Administration titled Required Warnings for Cigarette Packages and Advertisements.

Specifically, the proposed rule details a requirement of the Family Smoking Prevention and Tobacco Control Act that nine new larger and more noticeable textual warning statements and color graphic images depicting the negative health consequences of smoking appear on cigarette packages and in cigarette advertisements. The public has an opportunity to comment on 36 proposed images through January 9, 2011.

Key Dates

By June 22, 2011, FDA will select the final nine graphic and textual warning statements after a comprehensive review of the relevant scientific literature, the public comments, and results from an 18,000-person study. Implementation of the final rule (September 22, 2012) will ultimately prohibit companies from manufacturing cigarettes without new graphic health warnings on their packages for sale or distribution in the United States. In addition, manufacturers, importers, dis-

tributors and retailers will no longer be allowed to advertise cigarettes without the new graphic health warnings in the United States. By October 22, 2012, manufacturers can no longer distribute cigarettes for sale in the United States that do not display the new graphic health warnings.

The American Association for Cancer Research (AACR) applauded HHS for its newly launched comprehensive tobacco control program.

18 Different Cancers “Science has established that tobacco use can cause an astonishing 18 different cancers — not just lung cancer,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “Tobacco-related cancers are preventable. We must work together to build upon the renewed efforts of the HHS to implement effective evidence-based policies where they exist and to galvanize research activities where evidence is slim.”

“Although tobacco use in the United States has decreased remarkably over the last half century, an estimated one in five U.S. adults still uses tobacco on a regular basis,” said Roy S. Herbst, MD, PhD, of the University of Texas MD Anderson Cancer Center and Chair of the AACR’s Task Force on Tobacco and Cancer.

Tobacco kills more than 5 million people per year worldwide and nearly half a million people in the United States alone. Tobacco use takes an economic toll too: the estimated total annual economic burden of cigarette smoking, including direct health-care expenditures and productivity losses, is more than $190 billion in the United States alone.

■

Health warnings for U.S. Food and Drug Administration proposed regulation “Required Warnings for Cigarettes Packages and Advertisements.”

The ASCO Post (ISSN 2154-3283) is published 12 times annually by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodical Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Domestic: $75 for the print or online edition; $125 for both editions. International: $125 for print or online edition; $175 for both editions. Contact subscriptions@harborsidepress.com.

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The ASCO Post | DECEMBER 2010

PAGE 74

Opinion

Telehealth/Telemedicine: Join the Band(width)

By Richard J. Boxer, MD

T

elehealth and telemedicine— sometimes the terms are used interchangeably—is the access point to medicine for millions of Americans, and its use will continue to grow every year. ASCO members and all health professionals who care for individuals impacted by cancer have found or will find that electronic communication offers a tremendous advantage.

With the government mandating the use of electronic health records, the new health reform act (the Patient Protection and Affordable Care Act [PPACA]) resulting in more than 30 million newly insured patients, the estimate that there will be a shortfall of tens of thousands of physicians, and a Merritt Hawkins Consulting firm survey reporting that it takes patients 2 to 6 weeks to obtain a consultation, the need for affordable, accessible, quality health care is not just a current crisis.

It is going to get worse—a lot worse.

One part of the solution may be telemedicine. If used wisely, it will lead to greater access, affordability, convenience, and quality care.

Telemedicine Defined The use of electronic communications in health care is a huge business, expanding at a compound annual growth rate of more than 55% over the next 5 years.1 According to the American Telemedicine Association, Telemedicine is the use of medical information exchanged from one site to another via electronic communications to improve patients’ health status. Closely associated with telemedicine is the term ‘telehealth,’ which is often used to encompass a broader definition of remote healthcare that does not always involve clinical

services. Videoconferencing, transmission of still images, e-health including patient portals, remote monitoring of vital signs, continuing medical education and nursing call centers are all considered part of telemedicine and telehealth.2 Although telehealth is particularly well-suited to primary care, electronic communication has also been effectively used in dermatology, cardiology, mental health, ophthalmology, pathology, radiology, and fetal medicine. In 2004 (the last year for which data are available), there were 1 billion outpatient visits in the United States, including 104 million in emergency rooms, 430 million in primary care offices, 403���������������������������� ��������������������������� million in specialists’ offices, and another 63���������������� million ��������������� in hospital outpatient departments.3 At least 100���������������������������������� ��������������������������������� million visits were for non-emergent health conditions4; for example, 28 million were for symptoms of an upper respiratory infection. Many of these patients could easily have been treated via electronic communication.

Advantages and Limitations Rural populations commonly have difficulty getting to primary care physicians, and specialty care is extremely difficult for these patients. Telephonic or video consultations for acute, nonepisodic, non–life threatening conditions are cost-effective and convenient.

Of course, these people deserve quality care, and electronic communications do not replace a personal “handson” consultation when necessary, but it is not always necessary.

Telemedicine offers the opportunity to achieve many goals, but it is not the panacea that solves all of the seemingly insurmountable issues that are inundat-

ing our profession. The government demands more care, yet provides regulatory barriers to creative solutions. Fortunately, private insurance companies and government insurance are beginning to pay for telehealth consultations.

The perfect cannot be the enemy of the good. There needs to be alternative access to quality health care. Thus, new, creative, affordable, and convenient care fills a need that is being created by the economics of medicine.

Opportunity for Specialists Oncologists care for a critical subset of patients with special needs, some physical and some emotional.

Telehealth offers the opportunity for specialists to communicate and thus care for patients who are unable to access high-quality care in an affordable, convenient manner.

All health care is advanced and improved through robust communication. The basis of the medical home is communication. With electronic health records and a secure HIPAAcompliant interface, the patient and family can communicate with the oncologist to discuss any health issue. Family conferences can be easily conducted anywhere in the world.

Patients’ fears can be allayed. Routine follow-up visits can occur without the hassle of travel, whether urban or rural.

As with all technology and medical advancements, health professionals must be at the forefront of telemedicine’s introduction to ensure that it is used ethically, with the patient at the center of the process. Used responsibly, it will make our patients healthier and happier, and our practices more satisfying.

■

Richard J. Boxer , MD

References 1. Lewis N: Telehealth market in tight competition. Information Week/ Healthcare. Available at http://www.informationweek.com/news/healthcare/ interoperability/showArticle.jhtml?artic leID=227900284&cid=nl_IW_healthcare_2010-10-20_html. Accessed November 4, 2010.

2. American Telemedicine Association: Telemedicine defined. Available at http://www.americantelemed.org/i4a/ pages/index.cfm?pageid=3333. Accessed November 4, 2010.

3. Pitts SR, Carrier ER, Rich EC, et al: Where Americans get acute care: Increasingly it’s not at their doctor’s office. Health Affairs 29:1620-1629, 2010.

4. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, Maryland, 2007.

Available at: http://www.cdc.gov/nchs.

Dr. Boxer is Professor of Clinical Urology at the University of Miami, and Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin. Dr. Boxer is Chief Medical Officer of TelaDoc Medical Services Inc. where he has served as Chief Medical Liaison since January 2008. TelaDoc provides a network of board-certified, state-licensed primary care physicians providing cross-coverage consultations 24 hours a day, 7 days a week, and 365 days a year. TelaDoc physicians diagnose routine, non-emergency, medical problems via telephone, recommend treatment, and prescribe medication when necessary, excluding DEA-controlled substances. For more about TelaDoc, visit www.teladoc.com.

Is Telehealth/Telemedicine Part of Your Practice?

The ASCO Post wants to hear how you use or plan to use Telehealth/Telemedicine in your oncology practice.

Do you have recommendations or guidance for others looking to introduce this technology into their clinical practice?

Write to editor@ASCOPost.com and tell us more.

We invite you to share your experiences in your own words, or we will interview you for publication in a future edition of The ASCO Post.

Contact The ASCO Post at editor@ASCOPost.com

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

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

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis.

[See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTINÂŽ (bevacizumab) Suspend Avastin administration for â&#x2030;Ľ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in SpeciďŹ c Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

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

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.

[See Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: t Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] t 4VSHFSZ BOE 8PVOE )FBMJOH $PNQMJDBUJPOT [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] t )FNPSSIBHF [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] t /PO (BTUSPJOUFTUJOBM 'JTUVMB 'PSNBUJPO [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] t "SUFSJBM 5ISPNCPFNCPMJD &WFOUT [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] t )ZQFSUFOTJWF $SJTJT [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] t 3FWFSTJCMF 1PTUFSJPS -FVLPFODFQIBMPQBUIZ 4ZOESPNF [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] t 1SPUFJOVSJB [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

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

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

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

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.

Among patients requiring surgery on or within 60 days of receiving study treatment, wound IFBMJOH BOE PS CMFFEJOH DPNQMJDBUJPOT PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP PG QBUJFOUT XIP SFDFJWFE CPMVT *'- BMPOF In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage 5IF JODJEFODF PG FQJTUBYJT XBT IJHIFS WT JO QBUJFOUT XJUI N$3$ SFDFJWJOH CPMVT *'- QMVT "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP "MM CVU POF PG UIFTF FWFOUT were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic FWFOUT XFSF NPSF GSFRVFOU JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO XIFO DPNQBSFE UP UIPTF SFDFJWJOH CPMVT *'- QMVT QMBDFCP BOE JODMVEFE HBTUSPJOUFTUJOBM IFNPSSIBHF WT NJOPS gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving DIFNPUIFSBQZ BMPOF *O 4UVEZ QBUJFOUT PO UIF CPMVT *'- QMVT "WBTUJO BSN BOE QBUJFOUT PO UIF CPMVT *'- QMVT QMBDFCP BSN SFDFJWFE GVMM EPTF XBSGBSJO GPMMPXJOH B venous thromboembolic event. Among these patients, an additional thromboembolic event PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE PG QBUJFOUT SFDFJWJOH CPMVT *'- BMPOF The overall incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events in Study 1 was 15.1% in patients SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP *O Study 1, the incidence of the following Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP QBUJFOUT SFDFJWJOH CPMVT *'- QMVT placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of (SBEF PS OFVUSPQFOJB XBT JODSFBTFE JO N$3$ QBUJFOUT SFDFJWJOH *'- QMVT "WBTUJO

DPNQBSFE UP QBUJFOUT SFDFJWJOH *'- BMPOF *O 4UVEZ UIF JODJEFODF PG (SBEF neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH 1$ BMPOF 'FCSJMF OFVUSPQFOJB XBT also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

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

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

Congestive Heart Failure The incidence of Grade â&#x2030;Ľ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence PG (SBEF DPOHFTUJWF IFBSU GBJMVSF $)' XBT JODSFBTFE JO QBUJFOUT JO UIF "WBTUJO QMVT paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior BOUISBDZDMJOFT GPS .#$ UIF SBUF PG $)' XBT GPS QBUJFOUT SFDFJWJOH "WBTUJO BT DPNQBSFE to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo.

Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3â&#x20AC;&#x201C;4 adverse events and selected Grade 1â&#x20AC;&#x201C;2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3â&#x20AC;&#x201C;4) adverse events, which occurred at a higher incidence (â&#x2030;Ľ 2%) in patients receiving CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP CPMVT *'- QMVT QMBDFCP BSF QSFTFOUFE JO 5BCMF

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracilâ&#x20AC;&#x201C;based chemotherapy.

1.2 Non-Squamous Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonâ&#x20AC;&#x201C;squamous nonâ&#x20AC;&#x201C;small cell lung cancer in combination with carboplatin and paclitaxel.

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

The effectiveness of Avastin in MBC is based on an improvement in progression free survival.

There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

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

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

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

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

4 CONTRAINDICATIONS None.

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

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever.

Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

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

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery.

In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

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

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

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade â&#x2030;Ľ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%.

[See Adverse Reactions (6.1).]

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

In clinical studies in nonâ&#x20AC;&#x201C;small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%â&#x20AC;&#x201C;5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3â&#x20AC;&#x201C;4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of â&#x2030;Ľ1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was â&#x2030;¤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

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

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm.

Across indications, the incidence of Grade â&#x2030;Ľ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in SpeciďŹ c Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

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

Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3â&#x2C6;&#x2019;4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [â&#x2030;Ľ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. *'- 1MBDFCP *'- "WBTUJO Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).]

NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms #PEZ BT B 8IPMF Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).]

Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy.

14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick aCentral laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. reading should undergo further assessment with a 24-hour urine collection.

AVASTINÂŽ (bevacizumab) AVASTINÂŽ (bevacizumab) Grade 1â&#x20AC;&#x201C;4 adverse events which occurred at a higher incidence (â&#x2030;Ľ 5%) in patients receiving Table 4 CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP UIF CPMVT *'- QMVT QMBDFCP BSN BSF QSFTFOUFE JO 5BCMF NCI-CTC Grades 1â&#x2C6;&#x2019;5 Adverse Events in Study 9 Grade 1â&#x20AC;&#x201C;4 adverse events were collected for the first approximately 100 patients in each of 0DDVSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'/ Îą "WBTUJO WT *'/ Îą + Placebo) UIF UISFF USFBUNFOU BSNT XIP XFSF FOSPMMFE VOUJM FOSPMMNFOU JO "SN '6 -7 "WBTUJO

was discontinued.

4ZTUFN 0SHBO $MBTT *'/ Îą 1MBDFCP *'/ Îą + Avastin Preferred term* (n = 304) (n = 337) Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% 0DDVSSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'- "WBTUJO WT *'-

General disorders and administration Arm 1 Arm 2 Arm 3 site conditions

*'- 1MBDFCP *'- "WBTUJO '6 -7 "WBTUJO 'BUJHVF

(n = 98) (n = 102) (n = 109) Investigations 8FJHIU EFDSFBTFE

#PEZ BT B 8IPMF Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders 8FJHIU -PTT

Hypertension 9% 28% Dry Mouth 2% 7% 4% *Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic 5IF GPMMPXJOH BEWFSTF FWFOUT XFSF SFQPSUFE BU B GPME HSFBUFS JODJEFODF JO UIF *'/ Îą plus Thrombocytopenia 0% 5% 5% "WBTUJO BSN DPNQBSFE UP *'/ Îą alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1).

Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital BOE VOEFSMZJOH EJTFBTF 'PS UIFTF SFBTPOT DPNQBSJTPO PG UIF JODJEFODF PG BOUJCPEJFT UP "WBTUJO Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin.

Only Grade 3-5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3â&#x20AC;&#x201C;5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events) occurring at a higher incidence drug exposure. Ăś JO QBUJFOUT SFDFJWJOH '0-'09 QMVT "WBTUJO DPNQBSFE UP QBUJFOUT SFDFJWJOH Body as a Whole: Polyserositis '0-'09 BMPOF XFSF GBUJHVF WT EJBSSIFB WT TFOTPSZ OFVSPQBUIZ Cardiovascular: Pulmonary hypertension, RPLS (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Hemic and lymphatic: Pancytopenia neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia in Study 2.

7 DRUG INTERACTIONS Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected A drug interaction study was performed in which irinotecan was administered as part of the in Study 4. Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events (occurring '0-'*3* SFHJNFO XJUI PS XJUIPVU "WBTUJO 5IF SFTVMUT EFNPOTUSBUFE OP TJHOJĂĽDBOU FGGFDU PG at a higher incidence (â&#x2030;Ľ2%) in 427 patients receiving PC plus Avastin compared with 441 patients bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), be a difference in the mean exposure of either carboplatin or paclitaxel when each was febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 administered alone or in combination with Avastin. However, 3 of the 8 patients receiving or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin (3% vs. 0%). without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

Metastatic Breast Cancer (MBC) In Study 9, there was no difference in the mean exposure of interferon alfa administered in Only Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events were collected in combination with Avastin when compared to interferon alfa alone.

Study 5. Grade 3â&#x20AC;&#x201C;4 adverse events occurring at a higher incidence (â&#x2030;Ľ2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory 8 USE IN SPECIFIC POPULATIONS neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without 8.1 Pregnancy neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), Pregnancy Category C bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, (3% vs. 0.3%) and proteinuria (3% vs. 0%). including an increased incidence of speciďŹ c gross and skeletal fetal alterations. Adverse fetal outcomes Sensory neuropathy, hypertension, and fatigue were reported at a â&#x2030;Ľ 5% higher absolute incidence in were observed at all doses tested. Other observed effects included decreases in maternal and fetal the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

'BUBM BEWFSTF SFBDUJPOT PDDVSSFE JO PG QBUJFOUT XIP SFDFJWFE QBDMJUBYFM QMVT "WBTUJO Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ from the mother to the developing fetus, and has the potential to cause fetal harm when abdominal, and pain/weakness/hypotension (2). administered to pregnant women. Because of the observed teratogenic effects of known inhibitors Avastin is not approved for use in combination with capecitabine or for use in second or third of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential line treatment of MBC. The data below are presented to provide information on the overall benefit to the pregnant woman justifies the potential risk to the fetus. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, 8.3 Nursing Mothers controlled study in which all adverse events were collected for all patients. All patients in It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk.

Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in metastatic disease. Grade 1â&#x20AC;&#x201C; 4 events which occurred at a higher incidence (â&#x2030;Ľ5%) in patients substantial amounts. Because many drugs are secreted in human milk and because of the potential for receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to in Table 3. discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11â&#x20AC;&#x201C;50 days]) and the importance of the drug to the mother. [See Clinical Table 3 Pharmacology (12.3).]

NCI-CTC Grade 1â&#x2C6;&#x2019;4 Adverse Events in Study 6 (Occurring at Higher 8.4 Pediatric Use Incidence [â&#x2030;Ľ5%] in Capecitabine + Avastin vs. Capecitabine Alone) The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Capecitabine been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Capecitabine + Avastin to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and (n = 215) (n = 229) exposure). The incidence and severity of physeal dysplasia were dose-related and were partially #PEZ BT B 8IPMF reversible upon cessation of treatment.

Asthenia 47% 57% 8.5 Geriatric Use Headache 13% 33% In Study 1, severe adverse events that occurred at a higher incidence (â&#x2030;Ľ 2%) in patients aged â&#x2030;Ľ65 Pain 25% 31% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Cardiovascular hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Hypertension 2% 24% survival was similar in elderly patients as compared to younger patients.

Digestive *O 4UVEZ QBUJFOUT BHFE Ăś ZFBST SFDFJWJOH "WBTUJO QMVT '0-'09 IBE B HSFBUFS SFMBUJWF SJTL Stomatitis 19% 25% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

Metabolic/Nutrition In Study 4, patients aged â&#x2030;Ľ 65 years receiving carboplatin, paclitaxel, and Avastin had a 8FJHIU MPTT

greater relative risk for proteinuria as compared to younger patients. [See Warnings and Musculoskeletal Precautions (5.8).]

Myalgia 8% 14% In Study 5, there were insufficient numbers of patients â&#x2030;Ľ 65 years old to determine whether Respiratory the overall adverse events profile was different in the elderly as compared with younger patients.

Dyspnea 18% 27% Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were Epistaxis 1% 16% captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any Skin/Appendages severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition Exfoliative dermatitis 75% 84% to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased Urogenital cough, and voice alteration.

Albuminuria 7% 22% In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged â&#x2030;Ľ65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with Glioblastoma as compared to those receiving chemotherapy alone, regardless of age. However, All adverse events were collected in 163 patients enrolled in Study 7 who either received chemotherapy increase in arterial thromboembolic events incidence was greater in patients aged â&#x2030;Ľ 65 years Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and the vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination (8.5% with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated (5.5).]

10 OVERDOSAGE with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), 16 patients and with severe headache in three of 16 patients. epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade â&#x2030;Ľ3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1â&#x20AC;&#x201C; 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3â&#x20AC;&#x201C;5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3â&#x20AC;&#x201C;5 adverse events occurring at a IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH JOUFSGFSPO BMGB *'/ Îą) plus Avastin DPNQBSFE UP QBUJFOUT SFDFJWJOH *'/ Îą plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, 7453214 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Manufactured by: haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract Genentech, Inc. 4835706 hemorrhage, and traumatic hematoma). %/" 8BZ *OJUJBM 6 4 "QQSPWBM 'FCSVBSZ $PEF 3FWJTJPO %BUF +VMZ (SBEF o BEWFSTF FWFOUT PDDVSSJOH BU B IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH *'/ Îą plus 4PVUI 4BO 'SBODJTDP $" 94080-4990 Š 2009 Genentech, Inc "WBTUJO DPNQBSFE UP UIF *'/ Îą plus placebo arm are presented in Table 4.

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

To reach beyond convention…

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

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

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

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