SPECIAL ANNIVERSARY ISSUE
VOLUME 3, ISSUE 9
JUNE 15, 2012
Editor-in-Chief, James O. Armitage, MD
ASCOPost.com
Narratives in Oncology The ASCO Post profiles leaders in cancer care and research
Karen H. Antman, MD
Kathleen M. Foley, MD
Jay R. Harris, MD
Gabriel N. Hortobagyi, MD, FACP
Hagop M. Kantarjian, MD
David Khayat, MD, PhD
Lawrence N. Shulman, MD
Sandra M. Swain, MD
E. Donnall Thomas, MD
Daniel D. Von Hoff, MD, FACP
A Supplement to The ASCO Post™
A Harborside Press® Publication
The ASCO Post | JUNE 15, 2012 | SUPPLEMENT
PAGE 2
Special Anniversary Issue: Narratives in Oncology
Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center
John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center
ASSOCIATE EDITORS
William T. McGivney, PhD Philadelphia, Pennsylvania
Joseph S. Bailes, MD Texas Oncology
James L. Mulshine, MD Rush University Medical Center
Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center
Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System
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 E. David Crawford, MD University of Colorado 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 John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York 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
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 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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
he ASCO Post is pleased to present this special anniversary edition in recognition of the publication’s 3rd year serving the oncology community. We hope you enjoy this special commemorative issue profiling several of the many leaders in the oncology community. In coming issues of The ASCO Post and in future special editions, we will profile additional members of the oncology community. We invite you to contact The ASCO Post with your nominations of others who have taught and inspired, and helped in leading the way in cancer research
and treatment. Write to editor@ ASCOPost.com.
Inside This Special Issue Look for personal profiles about the following oncology leaders: E. Donnall Thomas, MD Karen H. Antman, MD Kathleen M. Foley, MD Jay R. Harris, MD Gabriel N. Hortobagyi, MD, FACP Hagop M. Kantarjian, MD David Khayat, MD, PhD Lawrence N. Shulman, MD Sandra M. Swain, MD Daniel D. Von Hoff, MD, FACP
The ASCO Post
Wants to Hear from You
William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada
The Editors encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com
Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France
The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, 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 Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.
Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong
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Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel
Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com.
Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan
Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.
Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa
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Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.
ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
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E. Donnall Thomas, MD
From Small-town House Calls to Bone Marrow Transplants, Nobel Laureate Continues Father’s Legacy “I echo the sentiments of many previous Nobel laureates when I say that the success we celebrate today was made possible by the work of many others in this and in related fields.”
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o ended the Nobel Lecture by E. Donnall Thomas, MD, the famed investigator and 1990 Nobel Laureate in Physiology or Medicine who pioneered bone marrow transplantation, marking a new era in the treatment of leukemia and other blood malignancies.
Humble Beginnings Dr. Thomas was born in the sunscorched farming town of Mart, Texas. He remembers his father—a general practitioner—as a kind and tireless family doctor who spent long hours driving country roads to see patients during the smallpox epidemic. “My father took me on house calls, and I decided to go into medicine when I was about 5,” Dr. Thomas remarked. Mart was a dot on the vast rural landscape and Dr. Thomas attended grade school in Prairie Hill in a oneroom structure with about 20 classmates, most of whom were children from nearby farms and ranches. “The school didn’t have highfalutin trappings, but we got a sturdy education in all the basics,” Dr. Thomas said. In 1933, his family moved to Coolidge where he went to high school. In 1937, Dr. Thomas went to the University of Texas in Austin as a chemistry major. “During my second year, my father was returning from a nighttime house call when he crashed into a farm truck that was stalled on
the dark road. He was killed instantly. Along with the grief of losing such a good father, his death left us without any viable support. I thought I’d have to quit college, but fortunately I was able to pick up work waiting tables in the girl’s dormitory,” Dr. Thomas said, noting that at the time, the nation was still in the grip of the Great Depression and jobs were scarce. Despite the emotional and financial hardships, good fortune came like a change in the weather. “A young stu-
My father and I journeyed from horseand-buggy house calls to high-tech scientific procedures such as bone marrow transplants. — E. Donnall Thomas, MD
dent named Dorothy Martin appealed to me greatly and we hit it off, literally. During a freak snowstorm in Austin, I was leaving my shift at the dorm dining room and pow! a snowball smacked me in the head. I turned and there was Dottie, smiling. We married 2 years later,” Dr. Thomas said, adding that Dottie would work with him in the lab throughout his career.
The Road to Medical School Dr. Thomas received a BA in chemistry in 1941 and an MA in chemical engineering in 1943. It was time to consider medical school, an almost untenable proposition for the young cou-
Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and
ple. After the United States’ entry into World War II in 1941, the U.S. military needed to increase the number of doctors in their ranks and thus launched the Army Specialized Training Program. “I had an army reserve commission, so it seemed natural to stay in the service and go to medical school and, thanks to Uncle Sam, finally stop worrying about money,” Dr. Thomas said. “Dottie and I decided that as long as the Army was paying for my education, why not try for a more famous school. I applied to Johns Hopkins and Harvard. Lo and behold, two weeks later a telegram from Harvard said that I’d been accepted—but the first class started in 10 days. So Dottie and I sold our few possessions and took the train to Boston, arriving in 8 inches of snow wearing sneakers,” Dr. Thomas said. Years later, he remembered how Worth Hale, MD, the Dean of Admissions at Harvard Medical School, quipped, “The main reason we accepted you was so we could get a look at this Texas guy who had the nerve to apply to Harvard 10 days before the start of the first semester.” After graduating from Harvard Medical School in 1946, Dr. Thomas did a hematology internship with Clement Finch, MD, at the Brigham Hospital. “Dr. Finch was a first-class mentor and he stimulated my interest in all aspects of clinical medicine, not just hematology. We also became lifelong friends. At the time, I had several patients with acute leukemia and I became very interested in things that stimulate bone marrow,” he said, pausing. “As for pivotal things that
PROFILE: E. Donnall Thomas, MD TITLE: Professor Emeritus, University of Washington; Director Emeritus, Clinical Research Division, Fred Hutchinson Cancer Research Center MEDICAL DEGREE: MD, Harvard Medical School RESEARCH INTERESTS: Bone marrow transplant, leukemia NOTABLE HONORS: Nobel Prize in Physiology or Medicine (1990); National Medal of Science (1990); Gairdner Foundation International Award (1990); Lifetime Achievement Award, American Society for Blood and Marrow Transplantation (2004) ON HIS PATH TO ONCOLOGY: “As for pivotal things that steered my career path, well, I really just followed my nose. There’s a certain amount of luck that goes with a success.”
steered my career path, well, I really just followed my nose. There’s a certain amount of luck that goes with a success,” Dr. Thomas commented with characteristic humility.
Pioneer in Bone Marrow Transplant A dizzyingly busy period in Dr. Thomas’s life ensued. He spent a year completing his army medical service requirements in postwar Germany, a year of postdoctoral work at Massachusetts Institute of Technology, and 2 years of medical residency (the last as the Chief Medical Resident at continued on page 6
the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.
In Advanced Renal Cell Carcinoma...
INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
IMPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Concomitant use of
VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. • Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. • Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were
observed. Use with caution in patients who are at increased risk for these events. • Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. • Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite antihypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence.
Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2
All patients
Treatment-naïve patients
Cytokine-pretreated patients
11.1 months (95% CI, 7.4-14.8)
7.4 months (95% CI, 5.6-12.9)
overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3
median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3
median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1.3
9.2 months (95% CI, 7.4-12.9)
NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than VOTRIENT as first-line treatment options
WARNING: HEPATOTOXICITY
Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. VOTRIENT: Safety Profile Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%
Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients; all grades, 53% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period
• Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. • Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient
develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT or discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%).
Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed March 22, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.
VOTRIENT.com
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E. Donnall Thomas, MD continued from page 3
the Peter Bent Brigham Hospital in Boston). In 1955, he was Physicianin-Chief at the Columbia University branch in Cooperstown, New York. “We immediately began to work on marrow transplantation first in dogs,
as outbred animals suitable for clinical care comparable to human patients, and later in human patients. Except for an occasional patient with an identical twin, we quickly learned that allogeneic marrow transplants in humans were going to be very difficult,” Dr. Thomas said.
Then, in 1963, the famous endocrinologist Robert Williams, MD, invited Dr. Thomas to join the faculty of the University of Washington School of Medicine. “Dottie and I packed up and moved to the Pacific Northwest. Dr. Williams understood that the school was in its infancy and initiated an affili-
BRIEF SUMMARY VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT® is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment. [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information.] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate
ation of all the relevant institutions in the area. It was within that framework that I established my research program in the Seattle Public Health Hospital,” Dr. Thomas explained. He said that after establishing the Seattle program, he was fortunate to recruit a host of brilliant young co-
hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT. [See Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information.] 5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension : In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a
ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
workers. “The rest of the story—demonstrating that some patients with advanced leukemia, aplastic anemia, or genetic diseases could be cured with bone marrow transplant—seems a bit short in retrospect. That said, I do acknowledge that my work and philosophy have been heavily influenced
by a wonderful group of dedicated colleagues,” Dr. Thomas said.
A Father’s Legacy Dr. Thomas noted that his father moved to frontier Texas with his family in a covered wagon in 1874. With almost no formal schooling he went
randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT VOTRIENT
Placebo
(N = 290)
(N = 145)
All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a
%
%
%
%
%
%
52 40 38 26 22 21 19 14 11 10
3 4 <1 <1 2 2 2 3 2 0
<1 0 0 0 0 <1 0 0 0 0
9 10 3 9 10 8 8 8 1 5
<1 <1 0 0 <1 2 1 0 0 0
0 0 0 0 0 0 1 0 0 0
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).
Parameters
Placebo (N = 145)
All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %
Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose 41 <1 0 33 1 0 increased Total bilirubin 36 3 <1 10 1 <1 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium 26 <1 1 14 0 0 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and
7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was
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Disclosure: Dr. Thomas has no potential conflicts of interest to disclose.
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VOTRIENT (N = 290)
placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of full prescribing information and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with antihypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a singlearm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%).
buggy house calls to high-tech scientific procedures such as bone marrow transplants,” said Dr. Thomas, whose scientific contribution ranks among the most significant medical advances of the 20th century.
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Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo
to the University of Louisville, Kentucky, where he received his MD. “My father’s first wife died of tuberculosis, and I was the only child of his second wife. He was 50 years old when I was born on March 15, 1920. So in the course of one generation, my father and I journeyed from horse-and-
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Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.
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The ASCO Post | JUNE 15, 2012 | SUPPLEMENT
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About the Writer
R
onald Piana is an independent writer and reporter with more than 15 years of experience in oncology communications and publishing. In addition to the profiles published
reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.
10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.
• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. —yellowing of the skin or the whites of the eyes (jaundice), —unusual darkening of the urine, —unusual tiredness, —right upper stomach area pain. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of GlaxoSmithKline.
©2012, GlaxoSmithKline. All rights reserved. Revised 03/2012 VTR:6BRS ©2012 The GlaxoSmithKline Group of Companies Companies All rights reserved. Printed in USA. VOT316R0 VOT219RO April April 2012 2012
Contact
The ASCO Post
Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657
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17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:
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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/ day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/ kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/ day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.
earlier years Ron lived in Paris before traveling worldwide as a merchant seaman, later working as a laborer, truck driver, and chef. His life-long boxing aspirations were halted after going a round in Gleason’s Gym with the legendary Roberto Duran on “one thrilling but boxing career–ending day.” Ron is also a writer of fiction and is currently working on his second novel. He lives in Huntington, New York with his wife Kristine.
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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/ kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/ kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N = 11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin > 3 X ULN regardless of the ALT value) was 200 mg per day (N = 14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/ min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.
in this special anniversary issue of The ASCO Post, Ron has written more than 100 articles, interviews, and profiles for leading medical publications. A native New Yorker, in his
ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
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Karen H. Antman, MD
Reflections on the Evolution of Clinical Cancer Research and Turning Points in a Distinguished Career
S
ince May 1, 2005, Karen H. Antman, MD, has served as Dean of Boston University School of Medicine and Provost of the Boston University Medical Campus, located in the historic South End of Boston. Her road to this esteemed institution was paved with prominent positions, such as former ASCO President, and high honors, notably ASCO’s Distinguished Award for Scientific Leadership. Even more important than her positions and honors are Dr. Antman’s achievements as a clinical investigator, which have moved the field of oncology forward.
Early Experiences Dr. Antman has always enjoyed people and science. While an undergraduate at Muhlenberg College in Allentown, Pennsylvania, she knew two patients with cancer who had markedly different outcomes, which demonstrated to her the possibilities held by science and set her on the path to a career in oncology. A neighbor developed leukemia and was told that it was incurable. “He was dead a year later, exactly as his doctors predicted,” said Dr. Antman. The following year, a classmate was diagnosed with advanced Hodgkin lymphoma and was
also given a fatal prognosis. However, when Dr. Antman showed up for class the following September, to her surprise, there he was. “A fellow student
a neighbor succumb to cancer and a classmate survive—was fortified during her fellowship at Dana-Farber as she watched many of her patients in
If you get standard treatment for an invariably fatal malignancy, you die. If you have experimental therapy, you have a chance to live. Research matters; it saves lives. — Karen H. Antman, MD
asked, ‘What are you doing here?’ He said he’d been at the NIH on a clinical protocol of combination chemotherapy and he was doing very well, thanks for asking,” said Dr. Antman. Oncology was already high on Dr. Antman’s list of possible specialties as she prepared to enter Columbia University’s College of Physicians and Surgeons. After completing internal medicine residencies at Columbia, Dr. Antman and her husband headed to Boston, where she was accepted for an oncology fellowship at Dana-Farber Cancer Institute, staying on as faculty. Experiential knowledge is a compelling tool in a doctor’s bag. Dr. Antman noted that the take-home experience from her early college years—seeing
PROFILE: Karen H. Antman, MD TITLE: Dean, Boston University School of Medicine; Provost, Boston University Medical Campus MEDICAL DEGREE: MD, Columbia University College of Physicians and Surgeons RESEARCH INTERESTS: Sarcoma, mesothelioma, breast cancer, bone marrow transplantation NOTABLE HONORS: Elected to the Institute of Medicine (2011); ASCO’s Distinguished Award for Scientific Leadership (2008) ADVICE TO YOUNG ONCOLOGISTS: “I would urge young physicians to choose oncology because it is a field in which they can truly make a difference in the world, in research and in the clinic… [Oncology is] what the system-at-large needs: a multidisciplinary, team-based care approach for individual patients.”
the clinic die. “If you get standard treatment for an invariably fatal malignancy, you die. If you have experimental therapy, you have a chance to live. Research matters; it saves lives.”
Pioneer in Sarcoma Research Prior to her Deanship at Boston University School of Medicine, Dr. Antman was President of the American Association for Cancer Research. In her Presidential address, she observed, “Sarcoma, long a no man’s land for cancer researchers, is slowly giving up its secrets.” Fittingly, it was Dr. Antman who led some of the early research in sarcoma’s “no man’s land” to uncover these secrets. In the 1980s, advanced sarcomas were treated with doxorubicin, which in phase II trials did not prolong survival. Dr. Antman’s European colleagues shared evidence about a new ifosfamide derivative showing activity in sarcomas. “But the agent sparked little enthusiasm in the United States,” she recalled. “For obvious reasons, Pharma isn’t particularly interested in uncommon tumors.” Undeterred, Dr. Antman did the paperwork herself and filed the investigational new drug (IND) application with the FDA. “I remember when the drug first arrived from Europe; the custom’s agent called me and asked, ‘What is this stuff?’ I explained that it was an investigational new cancer drug for a
clinical trial,” said Dr. Antman. However, despite the European evidence of activity, some patients on Dr. Antman’s seminal sarcoma study were refused hospitalization coverage, which raised bothersome questions about access to clinical trial research. “I remember a 24-year-old patient who was denied coverage because ifosfamide was deemed experimental. I argued to the insurance company that the Europeans reported that it was twice as effective as cyclophosphamide, which is covered. They replied, ‘We don’t tell you what drug to prescribe, we just won’t cover it.’ So the Dana-Farber Cancer Institute, to its credit, covered the costs for that patient’s hospitalization,” said Dr. Antman. Ifosfamide was indeed active in sarcomas, and Dr. Antman’s team studied the drug in a combination regimen that became standard for these malignancies. When the drug was found to be effective in both sarcomas and testicular cancer, the FDA finally took notice and cross-filed on Dr. Antman’s IND.
Streamlining Clinical Trial Regulations The young patient’s ordeal became a turning point in Dr. Antman’s medical career. “That specific patient gave me pause, and I made a decision to do patient advocacy. My team and I wrote an article in The New England Journal of Medicine on the crisis in clinical research, and we testified before Congress and at various subcommittees on the Hill about the crucial need to cover patients on clinical trials.” Dr. Antman noted that besides coverage, the clinical trial process itself posed an impediment to access. In 2004, she served as Deputy Director for Translational and Clinical Sciences at the National Cancer Institute (NCI). During her time at NCI, Dr. continued on page 10
The ASCO Post | JUNE 15, 2012 | SUPPLEMENT
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Kathleen M. Foley, MD
Trailblazing Neurologist Leads the Way in Advancing Treatment of Cancer Pain
K
athleen M. Foley, MD, began her life’s work in cancer pain management at a time when suffering was a universally accepted consequence of the disease. Since then, Dr. Foley’s tireless work in the clinic and public forum has advanced not only the clinical treatment of cancer pain, but also the global awareness that relieving pain is an undeniable human rights issue. “I graduated from Cornell Medical School in 1969, and following my residency in neurology at New York Hospital, Jerome Posner, MD, who was Chair of the Neurology Department at Memorial Sloan-Kettering Cancer Center (MSKCC), offered me a fellowship to study cancer pain. I confessed I knew nothing about cancer pain, and he wonderfully remarked, ‘Don’t worry; no one else does either.’” Dr. Foley recalled.
Establishes Nation’s First Cancer Pain Clinic In 1975, when Dr. Foley joined the Department of Neurology at MSKCC,
Karen H. Antman, MD continued from page 9
Antman recalled long meetings with multiple federal agencies, seeking ways to streamline the cumbersome clinical trial regulations. Her frustration was echoed during a conversation with another past ASCO President, Emil “Tom” Frei III, MD. “Tom said that we never would have cured childhood leukemia if we had today’s regulations. I have repeated that powerful quote over and over to junior faculty,” said Dr. Antman.
Teaching the Next Generation In a career as demanding as cancer care, where every success is tempered by the knowledge that this deadly
the modern pharmacology of treating pain was still in its infancy. “I began working with Dr. Raymond Houde, a clinical pharmacologist known for his studies of analgesics, to develop a clinical research program on cancer pain,” Dr. Foley said. The collaborative effort
said, explaining that the nascent field of neuro-oncology was quickly gaining traction at MSKCC. “We then developed a robust analgesics study group that combined basic and clinical research along with a pain physician and oncology nurse training program.”
Every day, patients with cancer across the country are being denied access to adequate pain control. Relieving needless suffering is what we should be focusing our energy on. — Kathleen M. Foley, MD
paid off: Within 2 years, Dr. Foley and her associates had created the nation’s first pain clinic within a cancer center. Building on that success, Dr. Foley expanded her research into areas that would capture the scope and intensity of undertreated cancer pain. “We wanted to quantify the prevalence of cancer pain and define the neurologic pain syndromes that occurred in the cancer patient population,” Dr. Foley
Access to Medical Opioids Is Critical
disease still holds its share of secrets, what keeps the professional fire burning? As Dean of Boston University School of Medicine, Dr. Antman is driven by her involvement in medical education and efforts to enhance the research and infrastructure capabilities on campus. She also teaches first-, second-, and fourth-year students, giving cancer lectures. “I’m still very engaged in teaching oncology to medical students,” she said. Dr. Antman was recently voted into the Institute of Medicine, another major recognition for her achievements in medicine. Along with her challenging duties at Boston University School of Medicine, she is on the board of a number of prominent international organi-
zations that foster worldwide medical education. Leading a life so robust in advancing the causes of oncology, Dr. Antman spends her time out of work on the simple pleasures, such as hiking with her grandchildren.
Dr. Foley’s early work in pain predated pain assessment tools and imaging technologies such as CT and MRI scans; thus, the etiology of pain remained somewhat obscure. Drug delivery methods were also limited, further hampering aggressive pain control. “At that time, patients with severe pain were being managed with
Why Oncology? Regarding the impending workforce shortage in oncology, Dr. Antman said, “I would urge young physicians to choose oncology because it is a field in which they can truly make a difference in the world, in research and in the clinic. To the public, scientific advances seem to come at a snail’s pace, but in actuality we have made incredible progress. When I was a second-year medical student and the
intramuscular morphine on an asneeded basis; there was no oral morphine available in the United States,” Dr. Foley said. The barriers to medical opioids became evident to Dr. Foley, and much of her initial work focused on establishing a scientific basis for morphine in managing cancer pain. “Using research data, our group argued strongly for the wide availability of oral morphine for cancer patients with pain. We also formed the concept of a continuum of opioid responsiveness in which some patients required higher doses of opioids. This may seem intuitive today, but it was a breakthrough concept in the early days of pain management,” Dr. Foley stressed. Dr. Foley explained that the foundation of the new pain program at MSKCC was based on the natural experiment of treating thousands of patients with cancer. “Our clinical research was able to dispel the myths of opioid addiction and prove that pain stimuli rather than tolerance alone dictate the need to increase the dose of pathology lecture turned to testicular cancer, the men in the class uniformly cringed. At that time it was about 90% fatal; now, the same disease is about 90% curable. And that progress happened rather rapidly,” she added. “Being part of the research and clinical possibilities in such a dreaded disease is certainly a compelling reason for a medical student to choose oncology. And in a broader sense, oncology can serve as a model for the future of our health-care system. For decades, oncology has been what the system-at-large needs: a multidisciplinary, team-based care approach for individual patients.”
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Disclosure: Dr. Antman reported no potential conflicts of interest.
ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
opioids,” Dr. Foley said. “As our work continued, it became very clear that although undertreated pain was a major issue, a more holistic approach was needed when caring for patients with cancer. It took a while, but in 1996 we broadened our reach and effectiveness in managing the symptoms related to cancer treatment by launching the Pain and Palliative Care Service at MSKCC.”
Tackling End-of-life Care Even prior to establishing MSKCC’s Palliative Care Service, Dr. Foley had begun to expand her horizons, seeing undertreatment of cancer pain as but one part of the often problematic way in which our culture at large views the process of illness. “In 1994, I led an initiative funded by the philanthropist George Soros called the Project on Death in America. Our primary goal was to advance palliative care and translate our existing knowledge into clinical care,” Dr. Foley said. “We chose this very in-your-face name for the Project because we wanted to directly attack the issue of endof-life care. Armed with a $45 million grant, we supported community efforts to improve care of the dying and review policy measures that affect endof-life care. We also built leadership teams that helped advance the growth of this underserved field,” Dr. Foley noted, adding that the data after more than 9 years show that the initiatives supported by the program have been enormously successful.
Debate over Physicianassisted Suicide Since the mid-1990s, discussions on what constitutes the best end-oflife care have included the debate on whether physician-assisted suicide is
medically and ethically appropriate. Although physician-assisted suicide seemed an unavoidable subject for the Project on Death in America, Dr. Foley said, “Our board members had strongly diverse opinions on the issue, but we made a collective decision not to address physician-assisted suicide, as too many other initiatives needed our attention and resources.” However, Dr. Foley did have a personal interest in physician-assisted suicide. “Throughout my career, patients who were in severe pain have asked me to end their lives. But when I relieved their pain, they no longer wanted to die. Therefore, I felt that lack of care
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anguished cry for help and a very ambivalent request to die.” “The debates got a bit contentious, but I learned a lot about tolerance. More importantly, every day, patients with cancer across the country are being denied access to adequate pain control. Relieving needless suffering is what we should be focusing our energy on,” Dr. Foley said.
Pain Management: A Global Issue Dr. Foley is the Medical Director of the International Palliative Care Initiative, another George Soros–funded project to help address the lack of pain control
PROFILE: Kathleen M. Foley, MD TITLE: Professor of Clinical Pharmacology and Neurology and Neuroscience, Weill Cornell Medical College; Attending Neurologist, Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center MEDICAL DEGREE: MD, Cornell University Medical College RESEARCH INTERESTS: Neurology, cancer pain, supportive care NOTABLE HONORS: Distinguished Service Award, American Cancer Society (1992); David A. Karnofsky Memorial Award, ASCO (1998); John D. Loeser Distinguished Lecture Award, International Association for the Study of Pain (2010) ON THE CURRENT GLOBAL BARRIERS TO MORPHINE: “If one has something that can relieve someone’s suffering and it is being willfully denied, yes, I call that torture.”
was the main driver behind most suicide requests,” Dr. Foley said. Multiple debates on physician-assisted suicide ensued, most notably in two New England Journal of Medicine articles and an ASCO forum in which Marcia Angell, MD, argued in favor of the practice. Dr. Foley and Herbert Hendin, MD, in their 2002 book, The Case against Assisted Suicide: For the Right to End-of-life Care, reasoned that patients in terrible pain “are making an
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around the world, especially in developing nations where arcane sociopolitical and regulatory barriers obstruct access to opioids. “These initiatives are happening in Central and Eastern Europe and in sub-Saharan Africa. We’ve been fortunate to have a major funding boost from the Global Access to Pain Relief Initiative. So again, fast forward 11 years and palliative care is now on the global public health policy agenda,” Dr. Foley said. Dr. Foley acknowledged that progress
in creating access to opioid analgesics in many regions of the world has been slow. “However, awareness of the problem is growing. For instance, in a very forceful statement, the World Health Organization (WHO) stated that access to morphine is a human rights issue. WHO estimates that about 5 billion people worldwide are denied basic pain relief. That is a staggering statistic.” On a singularly riveting note, Dr. Foley cited a video on the website Stop Torture in Health Care (http://www. stoptortureinhealthcare.org). Vlad, a young patient with cancer in the Ukraine, is paralyzed and bedridden, dying in excruciating pain because the law prohibits prescribing more than 50 mg of morphine per day, when doctors have determined that he needs at least 2,000 mg for adequate relief. Vlad subsequently died in agonizing pain. “The tragedy here is that Vlad was cared for by a loving mother and had everything in place to ensure a decent life before death—except enough morphine, which he was denied simply because the government has set an artificial level based on absolutely no evidence,” Dr. Foley said. Various experts in the field of pain control debate whether “torture” is actually taking place in health services around the world. Asked if Vlad’s situation was torture, Dr. Foley replied unequivocally, “If one has something that can relieve someone’s suffering and it is being willfully denied, yes, I call that torture.” Dr. Foley continues her daily work to advance the treatment of pain and palliative care and to increase global awareness that access to pain relief is a basic human right.
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Disclosure: Dr. Foley reported no potential conflicts of interest.
The ASCO Post | JUNE 15, 2012 | SUPPLEMENT
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Jay R. Harris, MD
On the Early Days of Breast-conserving Therapy and the Unique Relationship between Oncologists and Their Patients
J
ay R. Harris, MD, Chair of the Department of Radiation Oncology at the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital, Boston, helped pioneer the use of breast-conserving therapy in women with early-stage breast cancer. When asked why he chose to pursue a career in radiation oncology, Dr. Harris, who was a math major at Cornell University and also has a master’s degree in statistics, recalled an encounter that he had while attending Stanford University School of Medicine. A strong-willed female student sitting next to him, who had attended clinics with pioneering radiation oncologist Henry Kaplan, MD, as part of the oncology elective, told him that because of his background in math, he would “really love radiation oncology.” It took Dr. Harris almost 3 years to realize that she was right, and soon thereafter, that woman with strongly held opinions about his career path became his wife. After graduating from Stanford, doing an internship in medicine, and spending 2 years in the Army, Dr. Harris went to Boston to complete his radiation oncology training at the Joint Center for Radiation Oncology at Harvard Medical School. “At that time, Boston was one of the first places in the country where breast-conserving
therapy (lumpectomy followed by radiation to the breast) was being done, and I was fortunate to be part of clinical studies that helped shape this approach into a more effective and less toxic treatment,” said Dr. Harris.
Breast-conserving Therapy Once Seen as Controversial Although breast-conserving therapy is commonly accepted as a best
issues that were being challenged. We took pains to discuss the problematic issues, pointing out when procedures didn’t have perfect results and giving a balanced perspective, not just cheerleading the new approach. Importantly, studies of our complications and failures identified ways to minimize these problematic issues. The approach and the treatment worked, and eventually we were seen as serious,
It is exceedingly gratifying to help patients through their day-to-day struggles, whether I’m delivering curative or palliative therapy. The bond between oncologists and their patients is very meaningful. — Jay R. Harris, MD
practice today, in 1977, when Dr. Harris completed his training year, it was a source of controversy in most parts of the country. According to Dr. Harris, the atmosphere surrounding this emerging practice was nothing short of hostile, particularly among the nation’s leading breast surgeons. Controversy aside, Dr. Harris and his colleagues knew that dramatic clinical changes always endured growing pains along the way to acceptance. “Our intent was to try to objectify the
PROFILE: Jay R. Harris, MD TITLE: Chief, Department of Radiation Oncology, Dana-Farber Cancer Institute; Professor of Radiation Oncology, Harvard Medical School MEDICAL DEGREE: MD, Stanford University School of Medicine
legitimate investigators who improved the results of breast-conserving therapy,” said Dr. Harris. More recently, Dr. Harris has been involved in studies looking at how local therapy works in the context of biologic subtypes of breast cancer. “In 2008, the Journal of Clinical Oncology published our results on the importance of biologic subtypes to the outcome of breast-conserving therapy, and we have since updated the data. We then carried our deeper understanding of the relationship between biologic subtypes and local treatment into assessing this relationship in the context of increasingly effective systemic therapy,” explained Dr. Harris.
RESEARCH INTERESTS: Radiation oncology, breast cancer, breastconserving therapy
Importance of Physician– Patient Relationship
NOTABLE HONORS: ASTRO Gold Medal (2007); ASCO Gianni Bonadonna Breast Cancer Research Award (2008); Brinker International Award, Susan G. Komen Breast Cancer Foundation (2001)
Radiation oncology is a highly technical discipline that involves an understanding of the relevant clinical trials, physics, and extremely complex machines. It levies intense demands on practitioners trying to keep abreast of advances in the field, while simul-
ON MENTORING THE NEXT GENERATION: “It is an immensely satisfying legacy to have trained multitudes of bright young radiation oncologists who in turn have and will help shape the field.”
taneously sorting though the myths and facts of radiation oncology as they counsel and treat vulnerable patients with cancer. And it is patient contact that keeps Dr. Harris’s oncologic fire aglow. “It is exceedingly gratifying to help patients through their day-to-day struggles, whether I’m delivering curative or palliative therapy. The bond between oncologists and their patients is very meaningful,” said Dr. Harris. During his medical internship, Dr. Harris remembered spending a lot of time dealing with compliance issues, such as patients who refused to take blood pressure or diabetes medications, a duty rarely necessary in oncology practice. “Oncologists don’t usually need to spend their valuable time on patient compliance. This is a very focused and demanding field. Every patient has a potentially deadly disease and wants all the indicated treatment we can deliver,” said Dr. Harris. Of course, the life of an oncologist is also fraught with the reality of what occurs when the outer limits of medicine are reached. “Sometimes things don’t work out; tumors progress and patients die. This field is not for everyone,” said Dr. Harris, “But my mental calculation has always been that I am doing the best I possibly can, keeping at the cutting edge of new information, continually learning. And as long as I do everything in my power for my patients, I can remain comfortable with how things turn out.”
Mentoring Young Oncologists Aside from a heavy volume of patient care, Dr. Harris’s workdays as a department chair and clinical investigator are as varied as they are full. He is also in charge of the residency program, unusual for a department chair. “A major focus in my career has turned toward mentoring residents and our continued on page 13
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Gabriel N. Hortobagyi, MD, FACP
Tracing Breast Cancer Luminary’s Path to Oncology, from Hungary to Houston
G
abriel N. Hortobagyi, MD, FACP, ASCO Past President (2006-2007), grew up under the oppressive regime of communist Hungary during the Cold War. “As collegeeducated intellectuals, my family was among the ‘politically undesirables,’ and if we had not escaped Hungary, neither my two sisters nor I would have been allowed to finish high school,” Dr. Hortobagyi said. “Instead of becoming a doctor, I might have ended up digging ditches in the streets of some rural town.” During the height of the Cold War, the Hortobagyis were rounded up and placed in an internal concentration camp, sentenced to forced labor. When Joseph Stalin died 3 years later in 1953, they were released, but their lives were still in the grip of the dictatorship. “We were not allowed to live in Budapest, the capital. Even though my parents were highly educated, the regime consigned them to the most menial work,” Dr. Hortobagyi remembered.
Early Dreams Fulfilled There were no doctors in the family to serve as an inspiration for Dr. Hortobagyi’s future career. He recalled that his mother had dreamed of becoming a physician, but the culture of Eastern Europe in the early 1900s had other ideas for women. As a child, Dr. Hortobagyi was a voracious reader of science, “And as far back as I can remember, I always wanted to be-
Jay R. Harris, MD continued from page 12
junior faculty. It is an immensely satisfying legacy to have trained multitudes of bright young radiation oncologists who in turn have and will help shape the field,” said Dr. Harris. “I remember sitting next to the chairman of medicine at the Brigham
come a doctor,” he said. Fortunately, his father’s resolve and serendipitous connections helped the family escape Hungary, allowing Dr. Hortobagyi to follow his aspiration of becoming a doctor. “I went to the National University in Bogotá, Colombia; the first and only medical school I applied to,” Dr. Hortobagyi said.
I was the director, the pharmacist, the chair of internal medicine, head of surgery, gynecology, cardiology, radiology, lab medicines…everything. It was basically a onedoc show. — Gabriel N. Hortobagyi, MD, FACP
Dr. Hortobagyi graduated at the top of his class, but after completing his mandatory rotating internship there was yet another requisite prior to receiving his medical license. “In Colombia, before getting a medical license, every med school graduate is required to serve for 1 year in an economically challenged area of the country. The government selects the place and off you go, probably to be the only doctor in that particular sector,” Dr. Hortobagyi said. and Women’s Hospital at Harvard Medical School. At one point he turned to me and said, ‘If I had to do it all over again, I would become an oncologist because the translation of basic science to improve therapeutics is most evident in oncology.’ And that statement was coming from a world-famous cardiologist,” said Dr. Harris.
Running a ‘One-doc Show’ in the Andes Dr. Hortobagyi was sent to a far-off town of about 35,000 people (Pacho, Cundinamarca), nestled in the foothills of the Andes mountain range. He said that his government service turned out to be an incredible proving ground for a young doctor like himself. “There was a 100-bed hospital and I was the sole physician. My staff consisted of one nun who was head nurse and a couple of nuns who were basically licensed vocational nurses. I was the director, the pharmacist, the chair of internal medicine, head of surgery, gynecology, cardiology, radiology, lab medicines…everything. It was basically a onedoc show,” Dr. Hortobagyi said. “At first it was a bit frightening. It wasn’t like an internship or residency; there was no safety net, and all I had were my textbooks to consult. I remember doing surgery with only a licensed vocational nurse holding an ether mask to the patient’s nose or giving IV thiopental sodium (Pentothal), a short-term anesthesia, so I had to work very quickly,” Dr. Hortobagyi said. “I learned to think on my feet, to improvise with the tools at hand.” In addition to running the hospital, Dr. Hortobagyi had to service three smaller communities on a weekly basis. “Fortunately, this was before the extensive paperwork and documentation we see today, so I was able to make morning hospital rounds of 100 patients in 2 hours, and then hop a bus to one of
‘A Special Kind of Trust’ Dr. Harris is proud of his two sons. As he puts it, “They have glitzy jobs.” His son Dan, a correspondent and weekend anchor for ABC News, has covered the war in Iraq and Hurricane Katrina. His other son, Matt, is a managing director for Bain Capital Ventures. But Dr. Harris doesn’t believe
PROFILE: Gabriel N. Hortobagyi, MD, FACP TITLE: Chair, Department of Breast Medical Oncology, and Director, Breast Cancer Research Program, The University of Texas MD Anderson Cancer Center MEDICAL DEGREE: MD, National University of Colombia, Bogotá RESEARCH INTERESTS: Breast cancer NOTABLE HONORS: Bob Pinedo Cancer Care Prize, Society for Translational Oncology (2011); ASCO Statesman Award (2009); John Mendelsohn Lifetime Scientific Achievement Award (2009); Chevalier, Order of the Legion of Honor (2001) ON A CAREER-CHANGING MOMENT: “[Dr. Freireich’s talk at the American Cancer Society symposium] was a watershed event for me; it was the first time I had heard anyone talk about actually curing cancer.”
those outlying communities and see patients,” Dr. Hortobagyi said. This “fly-by-the-seat-of-your-pants” experience accelerated and honed his transition from intern to doctor, he noted. On the other side of the mountain range where the hospital was situated were Colombia’s largest emerald mines. “Between mining accidents and continued on page 14
that they could possibly have the same job satisfaction that he has. “The relationship between oncologists and their patients is unique. It is built over time, and a special kind of trust is needed. That’s why I love my work as a radiation oncologist,” said Dr. Harris.
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Disclosure: Dr. Harris reported no potential conflicts of interest.
The ASCO Post | JUNE 15, 2012 | SUPPLEMENT
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Hagop M. Kantarjian, MD
After 3 Decades at MD Anderson, Leukemia Researcher Shows No Sign of Slowing Down
H
agop M. Kantarjian, MD, Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, was born in Lebanon. The only member of his family to have pursued a career in medicine, he received his medical degree from the American University of Beirut (AUB), which was founded by American missionaries in 1866 and opened the doors of its School of Medicine a year later. AUB was an intensely egalitarian institution, and this quality was reflected in the university’s guiding principle: This college is for all conditions and classes of men without regard to color, nationality, race or religion…white, black, or yellow, Christian, Jew, Mohammedan or heathen, may enter and enjoy all the advantages of this institution.…
During his medical education at AUB, Dr. Kantarjian spent 4 months in the United States as part of a visit-
Gabriel N. Hortobagyi, MD, FACP continued from page 13
emerald smugglers shooting and stabbing each other, I got plenty of emergency surgical experience. But after the initial adrenaline rush, I began to feel restless and I began yearning for a situation where I could grow as a doctor and make more of an impact,” Dr. Hortobagyi commented.
A Career-changing Experience After receiving his medical license, Dr. Hortobagyi began applying for training positions in the United States in earnest. When he was accepted at St. Luke’s Hospital, part of the Case Western Reserve University Hospital System, he “got on the first plane to Cleveland, Ohio, to begin my second medical internship, during which a wonderful group of men-
ing medical student elective at The University of Texas MD Anderson Cancer Center. “These elective periods are very influential and can have a profound effect on the lives and careers of medical students from outside the United States. For me, it was an eyeopening experience and a world I never thought existed. I fell in love with MD Anderson’s oncology program,” Dr. Kantarjian, said.
MD Anderson. “I was accepted and joined the Department of Developmental Therapeutics in 1981. I never wanted to be at any other institution.”
Groundbreaking Work in Leukemia Since his initial exposure to MD Anderson some 3 decades ago, Dr. Kantarjian’s work has markedly advanced the field of hematologic cancers, par-
I was fortunate to come to MD Anderson and work with giants like Emil Freireich, MD, Kenneth McCredie, MD, and others, all of whom had a tremendous influence on the way I approach oncology, both in the lab and at the bedside. — Hagop M. Kantarjian, MD
After returning to Lebanon, Dr. Kantarjian applied for a fellowship at
ticularly in the areas of chronic myelogenous leukemia (CML) and acute
tors introduced me to the exciting world of the research lab. However, at that time there was not much activity in oncology in Cleveland. There were a couple of hematologists treating leukemia and lymphoma and an endocrinologist who treated breast cancers, mostly with major ablative surgery,” he said. During his second year at Case, Dr. Hortobagyi drove to a 1-day American Cancer Society symposium in Columbus and had a career-changing experience. “One of the speakers was ASCO Past President Dr. Emil J. Freireich. His talk was a watershed event for me; it was the first time I had heard anyone talk about actually curing cancer,” Dr. Hortobagyi said. Driving back to Cleveland, Dr. Hortobagyi was faced with a reality check. “I knew that I wanted to become an oncologist, but there was no training program
in Cleveland. It was 1971 and the oncology field was just emerging; I wrote to the few existing cancer programs, one of which was run by Dr. Freireich at MD Anderson. Then I got in my car and got on the highway, making interview rounds to places like Rochester, New York, Memorial Sloan-Kettering in New York City, and Boston University. But just before I went to Houston, a message arrived from Dr. Freireich saying that I was expected to report for duty at MD Anderson. That was it. No interview. So on the appointed date I reported to Dr. Freireich and grew up with the institution,” Dr. Hortobagyi said.
Leader in Breast Cancer Research Dr. Hortobagyi is currently Chair of the Department of Breast Medical Oncology and Director of the Breast
lymphocytic leukemia (ALL). “In the Department of Leukemia, we’ve focused intensely on clinical translational research, and several lines of inquiry over the decades have made a significant impact on the prognosis of our patients,” Dr. Kantarjian said. Early on, Dr. Kantarjian’s group focused their research efforts on the treatment of CML, starting with the original interferon studies. “I worked on this approach for about 2 decades until the first tyrosine kinase inhibitors came around. At that point, we expanded our research to include imatinib (Gleevec) and second-generation tyrosine kinase receptors to the point that today CML—which was once associated with an average survival of 3 to 6 years and a 10-year survival rate of less than 20%—has basically been transformed into a chronic indolent disease, as long as the patients adhere to their daily oral treatment and continue to be followed,” Dr. Kantarjian said. Cancer Research Program at The University of Texas MD Anderson Cancer Center, where he has been serving the cancer community since the day he was hired by Dr. Freireich. Although Dr. Hortobagyi’s contributions to breast cancer research and treatments have received worldwide honors, he still recalls his first published paper. “It was the early days of immunotherapy, and we had primitive tools compared to what we have today. But we thought we were really on to something. We later disproved the results, but I still remember the exact moment I got the acceptance letter from Cancer, which at that time was the number one oncology journal. It seemed to signal the beginning of something,” Dr. Hortobagyi said.
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Disclosure: Dr. Hortobagyi reported no potential conflicts of interest.
ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
Another encouraging development seen during Dr. Kantarjian’s career was led by a member of the Department of Leukemia, Michael J. Keating, MB, BS. Dr. Keating discovered the activity of fludarabine in refractory chronic lymphocytic leukemia (CLL). “Building on this discovery, we added cyclophosphamide and rituximab (Rituxan), constituting the FCR regimen. After the German randomized studies proved that it was more effective than the standard of care at the time, the FDA approved the FCR regimen in 2010 as the new standard of care. The combination has since improved survival in CLL. That was a major highlight in leukemia research,” Dr. Kantarjian said. In 1992, Dr. Kantarjian was instrumental in creating the hyperCVAD regimen for treating adult ALL. “We modified the regimen, added some components, and today we know that the hyper-CVAD regimen produces cure rates of about 40% to 50% in adults with ALL. Moreover, when we added tyrosine kinase inhibitors in Philadelphia chromosome–positive ALL, or rituximab for Burkitt’s leukemia and CD20-positive ALL, we markedly improved the survival of these patients,” Dr. Kantarjian noted.
Developing Previously Abandoned Drugs Another distinction of Dr. Kantarjian’s career has been his instrumental work with drugs that had previously been abandoned by other researchers. “In 1991, I developed clofarabine
(Clolar) through animal studies and phase I and II trials, which led to its FDA approval in 2006 for pediatric ALL. Another drug that everyone seemed to lose interest in was decitabine (Dacogen), which was originally developed in Europe. In 1992, I brought decitabine to the United States on an investigational new drug application, and together with Jean-Pierre Issa, MD, we developed the concept of epigenetic therapy. After
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Encouraged by 30 Years of Progress As Dr. Kantarjian looks back at the 30-year arc of his career, his optimism is bolstered by the increasing progress that he has witnessed and had a hand in. “I’ve been fortunate to have seen major advances in the prognosis of patients with subsets of leukemia. Those with CML who once had little chance of surviving more than a few
PROFILE: Hagop M. Kantarjian, MD TITLE: Professor and Department Chair, Department of Leukemia, and Associate Vice President, Global Academic Programs, The University of Texas MD Anderson Cancer Center MEDICAL DEGREE: MD, American University of Beirut Faculty of Medicine RESEARCH INTERESTS: Chronic myelogenous leukemia, acute lymphocytic leukemia, translational research NOTABLE HONORS: Waun Ki Hong Award for Excellence in Team Science, MD Anderson Cancer Center (2008); John Mendelsohn Lifetime Scientific Achievement Award, MD Anderson Cancer Center (2008); Ben Qurrah Award, Arab American Medical Association (2010) ON HIS TIME AS A VISITING MEDICAL STUDENT AT MD ANDERSON: “It was an eye-opening experience and a world I never thought existed. I fell in love with MD Anderson’s oncology program.”
continued work, we launched a trial in 1999 that led to FDA approval of the drug in the treatment of myelodysplastic syndromes,” Dr. Kantarjian said. More recently, Dr. Kantarjian has been working on some promising new research. “A team in our group, led by Susan O’Brien, MD, is looking at Bcell receptor inhibitors in CLL. Another promising line of investigation is in monoclonal antibodies for ALL,” Dr. Kantarjian commented.
years can now expect to live 25 to 30 years. In adult ALL, the cure rate has gone from less than 20% to about 50%, which is a remarkable achievement,” Dr. Kantarjian said. Progress in oncology is built on incremental successes; similarly, the most fruitful academic oncology careers are built on the shoulders of predecessors. “I was fortunate to come to MD Anderson and work with giants like Emil Freireich, MD,
Kenneth McCredie, MD, and others, all of whom had a tremendous influence on the way I approach oncology, both in the lab and at the bedside,” Dr. Kantarjian said. High-level academic oncology is extremely taxing, but after 3 decades in the trenches Dr. Kantarjian shows no sign of slowing down. “I’m usually up around 6:00 AM, work out for a half hour, then get ready and head off to the Center for a 12-hour workday. I see patients 3 or 4 days a week, and I typically do 2 to 3 months of inpatient care. We see about 1,800 new leukemia patients per year in our group. The rest of my time is devoted to clinical translational research,” Dr. Kantarjian said.
Thriving in His Adoptive Home When first making the transition from his native Beirut, known for its beauty and culture, to his new home in Houston, Dr. Kantarjian was warned that the Texas city was a bland and forgettable spot on the map. “Nothing could have been further from the truth,” he said, “I think Houston is one of the most beautiful, cosmopolitan cities in the country. I love it here,” Dr. Kantarjian enthused. Asked if he has any hobbies that allow him to decompress after his 12-hour days, Dr. Kantarjian answered, “Painting is my passion. I paint in the fauvist (from the French for ‘wild beasts’) style. I paint and take long jogs in the heat of Houston.”
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Disclosure: Dr. Kantarjian reported no potential conflicts of interest.
Coming in The ASCO Post Comprehensive coverage of the 2012 ASCO Annual Meeting, including this year's plenary program: ■■ Abstract LBA1: Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. Kimberly L. Blackwell, author/speaker. ■■ Abstract 2: Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). Martin J. Van Den Bent, author/speaker.
■■ Abstract 3: Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. Michael E. Williams, author/speaker. ■■ Abstract 4: Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial. Maha Hussein, author/speaker.
Visit The ASCO Post online at ASCOPost.com
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David Khayat, MD, PhD
Trailblazing Oncologist Had Instrumental Role in France’s War on Cancer
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avid Khayat, MD, PhD, Chair of the Department of Medical Oncology at the Pitié-Salpêtrière Hospital in Paris, was inspired to become an oncologist by an episode that could have been ripped from the pages of one of his best-selling novels. At the age of 18, Dr. Khayat was the witness at his best friend’s marriage in Nice, France. When the couple returned from their honeymoon, the 19-year-old bride suffered a genital hemorrhage and was diagnosed with advanced cancer. She went to Paris to see the famous hematologist Dr. Jean Bernard. “After each treatment, she would return to Nice to be with her husband. Only weeks before she was so young and radiant in her white wedding dress; now she looked like the living dead,” said Dr. Khayat. It was the early 1970s, and her diagnosis was presumed to be a death sentence. However, it turned out that the original pathology report was inaccurate; she actually had lymphoma, not a solid tumor. After two years of treatment, she was cured; her hair grew back and she returned to school. “I was a medical student at the time and on seeing her recovery I realized it was the beginning of a scientific revolution—I wanted to be aboard that train, so I decided to become an oncologist,” said Dr. Khayat.
About 10 years ago, the same woman, a smoker, had another bout with cancer and this time her oncologist was her life-long friend, Dr. Khayat. “I cured her lung cancer and she is
doctor involved starker decisions than in the United States. “We had to decide whether to be a general practitioner or a specialist, in which case you entered an extremely difficult specialist com-
On seeing [my friend’s] recovery I realized it was the beginning of a scientific revolution—I wanted to be aboard that train, so I decided to become an oncologist. — David Khayat, MD, PhD
still alive, having survived two malignant diseases. Despite success stories like my friend and others, it has been painful to watch so many of my other patients die slow deaths over the years. But that is the emotional price oncologists pay,” said Dr. Khayat.
Early Life Dr. Khayat was born in Tunisia into humble circumstances; his family immigrated to France when he was 4-years-old. “No one in my family was ever in the medical field, nor did they think about it. We were quite poor, so it was a great source of pride when I decided to become a doctor,” said Dr. Khayat. In France, the road to becoming a
PROFILE: David Khayat, MD, PhD TITLE: Chair, Department of Medical Oncology, Pitié-Salpêtrière Hospital MEDICAL DEGREE: MD, University of Nice; PhD, Pierre and Marie Curie University RESEARCH INTERESTS: Immunology, medical oncology, novel agents NOTABLE HONORS: ASCO Distinguished Achievement Award (2011); Officer, National Order of the Legion of Honor (2007); Commander, Order of the British Empire (2006); American Association for Cancer Research Public Service Award (2000) ON THE CHARTER OF PARIS AGAINST CANCER: “The first article stated that all those signing the Charter had to recognize that cancer patients’ rights are human rights.”
petition. I won an internship contest, and went to study oncology at a Parisian cancer institute,” said Dr. Khayat. Shortly thereafter, faced with mandatory national military service, Dr. Khayat opted to defer his enlistment in favor of representing France as medical emissary. He asked his boss, Professor Claude Jasmin, if he could serve in the French Caribbean, confiding a passion for windsurfing. “Professor Jasmin laughed, but he wasn’t amused. He said, ‘To hell with that. You’re too bright to waste time windsurfing! There’s a research lab in Israel where I think I can get you a position.’ So off I went, to Tel Aviv,” said Dr. Khayat.
From Israel to Mount Sinai and a PhD The 18-month research stint in Israel proved fruitful. While testing immunoglobulin Fc receptors, Dr. Khayat used mouse serum instead of cell lines; the test came back positive for soluble Fc receptors. After the lab’s chief of microbiology said that the results were just an artifact, Dr. Khayat redid the test 15 times, getting Fc-positive results each time. “When I presented this finding to the chief, he simply said, ‘Now it’s a repetitive artifact.’ I couldn’t accept that so I worked on identifying and isolating the proteins, and pub-
lished the results in major U.S. journals,” said Dr. Khayat. The papers caught the eye of microbiology researchers at Mount Sinai School of Medicine in New York who were investigating the same topic. Since Dr. Khayat had found the mouse cell serum connection first, they invited him to their lab in New York to continue the line of inquiry in human cells. “After about a year in the Mount Sinai lab, we identified the same protein marker in human serum. At the end of the day, it gave me my PhD and helped launch my research career,” said Dr. Khayat
The Charter of Paris against Cancer Dr. Khayat commented that his success is due in large part to the valuable relationships that he has cultivated since his earlier days in oncology. His friendship with ASCO Past President Gabriel Hortobagyi, MD, with whom he wrote the Charter of Paris against Cancer, is of particular note. “In 1999, Gabriel and I, along with some friends, were having dinner in a marvelous Parisian restaurant and discussing ways to commemorate the millennium by raising awareness about global cancer issues—one that doesn’t leave the patients on the sidelines,” said Dr. Khayat. Over fine wine and food, Dr. Khayat and nine other luminaries in the cancer community, including current ASCO President Sandra Swain, MD, hammered out a blueprint for a collection of articles that together would form the international Charter. “The first article stated that all those signing the Charter had to recognize that cancer patients’ rights are human rights,” said Dr. Khayat. The Charter was finished in June of that year. But Dr. Khayat saw more downstream potential by involvcontinued on page 17
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Lawrence N. Shulman, MD
Dana-Farber Researcher’s Work with Partners in Health Brings Quality Cancer Care to Rwanda
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Going Global with Partners in Heath
awrence N. Shulman, MD, Chief Medical Officer at Dana-Farber Cancer Institute, grew up in New York City. A product of the public school system, Dr. Shulman entered Syracuse University as a history major, only to realize that studying the past, although important, wasn’t for him. “I wanted a field that interacted with people and science, and medicine seemed to be the perfect combination,” Dr. Shulman said. By the end of his first year at Syracuse, Dr. Shulman had switched his major to chemistry, which led to premed and an acceptance to Harvard Medical School. It was 1971, a tumultuous time of transition in the United States. The Vietnam War was raging through its final stages as President Nixon signed the National Cancer Act—billed as the War on Cancer—into law, which finally brought the disease out of the closet and onto the national stage. “It was right around the time Nixon signed the National Cancer Act that I took my first course on hematology/
oncology. It was a very exciting period; we were actually seeing clinical successes in previously incurable diseases such as acute lymphoblastic leukemia, Hodgkin lymphoma, and large-cell lymphoma. By the end of my second year at Harvard Medical
School, I was pretty convinced that I wanted to do something in oncology,” Dr. Shulman said. During his fourth year, Dr. Shulman was involved in hematologic malignancies and stem cell research, which sealed his decision to pursue oncology.
by the cancer community for advancing breast cancer therapies and improving quality of life for patients with all stages of the disease. Moreover, his ongoing work in health information technology at Dana-Farber and at ASCO, where he is on the Health Information Technol-
David Khayat, MD, PhD
Art. After he was reelected in 2002, a reporter asked him what his next term’s legacy would be. He answered, “No more stones. This time, my legacy will be a War on Cancer.” Dr. Khayat was on holiday with friends in Turkey when President Chirac called and said bluntly, “Three years ago you convinced me to sign the Charter; now you are going to develop my War on Cancer plan.” Dr. Khayat politely demurred, explaining that he knew how to treat cancer patients, not lay plans on such a grand scale. “But Chirac was persuasive, and, well, it’s hard to say no to the President. When I returned from holiday, I met with all the stakeholders and began Chirac’s War on Cancer, which has been a great success in France,” said Dr. Khayat.
French National Cancer Institute
continued from page 16
ing friends in high places, notably French President Jacques Chirac. “I asked Chirac if he would endorse the Charter. He did, with enthusiasm. I then went to see the General Director of UNESCO. He also endorsed the Charter, giving it the organization’s imprimatur. The Charter was signed on February 4, 2000, at the Palais de l’Élysée, which is the French White House,” said Dr. Khayat.
Role in the War on Cancer Dr. Khayat explained that each French President is given the opportunity to leave a “legacy,” such as Charles de Gaulle Airport. During President Chirac’s first term in 1995, his legacy was the elegant Museum of Primitive
Since he entered the field of oncology, Dr. Shulman’s career has been based in Boston at the many Harvard-affiliated hospitals. His achievements in the clinic and research have been acknowledged
[Our goal is] to work with the Rwandan ministries in developing the policies and infrastructure needed for this work to take place throughout the country, and for it to be sustainable. Why should these people die of cancers that could be cured in Boston? — Lawrence N. Shulman, MD
A centerpiece of President Chirac’s grand plan was the creation in 2005 of the French National Cancer Institute (Institut National du Cancer), which sought, among other goals, to coordinate national cancer research and care. Dr. Khayat, who spearheaded the project as the Institute’s founding President, noted that this undertaking was not without its difficulties. “People in high places don’t like change and there were huge political issues with various health ministries, but I met regularly with Chirac and he handled most of the blockades I encountered,” he said. As per his agreement with President Chirac, Dr. Khayat stepped down as President of the French National Cancer Institute after 3 groundbreaking
ogy Work Group, is helping to reshape the intersection of technology and clinical oncology practice. However, Dr. Shulman’s work has not been limited to just the Boston area, instead taking on an increasingly global scope. Dr. Shulman has assumed the role of Senior Oncology Advisor for Partners in Health, helping to develop structured cancer programs in resourcelimited health-care sites in Rwanda, Malawi, and Haiti. Prior to taking a leadership role with Partners in Health, Dr. Shulman served as a case-by-case oncology advisor to the organization’s cofounder, Paul Farmer, MD, PhD, a onetime intern of Dr. Shulman’s. Dr. Shulman explained that Rwanda—Africa’s most densely populated country—has been the focus of the organization’s most intensive outreach efforts in sub-Saharan Africa, which began in 2005, when the Rwandan government invited Partners in Health to work in the country’s underserved continued on page 19
years. For his invaluable leadership, he was made Honorary President of the Institute. Not resting on his laurels, Dr. Khayat’s busy days now center on his patients, his research interests, teaching his interns, and running his department. As previously mentioned, Dr. Khayat is also a published author, with a string of best-selling novels and a recent book, also a list-topper, that he says is “the sum of our knowledge about diet and cancer.” Asked how he manages to balance his medical and artistic pursuits, Dr. Khayat paused, then said firmly, “I only write during my holidays or when on a plane or train. Not one second of my time as a doctor is devoted to anything but patients, science, and medicine.”
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Disclosure: Dr. Khayat reported no potential conflicts of interest.
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Lawrence N. Shulman, MD continued from page 17
areas. Dr. Shulman recently led a team of doctors and nurses from Dana-Farber to Rwanda to continue the ongoing mission of building a viable cancer delivery service. “Before we got to Rwanda in 2005, there were essentially no cancer care facilities in the country. There were no oncologists to treat the patients with cancer,” Dr. Shulman said.
Progress Made in Butaro As an example of the progress made, Dr. Shulman pointed to the new Butaro Hospital in northern Rwanda, which opened its doors in January 2011. “Part of the hospital was planned to house our cancer program, and accordingly it has some very innovative architecture, designed with air circulation safety factors for our many immunosuppressed patients,” said Dr. Shulman. Outfitting the Butaro Hospital with skilled oncology staff and medical technology is an ongoing project that requires a great deal of on-the-ground human interaction, in order to build the trust that ultimately becomes the bridge for progress. “During my last trip to Rwanda, we ran the first basic cancer training program for the entire country. We wanted to keep the program focused, so each regional hospital was allowed to send two physicians and two nurses. We ended up with about 35 physicians and 35 nurses,” Dr. Shulman said. The program, although one small step in a long journey, was a success.
Visit
“These are bright, capable people who simply have never had any cancer training. It needs to be a partnership; we provide the cancer care expertise, and our Rwandan partners provide the cultural know-how to deliver the care,” Dr. Shulman said.
Visual Power of Quality Care Cancer is a universal experience, and although doctors across borders share a common language, gaining the trust of patients in areas of the world such as Rwanda is built on a patient-by-patient
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woman with gastrointestinal stromal tumor (GIST). Her husband told us of going from hospital to hospital seeking help as his wife’s weight dropped from 70 kg to 35 kg. She was close to being comatose. The Max Foundation, in partnership with Novartis, provides free imatinib (Gleevec) to GIST patients. So we biopsied her to prove her diagnosis and got her imatinib. When we saw her again, her weight was up to 68 kg. Her husband said the people in his community who had seen his wife when she was so sick
PROFILE: Lawrence N. Shulman, MD TITLE: Chief Medical Officer and Associate Professor of Medicine, Harvard Medical School; Physician, Adult Oncology, Brigham and Women’s Hospital MEDICAL DEGREE: MD, Harvard Medical School RESEARCH INTERESTS: Breast cancer, Hodgkin lymphoma, health information technology, early therapeutics ON THE VISUAL POWER OF QUALITY CARE: “Initially we were met with skepticism, but the barriers break down once you treat a couple of people successfully. When people see others who look very ill suddenly get better, they begin lining up at the door for treatment.”
basis. “Initially we were met with skepticism, but the barriers break down once you treat a couple of people successfully. When people see others who look very ill suddenly get better, they begin lining up at the door for treatment,” Dr. Shulman said. Dr. Shulman illustrated the visual power of quality cancer care by describing a home visit he made while in Rwanda. “We visited a 40-year-old
were afraid that she might be contagious. Seeing her healthy again has changed the community’s perception about cancer and its treatment. This patient’s story is an example of what can be accomplished. People believe what they see, especially when it’s positive, ” Dr. Shulman said.
Importance of Sustainability Dr. Shulman said that the new 150-
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bed hospital in Butaro is situated on a verdant hillside nestled in a startlingly beautiful area of the world. The structure itself is somewhat beyond what many in the region would take for a hospital. “When the hospital was near completion, people in the surrounding area were convinced it was a resort for foreign tourists. I might return to Rwanda this summer to dedicate the new cancer center in Butaro, perhaps with President Bill Clinton and NASCAR driver Jeff Gordon, who have been great supporters of the initiative,” Dr. Shulman said. Acknowledging the overarching issues in such a poor country, Dr. Shulman said, “Our goal is not only to help bring cancer care to individual children and adults, but also to work with the Rwandan ministries in developing the policies and infrastructure needed for this work to take place throughout the country, and for it to be sustainable. Why should these people die of cancers that could be cured in Boston?” Despite being involved in multiple cancer initiatives on the national and international stage, Dr. Shulman still sees patients at Dana-Farber each week. “Treating patients with cancer, no matter where they are, is still the best part of my job. It is a constant reminder of why I decided to become an oncologist in the first place,” Dr. Shulman said.
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Disclosure: Dr. Shulman reported no potential conflicts of interest.
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Sandra M. Swain, MD
New ASCO President Reflects on Value of Mentorship and Addressing Health-care Disparities
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andra M. Swain, MD, Medical Director of the Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC, and ASCO President for the 2012 to 2013 term, is a leading authority on breast cancer treatment with a global reputation in cuttingedge clinical research. The daughter of a career Navy officer whose duties allowed his family to experience many postings throughout the United States and internationally, Dr. Swain graduated as valedictorian from a small Catholic high school in Florida. She was accepted to the University of North Carolina (UNC), where, intrigued by anatomy and physiology, she had decided to major in physical therapy, until one of her neighbors, a young woman about to enter law school, suggested she become a doctor—after all, she “certainly was bright enough.” Dr. Swain’s counselor at UNC agreed with her neighbor’s advice, and she switched her major to premed, setting the course for a distinguished career marked by extensive clinical trial investigations that have expanded our knowledge of adjuvant therapy for breast cancer and molecular targeted
therapy for advanced and inflammatory breast cancer.
Finding a Mentor in Medical School Thanks to her academic excellence at UNC, Dr. Swain successfully gained admission to the University of Florida College of Medicine, where she was mentored by Warren E. Ross, MD. This relationship was pivotal in helping focus Dr. Swain’s developing interest in on-
However, in the 1980s, medicine—especially oncology—was a male-dominated field. The Vanderbilt program was one of only two remaining medical schools in the country that still had a grueling every-other-night call, and Dr. Swain recalled, with humorous irony, a bit of offhand advice given to her by Vanderbilt’s Chair of Medicine: “Sandra, why don’t you just go into family practice?” Fortunately, Dr. Swain had kept in
Given my growing interest in health-care disparities, the position was a perfect fit. I felt I would be able to make a difference in Washington’s large underserved African American population. — Sandra M. Swain, MD
cology. “I liked oncology because you treated the whole person; it was a fascinating systemic approach, not just one procedure, or one organ. Following Dr. Ross’s advice to seek out the strongest residency program possible, I did my residency at the Vanderbilt University Medical Center, which had an excellent oncology program,” said Dr. Swain.
PROFILE: Sandra M. Swain, MD TITLE: Medical Director, Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC MEDICAL DEGREE: MD, University of Florida College of Medicine RESEARCH INTERESTS: Adjuvant therapy of breast cancer, moleculartargeted therapy for advanced and inflammatory breast cancer NOTABLE HONORS: ASCO President (2012-2013); Mentor of Merit award as a Distinguished Clinical Teacher at the NIH; NCI Mentor of Merit (2002, 2003, 2005); NIH Merit Award (2001); Claude Jacquillat Award for Achievement in Clinical Oncology, Paris (2012) ON BEING A MENTOR: “I love that part of my work. In fact, I have 8×10 black-and-white pictures of each [NCI] fellow lining the walls of my office. I’m known to be tough on them, but it is an incredible experience, watching them develop into skilled oncologists.”
touch with Dr. Ross and followed his sage guidance instead: “Anyone who is anyone in oncology did a fellowship at the NCI,” she remembered. Dr. Swain applied to the NCI and was accepted for a medical oncology fellowship during a period of seminal change in cancer care and research.
Walking with the Giants at NCI Even though more than 30 years have passed since Dr. Swain’s NCI fellowship, she counts that period as a transformative point in her career. “It was a wonderful time to be at NCI, especially working in Dr. Marc Lippman’s laboratory alongside Dr. Robert Dickson, whose breast cancer research truly advanced the field. Although I decided not to pursue bench research, the 2 exciting years I spent running clinical trials with Dr. Lippman at the NCI accelerated my clinical trial career,” said Dr. Swain. Dr. Swain recalled a time when the early giants in the field, such as Drs.
Bernard Fisher and Gianni Bonadonna, were leaving their footprints in oncology research. “I remember my very first presentation; it was in Paris at a meeting on adjuvant chemotherapy. Dr. Lippman couldn’t make it and he asked me to fill in for him; naturally it was a huge opportunity, but I was so nervous I could barely speak. Dr. Bonadonna was to introduce me and he calmed me, saying ‘how lucky I was to be so young and passionate about my work.’ His composure had a soothing effect, and the presentation went very well,” Dr. Swain said. More than 25 years later, at that same Paris meeting, Dr. Swain was honored with the Claude Jacquillat Award for Achievement in Clinical Oncology. “I also presented results from our clinical breast cancer research at Bernie Fisher’s NSABP [National Surgical Adjuvant Breast and Bowel Project] meeting, which was an additional shot in the arm for an upcoming researcher like myself. Bernie was another mentor, someone whom I saw, and still see, as an uncompromising role model for someone setting out to do rigorous clinical research,” said Dr. Swain, adding that she views her long relationship with the NSABP as being part of an extended family.
Focus on Health-care Disparities Dr. Swain is proud of her tenure at the NCI, where she served as the Deputy Director of the Medicine Branch and Chief of the Cancer Therapeutics Branch. However, feeling her career needed a more global reach, she left the NCI about 5 years ago to assume the directorship of the Washington Cancer Institute. “Given my growing interest in health-care disparities, the position was a perfect fit. I felt I would be able to make a difference in Washington’s large uncontinued on page 21
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Daniel D. Von Hoff, MD, FACP
When It Comes to Scientific Exploration, Renowned Clinical Investigator Lets the Work Guide His Path
I
nternationally renowned clinical investigator Daniel D. Von Hoff, MD, FACP, attended grade school in a one-room schoolhouse on the rural outskirts of Oshkosh, Wisconsin. Polio was a scourge at the time, and Dr. Von Hoff recalled lining up with his skittish classmates to get the newly developed Salk vaccine. “It had a lot of meaning for me because my friend had polio and was hospitalized in an iron lung. I visited him and even though I was in a strange environment, I remember thinking that the vaccine I’d been given prevented the same disease that had made my friend so sick. I had an inkling that medicine might be for me, and that some day there might be a lifesaving vaccine I could work on,” Dr. Von Hoff said.
Inspired by Dedicated Teachers Dr. Von Hoff, who received ASCO’s 2010 David A. Karnofsky Memorial Award, credits the dedication of his
Sandra M. Swain, MD continued from page 20
derserved African American population,” Dr. Swain said. When Dr. Swain began as Director of the Institute, she noticed a pattern in the weekly breast cancer conference. “Participants presented case after case of African American women who were diagnosed with early breast cancer and never followed up for treatment; consequently the next time we saw them the cancer was advanced. Although the incidence of breast cancer in African American women is lower than the national average, mortality is significantly higher. So I wanted to tackle this issue,” Dr. Swain said. Dr. Swain’s subsequent work in organizing early intervention strategies was funded by a grant from Susan G.
early teachers for much of the academic fuel that launched his medical career. “The one-room schoolhouse experience was terrific; all the grades were taught within earshot of each other, so I could listen and learn the more advanced lessons,” Dr. Von Hoff said.
school. Being a small college, we had one-on-one access to professors who were unflinching in their standards, placing the highest value on rigorous research,” Dr. Von Hoff said. On his advisor’s recommendation, Dr. Von Hoff decided to go to an out-
When I ask a new patient about expectations, they invariably say ‘quantity and quality,’ and I say as long as you keep up the fight, I’ll be there with you, because that’s my goal, too. — Daniel D. Von Hoff, MD, FACP
Dr. Von Hoff ’s academic excellence continued, culminating in a full scholarship to highly regarded Carroll College (now Carroll University), which was known as a proving ground for students bent on medicine. “If you got through biology at Carroll, you had a good chance of getting into medical
of-state medical school. He applied to Columbia University College of Physicians and Surgeons, 1,000 miles away from home in the daunting big city. However, Dr. Von Hoff was president of his fraternity at Carroll, and a prior fraternity president who was also a Columbia alumnus offered Dr. Von Hoff
Komen for the Cure®, an organization she holds in high regard for its commitment to sponsoring on-the-ground cancer initiatives that make a difference in health-care disparities. “Along with access to screening and early interventions, I also saw a huge need in boosting clinical trial accrual rate in African Americans. To that end, I wrote a Challenge Grant, and actually got NIH funding [only 2% are accepted] to set up an intervention initiative to increase clinical trial participation among African Americans. We made a video of the project, which is being shown at this year’s ASCO Meeting,” Dr. Swain said.
ties at Washington Cancer Institute, Dr. Swain is an active board member of her own hospital’s board and the NSABP, and still sees patients one day a week. “And ever since I’ve been in Washington, I’ve always had an NCI fellow working with me; I love that part of my work. In fact, I have 8×10 blackand-white pictures of each fellow lining the walls of my office. I’m known to be tough on them, but it is an incredible experience, watching them develop into skilled oncologists,” Dr. Swain said. Dr. Swain is also involved in developing a regional oncology plan with Georgetown University and four other hospitals in the MedStar system, a large project with multiple downstream health-care benefits. Asked how she manages such an ambitious agenda, she replied, “It sounds ex-
New ASCO President Wears Many Hats Along with her administrative duties and work in health-care dispari-
a hand, helping out with the airfare, hotels, and even the interview process. “Besides a few awkward moments over regional accents, being in New York City at Columbia was a rich learning experience. I studied alongside many of the medical luminaries of the day,” Dr. Von Hoff said. “I spent a lot of time with Houston Merritt, MD, the founding father of neurology; I followed him around like a puppy. He always pulled the diagnostic rabbit out of the hat, and by using the power of keen observation he saw what others didn’t. It was a great learning experience.”
A Stepping-stone into Oncology Dr. Von Hoff did his internship at the University of California, San Francisco (UCSF), where his last name acted as a serendipitous stepping-stone into oncology. “UCSF had one of the nation’s first cancer units, continued on page 23
hausting, but I relish the challenge to ensure global health equity, which can truly make a difference in the world of oncology. That’s one reason why I’m so excited about my ASCO Presidency, during which I’ll be pursuing solutions to global health-care inequities,” Dr. Swain said. How does this ultra-busy oncologist spend her few hours of leisure time? “I like the cinema, but not escapist movies—no fantasy or sci-fi. I like stories built on complex human drama, like my job. When I treat patients with cancer, they open up and tell me personal things about what they’re going through. It’s a sacred responsibility to be part of that intimate experience,” Dr. Swain said.
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Disclosure: Dr. Swain reported no potential conflicts of interest.
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ASCOPost.com | JUNE 15, 2012 | SUPPLEMENT
Daniel D. Von Hoff, MD, FACP continued from page 21
called the Cancer Research Institute. Because my name began with a V, the cancer unit was my first rotation; nobody else wanted to go. We did UCSF’s first bone marrow transplant when I was an intern. I remember the patient very well—her name was Charlotte. Transplantation was in its infancy and I called the leader in the field, Dr. E. Donnall Thomas, for advice. He actually got on the phone to help me through some difficult issues, such as graft-vs-host disease. Dr. Thomas went on to win the Nobel Prize, but he was a doctor first, always willing to do anything that benefited the patient.” Dr. Von Hoff liked all aspects of medicine—especially surgery, although he felt he didn’t have the requisite skills. It was a fellowship opportunity at the NIH, however, where he was fortunate to work with the giants in the emerging field of cancer research, that sealed the deal for his career path. “Dr. Vincent DeVita, my attending physician, was one of the best internists I’ve ever worked with. He told me to get patients feeling better so they can make clear decisions about their treatments,” Dr. Von Hoff said. From NIH, Dr. Von Hoff was recruited to the University of Texas at San Antonio (UTSA) to launch a new therapy unit. “Once again,” he continued, “I was blessed with a great teacher, Charles A. Coltman, MD, a world-class
oncologist and one of the country’s best clinical trialists. An ASCO Past President, Dr. Coltman also led the Southwest Oncology Group for many years. He, and many others at UTSA, inspired my clinical oncology career. I was at UTSA for 20 exciting years.”
Precision Medicine: The Next Step in Cancer Treatment Then a telephone call from an old friend and mentor once again changed
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Director.’ Despite the hardships on my family, I told him that I would. My wife Ann was Syd’s friend also, and I credit her resolve and flexibility for helping make the hard transition that much easier,” Dr. Von Hoff said. Despite early trepidation over the difficult administrative activities in his new role as Director, the experience was yet another rewarding stretch of road in Dr. Von Hoff ’s oncology journey. “After almost 5 years at UACC, a
PROFILE: Daniel D. Von Hoff, MD, FACP TITLE: Physician-in-Chief and Director of Translational Research, Translational Genomics Research Institute; Professor of Medicine, Mayo Clinic; Clinical Professor of Medicine, University of Arizona College of Medicine; Chief Scientific Officer, Scottsdale Healthcare Research Institute and US Oncology MEDICAL DEGREE: MD, Columbia University College of Physicians and Surgeons RESEARCH INTERESTS: Drug development, pancreatic cancer NOTABLE HONORS: David A. Karnofsky Memorial Award, ASCO (2010); Scripps Genomic Medicine Award (2011); ASCO Statesman Award (2007) ON HIS CHILDHOOD ASPIRATIONS: “I remember thinking that the [polio] vaccine I’d been given prevented the same disease that had made my friend so sick. I had an inkling that medicine might be for me, and that some day there might be a lifesaving vaccine I could work on.”
the course of Dr. Von Hoff ’s career. “Sydney Salmon, MD, who was Director of the University of Arizona Cancer Center (UACC) called and immediately said, ‘Dan, I’ve got pancreatic cancer. Would you help keep my dream alive? I want you to come to Arizona and take over as the Cancer Center’s
patient of mine asked about the next step in cancer treatment. We spoke about starting a new research institute called Translational Genomics Research Institute (TGen), which I was planning to join in the capacity of Physician-in-Chief,” Dr. Von Hoff said. His current work at TGen focuses on
“precision medicine,” which seeks to unearth new genetic markers and their corresponding targeted therapies for treating cancers. “My goal is to develop therapies that best help the individual patient sitting in front of me,” Dr. Von Hoff said. To that end, Dr. Von Hoff and his team are currently investigating 26 new compounds in phase I trials.
No End in Sight Asked if TGen is where he will hang his lab coat for the duration of his career, Dr. Von Hoff dismissed the idea of permanence when it comes to scientific exploration, preferring to let the work, such as his groundbreaking research in pancreatic cancer, guide his path. Despite much progress, cancer care is beset by relentless mortality issues, but Dr. Von Hoff remains eternally optimistic, focusing on one patient at a time. “When I ask a new patient about expectations, they invariably say ‘quantity and quality,’ and I say as long as you keep up the fight, I’ll be there with you, because that’s my goal, too.” What does Dr. Von Hoff—who stresses that he cannot “divorce” himself from patient care and research— do in his brief leisure time? “I have model trains, lots of them. In fact, two rooms in my house are full of trains,” Dr. Von Hoff said.
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Disclosure: Dr. Von Hoff reported no potential conflicts of interest.
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