SUPPLE M E NT
SPECIAL ANNIVERSARY ISSUE
VOLUME 4, ISSUE 9
JUNE 10, 2013
Editor-in-Chief, James O. Armitage, MD
Narratives in Oncology The ASCO Post profiles leaders in cancer care and research
Charles M. Balch, MD, FACS, PhD (hc)
Clara D. Bloomfield, MD
Franco Cavalli, MD, FRCP
Lawrence H. Einhorn, MD
Mary K. Gospodarowicz, MD, FRCPC
Clifford A. Hudis, MD
Maha Hussain, MD, FACP
Alexandra Levine, MD, MACP
Lee N. Newcomer, MD, MHA
Owen N. Witte, MD
Plus, a Tribute to Emil ‘Tom’ Frei III, MD A Supplement to The ASCO Post™
A Harborside Press® Publication
The ASCO Post | JUNE 10, 2013 | SUPPLEMENT
Editorial Board James O. Armitage, MD Editor-in-Chief
Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha
Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center
Michael P. Link, MD Stanford University Medical Center
Associate Editors Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network 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
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 William T. McGivney, PhD Philadelphia, Pennsylvania James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University 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 William C. Wood, MD Winship Cancer Institute, Emory University
Nancy E. Davidson, MD University of Pittsburgh Cancer Institute
Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria
George D. Demetri, MD Dana-Farber Cancer Institute
Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina
Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bishoy Morris Faltas, MD Weill Cornell Medical College
Nagi El-Saghir, MD American University of Beirut, Lebanon
Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital, Paris, France
Louis B. Harrison, MD Continuum Cancer Centers of New York
Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong
Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis
he ASCO Post is pleased to present this special anniversary issue in recognition of the publication’s 4th year serving the oncology community. We hope you enjoy this commemorative supplement profiling several of the many leaders in the oncology community. In coming issues of The ASCO Post and in future supplements, 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: ■■ Clifford A. Hudis, MD ■■ Charles M. Balch, MD, FACS, PhD (hc) ■■ Clara D. Bloomfield, MD ■■ Franco Cavalli, MD, FRCP ■■ Lawrence H. Einhorn, MD ■■ Mary K. Gospodarowicz, MD, FRCP ■■ Maha Hussain, MD, FACP ■■ Alexandra Levine, MD, MACP ■■ Lee N. Newcomer, MD, MHA ■■ Owen N. Witte, MD
The ASCO Post
Wants to Hear from You 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
Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada
John A. Fracchia, MD New York Urological Associates
Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center
Anniversary Issue: Narratives in Oncology
Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel
Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center
Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan
Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center
Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa
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ASCOPost.com | JUNE 10, 2013 | SUPPLEMENT
Emil ‘Tom’ Frei III, MD
Source: NCI; Dana-Farber Cancer Institute
Emil Frei III, MD, with nurse and child.
he pages of medical history are dog-eared with breakthroughs that have transformed medicine and saved lives. One of those dog-eared pages belongs to Emil Frei III, MD, known to his colleagues and friends as Tom. In the dawn of oncology, Dr. Frei, along with his associate, Emil Freireich, MD, did something new in the treatment of cancer—they combined chemotherapies, a transcendent therapeutic approach that accelerated the field and, in turn, saved millions of lives. Dr. Frei died on April 30 at the age of 89. Emil Frei III was born in St. Louis in 1924 into a free-spirited artistic family. He seemed destined for a life in the arts, but in his early teens, his interests turned toward science, which later seeded his passion to find a cure for cancer. In 1942, he entered St. Louis University as a premed student. A year later, at the onset of World War II, he was drafted into the Navy V-12 college training program. He would attend
Colgate University and later, in 1948, graduate from Yale with an MD. After that, he began his internship at the St. Louis University Hospital. Having been in the V-12 program, Dr. Frei was obligated for active duty, if it became necessary at a later date. “So when Truman sent the troops into Korea, I got a telegram fairly shortly
changing influence on him. “Dr. Zubrod took a position as the Clinical Director of the NCI and he asked me to join him, which I did in April 1955,” said Dr. Frei. It was Dr. Zubrod who introduced Dr. Frei to Dr. Jim Holland, who became a close friend and collaborator throughout his career. Soon after arriving at NCI, Dr. Frei also met Emil Freireich, MD. Although polar opposites in countenance—Dr. Frei was reserved, cool, contemplative, to Freireich’s intellectual flamboyance—the “two Emils” would become the closest of associates.
Adventurous Researchers Backed by a robust Federal government, the NCI was the right place to be for adventurous researchers. Drs. Frei and Freireich had everything they needed: a new clinic, lots of empty beds, a vast laboratory, and the enthusiastic support of the Institute’s Director, Dr. Zubrod. The two researchers decided to focus their clinical activities on acute lymphocytic leukemia (ALL) in children. Asked why they chose leukemia, Dr. Frei said, “There were several reasons. One is that Dr. Jim Holland, who had been there before us, started the program in leukemia, so we inherited his patients, if you will.”
In a career as lush with accomplishments, awards, positions, and publications as Dr. Frei’s, it was his patients that mattered most. after that. I was in the service for 2 years, 15 months of which were in the Far East and the Korean theater,” said Dr. Frei, during a National Cancer Institute (NCI) Oral History Interview. After the Korean War, Dr. Frei returned to St. Louis to finish his residency. One of the professors he conducted research under, Gordon Zubrod, MD, would have a career-
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
Working on limited scientific “leads” in ALL, Drs. Frei and Freireich attempted to sort out the “chaos in the field” at the time, which was largely a compilation of anecdotes; prospective experimental designs were lacking. At the time, there were two agents—6-mercaptopurine and methotrexate—that showed activity in ALL. At the insistence of Dr.
Zubrod, the two young researchers wrote protocols and defined what complete response was in advance, thus defining how to proceed tactically. It was a watershed event in experimental trial design; however, not without controversy. Dr. Frei explained, “It was controversial because it was felt that we were making patients fit a protocol, whereas you should instead fit the protocol to the patient. It sounds like a compelling argument, but if you don’t really know what you’re doing, you need to have a prospective protocol that asks a question and gets an answer.”
Paradigm Shift in Therapeutics Within a year, Dr. Frei was named Chief of NCI’s Leukemia Section and later, Chief of Medicine. Frustrated by the short-term remissions achieved in ALL that they were seeing with single-drug therapies, Drs. Frei, Freireich, and Holland began testing combinations of two or more agents to attack the various aspects of leukemia cells’ growth. Testing ideas through controlled experimentation requires a thirst for innovation and change, often in the face of a stubborn status quo. Dr. Frei and his colleagues persevered, marshaling in a paradigm shift in oncology therapeutics: combination chemotherapy. In 1965, Dr. Frei moved to The University of Texas MD Anderson Cancer Center in Houston, where he served as Associate Director of Clinical Research and Chair of the Department of Experimental Therapeutics. He joined Dana-Farber Cancer Institute in 1972, serving as Physician-in-Chief, succeeding the Institute’s founder, Sidney Farber, MD, who died later that same year. Just 1 year later, Dr. Frei was named Dana-Farber’s Director and Professor of Medicine at Harvard Medical School. continued on page 6
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For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab
EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2
median prior therapies
of patients received prior rituximab
of patients received prior alkylating agents
of patients received prior fludarabine and alemtuzumab
The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.
To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion
(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers
When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies
Overall response rate with ARZERRA 60 50 40
The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses
30 20 10
FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)
of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).
No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)
Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.
The ASCO Post | JUNE 10, 2013 | SUPPLEMENT B:22.5” T:21” S:19”
Emil ‘Tom’ Frei III, MD continued from page 3
Other Pioneering Work With Dana-Farber colleagues, Arthur Skarin, MD, and George Canellos, MD, Dr. Frei developed a treatment for adults with non-Hodgkin lymphoma, which was one of the first
regimens to produce substantial cure rates in the disease. In the 1970s, Dr. Frei’s work helped develop combination therapies that increased survival in breast cancer. During that time, he also participated in pioneering work in the use of bone marrow transplants for a variety of cancers. It is worth noting
that under his confident and meticulous stewardship, Dana-Farber became one of the world’s top-rated cancer centers. In tribute, Dana-Farber President Edward J. Benz, Jr, MD, said, “This approach has led to cures in many patients with cancer. The majority of pa-
tients with certain forms of childhood leukemia, Hodgkin disease, testicular cancer, and some other cancers can now expect to live long, high-quality lives because of his contributions.” Dr. Frei published more than 500 papers in scientific and professional journals and was the recipient of nu-
BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY ARZERRA® (ofatumumab) in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset for intravenous infusion in Study 1 andInjection, in the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing informationThe forfollowing is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabTotal Population AlemtuzumabTotal Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory (n = 154) Refractory (n = 154)of patients ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the treatment (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine andwith chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade All Grade All Grade All Grade alemtuzumab. The effectiveness of ARZERRA All is based on the demonstration alemtuzumab. The effectiveness of ARZERRA is based on the demonstration ≥3 Grades ≥3 Grades Body System/ of durable objective responses [see ClinicalGrades Studies (14) of ≥3 Grades ≥3full prescribing Body System/ of durable objective responses [see Clinical Studies (14) of full prescribing No data demonstrate an improvement in disease-related % % % % Adverse Event information]. No data demonstrate an improvement in disease-relatedinformation]. Adverse % % % % Event symptoms or Infections increased and survival with ARZERRA. symptoms or increased survival with ARZERRA. Infections and infestations infestations 23 14 25 15 Pneumoniaa 23 14 25 15 Pneumoniaa 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS 11 <1 19 2 Bronchitis 11 <1 19 2 Bronchitis 5.1 Infusion Reactionsb ARZERRA can cause serious infusion reactions 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions 8 8 10 10 Sepsis 8 edema,8pulmonary 10 10 Sepsisb dyspnea, laryngeal edema, manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonarymanifesting edema, as bronchospasm, 8 0 8 0 Nasopharyngitis 0 8 0 Nasopharyngitis flushing, hypertension, hypotension, syncope, 8cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, 6 1 7 2 Herpes zoster 6 and angioedema. 1 7 2 Herpes zoster back pain, abdominal pain, pyrexia, rash, urticaria, Infusion back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion 5 2 3 2 Sinusitis 5 2 Adverse 3 2 Sinusitis frequently with the first 2 infusions [see reactions occur more frequently with the first 2 infusions [see Adversereactions occur more Blood and lymphatic (6.1)]. Premedicate with acetaminophen, an antihistamine, and a Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, Reactions and a corticosteroidsystem [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing system disorders disorders information]. Interrupt infusion for infusion reactions of any5 severity. Institute information]. Interrupt infusion for infusion reactions of any severity. Institute 16 5 17 8 Anemia 16 17 8 Anemia medical fordisorders severe infusion reactions including angina or other medical management for severe infusion reactions including angina or other management Psychiatric disorders Psychiatric signs and symptoms of myocardial ischemia [see signs and symptoms of myocardial ischemia [see Dosage and Administration 7 0 10 0 Insomnia 7 Dosage 0and Administration 10 0 Insomnia (2.3) of full prescribing information]. In a study of patients with moderate (2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for which to severe chronic obstructive pulmonary disease, an indication for which 6 0 7 0 Headache2 of 5 patients developed 6 0 bronchospasm 7 0 Headache ARZERRA is not approved, Grade 3 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and 5 0 8 0 Hypertension 5 0 blood counts 8 0 Hypertension can occur with ARZERRA. Monitor complete thrombocytopenia can occur with ARZERRA. Monitor complete blood thrombocytopenia counts 5 0 3 0 5 0 and increase 3 0 Hypotension (CBC) and plateletHypotension counts at regular intervals during therapy, (CBC) and platelet counts at regular intervals during therapy, and increase 5 <1 7 2 5 <1 or 4 cytopenias. 7 2 Tachycardia the frequency of Tachycardia monitoring in patients who develop Grade 3 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. mediastinal disorders mediastinal disorders Consider PML in Cough any patient with new onset of Consider PML in any patient with new onset of or changes in pre-existing 19 0 19 0 19or changes0in pre-existing 19 0 Cough neurological signsDyspnea or symptoms. Discontinue 14 ARZERRA if PML neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, 14 2 19 5 2 is suspected, 19 5 Dyspnea and initiate evaluation for PML including consultation with a neurologist, and initiate evaluation for PML including consultation with a neurologist, Gastrointestinal disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation 18 0 19 0 Diarrhea 18 0 19 0 Diarrhea Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can 11 0 12 0 11 0 patients at 12high 0 Nausea following treatment with ARZERRA. Screen occur in patients following treatment with ARZERRA. Screen patients occur at highin patients Nausea Skin and subcutaneous Skin andbefore subcutaneous risk of HBV infection initiation of ARZERRA. Closely monitor carriers risk of HBV infection before initiation of ARZERRA. Closely monitor carriers tissue disorders disorders hepatitis B tissue for clinical and laboratory signs of active HBV infection during of hepatitis B for clinical and laboratory signs of active HBV infection of during 14 <1 17 2 Rashc and for 6 to 12 months 14 following<1the last infusion 17 2 Rashc treatment with ARZERRA treatment with ARZERRA and for 6 to 12 months following the last infusion 8 0 5 0 Urticaria ARZERRA in patients8who develop 0 viral hepatitis 5 or 0 Urticaria of ARZERRA. Discontinue of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation of viral hepatitis, and institute appropriate treatment. Insufficient 5 0 5 0 Hyperhidrosis 5 0 5 0 Hyperhidrosis datawith exist regarding the safetyand of administration of ARZERRA in patients with data exist regarding the safety of administration of ARZERRA in patients Musculoskeletal and Musculoskeletal active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients ARZERRA. Perform evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation 8 1 12 2 Backreceiving pain 8 a diagnostic 1 12 2 Back pain if obstruction is suspected. 5.6 Immunizations if obstruction is suspected. 5.6 Immunizations The safety of immunization 5 0 3 0 Muscle spasms 5 The safety0of immunization 3 0 Muscle spasms vaccinesdisorders during orand following administration of ARZERRA has with live viral vaccines during or following administration of ARZERRAwith haslive viral General General disorders and been studied. Do not administer live viral vaccines to patients who have not been studied. Do not administer live viral vaccines to patients whonothave administration site administration site recently recently received ARZERRA. The ability to generate an immune response to received ARZERRA. The ability to generate an immune response to conditions conditions any vaccine following administration of ARZERRA has not been studied. any vaccine following administration of ARZERRA has not been studied. 20 3 25 5 Pyrexia 20 3 25 5 Pyrexia 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS 15 0 15 0 Fatigue 15 0 15 0 Fatigue Thein following serious adverse reactions are discussed in <1 greater detail8in The following serious adverse reactions are discussed in greater detail 9 <1 8 2 Edema peripheral 9 2 Edema peripheral other sections of Chills the labeling: other sections of the labeling: 8 0 10 0 8 0 10 0 Chills • Infusion Reactions [see Warnings and Precautions (5.1)] • Infusion Reactions [see Warnings and Precautions (5.1)] a a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • Cytopenias [see Warnings and Precautions (5.2)] bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • Progressive b b Multifocal Leukoencephalopathy [see Warnings and Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c Rash includes rash, rash macular, and rash vesicular. includes [see rash,Warnings rash macular, and rash vesicular. • Hepatitis BRash Reactivation and Precautions (5.4)] • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • Intestinal Infusion Obstruction [see Warnings Precautions (5.5)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] Reactions: Infusion reactions occurred in 44% of patients on the Reactions: Infusionand reactions occurred in 44% of patients onInfusion the The most common adverse reactions(300 mg), (≥10%) in29% Study 1 were The most common adverse reactions (≥10%) in Study 1 were neutropenia, day of the first infusion (300 mg), 29% on the day of the second infusion day of the first infusion on the dayneutropenia, of the second infusion cough, anemia,during fatigue, dyspnea, infusions. rash, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash,pneumonia, pyrexia, (2,000 mg), and less frequently during subsequent infusions. Infections: A (2,000 mg), anddiarrhea, less frequently subsequent Infections: A nausea, bronchitis, upper respiratory tract infections. The most nausea, bronchitis, and upper respiratory tract infections. The most common total of 108 patients (70%) experienced bacterial, viral, or fungal infections. total ofand 108 patients (70%) experienced bacterial, viral, common or fungal infections. serious adverse reactions in Study 1 wereexperienced infections (including serious adverse reactions in Study 1 were infections (including pneumonia A total A total of 45 patients (29%) ≥Grade 3 pneumonia infections, of which 19 of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), (12%) neutropenia, and pyrexia. Infections wereinfections the most in common and sepsis), neutropenia, and pyrexia. Infections were the most common were fatal. The proportion of fatal the fludarabine-(12%) and were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Experience Because clinical counts trials are conducted varying Trials Experience Because clinical trials are conducted under widelyTrials varying with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 with normal neutrophil at baseline, 45under (42%)widely developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical of a drugSome patients conditions, adverse reaction rates observed in the clinical trials of a drug neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients neutropenia. Nineteen (18%) developed Grade 4trials neutropenia. cannot compared ratesGrade 4 in the clinical trials of>2 weeks another drug and cannot be directly compared to rates in the clinical trials of another drug andbe directly experienced new onset Grade 4 neutropenia >2 weeks in duration. experienced newtoonset neutropenia in duration. may not reflect rates observedThere in practice. The safety of monotherapy may not reflect the rates observed in practice. The safety of monotherapy 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic 6.2the Immunogenicity is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with samples relapsedfrom or refractory with ARZERRA was evaluated in 181 patients with relapsed or refractory such as ofatumumab. Serum samples from patients with CLL in proteins such as ofatumumab. Serum patients with CLL proteins in CLL in 2 open-label, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-arm studies. In these studies, Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for Study 1 non-randomized, were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered atantibodies 2,000 mg during beginning dose ARZERRA was administered at 2,000 mg beginning with the second dose anti-ofatumumab antibodies during and after the 24-week treatment period. anti-ofatumumab and with afterthe the second 24-week treatment period. for 11 dosesResults (Study 1were [n = 154]) (Study 2 The data for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data Results were negative in 46 patients after the 8th infusion and in 33 patients negativeorin3 doses 46 patients after[n = 27]). the 8th infusion and in 33 patients described in after Table 1 sections below are derived from 154 patients described in Table 1 and other sections below are derived from 154 patients afteronthe 12th infusion. Immunogenicity assay results are highly dependent on theand 12thother infusion. Immunogenicity assay results are highly dependent in Study 1. Allseveral patients received 2,000 mg from thespecificity, second dose in Study 1. All patients received 2,000 mg weekly from the second dose several factors including assay sensitivity and specificity, assay methodology, factors including assayweekly sensitivity and assay methodology, onward. Ninety percent of patients at collection, least 8 infusions of ARZERRA onward. Ninety percent of patients received at least 8 infusions of ARZERRA sample handling, timingreceived of sample concomitant medications,sample and handling, timing of sample collection, concomitant medications, and and 55% all 12 infusions. agecomparison was 63 years (range: 41of antibodies and 55% received all 12 infusions. The median age was 63 years (range: 41 received underlying underlying disease. For The thesemedian reasons, of incidence to disease. For these reasons, comparison of incidence of antibodies to to 86 years),ARZERRA 72% werewith male, 97% were White. to other products may be misleading. to 86 years), 72% were male, and 97% were White. ARZERRA with the incidence of antibodies to other products may be misleading. theand incidence of antibodies
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merous awards and honors. In 1972, he was awarded the Albert Lasker Medical Research Award in recognition of his scientific contributions.
Impact on Education Dr. Frei’s impact on medical education can not be overstated. He
trained oncologists at NCI, MD Anderson Cancer Center, and at Dana Farber Cancer Institute who “constitute a blue ribbon roster of today’s oncology leadership,” recalled Dr. Jim Holland. Further, Dr. Holland and Dr. Frei collaborated on the renowned Holland-Frei Cancer Medi-
7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.
cine textbook now in its eighth edition.
Patients Mattered Most Even still, in a career as lush with accomplishments, awards, positions, and publications as Dr. Frei’s, it was his patients that mattered most. His
Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)]
work helped bring about the first complete cures for pediatric leukemia patients and led to more effective treatments for adult malignancies ranging from breast cancer to bone cancer. In his early days working in childhood leukemia, when the outcomes were still grim, he remarked, “Children are a challenge, and also a joy to work with.” That he found joy in caring for desperately ill children is what his colleagues, friends, and patients will best remember him for. On Monday, February 12, 2007, Senator Dean Heller from Nevada stood on the floor of the U.S. Senate and said, “Madam Speaker, I rise today to pay tribute to Dr. Emil Frei III, a pioneer in cancer treatment, one of the world’s foremost oncologists, and a leader in medical education … His exceptional career deserves the highest commendation and praise.” The oncology community also rises in tribute. Hear, hear, Dr. Frei. n
The ASCO Post
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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).
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Clifford A. Hudis, MD
The Road to ASCO Presidency, Paved by Education and Persistence
SCO President Clifford A. Hudis, MD, grew up in northeast Philadelphia in the 1960s, a robust period in U.S. history dominated by American industry and ingenuity. His early memories are of a hard-working bluecollar neighborhood of identical row and semidetached twin houses and of a time of unparalleled optimism when everything seemed ready and freshly built, including his public school.
Pursuing the American Dream “My parents were focused on education. Schooling and grades took precedence over everything, even sports, which were a big deal in Philadelphia,” said Dr. Hudis. He recalled that the way the connected houses were configured, the corner home—often owned by a doctor or dentist—always seemed larger and more elaborate, like some reachable monument to success. “Perhaps this had a subliminal effect on my parents, because it got in their heads that the best way to chase the American dream was through a career in medicine,” said Dr. Hudis, adding, “So to some degree I was programmed from a very early age to become a doctor.” Along with his parent’s intense focus on hitting the books, Dr. Hudis lauded his public education experience, as well as the Quaker one that followed. “Even though I’m not a Quaker, I attended a
Quaker high school, which was not unusual in Philadelphia in those days. I received an incredibly personalized education with the Friends,” said Dr. Hudis. He was accepted into a 6-year combined BA/MD program at Lehigh University and the Medical College of Pennsylvania, due, in part, to this opportunity, he noted. It was 1977; Dr. Hudis observed that even though the Vietnam War was over, the country was still in recovery and young men like him, perhaps leery of being drafted into another conflict, were eager to get into college and graduate school. “When I was offered the oppor-
Unique Medical School Experience Dr. Hudis went to medical school at The Medical College of Pennsylvania, which was originally called the Female (later Woman’s) Medical College of Pennsylvania. Founded by Quakers in 1850, the school broke the gender barrier and became the first college in the world to offer medical education to women. Relishing the irony, Dr. Hudis said, “For a long time, Woman’s Medical College was the primary source of women physicians in America. Around 1969, the school began to accept men.”
I feel privileged and energized to be given the opportunity to serve our members. It’s the Society’s 50th anniversary, which in a way makes it even more special for me. — Clifford A. Hudis, MD
tunity to enroll into medical school right out of high school, I was very excited. Naturally, my parents were thrilled about me becoming a doctor, not to mention that the combined program meant several fewer years of college and tuition,” said Dr. Hudis. “I remember asking my mother, ‘What if I don’t want to become a doctor?’ She replied, ‘After medical school you can do anything you want,’” said Dr. Hudis.
NAME: Clifford A. Hudis, MD TITLE: Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center; President, American Society of Clinical Oncology; Professor of Medicine, Weill Cornell Medical College MEDICAL DEGREE: MD, The Medical College of Pennsylvania RESEARCH INTERESTS: Breast cancer, translational research, novel systemic therapies NOTABLE HONORS: Louise & Allston Boyer Young Investigator Award for Distinguished Achievement in Biomedical Research (1999); Drexel University College of Medicine WMC/MCP Achievement Award (2008); 16th Claude Jacquillat Award (2008)
The roots of Woman’s Medical College had a long-lasting and positive influence on Dr. Hudis. “In my medical school, the women students had fascinating allure. They were often older with a much wider range of experiences than what we see in the conventional high school through college path to medical school. They were teachers and lawyers and ex-military women, striving to become doctors. And I can only imagine what those worldly, already accomplished women thought about me, a 20-year-old med school freshman without their life experience,” said Dr. Hudis. As a third-year medical student, Dr. Hudis took a rotation at a major midwestern university medical center. He remembered looking up one day on rounds and asking the attending doctors, quite innocently, “Where are all the women?” His question was never fully answered, but for Dr. Hudis this was a moment that crystalized his understand-
ing of the rich and unusual environment of his own medical schooling. “It never occurred to the all-male attending doctors that I had come from an environment in which department heads and chairs were women. In fairness to American medicine, it has been transformed in the decades since I graduated. The glass ceiling has certainly been cracked, if not completely shattered,” said Dr. Hudis, mentioning that he came from an experience that was decades ahead of the women’s equality movement in medicine. The Woman’s Medical College of Pennsylvania (1867–1970) is now Drexel University College of Medicine.
Making a Difference in Medicine Fast-forward to 2013. Dr. Hudis’s mother’s medical ambitions for her son have been realized in a way that far surpasses the dream of becoming the doctor with the biggest house in the row. Dr. Hudis, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center (MSKCC), has dedicated his career to the treatment of patients with breast cancer. Initially mentored by ASCO Past President Larry Norton, MD, his international collaborations have centered on translational studies that look to develop better hormone therapies, improved chemotherapies, and more effective ways to deliver the newer forms of targeted therapies. For the past decade, with his collaborator Andy Dannenberg, MD, he has focused his scientific efforts toward achieving a greater understanding of the fascinating connections between obesity, inflammation, and cancer. When asked what a day in the life of Dr. Hudis consists of, he paused and noted that that was a big question needing proper reference. “In the world that I grew up in, the doctor had office hours Monday, Tuesday, and Wednesday mornings, then continued on page 10
The ASCO Post | JUNE 10, 2013 | SUPPLEMENT
Clifford A. Hudis, MD continued from page 9
Thursday and Friday. Plus, he made time to squeeze in house calls. The doctor was also the de facto authority in the neighborhood, one of the very few people who had an advanced degree, or any college degree for that matter. So that was really
the only role model I had for medicine,” said Dr. Hudis. He said that early on in his career he became interested in internal medicine because he found the physiology of health and disease interesting, serving as a chief medical resident after completing his initial training. “However, along the way I became
somewhat frustrated in the inner city hospital where I trained, because of problems that plague us today—compliance to care and the socioeconomic results of preventable disease, issues that as a doctor I had no control over. But toward the end of my formal training I was exposed to medical oncology, and, to me, it of-
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fered me a more expansive way to truly make a difference in medicine,” said Dr. Hudis. “That brought me to MSKCC, where I had the good fortune to meet a newly hired physician, Larry Norton, within days of his arrival.”
No Such Thing as a Typical Day “My typical day is far from anything that I ever imagined a doctor’s life would involve. For instance, this morning I was down at ASCO working on the Annual Meeting, then in the early afternoon I took the Metro to the airport, jumped on a shuttle flight back to New York, dealt with patient issues in the cab ride back to Memorial, then got ready for this interview with The ASCO Post. I’ll be working at my desk until late this evening when I will meet my wife for dinner. And that’s a typical day, even if it is not precisely like any other,” said Dr. Hudis. On top of that exhausting schedule, Dr. Hudis runs one of the largest services at Memorial Sloan-Kettering Cancer Center. “We have 23 faculty members in breast cancer medicine working full-time within a dedicated facility, The Evelyn H. Lauder Breast and Imaging Center of MSKCC. We also have a large and interesting clinical breast cancer research portfolio. So, describing a typical day ends up sounding like a word salad, my days are so varied,” said Dr. Hudis. He ended with this observation. “Coming in from the airport, as I was working on my mobile answering patient issues, I thought to myself, what am I really getting paid to do? I realized that although the variety of tasks makes it difficult to quantify, I’d do it even if I didn’t get paid, just because it’s so damn interesting and rewarding,” said Dr. Hudis. As for his upcoming ASCO Presidency, Dr. Hudis said, “I feel privileged and energized to be given the opportunity to serve our members. It’s the Society’s 50th anniversary, which in a way makes it even more special for me. That said, it is a huge responsibility, but I’m fortunate to be part of a great institution that supports me every step of the way,” said Dr. Hudis. Asked what an ASCO President does to wind down from an impossibly challenging schedule, Dr. Hudis said that he is an avid cycler, riding every chance he gets. “It goes back to my days as a kid mowing lawns in the neighborhood. I saved up to buy a Schwinn 10-speed SuperSport. It took me about a year,” said Dr. Hudis. That ability to focus on long-term goals and to persevere with patience has served him well. n
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Charles M. Balch, MD, FACS, PhD (hc)
Prolific Surgical Oncologist Understands the True Value of Mentorship
harles M. Balch, MD, FACS, PhD (hc), was born in Milford, Delaware, where his father was a research chemist for DuPont during World War II. “My father was part of the team that developed rayon for parachutes. It was a top priority program because they couldn’t get nylon from the Philippines. After the war, some venture capitalists offered to start a chemical company in Toledo, Ohio, and they attracted the scientists who were on the DuPont project. We moved to Toledo, where my father began work on a project that eventually developed the base material for saccharin. His company was the world’s sole supplier,” said Dr. Balch, adding, “I think I inherited my father’s discovery genes.”
of my residency, I was actually interested in cardiovascular surgery, so I went to the University of Alabama at Birmingham (UAB) where Dr. John Kirklin, one of the legends in cardiac surgery, was Chief of Surgery. Along the way, I did a fellowship in immunology at Scripps Clinic in California, which began to spark my interest in oncology. But it was actually my mentor, ASCO Past President Dr. John Durant, who drew me into the field.” Dr. Balch was one of the early sur-
Working to help people in other countries develop robust cancer programs and clinical trial groups helps enrich and connect the world’s oncology community. I’ve found that with proper support and education, places that have very limited resources can improve their cancer care over time.
An Indispensible Mentor Paves the Way Dr. Balch entered the University of Toledo in 1961. “While doing my undergraduate studies, I worked as a surgeon’s assistant at Toledo Hospital, which is where my interest in medicine and surgery started to bloom. With the help of some good mentors and a few good grades I was accepted to Columbia College of Physicians and Surgeons in 1963,” said Dr. Balch. He continued, “During the first part
riod, Dr. Balch was involved in many prospective randomized clinical trials in breast cancer, melanoma, and liver tumors. “When John left to take the lead at Fox Chase, I became the UAB Comprehensive Cancer Center’s interim director until they hired an official director. I wasn’t interested in the job as it would take me away from surgery. After 10 years at UAB, I was recruited by MD Anderson and became the cancer center’s Chief of Surgery,” noted Dr. Balch.
— Charles M. Balch, MD, FACS, PhD (hc)
gical oncologists to join ASCO, which he attributes to his mentor Dr. Durant. “Working with John, I was the Associate Director for Clinical Studies at the UAB Comprehensive Cancer Center. He taught me how to be an oncologist and also how to be a clinical investigator,” said Dr. Balch. During that pe-
NAME: Charles M. Balch, MD, FACS, PhD (hc) TITLE: Professor of Surgery, University of Texas Southwestern Medical Center MEDICAL DEGREE: MD, Columbia College of Physicians and Surgeons RESEARCH INTERESTS: Melanoma, breast cancer, clinical trials, sentinel lymph nodes, cancer biomarkers NOTABLE HONORS: President, Association for Academic Surgery (19841985); President, Society of Surgical Oncology (1991-1992); ASCO Special Recognition Award (2007); Society of Surgical Oncology Heritage Award (2007); Outstanding Achievement in Clinical Research Award, Association of Community Cancer Centers (2009); Honorary Doctorate, University of Crete, Greece (2009); Janeway Medal, American Radium Society (2010); Highest Alumni Award, University of Toledo (2010)
During Dr. Durant’s ASCO Presidency, he encouraged Dr. Balch to submit a paper to a journal that was getting ready to launch its inaugural edition— the Journal of Clinical Oncology. “So we had a major paper published in volume 1, issue 2 of JCO. The paper was a multifactorial analysis of stage IV melanoma, and on the Journal’s 25th anniversary, the article was noted as one of JCO’s most cited papers in its first year,” mentioned Dr. Balch.
ASCO Leadership Dr. Balch was elected to the ASCO Board of Directors in the early 1980s. “When ASCO decided to move toward self-management, I was on the transition committee, which was the group that recruited John Durant as the organization’s first Executive Vice President,” said Dr. Balch. Later, in 2000, Dr. Balch succeed-
ed Dr. Durant and became ASCO’s second Executive Vice President and Chief Executive Officer. “During the 5 years that I was Executive Vice President and CEO, ASCO more than doubled its membership up to 28,000 members from 50 different countries. We increased the breadth of the cancer education programs, including starting the Genitourinary and Gastrointestinal Symposia. Our Annual Meeting attendance increased from about 15,000 attendees in 2000 to over 28,000 attendees in 2006. We increased our fundraising from $2 million to $20 million in a 5-year period of time, which allowed us to grow a lot of new programs,” said Dr. Balch.
Contributions to Medical Literature Dr. Balch is regarded as one of the leading melanoma experts in the world. He is the editor of Cutaneous Melanoma, considered the authoritative textbook on melanoma, which is now in its 5th edition. His contributions to the melanoma literature include over 130 published articles, 6 books, and 152 book chapters or invited educational articles regarding his clinical investigations involving the natural history of melanoma, prognostic factors predicting clinical outcome, and standards of surgical treatment. Overall, he has over 700 publications that have been cited in the literature over 19,000 times. Dr. Balch is the founding Editor-inChief of the Annals of Surgical Oncology, which is recognized as the leading journal in the world in its field, with over 12,000 surgical and library subscribers.
Passion for Teaching In his current position as Professor of Surgery at the University of Texas continued on page 12
The ASCO Post | JUNE 10, 2013 | SUPPLEMENT
Clara D. Bloomfield, MD
Distinguished Researcher Changed the Face of Hematologic Malignancies
lara D. Bloomfield, MD, grew up in a steadfastly academic environment that spurned typical children’s entertainment such as comic books or television. Born in New York City during World War II, she moved to Washington, DC, with her family while her father, an expert on labor and industrial relations, served on the War Labor Board. “After the war, my father took a professor’s position at the University of Illinois. Many of his students were foreign and he often invited them for dinner. It wasn’t uncommon for me to be seated next to a student from Ethiopia or Chile. Our meals were filled with engaging, intellectual conversation,” said Dr. Bloomfield.
dependent and self-motivated mother also helped mold Dr. Bloomfield’s mettle and career drive. She recalls her mother as a feminist in her own right; she was one of the first women to attend the law school at the University of Illinois. “My mother began law school when I was in first grade and she re-
Path Set from an Early Age
ceived her law degree when I graduated high school,” said Dr. Bloomfield, adding, “When I was 9 my mother announced that she wasn’t spending enough time with the family so she decided to quit law school. My
it takes to complete law school. While attending the University of Illinois Laboratory High School, a mother-daughter conversation sealed the deal in Dr. Bloomfield’s mind about her desire to pursue a medi-
Juggling Academic Careers
CEO of the Patient Advocacy Foundation, succeeding Nancy DavenportEnnis. My daughter is a physician’s assistant in the gastrointestinal medical oncology unit at MD Anderson, and my youngest son is the IT project manager for the VA’s Central Office.” Dr. Balch’s current passion is teaching young doctors about the principles of oncology and oncology management, especially in the surgically treated cancer patient. “I’m also very passionate about patients being informed partners in their treatment. I helped start a publishing company called Patient Resource Cancer Guides, which is now one of the largest patient education companies in the world. We distributed over one and a half million cancer guides (with 10 different titles) to cancer patients last year, plus we run two websites for cancer patient informa-
tion,” said Dr. Balch. Dr. Balch’s lecture hall extends far beyond UT Southwestern. “I lecture all over the world—last year in 17 countries and this year in at least 15. I teach oncology management and about organizing clinical trials. I logged 260,000 flier miles last year,” said Dr. Balch.
ogy community. I’ve found that with proper support and education, places that have very limited resources can improve their cancer care over time, when needed resources are made more available. I helped establish a surgical training program in Addis Ababa University in Ethiopia, the sole program in the country for surgeons. I got the surgical chief of that unit to become a member of ASCO,” said Dr. Balch. What does Dr. Balch do to unwind from his duties at UT Southwestern, his publishing company, and his global lectures and project tours? He uses his frequent-flier miles. “Travel for me is an adventure that I love to share with my family. I’m drawn to places like the Galapagos Islands and Africa. And I always bring a camera; photography is another one of my passions,” said Dr. Balch. n
Looking back, Dr. Bloomfield said that growing up in an academicallyfocused family helped prepare her at a young age for her own career path into academic medicine. Having an in-
Charles M. Balch, MD, FACS, PhD (hc) continued from page 11
Southwestern Medical Center, Dr. Balch said that his activities center on three components: lecturing, teaching, and mentoring. “After my tenure as Executive Vice President of ASCO, I was recruited to Johns Hopkins by Dr. Julie Freischlag, their Chief of Surgery, and returned to full-time academic surgery. I thought I’d end my career there, but my oldest son Glen became a surgical oncologist. He came to UT Southwestern, where he and others here recruited me to come onto the faculty. So, my office is next to my son’s office,” said Dr. Balch, adding that all of his children have followed in his medical footsteps, in one form or another. “My second son, Alan, was recently appointed as the
younger brother and I started crying and screaming that we couldn’t have a mother who wasn’t going to law school,” laughed Dr. Bloomfield. She recalled that the state actually had to pass a law allowing her mother to obtain her law degree since her staggered schooling had passed the statute of limitations governing the time
Don’t be afraid to challenge authority, even if it’s the biggest name in the field. Look at what’s in front of you and trust your own analysis. That’s the way breakthroughs happen. — Clara D. Bloomfield, MD
Global Lecture Hall According to Dr. Balch, the extraordinary amount of miles and hours spent throughout the world is time and energy well spent. His global work takes him from challenged areas such as Ethiopia and India to sophisticated health-care systems in China and Japan. “Working to help people in other countries develop robust cancer programs and clinical trial groups helps enrich and connect the world’s oncol-
cal career. She even penned a 90-page paper about the history of women in medicine. “I had classmates who developed leukemia and, because of limited options in the early 1950s, they were sent to the National Cancer Institute for treatment. Then they’d return with steroid-bloated faces and soon die,” said Dr. Bloomfield. She continued, “I remember thinking to myself, how cool it would be to develop a medicine that could save kids from dying of childhood leukemia. I’d already decided to become a doctor, so seeing the real-life effects of cancer certainly helped shape my early desire to become an oncologist.” Dr. Bloomfield entered the University of Wisconsin in 1959 with a depression-era sense of self-sufficiency and fiscal responsibility. “I continued on page 14
The case for Vectibix® QQ2W dosing schedule1
– The recommended dose of Vectibix® is 6 mg/kg every 14 days
– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes
PPremedication not standardized1
– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown
NNo loading dose1
– No loading dose is required
– Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions
– Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy – Withhold Vectibix® for dermatologic toxicities that are ≥ grade 3 or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix® – If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than 2 doses of Vectibix®, treatment may be resumed at 50% of the original dose - If toxicities recur, permanently discontinue Vectibix® - If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached
Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Vectibix® is not indicated for the treatment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. IMPORTANT SAFETY INFORMATION WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of interstitial lung disease (ILD), including fatalities, have been reported in patients treated with Vectibix®. Interrupt Vectibix® therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix® therapy if ILD is confirmed. In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed. Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose. Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. The most common adverse reactions (≥ 20%) of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, diarrhea, including diarrhea resulting in dehydration, and constipation. The most serious adverse reactions of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix® administration. Terminate the infusion for severe infusion reactions. Vectibix® is not indicated for use in combination with chemotherapy. In a phase 3 study of patients with KRAS mutation-positive mCRC (n = 440) evaluating Vectibix® in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR = 1.24, 95% CI: 0.98–1.57). Please see brief summary of Prescribing Information on next page. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% Reference: 1. Vectibix® (panitumumab) vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- prescribing information, Amgen. treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/ mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). 04-13 NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs ©2013 Amgen Inc. All rights reserved. G61228-R2-V2 61007-R2-V2 4%) and included fatal events in three (< 1%) Vectibix®-treated patients.
The ASCO Post | JUNE 10, 2013 | SUPPLEMENT
Clara D. Bloomfield, MD
Client:out. AMGEN Issue: to 2013-May15_IP4C-PI which helped While doing my sity of Wisconsin. He wanted do to coordinate two academic careers,” 10109634 Trim: 7.875insaid x 10.75in premed, IJob#: became very interested in his postdoctoral work in a renowned Dr. Bloomfield. Coordinating continued from page 12 10109634_AMGEN-Vectibix_ASCOPost_2013-May15_IP4C-PI.pdf Bleed: 7.875in x 10.75in grew up having to earn each nickel of genetics. I actually did my honors research institute in La Jolla, Calicareers resulted in a commuter marmy allowance doing chores around research on radiation therapy’s effect fornia, so off they went to the West riage: Dr. Bloomfield’s husband acthe house. So I was not keen on sadon fruit fly eggs,” said Dr. BloomCoast. “I finished my last year of colcepted a chemistry professorship dling my parents with a huge bill. field. lege at San Diego State College, and offer at the University of Illinois and T: 7.875” The University of Wisconsin offered Dr. Bloomfield married a chemist then I was faced with the challenge she decided to go to medical school a couple of scholarship programs, during her junior year at the Univermany women in academia face: how at the University of Chicago. In the year prior to entering medical school, Dr. Bloomfield worked in a biochemistry lab at the prestigious Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Vectibix (panitumumab) Injection for intravenous Infusion Scripps Research Institute, which was Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Brief Summary of Prescribing Information. For complete prescribing information consult Grade* official package insert. Body System All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) at the cutting edge of scientific exploBody as a Whole Fatigue 26 4 15 3 WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS General Deterioration 11 8 4 3 ration. “At that time, a very prominent Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients Digestive Abdominal Pain 25 7 17 5 receiving Vectibix monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Nausea 23 1 16 <1 faculty member working where my Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in Diarrhea 21 2 11 0 postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)]. Constipation 21 3 9 1 husband was had Hodgkin disease Vomiting 19 2 12 1 INDICATIONS AND USAGE Stomatitis 7 0 1 0 Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) and he was traveling back and forth Mucosal Inflammation 6 <1 1 0 with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14.1) Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 in Full Prescribing Information]. to Stanford to see renowned HodgPeripheral Edema 12 1 6 <1 The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionRespiratory Cough 14 <1 7 0 free survival [see Clinical Studies (14.1) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related kin specialist Dr. Henry Kaplan. My symptoms or increased survival with Vectibix. Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Vectibix is not indicated for the tratment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Skin 90 14 6 0 mindset, from my grade school days Erythema 65 5 1 0 Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13 [see Warnings and Precautions, Clinical Pharmacology (12.1) and Clinical Studies (14.3) in Full Prescribing Information]. Dermatitis Acneiform 57 7 1 0 seeing classmates die of leukemia, was Pruritus 57 2 2 0 DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion Nail 29 2 0 0 over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration (2.2) Paronychia 25 2 0 0 that cancer was a death sentence—I in Full Prescribing Information]. Skin Exfoliation 25 2 0 0 Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Rash 22 1 1 0 was simply blown away by how well Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] Skin Fissures 20 1 <1 0 • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Eye 15 <1 2 0 my husband’s professor colleague • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, Acne 13 1 0 0 permanently discontinue Vectibix. Dry Skin 10 0 0 0 Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] was responding. That experience had Other Nail Disorder 9 0 0 0 • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade Hair 9 0 1 0 2 within 1 month, permanently discontinue Vectibix. a significant effect on my decision to • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Growth of Eyelashes 6 0 0 0 Vectibix, treatment may be resumed at 50% of the original dose. *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. study hematologic malignancies,” said – If toxicities recur, permanently discontinue Vectibix. Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, Dr. Bloomfield. ®
conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. As monotherapy: The incidence of binding antibodies (excluding pre-existing and transient positive patients) was 0.4% (3/717), as detected by the acid dissociation ELISA, and 3.8% (27/717) as detected by the Biacore® assay. The incidence of neutralizing antibodies (excluding pre-existing and transient positive patients) was 1% (7/717). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix. In combination with irinotecan- or oxaliplatin-based chemotherapy: The incidence of binding antibodies (excluding pre-existing positive patients) was 1% (11/1124) as detected by the acid dissociation ELISA and 0.8% (9/1123) as detected by the Biacore assay. The incidence of neutralizing antibodies (excluding pre-existing positive patients) was 0.2 % (2/1124). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval use of Vectibix. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology (13.3) in Full Prescribing Information]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions, and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v17, 03/2013 Rx Only Patent: http://pat.amgen.com/vectibix/ ©2006-2013 Amgen Inc.All rights reserved.
Grand Rounds with Dr. Kaplan At the University of Chicago, Dr. Bloomfield met and worked with Dr. Henry Rappaport, best known for his “Rappaport Classification,” in lymphoma. “The structure at the University was geared toward an academic career, which fit in to how I’d been brought up,” said Dr. Bloomfield. Between her junior and senior year, Dr. Bloomfield did a subinternship at the University of California at San Francisco (UCSF). “After a month or so, I saw this patient with Hodgkin disease who was not being treated with curative intent. I told them, this is terrible, you’re not giving this patient modern therapy,” said Dr. Bloomfield. To that, her attending replied, “Well, if you’re so smart, we’ll have you do grand rounds on how to treat Hodgkin disease.” Not one to back down from a challenge, but also wanting to be well armed, Dr. Bloomfield called Stanford, and asked the famous Dr. Kaplan for advice. “Henry was really nice; he said he’d be thrilled to come and help me do grand rounds,” said Dr. Bloomfield. To the surprise of the attending at UCSF, Dr. Bloomfield, a medical student, conducted grand rounds with her friend from Stanford, Dr. Henry Kaplan. T: 10.75”
Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning, and Adverse Reactions]. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling [see Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3-4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Mortality or Toxicity with Vectibix in Combination with Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In a randomized, open-label study enrolling 440 patients with KRAS mutation-positive mCRC; evaluating Vectibix in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR=1.24, 95% CI: 0.98-1.57). In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCICTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD): Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of ILD, including fatalities, have been reported in patients treated with Vectibix. Interrupt Vectibix therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix therapy if ILD is confirmed. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Mortality or Toxicity of Vectibix in Combination with Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis/ILD [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.
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Practice-changing Research In 1971, Dr. Bloomfield started her medical oncology fellowship at the University of Minnesota, where she became one of the institution’s first female Chief Residents. Her supervisor wanted Dr. Bloomfield to get an American Cancer Society junior clinical faculty fellowship. For that, she had to interview with external reviewers, one of which was Dr. Ed Henderson, an eminent leukemia expert. “Dr. Henderson asked what the focus of my research was. I panicked because I hadn’t thought about it. But I recovered and said, ‘I’ve been looking at the biologic features of leukemia and lymphoma to help predict outcome and select therapy,’” said Dr. Bloomfield. “He was impressed, and I got the fellowship. Interestingly, that line of inquiry, with certain variations, has essentially been the basis of my life’s research.” Dr. Bloomfield ended up running the acute leukemia and lymphoma service at the University of Minnesota, seeing every patient herself. She also conducted a study looking at all adult patients with acute leukemia seen at her institution over the past 10 years. “The majority had acute myeloid leukemia (AML). Our longest survivor was a 17 year old who lived for 33 months. Given the success we were beginning to see in childhood leukemia, I saw a real opportunity in adult disease. We stratified the pa-
tients by age and as a result I found that the older adult patients did just as well as the younger ones,” said Dr. Bloomfield. “I published a paper in JAMA with my results, showing that older patients responded just as well to treat-
Distinguished Career Dr. Bloomfield left Minnesota in 1989, taking a position at Roswell Park Cancer Institute, serving as Roswell’s Chair of the Department of Medicine. In 1997 a career turn took her to The Ohio State University
NAME: Clara D. Bloomfield, MD TITLE: Distinguished University Professor and William G. Pace III Professor of Cancer Research, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Solove Research Institute MEDICAL DEGREE: MD, University of Chicago RESEARCH INTERESTS: Adult leukemia and lymphoma, acute myeloid leukemia NOTABLE HONORS: Institute of Medicine of the National Academy of Sciences (2000), Joseph H. Burchenal Clinical Research Award, American Association for Clinical Research (2004); Distinguished Service Award for Scientific Achievement, American Society of Clinical Oncology (2006); Henry M. Stratton Medal, American Society of Hematology (2008); David A. Karnofsky Memorial Award, American Society of Clinical Oncology (2009); American Academy of Arts and Sciences (2011)
ment as their younger counterparts. At the time, the major hematologists contended that treating AML patients over 50 years of age was tantamount to malpractice. So you can imagine the stir I caused,” noted Dr. Bloomfield. “It was an important lesson,” she continued, “one that resulted in my telling my Fellows, don’t be afraid to challenge authority, even if it’s the biggest name in the field. Look at what’s in front of you and trust your own analysis. That’s the way breakthroughs happen.”
(OSU) where she served as Director of the Division of Hematology and Oncology and Director of the OSU Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Solove Research Institute (OSUCCC–James) until 2003. She is currently a Distinguished University Professor and William G. Pace III Professor of Cancer Research at OSUCCC–James. Dr. Bloomfield, whose work has been described in more than 950 pub-
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lications, is the recipient of oncology’s most prestigious awards. She has also chaired and served on boards in estimable organizations such as ASCO, AACR, NCCN, NCI, and WHO. But it is her translational work, especially in the field of genetics, that has changed the face of blood malignancies and is the hallmark of her career. She has discovered many genetic abnormalities that have changed how we classify and treat leukemia and lymphoma. Dr. Bloomfield’s work also showed for the first time that elderly patients with acute leukemia could be cured with chemotherapy. On the global scale, her work has changed the way we think about leukemia and the way we treat individual patients. Dr. Bloomfield is now married to Dr. Albert de la Chapelle, a geneticist and Professor in the Department of Molecular Virology, Immunology, and Medical Genetics at OSU and who, among many things, is the discoverer of XX male syndrome. “We’ve been married for 29 years, but as we have different names and are prominent in separate fields, lots of people don’t know we’re a couple,” said Dr. Bloomfield. Asked about the future, Dr. Bloomfield remarked, “I’ll be turning 71 this year. Besides my work at OSU, I’m very active on international leukemia projects. During the past 7 weeks, I traveled to six different meetings, two of which were in Europe. So there’s not much time for anything but work.” n
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Franco Cavalli, MD, FRCP
After a Distinguished Career, Trailblazing Swiss Oncologist Remains Devoted to Addressing the Global Cancer Challenge
witzerland, a landlocked country with a population about that of New York City, has four geographic regions, each with its own official language. Internationally regarded lymphoma and breast cancer expert, Franco Cavalli, MD, FRCP, was born and raised in Locarno, a town in the Italian region of Switzerland, which hugs the banks of the massive Lake Maggiore at the foot of the Alps. “I went from primary school on through college, and was the first in my family to achieve an advanced degree. At that time, there were three classical professions: lawyer, engineer, or physician,” said Dr. Cavalli. Dr. Cavalli concedes that since he didn’t like math and had mixed opinions about lawyers, becoming a doctor was essentially a process of elimination. His choice to become a doctor faced one hurdle: There was no medical college in the Italian-speaking region of Switzerland. “I had to go north of the Alps to either the French- or German-speaking region of the country. Since French is similar to Italian, I decided to go to medical school in the German region so I’d learn the language along with getting my medical degree,” said Dr. Cavalli.
Early Interest in Psychiatry Leads to Oncology Dr. Cavalli said that when he went
to medical school, there were an unlimited number of seats. “Today, medical school entrance is highly competitive, but I was accepted directly following college, after passing the entrance exam. To this day, all the universities in Switzerland are public, with very little variance in the quality of education. And the tuition is very low; anyone can afford to go to a university. This helped in my case, since I came from a family of meager means,” said Dr. Cavalli. Dr. Cavalli passed his final exam in medical school in 1968, a turbulent time in global politics. “I was very engaged in political movements when I
pulsory stint in internal medicine. “By the time I started the internal medicine, I was disappointed in psychiatry. During this period I met a fascinating professor named Kurt Brunner, MD, who influenced my decision to switch careers to oncology. He said that my combined interests in human behavior and science made oncology a perfect fit. He was right,” said Dr. Cavalli.
Founds Oncology Institute of Southern Switzerland Dr. Cavalli explained that several Swiss oncologists, Dr. Brunner among them, traveled to the United States to work and study at Roswell
By the year 2030, we could have about 28 million new cancer cases each year… It is a significant global challenge…that we cannot afford to ignore. — Franco Cavalli, MD, FRCP
was a young medical school student. There was so much anxiety in the air at that time among young students that I convinced myself to become a psychiatrist,” said Dr. Cavalli. After graduating medical school, he spent two and a half years studying psychiatry. Part of his training included a com-
NAME: Franco Cavalli, MD, FRCP TITLE: Scientific Director, Oncology Institute of Southern Switzerland; Professor of Medical Oncology, University of Bern, Switzerland; Chairman of the Scientific Committee of the European School of Oncology; Past-President, Union for International Cancer Control. MEDICAL DEGREE: MD, University of Bern RESEARCH INTERESTS: Malignant lymphoma, breast cancer, translational research, drug development, palliative care, health-care policy NOTABLE HONORS: ESO Recognition for Contribution to Oncology, Pezcoller Foundation (1994); New Drug Development Organization Honorary Award (1998); Greidinger Award (1992); Waldman Award (2001)
Park Cancer Institute, and it was the knowledge they brought back that, in part, launched Switzerland’s first cancer institutes. “It was an exciting time for me, as at that time Switzerland had the most aggressive clinical research programs in Europe,” said Dr. Cavalli. In 1978, after completing his medical training, Dr. Cavalli returned to the Italian region of Switzerland to practice oncology. “But there were no oncology programs at the time, so with a parttime secretary and part-time nurse I started and built what is now the Oncology Institute of Southern Switzerland (IOSI), the comprehensive cancer center for the Italian-speaking part of Switzerland,” noted Dr. Cavalli, adding, “I now have 250 coworkers in our center, which is based on the U.S. template of the multidisciplinary comprehensive cancer center.”
Addressing a Global Challenge In 1995, Dr. Cavalli’s lifelong sociopolitical passions were further realized when he became a member of the Swiss Parliament, where he continued to focus on debates about health care and health policy issues. He is particularly interested in palliative care and end-of-life issues, emphasizing underserved populations. More than 2 decades ago, Dr. Cavalli and fellow doctors in Italian-speaking Switzerland founded the Association for Medical Aid to Central America. Through this growing collaboration, Dr. Cavalli has coordinated many projects in Nicaragua, El Salvador, Guatemala, and Mexico. In 2006, he was voted Switzerland’s “Person of the Year” for his contributions to society, largely due to his work in cancer and palliative care in the developing world. “In 1980, the number of cancer deaths was the same in the developed and developing world. In 2002 there were 11 million new cancer cases. By the year 2030, we could have about 28 million new cancer cases each year with 80% of cancer deaths occurring in low- and middle-income countries. It is a significant global challenge. Cancer currently kills more people than tuberculosis, AIDS, and malaria combined. It’s a challenge that we cannot afford to ignore,” stressed Dr. Cavalli.
Focus on the Future of Oncology Although still vigorously pursuing multiple activities in global oncology, Dr. Cavalli was recently forced by Switzerland’s mandatory retirement age of 70 years to step down from his role as Director of the Oncology Institute of Southern Switzerland. “I’m still the Institute’s Scientific Director and my main focus is to further develop robust continued on page 17
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Lawrence H. Einhorn, MD
Pioneering Oncologist’s Research on Cisplatin Revolutionized Testicular Cancer Treatment
awrence H. Einhorn, MD, grew up in Dayton, Ohio, in a time and place that he describes as pleasant and community-oriented. Throughout his distinguished career, Dr. Einhorn has maintained strong roots in the Midwest. “After finishing high school, I did my undergrad at Indiana University and went to medical school at the University of Iowa; I did my medical internship and residency at Indiana University. I left Indiana for a fellowship in Houston at MD Anderson, which is the only time I’ve escaped from the Midwest,” said Dr. Einhorn, adding, “I joined the faculty at Indiana University in 1973, and I’ve been here ever since.”
A Father’s Influence Dr. Einhorn’s father was a doctor whose office was attached to the family’s home. “[He] was a family practitioner, which is sort of anachronistic in today’s world. He knew his patients at a level that’s hard to put into today’s perspective. By the time I reached high school, I knew I wanted to become a doctor,” said Dr. Einhorn. He stressed that his father’s practice had a profound influence on his worldview of medicine. “There was a TV show during that era called Marcus Welby, M.D.,
Franco Cavalli, MD, FRCP continued from page 16
translational research efforts. We have about 40 basic and bench scientists in labs. To that end, I want to increase our efforts in developing solid phase I trials,” said Dr. Cavalli. He continued, “I also want to continue working in malignant lymphomas, which has long been my major clinical interest. Working in concert with many of the world’s foremost experts, I led the development of the International Conference on Malig-
and our home had that same feel to it. My father was sort of the prototypical beloved country doctor. Not that Dayton was a small town, but everyone in the neighborhood knew my father. It was a very different environment in medicine from today. Patients paid my father what they could afford.
ogy, fascinated by the future that was just beginning to explode, full of new advances and scientific knowledge. And I wanted to be a part of it,” said Dr. Einhorn. He continued, “I had very little oncology experience before going to MD Anderson for my fellowship. Re-
Those preliminary studies [with cisplatin] truly show the value of doing trials with novel and untested agents. In order to move the clinical benefits forward, you can’t settle for the status quo. — Lawrence H. Einhorn, MD
He didn’t have a backroom staff doing coding and billing,” said Dr. Einhorn. He continued, “During my internship and residency at Indiana University, I was focused on internal medicine and cardiology, actually with the thought of joining my father’s practice after graduating. But he developed cardiac disease and wasn’t able to continue his practice, so that door closed.” During his internship Dr. Einhorn did an elective in hematology/oncology. “I was really seduced by oncol-
member, it was 1972, and at that time there were relatively few accredited places to receive oncology training. You had Memorial Sloan-Kettering, Dana-Farber, Roswell Park, and the NCI—those were about the only options.” He explained that when he arrived at MD Anderson for his fellowship, there were two separate oncology programs, the Department of Medical Oncology and the Department of Developmental Therapeutics, which was run by Dr. Emil Freireich. “Developmental Therapeutics was the far more fascinating of
nant Lymphoma in Lugano, Switzerland, the leading international forum for basic and clinical research in lymphomas. It is the most important gathering in the field of lymphomas. So I’m very proud of this continuing effort.” Asked about his view of oncology’s future, Dr. Cavalli said, “I remain an optimist. If you’re not an optimist, you won’t last in the field of oncology; it is too demanding—but it is also tremendously rewarding. I’ve seen great advances since my first rounds on the
oncology wards. Moving forward, we need to be mindful of strategies that involve new and extremely costly cancer therapies—an approach that is often proving unsustainable. We must make a better effort to advance proven ways to prevent cancer incidence. That’s an area where we can truly relieve the burden and suffering of cancer.” Dr. Cavalli has seven children and several grandchildren, one of whom is planning to follow in her famous grandfather’s footsteps by pursuing
Seduced by Oncology
the two, so I worked in Dr. Freireich’s department,” said Dr. Einhorn.
Return to Indiana University Fellowships are often the seeding ground where specialty interests are planted in young oncologists. Not so for Dr. Einhorn. “I doubt if I saw more than two testicular cancer patients at MD Anderson during my entire fellowship because most testes cancer patients were seen by Dr. Mel Samuels in the separate medical oncology program. After my fellowship, the two programs merged,” said Dr. Einhorn “When I returned to Indiana University in 1973 to join the faculty, I had lots of experience in many different clinical scenarios but no experience in testicular cancer. During that relatively early period in oncology, most doctors worked on a range of cancers, rather than focusing on a few select disease sites,” said Dr. Einhorn Dr. Einhorn said that he was interested in working on chemosensitive diseases such as leukemia, small cell lung cancer, and testicular cancer rather than those that were not. “I had the good fortune of joining a university that had a world-renowned urologic oncologic surgeon on staff, Dr. continued on page 18
a career in medicine. To recharge his battery, Dr. Cavalli seeks contemplative time alone with his dog, hiking in the towering mountains to a small cabin that is stocked with books. An avid and omnivorous reader, Dr. Cavalli said one of favorite writers is the American novelist Philip Roth. When it was pointed out that the octogenarian writer recently said he was finished, that there would be no more books, Dr. Cavalli thought a moment and then said, “I wonder why someone so talented would want to retire.” n
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Lawrence H. Einhorn, MD continued from page 17
John Donohue. Because of his reputation, large numbers of patients came to Indiana from across the country for surgical management of testicular cancer,” said Dr. Einhorn, adding, “So the patients that were not surgically cured became candidates for chemotherapy. Anyone can have an idea, but if you don’t have the patients to study the idea, it simply becomes an academic exercise.”
Practice-changing Research in Testicular Cancer With a steady influx of testicular cancer patients, Dr. Einhorn took his ideas and turned them into practicechanging therapies. In 1974, he began initial studies in chemotherapy in testicular cancer with cisplatin, which was an experimental drug at the time. “Those preliminary studies truly show the value of doing trials with novel and untested agents. In order to move the clinical benefits forward, you can’t settle for the status quo,” said Dr. Einhorn. In his first phase II trial, Dr. Einhorn and colleagues added cisplatin to vinblastine plus bleomycin, both of which were on the market. “The results were quite amazing. In fact, I think it was one of the first times when a regimen became a standard of
care based on a single phase II study,” said Dr. Einhorn. Over the next few decades, Dr. Einhorn led a series of clinical trials that showed we could significantly reduce the toxicity of cisplatin and its duration. “It was a time of fruitful experimentation during which we sought to cure patients who were not cured during their first round of therapy. We also learned how to use antiemetic medications. And most of these advances were largely the result of the initial breakthrough with cisplatin,” said Dr. Einhorn.
marrow transplant service for testes cancer patients receiving high-dose chemotherapy. It’s a rare disease, but we have 10 patients who failed prior regimens and came to our institution for treatment. That takes a good part of the morning, and then I see scattered off-scheduled patients until the afternoon, when I do rounds with a Fellow,” said Dr. Einhorn. Monday doesn’t end after rounds; Dr. Einhorn presides over a teaching conference until early evening. Tuesdays are filled with caring for patients
NAME: Lawrence H. Einhorn, MD TITLE: Distinguished Professor, Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine; Livestrong Foundation Professor of Oncology, Indiana University School of Medicine MEDICAL DEGREE: MD, University of Iowa RESEARCH INTERESTS: Solid tumor oncology, testicular cancer, lung cancer NOTABLE HONORS: American Cancer Society Medal of Honor (1983); Distinguished Clinician Award, Milken Foundation (1989); Kettering Prize for Cancer Research, General Motors Foundation (1992); David. A. Karnofsky Memorial Award, American Society of Clinical Oncology (2000); Member, National Academy of Sciences (2002); AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research (2012)
A Typical Week After more than 4 decades of groundbreaking research and clinical work at Indiana University, Dr. Einhorn shows no sign of slowing down. “On Mondays at 8 AM, we have a bone
with testicular cancer. “Wednesdays are very different. It’s my all-day lung cancer clinic. I tell my wife that on Mondays and Tuesdays after caring for testicular patients, I leave the clinic energized. But after a day with
lung cancer patients, because of the grimness of the disease, Wednesdays are very heart-heavy,” commented Dr. Einhorn. What’s the rest of the week like? More full days of clinics, research, and teaching. Asked why a doctor of his stature has remained at one university for an entire career, Dr. Einhorn responded, “Well, as you can imagine, I’ve had many offers for exciting positions over the years. But for my family and me, this is just the right place to be; we love the city and the lifestyle it provides. Also, I’m fortunate to be part of an academic environment that has allowed me the freedom and backing to pursue my work.” What does Dr. Einhorn do for relaxation? “I play a pretty good game of tennis, and I like the arts. Naturally, I have to travel to meetings and give lectures. But I always like coming back to Indianapolis. Family and work are my greatest pleasures.” “It’s a curious thing in life. Often, the secret to success is to find things that you’re good at and keep doing them. I’m lucky that I found those things. I never had the desire to become a director of a cancer center. I don’t enjoy things that come with a title—I want to care for patients and conduct research and teach bright young doctors,” said Dr. Einhorn. n
Coming in The ASCO Post Comprehensive coverage of the 2013 ASCO Annual Meeting, including: ■■ The effect of cardiorespiratory fitness on cancer incidence and
■■ Idelalisib (GS-1101), a first-in-class PI3Kδ inhibitor, for relapsed
■■ Is surveillance alone sufficient for men in remission of stage I
■■ Anti-PD-L1 antibody drug MPDL3280A in locally advanced or
■■ Standard-dose vs high-dose radiation therapy in patients
■■ The combined effect of two immunotherapies (the anti-PD-1
■■ The use of CT scans to detect relapses in patients with aggres-
■■ Plus coverage of plenary presentations, late-breaking abstracts,
mortality in men 50 and older seminoma?
with advanced non-small cell lung cancer undergoing chemotherapy sive lymphoma
or treatment-resistant chronic lymphocytic leukemia metastatic solid tumors
antibody drug nivolumab and ipilimumab [Yervoy]) in advanced melanoma educational sessiions, and much more
Visit The ASCO Post online at ASCOPost.com
Explore our latest research at BioOncology.com/research
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Mary K. Gospodarowicz, MD, FRCPC
UICC President Balances Innovation and Pragmatism to Reduce the Global Burden of Cancer
ary K. Gospodarowicz, MD, FRCPC, is determined to help reduce the worldwide burden of cancer, a problem of epic proportions. Her approach is simple: adopt what works and reject what doesn’t. Much progress in the fight against cancer can be made without waiting for the next paradigm-changing breakthrough, she asserts. Only someone with her “just do it” attitude could tackle the challenges of global cancer and maintain such a demanding schedule at the same time. Dr. Gospodarowicz, a radiation oncologist, is the Medical Director of Princess Margaret Cancer Centre in Toronto and President of the Union for International Cancer Control (UICC). Commenting on the importance of the UICC, she noted, “It is the only organization that aims to bring together the wide variety of players needed to achieve improvements.”
so I have triple boards,” explained Dr. Gospodarowicz. Like many academic oncologists, Dr. Gospodarowicz was drawn to the field by the opportunity to make advances in a disease with so much need; she also found the evolving research opportunities exciting. Dr. Gospodarowicz began her radiation oncology career at Princess Margaret Hospital and has never left. “In Canada we tend to stay put if it’s a good institution. There are some institutions in the United States that often hold their doctors for the duration of their careers, such as MD Anderson,
Memorial Sloan-Kettering, and DanaFarber, but doctors in the States tend to move about more than we do,” commented Dr. Gospodarowicz.
Born in Gdansk, Poland, Dr. Gospodarowicz began medical studies in her native country before immigrating to Canada, where she graduated from the University of Toronto Medical School. She then joined Princess Margaret Hospital. “I did my training in internal medicine there. I also trained in medical oncology and radiation oncology,
early on I was involved in cooperative group studies. In fact, in the mid 1990s, I chaired the genitourinary trial committee for the National Cancer Institute of Canada trial group, which is similar in its structure to the U.S. cooperative groups,” said Dr. Gospodarowicz. She continued, “In the late 1990s, I became very interested in precision radiotherapy, mainly because of the tremendous advances in the field. Because of funding issues, we were lagging behind where we should have been, so I took a leadership role as
The central question we posed was: Why does the UICC really exist? And we decided that the UICC’s basic function is to unite the very diverse global cancer community. — Mary Gospodarowicz, MD, FRCPC
Focus on Radiation Oncology At the onset of her academic career, Dr. Gospodarowicz immersed herself in clinical trial research. “My strength was in developing clinical trials, and
NAME: Mary K. Gospodarowicz, MD, FRCPC TITLE: Medical Director, Princess Margaret Cancer Centre; Professor, Department of Radiation Oncology, University of Toronto; President, Union for International Cancer Control MEDICAL DEGREE: MD, University of Toronto RESEARCH INTERESTS: Radiation therapy for lymphomas and genitourinary cancers, late effects of treatment, precision radiotherapy NOTABLE HONORS: Fellowship, ASTRO (2007); Gordon Richards Lecture, Canadian Association of Radiation Oncologists (2010); May Cohen Award for Women Mentors, Canadian Medical Association (2012); Janeway Medal, American Radium Society (2013); Lifetime Achievement Award, European Society for Radiotherapy & Oncology (2013)
Chair of Princess Margaret Hospital’s Department of Radiation Oncology. And for about 10 years, my main focus was increasing our image-guided precision radiotherapy capabilities.” In 2012, she finished her 11-year term as Chair of the Department of Radiation Oncology and Chief of the Radiation Medicine Program. Thanks largely to Dr. Gospodarowicz’s work, Princess Margaret Cancer Centre has one of the world’s largest radiation oncology programs with more than 40 radiation oncologists, 50 medical oncologists, 60 surgeons, and 18,000 new patients each year, mainly from the Toronto area. “Princess Margaret has a good record in redefining treatment standards, having for example persevered with work on stopping radiotherapy [following orchiectomy] for stage I testicular cancer and opting instead for active surveillance, which is now widely accepted as standard of care,” said Dr. Gospodarowicz.
As the Medical Director of Princess Margaret Cancer Centre, Dr. Gospodarowicz distills the institution’s cancer care philosophy into a simple but comprehensive message. “We need to work on three fronts: (1) Prevent cancer so fewer patients get cancer, (2) cure more cancers with better treatments, and (3) prevent side effects, or treat side effects to repair the damage. And throughout all this, support the person you are treating. After all, we are all people.”
The World Stage By nature, Dr. Gospodarowicz is a hard-driving visionary, but she’s also a pragmatist who realizes that the best way to get things accomplished in the complex world of oncology is by implementing guidelines. Dr. Gospodarowicz understands that health care—especially when operating on the macro level, as she does—is a business, and the principles that make businesses successful, such as standardizing operational functions, improve quality and efficiency. “If people in health care would understand that, they would treat guidelines differently and not as something that infringes on their medical autonomy,” said Dr. Gospodarowicz. This organizational philosophy is the underpinning of her work in the fundamental issue of tumor classification. It was her work in TNM staging that first brought her into contact with the UICC, which develops and maintains the system. “I’m currently cochairing UICC TNM Project. It was this work in staging that helped me get into more leadership roles, which eventually led to the presidency,” said Dr. Gospodarowicz.
Redefining the UICC In fact, she is the UICC’s first president from Canada. “We recently had a continued on page 21
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Maha Hussain, MD, FACP
Expert Genitourinary Oncologist’s Drive Led Her from Baghdad to the United States
orn in Baghdad, Iraq, renowned prostate and bladder cancer specialist Maha H. Hussain, MD, FACP, Professor of Medicine and Urology at the University of Michigan Comprehensive Cancer Center, remembers that she always wanted to become a doctor. She had strong role models in three uncles who were physicians, but she gives equal credit to her parents’ encouragement. “They knew the value of a medical profession, not only as a fulfilling career, but also as an opportunity to make a difference in the world,” said Dr. Hussain.
Medical School Experience Dr. Hussain noted that in Iraq, as in the United States, gaining admission to medical school was a very competitive process. “But unlike the United States, students in Iraq who want to apply for medical school must take a one-time national exam, and your absolute score is the key to acceptance. Naturally, it’s a pressure-filled process, but since medi-
Mary K. Gospodarowicz, MD, FRCPC continued from page 20
strategic retreat in which we redefined the purpose of the UICC. The central question we posed was: Why does the UICC really exist? And we decided that the UICC’s basic function is to unite the very diverse global cancer community. We have about 750 different members, so it’s no easy task. The scope ranges from the huge American Cancer Society to a community organization in Turkey of mothers whose children have leukemia,” said Dr. Gospodarowicz. She continued, “The purpose of UICC is to unite the cancer community to reduce the global cancer burden, to promote greater equity, and to integrate cancer control into the global
cal school entry requires the highestranking scores of any profession, the University of Baghdad College of Medicine gets the best students in the country. I scored very well, and was accepted to medical school directly after the test,” said Dr. Hussain.
1960s and 1970s. “I also knew women from my parents’ generation who had graduated in the 1950s. In fact, more than one-third of my class, which was well over 300 students, were women,” said Dr. Hussain. In Iraq, a doctor’s journey was very
This was the time when a cure for testes cancer was becoming possible, and better systemic therapies for advanced cancers were emerging. … The space and opportunity to contribute to the field of oncology became increasingly apparent, and I have never regretted my choice to become an oncologist. — Maha Hussain, MD, FACP
you could begin thinking about opening a practice, so you can imagine the added burden on women if they decided to marry and begin a family,” said Dr. Hussain. Dr. Hussain did her training as a medical student at Baghdad’s main teaching hospital, which drew the most complicated cases in all diseases. “It was especially distressing to see the cancer patients. It was the mid-1970s and there were no systemic prevention or screening programs in place in Iraq, so most patients seemed to present with advanced disease,” said Dr. Hussain, adding that smoking was widespread in the population during that period.
Looking Abroad Dr. Hussain went to medical school from 1974 to 1980. In contrast to many Western stereotypes of the Middle East, Dr. Hussain said that sexism was never an issue—many of her professors were women who had graduated in the
different from what is experienced in the United States. The first few years of training had demanding requisites, such as mandatory service in the country’s rural sections. “There were also several years of intense training before
“Although I hadn’t made up my mind about a specific career path, it struck me that something was critically wrong with the cancer care system in Iraq. People should not have to wait
health and development agenda.” Dr. Gospodarowicz explained that because of its strong international membership, the UICC has great potential to align and unite the voices necessary to bring about substantive changes, especially in underserved nations. To that end, Dr. Gospodarowicz contends that there clearly is a need for more health-care investment in low- and middle-income nations. “We do have industry financing for some of our programs, but we need to do much more with other organizations. Targeting philanthropists is difficult—you need a skilled execution body to create the tight proposals that agencies such as the Gates Foundation will act on. We need to capitalize more on our partnerships with WHO and IARC [International Agency for Research on
Cancer], and others such as GAVI, the global vaccines agency,” said Dr. Gospodarowicz, adding, “Naturally, fundraising is important, but you also need to make the most of the resources you have.”
treatments are effective,” said Dr. Gospodarowicz, “Cancer care in Canada is supported by jurisdiction-wide, population-based cancer-control strategies, but it does have its challenges regarding resources and timeliness of access to care,” she noted. “All in all, I think that both of our countries do a good job caring for our cancer patients.” Despite her overwhelming responsibilities as Medical Director of Princess Margaret Cancer Centre and her presidency of the UICC, Dr. Gospodarowicz said that first and foremost she is a physician. “I’m very proud of being able to look after patients because that’s the one thing that keeps you real. Coming back to the clinic and being inspired by your patient’s courage and commitment is what keeps me going,” said Dr. Gospodarowicz. n
Health Care in Canada The contentious debate over health care in the United States centers largely on spending and access. Asked if Canada faced similar issues in health care Dr. Gospodarowicz responded, “The ongoing challenges in both systems are the same: paying for highquality cancer care in a cost-effective manner. While my colleagues in the United States have to negotiate with multiple insurance companies, I have to negotiate with the government, which entails providing evidence that
continued on page 22
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Maha Hussain, MD, FACP
continued from page 21
Upon arriving in the United States, Dr. Hussain was offered a training position at Wayne State University, where her true momentum toward an oncology career was built. “Actually, my first month was spent doing internal medicine rotations at the Veterans Affairs (VA) hospital in Allen Park, Michigan, which is one of the oldest VA facilities in the country. During my training at Wayne State University, I was exposed to an array of medi-
to have care. Early detection and preventive programs needed to be prioritized,” said Dr. Hussain. Her first inspiration toward an oncology career came from two of her uncles. “One uncle trained in the UK and returned to Iraq to practice medicine. The other uncle trained in the United States before returning to Iraq. Both were oncologists,” she said, adding, “Although they were early advocates for a career in oncology, it wasn’t until my own venture in the United States that my path was chosen.” Pulling up roots and leaving one’s country is a life-changing, difficult decision. It was no different for Dr. Hussain, but the drive to succeed proved stronger than any border or flag. Encouraged by their families and recalling a memorable one-liner from her father—“Graduate from Baghdad College, then get your higher education in the United States”—Dr. Hussain and her husband left Iraq to pursue professional opportunities abroad. It was just a few weeks before the start of the long war between Iraq and Iran, and the couple was looking forward to a fresh start in the West. “Our first landing was actually in the United Kingdom. But after a year there, it became very clear that while there were opportunities to train, they were not the ones we were truly seeking. Although we’d just recently left our home in Iraq and didn’t relish another major move, we didn’t hesitate to pack up and head for America. It was the best decision we ever made,” said Dr. Hussain.
fied my already blooming interest in oncology,” said Dr. Hussain. She remembered those early days as an exciting period, fresh with therapeutic breakthroughs that fueled her drive to become an oncologist. Dr. Hussain continued, “This was the time when a cure for testes cancer was becoming possible, and better systemic therapies for advanced cancers were emerging. Moreover, organ preservation strategies were being looked at, and clinical and basic
NAME: Maha Hussain, MD, FACP TITLE: Professor of Medicine and Urology, University of Michigan Comprehensive Cancer Center; Associate Director for Clinical Research and Co-Leader, Prostate Cancer Program, University of Michigan Comprehensive Cancer Center; Associate Chief for Clinical Research, Division of Hematology/ Oncology, Department of Internal Medicine. MEDICAL DEGREE: MD (MB, ChB), Baghdad University School of Medicine RESEARCH INTERESTS: Prostate and bladder cancer, novel therapeutics NOTABLE HONORS: ASCO Statesman Award (2010); University of Michigan Medical School League of Research Excellence (2011); University of Michigan Medical School Clinical & Health Services Research Award (2012)
cal challenges that covered a broad socioeconomic slice of the population, from urgent care in indigent patients, to elderly veterans, to CEOs. It was very rewarding for a young doctor to be thrown into such an eclectic care environment,” said Dr. Hussain. Dr. Hussain continued her medical training at Wayne State University, where she became immersed in oncology. “I had the good fortune to closely connect with several members of the hem/onc faculty whom I consider wonderful mentors and who intensi-
research was rapidly expanding. The space and opportunity to contribute to the field of oncology became increasingly apparent, and I have never regretted my choice to become an oncologist.”
A Doctor at Heart A firm believer in the power of research to cure cancer, Dr. Hussain, a hands-on physician, not only practices in the clinic but is also involved in robust research activities. “I partner with basic scientists looking to
answer questions on how to develop novel therapeutic approaches with a special focus on prostate and bladder cancer,” said Dr. Hussain, adding that along with her clinical and research activities, she also wears an administrative hat as Associate Director for Clinical Research at the University of Michigan Comprehensive Cancer Center. At the national level, Dr. Hussain, the author of more than 185 articles and book chapters, has served in a variety of leadership capacities. She is the current Chair of the Integration Panel of the U.S. Army Medical Research and Materiel Command Prostate Cancer Research Program, served as the Co-Chair for the Prostate Cancer Subcommittee of SWOG GU Committee, was a member of the NCI Cancer Biomarker Study Section and the NCI’s Prostate Cancer Task Force, and has served as a member and the Chair for the FDA Oncology Drug Advisory Committee. She has also chaired several ASCO committees. Although the extraordinary demands of her career give little time for hobbies or avocations, Dr. Hussain always carries a camera with her as she travels to various destinations. “I love nature, and my photographs attempt to capture the most beautiful scenes of wherever I am, in the States or abroad,” said Dr. Hussain. After a brief pause, she added, “I like to cook, too. It’s a great medium for creativity. But before anything, I’m a doctor at heart. I want to help patients.” n
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Alexandra Levine, MD, MACP
The Power of Listening: From Candy Striper to the Front Lines of the Early AIDS Pandemic
lexandra Levine, MD, MACP, the Chief Medical Officer of City of Hope National Medical Center, has traveled to 74 countries, seeking out adventures in some of the world’s most far-flung regions. Her illustrious oncology journey has also been an adventure, from the front lines of the AIDS pandemic to working side-by-side with the storied researcher Jonas Salk, MD. And it all began with the simplest and often most overlooked skill in medicine: She listened to a patient’s story. Dr. Levine was born in Berkeley, California, and moved with her family to Los Angeles while still in grade school. Her father was a lawyer and although her mother, a multilingual language teacher, thought that her daughter should follow in her footsteps, Dr. Levine found the prospect of repeating lesson after lesson too boring. However, Dr. Levine said that she now relates to her mother’s love of teaching; in her current role as an academic, teaching bright young doctors is a cherished part of her job.
Answering a Call Dr. Levine embodies the spirit of the doctor who is “called” to medicine. Since grammar school, she had always wanted to be a doctor, but it was volunteering as a candy striper at the Los Angeles County+USC Medical Center when she was 16 years old that confirmed her path to medicine.
Independent at an early age, Dr. Levine drove herself to the county hospital on her first day. After orientation, the volunteers were given assignments. “Mine was to pass out water to patients on a certain ward, all of whom were very poor and disadvantaged. At one point, an elderly African American man
hospital at the end of the week, and for all practical purposes I never left,” said Dr. Levine. She added that years later when she applied to medical school, “I wanted to go to the University of Southern California so I’d be able to return to the county hospital where the seeds
For the rest of the week I wrestled with my decision to go back, or to become a doctor. But I kept thinking about the old man. Simply listening to him had apparently been a form of medical care. So I went back to the hospital at the end of the week, and for all practical purposes I never left. — Alexandra Levine, MD, MACP
asked if I would stop and talk for a few minutes. I sat on his bed and listened to his stories. After a while the head nurse came to shoo me along. I apologized to the man for having to leave, and as I got up to go, he thanked me profusely for helping him,” said Dr. Levine. Her drive home was difficult. At 16, she had never been intimate with the reality of illness or poverty. “My first day on that ward gave me a big dose of both. For the rest of the week I wrestled with my decision to go back, or to become a doctor. But I kept thinking about the old man. Simply listening to him had apparently been a form of medical care. So I went back to the
NAME: Alexandra Levine, MD, MACP TITLE: Chief Medical Officer and Deputy Director for Clinical Programs, City of Hope Comprehensive Cancer Center; Distinguished Professor of Medicine, University or Southern California MEDICAL DEGREE: MD, University of Southern California, Los Angeles RESEARCH INTERESTS: Lymphoma, Hodgkin disease, HIV/AIDS NOTABLE HONORS: Board of Scientific Councilors, National Cancer Institute (2012-2015); Master of the American College of Physicians (2008); Presidential Advisory Council on HIV/AIDS (1995-2001)
of my career were sown.” Dr. Levine made good on her internal promise, practicing medicine at Los Angeles County+USC Medical Center for more than 30 years.
Serendipitous Path to Oncology Dr. Levine said that she was fortunate in that her serendipitous career path in oncology was like walking through an open door that she entered freely, with no preconceptions to cloud her vision. “Throughout medical school and residency, I always wanted to go into ICU care. One day in 1974, the Head of the ICU at Los Angeles County Hospital, Dr. Wayne Wagers, approached me and said that we were getting a new service, something called medical oncology,” said Dr. Levine. Dr. Tom Hall, the new Chair of the Oncology Department was arriving in a month or so, but there was one problem: None of the other residents were willing to switch their electives into this new field. “Dr. Wagers proposed a deal. If I would switch my elective to oncol-
ogy for the department’s first month, he would allow me to be an attending in the ICU for a month, which at the time was a dream come true,” noted Dr. Levine. When Dr. Hall arrived, he went on the oncology consultation rounds with his young resident. Dr. Levine took exhaustive notes, patient after patient. “At the end of the day, Dr. Hall asked me if I had any questions. I said no, and he said, ‘Okay, I’ll see you in 2 weeks,’” said Dr. Levine, remarking that her trial-by-fire job in oncology was “to keep all the patients alive.” Although Dr. Levine still planned on returning to the ICU, after spending 2 weeks talking with cancer patients about their lives and how the disease affected them, she began to nurture a deeper appreciation for the “foreign” new field. When her husband, an epidemiologist with the Centers for Disease Control, was transferred to Atlanta, Dr. Levine applied for a fellowship at nearby Emory University. However, Emory didn’t have a program for ICU intensivists. “I didn’t know what I’d do in Atlanta for the next few years. But a luncheon arranged by my oncology mentor Dr. Hall with the head of Emory’s oncology program ended with an offer to apply for an oncology fellowship. I did. And from that moment on, I’ve been an oncologist,” said Dr. Levine.
Role in Early AIDS Pandemic In 1982, a young man who entered Dr. Levine’s office at USC County Hospital would profoundly affect Dr. Levine’s career. “He had very enlarged lymph nodes, and first I thought he had Hodgkin disease or lymphoma, so I arranged for him to have a biopsy. I remember looking at the tissue sample under a microscope with Robert Lukes, MD, the Head of Hematopacontinued on page 24
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Alexandra Levine MD, MACP continued from page 23
thology at USC. Dr. Lukes was a renowned pathologist, a cherished mentor of mine, so I was shocked when he looked up and said, ‘I’ve never seen anything like this,’” said Dr. Levine. She continued, “Considering the
reactive process Dr. Lukes was observing, he asked what the young man had been exposed to. I didn’t have an answer, so I went back to the patient and asked him to tell me everything that he’d been exposed to.” It turned out that he was gay. He explained that he went to bathhouses and had had mul-
tiple sexual partners. “It was an eyeopener. But I still couldn’t nail down the disease. So I asked if I could follow him as a regular patient in order to determine what was going on with his lymph nodes,” said Dr. Levine. He agreed. And within a month there would be about 20 young men
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waiting outside Dr. Levine’s office each morning, all with grossly enlarged lymph nodes. This was, of course, the onset of the AIDS pandemic. “AIDS was not yet described at the time, instead it was called GRID— gay-related immune deficiency,” said Dr. Levine. As time went on, a connection began to materialize. “They were all gay men with B-cell hyperplasia that was perhaps a reaction to a common exposure, and I hypothesized that given time, the very abnormal hyperplasia could eventually lead to the development of monoclonal Bcell lymphoma,” said Dr. Levine. She applied for a grant from the National Institutes of Health to study these patients, beginning her entrance into the AIDS era. “The patient who first entered my office was a young man named Mark, and over the years his case taught me what HIV/ AIDS was, in a clinical sense,” said Dr. Levine.
Sharing Knowledge Dr. Levine’s career was also influenced by her time spent working in the laboratory with noted virologist Jonas Salk, MD, a mentor she calls a man of a thousand ideas. “He’d call me at all hours to share his latest brainstorm. Some of his ideas bordered on crazy, but Jonas was alive in a way most people only dream of,” said Dr. Levine. Her rich experience with Dr. Salk helped reinforce “how important it is to keep an open mind, as a scientist and a clinician, but most important as a human being.” Her current position at City of Hope gives Dr. Levine the opportunity to share the knowledge gained from her diverse and accomplished career. “I spend a lot of energy putting people and programs together. I’m fully engaged in creating the robust milieu that encourages valuable collaboration between bright young investigators so we can move cutting edge research along from bench to bedside,” said Dr. Levine. In her time off, Dr. Levine and her husband travel the world, seeking out new adventures. She’s also a huge Lakers fan, holding season tickets, and is an avid hiker, a gardener, and a lover of the arts. There’s more, of course. And all this began when a young girl volunteering on a ward full of very sick people took time to sit on an old man’s bed and listen to him for a while. n
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Lee N. Newcomer, MD, MHA
Innovative Leader in Oncology Is Committed to Tackling the Most Critical Issues in Managed Care
’m a Nebraskan,” said Lee N. Newcomer, MD, MHA, a leader in the oncology community who is well known for his innovative efforts to align physician payment and quality of care in ways that will best configure to the rapidly changing health-care environment. Speaking in the flat vowels and neutral accent of his home state, Dr. Newcomer—with typical Midwestern directness—condensed his notable career into one word: change.
Medical School “I came from small-town U.S.A. By the time I got to school, everyone in town knew what I had for breakfast,” said Dr. Newcomer. “After graduating from Nebraska Wesleyan University, a small liberal arts college, in 1974, I marched up the interstate to Omaha and entered the University of Nebraska Medical School, which was just emerging as a major cancer center,” said Dr. Newcomer. “One of the young Fellows who had gone off to Iowa for his hem/onc training was invited back to the Nebraska Medical Center as a professor. He was a Nebraskan, too, by the name of Jim Armitage. He was clearly a mentor for a number of us, sparking our interest in oncology,” he added. “Another classmate was ASCO Past President Margaret Tempero. She was a year behind me but we had many rotations together. Jim Commers, another ASCO member, and I had our very first rotations as interns on
the oncology ward, and I found two things that I loved about oncology. It was the late 1970s and the field was exploding with exciting scientific information and important new drugs. The other thing was how intimately I got to know the cancer patients and their families,” said Dr. Newcomer. When he was in medical school, Nebraska was committed to recruiting family practitioners to serve the rural communities in the vast state. “In oncology you had all of the knowledge of the family that the community primary care doctor has, but you also got
medical oncology at Yale University in 1981. “I spent 1 year in Minneapolis, practicing at the Park Nicollet Clinic, which is a multispecialty institution. There were about 250 doctors there at the time and it gave me an early experience in both managed care and group practice, which I liked a lot,” said Dr. Newcomer. He continued, “But unfortunately, Minnesota is so cold that it’s uninhabitable, at least for me [at that time]. So I joined five other doctors in Tulsa, Oklahoma. They all came from heavy academic programs, and it was the best
Everyone just assumed that if the evidence were there, doctors would follow it. Not so. It was an instructional point in that we got to see how our data collection could have a positive effect on clinical practice. — Lee N. Newcomer, MD, MHA
to practice in a highly detailed specialty, so it was the best of both worlds,” noted Dr. Newcomer. During the first 2 months of his internship, Dr. Newcomer also cared for his cousin’s husband, who later died of Hodgkin disease. That experience, coupled with his work on the cancer ward, cemented his desire to pursue a career in oncology.
From Private Practice to Managed Care Following his residency, Dr. Newcomer completed a fellowship in
NAME: Lee N. Newcomer, MD, MHA TITLE: Senior Vice President, Oncology, Genetics, and Women’s Health, UnitedHealthcare MEDICAL DEGREE: MD, University of Nebraska College of Medicine; Masters of Health Administration, University of Wisconsin at Madison RESEARCH INTERESTS: Quality of care; cancer treatment and financing; payment models; physician performance profiling
of both worlds in that our practice was a major contributor to ECOG clinical trials. At the time I joined the private practice we were actually ECOG’s second largest patient contributor,” said Dr. Newcomer. “We were a hospital-based practice. William Warren, who owned the oil company that eventually became Gulf Oil, had a daughter with breast cancer. There was no one in Tulsa to care for her so he built a cancer center within the hospital and recruited us. However, we came to believe that a free-standing cancer center of our own would make better business sense and would be able to serve patients more efficiently,” said Dr. Newcomer. He and his associates eventually set up a freestanding clinic, and Dr. Newcomer was the managing partner for the transition. It was during that experience when Dr. Newcomer’s commercial
interest blossomed, but he also realized that he didn’t know enough about business. “I went back and got a masters of health administration degree at the University of Wisconsin. And then I went into managed care. It was a pivotal career move,” said Dr. Newcomer.
New Beginnings at UnitedHealthcare Dr. Newcomer took a position as Medical Director of CIGNA Health Care of Kansas City. “I was there about 8 months when a headhunter called about a position at UnitedHealthcare. To tell the truth, I’d never heard of UnitedHealthcare,” he admitted, but was convinced to go to Minneapolis and interview for the position. He got the job. “When I was hired, United was just starting a health services department. I took the lead building the medical department. At that time we had less than a million members covered over 16 sites with no full-time medical directors. We now serve about 70 million individuals nationwide, so it’s been a remarkable growth,” said Dr. Newcomer. Dr. Newcomer commended UnitedHealthcare’s forward-looking style, one that encouraged creative thinking. “Someone in the company had the vision to make our system one that’s capable of reporting data in addition to just paying claims. So, from day 1 we started looking at claims data to analyze how medicine was being practiced,” said Dr. Newcomer. One of the company’s first efforts was seeing if heart attack patients were given beta-blockers. “Even though there were 24 studies saying that these patients benefited from beta-blockers, only 30% of our heart attack patients were receiving them. continued on page 26
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Owen N. Witte, MD
For Renowned Researcher, Seeing Basic Science Turn into Promising Therapies Is the ‘Holy Grail’ of Oncology
rom bench to bedside” is a phrase that captures the essence of modern oncology: Researchers at the bench seek to solve the biologic puzzles of cancer that can translate into the development of therapeutics delivered at the bedside. Owen N. Witte, MD, has spent most of his career as a basic bench researcher, deciphering these oncologic riddles with great success. Dr. Witte was born in Brooklyn, but he grew up in the suburban Long Island town of Levittown. He said it was a fifth grade teacher, coincidently named Mrs. Levitt, who first sparked his passion for science. “She had a real hands-on approach that engaged you in a way that made science fascinating. She also recommended a great book called Microbe Hunters [by Paul de Kruif]. My friends and I read the book over and over. It really had a profound influence on my relationship with sci-
ence,” said Dr. Witte.
his undergraduate studies at Cornell University in Ithaca, New York. “This was during the Vietnam War, and I certainly wanted to stay out of it. Af-
al friend,” said Dr. Witte. “I began working with Irv on viruses that cause certain types of leukemia in mice. It was an eye-opening experi-
Once again at the interface of immunology and cancer, Dr. Witte studied a virus that had been isolated a few years earlier by Herbert Abelson, MD. “My work essentially helped characterize a protein produced by a gene in the Abelson virus. I also discovered the unique enzymatic activity in the gene, which is a tyrosine kinase. At the time, nobody knew what the discovery meant,” explained Dr. Witte. Further
Lee N. Newcomer, MD, MHA
did that for about 5 years, and then I got a call from UnitedHealthcare. They invited me back to take a look at starting a cancer-specific team at UnitedHealthcare,” said Dr. Newcomer. “I agreed, as long as I could focus on how we could deliver better, more affordable cancer care. In essence, they gave me what I’ll call ‘an extra room in the closet.’ We had a small staff of about 10 people, but we had a hall pass to go to any department in UnitedHealthcare and work with them to change the way they supported cancer care. It was a perfect way for me to explore exciting innovations backed by a very large company. On a professional level, it was the equivalent of heaven,” said Dr. Newcomer.
formed oncology division he had a rude awakening. “I was at a national cancer practice managers meeting. At least 25 speakers got up and said what a terrible job UnitedHealthcare was doing in cancer claims payment. In response, we developed a specialized cancer claims payment unit,” said Dr. Newcomer. It worked. Since the new unit was established, UnitedHealthcare’s physician satisfaction rate has gone from 60% to 93%, and its ranking in oncology has consistently occupied the number 1 slot. “We’re now able to focus our programs on things that make sense for oncology. In the past, a general medical director reviewed all conditions. Our new focused approach makes a lot more sense, especially in such a complex specialty like oncology,” said Dr. Newcomer.
The buy-and-bill system in medical oncology is arguably one of the most difficult issues facing cancer care. The debate rests on how to replace the oncology payment system with one that adequately reimburses oncologists for the intricate and valuable services they provide. Led by Dr. Newcomer, UnitedHealthcare has spearheaded a pilot program to test a bundled payment model for oncologists. The program pays a flat fee that factors in what the physicians would have made by charging the health plan a margin on the chemotherapy drugs provided to the patient. “It’s a much more collaborative process than the old model, and it’s a lot harder than any of us ever appreciated, ” said Dr. Newcomer, in his typical straightforward manner. He’s a Nebraskan, after all. n
continued from page 25
We pointed this out to the American College of Cardiology. They were shocked at our data. Everyone just assumed that if the evidence were there, doctors would follow it. Not so. It was an instructional point in that we got to see how our data collection could have a positive effect on clinical practice,” said Dr. Newcomer.
A Specialized Oncology Division Dr. Newcomer left UnitedHealthcare in 2001, feeling stifled by the mounting organizational activity needed to keep pace with the company’s expansion. “Managing the nuts and bolts of a company growing at that pace didn’t mesh with my entrepreneurial aspirations. I put together a startup business with several friends. I
Fascination with Immunology and Cancer The future researcher’s interest in science grew more intense during his high school years, and he completed
ter graduating Cornell, I headed to Stanford to get my medical degree. Through a whole bunch of happenstances, I ended up in the lab of Dr. Irv Weissman, who is now the Director of the Stem Cell Institute at Stanford. He became a terrific mentor and a person-
If you’re not brimming with optimism, you don’t belong in cancer research. Between government cutbacks and NIH funding freezes, it’s getting harder and harder to do our jobs. So you need to believe that by spending long hours in the lab, something good for mankind will come out of it. — Owen N. Witte, MD
Reforming the Oncology Payment Model On Dr. Newcomer’s second day as head of UnitedHealthcare’s newly
ence at the interface of immunology and cancer. After I graduated medical school, I dipped my toe in clinical medicine during an internship and realized I really didn’t like it. The clinic was not where I was going to make my stand,” said Dr. Witte. “So I went back to research, doing a postdoctoral at MIT with David Baltimore, PhD,” he continued.
Breakthrough Research in Tyrosine Kinase Activity
ASCOPost.com | JUNE 10, 2013 | SUPPLEMENT
experimentation gave a clue. “We were quite sure that the kinase activity was linked to the biological activity, but at that point we had no idea about these kinase networks, and how the signaling integrated, creating this master driver of the cancer cell.” In 1980, Dr. Witte left MIT and joined the faculty at UCLA. He stayed in contact with Drs. Weissman and Baltimore, two great influences on his career with whom he would collaborate over the years. “At UCLA, a graduate student of mine named James Konopka, made an observation that changed my life. He discovered the abnormal tyrosine kinase in human leukemia we now call Bcr-Abl. This was the work that really defined how a common gene in mouse and human leukemia works by a similar genetic activation mechanism. And of course that storyline led to the development of imatinib (Gleevec), in which many people played important roles,” said Dr. Witte. Dr. Witte has always been a scientific explorer, looking for new challenges. In the 1990s, his research led to the discovery of Bruton’s tyrosine kinase enzyme, which is required for normal B-lymphocyte development. “That gene, as it turns out, was responsible for a genetic defect in the immune system called Bruton’s X-linked agammaglobulinemia. It basically means that you don’t make B cells and you don’t make immunoglobulins,” said Dr. Witte. From this work, it became apparent that Bruton’s tyrosine kinase would be
an important drug target for treating immune disorders and certain lymphomas and leukemia. “And that target has been realized and used to produce therapies. In fact, there are new drugs, including ibrutinib, coming out this year in which Bruton’s tyrosine kinase is the target. So this is a consistent theme of my career, trying to understand the basic biology and genetics of the system—be it B-lymphoid system or chronic myeloid leukemia—and define what the key target is,” said Dr. Witte. More recently, he has turned his attention to prostate cancer and the role of tissue stem cells in cancer progression.
Keeping an Eye on the Pipeline In addition to running his own research laboratory of nearly 25 individuals, which is made of equal parts technical staff, graduate students, and post-docs and clinical fellows, Dr. Witte also has a major administrative role as Director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “That role helps to coordinate something that I believe is very important: pushing basic science through the translational pipeline and into the clinic. I spend a lot of time organizing research efforts between and among groups, essentially making sure these important efforts have the resources they need to move their research ahead,” commented Dr. Witte. He stressed, “It is very difficult and
NAME: Owen N. Witte, MD TITLE: Director, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research; President’s Chair, Developmental Immunology, UCLA; Distinguished Professor, Department of Microbiology, Immunology, and Molecular Genetics, UCLA; Professor, Department of Molecular and Medical Pharmacology, UCLA; Investigator, Howard Hughes Medical Institute MEDICAL DEGREE: MD, Stanford University RESEARCH INTERESTS: Lymphoma, leukemia, prostate cancer, stem cell research NOTABLE HONORS: Member, American Academy of Arts and Sciences (1996), National Academy of Sciences (1997), and the Institute of Medicine (2003); Richard and Hinda Rosenthal Memorial Award, American Association for Cancer Research (1991); William Dameshek Prize, American Society of Hematology (1993); Alpert Foundation Prize; de Villiers International Achievement Award, Leukemia and Lymphoma Society (2003); UCLA Faculty Research Lecture (2007); President’s Cancer Panel (2011)
expensive to transition an idea into a clinical trial. We’ve even built our own good manufacturing process facility to buttress our efforts. And the good news is that all the hard work is paying off with exciting new cellular therapies under development.” Dr. Witte remains enthusiastic about his continuing work ushering discoveries from the laboratory into the pipeline. In this veteran scientist’s view, what is an essential attribute for a researcher coming into the field to have? Optimism, he says. “If you’re not brimming with optimism, you don’t belong in cancer research. Between government cutbacks and NIH funding freezes, it’s getting harder and harder to do our jobs. So you need to believe that by spending long hours in the lab, something good for mankind will come out of it,” said Dr. Witte.
Dr. Witte says that it reenergizes him to try something new in the lab. Like space, the world of genetics and microbiology remains a limitless frontier of unending exploration. Dr. Witte has never looked back at his decision to pursue a career in the laboratory instead of the clinic. “To me, the Holy Grail is seeing basic science turn into new and hopeful therapeutics entering the field of cancer care.” To relax, Dr. Witte takes spin classes, considering himself a borderline “exercise nut.” He also likes to cook. “I love to experiment with different recipes. In fact, at one point in my youth I toyed with the idea of becoming a professional chef,” said Dr. Witte, adding with a laugh, “But that’s way too much work.” His suggested reading for young students? You guessed it, a book called Microbe Hunters. n
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Published on Jun 10, 2013
Published on Jun 10, 2013
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