TAP Vol 2 Issue 7

A Harborside Press Publication

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

VOLUME 2, ISSUE 7

MAY 1, 2011

The great American scientist and phy-sician, Dr. Irving Selikof, said that Statistics are people with the tears wiped away. At this years ASCO Annual Meeting, we will be introduced to new ideas, discov-eries that open windows of opportunity for improving our patients quality and quan-tity of life, and creative methods of reduc-ing the ravages of disease. Data, statistics, facts, and erudite discussions will inundate our week. But we must realize that all of this new information and all the biotechnologic marvels that are displayed in the conven-tion hall are meaningless to the person with cancer unless we are patient-focused.

Unapplied ResearchTo paraphrase Dr. Otis Brawley, too

many patients are dying, not because of a lack of research but because the research is not being applied to them. Translating

continued on page 13


MORE IN THIS ISSUE

A Conversation with Larry Norton ............. 7Oncology Worldwide........................... 11, 17FDA Update ..........................................19, 33Gastrointestinal Cancers ............................21Direct from ASCO .......................................22TAP on Technology .....................................31ACCC 37th Annual National Meeting ......36

Patient-centered Care vs Health-care

Economics

A recently released policy statement by ASCO makes clear that individualized therapy is a best practice throughout the full course of treat-ment, encompassing the diverse needs of patients diagnosed with advanced cancer. ASCO CEO Allen S. Lichter, MD, spoke with The ASCO Post about the Societys 15-year role in advancing awareness and knowledge in the ad-vanced cancer setting.

Enhancing End-of-life Cancer Care What is some of the background that led to ASCOs

statement on improving doctor-patient communication

Personalized Therapy in Advanced Cancer a PriorityA conversation with Allen S. Lichter, MDBy Ronald Piana

continued on page 2

Metastatic melanoma 3 | Nonsmall cell lung cancer 6 | Breast implants and lymphoma 43

In updated results from the RADIANT tri-als of treatment for ad-vanced neuroendocrine tumors, everolimus pro-vided a 2.4-fold increase in median progression-free survival (PFS) for patients with pancreatic neuroendocrine tumors. In combination with the long-acting formulation of the somatostatin ana-log octreotide (Sandostatin LAR) in patients with carcinoid syndrome, however, the benefit was more questionable. The updates were reported at the 2011 Gastrointestinal Cancers Symposium.

The phase III RADIANT-3 trial randomly as-signed 410 patients with advanced pancreatic neu-roendocrine tumors to everolimus (10 mg/d) or

Everolimus Benefits in Pancreatic Neuroendocrine Tumors Sustained in Updated RADIANT TrialsSunitinib demonstrates similar benefits, other studies find.By Caroline Helwick

By Richard J. Boxer, MD

about end-of-life care?When ASCO released its statement on barriers

and recommendations to improving physician-initiated conversations regarding care options for patients with advanced cancer, it received quite a bit of national atten-tion. But in fact, provid-ing quality care for pa-tients at the end of life has been a priority for ASCO for many years. In 1997, ASCO President Robert

Mayer, MD, made end-of-life care the focus of his Presidency. This began a significant effort in end-

Dr. Boxer is Professor of Clinical Urology at the University of Miami and Clinical Professor at the University of Wis-consin, Madison, and the Medical College of Wisconsin.

Gastrointestinal Cancer

End-of-life Care

Oncologists across the country understand that

high-quality care does not end with a diagnosis of

incurable disease. Allen S. Lichter, MD

Editors note: The Oncologic Drugs Advi-sory Committee (ODAC) of the FDA recently recommended that everolimus (Afinitor) be ap-proved for the treatment of advanced pancreatic neuroendocrine tumors. In a decision made that same day (April 12, 2011), the ODAC commit-tee voted to recommend that the multikinase inhibitor sunitinib (Sutent) be approved for the treatment of unresectable pancreatic neuroendo-crine tumors.

ODACs unanimous decision to recommend approval of everolimus was based on data from the clinical trials described in this report show-ing a significant increase in median progression-free survival for patients with pancreatic neu-roendocrine tumors who received everolimus compared to those who received placebo and best supportive care.

Manisha H. Shah, MD

The ASCO Post | MAY 1, 2011

Opinion

research and applying compassion will save more lives, bring greater comfort to our patients, and bring greater satisfaction to our profes-sional lives.

Wrenching DecisionsBut how can our society pay for

the scientific discoveries that may lead to cures, prolongation of life, or simply a slight delay of death? Like so many wrenching decisions being considered in the face of our nations debt, we need to consider econom-ics when health care becomes too expensive and crushes other societal needs.

And how shall we pay for the short- or long-term therapies, the potential cures, and the desired pre-ventions? Should economics be fur-ther introduced into the decision-making of the care we render? If a patient and family were told that a therapy being offered has a 50% chance of prolonging life by 2 to 4 months, would the patient endure the further care? If that care were to cost the patient or his/her future estate $100,000, would that alter the decision? For patients who can af-ford such therapy, perhaps on a slid-ing scale, should society be asked to fund it, essentially funding the monies passed down to the patients heirs? At what point does society state that decisions impacting the economics of health care are no dif-ferent than those involving the eco-nomics of other aspects of life?

Where clinical studies have prov-en that a therapy (medication, radia-

tion, or surgery) clearly prolongs a quality productive life, particularly in the young, society should pro-vide the care when insurance is not adequate. However, when the treat-ment is limited in its ability to im-prove life, the patient and his family should consider all the implications.

The Financial Burden on Family

I will never forget the elderly pa-tient with widely metastatic prostate cancer who came into my office with his wife of 50 years. He had Medi-care, but no other insurance. He was

faced with the decision of whether to continue his depot LHRH agonist because of the co-pay of several hun-dred dollars. He tearfully said that he could no longer live with the idea that the medication may prolong his life a few more months, but he be-lieved his memory would be sullied in his wifes mind because she would have less money to live on when he was gone. I tried to dissuade him and spoke to the manufacturer about ob-taining the medication on a compas-sionate care basis, and the company responded favorably. The patient refused the medication, however, and he died soon thereafter satisfied

Health-care Economicscontinued from page 1

with his decision.Considering that a significant

amount of ones lifetime health-care expenditure occurs in the last year of life, and that there is not a limitless amount of money, personal health-care economics may need to be con-sidered as our nation struggles with controlling the debt.

The Impatient Patient Whether we are in research,

clinical care, or both, our goals are to provide the best care for our pa-tients. There is no reasonable meth-od of determining whether a discov-

ery will lead to a cure, or better and longer health for patients. So the pursuit must continue with greater energy, enthusiasm, and funding. That is critical. The public has been convinced of the primacy of sci-ence and the real value of research. Our nation has made the decision to fund biomedical research at the expense of other less valued servic-es and industrial output. But there seems to be a limit, and the ultimate consumer, the patient, is getting im-patient.

Some Americans believe that they are not getting their moneys worth. Science for the sake of sci-

ence may be peaking in its perceived value. Application and translation of science for the betterment of health has begun to take hold of the politi-cal (and the kitchen table) discus-sion. Is the country improved by funding remarkable discoveries that will have no chance of improving anyones health? Scientists often say that one cannot predict what small finding will lead to major changes, and that is true. But there are limits to the logic, and with limited funds and a crushing debt, one must use common sense.

Consider Risk-sharingThus, we must continue advanc-

ing the discoveries, the exciting sci-ence, the exhilaration of lighting the darkness of the unknown, but we should consider risk-sharing. If proj-ects are worthy and show the prom-ise of translating into long-term therapies, preventions, or cures, the nation must promote them. But those who benefitwhether busi-nesses or patientsand have the means must also be willing to cover the cost through risk-sharing, direct payment, or probate.

Financial Disclosure: Dr. Boxer reported no potential conflicts of interest.

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

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Correspondence: Address general inquiries to Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: [email protected].

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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 the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press, HSP News Service, LLC, and ASCO assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

Policy

Scientists often say that one cannot predict what small finding will lead to major changes,

and that is true. But there are limits to the logic, and with limited funds and a crushing debt, one

must use common sense.

Whats Your Opinion?The ASCO Post wants to hear from you. Write to [email protected]. All correspondence will be acknowledged. Selected letters will be published in future issues of The ASCO Post.

ASCOPost.com | MAY 1, 2011 PAGE 3

News

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

ASSOCIATE EDITORS

Joseph S. Bailes, MD Texas Oncology

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Miami

Harold J. Burstein, MD Dana-Farber Cancer Institute

Robert W. Carlson, MD Stanford University Medical Center

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Jay S. Cooper, MD Maimonides Medical Center

John Cox, DO Texas Oncology

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Michael P. Link, MD Stanford University Medical CenterJohn L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown UniversityMary McCabe, RN Memorial Sloan-Kettering Cancer Center

William T. McGivney, PhD National Comprehensive Cancer Network

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Virginia Commonwealth University

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

William C. Wood, MD Winship Cancer Institute, Emory University

INTERNATIONAL EDITORS

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Conor Lynch, Executive Editor [email protected]

Cara H. Glynn, Director of Editorial [email protected]

Andrew Nash, Associate Director of Editorial [email protected]

Sarah McGullam, Assistant Editor [email protected]

Michael Buckley, Graphic Designer [email protected]

Wendy McGullam, Director of Production [email protected]

Leslie Dubin, Vice-President, Director of Sales [email protected]

Anthony Cutrone, President [email protected]

John A. Gentile, Jr., Chairman [email protected]

Editorial Board

Harborside Press Publishing Staff

Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations; Artwork on page 31 by DNA Illustrations, Inc.

Financial disclosure information available at ASCOPost.com.

Fantastic and the next big thing were how two of the principal investigators described the results of an interim analysis of the phase III trial of PLX4032, the harbinger of a significant breakthrough in the treat-ment of metastatic melanoma.

PLX4032 works by inhibiting a protein produced by a gene mutation in melanoma cells. In phase I and II trials, many of the patients whose tu-mor cells manifested the BRAF V600 mutation responded to the drug with tumor shrinkage that lasted for an av-erage of 6months.

Now, a controlled phase III trial pitting PLX4032 against dacarbazine showed that patients who received the investigational drug had a sig-nificant survival advantage, as well as increased time to disease progression when compared to standard therapy.

How much extra survival? We dont know the answer to that yet, said Keith Flaherty, MD, Director of Developmental Therapeutics, Mas-sachusetts General Hospital Cancer Center, and one of the principal in-vestigators for the study. The data will be presented at the ASCO An-nual Meeting.

Melanoma Treatments Not Effective

Dacarbazines response rate in metastatic melanoma is 10% to 15%. In the prior phase I and II trials, more than 50% of the patients with mela-noma who had the BRAF mutation responded to PLX4032.

We knew going into the phaseIII trial that the response rate to PLX4032 would be higher than to da-carbazine. We also knew that these re-sponses were typically not long-last-ing. The average duration of response observed in earlier studies suggested but did not prove that survival would be improved for PLX4032, said Dr. Flaherty. Hence, a study with survival as the primary endpoint was clearly needed.

Dr. Flaherty also noted that da-carbazine was approved more than 30 years ago. If it had been submitted for approval in todays more stringent

regulatory environment, it would not have made the grade, he speculated.

Prior to 2011, only two drugs (da-carbazine and high-dose interleukin-2 [Proleukin]) had been approved for treating metastatic melanoma, and neither one of these results in accept-able survival. A third, ipilimumab (Yervoy), was recently approved by FDA on March 25, 2011. Ipilimumab is a monoclonal antibody that inhib-its the cytotoxic T lymphocyteasso-ciated antigen 4 (CTLA-4). Several phase II studies have shown that ipi-lumumab can provide 1-year survival rates of nearly 50%. Ipilimumab has been associated with potentially life-threatening toxicity, including gastro-intestinal perforation and sepsis.

In June 2010, The New England Journal of Medicine published a re-port1 of a phase III study of 676 pa-tients with stage III or IV melanoma (which was initially presented at the Plenary Session of the 2010 ASCO Annual Meeting). They were ran-domly assigned to receive ipilimumab plus a glycoprotein 100 peptide vac-cine (gp100), ipilimumab alone, or gp100 alone. Median overall survival was significantly better in patients who received either the combination or ipilimumab alone (10 and 10.1 months, respectively) compared to those on gp100 alone (6.4 months). However, it should be noted that 14 deaths were related to study drugs.

The Present TrialThe BRIM3 trial, sponsored by

Roche and Plexxikon, a biotech com-pany in Berkeley, California, was be-gun in January 2010 with 675 patients with previously untreated melanoma who had the BRAF V600 mutation. (It was stopped only a year laterthe shortest phase III trial on record.) It was randomized, controlled, open-label, and multinational, with the primary endpoint of overall survival and secondary endpoints of time to disease progression and duration of response. Half the patients were giv-en dacarbazine and half were given PLX4032. Patients continued on the

Phase III Trial Shows Increased Survival in Metastatic MelanomaGenetics will be the key to better response, longer survival, and counteracting resistance.By Margot Fromer



News

ASCO has issued a provisional clini-cal opinion on the clinical use of epi-dermal growth factor receptor (EGFR) mutation testing to identify patients with

advanced lung cancer who may benefit from treatment with EGFR tyrosine ki-nase inhibitors, including gefitinib (Ires-sa) and erlotinib (Tarceva). The opinion,

which is based on the results of five recent randomized clinical trials, recommends that patients with advanced nonsmall cell lung cancer who are being consid-

ered for first-line therapy with an EGFR tyrosine kinase inhibitor should first have their tumor tested for EGFR mutations. Such testing is currently available both at academic medical centers and at some community medical centers.

A panel convened by ASCO exam-ined evidence compiled through a review of the medical research literaturein addition to suggestions by panel mem-bersto develop its recommendation. The opinion was published online in the Journal of Clinical Oncology.1

EGFR testing helps us move toward the goal of tailoring cancer treatments for each patient, said Panel Cochair Vicki Keedy, MD, Assistant Professor of Medicine at Vanderbilt-Ingram Can-cer Center. Weve learned over the years that nonsmall cell lung cancer is really a collection of genetically distinct diseases. We want to treat patients with drugs that target the molecular drivers of their spe-cific tumors, rather than using a one-size-fits-all approach. But how this approach affects the patients overall outcome re-mains uncertain.

IPASS TrialThe major impetus

for the opinion was the Iressa Pan-Asian Study (IPASS), a phase III multicenter trial com-paring gefitinib with standard carbopla-tin and paclitaxel chemotherapy as first-line treatment in patients in East Asia who had advanced nonsmall cell lung cancer and were either nonsmokers or light smokers. The IPASS trial found that among patients with negative tests for EGFR mutation, progression-free surviv-al and response rates were greater in pa-tients treated with chemotherapy, while patients with mutated EGFR had better progression-free survival and higher re-sponse rates when treated with gefitinib.

Four smaller studies examining the use of gefitinib (and in some cases, er-lotinib) as first-line treatment report-ed similar results. None of the studies showed differences in overall survival between those who tested negative for EGFR mutations and those with mutations. Reference

1. Keedy VL, Temin S, Somerfield MR, et al: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol April 11, 2011 (early release online).

ASCO Issues Provisional Clinical Opinion on EGFR Mutation Testing for Advanced Lung Cancer

SEE PAGE 47

JCO Spotlight


Experts Corner

The origin and journey of meta-static cancer cells is a perplex-ing process, often portending a dire prognosis for patients. The concept of tumor self-metastasis, or self-seeding, originated at Memorial Sloan-Ketter-ing Cancer Center, based on work led by Joan Massagu, PhD, head of the Metastasis Research Center, and Larry Norton, MD, Deputy Physician-in-Chief of the MSKCC breast cancer programs. Dr. Norton spoke with The ASCO Post, shedding light on their on-going research in tumor self-seeding and how this fascinating concept could influence the timing and nature of can-cer treatment.

Early Publications What have you published describing

your work on tumor self-seeding?In 2006, Dr. Massagu and I pub-

lished a hypothesis paper on self-seed-ing in the journal Nature. It was based on reasoning from several points of view including biology and clinical observa-tions. But proof of concept demands experiments. In the December 25, 2009 issue of the journal Cell, our colleagues and we published the findings of many studies not only demonstrating that self-seeding of tumors by circulating tumor cells (CTCs) occurs, but also showing how it enhances the growth of tumors by chemical signaling, includ-ing the induction of angiogenesis and recruitment of the microenvironment. The Cell paper has garnered a lot of at-tention and has already been cited nu-merous times in the literature.

Solving MysteriesWhat are some of the clinical applica-

tions of the self-seeding concept?Self-seeding might help solve a num-

ber of clinical quandaries. For instance,

in breast cancer, when you excise the primary tumor to clear margins, why is it that we still must irradiate the remain-ing breast tissue? That is, why does irra-diation of the breast decrease not only the incidence of local recurrences, but also the incidence of systemic recur-rences, even in patients who do not de-velop locally recurrent disease? This has been a mystery that self-seeding may help solve. CTCs that seed the tumor also seed the region near the tumor, and then might grow locally or seed other sites later if not eradicated by the radia-tion therapy.

As another example, given that sen-tinel node mapping has shown that can-cer cells use lymphatic flow patterns to reach the axillary lymph nodes, why do some patients without axillary nodal in-volvement still develop systemic metas-tases? And why do some patients with axillary nodal metastases not develop metastases elsewhere, even if those nodal metastases are not removed by surgery or irradiated? The answer may

be that metastases are site-specific, with the primary tumor being one of those specific sites, as are nodes and distant organs. The genetic tools that a cancer needs to self-seed may overlap but may not be the same as the ones that it needs to seed lymph nodes, which again may overlap but not be the same as the ge-netic tools needed to seed other parts of the body. So we are dealing with corre-lations rather than certainties regarding metastatic behavior. We are just begin-ning to elucidate the different gene sets that cancers use to accomplish their di-verse behaviors.

Another mystery: Why is it that so few patientsless than 5% in the devel-oped worldpresent with metastatic disease, even when their tumors are large by virtue of growing in the breast, un-

treated, for a long time. Distant metasta-ses become evident well after the prima-ry tumor is eradicated, so CTCs would have had to be present but invisible at the time of initial diagnosis. Why didnt they show up as gross disease in distant sites at the same time the primary tumor became apparent, or soon thereafter? An answer may be that these CTCs prefer-entially went to the primary site when it was still viable, going to and colonizing distant sites only when the primary site was no longer available. In other words: these tumors are metastatic, but they are metastatic to themselves!

In this regard, it is interesting to note that in the early to mid 19th century, before patients with breast cancer were routinely treated by mastectomy, most women died of extensive local disease. Now that our surgical and radiothera-peutic procedures gain excellent local control, we have actually permitted the development of distant metastases be-cause, basically, the CTCs have no other place to go.

Ongoing ResearchWhat other current areas of investiga-

tion focus on self-seeding?The concept of self-seeding has

opened up many areas of investigation with clinical implications. Understand-ingat the level of biology and not just clinical correlationsthe gene sets re-sponsible for all metastases, distant and self, is the most important goal. This should lead to the identification of new targets for targeted therapies.

Some of the genes already identified by Dr. Massagus group are possible targets for drug therapy. This includes the actin cytoskeleton component fas-cin-1, which is an important factor for making cancer cells rigid and correlates with the clinical aggressiveness of tu-mors. Others are the two molecules that

are most important for attracting the seeds back to the primary site, the cyto-kines IL-6 and IL-8. We know that the relationship between inflammation and cancer is very real, and these cytokines are intrinsic to the inflammatory pro-cess. Inflammatory cytokines, after all, are important for attracting white blood cells to areas of infection. This is good regarding the bodys ability to contain and cure bacterial infections, but may be very bad regarding cancer.

In addition, a unique new avenue is opening for us, seeking to exploit the phenomenon of cells returning to their home base. The tumor is acting as a sponge for soaking up CTCs. Can we make it a poisoned sponge? In other words, can we find ways to con-vert a tumor into a site to both receive and kill cancerous cells? We have a number of ongoing research projects in this area.

Better Use of ResourcesWhat is the future of this research?Obviously, the scientific field of on-

cology has made massive strides over the past few decades. The speed with which we are finding answers to ques-tions with clinical relevance has been much faster than ever before. Howev-er, I think that we have reached a point in our history where we really need to reinvent the way we utilize those bio-logic answers in developing real medi-cal advances.

The system by which we develop new drugs needs to be constructively scrutinized. Perhaps smaller, more nimble biotechnology companies with stronger affiliations to academic cen-ters would yield better results. Also, we would certainly benefit from more ex-tensive international academic collab-oration. But most important, the me-chanics of converting discoveries into clinical advances need to be improved.

This is not just about getting more money into oncologic research, which as an enterprise has always been under-funded; its about using our financial resources more wisely. Molecular pa-thology has changed the game, so now it is time to change the rules. In addition to laboratory and clinical science, this is another area that deserves thought and action over the next decade.

Financial Disclosure: Dr. Norton reported no potential conflicts of interest.

A Conversation with Larry Norton, MDTumor self-seeding may explain mysteries, expand possibilities.By Ronald Piana

Before patients with breast cancer were routinely treated by mastectomy, most women

died of extensive local disease. Now that our surgical and radiotherapeutic procedures gain

excellent local control, we have actually permitted the development of distant metastases.

Larry Norton, MD

Translational Research

Larry Norton, MD


Global Perspective

The National Cancer Registry of South Africa, which publishes pathology-based cancer incidence data, was first established in 1986. Some 36,000 new cases were record-ed in South Africa that year, and the National Cancer Registry currently receives information about 60,000 new cases annually. The main ob-jective of the Registry is to monitor cancer burden in South Africa and report cancer incidence for each year, stratified by sex, age, and popu-lation group, as well as time trends over the past 20 years.

Programs to control cancer need to be evaluated using accurate in-formation on incidence, prevalence, and cancer patterns in different parts of the country. These parameters vary widely as a result of differences in access to health care, sociodemo-graphics, lifestyle, and environmen-tal factors.

Most currently available informa-tion on cancer incidence is derived from developed countries. With the technical assistance of the Interna-tional Agency for Research on Can-cer, the number of cancer registries in Africa has recently increased. The major challenge facing cancer regis-tries in developing countries is the implementation of World Health Organization-recommended, popula-tion-based cancer registries, to obtain accurate data that will better inform government policy. An added chal-lenge is the need to overcome finan-cial constraints and limitations im-posed by a lack of trained personnel, to ensure long-term sustainability.

South African DataSouth Africa has a land area of

1.2 million km2, with the latest Na-

tional Census (1996) estimating a population of 42million inhabitants (75% black, 14% white, 8.6% mixed race, 2.4% Asian).

Cancer remains a major killer throughout the developed and de-veloping world, including South Africa. Cancer incidence rates in South Africa are among the high-est reported in Africa. According to the latest 2002 data from the Na-tional Cancer Registry, South Afri-can males have an overall age stan-dardized incidence rate of cancer of 135.89 per 100,000 and a lifetime

risk of developing cancer of 1 in 7, whereas South African females have an age standardized incidence rate of 115.53 per 100,000 and an lifetime risk of developing cancer of 1 in 8.

In 2002, 28,126 males developed

cancer; cancers of the prostate (1 in 23), unknown primary site (1 in 64), lung (1 in 71), esophagus (1 in 91), colon/rectum (1 in 99), and bladder (1 in 109) predominated. The same year, 28,430 women were

diagnosed with cancer, with cancer of the breast (1 in 29) and cancer of the uterine cervix (1 in 36) pre-dominating; cancers of an unknown primary site (1 in 91), corpus uteri (1 in 148), colon/rectum (1 in 158), and esophagus (1 in 199) followed.

Toward A More Accurate Picture

In South Africa, lung cancer re-mains a growing health problem in both sexes. Although lung cancer risk in males (lifetime risk of 1 in 71) far exceeds that in females (life-

time risk of 1 in 233), the long-term effects of smoking will result in in-creasing incidence of lung cancer in females as well as males for years to come. It will be decades before re-cent antismoking drives and legisla-

tion will reduce these figures.Some cancers are suboptimally

reported because of a lack of tissue diagnoses. An important example is hepatocellular carcinoma, which is diagnosed clinically and by blood

tests (alpha-fetoprotein)without tissue diagnosisbut still remains among the top 15 most common cancers. Approximately 700,000 new cases yearly are diagnosed worldwide, especially in southern Africa and the Far East, which are endemic for hepatitisB virus. Future population-based registries, as well as better cancer diagnoses, especial-ly in rural areas, will give us a more accurate picture of this usually fatal malignancy, as well as other patho-logically underdiagnosed cancers.

In considering cancers associated with HIV/AIDS, Kaposis sarcoma was the third most common cancer in South African males and females aged 15 to 29 years, comprising ap-proximately 9% of all cancers in this group. Contrary to most cancers where the age standardized inci-dence rate peaks at older ages, the rate for Kaposis sarcoma showed a bimodal pattern in most racial groups, with the highest peaks at ages 25 to 29 in women and 35 to 39 in men.

ConclusionsMonitoring cancer incidence is

important in detecting changes in cancer patterns that might occur as a result of environmental conditions or in association with other diseases (for example, HIV/AIDS). Such re-cords are also essential for the detec-tion of new cancers, and to measure effectiveness of cancer control pro-grams.

Future legislation in South Africa will make cancer a reportable dis-ease by both pathologists and clini-cians, enhancing the existing pathol-ogy-based registry while developing population-based registries.

Financial Disclosure: Dr. Vorobiof and Dr. Ruff reported no potential conflicts of interest.

Dr. Vorobiof is Oncology Director of the Sandton Oncology Centre, Johan-nesburg , South Africa, and a member of The ASCO Posts International Editorial Board. Dr. Ruff is Professor of Medical Oncology at the University of the Wit-watersrand, Faculty of Health Sciences, Johannesburg.

Cancer in South Africa and the Role of the National Cancer RegistryBy Daniel A. Vorobiof, MD, and Paul Ruff, MD

Daniel A. Vorobiof, MD

The major challenge facing cancer registries in developing countries is the implementation of World Health Organization-recommended,

population-based cancer registries, to obtain accurate data that will better inform

government policy.


End-of-life Care

of-life and palliative care, creating in-structional materials to make this issue much more visible within the cancer community.

Today, the Art of Oncology series published in the Journal of Clinical On-cology, addresses how oncologists deal with end-of-life issues. Weve main-tained our interest and efforts in evolv-ing the quality of care in advanced disease for the past 15 years. So the re-lease of the statement is a continuation of ASCOs work in this area.

Moreover, the recent health-care debate leading up to passage of the Affordable Care Act reinforced some of the misconceptions that surround end-of-life care. The politicized debate about these discussions demonized the act of providers engaging patients in these difficult, yet necessary conver-sations. As the worlds leading profes-sional oncology society, we felt that we had a responsibility to reframe the issue from the perspective of profes-sionals who deal with end-of-life care on a daily basis. Thats how we arrived at this point.

Impact on Public PerceptionWhat is the practical effect of an

ASCO policy statement?ASCOs goal is to ensure that can-

cer care planning throughout the tra-jectory of care remains a very active part of the current dialogue within the oncology community. The release of the ASCO statement provided much needed medical perspective on this

issue at the national level, and that is a positive step in helping patients and their families talk about the difficult issues patients face when diagnosed with advanced cancer. We intend to follow up with additional practice guidance and more educational ma-terials to ensure that our members are informed, educated, and prepared to initiate these discussions with their patients.

The ASCO statement recommends specific steps for physicians to con-duct candid discussions about the full range of palliative care and treatment options soon after patients diagnosis

with advanced cancer, which is defined as incurable disease. While ASCOs efforts received broad news coverage among consumer media, we still have a long way to go in educating people about palliative care and hospice.

However, this is the first time since Ive been working at ASCO that Ive received mail from the general pub-lic, saying thank you for making this statement. Some people shared sto-ries of caregiving for family members

Personalized Therapycontinued from page 1

with cancer and how the experience was less than optimal. They encour-aged us to continue with this work. So I think we are beginning to have a small, but meaningful influence on the publics perception about the role of these honest discussions, and how timely doctor-patient communication is essential to optimal care during this difficult time.

A Learning ProcessWhat sort of research is being con-

ducted in the terminal cancer setting?As with any aspect of care, we are

learning, testing, and researching

to find ways to improve care for our patients at the end of their lives. In ASCOs statement, Jeffrey Pepper-corn, MD, and colleagues addressed ASCOs vision for improved commu-nication with patients who have been diagnosed with advanced cancer. One of the most important points of the pa-per is the need for more research to de-termine better ways to care for patients with terminal disease.

For example, ASCOs Conquer Cancer Foundation sponsored re-search about early initiation of pal-liative care in patients with nonsmall cell lung cancer that was published in The New England Journal of Medicine by Jennifer S. Temel, MD, and colleagues. They found that patients who received early palliative care integrated with standard care had better quality of life and longer median survival than those who received standard care alone.

The Temel paper was provocative and will certainly lead to future stud-ies that seek to replicate the results. An important question that will be asked in future studies is what are the special components of early palliative care intervention that lead to better out-comes? Once we have the answers to

that question, we will be able to better tailor our care in a more personalized manner.

Closing Thoughts How do political debates over physi-

cian reimbursement complicate these is-sues?

Oncologists across the country un-derstand that high-quality care does not end with a diagnosis of incurable disease. However, it is important to note that during the debate over the Affordable Care Act, the issue of pay-ment for these cancer care planning discussions was a sticking point. Un-fortunately, efforts to compensate on-cologists for delivering this important aspect of cancer care were politicized, warping the important underlying message.

Our current reimbursement system is heavily weighted toward procedures, and the highly complex cognitive services provided by oncologists go largely uncompensated. In fact, most public and private insurance plans provide little or no compensation for discussions with patients about pallia-tive care options, despite their demon-strated value.

Professionals such as lawyers are paid for their time spent speaking with and advising clients about estate planning, wills, and other end-of-life issues, and we accept that as common practice. But somehow policymakers feel that the very difficult and complex discussions doctors have with their patients surrounding their preferences and decisions for the future when di-agnosed with advanced cancer should not be paid for. This attitude does a disservice to doctors and their patients whose quality of life would be greatly enhanced by these conversations

Patients want and need informa-tion about optimal advance care plan-ning. Oncologists have a responsi-bility to provide that information to their patients, and they should be ap-propriately compensated for the time it requires to have those necessary conversations. That said, our position statements, educational efforts, and work in this important patient care area is going to continue, regardless of whether there is a specific compen-sation mechanism in place for these valuable services.

Caring for Patients with Incurable Disease

Key elements to individualizing advanced cancer care include the follow-ing considerations: Physicians should initiate frank discussions about prognosis with their pa-

tients soon after an advanced cancer diagnosis. Such conversations occur with less than 40% of patients.

Quality of life should be a priority throughout the course of advanced can-cer care. Physicians must help their patients fully understand their prognosis, the potential risks and benefits of available cancer treatments, and quality-of-life considerations. In cases where active treatment is unlikely to extend sur-vival, palliative care should be discussed as a concurrent or alternate therapy.

Clinical trial opportunities should be increased. Currently, very few patients with advanced cancer participate in trials because of strict eligibility criteria. Increasing opportunities for these patients to potentially benefit from trials and to contribute to improving cancer care should be a high priority.

Timely doctor-patient communication is essential to optimal care during this

difficult time.

Allen S. Lichter, MD

Policy


News

Neuroendocrine Tumorscontinued from page 1best supportive care, with crossover allowed upon progression. Median duration of exposure was 38 weeks for the active arm and 16 weeks for the placebo arm.

Median PFS was 11.0 months with everolimus and 4.6 months with placebo, for a highly significant 65% reduction in risk (P < .0001). The 18-month PFS rates were 34% and 9%, respectively, reported Manisha H. Shah, MD, of Ohio State Univer-sity Comprehensive Cancer Center in Columbus, Ohio.1

To control symptoms, 50% of pa-tients on each arm had prior soma-tostatin analog use, and 40% used these drugs concomitantly with study treatment. Prior or concomitant use of somatostatin analogs was not asso-ciated with any detriment in efficacy. Everolimus showed a consistent ben-efit in all subgroups regardless of the presence or absence of somatostatin analog treatment, she said.

Everolimus Plus Octreotide LAR

In RADIANT-2, which was con-ducted in 429 patients with advanced neuroendocrine tumors and a history of secretory symptoms, everolimus added to long-acting octreotide at 30 mg monthly demonstrated a clinical-ly meaningful prolongation of median PFS, according to James Yao, MD, of The University of Texas MD Ander-son Cancer Center, Houston.2

However, the 5.1-month prolonga-tion of median PFS (HR = 0.77; P = .026) did not reach statistical signifi-cance by central review, according to the prespecified P value (P = .0246).

The combination narrowly missed the prespecified boundary, he noted. By local assessment, the same risk re-duction was seen (HR = 0.78) but the P value was significant at P = .018.

According to Dr. Yao, the lack of statistical significance can be attribut-ed to the informative censoring, in which patients with progressive dis-ease per investigator but who are later judged to have nonprogressive disease on central review are informatively censored in the central PFS analysis due to a change in therapyand this can create bias. To correct for this, the RADIANT-2 investigators used an in-verse probability of censoring weights (IPCW) analysis. This produces a corrected treatment effect estimate that, in this case, became statistically significant, he said (Table 1).

In all three analyses the hazard ratios favor everolimus, and the pre-specified statistical analysis [inverse probability of censoring weights] adjusting for informative censor-ing, loss of power, and imbalances

in baseline prognostics factors dem-onstrate a consistent benefit, Dr. Yao reported.

Exploratory AnalysisIn an exploratory analysis, patients

without prior somatostatin analog use had greater absolute and relative ben-efits, he added. In this group, median PFS with the combination was 25.2 months compared with 13.6 months for long-acting octreotide alone; in patients with prior use of these agents, PFS was 14.3 vs 11.1 months, respectively.

The treatment was well tolerated, but more treatment-related adverse

events were seen in the everolimus arm, especially stomatitis, which oc-curred (all grades) in 62% of evero-limus patients vs 14% of placebo pa-tients with the single agent; grade 3 or 4 stomatitis was seen in 7% and 0%, respectively. Rash, fatigue, and diar-rhea were also greater with everoli-mus plus long-acting octreotide.

Financial Disclosure: Dr. Shah and Dr. Yao reported no potential conflicts of interest.

References1. Shah MH, Ito T, Lombard-Bohas

C, et al: Everolimus in patients with ad-vanced pancreatic neuroendocrine tu-

mors: Updated results of a randomized, double-blind, placebo-controlled mul-ticenter phase III trial (RADIANT-3). 2011 Gastrointestinal Cancers Sympo-sium. Abstract 158. Presented January 21, 2011.

2. Yao JC, Hainsworth JD, Baudin E, et al: Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors: Updated results of a random-ized, double-blind, placebo-controlled, multicenter phase III trial (RADI-ANT-2). 2011 Gastrointestinal Cancers Symposium. Abstract 159. Presented January 21, 2011.

Expert Point of View

Mary F. Mulcahy, MD, of Northwestern Uni-versity School of Medicine, Chicago, said that everolimus provided a significant and durable benefit in previously treated patients with pancre-atic neuroendocrine tumors. Dr. Mulcahy was a dis-cussant for the updated data from the RADIANT trials presented at this years Gastrointestinal Can-cers Symposium.

However, she had concerns about everoli-mus combined with long-acting octreotide in the broader neuroendocrine tumor population of

RADIANT-2. For the population studied, the benefit of everolimus with long-acting octreotide is undefined, and activity is demonstrated but is asso-ciated with significant adverse events, she said.

In particular, she questioned the large discrepancy in PFS by local assess-ment (12.0 months) vs central review (16.4 months). I think this tells us that PFS may not be the right endpoint for evaluating disease with secretory symptoms. The clinician may think the patient is progressing, and the patient would be censored, while by radiologic review the disease is actually stable, she pointed out.

Questionable Benefit Dr. Mulcahy noted that in the RADIANT-2 study 70% of the everolimus

arm came off study due to progressive disease or adverse events, compared with 75% on the placebo arm. The median duration and range of exposure to everolimus was comparable in each arm. Either way, this represents a fail-ure of treatment, she maintained. I have concerns about the drugs benefit. There is a signal, but it is not well-defined, she said.

She also noted that outcomes with the tyrosine kinase inhibitor sunitinib (Sutent) have been strikingly similar to those seen with everolimus, with nearly a 60% reduction in risk of progression as well. Future studies should determine how to sequence these classes of agents, she suggested.

Regarding tolerability, she agreed with the investigators that the study arms of both trials showed acceptable toxicity, with little grade 3 or 4 toxicity, but you cant discount grade 1 and 2, she added. This can be concerning when you treat for 11 months.

Financial Disclosure: Dr. Mulcahy reported no potential conflicts of interest.

Mary F. Mulcahy, MD

Table 1: RADIANT-2 Progression-free Survival ComparisonMedian PFS

Assessment Hazard Ratio P Value* Everolimus + OctreotidePlacebo +

Octreotide

Local (investigator) 0.78 .018 12.0 mo 8.6 mo

Central 0.77 .026 16.4 mo 11.3 mo

IPCW (central) 0.60 .0014 13.8 mo 8.3 mo*P value prespecified for statistical significance was P < .0246.IPCW = inverse probability of censoring weights; PFS = progression-free survival.

Gastrointestinal Cancers

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The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

CRI00102/280033-01 2011 Pfizer Inc. All rights reserved.


News

study until disease progression or un-til unacceptable toxicity.

Although the final results from BRIM3 are currently unknown, in a phase I trial PLX4032 provided an average remission of approximately 7 months from initiation of treat-ment. The longest responders have been taking the drug for 2 years. Paul Chapman, MD, Attending Physician in the Melanoma-Sarcoma Services Department, Memorial Sloan-Ket-tering Cancer Center, said This is the first-ever drug for melanoma that correlates improved survival with im-proved response rate. We had hoped this would happen, but we didnt know until we did the trial.

Adverse events for PLX4032 included keratoacanthoma, a rela-tively common, benign skin lesion, increases in liver enzymes, rash, pho-tosensitivity, joint pain, hair loss, and fatigue.

Dr. Flaherty believes that PLX4032 will receive accelerated approval this year or early in 2012. This is the next big thing, he said, and until it is improved upon, it will become the standard treatment for metastatic melanoma.

Dr. Chapman agreed. Its fantas-tic. Now we have something solid to build on. For the first time, we know the mechanism of action of a drug that improves survival, and although single-drug treatments are never the most effective, PLX4032 has given us a huge leg up in the search for a suc-cessful combination.

The Genetics of Melanoma Metastatic melanoma is associ-

ated with an average life expectancy of 8months after diagnosis. Not only are there few treatment options, there has been no significant improvement in treatment for 30 years. Moreover, the incidence is expected to double over the next decade.

About half of the 68,000 people di-agnosed every year have the BRAF mu-tation, which results in increased cell proliferation and apoptosis. PLX4032 is designed to selectively inhibit the mutated form of the BRAF protein and has been shown to significantly delay growth in tumors harboring the BRAF V600 mutation.

However, PLX4032 is not exempt from inevitable drug resistance. Ev-eryone develops resistance sooner or

later, said Dr. Flaherty.There might be a secondary muta-

tion in the BRAF gene that prevents binding, but resistance can occur even in its absence. Preliminary analyses of tumors collected from patients whose disease has progressed suggest some-thing other than mutations in BRAF. It may be other mutations and/or signal

transduction alterations or activation of a parallel signal pathway, said Dr. Flaherty.

Meenhard Herlyn, DVM, DSc, Leader, Molecular and Cellular On-cogenesis Program, Wistar Insti-tute, and his Wistar colleague, Jessie Villanueva, PhD, Staff Scientist, noted that even if inhibition of mutant

BRAF shuts down a major pathway, some cancer cells can use an alternate pathway and survive. Thus, resistant cells can reroute their signal around BRAF by switching to an alternate pro-tein that promotes tumor cell growth.

Combination therapies may over-come resistance. Drs. Herlyn and Vil-lanueva have developed a model that allows melanoma cells to grow in vitro to determine which are vulnerable to various drug combinations. They also found that tissue samples taken from patients in phase I and phase II trials both before treatment and after they developed resistance show that an in-creased expression of one particular receptor is associated with resistance to BRAF inhibitors. And they noted an association between the loss of the tu-mor suppressor PTEN and resistance to BRAF inhibitors in melanoma cell lines. In fact, the relapsed tumor of one patient lost the PTEN gene even though it was present before treatment, suggesting that loss of PTEN could be an additional path to resistance.

BRAF mutations are probably necessarybut insufficientto turn a cell into a melanoma, Dr. Chap-man added. There are still a lot of unknownsfor instance, why some patients with the BRAF mutation re-sponded to PLX4032 and some didnt. But, we are racing to understand the

mechanism of resistance and find oth-er agents to combine with PLX4032.

Drs. Flaherty and Chapman agreed that all patients with melanoma should be tested for the BRAF mutation and other genetic characteristics at diag-nosis, preferably as part of the original pathologic examination. To that end, a number of diagnostic tests have been developed, one of which is Roches co-bas 4800 BRAF V600 Mutation Test.

Whats Next for PLX4032?Dr. Flaherty believes that PLX4032

has blown the door off the barriers to therapeutic response to a melanoma drug. PLX4032 will be used as a step-ping stone to more trials with a variety of drug combinations, some perhaps with other MAP kinase pathway inhib-itors and some with compounds that affect other mutated pathways.

PLX4032 is available through an expanded-access program from Roche, since the drug is cur-rently investigational and not FDA ap-proved. Dr. Flaherty is a proponent of this and other expanded-access programs.

Were in the business of finding drugs to treat people, and when we find one, they should be given access, he said, but that doesnt mean that pa-tients with cancer should have access to any compound that comes down the pike. Its preposterous to give people an unproven drug. Thats the road back to the bad old snake oil days. But if theres a drug that works and is on its way to approval, then of course, patients should have it.

Financial Disclosure: Dr. Chapman reports serving as a consultant for Roche Pharmaceuticals. Dr. Flaherty reports serving as a consultant for GlaxoSmithKline and Roche Pharmaceuticals. Dr. Herlyn reported no potential conflict of interest. Dr. Turnham is an employee of the Melanoma Research Foundation. Dr. Villanueva reported no potential conflict of interest.

Reference1. Hodi FS, ODay SJ, McDermott DF,

et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.

Metastatic Melanomacontinued from page 3

Advocate Perspective

Timothy Turnham, PhD, Executive Director of the Melanoma Research Foundation in Washington, commented about PLX4032. The problem in withholding a drug such as PLX4032 is that it might be lifesavingor at least life-extending. Does this affect the way research is done? Probably, which is why we desperately need a series of conversations among FDA, pharma, and researchers. We have got to find a way to improve and speed up the pro-cess of drug research. It is now way too slow and way too costlyand patients are dying in the meantime.

SEE PAGE 47

Targeted Therapy

Visit The ASCO Post website at: ASCOPost.com

Paul Chapman, MD Meenhard Herlyn, DVM, DScKeith Flaherty, MD


OncologyWorldwide

The worldwide oncology commu-nity shares a common language based on evidence, clinical trials, and shared anecdotal results of the day-to-day care of patients with cancer. However, diverse political, economic, and cultural issues in different geo-graphic regions present varying chal-lenges to the delivery of oncology services. This column kicks off an ongoing series of articles, Oncology Worldwide, which will explore those similarities and differences on an oc-casional basis.

Hatem Azim, MD, an oncolo-gist from Cairo, Egypt, now working in Brussels, Belgium, recently spoke with The ASCO Post about his expe-rience as an international oncologist.

Career ChoicesWhy did you choose a career in oncology?In my last 2 years of medical

school, I was fortunate enough to

be offered an internship at the Uni-versity of Nebraska Medical Center (UNMC). I worked closely with experts in the field of lymphoma at the UNMC Eppley Institute for Re-search in Cancer and Allied Diseases and became impressed with the chal-lenges and potential in the field of hematologic malignancies, on the clinical as well as the research side. I believe my experience in the United States was a pivotal point in my deci-sion to become an oncologist. In ad-dition, observing the progress of my father, who is a successful Egyptian

oncologist, and being close to him on the personal level, unsurprisingly provided an extra nudge to seal my decision.

Cancer Care in EgyptYour career choice was influenced by

your experience in the United States, a country with vast resources. What chal-lenges did you face as a practicing on-cologist in Egypt?

In Cairo, I was working at the National Cancer Institute, which is

the largest cancer center in Egypt, seeing around 20,000 newly diag-nosed cancer cases per year. I was a resident in the Department of Medi-cal Oncology for 3 years; then I spent 1 year as an assistant lecturer. During this period, I faced several challenges that are endemic in the Egyptian can-cer care system, where the number of accumulated patients with cancer rep-resents about three times the amount of new patients, and the patient load is expanding.

Naturally, access to care in Egypt is an issue. We have extremely busy out-

patient clinics; at times, I used to see 40 to 50 patients a day! The demand on patient admissions always exceed-ed the available resources. That short-age was also true in chemotherapy, especially expensive drugs and newer targeted agents. Moreover, we lacked a systematic way of discussing cancer cases in the outpatient clinic, which was compounded by an absence of multidisciplinary meetings and tu-mor boards.

Because of a number of cultural awareness and barriers-to-access is-sues, Egyptian patients with cancer usually present at a relatively ad-vanced stage in their disease, which has a negative impact on treatment results. Adding to that dilemma, pa-tients also face long waiting lists to get basic radiologic and other diagnostic examinations, presenting significant delays in treatment initiation.

Policy ProblemsHow does the political machine in

Egypt affect cancer care?Health-care policies as they per-

tain to managing patients with cancer were very poorly addressed at the time I was practicing oncology in Egypt.

When someone is diagnosed with cancer, it takes their insurance pro-vider an inordinate amount of time to cover health costs, and in most cases, the coverage did not exceed 20% to 30% of the patients real costs.

This situation forces patients to start and stop therapy until they can sort out the problem with the insur-ance carrier. Consequently, we spent a lot of time writing reports for pa-tients, requesting increased coverage from their insurance provider. This compromises the quality of medi-cal care patients receive and places a huge administrative burden on pro-viders. It is a major barrier to the de-livery of cancer care, especially since many patients in Egypt are resource-challenged.

On to BrusselsYou are currently in Brussels. Could

you briefly explain your work there?I moved to Brussels in 2009 to

work as a fellow in the Department of Medical Oncology at Institut Jules Bordet, working exclusively in the field of breast cancer. My main task was acting as a medical advisor for large, international phase III clinical trials conducted by the Breast Inter-national Group (BIG). In addition, I was involved in writing, discuss-ing, and developing new clinical and translational research protocols in breast cancer.

At the same time, I was enrolled in the PhD program of the Universit Libre de Bruxelles. In 2010, I earned a transla-tional research grant from the European Society for Medical Oncology (ESMO) and moved to the Breast Cancer Transla-tional Research Laboratory in the same institute. There I am developing my PhD project on the biology and prognosis of breast cancer diagnosed during pregnan-cy, using gene expression profiling, while continuing to do my clinical research work as well.

U.S. vs European PracticeWhat about the European oncology

experience is different from how oncol-ogy is practiced in the United States?

From Cairo to Brussels: An International Perspective Hatem Azim, MD, discusses cancer care abroad.By Ronald Piana

Egyptian Cancer Epidemiology at a Glance

There is no population-based cancer registry in Egypt; however, based on hospital-based registries, the leading cancers in Egypt are those of the urinary bladder (32.67%), gastrointestinal tract (22.24%), and breast (13.15%),followed by lymphoma (9.8%). Egyptian patients have some fea-tures in common with those observed in developed countries, including a high incidence of breast and gastrointestinal cancers.

Currently, the most distinct cancer patterns in Egypt are liver cancer sec-ondary to endemic hepatitis C virus (around 15% of the population) and mesothelioma due to the wide use of asbestos in the local industry. Bladder cancer secondary to schistosomiasis was common in Egypt over the past 2 to 3 decades, but with the proper treatment of schistosomiasis, the inci-dence of bladder squamous cell carcinoma secondary to this disease is sig-nificantly declining.

Hatem Azim, MD


Because of a number of cultural awareness and barriers-to-access issues, Egyptian patients

with cancer usually present at a relatively advanced stage in their disease.


Oncology Worldwide

I have worked in two large can-cer institutes in Europe: the Euro-pean Institute of Oncology in Milan (2008) and where I now work, the Institut Jules Bordet in Brussels. I also had the opportunity to visit

From Cairo to Brusselscontinued from page 17

a couple of cancer centers in the United Statesthe University of Nebraska Medical Center and Beth Israel Deaconess Teaching Hospital in Boston. In my opinion, the qual-ity of cancer care is actually quite comparable in the United States and Europe.

In my experience at various insti-tutes, I did not witness significant differences in the quality of the mul-tidisciplinary discussions. Likewise, I found a universal appreciation of the importance of conducting high-quality research that translates into clinical benefits. Any differences in

approach between Europe and the United States might be determined more by cultural and political envi-ronments, but I found the quality of research and cancer care to be on the same level.

Financial Disclosure: Dr. Azim reported no potential conflicts of interest.

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TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles

TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176)

The most common non-hematologic adverse reactions (frequency 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency 15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkins lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Selected Safety Information Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis,

tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur

Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA

TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

TREANDA is his chemo. This is his therapy.

* Overall response rate (ORR) was de ned as a best response of a complete response (CR), uncon rmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modi ed International Working Group response criteria (IWG-RC). Modi cations to IWG-RC speci ed that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be 20 mm.

CI=confi dence interval.

Patients responding (%)

(n=57)

(n=17)

0 20 40 60 80 100

ORR*: INDOLENT B-CELL NON-HODGKINS LYMPHOMA (NHL) THAT HAS PROGRESSED

PR

CR/CRu 17%

57%74%Total ORR

(95% CI: 64.3, 82.3)

2011 Cephalon, Inc. All rights reserved. TRE-2216 January 2011 Printed in USA.

Discover the elements of effi cacy and safety

Built for Action

LEARN MORE AT TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

Single-agent TREANDA produced a 74% ORR* in patients with indolent B-cell NHL that had progressed

S:14.5

S:10

T:15.5

T:10.5

B:17.25

B:11.125

F:7.75

FS:7

F:7.75

FS:7

I0574_NHL_JA.indd 1 3/1/11 1:30 PM


FDA Update

The FDA recently ap-proved vandetanib, a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid can-cer in patients with unresectable, local-

ly advanced, or metastatic disease. The use of van-detanib in patients with indolent, asymptomatic,

or slowly progressing disease should be carefully considered because of the

treatment-related risks of vandetanib.The approval was based on an

international, multicenter, random-ized, double-blind trial conducted in patients with unresectable locally advanced or metastatic medullary

thyroid carcinoma. Patients were ran-domly assigned (2:1) to receive either vandetanib, 300mg/d orally, (n = 231) or placebo (n = 100). The primary ob-jective was demonstration of improve-

Vandetanib Approved for Medullary Thyroid Cancer


DRAFT FCB HealthCareFile Name: 10574_NHL_JA.inddLocation: PrePressClient: CEPHALONProduct: TREANDAJob #: 2CEP-TREA-I0574Live Area: 7"W x 10"H EACHSmall Trim: 7.75W x 10.5H EACHBleed: 17.25W x 11.125H Gutter: .25 EACH SIDE OF GUTTERColors: 4C

CAD RouterArt Director: Ella (x3506)

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SIGN-OFF Date Time OK Correx QueryStudio ManagerTraffi cVisual QCEditorCopywriterCopy SupervisorArt DirectorArt SupervisorAcct. ExecutiveAcct. ExecutiveProduction

COMMENTSROB RELEASES AS PDFX1A.2/7/11 Corrections, split PI off into a new single-page setup, corrections PL

FILE 1 of 2

TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles

TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176)

The most common non-hematologic adverse reactions (frequency 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency 15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkins lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Selected Safety Information Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis,

tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur

Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA

TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

TREANDA is his chemo. This is his therapy.

* Overall response rate (ORR) was de ned as a best response of a complete response (CR), uncon rmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modi ed International Working Group response criteria (IWG-RC). Modi cations to IWG-RC speci ed that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be 20 mm.

CI=confi dence interval.

Patients responding (%)

(n=57)

(n=17)

0 20 40 60 80 100

ORR*: INDOLENT B-CELL NON-HODGKINS LYMPHOMA (NHL) THAT HAS PROGRESSED

PR

CR/CRu 17%

57%74%Total ORR

(95% CI: 64.3, 82.3)

2011 Cephalon, Inc. All rights reserved. TRE-2216 January 2011 Printed in USA.

Discover the elements of effi cacy and safety

Built for Action

LEARN MORE AT TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

Single-agent TREANDA produced a 74% ORR* in patients with indolent B-cell NHL that had progressed

S:14.5

S:10

T:15.5

T:10.5

B:17.25

B:11.125

F:7.75

FS:7

F:7.75

FS:7

I0574_NHL_JA.indd 1 3/1/11 1:30 PM


FDA Update

in the assessment of progression-free survival and objective response rate. Upon objective disease progression, patients were given the option of re-ceiving open-label vandetanib.

Key DataAn improvement in progression-

ment in progression-free survival with vandetanib compared to placebo. Oth-er endpoints included evaluation of overall survival and objective response rate. A central, independent blinded review of the imaging data was used

Thyroid Cancercontinued from page 19

free survival was observed for patients randomly assigned to receive vande-tanib (HR = 0.35; 95% CI = 0.240.53; P < .0001). Analyses in the sub-groups who were either symptomatic or who had disease progression within 6 months prior to enrollment showed similar progression-free survival re-

sults: hazard ratios of 0.31 (95% CI = 0.190.53) and 0.41 (95% CI = 0.250.66), respectively. At the primary progression-free survival analysis, 15% of the patients had died; no significant overall survival difference was noted. The objective response rate was 44% vs 1% for patients randomized to receive vandetanib or placebo, respectively. All objective responses were partial re-sponses.

QT prolongation, torsades de pointes, and sudden death are in-cluded in a boxed warning. Because of vandetanibs prolonged half-life of 19 days, ECGs and levels of serum potas-sium, calcium, magnesium, and TSH should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after start-ing treatment, and subsequently every 3 months. Electrolytes and ECGs may require more frequent monitoring in patients experiencing diarrhea. Only prescribers and pharmacies certified through the Vandetanib Risk Evalua-tion Mitigation Strategy Program, a re-stricted distribution program, are able to prescribe and dispense vandetanib.

Adverse EffectsThe most common ( 20%) grade

14 adverse reactions included diar-rhea/colitis, rash, dermatitis acne-iform, nausea, hypertension, head-ache, fatigue, decreased appetite, and abdominal pain. Laboratory abnor-malities in > 20% of patients included decreased calcium, increased ALT, and decreased glucose. The most common ( 5%) grade 3/4 adverse reactions were diarrhea/colitis, hypertension and hypertensive crisis, QT prolon-gation, fatigue, and rash. Adverse re-actions resulting in death in patients receiving vandetanib (n = 5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. In addi-tion, two deaths in patients receiving vandetanib (one sudden death and one death from cardiopulmonary arrest) were noted after data cutoff.

Vandetanibs approval underscores FDAs commitment to approving treat-ments for patients with rare and dif-ficult to treat diseases, said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDAs Center for Drug Evaluation and Re-search.

Vandetanib is marketed by Astra-Zeneca Pharmaceuticals LP of Wilm-ington, Delaware. There is no trade name established for the drug at this time.

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkins Lymphoma That Has ProgressedINDICATIONS AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkins lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be 1 x 109/L and the platelet count should be 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm wh

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