TAP Vol 5 Issue 18

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

ESMO Congress

The treatment of acute promyelocytic leu-kemia (APL) represents one of the major triumphs in the field of hematologic malig-nancies. With either the vitamin A derivative all-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy or ATRA plus arsenic trioxide (Trisenox), approximately 85% to 90% of all patients can be cured of their disease if they survive induction therapy. Re-lapse after complete remission is achieved has become very uncommon even among high-risk patients (those with a presenting white blood cell count > 10,000/L).

Such success is due to the convergence of

The Next-to-Last Frontier in Managing Acute Promyelocytic

Leukemia

By Martin S. Tallman, MD

Oncology Meetings CoverageESMO 1, 42-47, 51-55, 64-67, 71-76Quality Care Symposium 3-5, 8-9Best of ASCO 14-15, 24-26Breast Cancer Symposium 30, 34

Jeremy S. Abramson, MD, on Indolent Lymphoma 27Direct From ASCO 78-81Andreas du Bois, MD, PhD, on Pazopanib in Ovarian Cancer 106Margaret Tempero, MD, on Pancreatic Cancer in 2014 120Hansjochen Wilke, MD, on Ramucirumab in Gastric Cancer 155

MORE IN THIS ISSUE

continued on page 175

Perspective

IMPRESS Trial: Lung Cancer Progression on First-Line Tyrosine Kinase Inhibitor Indicates the Drug Should Be StoppedBy Alice Goodman

The IMPRESS trial found no benefit for continu-ing treatment with the epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor gefitinib (Iressa, discontinued in the United States) plus che-motherapy vs chemotherapy alone in patients with EGFR-mutated nonsmall cell lung cancer (NSCLC) who had disease progression on treatment with gefi-tinib. Progression was defined according to RECIST criteria in the IMPRESS trial, and not by clinical symptoms or metastatic spread.

Hotly Debated IssueThis study resolves a hotly debated issue, and

the results demonstrated that EGFR tyrosine kinase inhibitors should not be continued beyond progres-sion. The standard treatment at progression remains platinum-based chemotherapy, stated lead author Tony S.K. Mok, MD, Professor of Clinical Oncology

at the Chinese University of Hong Kong, and the Eu-ropean Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1

EGFR tyrosine kinase inhibitors are the standard first-line treatment for pa-tients with EGFR-positive NSCLC. Gefitinib is the EGFR tyrosine kinase inhibitor of choice in Asia and Europe, whereas erlotinib is used in the United States.

Most patients who initially respond to first-line therapy with an EGFR tyrosine kinase inhibitor expe-rience disease progression with acquired resistance. At that time, there are two options: to discontinue the EGFR tyrosine kinase inhibitor or to continue it and

Tony S.K. Mok, MD

Boom in Bilateral Mastectomies 103 | Sexual Concerns in Cancer Survivors 126 | BRAF/MEK Inhibition in Melanoma 148 VOLUME 5, ISSUE 18NOVEMBER 15, 2014



My main goal for writing the article was to start a conversation about the importance of quality rather than quantity of life, but Im very comfortable with lots of people not agreeing with my view.

Ezekiel J. Emanuel, MD, PhD

Dr. Tallman is Chief of the Leukemia Service at Memo-rial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College in New York.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

A Harborside Press PublicationNovember is Pancreatic Cancer and Lung Cancer Awareness Month

Striving for Quality, Not Quantity, of LifeA Conversation With Ezekiel J. Emanuel, MD, PhDBy Jo Cavallo

Advances in science and medicine have led to humans living longer than at any other time in history. According to a new report1 on mortality from the Centers for Disease Control and Preventions Na-tional Center for Health Statistics, life expectancy in the United States is at an all-time high of 78.8 years, up 0.1 year since 2011. Good news, America: Were living longer! read the opening line in a story in USA Today2 announcing the reports findings.

But those extra years do not necessarily add up

to quality ones. Advances in health care have not so much slowed the aging process as they have the dy-ing process, contends Ezekiel J. Emanuel, MD, PhD, Chair, Medical Ethics & Health Policy at the Univer-sity of Pennsylvania in Philadelphia, in an essay he penned in the October issue of The Atlantic.3

Titled Why I Hope to Die at 75, the article has set off a firestorm of controversy, including accusations by critics that Dr. Emanuel is advocating health-care rationing, death panels, and even legalized euthanasia

for people living beyond 75, none of which is true.

Instead, Dr. Emanuel writes about his personal preference to refrain from taking life-sustaining medi-cal steps once he reaches 75.

While it is doubtless that death is a loss, liv-ing too long is also a loss, wrote Dr. Emanuel. It

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Associate EditorsJame Abraham, MD Cleveland Clinic

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Laurence H. Baker, DO University of Michigan Health System

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

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

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

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John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Moffitt Cancer Center

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Hagop M. Kantarjian, MD MD Anderson Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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

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Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Steven T. Rosen, MD City of Hope National Medical Center

Lee S. Schwartzberg, MD University of Tennessee Health Science Center

Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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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

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ASCOPost.com | NOVEMBER 15, 2014 PAGE 3

Quality Care Symposium

Overutilization a Key Target in Efforts to Control Health-Care CostsBy Alice Goodman

O verutilization of health-care in-terventions has become a prime target of efforts to rein in health-care costs. Overtreatment of cancer patients is associated with a number of common harms to the patientnot just financial harm to the health-care system. At the recent ASCO Quality Care Symposium

in Boston, Lisa K. Hicks, MD, MSc, a staff physician at St. Michaels Hospital and Assistant Professor of Medicine at University of Toronto, discussed driv-ers of overtreatment, gave an example from her practice, and listed common harmful effects.1

In 2012, an Institute of Medicine report called for better care at lower cost.2 The re-port estimated that $750billion were wast-ed each year and attributed $210billion of these dollars to unnecessary care.

The patient should be foremost in our thinking. Consider the harms and benefits of treatment, and if the harms

outweigh the benefits, the treatment should not be prescribed, Dr. Hicks told the audience.

Multiple Causative FactorsEmanuel and Fuchs were the first

to describe a perfect storm that cre-

ates overutilization.3 The medical cul-ture emphasizes data and thoroughness and is uncomfortable with uncertainty. Many physicians practice defensive medicine, Dr. Hicks continued.

Overutilization is driven by cultural, medical, financial, and social factors. They include an emphasis on diligence and exhaustive testing, financial incen-tives that encourage doing over ob-serving, rapid pace of science and so-phisticated marketing, using high tech because reimbursement is higher, rapid pace of medical science and sophisticat-ed marketing, and direct-to-consumer marketing.

Overtreatment occurs in four differ-ent settings: screening, investigations, treatment, and physician visits.

Patients receive fragmented care delivery, and their needs are often mis-aligned with resources. Quality metrics are needed, as are guidelines, but most guidelines focus on what to do, not on what not to do, she emphasized.

Dr. Hicks commended the Choos-ing Wisely campaign for getting the

buy-in from various medical societ-ies to list five tests or procedures each year that should not be routinely used. ASCO, the American Society of Hema-tology, the American Society for Radia-tion Oncology, and other medical soci-eties are participating in this campaign, she said.

Overutilization can cause patient harms, she continued.

Cascade of EffectsDr. Hicks gave listeners an example

from her own practice. A 30-year-old male patient was treated for mediasti-nal diffuse large B-cell lymphoma and achieved remission. Two years later, he had a slight increase in residual mass on a surveillance computed tomography (CT) scan, but otherwise he was feeling well and his lab tests were all normal.

I was worried so I ordered a [pos-itron-emission tomography] scan and hoped for a normal result, but the find-ings were indeterminate. We elected to observe him, and he had a scan

Choosing Wildly: A Patients Perspective on Overtreatment and Quality CareBy Ronald Piana

Over the past decade, there has been growing concern in the on-cology community about overdiagno-sis and overtreatment of cancers that prove to be indolent and nonlethal, re-sulting in unnecessary and sometimes harmful procedures. At this years ASCO Quality Care Symposium in Boston, this important issue was tack-led from the patients perspective, by cancer survivor and nationally regard-ed patient advocate Ellen L. Stovall in a presentation subtitled Health Policy in an Era of Choosing Wildly Wisely.1

Wild West of Cancer Ms. Stovall, who is Senior Health

Policy Advisor at the National Coali-tion for Cancer Survivorship (NCCS), said that she was originally asked to speak about the Choosing Wisely pro-gram from the patients perspective, but she featured the substitution of wisely for wildly in her title, explaining, I think that the way cancer care has been delivered historically is more like the Wild West than the wise way we

would like to think that patients are choosing the care they would like to receive.

Ms. Stovall noted that her organi-

zations central goal is to help foster a cancer care system that is evidence-based, quality-focused, and affordable and accessible to all. After that, were addressing World Peace, she joked.

The Choosing Wisely campaign,

as we see it from the patient advocacy view, is mainly geared toward physi-cians, and many in our community question whether Choosing Wisely is

designed to do less in all circumstanc-es regarding cancer treatment, noted Ms. Stovall. She emphasized that from a patients perspective it is difficult to parse out the underlying messages of campaigns like Choosing Wisely that

are designed to address overuse and also maintain high-quality care.

Personalize Patient Information

Ms. Stovall cited a recent article in The New England Journal of Medicine, in which the author noted that the Choosing Wisely campaign had part-nered with Consumer Reports to create educational materials for patients on low-value care, presenting accessible in-formation on specific health services.2 Patient-information and decision-aid approaches are promising, but their cre-ation and use need to be supported and studied, stressed Ms. Stovall.

Within the context of Choosing Wisely, Ms. Stovall focused her attention on the delivery of high-quality cancer care, citing the 2013 Institute of Medi-cine (IOM) report, Delivering High-Quality Cancer Care: Charting a Course for a System in Crisis.3 The recommenda-tion from the IOM report that weve tak-en to heart is that the cancer care team

Health-Care Policy

Issues in Oncology

continued on page 4

continued on page 4

Physicians need to be honest and have a frank conversation with their patients, starting with explaining whether their cancer is curable or incurable, and what the available options are. This lays the groundwork for a shared decision-making conversation that addresses the patients needs and values moving forward.

Ellen L. Stovall

Doing unnecessary tests and giving unnecessary treatment create a cascade of effects.

Lisa K. Hicks, MD, MSc



6weeks later with the same result. But he was so anxious and had chest pain, so we went on to biopsy. The good news is there was no cancer and he had reactive tissue. He is currently in remission, but he has a secondary di-agnosis now of anxiety disorder with panic attacks. I think our testing may have worsened existing anxiety, and it may have precipitated panic attacks, she acknowledged.

Other harms of additional imaging studies include increased risk of second-ary cancers (estimated at 0.05% lifetime per CT scan for a 30-year-old man), risks of general anesthesia, discomfort, lost time, and worsened anxiety leading to fi-nancial hardship.

Types of harm from overtreatment in-

clude adverse events, direct and indirect financial harm, psychological distress, so-cial stigma, lost time (not just work, but sitting in waiting rooms), and incidental findings that lead to further investiga-tions, each of which carries a risk of ad-verse events.

Dr. Hicks cited a meta-analysis showing that 30% of CT scans pick up incidental findings,4 and this is likely to be higher among cancer patients, Dr. Hicks said.

Doing unnecessary tests and giving unnecessary treatment create a cascade of effects, she noted.

I challenge you, when you go back home, to identify examples of overuti-lization in your own practice/hospi-tal/provider community. Think about whether there is one test or procedure you could act on immediately. I sus-

pect you will have no difficultly com-ing up with a long list. Try to change one thing that week, that day, she en-couraged listeners. n

Disclosure: Dr. Hicks reported no potential conflicts of interest.

References1. Hicks LK: Harms of care (over-

treatment) and quality implications. ASCO Quality Care Symposium. Pre-sented October 17, 2014.

2. Institute of Medicine: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Wash-ington, DC, National Academies Press, September 6, 2012.

3. Emanuel EJ, Fuchs VR: The per-fect storm of overutilization. JAMA 299:2789-2791, 2008.

4. Lumbreras B, Donat L, Hernndez-Aguado I: Incidental findings in imaging diagnostic tests: A systematic review. Br J Radiol 83:276-289, 2010.

Overutilization a Key Targetcontinued from page 3

should communicate and personalize all the information for their patients at key decision points along the continuum of care, using decision aids when available, said Ms. Stovall, adding, We also agree with the reports recommendation that physicians should collaborate with their patients to develop a care plan that re-flects their patients needs, values, and preferences and considers palliative and psychosocial support throughout the full course of care.

Cancer Care PlanningShe then turned her focus to the

NCCS perspective. At NCCS, our main focus is on cancer care planning, both in the delivery of care and on pay-ment reforms. We look at this in four buckets: the patient, reimbursement, providers, and our central goal, which is cancer care planning at diagnosis and major transition points during treat-ment and survivorship, she explained.

Ms. Stovall said that the delivery and payment reforms that are essential to at-taining quality improvement in cancer care need to begin by changing the con-versation. Physicians need to be hon-est and have a frank conversation with their patients, starting with explaining whether their cancer is curable or incur-able, and what the available options are.

This lays the groundwork for a shared decision-making conversation that ad-dresses the patients needs and values moving forward, she noted.

On the subject of payment reforms, Ms. Stovall noted that payment reforms must be aligned to reflect improvement in communication, treatment deci-sion-making, symptom management, and coordination of care. The Center for Medicare & Medicare Innovation (CMMI) care model is the main focus of NCCS payment reforms. The cur-rent proposal by CMMI looks at low-ering costs using a three-part payment structure reform and quality metrics intended for determining performance payments, said Ms. Stovall.

Uphill BattleWeve also had a legislative pro-

posal moving through six sessions of Congress that ASCO and many other cancer and patient advocacy organiza-tions have supported. Moreover, weve worked with the main private payers and with ASCO and the Center for American Progress on payment re-form, said Ms. Stovall.

She then enumerated the NCCS principles for payment reform, stating that any alternative payment system must: (1) include protections against underutilization or overutilization, (2) incorporate outcome, process, and

patient-reported outcome measures, developed with input from patients, (3) ensure that therapeutic innovations will be rapidly incorporated into standard of care, and (4) reimburse for coordi-nation of care, from screening through survivorship.

Summing up the challenges to en-hancing quality care while also address-ing payment reforms, such as those she previously discussed from the IOM re-port, Ms. Stovall said, Having worked with the IOM over the past 15 years, I can say from experience that putting out proposals, supporting quality care and reform legislation, and at the same time helping patients choose wiselywell, it is a tough nut to crack.

Beyond Choosing WiselyMs. Stovall stated that the goal of

NCCS and other advocacy groups is to get beyond Choosing Wisely and the narrow range of issues that it lays out for physicians and their patients to consider.

Matters related to overtreatment and undertreatment need to be ad-dressed. Equally important, cost and value of interventions must be made transparent and factored into the doctor-patient discussion about their care. And along with a frank conversa-tion about diagnosis and prognosis, patients fears about restricted access to costly treatment must be addressed

when choosing which therapies are best suited to support their agreed-to goals of treatment, she concluded. n

Disclosure: Ms. Stovall reported no potential conflicts of interest.

References1. Stovall E: Patient perspective on over-

treatment: Health policy in an era of choos-ing wildly wisely. ASCO Quality Care Sym-posium. Presented October 17, 2014.

2. Colla CH: Swimming against the cur-rentWhat might work to reduce low-value care? N Engl J Med 371:1280-1283, 2014.

3. Levit L, Balogh E, Nass S, et al (eds): Delivering High-Quality Cancer Care: Charting a Course for a System in Crisis. Washington, DC, National Academies Press, 2013.

Overutilization in Oncology

Cultural, medical, financial, and social factors have converged to create a perfect storm of overutilization of health-care interventions.

Overutilization causes patient and financial harms.

Oncologists should follow the Choosing Wisely recommendations for cancer care and identify and reduce overutilization in their own practices.

Choosing Wildlycontinued from page 3

Choosing Wisely Campaign

ASCO participates in the Choosing Wisely Campaign, which is an ini-tiative of the American Board of Internal Medicine Foundation intended to spark conversations between providers and patients, to ensure that the right care is de-livered at the right time. ASCOs annually updated Top Five List of things physicians and patients should question is available at www.asco.org/practice-research/top-five-list.

Coming Next MonthCoverage of the 2014 Palliative Care in Oncology Symposium, Boston



The Silver Oncologic Tsunami: Rise in Elderly Cancer Patients Brings New Challenges to Oncology Workforce By Alice Goodman

The graying of America poses in-creasing challenges for the cancer community in terms of rising numbers of cases of cancer and costs associated with geriatric care. The scope of this problem and potential solutions were explored by Andrew E. Chapman, DO, FACP, at the ASCO Quality Care Symposium in Boston.1 Dr. Chapman is Director of Regional Cancer Care and Co-Director of the Jefferson Se-nior Adult Oncology Center at the Sidney Kimmel Cancer Center, Thom-as Jefferson University, Philadelphia.

Aging and CancerThe silver oncologic tsunami is

coming. Demographics drive the is-sues. Cancer is a disease associated with aging, he said. Factors associat-ed with agingtelomere shortening, telomerase activity, chronic inflamma-tion, DNA instability, and loss of im-

mune surveillanceare also thought to be implicated in cancer.

Geriatric patients have a high dis-ease burden, he continued. Sixty per-cent of all cancers occur in people aged 65 or older, and 69% of cancer-related deaths occur in the same age group.2,3 The exploding population of elderly people coupled with the rising costs of cancer care and the fragmentation of delivery of complex geriatric care cre-ates a perfect storm.

To address this, we have developed an urgent to-do list with some basic goals, Dr. Chapman said. They include

empowering the health-care workforce to improve health-care delivery in the geriatric setting, develop health-care delivery models focused on the elder-ly, develop oncology-based relevant data sets, and establish new standards of care to be able to implement the data and modeling in clinical practice.

Workforce IssuesOver the next 15 years, even with

nurse practitioners and physician as-sistants, there is a projected shortage of practitioners. On top of that, there are inadequate numbers of geriatri-cians. In 2030, there will be one geri-atrician for every 4,000 persons aged 75 and older, he said.2,3

Empowering the workforce entails recognizing the needs of elderly patients. Geriatric patients pose unique challeng-es in terms of comorbidities, nutritional status, cognitive impairment, geriatric

syndromes, polypharmacy, psychologi-cal status, and social support.

These issues are not commonly encountered in younger adult popula-tions and raise major risks, Dr. Chap-man noted. Data are limited from clinical trials on management of el-derly cancer patients. There are risks of overtreatment and undertreatment due to inadequate assessment of cog-nitive and functional status, he added.

The health-care community needs to develop core competencies geared to-ward treating elderly patients and incor-porate those into health-care training

and education. New models are needed to promote team-based care coordina-tion, he continued. Possible ways to im-prove delivery of care include funding the National Workflow Commission and eliminating reimbursement barri-ers to team-based care (ie, the siloing of care and payment models).

Patient InvolvementThe development of deeper data sets

is another goal. We want to give el-derly patients the treatment they need and want. They need to be enrolled in clinical trials, and this may require in-centives for pharmaceutical companies to do these trials. One way to do this could be to lengthen drug patents so that compounds can be studied in aging populations, he suggested.

Elderly patients should be engaged in the process of developing new stan-dards of care based on their needs, values, and preferences, Dr. Chapman said. Communication with patients should rely on giving understandable, relevant, and evidence-based informa-tion. Development of decision aids would be helpful, but this must be done in collaboration with patients and palliative care experts, he said.

End-of-life care is a critical area that needs to be addressed. Earlier palliative care is needed. End-of-life care should be a new standard. We should get these discussions out on the table early in the course of care for patients and families, emphasizing palliative care early on,

he contended. We need to create pay-ment models for these discussions.

He added, We can improve care of the elderly if we right-size the care, make it coordinated, meet patients val-ues and preferences, provide early pal-liative care and psychosocial support, and refer them to hospice in a timely manner. We need studies of drugs in the elderly, Medicare to negotiate drug pricing, and efficient coordinated health-care delivery system models.

Dr. Chapman concluded with a call to action for addressing cancer care in geriatric patients. A new battle is emerging in this war on cancer, with significant moral, ethical, and financial implications. It is a battle we cannot afford to lose. We need your help, he told the audience. n

Disclosure: Dr. Chapman reported no potential conflicts of interest.

References1. Chapman AE: Healthcare delivery

in senior adult oncology patients. ASCO Quality Care Symposium. Presented Oc-tober 17, 2014.

2. Levit LA, Balogh EP, Nass SJ, et al: Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Institute of Medicine, National Academies Press, Washington, DC, 2014.

3. Hurria A, Naylor M, Cohen HJ: Im-proving the quality of cancer care in an ag-ing population: Recommendations from an IOM report. JAMA 310:1795-1796, 2013.

Geriatric Oncology

Earlier palliative care is needed. End-of-life care should be a new standard. We should get these discussions out on the table early in the course of care for patients and families.

Andrew E. Chapman, DO, FACP

Geriatric Cancer Care

The elderly population is increasing and will continue to do so over the next decades, leading to increasing numbers of elderly cancer patients; a workforce shortage will make it difficult to deal with this onslaught.

To meet the challenges of geriatric cancer care, the health-care community needs to address several critical issues, including workforce inadequacies, the need for deeper data on elderly patients from clinical trials, collaboration with patients and palliative care experts to develop models, and establishment of new standards of care.

Visit The ASCO Post website at ASCOPost.com

ONCUS14UB00597-02-01 Trim Size: 10.5 x 14

2014 Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB00597-02-01 04/14 Printed in USA.

References: 1. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 2. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 3. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 5. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 7. Trapani JA, Smyth MJ. Functional signifi cance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735-747. 8. Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells.Blood. 2008;111(7):3635-3643. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

PD-1=programmed death 1; PD-L1=PD-1 ligand 1; PD-L2=PD-1 ligand 2.

Through tumor immune evasion, tumors can convert active T cells to inactive T cells through the PD-1 checkpoint pathway to inhibit normal immune response1-3,8

In some cancers, tumor cells express PD-L1 and/or PD-L2. Either of these ligands can bind to the PD-1 receptors on T cells to exploit the immune checkpoint pathway1-3,8,9

Binding of the PD-1 receptor on T cells to either PD-L1 or PD-L2 ligands on tumor cells can inhibit activated T cells, suppressing T-cell attack and negatively regulating immune response1-3,8,9

Tumor Immune Evasion

Normal State

Tumor

Apoptosis-inducing proteins

In a normal state, the immune system recognizes tumors and can mount an active antitumor response4,5

Tumors release antigens that are collected by circulating antigen-presenting cells6

Antigen-presenting cells activate T cells that proliferate and migrate to the tumor. T cells then release apoptosis-inducing proteins, which attack tumor cells6,7

The PD-1 checkpoint pathway plays a key, distinct role in modulating the immune system1-3

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity1-3,8

In the research of advanced cancers

What if inhibiting the PD-1 checkpoint pathway helped restore immune response to tumor cells?

The PD-1 immune checkpoint pathway: an innovative target for cancer research By exploiting the PD-1 immune checkpoint pathway, cancer cells can evade the normal immune response and continue to proliferate1-3,8

Understanding the PD-1 pathway has the potential to change the way we approach certain cancers

Through tumor immune evasionThrough tumor immune evasion, tumors can convert active T cells to inactive T cells through the PD-1 checkpoint pathway to inhibit normal immune response1-3,8

PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity

Tumor

Inactive T cells

Antigen-presenting cell

Active T cells

Antigens

Tumor cell

Inhibited T cell

PD-L1ligand

PD-L2ligand

PD-1receptor

PD-1receptor

Bristol-Myers Squibb is researching ways of inhibiting the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands, allowing the immune system to restore T-cell attack on tumor cells, which may play a role in helping the body fight cancer3,10

Normal State

Tumor Immune EvasionTumor Immune Evasion Antigen-presenting cell

Antigen-presenting cell

Antigens

Active T cells

14150706_0059702_MOP_Ad_ASCO_10_5x14_v2_M.indd 1 4/17/14 12:12 PM

2014 Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB00597-02-01 04/14 Printed in USA.

References: 1. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 2. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 3. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 5. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 7. Trapani JA, Smyth MJ. Functional signifi cance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735-747. 8. Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells.Blood. 2008;111(7):3635-3643. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

PD-1=programmed death 1; PD-L1=PD-1 ligand 1; PD-L2=PD-1 ligand 2.

Learn more at www.pd1pathway.com Experience the PD-1 checkpoint pathway through an immersive video Hear a leading oncologist answer questions about the PD-1 checkpoint pathway Learn more about how Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity1-3,8

What if inhibiting the PD-1 checkpoint pathway helped restore immune response to tumor cells?

The PD-1 immune checkpoint pathway: an innovative target for cancer research By exploiting the PD-1 immune checkpoint pathway, cancer cells can evade the normal immune response and continue to proliferate1-3,8

Understanding the PD-1 pathway has the potential to change the way we approach certain cancers

Bristol-Myers Squibb is researching ways of inhibiting the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands, allowing the immune system to restore T-cell attack on tumor cells, which may play a role in helping the body fight cancer3,10

Active T cell

PD-L1 ligand

PD-L2 ligand PD-1 receptor

X

X

X

X

Tumor

Apoptosis-inducing proteins

14150706_0059702_MOP_Ad_ASCO_10_5x14_v2_M.indd 2 4/17/14 12:12 PM


Quality Care SymposiumCost of Care

Financial Toxicity in Cancer Care

Costs of cancer care have spiraled out of control, and financial stress can adversely affect patients quality of life.

Even insured patients may pay high out-of-pocket costs for cancer drugs.

Financial toxicity is associated with adverse outcomes and should be assessed early in the course of cancer care.

It is still debatable who should assess a patients financial situation and when discussions about cost should take place.

Financial Toxicity Potentially Harmful Treatment-Related EffectBy Alice Goodman

It turns out that in addition to treat-ment-related toxicity, cancer patients commonly experience financial toxic-ity, a phrase that is increasingly coming into parlance in the cancer community. Patients should be assessed for financial toxicity as early as possible following di-agnosis so that they can get help before they suffer its impact, according to a pre-

sentation at the 2014 Quality Care Sym-posium, held recently in Boston.1

Although financial toxicity is more common than one might expect, oncolo-gists typically do not discuss cost of treat-ment with patients. Moreover, they are often unaware of the actual costs of treat-ments they prescribe. Discussion with pa-tients about financial concerns represents a clear unmet need, but it is a matter of de-bate as to who should initiate these discus-sions and the optimal timing.

Elephant in the RoomFinancial toxicity is the elephant in

the room. You can ask your patients one simple question about whether their can-cer care is covered by a drug plan to get the conversation started, said S. Yousuf Zafar, MD, MHS, a medical oncologist at Duke University Medical Center, Dur-ham, North Carolina.

In his presentation, Dr. Zafar sought to sensitize oncologists in the audience to the widespread problem of financial toxicity in cancer care. Many patients who are insured do not have adequate drug plan coverage and end up in bankruptcy. He gave an example from his practice of a patient who exhausted his savings to pay for his treatment, even though he had medical insurance and a drug plan.

Even when we do choose wisely, he said, patients sometimes cannot afford their medications. The average amount for drugs that a cancer patient pays per year is $4,800, he told listeners. And many patients pay much more than that.

It would take at least 2 days to discuss why out-of-pocket costs are so high, but we can start with a well-known culprit

the cost of drugs themselves, he said.Drug costs are wildly out of hand,

with the current average cost of 1month of chemotherapy estimated at $10,000, he continued. In addition to the very high costs of biologics and oral chemo-therapy, insurance premiums are higher than in the past, and patients are being asked to pay higher copays, he explained.

He cited the following examples of spiraling costs: Between 2007 and 2014, the price of

erlotinib increased by 91%, the price of dasatinib (Sprycel) increased by 130%, and the price of imatinib (Gleevec) increased by 158%.

From 1999 to 2013, insurance pre-miums increased by 182% and workers contributions increased by almost 200%.Four-tiered formularies are now in

place in many drug plans. In 2013, one out of every four patients was enrolled in four-tiered formulary drug plans. Cancer drugs mainly fall in the two highest-price tiers.

Together, these costs can result in financial toxicity for patients, he stated.

Mounting EvidenceDr. Zafar and colleagues looked at a

cohort of 254 insured cancer patients treated at an academic medical center.2 Approximately 75% applied for drug copayment assistance; 42% found their cancer treatment a significant or cata-strophic burden; 46% stinted on food and clothing to pay for their medica-

tions, and 46% used their savings to defray costs. Adherence was compro-mised in 63%, and 24% avoided taking the drugs altogether.

A separate study showed that cancer patients had a 2.65 times higher risk of bankruptcy compared with the general population in the State of Washington.3

There is mounting evidence that increasing out-of-pocket costs impact patient well-being, Dr. Zafar stated.

Adherence to drug therapy is the first victim of financial toxicity. One study showed that higher copays led to a 42% increased likelihood of nonadherence to imatinib, he said.4 Another study showed that 45% of patients reported that they were nonadherent to save money.5

Financial toxicity has an impact on quality care. There is a growing list of financial adverse events as a result of the care we are providing. They include delaying care, nonadherence, missed appointments, and taking fewer medi-cations, he continued.

We know nonadherence affects out-comes. We havent been able to measure yet whether it affects survival. We need to address the elephant in the room. It is time to intervene, Dr. Zafar said.

Levels of InterventionHe cited three levels of intervention:

individual, interpersonal, and systemic. At the individual level, patients

should be given information about the cost of health care. One of our goals should be greater health literacy related to costs of care. Our patients do not have high health cost literacy, Dr. Zafar said.

He mentioned that one study showed that 60% of insured patients did not understand what a deductible is and noted that many patients do not understand the complexities of the Af-fordable Care Act.

Forty percent of patients pay more than they expect to. Some patients are not aware of copayment assistance pro-grams or are enrolled in inadequate

insurance plans. We need to promote greater cost literacy, he told listeners.

On the interpersonal level, a study at our institution showed that about 50% of cancer patients wanted to talk to their oncologists about cost, but only 19% had that discussion.6 Barriers to communica-tion include the perception that it is not the oncologists job to discuss cost. Of the 19% who did have the discussion with their doctor, 57% said that their out-of-pocket costs decreased as a result of the conversation. This is an exploratory find-ing that is hypothesis-generating, but 75% of the time, the costs were decreased with-out changing treatment, he said.

Most oncologists are resistant to ad-dressing cost, but they can intervene ear-lier and more aggressively to let patients know about assistance programs and other avenues of relief, Dr. Zafar said.

On a systemic level, high-risk pa-tients should be identified before they accumulate debt. Although this can be difficult at a large-volume center, we need to do a better job. We have some good screening tools, and we need to test them on a broader scale and begin to implement them. We also need to address price transparency, as there are data to suggest that greater price trans-parency can decrease cost, he said.

We need to corral our resources in health literacy, patient engagement, and health-care delivery to start intervening in this problem of financial toxicity, he stated.

We should consider financial tox-icity a patient-reported outcome and assess this as we would other symp-toms. If we did as good a job at this as on other side effects, we could improve outcomes, Dr. Zafar stated.

Audience CommentsDuring the question-and-answer ses-

sion following Dr. Zafars talk, it became clear that there is no agreement about which health professional should ad-dress financial toxicity with a patientan oncologist, a nurse, a nurse navigator, a social worker, or other clinicianand when these conversations should occur. Nevertheless, Dr. Zafar said that even if oncologists dont initiate a discussion of drug coverage, they need to be aware of the costs of treatment.

Jane Perlmutter, PhD, founder and President of Gemini Group, Ann Arbor, Michigan, and a 30-year cancer survivor and patient advocate, shared her point of view: The benefits of cancer drugs are generally overestimated and the

Most oncologists are resistant to addressing cost, but they can intervene earlier and more aggressively to let patients know about assistance programs and other avenues of relief.

S. Yousuf Zafar, MD, MHS

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KADCYLA: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

IndicationKADCYLA (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety InformationBoxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY Do not substitute KADCYLA for or with trastuzumab Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA.

Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin

Cardiac toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function

Embryo-fetal toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception

Please see the following pages for additional important safety information and brief summary of full Prescribing Information, including Boxed WARNINGS.

C M Y K

Cosmos Communications 1

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Jane Perlmutter, PhD

harms are underestimated. I do think finances should be part of the discus-sions. It would be great if patients could

get information on their insurance cov-erage for drugs and required copays in the context of harms and benefits of drug therapy.

Jonas de Souza, MD, Assistant Professor at the University of Chicago Medicine, also believes that financial toxicity is critical to address with pa-tients. He and his colleagues inter-viewed 155 cancer patients to develop a patient-reported outcome measure called COST (COmprehenstive Score for financial Toxicity)7 to evaluate fi-

nancial toxicity in the clinical setting. To date, they have validated the tool in 50 cancer patients (of a planned 200), finding that COST can indeed measure financial toxicity and that a high degree of financial toxicity is associated with worse quality of life.8

Regarding Dr. Zafars presentation, Dr. de Souza said that it is important to assess financial toxicity, and several questions remain about the cost con-versation with patients, including opti-mal timing and who should initiate the discussion. n

Disclosure: Drs. Perlmutter, Zafar, and de Souza reported no potential conflicts of interest.

References1. Zafar Y: The elephant in the room:

How does financial toxicity impact cancer care delivery? Quality Care Symposium. Presented October 17, 2014.

2. Zafar SY, Peppercorn JM, Schrag D, et al: The financial toxicity of cancer treat-ment: A pilot study assessing out-of-pocket expenses and the insured cancer patients experience. Oncologist 18:381-390, 2013.

3. Ramsey S, Bough D, Kirchoff A, et

al: Washington state cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Affairs 6:1143-1152, 2013.

4. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2013.

5. Zullig LL, Peppercorn JH, Schrag D,

et al: Financial distress, use of cost-coping strategies, and adherence to prescription medication among patients with cancer. J Oncol Pract 9(6S):60s-63s, 2013.

6. Zafar Y, Abernethy AP, Tulsky JA, et al: Financial distress, communication, and cancer treatment decision making: Does cost matter? ASCO Annual Meeting. Ab-stract6506. Presented June 3, 2013.

7. de Souza JA, Yap BJ, Hlubocky FJ, et al: The development of a financial toxicity pa-tient reported outcome in cancer: The COST measure. Cancer 120:3245-3253, 2014.

8. de Souza JA, Yap BJ: Relationship be-tween financial toxicity and health-related quality of life in patients with advanced solid tu-mors. 2014 ASCO Quality Care Symposium. Abstract 31. Presented October 17, 2014.

Jonas de Souza, MD

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KADCYLA: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

IndicationKADCYLA (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety InformationBoxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY Do not substitute KADCYLA for or with trastuzumab Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA.

Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin

Cardiac toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function

Embryo-fetal toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception

Please see the following pages for additional important safety information and brief summary of full Prescribing Information, including Boxed WARNINGS.

C M Y K


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Studies Address Impact of Social Factors on Cancer Treatment Disparities

N ew studies reported at ASCOs 2014 Quality Care Symposium provided insight on the role social fac-tors play in cancer treatment dispari-ties, as well as effective approaches to improving the quality of care.

The research presented [here]

highlights how the conditions facing people living with cancer can affect their care, but also provides approaches to how we can overcome some of these potential disparities, said Gregory A. Masters, MD, FACP, FASCO, Chair of ASCOs Cancer Communications

Committee. Improving the quality of care we provide is a continuous goal for oncologists.

Each of the studies will be presented in more detail in an upcoming issue of The ASCO Post. They include the following:

Having dependent children moti-vates advanced cancer patients to pursue more aggressive care: A pilot study of people with advanced cancer indicates that parental status is an im-portant factor in treatment decision-making, with the majority stating that

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The next era of treatmentKADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker1-3

In preclinical studies:

Maintains the HER2 suppression and anticancer activities of trastuzumab1

Delivers cytotoxic DM1 to target HER2-expressing cells1

Many normal cells express HER24

Some cancer cells overexpress up to 200 times more HER2 than normal cells4

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Superior efficacy with a single agent1

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

Additional Important Safety InformationLeft Ventricular Dysfunction (LVD) Patients treated with KADCYLA are at increased risk of

developing LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLA-treated group and in 3.3% in the comparator group. Permanently discontinue KADCYLA if LVEF has not improved or has declined further

Pregnancy Registry Advise patients to contact their healthcare provider immediately

if they suspect they may be pregnant. Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

Pulmonary Toxicity Cases of interstitial lung disease (ILD), including pneumonitis,

some leading to acute respiratory distress syndrome or fatal outcome, have been reported in clinical trials with KADCYLA. In EMILIA, the overall frequency of pneumonitis was 1.2%

Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis

Infusion-Related Reactions, Hypersensitivity Reactions Treatment with KADCYLA has not been studied in patients who

had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%

KADCYLA treatment should be interrupted in patients with severe IRRs and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRRs, especially during the first infusion

Hemorrhage Hemorrhagic events, sometimes fatal, have been reported in clinical

trials. In EMILIA, the incidence of Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the comparator group (overall incidence 32.2% and 16.4%, respectively)

In some of the observed cases the patients were also receiving anticoagulation therapy or antiplatelet therapy, or had thrombocytopenia; in others, there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary

Thrombocytopenia In EMILIA, the incidence of Grade 3 thrombocytopenia was 14.5%

in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively)

Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Neurotoxicity In EMILIA, the incidence of Grade 3 peripheral neuropathy was

2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively)

Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade 2

HER2 Testing Detection of HER2 protein overexpression or gene amplification

is necessary for selection of patients appropriate for KADCYLA. Perform using FDA-approved tests by laboratories with demonstrated proficiency

Extravasation In KADCYLA clinical studies, reactions secondary to extravasation

have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

Nursing Mothers Discontinue nursing or discontinue KADCYLA, taking into

consideration the importance of the drug to the motherAdverse Reactions The most common (frequency >25%) adverse drug reactions

(ADR) across clinical trials with KADCYLA were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, constipation, and epistaxis. In EMILIA, the most common NCI-CTCAE (version 3) Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.For more information on KADCYLA, visit KADCYLA.com.

2014 Genentech USA, Inc. All rights reserved. TDM0001944701 Printed in USA. (08/14)

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS.

References: 1. KADCYLA Prescribing Information. Genentech, Inc. July 2014. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791 and Supplementary Appendix. 4. Hicks DG, Kulkarni S. Review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.

DM1* (cytotoxic maytansinoid) Inhibits tubulin polymerization to induce cell-cycle arrest and cell death

Trastuzumab (monoclonal antibody)Binds to HER2 at subdomain IV to suppress downstream signaling

MCC* (stable linker)Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

Months

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2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

10

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90HR=0.68295% CI: 0.548, 0.849P=0.0006

KADCYLA (n=495)No. of events: 149

lapatinib + capecitabine (n=496)No. of events: 182

No. at risk:

lapatinib + capecitabine

KADCYLA 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4

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being a parent motivates them to pur-sue life-extending treatments.

Medicares subsidy program im-proves hormone therapy adher-ence after breast cancer surgery and reduces racial disparities: A study of more than 23,000 women suggests that the Medicare Part D Extra Help program improves adher-

ence to hormone therapy after breast cancer surgery in all racial/ethnic groups and reduces disparities.

Oncologist participation in tumor board meetings may be associated with improved outcomes for pa-tients with lung or colorectal can-cers: A new population-based study of close to 5,000 patients and 1,600

oncologists found that physician participation in weekly tumor board meetings was associated with im-proved survival for patients with stage IV colorectal cancer and stage IV/extensive-stage small cell lung cancer.

Death of patients within 1 month of cancer surgery influenced by social and demographic factors: In a new

study of more than 1.1 million patients who underwent surgery for the most common or deadly cancers reports nearly 1 in 20 died within 1 month of the procedure. The risk of death was highest among patients who were not married, uninsured, non-white, male, older, less educated, poorer, or had advanced-stage cancer. n

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The next era of treatmentKADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker1-3

In preclinical studies:

Maintains the HER2 suppression and anticancer activities of trastuzumab1

Delivers cytotoxic DM1 to target HER2-expressing cells1

Many normal cells express HER24

Some cancer cells overexpress up to 200 times more HER2 than normal cells4

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Superior efficacy with a single agent1

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

Additional Important Safety InformationLeft Ventricular Dysfunction (LVD) Patients treated with KADCYLA are at increased risk of

developing LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLA-treated group and in 3.3% in the comparator group. Permanently discontinue KADCYLA if LVEF has not improved or has declined further

Pregnancy Registry Advise patients to contact their healthcare provider immediately

if they suspect they may be pregnant. Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

Pulmonary Toxicity Cases of interstitial lung disease (ILD), including pneumonitis,

some leading to acute respiratory distress syndrome or fatal outcome, have been reported in clinical trials with KADCYLA. In EMILIA, the overall frequency of pneumonitis was 1.2%

Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis

Infusion-Related Reactions, Hypersensitivity Reactions Treatment with KADCYLA has not been studied in patients who

had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%

KADCYLA treatment should be interrupted in patients with severe IRRs and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRRs, especially during the first infusion

Hemorrhage Hemorrhagic events, sometimes fatal, have been reported in clinical

trials. In EMILIA, the incidence of Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the comparator group (overall incidence 32.2% and 16.4%, respectively)

In some of the observed cases the patients were also receiving anticoagulation therapy or antiplatelet therapy, or had thrombocytopenia; in others, there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary

Thrombocytopenia In EMILIA, the incidence of Grade 3 thrombocytopenia was 14.5%

in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively)

Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Neurotoxicity In EMILIA, the incidence of Grade 3 peripheral neuropathy was

2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively)

Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade 2

HER2 Testing Detection of HER2 protein overexpression or gene amplification

is necessary for selection of patients appropriate for KADCYLA. Perform using FDA-approved tests by laboratories with demonstrated proficiency

Extravasation In KADCYLA clinical studies, reactions secondary to extravasation

have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

Nursing Mothers Discontinue nursing or discontinue KADCYLA, taking into

consideration the importance of the drug to the motherAdverse Reactions The most common (frequency >25%) adverse drug reactions

(ADR) across clinical trials with KADCYLA were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, constipation, and epistaxis. In EMILIA, the most common NCI-CTCAE (version 3) Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the F

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TAP Vol 5 Issue 18