June 2014

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM •June 2014 • Vol. 9, No. 6

SPECIAL FEATURE The state of palliative care in the U.S. ...........................

9

HEMATOLOGIC DISEASE Transplant readmission predicts decreased survival ...........................................

4

CURRENT PRACTICE Maurie Markman, MD: Modifying ‘standard of care’ based on lessthan-definitive evidence ........................................

Clinical Conundrums ...........

8

22

Outcomes more similar than different, study suggests, with a net positive San Antonio—In recent years, mammography has come under fire, with several studies concluding that screening may cause more harm than good.

But other studies have demonstrated that screening is more beneficial than harmful and essential in the war on breast cancer. Now, a new analysis demonstrates that when you level the playing field, the study conclusions are not all that different, and show a substantial benefit associated with screening.

“Modern measures of effectiveness see MAMMOGRAPHY, Y page 16

by the

numbers

Survivorship 64% | Oncologists who

always or almost always discuss survivorship care recommendations with patients

32% | Oncologists who

tell these patients who they should see for cancer-related follow-up care

<5% | Oncologists who

provide a written survivorship care plan to the survivor

Source: “Provision and Discussion of Survivorship Care Plans Among Cancer Survivors: Results of a Nationally Representative Survey of Oncologists and Primary Care Physicians.” J Clin Oncol.

2014;32:1578-1585, PMID: 24752057.

IMAGES in ONCOLOGY

Mammography Debate Rages On

INSIDE

Image courtesy of Science Photo Library

Knowledge Gaps Common in Blood Cancer Treatment

How I Manage…

Use of TKIs a particularly weak area New Orleans—A study designed to identify practice gaps among oncologists in the treatment of acute lymphoblastic leukemia (ALL), B-cell lymphoma (BCL) and chronic myelogenous leukemia (CML) found plenty, particularly related to the optimal use of tyrosine kinase inhibitors (TKIs). According to the study, only about one-third of clinicians recognized the prognostic significance of a major molecular response (MMR) with a TKI, and less than onethird were familiar with prevailing expert opinion regarding the timing and frequency of cytogenetic analyses. see SUBOPTIMAL CARE, E page 17

Pancreatic cancer cells.

Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome M

yelodysplastic syndrome (MDS) is comprised of a heterogeneous group of hematologic diseases characterized by a clonal abnormality of hematopoietic stem cells resulting in cytopenias, abnormal blasts and risk for transformation into acute myelogenous leukemia (AML). The clinical course of the disease varies from indolent over several years to a more rapid progression to AML within months.1,2 The median age at diagnosis is around 75 years.3 Allogeneic hematopoietic cell transplantation (allo-HCT) is considered a curative treatment strategy for patients with MDS, and its Nicolaus Kröger, MD role in the treatment of “younger” adults with MDS is well established, even if the outcomes data come mainly from retrospective studies.4-8 The introduction of reduced-intensity or non-myeloablative conditioning regimens has resulted in a substantial reduction in transplant-related toxicity and mortality, and a rapid increase see HOW I MANAGE, E page 18

RE VIE WS & COMMENTAR IES

Expert Insights From The Ohio State University—The James In selected NSCLC patients with brain metastasis, be aggressive ............... 13 David Carbone, MD, PhD

Genetic screenings for breast cancer personalize therapy ..................... 16 Charles Shapiro, MD

2

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

Transplant Readmission Predicts Decreased Survival Readmission more than a cost and quality-of-life issue New Orleans—Early readmission after hematopoietic stem cell transplant (HSCT) predicts lower five-year overall survival (OS), according to a large retrospective review. The relative risk appears to be slightly higher in those who received reduced-intensity conditioning (RIC), but OS was significantly lower for both RIC and myeloablative regimens if a readmission occurred

within 30 days of discharge after HSCT. The study data draws attention to the adverse impact of early complications on long-term outcomes and the potential to reduce mortality if these complications can be avoided. In this study, infection was the most common cause of readmission, according to Laura Spring, MD, a clinical fellow at Brigham and Women’s Hospital, in Boston. She presented the

Visit

ClinicalOncology.com

findings of this review, based on 1,097 cancer patients undergoing HSCT at Dana-Farber Cancer Institute between 2005 and the end of 2010, at the 2013 annual meeting of the American Society of Hematology (ASH).

The study suggested that readmission rates after HSCT are high overall. Of the 495 patients who received myeloablative therapy, 26.3% were

readmitted within 30 days of discharge after HSCT and 39.4% by day 100 following HSCT. Of the 601 patients who received RIC, 17.4% were readmitted within 30 days of discharge after HSCT and 30.7% by day 100. In order of importance, the reasons for readmission after both myeloablative and RIC HSCT were infection (27.6% and 26%, respectively), fever without a source

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JUNE 2014 â&#x20AC;˘ CLINICALONCOLOGY.COM

(19.1% and 19%, respectively) and graftversus-host disease (GVHD; 17.9% and 15.1%, respectively).

Among patients receiving myeloablative HSCT, at five years the OS was 42% for those with a readmission within 30 days versus 56% for those not readmitted (P ( =0.0026). Among patients in the RIC group, the five-year OS was 26% for those readmitted within 30 days versus 50% for those who were not ((P<0.0001).

Similar disparities were observed in OS when calculating readmission by day 100, although the difference in the myeloablative group ((P=0.058), unlike

Readmission after hematopoietic stem cell transplant is considered a major source of increased costs of care and would be expected to cause distress and concern to patients, but these data suggest that early readmission may be a potentially modifiable barrier to long-term survival. the RIC group ((P<0.0001), was of borderline significance.

After adjusting for age, donor type and disease risk index in a multivariate analysis, the hazard ratios (HR)

for decreased survival at five years remained statistically significant for 30-day readmission for both myeloablative (HR, 1.58; P=0.0018) and RIC (HR, 1.68; P=0.0002) HSCT (Table). When

expanded to readmission within 100 days of HSCT, the HR for poorer survival increased in the RIC group (HR, 2.31; P<0.0001) but fell to borderline significance in the myeloablative group (HR, 1.325; P=0.68).

Readmission after HSCT is considered a major source of increased costs of care and would be expected to cause distress and concern to patients, but these data suggest that early readmission may be a potentially modifiable barrier to long-term survival. If the causes of readmission can be identified, it may create see READMISSION, N page 4

3

4

HEMATOLOGIC DISEASE

READMISSION continued from page 3

opportunities to improve outcomes.

“A better understanding of the risk factors for readmission in the HSCT population will allow for more transitional care and clinical resources to be focused on the highest-risk patients,” Dr. Spring said. In particular, she recommended more research “to better learn how to balance early discharge with preventable readmissions.”

Navneet Majhail, MD, the director of the Blood and Marrow Transplant

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

Table. Effect of Readmission After Hematopoietic Stem Cell Transplantation on Survival Five-Year Overall Survival Conditioning

<30 day Readmission

<100 day Readmission

MAC

HR, 1.58; P=0.0018

HR, 1.325; P=0.068

RIC

HR, 1.68; P=0.0002

HR, 2.31; P<0.0001

‘The risk factors for readmissions are likely going to be very different at different centers.’

—Navneet Majhail, MD

HR, hazard ratio; MAC, my myeloablative yeloablative conditioning; RIC, reduced reduced-intensity intensity conditioning

Program at the Taussig Cancer Institute at the Cleveland Clinic in Ohio,

said he was not surprised by the association between early readmission and

Read Clinical Oncology News Anywhere, Anytime!

Download the iPad App here.

decreased long-term survival.

“Most readmissions occur for infections, GVHD and relapse, and these events account for the majority of posttransplant mortality, and their occurrence frequently portends a poor prognosis for patients,” Dr. Majhail said. He believed, however, that the data suggested potential opportunities to improve care.

“The study highlights risk factors for readmissions, and although more research is needed, it tells us that we can potentially identify patients who are more likely to get rehospitalized. Transplant programs can consider strategies where more resources are dedicated to these ‘high-risk’ patients to prevent readmissions,” Dr. Majhail said.

“However, the study may not be very generalizable, as the findings are very specific to the resources and treatment practices at the author’s institution, and we know that there is tremendous variation among transplant centers in their models of care. The risk factors for readmissions are likely going to be very different at different centers,” he added.

But Dr. Majhail suggested that it was worth considering ways to reduce early complications, whether or not outcomes can be improved.

“As the study authors rightly point out,” Dr. Majhail said, “early post-transplant readmissions are a source of distress for patients and their families, and add to transplant costs.”

—Ted Bosworth Drs. Spring and Majhail reported no relevant financial conflicts of interest.

Clinical Oncology News TWEETS! Follow us @ ClinOncNews And send your Twitter handle to managing editor Sarah Tilyou at smtilyou@mcmahonmed.com so we can follow you.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD University of California, San Diego, CA

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Oncology Nursing

Hematologic Malignancies Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Mayo Clinic Rochester, MN

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Medical Oncologist New York, NY

Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Albert Einstein College of Medicine, New York, NY

Infection Control

Mercy Medical Center St. Louis, MO

Edward S. Kim, MD

Richard J. Gralla, MD

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

John W. Finnie, MD

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

Matt Brow

Community Oncology

Genitourinary y Cancer Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

Ephraim Casper, MD

Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Alabama Birmingham, AL

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

5

6

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

Modifying ‘Standard of Care’ Based on less-than-definitive evidence EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs National Director for Medical Oncology Cancer Treatment Centers of America, Philadelphia

F

ew would disagree with the statement that the results of welldesigned and -conducted Phase III randomized trials have formed the cornerstone of rational, evidence-based management strategies in oncology.

While the highly problematic issue of defining optimal therapy in uncommon malignant conditions or in small molecularly-based patient subsets— where the performance of Phase III trials is very difficult, if not impossible—has generated considerable interest, my intent with this commentary is to briefly highlight a similar (but actually quite different) question that also is worthy of discussion within the oncology community: What level of evidence should be required to modify a standard-of-care therapeutic option when data in related settings have revealed therapeutic equivalence (e.g., progression-free or overall survival) between the approaches but where clinically meaningful superiority (e.g., reduced toxicity, improved ease of administration) associated with the proposed modification has been observed?

Consider, for example, the previously frequently asked question of the acceptability of substituting carboplatin for the “old standard” cisplatin in treatment programs, where it was the cisplatin-based treatment program that had been documented to improve clinical outcomes. Although not universally applicable, in the gynecologic cancer arena (specifically both ovarian and

®

endometrial cancers), carboplatin has been shown in Phase III clinical trials to produce equivalent survival outcomes with an improved toxicity profile compared with cisplatin.1,2 Therefore, the specific question to be addressed is as follows: Are there other settings within the sphere of gynecologic malignancies where one might rationally consider employing this therapeutic substitution?

Cisplatin-based therapy has been shown to favorably affect survival when delivered by the intraperitoneal route in patients with small-volume residual advanced ovarian cancer, and when used as a component of a concurrent chemoradiation strategy in locally advanced cervix cancer.3,4 Would it be appropriate to consider the substitution of carboplatin for cisplatin in these settings (of course assuming acceptable toxicity based on Phase I data)? And would peer-reviewed Phase II trial data (or extensive retrospective institutional experiences) that demonstrate evidence of efficacy provide a sufficient rationale to consider this approach outside the confines of a clinical trial, again acknowledging the absence of randomized trial data on the topic?

In both the setting of intraperitoneal chemotherapy for ovarian cancer and the delivery of a platinum drug concurrent with radiation for cervical cancer, carboplatin has been shown to result in an acceptable toxicity profile and produce a satisfactory clinical outcome.5,6 But Phase III trial data are not available.

It also is important to acknowledge that such questions, as important as they may appear, are less likely to be specifically addressed in definitive Phase III trials, due to lack of pharmaceutical company support and the acknowledged existence of other strategies (including novel antineoplastic agents), which surely will

generate greater individual investigator and organizational interest, from, for example, academic medical centers and cooperative trial groups. Further, in considering this unfortunate reality, it is not unreasonable to suggest that this “limited interest” (particularly among investigators and potential non-commercial governmental sponsors) may exist even in settings where the genuine clinical relevance of the question is at least as great as—if not far greater than—alternative strategies where Phase III trials have been or currently are being conducted.

In my opinion, one highly rational approach to dealing with the dilemma of less-than-definitive data supporting the use of modified approaches is to simply consider employing these strategies in the non-investigative setting, but at the same time clearly and quite directly acknowledge the limitations of the evidence in discussions with prospective patients.

Thus, in the specific examples provided here, an ovarian cancer patient who is a candidate for intraperitoneal drug delivery can elect to receive cisplatinbased therapy or may decide to undergo regional therapy with carboplatin.5 However, the key would be clearly providing the limitations of the available carboplatin-based data in this setting.

Similarly, a patient undergoing platinum-based chemoradiation would be informed of the solid evidence generated with the use of cisplatin, but the discussion might also acknowledge that there is limited experience suggesting that the substitution of carboplatin appears to achieve equivalent efficacy with potentially reduced side effects.6 Although a thorough discussion of these issues would be required to be certain the patient understands and appreciates the differences in the underlying quality of available data between the two platinum agents, in my opinion

there is no inherent reason to believe an individual patient cannot make her own rational decision, likely in consultation with her family and personal advisors, based on the existing evidence.

EDITORIAL STAFF

Michael Enright, Publication Sales menright@mcmahonmed.com

Brandy Wilson, Circulation Coordinator

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com McMahon Publishing is a 42-year-old, family-owned medical publishing and medical education company.

McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp.

Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2014 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Sarah Tilyou, Managing Editor smtilyou@McMahonmed.com James Prudden, Group Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

SALES STAFF

Jeanette Fritzky, Publication Sales jfritzky@mcmahonmed.com Nancy Parker, Classified Advertising Sales nparker@mcmahonmed.com

References 1. Ozols RF, Bundy BN, Greer BE, et al.

Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:31943200, PMID: 12860964.

2. Miller D, Filiaci V, Fleming G, et al. Randomized phase III non-inferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;125:771-773.

3. Elit L, Oliver TKI, Covens A, et al. Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systemic review with meta-analysis. Cancer. 2007;109:692-702, PMID: 17238181.

4. Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systemic review and meta-analysis of individual patient data from 18 randomized trials.

J Clin Oncol. 2008;26:5802-5812, PMID: 19001332.

5. Fujiwara K, Markman M, Morgan M, et al.

Intraperitoneal carboplatin-based chemotherapy for epithelial ovarian cancer. Gynecol Oncol. 2005;97:10-15, PMID: 15790431.

6. Nam EJ, Lee M, Uim GW, et al. Comparison of carboplatin- and cisplatin-based concurrent chemoradiotherapy in locally advanced cervical cancer patients with morbidity risks. Oncologist. 2013;18:843-849, PMID: 23821328.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Sarah Tilyou at

smtilyou@mcmahonmed.com

Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING

ART AND PRODUCTION STAFF

Raymond E. McMahon, Publisher & Managing Partner

Michele McMahon Velle, Creative Director, MAX Graphics

Van Velle, President, Partner

Van Velle, President vanvelle@mcmahonmed.com

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Dan Radebaugh, Director of Production and Technical Operations

Matthew McMahon, General Manager, Partner Lauren McMahon Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

On the Spot With Colleen Hutchinson

The State of Palliative Care in the U.S. T

his edition of “On the Spot” focuses on palliative care, an aspect of patient care that has evolved considerably over the past 20 years. But according to those who shaped this growth—and continue to champion its development—there is still work to be done. I would like to extend

sincere thanks to Betty Ferrell, RN, PhD, professor and research scientist at City of Hope and editor-in-chief of Journal of Hospice & Palliative Nursing, for sharing her perspective from 35 years in oncology and palliative care medicine. Dr. Ferrell is a fundamental part of the history

of the palliative care movement and has been repeatedly recognized as such, most recently being named as one of the 30 most influential leaders in hospice and palliative care medicine. And thank you also to all of the contributors for sharing their thoughts and expertise.

P ARTICIPANTS Amy Abernethy, MD, PhD Hematologist/oncologist, palliative care physician and Director, Duke Center for Learning Health Care Duke University Durham, North Carolina

R. Sean Morrison, MD Director, Hertzberg Palliative Care Institute and National Palliative Care Research Center Mount Sinai Hospital New York, New York

Kimberly Bower, MD Clinical Medical Director, The Institute for Palliative Medicine, San Diego Hospice San Diego, California

Timothy Quill, MD Gosnell Distinguished Professor of Palliative Care, University of Rochester Medical Center, Immediate Past-President, American Academy of Hospice and Palliative Medicine Rochester, New York

Gail Austin Cooney, MD President, Hospice Medical Director Certification Board, American Academy of Hospice and Palliative Medicine West Palm Beach, Florida

Thomas Smith, MD Director of Palliative Medicine Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland

Although the Institute of Medicine (IOM), in its recent guidelines, and the U.S. health care system in general have evolved appropriately in terms of recognizing the legitimate need for palliative care in oncology over the past couple of decades, and great strides have been made in palliative care development and standardization, barriers exist that make the implementation of current guidelines and recommendations unrealistic.

Timothy Quill, MD: Agree. The two biggest barriers to implementing these guidelines are the lack of standardization of required training and quality measurement in these domains for all oncologists—both trainees and those already in practice—and the lack of adequate numbers of palliative care specialists to help care for the more challenging patients and to help train all oncology practitioners in primary palliative care. Even among academic medical centers, the variation in implementation in both domains is very wide, and the further outside of these academic centers one ventures, the more uneven the availability and presence of primary or secondary palliative care become.

Jamie Von Roenn, MD: Disagree. It is difficult but possible even in the current environment. There is the misperception that integrating palliative care is unrealistic because “it takes too much time.” Some simple strategies that add little time to routine office visits include the use of brief symptom assessment tools and triggers for palliative care/hospice referrals. Furthermore, structured prognosis and goal-setting conversations have been documented to take less time than many clinicians anticipate.

Kimberly Bower, MD: Agree. Many of the current barriers to the implementation of palliative care programs are financial. Palliative medicine is a high-touch field that requires physicians to step back in order to see all of the factors that are affecting a patient’s health in the context of the patient’s life circumstances and values. This approach is time-intensive and requires an interdisciplinary team. It is effective in ensuring that the patient’s goals and values are driving the medical treatment plan and that everything possible is done to maximize not only the length of a patient’s life but also the quality of the patient’s life. This approach often increases patient satisfaction and leads to better utilization of limited health care resources. Despite these advantages, in a fee-for-service medical model that pays better for procedures than for face time with patients, reimbursement alone is not adequate to support the growth of palliative medicine programs. With each additional

Porter Storey, MD Executive Vice President American Academy of Hospice and Palliative Medicine Denver, Colorado

Jamie Von Roenn, MD Professor of Medicine, Northwestern University Senior Director of Education, Science and Professional Development American Society of Clinical Oncology Chicago, Illinois

Susannah Ellsworth, MD Radiation oncologist Johns Hopkins University Baltimore, Maryland

palliative care service that is added, the cost of the program to the institution increases. If cost avoidance is not taken into account, then the larger the palliative care program becomes, the more money it appears to lose.

Gail Austin Cooney, MD: On the fence. I have to say “on the fence” because implementation is challenging but not unrealistic. Two of the greatest barriers to implementing successful palliative care are time and money. Physician time is a limited commodity, and excellent communication takes time. Additionally, palliative care is grounded in the concept of interdisciplinary care, but usually only the physician or physician-level provider is able to bill. The payor systems in the United States compound this problem by focusing on payment for tests and treatments—a curative model of care that does not meet the needs of many patients and families with potentially life-limiting disease.

Amy Abernethy, MD, PhD: Agree. More palliative care is needed in oncology—there is clear consensus from the IOM, health system executives, the American Society of Clinical Oncology (ASCO), guideline statements, oncologists, patients and caregivers. But the impediments are real. For the oncologist, not only is it a problem of needing basic palliative care skills and tools, there is the reality of multiple competing demands; the same person is expected to manage complex biology, see ON THE SPOT, T page 8

7

8

CURRENT PRACTICE

ON THE SPOT continued from page 7

a dizzying array of new biomarkers and drugs that expands daily, comorbid illnesses, financial hardship of patients, data and information overload, shifting regulatory expectations, a busy clinical practice and the complex emotional and symptom landscape of advanced cancer care. It is simply hard to fit it all in. Meanwhile, adding more palliative care specialists isn’t very feasible either. Reimbursement challenges make it hard to adequately pay for palliative care; quite simply, this needs to be fixed. But, even if we fix reimbursement, there simply aren’t enough palliative care specialists—nor specialists in training—to be able to fill the expanding gap.

We need new models for palliative medicine education and training, for example, mid-career pathways; expansion of the palliative care discipline to diverse kinds of providers such as physician assistants; and tools to support efficiency in palliative care practice, such as health information technology, just to name a few.

R. Sean Morrison, MD: Disagree. Palliative care is a relatively new interdisciplinary specialty that has emerged in response to the unmet needs of patients with serious illness and their families. Palliative care, delivered by teams comprised of doctors, nurses, social workers, chaplains and child life specialists (when appropriate), focuses on relieving suffering and achieving the best possible quality of life for patients and their caregivers. It is appropriate at the point of diagnosis of a serious illness.

Palliative care goes beyond hospice care to offer patients and their families treatments focused on improving quality of life while they are receiving lifeprolonging and curative treatments. It involves symptom assessment and treatment; help with decision making and establishing goals of care; practical support for patients and their caregivers; mobilization of community support and resources to assure a secure and safe living environment; and collaborative and seamless models of care (hospital, home and hospice). It is offered simultaneously with life-prolonging therapies for individuals living with serious or complex illness.

Over the past decade, we have seen dramatic growth in the numbers of palliative care teams such that 66% of all American hospitals and almost 90% of those with more than 300 beds report having palliative care teams. A solid business case exists for the integration of palliative care teams in hospitals and cancer centers, and new successful models of community-based palliative care have been developed but need dissemination.

What then are the barriers? First, we need to develop an adequate workforce—all cancer clinicians need to be trained in the fundamentals of palliative care.

Educational materials exist—they need to be disseminated. Second, we need to enhance the evidence base.

To date, the National Cancer Institute spends less than 0.5% of its annual research budget on palliative care— this needs to change, and funds need to be reallocated. Third, we need to disseminate existing successful models of palliative care—models exist, they need to be implemented. Fourth, we need a public education campaign. A recent national public opinion survey revealed that more than 95% of the American public wanted palliative care for their loved ones when informed about it; however, only 8% knew what it was.

Porter Storey, MD: Agree. Oncology and hospital programs are integrating palliative care, but there are few

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

trained professionals to meet the needs of these expanding programs. Astronomical costs of newer chemotherapy agents are draining crucial resources from oncology programs that could have been used for palliative care programs. Radical cuts to hospice reimbursement are denying hospice care to patients with a few months to live. Palliative care teams are scrambling to fill these gaps.

Susannah Ellsworth, MD: Disagree. The evidence base for palliative medicine is expanding rapidly, as is the number of physicians with formal training in palliative medicine. One of the most important barriers to more widespread use of palliative care is a lack of access, with access to care varying depending on geographic area, health care business models and referral patterns; however, a growing number of trained palliative care practitioners will increase access, although this will take time, and an increasing awareness of the value of palliative care will broaden the referral base and increase the acceptance of palliative care in the community.

Thomas Smith, MD: Agree. There aren’t enough hospice and palliative medicine docs and nurse practitioners. But even with five randomized controlled trials showing benefit, less than 10% of lung cancer patients get referred to palliative care, and usually only for end-of-life care in the last two weeks. The barriers are oncologists who never refer; families who won’t accept that their loved one could possibly die from this; patients who won’t accept that medical science cannot cure everything; patients and families who would prefer to avoid the tough issues, hoping they will go away; and insurance companies that won’t reimburse.

Better implementation is possible, probable even, with education.

Dr. Van Roenn: Agree. We can’t do what we don’t know how to do. Physicians want to do what’s best for their patients. Skill in communication promotes greater understanding of patient–family concerns, clarity with regard to goals of care and a richer doctor–patient relationship. Recognizing and treating symptoms effectively, regardless of the goals of care and prognosis, leads to a better patient–family experience.

Dr. Bower: Agree. Part of the role of palliative medicine is to change the culture of medicine so that skillful communication with patients is valued as highly as skillful disease management, and so that treatment plans are based on achieving patient goals as opposed to being based on attempting to fix individual organ systems. Didactic teaching alone may have minimal effect on providers’ behavior, but didactic teaching in combination with role modeling by palliative medicine specialists will gradually improve other providers’ palliative care skills. As other providers’ skills in primary palliative medicine improve, palliative medicine subspecialists will be able to focus on treating the most complex patients. Additionally, as providers become more familiar with the positive effects that palliative medicine can have in the management of their patients, they will demand better access to

palliative care services. As demand grows, administrators will be more likely to invest resources in the implementation of palliative care services. With advancements in medicine, we are able to extend the lives of sicker and sicker patients. In this context, the need for palliative medicine will only continue to grow. There will never be enough palliative medicine specialists to meet the demand for palliative care services, so part of the mandate of palliative medicine specialists is to train other providers in primary-level palliative care.

Dr. Smith: Education never killed anyone, but it rarely changes practice. Better results change practice. Making oncologists’ lives easier and better changes practice. The first time an oncologist has a good referral—“They really solved his apathy and depression”—or gains some time—then they start referring more. The benefits to the patient and family are a real bonus.

Dr. Quill: Agree. The one caveat being that although pain and symptom management may be teachable in large-group formats with a mix of didactic presentation and then practice calculations on representative cases, the teaching of the requisite communication skills is much more challenging. The latter requires practice in observed small-group learning situations, using role play, interview of standardized patients and observation in real time with actual patients. The rate-limiting parts are protecting enough time for the clinicians to practice, and developing and supporting oncology and palliative care clinicians with the key associated communication skills. Such training is critical, but labor- intensive. On the other hand, we do not let surgeons operate without demonstrating highlevel skills under supervision, and the same should be said about having such critical conversations with patients and families facing difficult oncologic decisions.

Dr. Cooney: Disagree. Sadly, there’s very little evidence to support changing practice through education. The focus needs to be on changing our systems of care.

Dr. Abernethy: Agree. Basic palliative care education will help. Why do I say that, when I just said that the oncologist is too busy anyway? Efficiency comes when things are second nature. I always say that you need your palliative care skills in your “hip pocket,” so that you can pull them out at a moment’s notice without really thinking too hard about it. For example, Communication 101: How are you going to structure the conversation to confidently and safely present bad news? Or, do you know the starting dose for morphine to manage shortness of breath? Have you practiced this enough times that it is second nature and you don’t have to think about it? So, yes, education can help. Education also provides confidence—confidence to be ready to acknowledge, intervene and help, as well as to know when to call in the specialist palliative care doctor. Often, this is what patients and families want most—a sense of their doctor’s confidence in how to manage the situation and help keep the patient and family safe, even in very difficult circumstances.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

Oncology fellowship programs have made progress with regard to including palliative care in training, but they are still not adequate.

Dr. Van Roenn: Agree. There are nearly 30 U.S. oncology fellowship programs with required palliative care rotations and about 20 with an optional elective rotation. Although this is a significant improvement, it represents only about one-third of programs. All patients with cancer need attention to symptom prevention and/or treatment, clear discussions about expectations and prognosis, and attention to the effect of disease and treatment on quality of life, in the broadest sense.

Dr. Smith: Don’t know. Fellowship training is OK, but if the fellow never sees a “goals of care discussion” on the wards, and is allowed to admit a dozen patients with no tracking of goals of care, advance directive discussions, pain scores and hospice referrals—well, you don’t need to be a weatherman to know which way the wind blows. Peer pressure and good role models change practice. Wanting to be seen as competent in the eyes of your peers changes practice. Fellowship lectures, not so much.

Dr. Abernethy: Agree. There has been remarkable progress since I was a fellow. When I was an oncology fellow in 1998, I wanted to do concentrated training in palliative care. It didn’t exist, so we called it “cancer pain”—that was the closest option. To actually study palliative care, I had to go to Australia. Now, there are three faculty in my group with formal oncology and palliative medicine training and we have a new fellow every year. Meanwhile, the general oncology fellows, even those interested in the basic sciences, are hungry to learn palliative care skills. So, why do I say that it isn’t enough? It’s about practice. If, as oncologists, we are going to get to the point of being practiced enough in palliative care skills that we are efficient in pulling out the palliative care tools when we need them without really thinking about it, then it takes practice—not just lectures or deep-dive research. Our task is to continue to push the envelope and increase the amount of education available to fellows and then reinforce the expectation to practice, practice, practice.

Dr. Morrison: On the fence. There has been substantial investment in palliative care education for oncology fellows,

but to date, these efforts have occurred largely outside of formal fellowship training programs. Although pain is increasingly covered, key palliative care knowledge and skills remain outside the curriculum of most oncology fellowship programs. For example, skills such as communicating difficult news, establishing goals of care, discussing prognosis and transitioning to hospice rarely are formally taught and even more rarely are taught using the state-of-the-art pedagogy of standardized patients and video review. Similarly, most oncology fellows rarely rotate on palliative care

teams and, thus, gain little experience and knowledge of specialty-level palliative care. Every medical school is associated with a hospital with a palliative care team so, in theory, local expertise does exist to enhance training.

Dr. Bower: Agree. The [Accreditation Council for Graduate Medical Education] program requirements for graduate medical education in hematology and medical oncology state that oncology fellows must show competency in palliative care. Despite this requirement, many

9

programs still provide minimal training in palliative medicine and would benefit from strengthening this aspect of their programs. Along with additional training in pain and symptom management, strengthening training in palliative medicine would provide an opportunity to focus on the humanistic aspects of medicine. This would include additional training in communication skills, working with an interdisciplinary team, and the risk for burnout and compassion fatigue that oncologists face. Acknowledging the emotional toll that taking see ON THE SPOT, T page 10

REGISTER NOW AT

www.ctcareviewcme.org

THIRD ANNUAL

CTCAREVIEW 2014 Cancer Treatment Centers of America®

ADVANCES & CONTROVERSIES IN MALIGNANT HEMATOLOGY & ONCOLOGY Saturday, July 26, 2014 The Trump International Hotel & Tower® Chicago, Illinois

REGISTER NOW!

Syed A. Abutalib, MD Program Chair Hematology Course Director

Comprehensive CME/CE Review Course

Maurie Markman, MD Oncology Course Director

Faculty Jaffer A. Ajani, MD Al B. Benson III, MD, FACP Jennifer R. Brown, MD, PhD Robert A. Kyle, MD Richard A. Larson, MD Robert J. Motzer, MD Joyce A. O’Shaughnessy, MD

Farhad Ravandi, MD Ravi Salgia, MD Ayalew Tefferi, MD Everett E. Vokes, MD Glen J. Weiss, MD, MBA Andrew D. Zelenetz, MD, PhD

CME/CE credits will be available!

Complimentary for Oncology or Hematology Fellows!

Jointly provided by Dannemiller and Athena Education Group.

Dannemiller and Athena Education Group gratefully acknowledge an educational grant from the Cancer Treatment Centers of America® in support of this continuing medical education activity.

Partially supported by Cancer Treatment Centers of America®.

Follow us on Twitter #CTCAReview

10

CURRENT PRACTICE

ON THE SPOT continued from page 9

care of very sick and dying patients can have on oncologists, and teaching fellows effective ways to cope may be undervalued in some oncology training programs.

Ultimately, having strong skills in communication and symptom management, and having access to palliative medicine subspecialists to help with the most difficult patients, will decrease the stress that physicians experience when they see patients suffer and feel inadequately prepared to help them.

Dr. Cooney: On the fence. As important as it is to expose oncology fellows to the basic tenets of palliative care, I do not think that education alone will change care delivery. I wish that it could, believe me!

Dr. Quill: Agree. There are a growing number of centers where palliative care is integrated into oncology treatment programs, but the depth and breadth of the integration into the educational process is dependent on two variables: One, the centers need to have skilled palliative care clinicians who also are trained and skilled in teaching, and are given protected time and resources to provide the teaching; and two, the site-specific oncology leadership would have to understand the importance of primary palliative care training for all of their oncology trainees and practitioners, and be able to find the resources to support the trainers and the time in the training program to devote to this purpose. The ideal training program would include some basic training early on, including pain and symptom management and some observed clinical interaction with simulated and real patients related to key communication skills, and then ongoing case conferences where more challenging cases can be discussed and responded to. The number of training programs where all of these variables line up is probably low.

Dr. Ellsworth: Agree. Because my background is in radiation oncology, I will discuss how palliative care training can be integrated into radiation oncology training here. Incorporating formal training in palliative care can be very challenging for radiation oncology programs that already are trying to fit multiple other mandated priorities into the training program. Radiation oncologists have to take three separate sets of board exams, so there already are a tremendous number of specific educational requirements for trainees. Nevertheless, I think the programs absolutely need to begin considering how to incorporate some form of a palliative care curriculum into residency training.

There are some simple and basic skills that should be included in this sort of curriculum—for example, communication skills. Every physician needs to learn how to talk with patients, convey good news and bad, and explain the clinical situation in a clear and compassionate way, which doesn’t always come naturally.

Another important aspect of such training is symptom management. You can vastly improve the likelihood that a patient will finish treatment if you can help fix a troublesome symptom like pain or nausea. Good symptom management also helps to build a rapport with patients, making future communication easier. So clinically, there is really no downside to having some formal training in these two very basic palliative care skills—communication and symptom management.

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

Radiation oncologists have generally learned these types of things through experience, by learning from mentors and more senior clinicians, but we need to teach these skills more formally to ensure that we all have some basic competencies in palliative care.

Cancer care providers currently are trained and educated inadequately to provide primary- and secondary-level palliative care across the trajectory of cancer care.

Dr. Morrison: Agree. In the United States, approximately 14 million people have had cancer and more than 1.6 million new cases are diagnosed each year. By 2022, it is projected that there will be 18 million cancer survivors and, by 2030, cancer incidence is expected to rise to 2.3 million new diagnoses per year. Although medical advances have transformed cancer into a disease that people can live with for many years, they have not been accompanied by corresponding improvements in quality of life for these patients and their families.

Living with or surviving cancer should not mean living in pain or experiencing distressing symptoms. Abundant evidence suggests that the advanced stages of cancer for most are characterized by inadequately treated physical distress; fragmented care systems; poor communication between doctors, patients and families; and strains on family caregiver and support systems.

Indeed, the recently published Institute of Medicine report, “Delivering High Quality Cancer Care,” concluded that “cancer care often is not patient-centered, many patients do not receive palliative care to manage their symptoms and side effects from treatment, and decisions about care often are not based on the latest scientific evidence.” It is clear that if we’re going to improve the care of persons living with cancer and their families, we will require a workforce that can provide specialist-level palliative care to the most complicated patients through palliative care teams and primary palliative care—routine pain and symptom management, goals of care discussions and assistance with community resources—through the primary cancer provider.

Dr. Smith: Agree. I never got any training during hem/onc training. Most of us don’t have specific ways of doing goals of care discussions, don’t use a symptom assessment tool and don’t inquire about spiritual needs. And we refer too late to hospice or not at all.

Less than half of cancer patients died with hospice last year. After 40 years of hospice showing patients receiving better care and maybe even living longer— c’mon, folks, we can do better.

Dr. Abernethy: On the fence. Cancer care providers are just like the rest of us: They have an uneven skill base, and this time the patchwork is palliative care skills. I find that oncologists generally are motivated and interested in making sure that they have the basic tools—for example, communication skills and pain management—even if every oncologist is not prepared with those tools. They have formed close bonds with their patients, and it is hard to transition care to someone else just because times are tough and the disease has progressed. That being said, oncologists that I meet are interested in having input from specialist palliative medicine providers as an “extra set

of eyes” when the situation is complex; in my experience, younger practitioners who have been trained at a time when palliative care has been more commonplace are more willing to request palliative care help.

The ground is fertile for oncologists to provide primary palliative care, and when available, transition patients to specialists for complex cases. There is the opportunity to expand the skill base in basic palliative care skills for the oncologist so that everyone has the basic tools. This way we can ensure that there is a consistent knowledge base for oncology that extends beyond basic pain management to include the enlarging basis of primary palliative care knowledge.

Dr. Von Roenn: Agree. Despite favorable physician self-assessments of their knowledge in primary and secondary palliative care, multiple examinations of their skills, as reported in the Journal of Clinical Oncology and other journals, have noted a lack of adequate proficiency in initiating and titrating opioids, treating common treatment- and cancer-related symptoms, timely referral to hospice and accurate communication about prognosis. Furthermore, the majority of oncology training programs do not have required rotations in palliative medicine and the majority of fellows do not receive formal feedback assessing their skill in communicating difficult news or leading family meetings.

Dr. Ellsworth: On the fence. Although resources exist to support oncologists who wish to obtain midcareer training in palliative medicine, this training can be time-consuming for practitioners who already have many competing scheduling demands. Furthermore, current oncology practice models do not always support practitioners’ efforts to obtain this training or to devote additional clinic time to providing palliative care hand in hand with cancer care. Creative solutions are needed to support oncologists in obtaining additional palliative care training and taking the time to implement it in the clinic setting.

Dr. Cooney: Agree. Oncology training programs now include exposure to palliative care concepts, but I do not believe that it is sufficient to enable most oncologists to provide the generalist palliative care interventions that their patients need, including open and honest communication about prognosis and treatment options, setting of appropriate goals and symptom management. Oncologists should not be expected to provide secondary, specialist-level palliative care.

Rather, they must recognize when it is needed and ensure that, within their health care system, this care is available to their patients and families.

Dr. Quill: Agree. All oncology providers should be trained to provide basic palliative care, which should include basic pain and symptom management, basic discussions about prognosis, the risks and benefits of oncologic treatments and lack of efficacy of CPR [cardiopulmonary resuscitation] in the presence of severe oncologic illness. More complex symptom management and difficult medical decision making should more often be the domain of specialty palliative care. Teaching oncologists about the basic communication skills needed to inform and support cancer patients is much more challenging than basic see ON THE SPOT, T page 21

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

Expert Insights From The Ohio State University Comprehensive Cancer Center Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care.

This month we continue with the Ohio State University Comprehensive Cancer Center. We hope you find this Reviews & Commentaries section, both here and with additional commentaries at ClinicalOncology.com, to be a valuable tool.

In Selected NSCLC Patients With Brain Metastasis, Be Aggressive From the International Journal of Radiation Oncology, Biology, Physics

N

on-small cell lung cancer (NSCLC) patients with synchronous solitary brain metastasis (SSBM) benefit from aggressive surgical or radiosurgical treatments.

This retrospective study included 63 patients with NSCLC and SSBM. All of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1; were less than age 70 years; and had adequate pulmonary, hepatic and renal functions.

Patients received thoracic radiation therapy (TRT) with a dose of 66 Gy in 2-Gy fractions together with two

cycles of cisplatin-based chemotherapy. All patients received the prescribed TRT; additionally, 45 patients (71.4%) received two full-dose cycles of chemotherapy, while dose reductions of 25% (17.5% of patients) and 50% (11.1% of patients) were required in 18 patients.

Treatment for brain metastasis was by one of two methods: surgical resection followed by 30 Gy of whole-brain radiation therapy (WBRT; n=33) or, if the lesion was inaccessible or if the patient refused surgery, stereotactic radiosurgery (SRS) by Gamma Knife or CyberKnife followed by 30 Gy of WBRT (n=30).

In the study, which was published in the International Journal of

EXPERT INSIGHT David Carbone, MD Barbara J. Bonner Chair in Lung Cancer Research Director, Thoracic Oncology Program The Ohio State University Comprehensive Cancer Center— Arthur G. James Cancer Hospital & Richard J. Solove Research Institute Columbus, Ohio

M

etastasis to any site is a poor prognostic factor in lung cancer. However, it has long been recognized that aggressive therapy of both the brain and primary lesion in the setting of brain-only metastasis can result in longterm cures. Aggressive management of

brain-only metastases with surgery or SRS in lung cancer in the context of a surgically resectable primary tumor is thus now standard of care.

Parlak et al studied aggressive management of brain oligometastatic disease by surgery or SRS in the context

Radiation Oncology, Biology, Physics (2014;88:885-891, PMID: 24495594), Cem Parlak, MD, and his Turkish coauthors found that 28 patients (44.4%) had an objective response, 15 (23.8%) had stationary disease and 20 (31.7%) had progressive disease. There was no difference between the groups treated with SRS or surgery, and survival rates between the two groups revealed no significant differences.

At a median follow-up time of 25.3 months (7.1-52.1 months), 25 patients (39.7%) were still alive, and nine were free of disease progression. Median months of overall survival, locoregional progression-free survival (PFS), neurologic PFS, and PFS were 28.6,

17.7, 26.4 and 14.6 months, respectively.

The most common initial failure was isolated extracranial distant relapses (n=22; 34.9%). Overall, the intracranial control rate was 84.1% and only five patients (7.9%) exhibited isolated intracranial relapse.

The authors concluded that the relatively high survival rates achieved were due to aggressive treatments directed at the SSBM and the concurrent TRT in a highly selected group of stage III NSCLC patients with good performance status. The authors recommended future prospective trials to test “the encouraging outcomes observed here that suggest prolonged survival after aggressive treatment.”

This study reinforces an aggressive treatment approach for both primary and brain-only diseases, even in the context of nonsurgically managed primary disease. of chemoradiation therapy for the lung primary. They found a PFS of 14.6 months, which is comparable with other studies of thoracic chemoradiation in the absence of brain metastases. Additionally, they found that patients whose brain metastases were surgically resected and then underwent WBRT had a comparable outcome to those treated with SRS followed by WBRT.

This study reinforces an aggressive treatment approach for both primary and brain-only diseases, even in the context of nonsurgically managed primary disease.

Dr. Carbone is the president-elect of the International Association for the Study of Lung Cancer. He reported no relevant financial conflicts of interest.

11

In the research of advanced cancers

What if inhibiting the PD-1 helped restore immune

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

Normal State Antigens

Active T cells

Apoptosis-inducing proteins Tumor

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

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 activity 1-3,8 Tumor Immune Evasion

Antigen-presenting cell

Antigens Inactive T cells

Active T cells

PD-L1 ligand

Tumor cell

PD-1 receptor

Inhibited T cell

Tumor PD-L2 ligand

PD-1 receptor

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

checkpoint pathway response to tumor cells?

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 cancer 3,10 Active T cell

X

X

X Apoptosis-inducing proteins

PD-L2 ligand

X

PD-L1 ligand

PD-1 receptor

Tumor

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

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

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

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 significance 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.

©2014 Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB00597-03-01 04/14 Printed in USA.

14

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

Genetic Screenings for Breast Cancer Personalize Therapy From Lancet Oncology

P

atients with metastatic breast cancer were screened for genetic abnormalities to uncover the hurdles involved in identifying and treating patients with emerging targeted therapies.

Fabrice Andre, MD, and his French co-authors recently published the results from their multicenter, prospective trial, known as SAFIR01/UNICANCER, in Lancet Oncology (2014; 15:267274, PMID: 24508104). To find patients to participate in clinical trials and, specifically, those who would benefit from

existing treatments targeting specific mutations, the authors sought to identify subpopulations of patients by screening for genetic alterations.

Between June 2011 and July 2012, 423 patients with metastatic breast cancer from 18 cancer centers in France, who had a performance status (PS) of 0 or 1 and stable disease were enrolled in this study. Participants underwent a biopsy of the metastases or primary tumor. Liver, lymph node and skin were the most common biopsy sites. The samples were then sent to one of five genomic centers for comparative genomic hybridization array and Sanger sequencing on

EXPERT INSIGHT Charles Shapiro, MD Professor and Director, Breast Medical Oncology Program The Ohio State University Comprehensive Cancer Center— Arthur G. James Cancer Hospital & Richard J. Solove Research Institute Columbus, Ohio

T

here is a sea change coming in the way in which treatment is selected for advanced breast cancers. As we learn about the mutated genes, multiple copies of genes (or gene amplification) and key pathways that drive the growth of a primary cancer and its metastases, and as we develop specific drugs that target these abnormal genes or pathways, the hope and promise is for more effective therapies with improved quality of life for those diagnosed with breast cancer. Are the fundamental underpinnings of such a treatment approach really new? Lest we forget about the original target, the estrogen receptor, and drugs like tamoxifen that block estrogen from binding to the estrogen receptor, or aromatase inhibitors that reduce circulating endogenous estrogens. Likewise, identification of the erb-2 receptor led to development of trastuzumab and changed the

natural history of erb-2–overexpressing advanced and early-stage breast cancers. Thus, the precedent of “targeted treatment” is well established in breast cancer, but there are other targets and new drugs to test, and this article by Andre et al gives us a real-world perspective of where we are in 2014.

The SAFIR01 trial to my knowledge is the largest such trial, and enrolled 423 women with metastatic breast cancer from 18 centers, biopsied a metastatic site in most, sequenced the DNA in about 75%, and, ultimately, treated 55 (13%) of them with a targeted therapy. The trial eligibility criteria identified women who had had limited prior chemotherapy, PS 0 or 1, and a non– bone metastatic site to biopsy. This is a selected group not wholly representative of the spectrum of women with metastatic disease, especially those with bone-only metastases, which

PIK3CA and AKT1.

After exclusions—the majority due to low percentages of tumor cells in the biopsy—299 samples were analyzed. Of the 423 enrolled patients, 195 (46%) had at least one targetable genomic alteration identified, and 107 of these patients (55%) had more than one genetic target. PIK3CA mutation (n=74), CCND1 amplification (n=53) and FGFR1 amplification (n=36) accounted for more than half of the identified alterations. Rare targetable genomic alterations (<5% of this population) were found in 117 patients (39%).

By September 2013, 55 patients in

the study had received targeted treatments based on their genomic variations, including 28 patients enrolled in ongoing Phase I or II trials.

Enrollment for this study, which was initially expected to take three years, was completed in 13 months.

The authors concluded there is high acceptance and expectations for personalized medicine from both patients and physicians. Reducing the costs and complexity of the sequencing, and finding easier, safer methods for biopsy collection will advance clinical research and lead to improved individualized patient care.

There is a sea change coming in the way in which treatment is selected for advanced breast cancers. represents up to 40% of women. Current technology limits genomic analysis from bone biopsies. The most prevalent mutations were those of PI3 kinase (25%), which has been noted in other reports, followed by CCND1 (18%) and FGFR1 (12%), respectively, and AKT1 mutations (4%). Of the women who received targeted therapy, 13 (~30%) derived clinical benefit. The trial was sponsored in part by the French National Cancer Institute and included access to a very robust portfolio of at least 10 different targeted drugs.

What are the lessons of the SAFIR01 trial going forward? About one-third of metastatic core biopsies were not sequenced because they contained too few tumor cells. As functional imaging/biopsy techniques and methodologies that use smaller amounts of DNA improve, so will the number of women who have usable biopsies. Additionally, many more tumor biopsies need to be sequenced to benefit a relatively small number of women (i.e., in SAFIR01 13 of 299, or 4%).

There are a limited but expanding number of novel targets and novel

drugs. This is bound to improve, as in the relatively recent example of the CDK 4/6 inhibitor, palbociclib, in combination with an aromatase inhibitor for women with estrogen receptor–positive metastatic disease. Newer approaches to Phase I and II trials using Bayesian methods—as well as multiple targeted drugs that are based on the genomic profiling of primary tumors or metastases—are being designed or activated. The enthusiasm and excitement about these approaches ultimately will have to be tested in properly powered and controlled Phase III or randomized Phase II trials for rare mutations, involving unprecedented degrees of cooperation between treating clinicians in the community, academic cancer centers, the pharmaceutical industry and, especially, federal funding agencies. This represents the real sea change, and the SAFIR01 trial demonstrates that it can be done and provides a model for subsequent studies.

Dr. Shapiro reported no relevant financial conflicts of interest.

More REVIEWS & COMMENTARIES from THE OHIO STATE UNIVERSITY—THE JAMES Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com Experts provide clinical perspectives on important recently published studies.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

Full-Spectrum Endoscope Best at Detecting Colorectal Adenomas From Lancet Oncology

A

new full-spectrum endoscope, with a wider field of view, proved superior to a standard forward-viewing endoscope for detecting colorectal adenomas.

Patients at six international sites who were referred for colorectal cancer (CRC) screening, polyp surveillance or diagnostic assessment were invited to participate in a study that compared endoscopies and adenoma miss rates.

Patients were assigned to receive a colonoscopy using a standard forward-viewing endoscope, offering a viewing field of up to 170 degrees, or a full-spectrum

endoscope (Fuse, EndoChoice), providing imaging from the forward tip as well as both sides, amounting to a 330-degree viewing field. After completing the initial first-pass examination with either of the randomly assigned endoscopes, patients would immediately be given a second colonoscopy using the other technology. The endoscopist and room would remain the same for both procedures.

In a report published in Lancet Oncology (2014;15:353-360, PMID: 24560453), Ian M. Gralneck, MD, and his co-authors confirmed that the miss rate was significantly lower in patients examined with the full-spectrum

EXPERT INSIGHT Peter P. Stanich, MD The Ohio State University Comprehensive Cancer Center— Arthur G. James Cancer Hospital & Richard J. Solove Research Institute Division of Gastroenterology, Hepatology & Nutrition The Ohio State University Wexner Medical Center Columbus, Ohio

C

olonoscopy with polypectomy has emerged as the preeminent tool for CRC screening and, more importantly, prevention. Recent work by Nishihara et al investigating outcomes of a large, prospective cohort showed a significant reduction in both death from CRC after screening colonoscopy (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.24-0.45) and CRC incidence after colonoscopy with polypectomy (HR, 0.57; 95% CI, 0.45-0.72), which confirms multiple previous retrospective studies with similar results.1 Despite this laudable clinical effect, interval CRC still occurs, more than half of which have been found to be due to missed polyps at time of colonoscopy.2 In a similar vein, Corley et al recently published their findings that higher adenoma detection rates (ADRs) by gastroenterologists were associated with lower risks for interval CRC and fatal interval cancer.3 It is in this setting that the importance of polyp detection during colonoscopy is now being stressed. This is typified by quality measures proposed by the U.S. MultiSociety Task Force on Colorectal Cancer and endorsed by the major national gastroenterology organizations, which recommend ADRs of at least 25% in men and 15% in women during firsttime screening examinations.4 The full-spectrum colonoscope that was investigated in the current study

increases the field of view from the standard 170 degrees shown on a single monitor to 330 degrees shown on three contiguous monitors. This new technology performed remarkably well in this randomized, multicenter tandem colonoscopy trial in 197 patients (185 were included in the per-protocol analysis). The adenoma miss rate with fullspectrum endoscopy was significantly lower (7% vs. 41%; P<0.0001). The predominance of adenomas missed by standard colonoscopy was right-sided (proximal to the splenic flexure), which is an area known to harbor subtle lesions that are easily overlooked.

This fits with current data showing that standard colonoscopy is less effective in preventing right-sided colon cancer in comparison to the left side.1 The findings would also affect immediate clinical recommendations, as five patients with no polyps on standard colonoscopy were subsequently found to have polyps with full-spectrum endoscopy.

This would usually decrease the interval for repeat procedure by five years per patient.

One important caveat is the difference in withdrawal times between the standard forward-viewing colonoscopy and the full-spectrum colonoscopy. Within this study, full-spectrum colonoscopy had a significantly longer withdrawal time as well as total procedure time. Notably,

technology. Of the 88 patients (48%) who received standard colonoscopy first, 29 adenomas were identified in 25 patients. Those patients were then examined on a second pass with the full-spectrum device, and an additional 20 adenomas in 15 patients were identified (69% increase). Five of these patients (6%) had no adenomas identified during the first examination.

In the full-spectrum colonoscopy first group, 97 patients (52%) were evaluated; 60 adenomas and two cancers were identified in 33 patients.

When those patients received a second-pass standard colonoscopy, five additional adenomas were detected.

On a per-lesion analysis, the adenoma miss rate was significantly lower in the full-spectrum group than the standard group: five of 67 (7%) missed versus 20 of 49 (41%; P<0.0001).

The authors also found fewer falsenegative results with the full-spectrum colonoscopy (0 of 97 patients) than the standard forward-viewing colonoscopy (five of 88; 6%). The time to complete the colonoscopies was similar, as were reports of adverse events. As this new technology offers advanced optics and a wider-angle field of view, the increased visualization should optimize surveillance of the colonic mucosa and improve the effectiveness of CRC screening.

If the results of the study can be replicated and if the system is financially competitive, it should be at the forefront of emerging technologies to aid in polyp detection and help clinicians exceed the current colonoscopy quality indicators. the forward-viewing exams did not meet the recommended minimal mean withdrawal time of six to 10 minutes.4 Although the authors downplayed the clinical significance of this, previous publications have routinely found that longer withdrawal times are associated with increased ADRs.5 Interestingly, it is not clear if this is a confounding factor that should be controlled for in future studies or an intrinsic component of full-spectrum endoscopy (to clarify, does the increase to three screens to inspect during the procedure consistently cause longer withdrawal times?). This deserves attention in future studies of this technology.

Endoscopists and health systems have been slow to embrace new technologies that have previously been shown to increase polyp detection.

This is likely due to either cost (such as high-definition endoscopy systems) or unfamiliarity (such as virtual chromoendoscopy or cap-assisted colonoscopy). Using the full-spectrum endoscopy system would necessitate the purchase of new colonoscopes, processors and monitors at a significant price.

It remains to be seen if this financial hurdle to widespread incorporation of this technology can be overcome. It may be more enticing if, in the future, colonoscopy reimbursement becomes tied to meeting minimal quality benchmarks, as many anticipate.

Overall, full-spectrum endoscopy

is an exciting advance in endoscopic technology. If the results of the study can be replicated and if the system is financially competitive, it should be at the forefront of emerging technologies to aid in polyp detection and help clinicians exceed the current colonoscopy quality indicators.

References 1. Nishihara R, Wu K, Lochhead P, et al.

Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med. 2013;369:1095-1105, PMID: 24047059.

2. Robertson DJ, Lieberman DA, Winawer SJ, et al. Colorectal cancers soon after colonoscopy: a pooled multicohort analysis. Gut. 2013 Jun 21. [Epub ahead of print], PMID: 23793224.

3. Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298-1306, PMID: 24693890.

4. Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97:1296-1308, PMID: 12094842.

5. Barclay RL, Vicari JJ, Greenlaw RL. Effect of a time-dependent colonoscopic withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol. 2008;6:1091-1098, PMID: 18639495.

Dr. Stanich reported no relevant financial conflicts of interest.

15

16

SOLID TUMORS

MAMMOGRAPHY continued from page 1

largely depend on whether you are talking about the relative risk or the absolute risk, whether the intervention is measured by invitation to screening or exposure to screening, and the duration of follow-up. Commonly, these elements are not expressed in these estimates and that is a big factor in why they differ so much,” said lead study author Robert Smith, PhD, a cancer epidemiologist and the senior director of the Cancer Control Science Department at the American Cancer Society, Atlanta.

A comparison of data from a 2009 meta-analysis by the U.S. Preventive Services Task Force (USPSTF) and the Swedish Two County Trial underscores the differences that can arise when invitation to screen or actual screening is used (Cancerr 2012;118:5728-5732, PMID: 22605639; Ann Intern Med d 2009;151:727– W242, PMID: 19920273). In the Swedish Two County Trial, the number needed to screen to prevent one breast cancer death was 464. In the USPSTF study, the number needed to invite to screening to prevent one breast cancer death was 1,224. “We can all recognize that an invitation to screen is not likely to help any woman unless she actually attends screening,” Dr. Smith said.

Data from the Swedish trial also illustrates the big role that long-term follow-up plays in estimates of benefit.

With 10 years of follow-up, 922 women were required to be screened to prevent one death, but this fell to 414 with 29 years of follow-up. “The absolute benefit grows steadily better with longer follow-up,” Dr. Smith said. “You are not able to observe half the deaths prevented at 10 years of follow-up. It is important to emphasize that you need at least 20 years of follow-up in the evaluation of breast cancer screening to observe most of the benefit.”

The new study, presented at the San Antonio Breast Cancer Symposium (SABCS), analyzed four mammography benefit estimates: a 2012 meta-analysis from the Independent UK Panel on Breast Cancer Screening, the 2009 USPSTF study, a 2011 Nordic Cochrane review and a 2012 EUROSCREEN metaanalysis ((Br J Cancer 2013;108:22052240, PMID: 23744281; Cochrane Database Syst Rev 2013 Jun 4;6:CD001877, PMID: 23737396; Br J Cancer 2013;108:2205-2240, PMID: 23744281).

Three of the studies used many of the same clinical trials for their data, and the EUROSCREEN group evaluated observational studies of the European screening programs, yet the estimates differ by almost 20-fold, from 90 to 2,000 women needed to screen to prevent one death (Table 1).

According to Dr. Smith, methodology is to blame. The studies included women

CLINICAL ONCOLOGY NEWS •JUNE 2014 • CLINICALONCOLOGY.COM

Table 1. Quoted Absolute Benefits Reveal 20-Fold Difference: Number Needed To Screen vs. Number Needed To Invite Study

Number Needed To Screen

Follow-up Period, y

U.K. Review (2012)

180a

20

USPSTF, depending on age (2009)

377-1,904b

15

Nordic Cochrane Review (2011)

2,000b

10

a

30

EUROSCREEN (2012)

90

a

Number of women needed to screen for 10 years to prevent one breast cancer death

b

Number needed to invite to screening

USPSTF, U.S. Preventive Services Task Force

When you level the playing field, the study conclusions are not all that different, and show a substantial benefit associated with screening.

Table 2. Adjusted Absolute Risk Estimates Of Number Needed To Screen To Save One Life Based on U.K. Review Standard

Study

Number Needed To Screena/Inviteb (original)

Number Needed To Screen (adjusted)

U.K. Review (2012)

180a

180

USPSTF, depending on age (2009)

377-1,904b

193

Nordic Cochrane Review (2011)

2,000b

257

EUROSCREEN (2012)

90a

96

a Original estimates are adjusted to the same scenario used in the U.K. Independent Review. In the U.K., women aged 50 to 70 are invited to screening every three years. The study applied the relative mortality of 20% to the observed cumulative absolute risk for breast cancer death over the ages of 55 to 79 years.

US S , U USPSTF, U.S. S Preventive eve t ve Services Se v ces Task as Force o ce

of different ages, with different periods of follow-up, and, in fact, investigated different things, with some analyzing actual screening and others examining invitation to screening.

To level the playing field, Dr. Smith and his colleagues adjusted the Cochrane, USPSTF and EUROSCREEN meta-analyses to mirror the conditions in the U.K. study. In that study, women aged 50 to 70 years were invited to screening every three years. The study applied the relative mortality of 20% to the observed cumulative absolute risk for breast cancer death over the ages of 55 to 79 years, with a follow-up of 20 years.

The Cochrane review used an estimate of absolute benefit based on a 15% reduction in breast cancer mortality. It had a screening period of 10 years and a follow-up period of 10 years, but they were contemporaneous. The study’s estimate, based on invitation to screening among women aged 40 to 74, was that one breast cancer death would be prevented per 2,000 women invited to screen.

Using the 20% estimate of absolute benefit as in the UK Study, and the estimated number needed to screen versus the number needed to invite, then 1,100 women would need to be screened to prevent one breast cancer death,” Dr. Smith said. “If you adjust the data to follow women for 20 years instead of 10, then 600 women would be needed to screen to prevent one breast cancer death. Since the Cochrane estimate was heavily dependent on trials with women in their 40s, where there is a lower prevalence of breast cancer, if we adjust them up to women ages 50 to 69, as the U.K. independent review did, we are now down to close to 300 needed to screen to prevent one cancer death. These estimates become more similar” (Table 2).

The USPSTF study concluded that 1,339 were needed to invite to save one life among women aged 50 to 59, and 377 were needed to invite if women were between the ages of 60 to 69. The researchers used these numbers to create a weighted average for women aged

50 to 69, adjusted it to the number needed to screen instead of the number needed to invite, and converted it to the same follow-up period as in the U.K. review.

The new number was 193. Adjusting the EUROSCREEN data in a similar way achieved similar results.

“When we adjust all of these studies to the U.K. Review standard … we go from about a 20-fold difference in the estimates of absolute benefit to about a 2.5fold difference,” Dr. Smith said.

He pointed out that some clinicians have argued that mammography is harmful because it creates an overdiagnosis problem, but a 2012 study revealed that the wide range of estimates of overdiagnosis also were the product of different methodologies (J ( Med Screen 2012;19:Suppl 1:42-56, PMID: 22972810).

This study concluded that the most plausible estimates of overdiagnosis range from 1% to 10% and that substantially higher estimates of overdiagnosis reported in the literature are due to the lack of adjustment for breast cancer risk and/or lead time.

Dr. Smith concluded that the data show “very clearly that the balance of benefits and harms is substantially in favor of regular mammography screening.”

In contrast, Archie Bleyer, MD, a clinical research professor at Oregon Health & Science University, in Portland, and Gilbert Welch, MD, MPH, a professor of medicine and community & family medicine at the Dartmouth Institute for Health Policy & Clinical Practice, in Hanover, N.H., disagree. Their recent publication in The New England Journal of Medicine concluded that despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer (N ( Engl J Med d 2012;367:1998-2005, PMID: 23171096). Their study concluded that the “imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers.”

Dr. Welch made the case against mammography screening in the same morning session at SABCS. He pointed out that three other studies concluded that screening has had little or no effect on breast cancer mortality ( (BMJ 2011;343:d4411, PMID: 21798968; J Natl Cancer Inst 2012;104:1080-1093, PMID: 22811439; and N Engl J Med 2010;363:1203-1210, PMID: 20860502).

“All of these comparisons suggest that the addition of screening in this era has little, if any, role in reduced breast cancer mortality,” Dr. Welch said. “Breast cancer mortality has fallen by 30% over the last 20 years. Breast cancer treatment has improved a lot over the last 20 years. Screening mammography appears see MAMMOGRAPHY, Y page 19

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

SUBOPTIMAL CARE continued from page 1

The results of this study “suggest that a significant proportion of U.S. hematology and oncology specialists are not applying optimal care for patients with ALL, BCL and CML,” concluded the authors, led by Kevin L. Obholz, PhD, the senior managing editor at Clinical Care Options, in Reston, Va., who presented the data at the 2013 annual meeting of the American Society of Hematology (abstract 901). B. Douglas Smith, MD, an associate professor of oncology at Johns Hopkins’ Sidney Kimmel Cancer Center, in Baltimore, was the senior author.

In this two-phase study, hematologists and oncologists were required to treat at least two cases of ALL, BCL and CML annually and at least 10 cases of these diseases combined, to participate. An exploratory qualitative phase included a Web-based survey, in which 27 participants were invited to answer case-based questions as well as a 45-minute telephone interview. In this phase, the goal was to determine the reasoning behind clinical decisions, to guide development of the second, quantitative phase.

In the second phase, participants answered multiple-choice questions on clinical decisions based on case vignettes. The answers submitted by the participants to these questions were compared with answers derived from guidelines and expert options reflecting optimal practice. Of the 209 subjects initially recruited, 121 who met study eligibility criteria completed this phase.

Disparity among responses suggests that there are major gaps in practice and particular confusion about the goals of treatment with TKIs. Of the answers in the second phase that were most worrisome, only 38% of participants agreed that achieving an MMR with a TKI substantially reduces the risk for disease progression. Moreover, only 33% recognized that early molecular responses to a TKI correlate with better outcomes among patients with chronic-phase disease. When asked about timing and frequency of cytogenetic analyses, only 22% provided answers that were consistent with currently recommended schedules.

These disparities indicate that there are practice gaps that could threaten optimal outcomes. For example, these data suggest that a large proportion of clinicians would be unable to individualize patient care because they are unfamiliar with the goals of TKI treatment.

Beyond the fact that many clinicians were uncertain about how to identify a suboptimal TKI response, less than 30% of clinicians could name the targets of promising agents in Phase III trials, which included, at the time of this survey, idelalisib (Gilead) and obinutuzumab (Gazyva, Genentech). This lack

Only about one-third of clinicians recognized the prognostic significance of a major molecular response with a TKI, and less than one-third were familiar with prevailing expert opinion regarding the timing and frequency of cytogenetic analyses. of knowledge suggests a potential barrier to referring patients to clinical trials, as well as a barrier to using these novel agents, if they are approved.

The main message of this study, according to the investigators, is that more educational initiatives are needed

to reach practicing physicians about pathways of managing ALL, BCL and CML, particularly in relation to TKIs. The authors specifically recommended performance improvement interventions, because molecular targets make individualized treatment increasingly

17

important for patients with hematologic malignancies.

Elias J. Jabbour, MD, an associate professor of medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston, suggested that asking community oncologists to become experts on TKIs to optimize management of CML and other uncommon hematologic malignancies may be setting the bar too high. He noted that CML, for example, is a rare cancer that a community oncologist might encounter only one or see SUBOPTIMAL CARE, E page 19

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key efficacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Montefiore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify effective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics.

4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour

Sponsored by

DESIGNATION OF CREDIT PHYSICIAN CONTINUING EDUCATION Accreditation Statement Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical

Supported by an Educational Grant from

Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. ™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

PHARMACIST CONTINUING EDUCATION Educational Concepts Group, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Educational Concepts Group, LLC designates this continuing education activity for 1.0 contact hour (0.10 CEU) (UAN 0199-0000-13-034-H01-P).

TYPE OF ACTIVITY Knowledge-based

METHOD OF PARTICIPATION There are no fees for participating and receiving CME/CE credit for this activity. During the period October 1, 2013 through September 30, 2014, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; and 3) complete the post-activity assessment.

CME/CE CREDIT Physicians and pharmacists who complete the postactivity assessment with a score of 70% or better may view and print their credit letter or statement of credit via the website, www.educationalconcepts.net.

Distributed via

18

CURRENT PRACTICE

HOW I MANAGE continued from page 1

Nicolaus Kröger, MD Medical Director Clinic for Stem Cell Transplantation University Medical Center Hamburg-Eppendorf Hamburg, Germany

in allo-HCT. According to the European Group for Blood and Marrow Transplantation (EBMT), the number of allo-HCT procedures for MDS/AML increased from 737 in 2001 to 1,636 in 2010. In parallel, the percentage of allo-HCT procedures in older adults (>65 years) with MDS increased from 2% in 2001 to 14% in 2010.

Which patients with MDS should be referred for allo-HCT and why?

The treatment strategy with the highest curative potential for patients with MDS is allo-HCT. After standard myeloablative (MA) conditioning and HLAmatched sibling donor transplantation, disease-free survival rates are between 29% and 40%.

However, transplantation is hampered by substantial treatment-related morbidity and mortality. The decision algorithm for allo-HCT is based on disease-specific

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

factors as well as transplant-specific and patient-specific factors, all of which influence transplant outcomes. Prognostic scoring systems, such as the International Prognostic Scoring System (IPSS), which includes number of blasts, cytopenias and cytogenetics, or the World Health Organization’s prognostic scoring system, which also includes transfusion dependency, may help to determine the prognosis of patients with MDS at diagnosis and during the course of the disease.1,9,10 In low- and intermediate 1-risk groups of MDS patients, the selection of therapy relies on multiple factors. In low-risk asymptomatic patients, watchful waiting is reasonable; for selected patients in the intermediate 1-risk group, allo-HCT is recommended, specifically if there is a poor cytogenetic profile, transfusion dependency that is unresponsive to hypomethylating agents or other therapies, or increasing number of blasts.11 There is general agreement that allo-HCT should be offered to patients with intermediate 2- or highrisk disease according to IPSS criteria.11 Overall, in all patients the risk for nonrelapse mortality (NRM) should be taken into account and carefully balanced with nontransplant approaches.12

Is there any benefit of treating MDS patients with hypomethylating agents before allo-HCT? The number of blasts and not being in complete remission (CR) at the time

AT A GLANCE • The ELN recommends that cytoreductive therapy before allo-HCT should be considered for patients with 10% or more bone marrow blasts within a clinical trial or a prospective registry.

• Studies from EBMT and CIBMTR suggest that recipient age alone cannot be considered a contraindication for allo-HCT. • The available literature suggests that age per se should not be a criterion for selecting the intensity of the conditioning regimen rather than performance status or comorbidity and the status of the disease at time of transplant.

• The recent discovery of mutations in patients with MDS by modern sequencing techniques should allow for screening patients before transplantation for specific mutations and can be used after transplantation as a marker for residual disease and as a guide for adoptive immunotherapies to prevent clinical relapse.

• Allo-HCT should be included early in the treatment plan for patients with MDS, which includes intensive chemotherapy and novel compounds such as hypomethylating agents to achieve cytogenetic response and reduction of the number of blasts before transplantation.

of transplantation are the most significant factors leading to an inferior outcome, especially after reduced-intensity conditioning (RIC) transplants in MDS.5,13-15 The issue of induction chemotherapy before transplantation has been discussed controversially. Retrospective, small, single-center studies have not produced conclusive results, but it is very likely that the reported results are biased by the selection of patients who received intensive chemotherapy before transplantation, and those who did not achieve CR were not treated with alloHCT.14,16,17 The European Leukemia Net (ELN) recommends considering cytoreductive therapy before allo-HCT in patients with no less than 10% bone marrow blasts within a clinical trial or a prospective registry.11 Agents such as 5-azacytidine (AZA; Vidaza, Celgene) or decitabine (Dacogen, MGI Pharma), which have been shown to be active in MDS, also may be used as pretransplant cytoreductive therapy.18,19 A retrospective French study analyzed use of this strategy compared with intensive chemotherapy before allo-HCT. The study did not find any difference in three-year overall survival.20 AZA alone led to outcomes similar to those with standard induction chemotherapy. Although CR rates are approximately 10% lower compared with conventional induction chemotherapy, reported trials have been unable to demonstrate superiority of induction chemotherapy over AZA before allo-HCT.21,22

Is age alone a contraindication for allo-HCT in MDS? No. The majority of the large retrospective trials consider a patient’s age as a major prognostic factor for therapy-related mortality; however, with the advent of reduced toxicity and RIC regimens, this might not hold true.5,6,15 Two recent large registry trials reported on behalf of the EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) addressed this particular issue.23,24 Both studies suggest that recipient age alone cannot be considered a contraindication for allo-HCT. Because patient age alone is not a major risk factor, other factors such as comorbidities that by nature develop with increasing age, are taken into account. The Hematopoietic Cell Transplantation Comorbidity Index, developed by Mohamed L. Sorror, MD, MSc, of the Fred Hutchinson Cancer Research Center in Seattle, has been demonstrated to be useful in patients with MDS or AML who underwent allo-HCT after RIC or standard conditioning regimens.25 Other reports have confirmed inferior survival among MDS patients with higher comorbidity scores after allo-HCT, independent of chronological age.26,27

How does disease status before allo-HCT influence outcome in patients with MDS? Disease status defined by IPSS has been validated in a nontransplant MDS cohort and the scoring system also has proven useful as a predictive model for outcomes after allo-HCT.28,29 There is a clear correlation between disease status at time of transplantation and outcome after transplantation, which favors transplantation in an early stage of the disease based on low incidence of relapse.12,30 Cytogenetic abnormalities have a major effect on outcome after allo-HCT for MDS. The established risk groups regarding cytogenetic abnormalities within the IPSS and IPSS-Revised and monosomal karyotype also have a major effect on outcome after allo-HCT.31-35 In addition to cytogenetic abnormalities, modern genomic techniques, such as next-generation sequencing and mass spectrometry– based genotyping, allow for the detection of molecular abnormalities—such as mutations in TP53, EHZ2, ETV6, RUNX1, TET2 and ASXL1—even in cytogenetically normal patients—which influences survival in a nontransplant setting.36 Furthermore, newly discovered mutations of the splicing machinery have become the most common detectable mutations in MDS patients, which might also have an effect on outcomes in a nontransplant setting.37,38

How should preparative regimens for MDS patients undergoing allo-HCT be selected?

The exploration of RIC regimens has resulted in less toxicity and broadened the application of allo-HCT, especially in older adults with hematologic malignancies. Data from retrospective registry studies from the EBMT and CIBMTR suggest lower NRM but a higher risk for relapse with RIC regimens compared with MA regimens.13,39 The major achievement of the new conditioning regimens is the reduced organ toxicity that broadens the application of alloHCT to older adults with MDS. Importantly, reducing organ toxicity does not exclude myeloablation or reduced antileukemic activity. For instance, using a targeted drug level and IV formulations as part of the conditioning regimen each have substantially reduced the toxicity of busulfan; both have been shown to reduce transplant-related complications and improve outcomes for patients with MDS, allowing for the safe use of this drug at myeloablative doses.40 Furthermore, cyclophosphamide as a toxic drug with only limited antileukemic activity, can be replaced by fludarabine, inducing less organ toxicity without obvious loss of antileukemic activity.41 Other alkylating drugs, such as treosulfan, also can be used safely as part of an MA regimen, with low toxicity and NRM in patients

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

with MDS.42,43 The available literature suggests that age per se should not be a criterion for selecting the intensity of the conditioning regimen, rather than performance status or comorbidity and the status of the disease at time of transplant.

The current data also suggest that there is no “one-size-fits-all” conditioning regimen in patients with MDS, and the selection of regimen intensity should be individualized according to comorbidities and risk for relapse.

What strategies are needed or are in clinical trials to prevent relapse after allo-HCT in MDS? Relapse has become the main reason for treatment failure after allo-HCT in patients with MDS.44 Because treatment of relapse has proven disappointing, preventing relapse after allo-HCT in this patient population is an active area of research and remains an unmet need. Experience with donor lymphocyte infusions (DLIs) for relapse treatment or prevention is limited but exists: Only 14% to 22% achieved a CR that lasted in two patients for more than five years; prophylactic DLI in a nonrandomized trial improved relapse-free survival, but the results might be biased by patient selection.45-47 AZA in combination with DLI has shown activity with CR rates of 23% after allo-HCT in patients with relapsed AML/MDS.48 AZA has been tested in a dose-finding study as maintenance therapy after transplantation in high-risk patients with AML and MDS. No severe side effects were observed, and there was no effect on graft-versus-host disease and chimerism.49,50 Monitoring CD34-positive lineage-specific chimerism might be a way to detect residual disease or early relapse and may allow successful intervention with AZA.51 The recent discovery of mutations in patients with MDS by modern

sequencing techniques should allow for screening patients for specific mutations before transplantation and can be used after transplantation as a marker for residual disease and as a guide for adoptive immunotherapies to prevent clinical relapse.36,52

Conclusions Allo-HCT is well accepted as a curative treatment approach in patients with MDS, which has become one of the most frequent indications for allo-HCT. In addition to chronological age, comorbidities should be taken into account when selecting patients for transplantation.

The intensity of the conditioning regimen should be based on comorbidities and risk for relapse. Allo-HCT should be included early in the treatment plan for patients with MDS, which includes intensive chemotherapy and novel compounds such as hypomethylating agents to achieve cytogenetic response or reduction of the number of blasts before transplantation.

Dr. Kröger would like to thank the staff of the Department of Stem Cell Transplantation at the University Medical Center Hamburg in Germany for providing excellent care of patients, and the members of the MDS subcommittee of the Chronic Leukemia Working Party of EBMT.

8. Blood. 2000;95:1188-1194, PMID: 10666189.

38. Blood. 2011;118:6239-6246, PMID: 21998214.

9. J Clin Oncol. 2005;23:7594-7603, PMID: 16186598.

39. Bone Marrow Transplant. 2012;47:203-211, PMID: 21441963.

10. J Clin Oncol. 2007;25:3503-3510, PMID: 17687155.

40. Biol Blood Marrow Transplant. 2002;8:145154, PMID: 11939604.

11. Blood. 2013;122:2943-2964, PMID: 23980065.

41. Blood. 2004;104:857-864, PMID: 15073038.

12. Br J Haematol. 2009;146:627-636, PMID: 19604243.

42. Haematologica. 2011;96:1344-1350, PMID: 21659356.

13. Blood. 2006;108:836-846, PMID: 16597592.

43. Bone Marrow Transplant. 2006;37:339-344, PMID: 16415898.

14. Leukemia. 2005;19:396-401, PMID: 15674354.

15. Blood. 2002;100:1201-1207, PMID: 12149198.

44. Biol Blood Marrow Transplant. 2011;17:443454, PMID: 21224011.

16. Biol Blood Marrow Transplant. 2005;11:6573, PMID: 15625546.

45. Bone Marrow Transplant. 2007;40:965-971, PMID: 17846603.

17. Biol Blood Marrow Transplant. 2007;13:454462, PMID: 17382251.

46. Bone Marrow Transplant. 2004;33:531-534, PMID: 14716345.

18. J Clin Oncol. 2002;20:2429-2440, PMID: 12011120.

47. Blood. 2006;108(abstract 324).

19. Lancet Oncol. 2009;10:223-232, PMID: 19230772.

20. J Clin Oncol. 2012; 30:4533-4540, PMID: 23109707.

49. Cancer. 2009;115:1899-1905, PMID: 19235255.

21. Bone Marrow Transplant. 2009;43:839-843, PMID: 19151791.

50. Cancer. 2010;116(23):5420-5431, PMID: 20672358.

22. Bone Marrow Transplant. 2010;45:255-260, PMID: 19543327.

51. Leukemia. 2012;26:381-389, PMID: 21886171.

23. J Clin Oncol. 2010;28:405-411, PMID: 20008642.

24. J Clin Oncol. 2010;28:1878-1887, PMID: 20212255.

25. J Clin Oncol. 2007;25:4246-4254, PMID: 17724349.

26. Bone Marrow Transplant. 2010;45:633-639, PMID: 19767782.

27. Eur J Clin Invest. 2008;38:945-952, PMID: 19021720.

References

28. Blood. 2008;112:895-902, PMID: 18497321.

1. Blood. 1997;89:2079-2088, PMID: 9058730.

29. Leukemia. 1998;12(suppl 1):S25-S29, PMID: 9777891.

2. Blood. 2008;111:4841-4851, PMID: 18467609.

3. WHO Classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer; 2008.

4. Biol Blood Marrow Transplant. 2009;15:137172, PMID: 19167676.

5. Br J Haematol. 2000;110:620-630, PMID: 10997974.

6. Blood. 2002;100:1997-2004, PMID: 12200358.

7.

Leukemia. 2003;17:859-868, PMID: 12750698.

48. Annual meeting of the American Society of Hematology. 2011;abstract 656.

30. Blood. 2002;100:1201-1207, PMID: 12149198.

31. Biol Blood Marrow Transplant. 2009;15:205213, PMID: 19167680.

32. Blood. 2006;108(abstract 2653).

33. Annual meeting of the American Society of Hematology. 2009;abstract 293.

34. Blood. 2011;118(abstract 666).

35. Blood. 2014;123:2333-2342, PMID: 24558201.

36. N Engl J Med. 2011;364:2496-2506, PMID: 21714648.

52. J Clin Oncol. 2011;29:2499-2506, PMID: 21576631.

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Coming Soon Evolving Role of Autologous Transplantation in Multiple Myeloma

by Sagar Lonial, MD Emory University

37. Nature. 2011;478:64-69, PMID: 21909114.

HEMATOLOGIC DISEASE

SOLID TUMORS

MAMMOGRAPHY

SUBOPTIMAL CARE

continued from page 16

continued from page 17

to have little to do with the ongoing decline in breast cancer mortality.”

Kent Osborne, MD, the director of the Lester and Sue Smith Breast Cancer Center at Baylor College of Medicine, in Houston, said Dr. Smith’s analysis makes sense. “These trials set out to invite 50,000 or so women to participate in a screening program, and when you do that, you have to analyze all 50,000, even if they didn’t show up to be screened,” he said. “I think it is pretty easy to understand that it is going to be an underestimate of the true benefit.”

Dr. Osborne also agreed that adjusting the follow-up time was logical. “Breast cancer is a more indolent disease than we thought. Many patients don’t [have a recurrence] and die of their breast cancer for a decade or more,” he said. “So, if you are not following patients long enough to catch all of the recurrences and deaths from the disease, then you don’t get a full assessment of the value of screening.”

two times in a year.

“The treatment options for CML are growing more complex. While it may be important for the community oncologist to be familiar with newer therapies, these cases should be managed at least in collaboration with an academic center where there is expertise and a higher volume of cases,” said Dr. Jabbour, noting that there is data demonstrating better outcomes with TKIs in hematologic malignancies at academic centers.

“The use of TKIs is getting increasingly individualized,” Dr. Jabbour said. It is important, for example, “to understand the milestones of response” to optimize care and consider alternative agents in a rational sequence. While not all care has to be delivered at an academic center, he said that he believes that it is more important to offer care in collaboration with an expert than attempt to master this expertise in a practice where the number of patients with these types of malignancies is limited.

—Kate O’Rourke

—Ted Bosworth

Drs. Smith and Osborne reported no relevant financial conflicts of interest.

Dr. Welch disclosed royalties from Beacon Press.

Drs. Obholz and Smith reported no relevant financial conflicts of interest. Dr. Jabbour disclosed financial relationships with Ariad, Bristol-Myers Squibb, Novartis and Pfizer.

19

20

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Highlights from NEJM, Blood and d JCO QUESTIONS

1. True or False. In a study pub-

lished in the Journal of Clinical Oncology ( (JCO ), detection of t(14;18) in the blood of otherwise healthy individuals by polymerase chain reaction had no relationship with the development of follicular lymphoma (FL).

2. True or False. According to the

mantle cell lymphoma (MCL) International Prognostic Index (MIPI), the five-year overall survival (OS) of patients with low-risk disease is approximately 83%.

with immunochemotherapy who achieved an event-free survival (EFS) of 24 months had an OS equivalent to that of the age- and sex-matched general population.

(IN-RT) could be safely omitted without compromising progression-free survival (PFS) in patients who achieve a negative early positron emission tomography (PET) scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) compared with standard combined-modality treatment in patients with favorable and unfavorable stage I/II Hodgkin lymphoma.

7.

True or False. A study from The University of Texas MD AnderPrimum non nocere. son Cancer Center in Houston, published in (First, do no harm.)

Blood, showed that fludeoxyglucose (FDG)/PET scanning was a useful diagnostic tool in patients with True or False. In a non–random- chronic lymphocytic leukemia (CLL) ized controlled trial published in JCO, and suspected transformation. consolidation RT to bulky (≥7.5 cm) sites abrogated bulky disease as a risk factor True or False. Pancreatitis should and improved the outcome of elderly not be considered in the differential patients with aggressive B-cell lympho- diagnosis of abdominal pain after brenma (predominantly diffuse large B-cell tuximab vedotin (BV; Adcetris, Seattle lymphoma [DLBCL]).

Genetics) therapy.

3. All of the following parameters are 5.

included in the MIPI model except: a. Age b. Performance status c. White blood cell count d. Lactate dehydrogenase (LDH) levels e. Bone marrow involvement

4. True or False. The randomized

EORTC/LYSA/FIL Intergroup H10 trial showed that involved-node radiotherapy

ANSWERS

1. False. In this study, 100 individ-

ual who developed FL were identified among 520,000 healthy participants enrolled in the EPIC (European Prospective Investigation Into Cancer and Nutrition) trial. Prediagnostic blood from these and 218 controls were screened for t(14;18) translocations using sensitive PCR-based assays. Remarkably, risk estimates remained high and significant up to 15 years before diagnosis of FL. Roulland S, Kelly RS, Morgado E, et al. t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma. J Clin Oncol. 2014;32:13471355, PMID: 24687831.

2. True. The five-year OS rates for

patients in the MIPI intermediateand high-risk groups are 63% and 34%, respectively. This model was developed in 2008 and was validated in a recent publication in JCO on behalf of the European Mantle Cell Lymphoma Network.

Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle cell lymphoma international prognostic index in randomized trials of the European mantle cell lymphoma network. J Clin Oncol.

2014;32:1338-1346, PMID: 24687837.

3. e. Four clinical baseline character-

istics used in the MIPI model were confirmed as independent prognostic factors for OS and time to treatment failure (TTF) in the study published in JCO. In

8.

6. True or False. In a study published 9. The current definition of monoin JCO, patients with DLBCL treated

clonal B-cell lymphocytosis (MBL)

this study, the validity of the MIPI was independent of trial cohort and treatment strategy. Bone marrow involvement is not part of the MIPI model.

involved-field RT (36 Gy) to sites of initial bulky (≥7.5 cm) disease and extralymphatic involvement—was compared with a cohort receiving the same immunochemotherapy but without RT in patients between the ages of 61 and 80 years. It is important to note that there are many caveats to this study, as pointed out in an excellent editorial that accompanies this publication in JCO. In the era of PET scanning, whether patients who are PET-negative complete responders after immunochemotherapy can be spared RT must be addressed in appropriately designed prospective trials, for example the OPTIMAL>60 trial.

Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle cell lymphoma international prognostic index in randomized trials of the European mantle cell lymphoma network. J Clin Oncol.

2014;32:1338-1346, PMID: 24687837.

4. False. In the preplanned interim

futility analysis of this study published in JCO, an independent data-monitoring committee concluded that the experimental arm was unlikely to show noninferiority in the final results and advised stopping random assignment for early PET-negative patients. Thus, omitting IN-RT in early PET-negative patients resulted in a higher percentage of early relapses than combined-modality treatment. A final trial analysis will reveal mature outcome data.

Raemaekers JM, André MP, Federico M, et al.

Omitting radiotherapy in early positron emission tomography-negative stage I/II hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32:1188-1194, PMID: 24637998.

5. True. The best arm of the RICOVER-60 trial—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) administered once every two weeks plus two additional applications of rituximab plus

Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol.

2014;32:1112-1118, PMID: 24493716.

Kahl BS. Bulky aggressive B-cell lymphoma: to radiate or not to radiate—that is the question. J Clin Oncol. 2014;32:1097-1098, PMID: 24550422.

6. True. An “event” was defined as

“relapse, re-treatment, unplanned consolidative radiation therapy and death.”

Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled into the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

encompasses all of the following statements except: a. Presence of circulating small B-cell clones at a level of less than 5×109/L persisting for more than three months in healthy individuals b. No evidence of lymphadenopathy, organomegaly, an associated autoimmune disease, or any other feature diagnostic of a B-cell lymphoproliferative disorder c. Absence of a paraprotein

10. True or False. Clonal B-cell

lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin (CBL-MZ) appears to be a distinct entity and, similar to well-defined “MBL,” does not require therapy in the absence of progressive disease.

2002 to 2009. The results from this study were confirmed in 820 patients from the GELA study and registry in Lyon, France.

Maurer MJ, Ghesquières H, Jais JP, et al. Eventfree survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.

J Clin Oncol. 2014;32:1066-1073, PMID: 24550425.

7. True. Disease transformation in

CLL, or Richter syndrome, which is frequently overlooked, has an extremely poor prognosis and requires aggressive therapy. A positive FDG/PET not only supports the possibility of transformation but points to the site where a biopsy is more likely to be informative. On the other hand, current data does not justify using FDG/PET routinely in the prognostic evaluation or response to therapy assessment of patients with unsuspected transformed CLL. Falchi L, Keating MJ, Marom EM, et al. Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia. Blood. 2014;123:2783-2790, PMID: 24615780.

Molica S. FDG/PET in CLL today. Blood.

2014;123:2749-2750, PMID: 24786452.

8. False. Pancreatitis should be con-

sidered in the differential diagnosis of abdominal pain after BV therapy. In a study in Blood, the median time to presentation was 26 days from the first BV exposure and 12 days from the most recent treatment, with all cases (n=8)

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2014 • CLINICALONCOLOGY.COM

occurring by the third cycle of therapy.

Two patients were retreated with BV after their initial episodes of pancreatitis, including one patient who developed recurrent pancreatitis and one who never redeveloped symptoms. Two patients experienced progressive multiorgan dysfunction as a consequence of pancreatitis, leading to death.

Gandhi MD, Evens AM, Fenske TS, et al. Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious

adverse event. Blood. 2014;123:2895-2897, PMID: 24786458.

9. C. Presence of a paraprotein is

allowed within the current criterion of MBL. The diagnostic criteria for CLLlike clinical MBL have been used to refine the diagnosis of CLL, and the cutoff of 5×109/L circulating clonal B lymphocytes for distinguishing clinical MBL from CLL is arbitrary, lacking clinical or biological justification.

ON THE SPOT

Marti GE, Rawstron AC, Ghia P, et al. International Familial CLL Consortium. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130:325-332, PMID: 16042682.

Shanafelt TD, Ghia P, Lanasa MC, et al. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia.

2010;24:512-520, PMID: 20090778.

10. True. Although not readily clas-

sifiable within the World Health Organization, classification would raise the possibility that CBL-MZ should be

care providers often enable patients to tolerate lifeextending therapies by addressing these concerns.

continued from page 10

symptom management because it requires practice in an observed environment over time. Excellent programs such as Oncotalk have been developed, and many recent oncology trainees have been exposed to it, but there remain large numbers of oncology practitioners and trainees who have never been taught basic symptom management or been observed having these discussions with patients and families.

Dr. Storey: Agree. The administration of chemotherapy and radiation are complex and these areas demand close attention. Comfort, quality of life and family support can become secondary concerns but are very important to the patient and family. Palliative

Dr. Bower: Agree. Cancer providers vary in their interest and aptitude in providing palliative care.

Most providers received minimal exposure to palliative medicine in their training, yet do a significant amount of primary-level palliative care as they manage the multitude of symptoms associated with cancer and its treatment, discuss treatment options with patients and care for patients through the end of life.

Although many oncologists can provide primary-level palliative care, they deserve the support of palliative medicine specialists in managing patients who have a significant symptom burden, refractory pain or a prognosis that is uncertain or poor. Oncologists are busy enough keeping up with advancements in

considered as a new provisional entity within the spectrum of clonal MZ disorders. In this retrospective analysis with a median follow-up of five years, 85 cases remained stable, whereas 17 cases progressed, of whom 15 developed splenomegaly.

Xochelli A, Kalpadakis C, Gardiner A, et al.

Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity? Blood.

2014;123:1199-1206, PMID: 24300853.

oncology and designing treatment plans for complex patients. It is unreasonable to expect them to also have an expertise in the management of the most complex refractory symptoms, and it is imperative that patients’ symptoms are not ignored but instead are managed just as aggressively as their underlying disease.

Colleen Hutchinson is a medical communications consultant based in Philadelphia and can be reached at colleen@cmhadvisors.com.

For a table with more of the panelists’ views on palliative care, go to clinicaloncology.com.

Digital Physician: Getting Started With Social Media A

lthough some physicians remain skeptical of social media platforms such as Twitter, many oncologists are finding that social media offers effective methods of sharing and discovering study results, driving participation in clinical trials and promoting professional reputations.

“I would encourage everyone to get on Twitter,” said Don Dizon, MD, an assistant in medicine at Massachusetts General Hospital, in Boston, and immediate past chair of the American Society of Clinical Oncology’s Integrated Media and Technology Committee. Dr. Dizon said that he often finds that by checking Twitter, blogs and YouTube videos, he’s the first in his circle to know about breaking medical news.

Use of Twitter—a 140-character social messaging platform—has been increasing during professional meetings, providing oncologists with a real-time way to assess presentations they may, or may not, want to attend. Twitter usage at American Society of Clinical Oncology annual meetings, for example, has grown significantly from 2009 to 2012, according to Robert Miller, MD, a clinical associate with the Breast Cancer Program at Johns Hopkins Kimmel Cancer Center, in Baltimore.

At the 2011 meeting, he said, 34

Oncology is a specialty that particularly lends itself to social media.

physician Twitter users sent 1,477 tweets (of a total 1,537 users sending 8,188 tweets), predominantly to broadcast results of clinical data presentations and disseminate their perspectives on the treatment implications of data. Some users not in attendance used Twitter as a vehicle to learn about new studies, provide commentary and broadcast results to their followers. Others used Twitter to promote their presentations.

Twitter, Facebook and YouTube also can be used to promote clinical trials through a sentence or two, links to a description on the clinicaltrials.gov website, or a short video about the study. Anas Younes, MD, the chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, in New York City, said he

has recruited many participants that way.

Having a social media presence also can enhance a physician’s professional reputation, Dr. Miller said. The University of California, Irvine, invited him to give a grand rounds lecture on “social media and the digital physician,” largely because of his tweets and a blog he writes about breast cancer.

Social media does not have to take up large chunks of time, said Dr. Younes. He follows Twitter feeds from scientific journals, so he sees article updates “in real time, instead of waiting to have time to sit and check PubMed.” He also uses a free Twitter application called paper.li, which compiles articles on subjects of interest to him into an electronic newspaper format that is sent daily to his Twitter account

and to his followers (see http://paper.li/ DrAnasYounes/Newspaper#). He spends about 20 minutes before dinner skimming through the stories.

One thing that oncologists should not do is get personal, both Drs. Dizon and Miller said. Those using Facebook to communicate information to patients should create a professional account so it avoids the perception of friending patients. Provide only basic general educational information; never offer specific recommendations or discuss patients’ health online.

Oncology is a specialty that particularly lends itself to social media because there is “so much information that is valuable to our patients,” Dr. Miller said. Oncologists looking to jump into social media can start by “lurking,” reading blogs or others’ Twitter feeds, they said. If you identify a person you find interesting, see who they follow and follow those people, too. If you find articles, blog posts or tweets that you think would interest your colleagues, pass them along in your own tweets or start a blog and link to them. It may take a few months to develop your own presence, Dr. Miller said. When you do, use your real name and photo to help build your identity.

—Karen Blum

21

Now Available!

Our brand new iPad app Scan here to download