September 2014 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • September 2014 • Vol. 9, No. 9

SOLID TUMORS Trial promotes lenvatinib as potential standard for thyroid cancer ...............

HEMATOLOGIC DISEASE Clinical Conundrums .....................

Bipin Savani, MD: How I manage survivorship issues after allogeneic transplantation ................. 22

by the

numbers

See story on page 15.

17.2 Bladder cancer

14.9 Lung cancer

11.6 Ovarian cancer

7.6 Melanoma

7.3 Kidney cancer

6.8 Colorectal cancer 6

Smoking rates, %

Arlington, Va.—Several years ago, physicians at Aurora Sheboygan Medical Center, in Wisconsin, noticed that their lung cancer volumes were dropping. An internal analysis revealed a 33% decline in the number of lung cancer patients from 2006 to 2008, and local lung cancer statistics showed that patients were leaving the county for care. As a result, local medical and radiation oncologists joined forces with a thoracic surgeon from an in-network tertiary hospital in Milwaukee to start a lung cancer multidisciplinary clinic in which multiple specialists came together to review patient cases and devise treatment plans. Administrators launched a comprehensive marketing see CANCER CENTERS, S page 17

ur pa photog Dr. Sica dermat Dr. Si microsc the min shift oc approa If yo work fr imager www.b

Untitled (rotated); rectal carcinoma mimicking a beautiful, starry night sky. For more information about this image, see page 3.

Ca Centers Adapt And Evolve To Meet Changing Needs

is high among cancer survivors.

Chicago—It’s one of the cruel truths about cancer: The price of survival comes with an increased risk for a second cancer. Although this has been known for decades, what’s changed is that oncologists and primary care doctors are seeing a significant upsurge in patients with second cancers as survivors age—a “rising tide of second cancers,” according to one National Cancer Institute (NCI) investigator. This rise is accompanied by a growing awareness that different groups of survivors bear an unequal burden of see SECOND CANCERS, S page 16

Smoking prevalence

IMAGES IN ONCOLOGY

Second Cancer: For Many, It’s the Price of Survival

INSIDE

Vogl, NY...

Be Cautious About Applying SOFT and TEXT Adjuvant ovarian suppression: Its time has not come, and likely will not come soon

ime and progress have conspired against the development of data to support the use of adjuvant ovarian function suppression (OFS) with more modern endocrine therapies for localized breast cancer. Time has improved prognosis of breast cancer patients, especially those with hormone receptors in their tumors, so that event rates have fallen and it is much harder to demonstrate outcome differences with statistical significance. Progress has shown that endocrine therapy benefits accrue out to Steven Vogl, MD 10 years of therapy, and that delayed therapy with either tamoxifen or aromatase inhibitors (AIs) still has considerable benefit. SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial), which were presented at a plenary session at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO) and published in The New England Journal of Medicine,1 looked at 5 years of OFS with either tamoxifen or the AI exemestane in premenopausal breast see VOGL, NY, Y page 9

Clinical Relevance of Intrinsic Subtypes in Early-Stage Breast Cancer See page 6

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MODEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself. C L I N I C A L E X PE R T I SE

T R A N SPL A N TAT I O N

C L I N I C A L T R I A L S A N D R E SE A RC H

More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in speciﬁc malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology.

In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

t Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem cells for peripheral blood transplants t Four ICU beds integrated with Carolinas HealthCare System’s virtual ICU, which provides 24/7 oversight of all patients t Patient support, including familyfriendly patient rooms, an exercise room, a laundry room and lounge t Patient navigation

t First-in-man clinical trials testing novel therapies and treatment options t Access to high-quality care, and expertise from physicians who subspecialize in treating speciﬁc diseases t The ability to enroll patients in the newest, most promising trials, whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 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, PhD

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

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

University of Texas, MD Anderson Cancer Center Houston, TX

Policy and Management Mary Lou Bowers, MBA Mitchell Cancer Institute Mobile, AL The Pritchard Group, Rockville, MD

University of Alabama Birmingham, AL

Pharmacy 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

University of California San Diego, CA

Mayo Clinic Rochester, MN

Cindy O’Bryant, PharmD

Matt Brow

University of Colorado Cancer Center Denver, CO

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

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

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

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

Gastrointestinal Cancer and Sarcoma

Sara S. Kim, PharmD

Richard Stone, MD

The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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

Syed A. Abutalib, MD

On the Cover

Cancer Treatment Centers of America Zion, Illinois

ur cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art photography project focuses on imagery of human disease. Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology. Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigm shift occurring in medicine toward the inclusion of holistic approaches and the role of creative arts in the healing process. If you are interested in purchasing this piece or other work from her collection, Dr. Sicari may be reached at imageryMD@gmail.com. Her collection may be viewed at www.behance.net/MarieSicari

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

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

Infection Control

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

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

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

Steven Vogl, MD Medical Oncologist New York, NY

Mission Statement Symptom Control and Palliative Care Memorial Sloan-Kettering Cancer Center New York, NY

Edward S. Kim, MD

Steven D. Passik, PhD

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

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 providing the best possible care for their patients.

William S. Breitbart, MD

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

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

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

Editorial Philosophy 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 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. 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. How I Manage articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2014 • CLINICALONCOLOGY.COM

Hereditary Breast and Ovarian Cancer

Guidelines Void Exists for At-Risk Young Women Chicago—There is large variability in how young women between the ages of 18 and 24 years are counseled about hereditary breast and ovarian cancer (HBOC) testing, according to a study presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 1546). “Guidelines don’t recommend for or against counseling or testing [in this patient population], and there is very little in the way of information about what to do if a woman finds herself BRCA mutated,” said study investigator Julia Trosman, PhD, MBA, the director of the Center for Business Models in Healthcare and an adjunct professor in obstetrics and gynecology at Northwestern University Feinberg School of Medicine, in Chicago. Dr. Trosman and her colleagues interviewed genetic counselors about counseling practices at 11 different National Comprehensive Cancer Network (NCCN) cancer centers, roughly half of the NCCN centers in the country. They plan to expand their study to gather information from all 25 NCCN centers. Of the counselors surveyed, 55% said they do not routinely recommend genetic testing in women aged 18 to 25 (Figure). Dr. Trosman pointed out that there was no consensus in the answers, although the counselors were from “premier” cancer centers. Of the 45% of counselors who do routinely test women aged 18 to 25, reasons for testing included the patient’s desire for genetic information for health/family planning (45%) and a diagnosis of cancer (27%).

Eighty percent of counselors who do not routinely recommend testing in this age group said they would make exceptions if a woman had a family history of “young” cancer diagnosis (27%), if a woman repeatedly asked for testing and demonstrated an understanding of the implications (45%) and if a woman needed the information for family planning (27%). The counselors identified perceived barriers to routine HBOC risk testing for young women. These included concerns that parents were coercing women into testing (82%), a lack of screening/ risk management guidelines for women under the age of 25 (64%), a lack of guidelines about when to test women (45%) and a perceived lack of understanding of options (45%). Roughly 20% thought women should not be worrying about BRCA risk until they were age 25. Dr. Trosman said that the variability indicates that some patients may be receiving suboptimal care and highlights the need for formalized guidelines. “We need guidelines [that specify] when to test these women and what to do if a woman is found positive,” she said. “There is no evidence for or against specific intervention or monitoring strategies. Mammograms are not indicated for women under age 25. If you find yourself BRCA-positive, how often do you need to go for a mammogram, or a mammogram and an MRI [magnetic resonance imaging] alternated at six months, or an MRI every year? There is no evidence for or against any specific strategy.” Tuya Pal, MD, FACMG, a board-certified clinical geneticist at the Moffitt

EDITORIAL STAFF 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

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45%

55%

Do not routinely recommend genetic testing for women 18-25 y Routinely recommend genetic testing for women 18-25 y

Figure. Frequency of recommending genetic testing.

Cancer Center, in Tampa, Fla., who was not involved with the research, said the study’s take-away message is that HBOC guidelines for young women need to be developed. “There are specific issues to be addressed when counseling young

Michael Enright, Publication Sales menright@mcmahonmed.com

—Kate O’Rourke Drs. Trosman and Pal reported no relevant financial relationships.

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at-risk women for HBOC. However, this needs to be seen in the context of the overall issue of ensuring an adequate standard of care for any individual who undergoes genetic testing for HBOC, as well as other inherited cancer predisposition syndromes,” Dr. Pal said. “Currently, there are wide variations in the quality of services pertaining to cancer genetic risk assessment. In fact, most individuals receive BRCA testing in the community setting without involvement of a certified genetic counselor.” Ideally, guidelines would be based on prospective studies testing interventions, but such trials may be difficult and expensive to run, Dr. Trosman said. Thus, she added, “sometimes guidelines could be based on consensus, and, potentially, some of the evidence could come from observational studies.”

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2014 • CLINICALONCOLOGY.COM

No Glimmer of Sun After the STORM Trial Chicago—Patients with hepatocellular carcinoma (HCC) who receive sorafenib after resection or ablation of their tumor are not protected from recurrence of the cancer, according to new Phase III data. Because sorafenib (Nexavar, Bayer/ Onyx) has become a standard of care in unresectable HCC, clinicians had predicted that it would be beneficial when used in earlier stages of liver cancer. So these new findings, from the Phase III STORM (Sorafenib as Adjuvant Treatment in the Prevention Of Recurrence of Hepatocellular Carcinoma) trial, came as a surprise and disappointment to experts. “This is a major disappointment in the field, and questions are being asked about why this happened,” said Milind Javle, MD, an associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved with the study.

although investigators had planned to provide adjuvant therapy for four years, the median duration of treatment was only 12.5 months in the sorafenib arm and 22.2 months in the placebo arm. The mean dose of sorafenib (578 mg/day) was roughly half of what was planned. Both Dr. Javle and Lee Ellis, MD, a professor of surgery and molecular and cellular oncology at MD Anderson, pointed out that the study planned for four years of treatment, but despite

similar rates of recurrent disease, early discontinuation of sorafenib was much higher than that of placebo. “Anyone who has used the drug knows that [four years of sorafenib] is somewhat hard to achieve,” Dr. Javle said. Both clinicians noted that the purpose of adjuvant therapy is to increase the cure rate by eradicating microscopic deposits of tumor. However, for the most part, sorafenib and other agents that target vascular endothelial growth factor are

not directly cytotoxic to tumor cells, Dr. Ellis said, noting, “We are asking a cytostatic drug to do a cytotoxic job.” —Kate O’Rourke Dr. Bruix reported relationships with ArQule, Bayer, Biocompatibles, Bristol-Myers Squibb, Daiichi Sankyo, Novartis and Roche. Dr. Ellis reported relationships with Amgen, Genentech, Kanghong Biotechnology, Lilly/ ImClone and Roche. Dr. Javle reported no relevant financial relationships.

‘We are asking a cytostatic drug to do a cytotoxic job.’ —Lee Ellis, MD The STORM investigators randomized patients without residual HCC after surgical resection or local ablation to receive sorafenib (n=556) or placebo (n=558). Patient characteristics were well balanced between the two arms with respect to the region of the world they lived in, as well as their risk for recurrence, Child-Pugh A and B status, presence of liver cirrhosis, Eastern Cooperative Oncology Group performance status, number of lesions, maximum tumor size and other factors. Presenting the results at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 4006), investigator Jordi Bruix, MD, reported that sorafenib did not improve the primary end point of recurrence-free survival, which was defined as first documented recurrence of disease by independent radiologic assessment or death from any cause, whichever occurred first (hazard ratio [HR], 0.940; P=0.26). Dr. Bruix, head of the Oncology Liver Unit at Hospital Clínic de Barcelona, in Spain, also said there was no difference in overall survival among patients who received sorafenib compared with those who received placebo (HR, 0.995; P=0.48). Subgroup analysis failed to identify any cohort of patients who benefited from sorafenib. Adverse events were more common in patients who received sorafenib. Discontinuation rates were similar in the two arms, 84.7% in the investigational arm and 80.1% in the placebo arm. However,

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This international symposium aims to achieve a balance of clinical, translational, and basic research, providing a forum for interaction, communication, and education for a broad spectrum of researchers, health professionals, and those with a special interest in breast cancer.

▶ DISCOUNTED REGISTRATION CLOSES OCTOBER 31

COMPLETE PROGRAM SCHEDULE AVAILABLE AT

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Clinical Relevance of Intrinsic Subtypes in Early-Stage Breast Cancer Matthew J.C. Ellis, MB, BChir, PhD

uniform, global standard for intrinsic subtyping applicable to both research and clinical practice and advance a more personalized approach to treating early-stage breast cancer.

Director, Lester and Sue Smith Breast Center Baylor College of Medicine Houston, Texas

Identification of Intrinsic Subtypes

Faculty

Introduction Breast cancer is a heterogeneous malignancy that varies clinically and molecularly from patient to patient, with implications for prognosis.1,2 Over the past decade, the advent of complementary DNA (cDNA) microarray and genomic sequencing allowed the molecular classification of breast cancers into 4 intrinsic subtypes2-4: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal-like subtypes. Each intrinsic subtype, identified by its gene expression patterns, has a distinct profile for risk and clinical features. Oncologists can benefit from the prognostic power of intrinsic subtypes. However, unlocking the full potential of subtyping depends on the availability of a robust diagnostic method, which can be run from routine pathologic samples and can support a

Researchers identified the intrinsic subtypes in the early 2000s.3 Working from the hypothesis that phenotypic diversity in breast tumors might correlate with molecular diversity, Perou and colleagues conducted cDNA microarrays to identify variations in gene expression in the breast tumor specimens of 42 patients, encompassing 8,102 genes.3 Using hierarchical cluster analysis (HCA)—a statistical approach that allows subtype grouping by similarity of expression patterns—the researchers were able to determine a unique molecular portrait for each subtype.3 Subsequent research, including work by The Cancer Genome Atlas, made use of ever-improving genomic tools and continued to employ HCA to refine the subtypes.4 By locating gene expression patterns using HCA, these studies ensured rigorous subtype identification. Hierarchical clustering does not start from a preconceived notion of subtypes, but rather generates subtype groupings solely on the basis of patterns that emerge from the data. There

is a distinct methodologic advantage to this process. It begins with tumor biology, and then builds up profiles of intrinsic subtypes with distinct clinical features. This is a more accurate and valid method than the conventional approach of finding a clinical feature based on clinical trial observations followed by a biological explanation.

Defining Intrinsic Subtypes It is useful to think about intrinsic breast cancer subtypes as distinct clinical entities. An analogy to another cancer, lymphoma, is instructive. Some lymphomas, such as follicular lymphoma (FL), are considered indolent diseases; others, such as diffuse large B-cell lymphoma (DLBCL), are considered aggressive diseases. FL, DLBCL, and other lymphomas are considered separate diseases with their own prognoses and modes of treatment. Similarly, different breast cancer subtypes can be considered separate diseases.

Luminal A Luminal A is the most common intrinsic breast cancer subtype.5,6 In a 2010 study, luminal A accounted for 44% of breast cancers in a cohort of approximately 4,000 newly diagnosed patients.7 In 2012, a study reported the incidence of luminal A tumors to be 66% among 934 newly diagnosed patients.5 The luminal A subtype is relatively indolent,

Luminal B Luminal B is a more aggressive, treatmentresistant tumor with a worse prognosis than luminal A.8,9 These tumors are typically HR positive—especially estrogen receptor (ER) positive—and often are HER2 negative.5,9 They generally display high Ki67 scores, indicative of rapidly proliferating tumors.9 Potential

HER2-E

100

OS probability

RFS probability

HER2-E

with a favorable prognosis and prolonged survival.5,7,8 In an analysis of 1,951 node-negative, early-stage breast cancer patients from trials of the International Breast Cancer Study Group, Metzger-Filho and colleagues reported a 10-year breast cancer-free interval (BCFI) of 86% and a 10-year overall survival (OS) of 89% for patients with hormone receptor (HR)-positive luminal A tumors.8 The BCFI and OS rates in luminal A tumors were higher than rates for other subtypes (P<0.001). Although luminal A tumors show a marked diversity of mutated genes—such as the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1—they have the lowest mutation burden of all 4 intrinsic subtypes.4 Luminal A subtype tumors often are HR positive and HER2 negative.4 TP53 mutations— associated with a loss of tumor suppression and poor prognosis—are uncommon in luminal A, with an incidence of 12%.4 Luminal A tumors also have a high level of tumor suppressor activity via the RB1 pathway.4

20 Overall log-rank: P=0.02

Overall log-rank: P=0.07

0 0 49 56

2 33 29

4 28 19

6 27 16

8 25 15

Time from randomization, y At risk (CEF) At risk (CMF) CEF CMF

10 14 6

12 0 0

0 49 56

2 42 46

4 32 28

6 30 21

8 27 19

10 14 8

Time from randomization, y At risk (CEF) At risk (CMF) CEF CMF

Figure. Univariate RFS and OS for HER2-enriched subtypes treated in the NCIC CTG trial MA.5. Kaplan–Meier plots compare treatment arms. CEF, cyclophosphamide-epirubicin-fluorouracil; CMF, cyclophosphamide-methotrexate-fluorouracil; HER2, human epidermal growth factor receptor 2; OS, overall survival; RFS, relapse-free survival Adapted from reference 12.

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2014

12 0 0

Supported by

HER2-Enriched Subtype HER2-enriched tumors constitute about 10% of breast tumors.5,7 This subtype cannot be viewed as coterminous with HER2 positivity because in a minority of cases tumors in the profile are HER2 negative; moreover, there are HER2-positive cancers that fall within other intrinsic subtypes.4 Nevertheless, about 80% of HER2-enriched subtype tumors have the HER2 amplification, and about 50% of all clinically determined HER2-positive tumors fall into this subtype. 4 An important aspect of the molecular portrait of the HER2-enriched subtype is the composite HER2/endothelial growth factor receptor (EGFR)/phosphorylated EGFR signature, which defines a key signaling pathway.4 The HER2-enriched subtype is more likely to be HR negative than luminal subtypes.4 HER2-enriched tumors also have a high frequency (72%) of TP53 mutations.4 The risk for regional and local metastases is relatively high,7 and there is a trend toward larger tumor sizes, ductal location, and poor tumor differentiation.10 Offsetting these risks, however, is the sensitivity of the HER2-enriched subtype to targeted therapy, such as trastuzumab. Carey and colleagues recently conducted a subtype analysis of samples from the Cancer and Leukemia Group B 40601 trial (N=305), which showed that patients with HER2-enriched subtype tumors attained a pathologic complete response (pCR) of 71% with paclitaxel plus trastuzumab and 80% with paclitaxel, trastuzumab, and lapatinib (another HER2-targeting agent).11 The positive result with the 2-drug regimen suggests that more aggressive therapy may not be necessary in this intrinsic subtype.11 Moreover, the HER2-enriched subtype strongly predicts sensitivity to anthracycline chemotherapy. This was observed by Cheang and colleagues in a subtype analysis via PAM50 assay of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.5, a clinical trial on nodepositive breast cancer patients randomized to adjuvant therapy with CMF (cyclophosphamide-methotrexate-fluorouracil) versus anthracycline-containing therapy with CEF (cyclophosphamide-epirubicin-fluorouracil).12 HER2-enriched subtypes demonstrated

a significantly better response to CEF than to CMF (62% vs 22%; P=0.0006). Although HER2-enriched subtype was associated with relatively poor clinical outcomes overall, treatment with CEF prolonged survival compared with CMF therapy. Among all 4 subtypes, HER2-enriched tumors showed the greatest benefit from CEF than from CMF, with improvements of 21% for 5-year relapsefree survival (RFS) and 20% for 5-year overall survival (OS; Figure). For both RFS and OS, interaction between HER2-enriched subtype and anthracycline sensitivity was significant (P=0.03). Although luminal B also showed a risk reduction with CEF rather than CMF, this difference did not reach the statistical significance for the HER2 subtype.12

Basal-Like Tumors Basal-like tumors represent about 10% to 20% of breast cancer cases.5,7 Many, but not all are triple-negative tumors: ER negative, progesterone negative, and HER2 negative.4,5 Basal-like tumors exhibit TP53 mutations frequently, with 80% of tumor samples positive for these risk-conferring mutations.4 The tumors tend to be highly proliferative.4 They are considered higher risk than luminal A tumors but lower risk than HER2-enriched and luminal B subtypes.2,5 Basal-like tumors are relatively sensitive to chemotherapy.12 Similarities have been reported between basal-like subtype tumors and tumors carrying BRCA1 mutations. Inactivation of BRCA1 and RB1 are among the many genomic features that basal-like tumors share with ovarian tumors.4 The basal-like subtype is especially prevalent in premenopausal, black women; analysis of a population-based study showed prevalence rates of 39%, 14%, and 16% for premenopausal black women, postmenopausal black women, and nonblack women of any age, respectively.1

The Emerging Role of Intrinsic Subtypes in Treatment To maximize the clinical utility of intrinsic breast cancer subtypes, research must answer a key question: How can we design a treatment paradigm based on intrinsic subtypes? Currently, it is possible to speculate on some general trends. Tumors of the luminal A subtype have a good prognosis, and are treatable with available standards of care, including endocrine therapies13 and conventional chemotherapies such as weekly paclitaxel.12 Luminal B is quite resistant to both endocrine therapy and chemotherapy9; thus, it is a prime candidate for development of novel, targeted therapies. The HER2-enriched subtype is sensitive to chemotherapy, with notable anthracycline sensitivity, as well as to HER2-targeted drugs.11,12,14 Available evidence suggests a therapeutic dilemma. On the one hand, because tumors of the HER2-enriched subtype respond well to anthracyclines12 and

trastuzumab plus a taxane,11 it is standard to offer patients a 4-drug combination (eg, anthracycline-cyclophosphamide then trastuzumab-taxane). On the other hand, since pCR to 2-drug therapy with trastuzumab plus a taxane is quite high, it may not be necessary to risk the significant amount of toxicity that would be incurred by adding an anthracycline or another HER2 targeted drug in all patients.11 Resolution of this dilemma requires the accrual of more data and experience. For example, dual HER2targeted therapy with lapatinib and trastuzumab may be optimal only in the subset of HER2-enriched tumors that also are HER2 positive. Basal-like subtypes also are relatively sensitive to chemotherapy, including anthracycline-based chemotherapy.12,14,15 It is unclear, however, whether the toxicity risks associated with anthracycline therapy are warranted in this subtype, given that the analysis of the NCIC CTG trial MA.5 showed only a trend and not a significant difference in risk reduction with CEF versus CMF.12 To move beyond speculation, more data linking subtype to treatment efficacy demonstrated in large clinical trials is needed. These data would optimally derive from a standard assay applied to pathologic samples from these trials. An important feature of this assay is the ability to use paraffinembedded tumor samples. This approach would allow investigators to run subtype analyses on trials with many years of outcomes data—going back to the banked samples from the initial patient workup to link subtype to survival data. This was done using the PAM50 assay for the NCIC CTG trial MA.512 and Austrian Breast and Colorectal Cancer Study Group 8 trials,13 generating useful information on the efficacy of specific treatments across subtypes. Using the same globalized assay in the clinical setting would support the translation of research from bench to bedside. As more analyses of this type become available, it also may be possible to describe relationships between intrinsic subtype and other prognostic indicators, such as receptor status, menopausal status, and staging at diagnosis, yielding more personalized treatment approaches. Additionally, ongoing work to elucidate the genomics of breast cancer continues to divulge novel treatment targets within subtypes. For example, there is a strong signature for PI3K activity in both basal-like and ER-positive luminal (A or B) breast tumors, but the frequencies of PIK3CA mutations and negative pathway regulators differ between basal-like and luminal subtypes.16 These differences have implications for how the PI3K pathway is targeted in the different subtypes.

clinical entities, each with its own clinical and molecular profile and, ultimately, its own treatment responsiveness. Harnessing the power of subtypes will require a robust subtype assay, to standardize subtyping in both research and clinical practice.

Conclusion

Disclosure

The intrinsic subtypes are established predictors of risk in breast cancer. The subtypes delineate breast cancer into distinct

References 1.

Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-2502.

Parker JS, Mullins M, Cheang MCU, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-1167.

3. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature. 2000; 406(6797):747-752. 4. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. 5. Haque R, Ahmed SA, Inzhakova G, et al. Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1848-1855. 6.

Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):e1000279.

7. Voduc KD, Cheang MCU, Tyldesley S, et al. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010;28(10):1684-1691. 8.

Metzger-Filho O, Sun Z, Viale G, et al. Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol. 2013;31(25): 3083-3090.

9. Tran B, Bedard PL. Luminal-B breast cancer and novel therapeutic targets. Breast Cancer Res. 2011; 13(6):221. 10. Yang XR, Sherman ME, Rimm DL, et al. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev. 2007;16(3):439-443. 11. Carey LA, Barry T, Pitcher B, et al. Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa). J Clin Oncol. 2014; 32(suppl): Abstract 506. 12. Cheang MC, Voduc KD, Tu D, et al. Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 trial. Clin Cancer Res. 2012;18(8):2402-2412. 13. Gnant M, Filipits M, Greil R, et al. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 risk of recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345. 14. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678-5685 15. Carey LA, Dees EC, Sawyer L, et al. The triplenegative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-2334. 16. Ellis MJ, Perou CM. The genomic landscape of breast cancer as a therapeutic roadmap. Cancer Disc. 2013;3(1):27-34.

BB1422

drivers of proliferation in luminal B tumors may be TP53 mutations, which occur in 29% of cases, and transcriptional hyperactivation of MYC and FOXM1 pathways.4 Luminal B breast cancers also are associated with clinical risk factors, such as an earlier distant metastasis than luminal A and a propensity for relapse in bone and pleura.9 Luminal B breast cancer is a significant proportion of breast cancers and many breast cancer deaths are attributed to this subset5,7 because these cancers are relatively insensitive and poorly responsive to both endocrine therapy and chemotherapy.9

Dr. Ellis has reported that he is a consultant for Astra-Zeneca, Novartis, and Pfizer, Inc. He is also a patent holder for the PAM-50 assay.

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For Thyroid Cancer…

SELECT Promotes Lenvatinib as Potential Standard Chicago—Lenvatinib appears to be the most effective tyrosine kinase inhibitor (TKI) so far evaluated for the treatment of progressive radioactive iodine–refractory differentiated thyroid cancer. None of the TKIs have been directly compared, but in a Phase III trial called SELECT, lenvatinib (Eisai) resulted in a much longer progression-free survival (PFS) than has been seen previously, including in the Phase III DECISION trial that has led to widespread use of sorafenib (Nexavar, Bayer/Onyx) for this indication. In SELECT (Study of [E7080] LEnvatinib in differentiated Cancer of the Thyroid), the median PFS was 18.3 months among the 261 patients in the lenvatinib group versus 3.6 months among the 131 placebo patients, producing a hazard ratio (HR) of 0.21 ((P<0.0001; Figure), according to data presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; LBA6008). Principal investigator Martin Schlumberger, MD, from the Institute Gustave Roussy at University Paris Sud, in Villejuif, France, reported that he and his colleagues found that the advantage of lenvatinib was relatively consistent whether or not patients

previously had received therapy inhibiting the vascular endothelial growth factor receptor pathway. This response appears to be different from that observed with sorafenib in the DECISION trial, which had been presented at the 2013 ASCO annual meeting and recently was published in The Lancet (Brose et al. 2014;384[9940]:319328, PMID: 24768112). In that study, the median PFS for sorafenib was 10.8 months, versus 5.8 months for placebo. Additionally, the objective response rate and median tumor shrinkage were 12.2% and 15%, respectively, among those taking sorafenib in DECISION versus 65% and 45%, respectively, among those taking lenvatinib in SELECT. The median response with sorafenib was 10.2 months, but it has not been reached with lenvatinib. In SELECT, 392 patients with 131 I-refractory differentiated thyroid cancer were randomized in a 2:1 ratio to active therapy or placebo. The advantage of lenvatinib was observed across all stratifications, including age. The most common grade 3 or higher adverse event was hypertension (42%). Other grade 3 or higher adverse events

included proteinuria, weight loss and diarrhea, but none of these occurred at rates greater than 10%. According to the ASCO-invited discussant for the presentation, A. Dimitrios Colevas, MD, a head and neck specialist from Stanford University, in California, no agent has achieved the degree of activity observed in progressive thyroid cancer that approaches that observed with lenvatinib. Although he cautioned against cross-study comparisons, he suggested that the greater overall activity of lenvatinib is compelling. Although biomarkers yet may be identified to show relative differences between TKIs in individual patients, the activity of lenvatinib overall so far is superior to that observed with any other treatment. In the absence of a direct comparison, the tolerability of lenvatinib relative to sorafenib or other TKIs is difficult to judge. In his analysis, and again emphasizing the limitations of crossstudy comparisons, Dr. Colevas used data from DECISION to suggest that grade 3 or higher hand–foot syndrome is probably more common on sorafenib and data from SELECT to suggest that grade 3 or higher hypertension is more

common on lenvatinib. Neither lenvatinib nor sorafenib was associated with an overall survival (OS) benefit in their respective trials, each of which employed a crossover design. This crossover may be diluting the ability of early use of the TKI to exhibit a significant OS improvement, but Dr. Colevas pointed out that it also may suggest that delayed initiation of therapy may result in OS that is similar to that seen with early initiation. To the extent that TKI diminishes quality of life, he suggested that more data are needed to explore this possibility. However, despite these reservations, Dr. Colevas characterized the SELECT data as “a big deal.” Specifically, he suggested that lenvatinib “is clinically superior to placebo and to the best of my ability to compare across trials, it is better than sorafenib. It should be considered the new standard.” —Ted Bosworth Dr. Schlumberger reported financial relationships with AstraZeneca, Bayer, Eisai and Genzyme/Sanofi. Dr. Colevas reported no relevant financial relationships.

1.0 0.9

Median PFS, mo (95% CI)

0.8

Lenvatinib: 18.3 (15.1-NR) Placebo:

0.7

3.6 (2.2-3.7)

HR (99% CI): 0.21 (0.14-0.31) Log-rank test: P<0.0001

0.6

PFS

0.5 Progression events, 41%

0.4 0.3 0.2

Progression events, 96%

0.1 0.0 0

Time, mo

Number of subjects at risk: Lenvatinib 261 Placebo

131

225

198

176

159

148

136

Figure. Primary end point: Kaplan-Meier estimate of PFS. CI, confidence interval; HR, hazard ratio; NR, not reached; PFS, progression-free survival Source: Martin Schlumberger, MD.

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VOGL, NY continued from page 1

cancer patients (see related story, bit. ly/1lwcUns). Survival at 5 years was 96% to 97% in each arm, disease-free survival (DFS) was about 4% better with the AI, but only about 60% of the DFS improvement (affecting 2% of patients) was in survival without distant metastases (the augur of impending death from breast cancer). More women stopped all therapy early in the AI arm (16% vs 11%). Both arms had a high percentage of depression (50%), insomnia (59%), fatigue (62%), hot flashes (92%), vaginal dryness (52% for the AI vs 47% for tamoxifen), decreased libido (45% vs 41%), and dyspareunia (31% vs 26%), suggesting that early chemical menopause was difficult for these women.

Table 1. Strengths Of SOFT and TEXT • Huge international undertaking • Very large studies • Careful statistical analysis • Cautious data interpretation and restrained conclusions SOFT, Suppression of Ovarian Function Trial; TEXT,, Tamoxifen a o e and a d Exemestane e esta e Trial a

SOFT and TEXT Designed Based on INT 0101 SOFT and TEXT were designed based in part on early results from INT 0101, a US trial that randomized menstruating women with node-positive, hormone receptor (HR)-positive breast cancer to 1 of 3 groups: CAF (cyclophosphamide, doxorubicin, and fluorouracil), CAF-Z (CAF plus OFS using goserelin [Zoladex, AstraZeneca]), or CAF-Z plus tamoxifen (CAFT-Z).2 The results at 9 years showed that adding tamoxifen to CAF-Z resulted in a slight nonsignificant overall survival (OS) benefit (76% for CAFT-Z vs 73% for CAF-Z) and a significant DFS benefit (68% for CAFT-Z vs 60% CAF-Z). Additionally, there was a nonsignificant DFS benefit from adding OFS to chemotherapy alone (61% for CAF-Z vs 58% for CAF). All the women in INT 0101 had positive nodes, and their outcome was only fair—9-year DFS of about 60% and OS of about 73%. The CAF regimen in INT 0101 used oral cyclophosphamide on days 1 to 14 for 6 monthly cycles, and so produced a high rate of permanent amenorrhea, especially among women over the age of 40. Cyclophosphamide remains the major gonadal toxin among the currently used adjuvant chemotherapy drugs, 25 years after INT 0101 began accruing patients. The SOFT designers hoped to show that OFS added to tamoxifen (which became the standard adjuvant hormonal

therapy for premenopausal women years after INT 0101 was designed), and both TEXT and SOFT looked at substituting an AI for tamoxifen in addition to OFS, hoping, based on the early DFS results from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial,3 that further estrogen suppression from 5 years of an AI added to OFS would be superior to 5 years of tamoxifen added to OFS.4 Table 1 outlines some of the strengths of SOFT and TEXT.

What the Designers of SOFT And TEXT Could Not Know In the decade before these studies, the duration of tamoxifen adjuvant therapy had gone from 1 year to 2 years to 5 years. Among other things, the SOFT and TEXT investigators could not know that the second 5 years of endocrine therapy would prove to be about as important as the first 5 years (Table 2). For women who were premenopausal at diagnosis, adding 5 years of an AI after they lost ovarian function reduced DFS events by a whopping 74%.5 In those who were postmenopausal at diagnosis, the reduction was only about 33%.5 Late introduction of effective hormonal therapy after a hiatus from therapy, either tamoxifen as initial therapy6 or an AI after 5 years of tamoxifen,7 still produces considerable benefit. Instead of being a disease in which 5 years of treatment is considered long term, HR-positive breast cancer became a disease in which 15 years of intervention is now conceivable!

The SOFT and TEXT investigators expected that the prognosis of women entered on the studies would be similar to that reported in INT 0101. That TEXT and SOFT patients did much better meant that the investigators had to scrap initial statistical plans and undertake combined analyses with reduced power, even in these very large studies.4 Finally, the SOFT and TEXT designers could not know that methods to detect changes in tumor biology and measure tumor mRNA would become key means of classifying tumors and deciding treatment 15 years after they embarked on the trials. The Oncotype Dx test, the best studied of these methods, defines prognosis and predicts the benefits of tamoxifen over observation and the benefits of chemotherapy when added to tamoxifen. Because low ESR1 (the gene that codes the estrogen receptor-α) α mRNA levels by Oncotype Dx predict no benefit from tamoxifen therapy,8 it is important to determine if OFS benefit is similarly restricted. If it is, then those with low levels, who will not benefit, could be spared toxicity, and the benefits for the correctly selected population will be shown to be greater and might be worth the toxicities.

Why SOFT Is Not Likely To Establish Adjuvant OFS As Standard Table 3 lists the reasons DFS is the wrong end point for an intervention as severe as early menopause. Almost

Table 2. What SOFT and TEXT Designers Didn’t Know • Prolonged endocrine therapy would work, and AIs work especially well for premenopausal women who become postmenopausal • Prognosis of resected breast cancer would improve • Chemotherapy would move toward less cyclophosphamide, so more chemotherapy patients at a more advanced age would keep their menses and be eligible for TEXT • Prognostic and predictive factors would be developed for tamoxifen and AIs AI, aromatase inhibitor; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial

Table 3. Why December 2014 Analysis of SOFT Likely Won’t Establish OFS as Treatment of Choice, Even if DFS Prolonged • • • • •

Wrong end point Insufficient duration of follow-up Lack of long-range treatment plan No information on gene expression subsets Even if difference in OS is shown, it is unlikely to be big enough in absolute terms to subject large numbers of women who otherwise do well to early menopause with its severe toxicities • Therapies introduced 5 to 8 y after diagnosis change prognosis, ie, one cannot project long-term benefit from small early advantages DFS, disease-free survival; OFS, ovarian function suppression; OS, overall survival; SOFT, Suppression of Ovarian Function Trial

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist New York City

half the DFS events are a mix of second breast cancers, other primaries, and local recurrences that lack the dire consequences of distant metastases. Distant disease-free survival (DDFS) as an end point has problems of ascertainment bias—one only finds them if one looks for them, albeit smart clinicians always will look when the patient has severe or protracted symptoms. In the coming analysis of SOFT, comparing tamoxifen with tamoxifen plus triptorelin, there may be an ascertainment bias against the triptorelin arm because these patients had to be seen monthly for their injections, whereas tamoxifen patients would have to be seen only every few months. Mild symptoms in the latter group are more likely to escape attention until the patient is seen by medical personnel. Finally, some women with breast cancers that are either very indolent or very sensitive to hormone therapies can live a decade or more despite the presence of metastatic disease. For these women, who often are asymptomatic and functional despite their metastases, DDFS is a poor surrogate for quality or duration of life. Paradoxically, these also probably are the women who benefit the most from adjuvant hormone therapy in delaying emergence of distant metastases. The end point with the least bias and the greatest importance is OS. Although it provides little information on the quality of life, all agree that death is undesirable, and there is never controversy over its coding. OS is the proper end point for adjuvant therapy trials, especially in goodprognosis populations in which the majority of patients will not benefit from the intervention because they will do well anyway. In such groups, only doing a lot of good for the minority that benefits by prolonging total life (rather than transiently improving symptoms) would justify the sacrifices made by the majority who do not benefit. With 5-year survivals of 96% to 97%, SOFT and TEXT participants clearly qualify as good prognosis. In this young and presumably otherwise healthy population, deaths from intercurrent disease will be rare in the first 15 years. A median follow-up of 68 months is far too short for the 15-year disease that HR-positive breast cancer has become. It is easy to conceive of a real 2% reduction in distant metastases at 5 years see VOGL, NY, Y page 10

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that is reversed at subsequent followup; most of the patients are still at risk, and most will undergo at least 5 years more of endocrine therapy, which could equalize deaths in the long run.

SOFT and TEXT Did Not Specify Treatment for Years 6 to 10 SOFT and TEXT specified only the first 5 years of therapy, allowing heterogeneity in each randomized arm from therapies that came after the trials’ initiations. Because introduction of an AI after tamoxifen reduces DFS events by 74%,5 these agents can have a major effect on outcomes. One cannot assume that the initial assignment of a hazard rate for recurrence or death will continue beyond the initial 5 years because we know later therapies can profoundly alter the hazard rate. Statistical models of future events do not apply if very effective treatments are introduced after the therapies being evaluated. Although the SOFT and TEXT investigators could not know it in 2000, what need to be compared are differing longterm strategies for endocrine therapy. A 5-year plan of treatment is no longer sufficient. One possible control group against which to compare initial OFS plus exemestane would be tamoxifen until natural menopause (whether influenced by adjuvant chemotherapy or not), followed by exemestane for 5 years.

Why Studies of OFS Are Hard Table 4 summarizes why studies of OFS are difficult from the start. If one thinks of each intervention as a component of a multidrug regimen, then adding OFS to modern adjuvant therapy is adding a sixth drug to doxorubicin, cyclophosphamide, a taxane (ACT), plus tamoxifen and an AI. Indeed, OFS is generally achieved with a drug injected monthly. If one gives response-modified neoadjuvant chemotherapy, which was shown to improve DFS at 6 years in GEPAR-TRIO,9 OFS could be the eighth drug added to ACT plus navelbine, capecitabine, tamoxifen, and an AI. Although the improving prognosis of breast cancer and decades of clinical trial results attest to the efficacy of the baseline 5 or 7 drugs, how much more benefit can one expect from the eighth? Despite a trend in favor of improved survival from OFS, no significant survival benefit for adding OFS was found in the 2007 meta-analysis.10 An earlier analysis by the Early Breast Cancer Clinical Trials Group found an OS benefit for OFS compared with observation that was statistically significant (despite estrogen-receptor status not being tested in 63% of patients) but only when OFS was used alone,

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Table 4. What Are We Asking of OFS In Modern Therapeutics? • For low-risk women: that it add substantially to 10 to 15 y of endocrine therapy with tamoxifen and AI (OFS is the third drug) • For higher-risk women who will also get chemotherapy: that OFS improve prognosis when added to chemotherapy with ≥3 drugs plus tamoxifen plus AI plus early menopause from chemotherapy that already will improve prognosis (OFS is the sixth to ninth drug) • That it be shown to add substantially to sequential therapies that the patient will receive over the 15 y after diagnosis • That the benefits are sufficiently large to justify the immediate and lifelong toxicities of a sudden and early menopause, which are substantial according to the published analysis of SOFT and TEXT AI, aromatase inhibitor; OFS, ovarian function suppression; SOFT, Suppression of Ovarian Function Trial; TEXT,, Tamoxifen a o e and a d Exemestane e esta e Trial a

Table 5. Why Not Adopt OFS Plus Exemestane As Standard Endocrine Therapy Now? • SOFT and TEXT asked the wrong question: whether to give an AI or tamoxifen with OFS • The right questions are: -When and for how long should an AI be given? -When and for how long should tamoxifen be given? -Should menopause be induced early or allowed to occur naturally? -If menopause should be induced early, at what point, and for how long? • Regimen used is too toxic • Too many women stop therapy early • Short follow-up, wrong end point, small difference in distant metastases, no information about which patients benefit more AI, aromatase inhibitor; OFS, ovarian function suppression; SOFT, Suppression of Ovarian Function Trial; TEXT,, Tamoxifen a o e and a d Exemestane e esta e Trial a

Table 6. What SOFT and TEXT Investigators Should Do Next • Get more funding that allows them to: -Characterize the tumors at entry by Oncotype DX score and ESR11 mRNA levels -Randomize women finishing 5 y of OFS plus exemestane to observation versus tamoxifen -Randomize women who resume menses after 5 y of OFS plus tamoxifen to continued tamoxifen versus OFS plus exemestane -Use DDFS as the primary end point in these analyses; the numbers will probably be too small to use OS DDFS, distant disease-free survival; OFS, ovarian function suppression; OS, overall survival; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial SOFT,

not when it was added to other effective adjuvant therapies.11 This is consistent with my arguments that adding a fourth to ninth effective drug likely will add little, and that adding a drug to suppress ovarian function that has already been obliterated by chemotherapy will result in little benefit. Perhaps subsets exist in which greater benefits accrue from early addition of OFS, but this probably depends on the existence of differing prognostic factors for benefit between OFS versus tamoxifen. To my knowledge, there is no evidence for this. From the published toxicities of OFS plus tamoxifen or exemestane,1 it seems that OFS was quite toxic—about 50% of

patients had depression added to the physical and emotional stresses of early and sudden menopause. It seems unlikely that the OS benefits for early OFS to be shown in the next installment of the SOFT analysis (promised for December 2014) will be big enough to justify putting any but the highestrisk women through the toxicity of early menopause on a routine basis. Table 5 summarizes the reasons not to adopt OFS plus an AI as initial standard therapy for all premenopausal women.

SOFT and TEXT Still Can Contribute Valuable Information If the investigators can get funding to do Oncotype DX mRNA expression

testing on the tumor blocks, they can use the biologic information gained to determine whether tumors benefit differentially from tamoxifen, OFS, and exemestane (Table 6). If such differences exist, knowledge of them could spare many women years of toxic therapies. Women coming off 5 years of OFS plus exemestane could be randomized to 5 years of tamoxifen versus observation—to date, we still have no information on whether there is benefit from tamoxifen after 5 years of AI therapy. Because all the drugs are available as generics, no drug company has an interest in funding such a study. Women who resume ovarian function after 5 years of OFS plus tamoxifen could be randomized to continued tamoxifen versus OFS plus exemestane. The very high activity of letrozole after menopause during the 5 years of tamoxifen shown in MA.17 (hazard ratio for recurrence, 0.26)12 suggests that OFS plus an AI would be very active, and so especially attractive to women with higher risks for metastases. The second randomization to immediate menopause versus a simple pill might not be such a difficult “sell” in this population because SOFT participants already consented to such a randomization, and because all TEXT patients have just undergone such therapy.

Where Does This Leave Adjuvant OFS? SOFT and TEXT have shown that OFS plus exemestane is slightly more effective than tamoxifen plus OFS for the wrong end point (DFS rather than OS) and over a short 5-year follow-up. I probably will not recommend OFS plus exemestane to my patients unless circumstances exist that make tamoxifen therapy unacceptable, such as unique toxicities from tamoxifen, a clotting tendency that cannot be managed by routine anticoagulation, essential administration of a drug that inhibits tamoxifen activation (such as fluoxetine), or yet-to-be-confirmed evidence that cytochrome P450 2D6 polymorphisms in some hosts render tamoxifen inactive. In these circumstances, it is nice to know OFS plus an AI for 5 years is at least as good as tamoxifen. The latter is especially reassuring because OFS for 3 years plus anastrozole for 3 years was slightly inferior to OFS plus tamoxifen in the ABCSG (Austrian Breast and Colorectal Cancer Study Group)-12 trial, with an OS hazard ratio of 1.75 ((P=0.02) in favor of OFS plus tamoxifen in a very low-risk population.13 An unplanned subgroup analysis suggested that this was especially the case in the overweight women in the ABCSG-12 trial.14 I would be surprised if any group tries again to test adjuvant OFS in a high-risk population as part of a 15-year program

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of adjuvant hormone therapy for HRpositive breast cancer. I doubt such a study will ever be done again, both because prognoses have improved and because the duration of follow-up needed would be so long. Given our recent progress in understanding cancer biology and signaling, questions that we think are of great interest now may prove of little importance in 15 years, when, hopefully, therapy will be both better and different. Given what has already been achieved, adjuvant hormone therapy in 15 years likely will be only somewhat better than what we are giving now. One hopes that it will be much less toxic, and one fears that it will be much more expensive. The excessive cost of new anticancer therapies in the United States and Europe may make most of the world stick to currently available cheap and generic hormone therapies for decades into the future.

(TAM-02 trial). Ann Oncol. 2000;11(5):515519, PMID: 10907942. 7.

Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment with letrozole improves outcome in women with earlystage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008;26(12): 1948-1955, PMID: 18332475.

8. Kim C, Tang G, Pogue-Geile KL, et al. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol. 2011;29(31):4160-4167, PMID: 21947828. 9. von Minckwitz G, Blohmer JU, Costa SD, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol.

31(29):3623-3630, PMID: 24002511. 10. LHRH-agonists in Early Breast Cancer Overview group, Cuzick J, Ambroisine L, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007;369(9574):1711-1723, PMID: 17512856. 11. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717, PMID: 15894097. 12. Goss PE. Preventing relapse beyond 5 years:

the MA.17 extended adjuvant trial. Semin Oncol. 2006;33(2 suppl 7):s8-s12, PMID: 16730271. 13. Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011;12(7):631-641, PMID: 21641868. 14. Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29(19): 2653-2659, PMID: 21555684.

makes all the difference References 1. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118, PMID: 24881463. 2. Davidson NE, O’Neill AM, Vukov AM, et al. Chemoendocrine therapy for premenopausal women with axillary lymph nodepositive, steroid hormone receptor-positive breast cancer: results for INT 0101 (E5188). J Clin Oncol. 2005;23(25):59735982), PMID: 16087950. 3. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group, Forbes JF, Cuzick J, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008;9(1):45-53, PMID: 18083636. 4. Regan MM, Pagani O, Fleming GF, et al. Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials. Breast. 2013;22(6)1094-1100, PMID: 24095609. 5. Goss PE, Ingle JN, Martino S, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebocontrolled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol. 2013;24(2):355-361, PMID: 23028039. 6. Delozier T1, Switsers O, Génot JY, et al. Delayed adjuvant tamoxifen: ten-year results of a collaborative randomized controlled trial in early breast cancer

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BAM: A Major Cause of Diarrhea in Cancer Patients Chicago—Poor absorption of bile acid is the cause of chronic diarrhea in a large proportion of cancer patients, new research shows. The study of 506 patients with diarrhea and a variety of cancer types found that 43% had bile acid malabsorption (BAM), suggesting an opportunity to substantially improve quality of life in patients with this complication. The study provides the basis for a more focused approach to diarrhea in cancer

patients, said Frank Phillips, MD, a trainee gastroenterologist at the Royal Marsden Hospital, in London, England, who presented the study at Digestive Disease Week 2014 (abstract 318). In the study, patients referred to the clinic with chronic diarrhea were tested with selenium homocholic acid taurine (SeHCAT), a radiolabeled bile acid analog that is readily measured with a gamma camera without the need to collect stool samples. Of the 506 patients referred over

a four-year period, 34% had urologic cancers, 31% had cancers of the upper or lower GI tract, 25% gynecologic cancers and the rest had other cancers. Rates of BAM were particularly high in patients with cancers involving the upper pelvis. Among urologic malignancies, for example, BAM was more common in cancer of the bladder (50%) than the prostate (22%). In gynecologic cancers, the same was true for those involving the endometrium (42%) relative to

vulvovaginal tissues (less than 20%). For GI cancers, BAM was identified more frequently in those with disease of the lower tract (50%) than of the upper (35%). Chemotherapy may sensitize the terminal ileum to damage from radiation, according to Dr. Phillips. The role of this collateral damage is suspected because dysfunction of the terminal ileum is a well-established cause of BAM. High rates of BAM also were observed

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Smoking Prevalence Is High Among Cancer Survivors N

early 10% of cancer survivors in the United States smoke nine years after diagnosis, with bladder cancer survivors having the highest smoking rate, at 17.2%, according to a recent study conducted by researchers at the American Cancer Society (Figure, page 1). Underscoring the magnitude of the problem in a press release from the American Association of Cancer Research (AACR), lead investigator Lee Westmaas, PhD, said, “we need to follow

up with cancer survivors long after their diagnoses to see whether they are still smoking and offer appropriate counseling, interventions and possible medications to help them quit.” With 83% of these cancer-surviving smokers being daily smokers, averaging nearly 15 cigarettes per day, Dr. Westmaas urged the oncology community to “do more to intervene with these patients.” Although not involved in the study,

Roy Herbst, MD, PhD, the chief of medical oncology at Yale University, New Haven, Conn., and chair of the AACR’s Tobacco and Cancer Subcommittee, agreed there is a need for intervention, noting that “smoking can cause new mutations among cancer survivors that can lead to secondary and additional primary cancers. It can also affect physical function and interfere with the efficacy of therapies.” Of the 2,938 patients who participated

in the study, which was published in the AACR’s journal Cancer Epidemiology, Biomarkers & Prevention (2014 Aug. 6 [Epub ahead of print]), about 40% indicated that they planned to quit in the next month, but fewer married, older or heavier smokers shared this intention. The study indicated that smoking was more prevalent among patients who were younger, had a lower income, were less educated and drank more alcohol. —Natasha Albaneze

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Early Palliative Care Shows Survival Benefit Chicago—Expanding the evidence that palliative care has measurable clinical benefits in cancer patients, a new randomized study has found that patients who receive palliative care starting soon after the cancer diagnosis have a reduced risk for death at one year compared with patients whose palliative care is delayed by three months. Although palliative care has been shown to offer benefit, it “is often given weeks or even hours before death,” observed Marie

Bakitas, DNSc, CRNP, the associate director of the University of Alabama, Birmingham’s Center for Palliative and Supportive Care. According to Dr. Bakitas, who presented the randomized trial results at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), this practice will continue in the absence of evidence-based guidance delineating how palliative care should be administered to achieve optimal benefit. This study was designed to answer the

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question of when palliative care is best initiated. In this trial, which is the third in a series of multicenter studies called ENABLE (Educate, Nurture, Advise Before Life Ends), newly diagnosed patients with advanced cancer were randomized to receive palliative care starting immediately or three months later (abstract 9512). Other aspects of cancer management were the same. In addition to survival, other primary end points included validated measures of quality of

life, symptom impact and mood. The palliative care protocol consisted of an initial in-person consult, followed by six structured telephone calls by specially trained advanced practice nurses, during which the nurses assisted with symptom management, problem solving and advanced care planning. Along with palliative care, most patients in both arms received chemotherapy or other treatments to control their disease. Baseline characteristics, including measures of

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quality of life and symptoms, were generally comparable, with the exception of education, which was significantly lower in the delayed-care arm. Median survival was substantially longer in the immediate palliative care group (18.3 vs. 11.8 months), although this difference did not reach statistical significance ( =0.17). There was, however, a highly (P significant difference in survival at one year, producing a hazard ratio (HR) of 0.72 in favor of immediate versus delayed palliative care ((P=0.003). “The potential explanations for this difference include enhanced medical care,

reduced aggressive care, longer access to hospice care and the biological impact from an improvement in quality of life,” Dr. Bakitas reported. She said that additional data analyses are being launched to better define the mechanism(s) by which the survival advantage was achieved. There were no measurable differences in other primary end points, such as the number of hospital days, over the course of follow-up, but Dr. Bakitas noted that the delay in palliative care in routine practice typically is far longer than the three months evaluated in this study. In fact, Dr. Bakitas suggested that

patients in both arms appeared to have better palliative care than typically found. For example, “only 7% of patients were receiving chemotherapy within two weeks of death, which is low,” Dr. Bakitas observed. There already is good evidence that providing palliative care, concurrent with standard oncology care, has meaningful benefits in patients with advanced cancer, but this study suggests that early initiation is preferable. The data imply that centers that deliver cancer care should have an organized and standardized approach to initiating early concurrent palliative care

that employs evidence-based principles of optimal management. Asked to comment on the research, Arif H. Kamal, MD, the director of quality and outcomes at Duke Cancer Institute, in Durham, N.C., said that “palliative medicine is increasingly embracing a discipline-wide responsibility to grow the evidence base simultaneous to growing its clinical services.” Dr. Kamal suggested that this and other studies that “critically examine how, when and to whom service is provisioned, are needed to move the field forward and further define what entails high-quality palliative care.” —Ted Bosworth Drs. Bakitas and Kamal reported no relevant financial relationships.

BAM continued from page 12

in patients with pancreatic cancer, particularly after a Whipple procedure, which can damage the bile duct and lead to adverse changes in bile metabolism. BAM was particularly common in patients with hematologic malignancies and diarrhea. Far lower, but still clinically meaningful, rates of diarrhea were observed in other forms of cancer, such as breast and lung. Testing for BAM may be justified even in these groups when other causes of chronic diarrhea have been ruled out, Dr. Phillips said. In the United States, however, SeHCAT is not available. Stool analysis is an option, but many patients do not like collecting and submitting samples. The next best option may be empiric treatment with a bile acid sequestrant. Several are available, and an improvement in symptoms provides strong evidence of the underlying etiology. Although Dr. Phillips said he preferred a definitive diagnosis, relief of symptoms is the major goal. “Control of BAM to relieve chronic diarrhea improves quality of life and can prevent interruptions in cancer therapy,” he said. Lowell B. Anthony, MD, the chief of the Division of Medical Oncology at the University of Kentucky’s Markey Cancer Center, in Lexington, said the study “identifies the frequency of BAM as a cause of diarrhea in the cancer patient.” He suggested that this information might encourage a more systematic approach to diarrhea in the context of cancer. “Practitioners currently rely more on clinical indicators rather than specific tests to manage diarrhea in their patients.... With better testing and diagnosis, therapy directed specifically to the cause offers the hope of better control.” —Ted Bosworth Dr. Phillips reported no relevant financial relationships. Dr. Anthony reported a financial relationship with Novartis.

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25 5

SECOND CANCERS continued from page 1

the subsequent malignancies. For some patients, their increased risk appears to be driven by genetic susceptibility; for others, the risks are strongly related to the treatment they underwent for their primary cancer. The challenge is figuring out exactly who is at risk and how best to screen these patients, said oncologists speaking at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). “This is a serious clinical problem, not just a research problem,” said speaker Kenan Onel, MD, PhD, an associate professor of pediatrics and a specialist in oncology and cancer genetics at the University of Chicago. Several decades ago, individuals with a second cancer accounted for less than one in 10 cancer diagnoses. Figures presented at ASCO indicate that today these second cancers occur much more frequently, representing 19% of all new cancer diagnoses, nearly one in five, said Lindsay Morton, PhD, a cancer epidemiologist with the NCI. Dr. Morton attributed the surge in secondary cancers to two ongoing phenomena: an increasingly aging population and significant improvements in cancer survival rates. Both trends will accelerate further in coming years. By the end of this decade, it is expected that 18 million cancer survivors will be alive in the United States. “Thus, understanding the causes of second cancers has both public health and clinical importance,” Dr. Morton said. Researchers have zeroed on this population of cancer survivors, trying to understand who is at greatest risk for another cancer and why. In the past, most research into second cancers focused on incidence data using cancer registries and studies of treatment-related second cancers. Today, researchers can draw on a broader set of tools, including genetics and genomics, and the Childhood Cancer Survivor Study (CCSS). In the CCSS, the largest study in history focused on childhood cancer survivors, investigators enrolled 14,359 children diagnosed between 1970 and 1986 with leukemia, lymphoma, neuroblastoma, and CNS, bone, soft-tissue and kidney cancers. Now, these adults have been followed for decades. About 4,000 siblings are used for comparison. These survivors provide researchers with a rich data source for studying second cancers, said Gregory T. Armstrong, MD, MSCE, a pediatric oncologist at St. Jude Children’s Research Hospital, in Memphis, Tenn. (CCSS investigators have expanded the cohort so they can identify any new patterns of second cancer development in children treated with more modern therapies. By the end of summer 2014, results from an additional 10,000 survivors who were treated during

Second S neoplasm

Cumulative Incidence, %

20 0

25 5 Second S malignant neoplasm ( (SEER d defined)

10 0

We can intervene on some of these critical questions, critical gaps.” Oncologists are evaluating interventions that could improve screening rates, looking at things such as motivational interviews, Web-based materials and, in the case of skin cancer, a dermoscopic lens that can be attached to mobile phones, allowing survivors to have instant access to dermatologic consultation.

Genetics May Help Management 0 5

Years From Initial Cancer

Figure. Second neoplasms among 5-year survivors of childhood cancer in CCSS. CCSS, Childhood Cancer Survivor Study; SEER, Surveillance, Epidemiology and End Results

a more recent treatment era [1987-1999] will be available for analysis.) By following children into adulthood in the CCSS, researchers found that almost three decades after their initial diagnosis in childhood, these adults suddenly experience a sharp rise in mortality (Figure). Dr. Armstrong said 25 years after the primary cancer diagnosis, these deaths are most often attributable to a second cancer or cardiac issues related to their prior cancer treatment. “Something happens 25 to 30 years out. This is an important time period. These survivors are now midlife. They are soccer moms and soccer dads. They are mid-career executives. And their risk is very different than [that in] the general population.” According to the most recent analysis from CCSS, 22% of children will go on to develop a subsequent neoplasm (benign or malignant) in the 30 years after their first cancer diagnosis. Eleven percent will be diagnosed with a subsequent malignant neoplasm. Those figures alone are “stunning,” Dr. Armstrong said. But it’s the standardized incidence ratios that demonstrate how truly striking the risk is for childhood cancer survivors compared with the general population, he explained. Childhood cancer survivors have a 15-fold increased likelihood of developing a bone tumor as a second cancer compared with the general population. They have about a 10-fold increased risk for thyroid cancer, a central nervous system malignancy or breast cancer.

What’s Driving Increased Risk? Investigators do not understand precisely why this happens, but they have identified several risk factors. There are the obvious factors, notably primary cancer treatments, including radiotherapy and, to a lesser extent, chemotherapy. Women appear to be at higher risk for developing second cancers, particularly breast cancer. And patients who were younger at the time of their first diagnosis or who received radiotherapy at a young age also were at higher risk.

Important questions still need to be answered, Dr. Armstrong said. “What’s driving this? Is it treatment? Is it an underlying genetic propensity, or is it both?” Evaluation of the first CCSS cohort has allowed identification of strong treatment-related associations with secondary cancers, including dose–response relationships with radiotherapy. Updated analyses presented at ASCO show that women who are exposed to chest radiotherapy face far higher risks for second cancers than previously reported. Using the detailed treatment data collected as part of the CCSS, investigators studied 1,230 female survivors who had received chest radiotherapy. The cumulative incidence of breast cancer was 30% by age 50 and even higher, 35%, among those who had been treated for Hodgkin lymphoma (HL). “That means one in three women by age 50 who received chest-directed radiotherapy in this cohort developed breast cancer. That’s stunning when you try to process that,” Dr. Armstrong said. In comparison, Surveillance, Epidemiology and End Results data suggest that the risk for breast cancer by age 50 in the general population is 4%. “You can begin to think of our population, Hodgkin survivors, as compared to BRCA1 carriers, who have a [similar breast cancer] risk of 31% by age 50,” Dr. Armstrong said.

Screening Rates Are Too Low Screening rates in HL survivors do not keep pace with their risk, he noted. The International Late Effects of Childhood Cancer Guideline Harmonization Group recommends annual surveillance with both mammography and breast magnetic resonance imaging for women who received 20 Gy or higher of chest radiation by age 25 or eight years after diagnosis (Lancet ( Oncoll 2013;14[13]:e621-e629, PMID: 24275135). But actual screening rates are far lower, Dr. Armstrong said. “Screening rates in this very high-risk population are low, too low,” he said. “That’s one thing we can do.

Other research looking into genomics holds real promise for identifying children and adults who may be genetically susceptible to second or even third cancers, Dr. Onel said. In 2011, in collaboration with the CCSS, he led a unique genome-wide association study of long-term survivors of HL ((Nat Med d 2011;17[8]:941-943, PMID: 21785431). Dr. Onel and his colleagues analyzed the genomes of 178 HL patients who had been treated with chemotherapy and radiation therapy between the ages of 8 and 20. Within 30 years after treatment, 96 of the patients had developed second cancers. Based on assessments of each patient’s genome, investigators identified two variants in chromosome 6 involved in the etiology of radiation-induced second cancers. They then completed functional studies in vitro that implicated PRDM1 as a radiation-responsive tumor suppressor. When the authors investigated the prevalence of this risk locus, they found that almost 30% of survivors of HL with the risk haplotype developed a second cancer within 30 years versus only 3% with the protective haplotype. Although preliminary, this type of germline genetics may help direct clinical management of patients in future, he said. For now, it’s a challenge to busy oncologists to keep up with the fast-moving field of genomics, said Charis Eng, MD, PhD, the chair of the Genomic Medicine Institute at the Cleveland Clinic in Ohio. “We are likely in the dark ages except for a few pockets of oncologists in academia. Hopefully, with dissemination and education, using genetic-informed risk assessment for prediction of second primary cancers will be embraced.” Dr. Eng recommended that clinical oncologists work with genetic counselors so patients have informed cancer risk assessment and management. “Genetic counselors, our midlevel providers, have been for a long time … our invaluable partners in translating the meaning of this complex field, genetic diagnosis, gene testing to the patient and their family.” —Christina Frangou None of the sources reported any relevant financial relationships. The CCSS is an NCI-funded resource to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. For more information, go to http://ccss.stjude.org.

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CANCER CENTERS continued from page 1

plan to target local physicians and the public, and a cancer care coordinator facilitated patient/family navigation, education and care plans. The program saw 46 patients in its first year, during which the average time from diagnosis to treatment initiation was reduced from 24 to 18 days. Ninety-four percent of patients who came to the clinic stayed within the Aurora system for their care. The center also realized a 28% increase in lung cancer volume and a 9% increase in gross revenue. Clinics like this are one way that cancer programs can differentiate themselves in a changing cancer marketplace, Trever Burgon, PhD, told a packed room at the annual meeting of the Association of Community Cancer Centers (ACCC). A vice president of the health care analytics firm Sg2, in Skokie, Ill., Dr. Burgon led a session on strategies for growth in cancer care delivery. Changes in insurance and the Affordable Care Act (ACA) also will affect opportunities for the growth of cancer centers, he said. For example, few comprehensive care centers have been included in the new state-based insurance exchanges. “For cancer patients with significant disease burden and outof-pocket costs, going out of network to an [National Cancer Institute]-designated cancer center is going to be more and more prohibitive. One of the opportunities for community cancer programs is to make sure that your networks and programs offer the full breadth of services to be able to handle these patients.” Insurance expansion under the ACA will predominantly impact patients under age 65, Dr. Burgon said. In 2013, the cancers with the highest outpatient volumes for this age group were breast, cervical, thyroid, testicular and brain cancers and Hodgkin lymphoma, he noted. Uninsured patients are much less likely to seek timely care, especially screening services, and have poorer outcomes as a result. So, he said, “engaging newly insured patients, especially [about] cancer screening, represents a new opportunity to drive growth and improve quality.” At the same time, growth in the older population will also drive growth in cancer care. By 2020, Dr. Burgon said, nearly 20% of the U.S. population will be eligible for Medicare: “That has huge implications on cancer as largely a disease of the elderly.” Thus, the demand for cancer services will continue to grow, but there will be a shift toward higher need for outpatient care, especially for office visits, advanced imaging and chemotherapy, he said. According to projections from his company, there will be a 31% increase in outpatient cancer volumes between 2013 and 2023. Additionally,

‘The number of cancers cured with operations is really diminishing, and more and more treatment is multidisciplinary in nature.’ —James Weese, MD

The demand for cancer services will continue to grow, but there will be a shift toward higher need for outpatient care, especially for office visits, advanced imaging and chemotherapy. —Trever Burgon, PhD inpatient cancer growth will continue for lung, colorectal and brain cancers. Matthew Sturm, a senior manager with ECG Management Consultants’ Seattle office, agreed that outpatient care needs are increasing, with as much as 85% to 90% of cancer care being delivered in an outpatient setting. Only a few years ago, one of his clients was going to put an ambulatory surgery center in a cancer center but thought there was no need. Today, such an investment could make sense, he said, given the growth in outpatient oncologic surgery.

Become Indispensable In this changing environment, cancer centers can build a program that is indispensable to patients and payors by offering services that are unique to their location, providing strong patient service and education, reducing unnecessary expenditures, and providing convenient access to multiple specialists and clinical trials through partnerships with other centers. At Aurora, the clinic was so successful that the system has since added several others for breast cancers, gastrointestinal cancers, thoracic (lung/esophageal) cancers, brain tumors, head and neck tumors, and gynecologic tumors at its 15 locations from Kenosha to Green Bay. “We feel that multidisciplinary care is the wave of the future,” said James Weese, MD, the vice president of Aurora Cancer Care. “The number of cancers cured with operations is really diminishing, and more and more treatment is multidisciplinary in nature.” For example, it may not pay to have a minimally invasive thoracic surgeon on staff at each center, but such a specialist can see patients at a center’s one-day

clinic and help devise a diagnostic and treatment plan for those patients. The patients then can travel to the specialist’s hospital for surgery, returning to their local center for follow-up care. Videoconferencing is available through some of the clinics, so even if a patient travels to another center, local oncologists can be involved in treatment decisions. “Patients are much more savvy than they used to be,” Dr. Weese said. “In smaller, rural towns, people listened to what their doctor told them. Now with the Internet, patients even in smaller communities expect the services [that are] available at larger centers,” he added, noting that the clinics were “quite an undertaking but well worth it.”

Develop Screening Programs For Earlier Detection Cancer programs also can differentiate through technology, Dr. Burgon noted. In Massachusetts, physicians with the Lahey Hospital and Medical Center, in Burlington, started their Rescue Lung, Rescue Life program to provide free lowdose computed tomography (CT) screening for those at high risk for developing lung cancer. The program started after results from the National Lung Screening Trial were published in spring 2011 and Lahey’s physicians wanted to bring the service to local patients, said Andrea McKee, MD, the center’s chair of radiation oncology. They adopted screening guidelines from the National Comprehensive Cancer Network and initially offered low-dose CT screening for $350. But after only four patients, all participants in an executive health plan, signed up in the first nine months, the physicians decided to make the CT screening

available at no cost to patients, developing a standardized reporting system called Lung-RADS to help communicate screening results to primary care physicians and develop follow-up recommendations. They also used the CT machine during downtimes to reduce expenses. Unlike most programs, Dr. McKee and her colleagues spent no money on advertising and, instead, relied on educating staff and referring physicians about the program. The program has screened 2,300 patients since January 2012, identifying 35 lung cancers, Dr. McKee said. Currently, there is a 15% five-year survival for lung cancer because of late detection, but, she said, screening programs like this can help detect cancers earlier. “We’re at a point in history where in high-risk patients, we can change the natural history of the disease by diagnosing 70% of cases in the earliest stages through screening, whereas in the absence of screening, 70% of cases are diagnosed in the latest stages. This will have a huge impact on lung cancer treatments, outcomes and cancer programs in general.” (The U.S. Preventive Services Task Force requires private insurers and state exchanges to cover the service starting next January, Dr. McKee said. The Centers for Medicare & Medicaid Services will make its ruling on lung screening coverage in November.) Sometimes strengthening a cancer program may rely on multiple steps. Saint Agnes Medical Center in Fresno, Calif., is in the midst of several initiatives, said Paula Jordan, RN, the hospital’s serviceline leader for oncology programs. “What we were finding is that cancer care was really disjointed,” Ms. Jordan said. “Patients would see their primary care doctor, their surgeon and their medical oncologist, but it was less coordinated.” Two years ago, the hospital launched a multidisciplinary breast cancer clinic and just started multidisciplinary clinics for lung and brain cancers. It is in the process of establishing clinics for gynecologic and colorectal cancers, including recruiting qualified surgeons. The medical center also plans to better educate area primary care physicians and the community on its services, launch a lung cancer screening program, and expand nutrition and social work services—now offered only to patients undergoing radiation treatments—to all patients. Additionally, the staff wants to better coordinate palliative care and hospice services and to develop a survivorship program. Providing such programs that go beyond acute clinical care will likely be a growing trend, according to Mr. Sturm. He predicted that with increasing survival times, managing patients’ ongoing care, recurrence and surveillance “could be the next major evolution” in cancer. —Karen Blum

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Clinical Conundrums

lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous hematopoietic cell transplantation at high risk for early MM progression-related death.

Highlights from Blood, JCO, NEJM, Lancet Oncology, and FDA

4. True or False? According to a

Prepared by

Primum non nocere. (First, do no harm.)

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

QUESTIONS

1. True

or False? Erythropoietin therapy does not reduce transfusion requirements after allogeneic hematopoietic cell transplantation (allo-HCT).

ANSWERS

1. False. In this first prospective ran-

domized trial, erythropoietin therapy (500 U/kg/wk) hastens erythroid recovery and decreases transfusion requirements when started 1 month after alloHCT. The proportion of complete correctors (ie, hemoglobin ≥13 g/dL) before day +126 post-transplant was 8.1% in the control arm (median not reached) and 63.1% in the erythropoietin arm (median, 90 days; P<0.001). Hemoglobin levels were higher and transfusion requirements decreased (P<0.001) in the erythropoietin arm. Of note, when erythropoietin therapy was started on day +28, only 5 patients had a hemoglobin level higher than 11 g/dL (mean hemoglobin ∼9 g/ dL), in keeping with current guidelines for initiation of ESA therapy.

review published in The New England Journal of Medicine (NEJM), the National Marrow Donor Program (NMDP) facilitated nearly 3,000 allogeneic hematopoietic cell transplants in 2012.

2. True or False? A Phase II study 5. True or False? According to a

from the Chronic Lymphocytic Leukemia Research Consortium showed that the combination of lenalidomide (Revlimid, Celgene) and rituximab (Rituxan, Genentech) is a highly active immunebased therapy for patients with treatment-naive chronic lymphocytic leukemia (CLL), in particular those with highrisk cytogenetics.

review published in NEJM, the likelihood of finding a 6/6 HLA-matched cord blood unit is much higher than the likelihood of finding an 8/8 HLA-matched unrelated adult donor.

7. True or False? The FDA-approved

treatment options are generally ineffective in relapsed and refractory acute myeloid leukemia (AML), except the recently tested novel agent, elacytarabine, which demonstrated remarkable activity in a Phase III randomized clinical trial.

8. True or False?

The FDA has approved 2 new oral B-cell signaling pathway inhibitors, ibrutinib (Imbruciva, Pharmacyclics) and idelalisib (Zydelig, Gilead), for the treatment of relapsed or refractory CLL.

9. True or False?

The FDA has approved idelalisib for the treatment of patients with relapsed follicular lymphoma (FL) who have received at least 2 prior systemic therapies.

6. True or False? In the umbili- 10. True or False? On July 3, 2014,

International Scoring System 3, high

cal cord blood inventory of the NMDP, almost all white Europeans, but only 81% of blacks, older than 20 years, will have a 4/6 or higher HLA-matched unit(s) with an adequate cell dose.

the FDA granted accelerated approval to belinostat (Beleodaq, Spectrum) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Jaspers A, Baron F, Willems E, et al. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial. Blood. 2014;124(1):33-41, PMID: 24850754.

progression-free survival (PFS) associated with this 7-cycle course of therapy was similar between the 2 groups.

most effective strategies. According to this model, the group of patients with a score of 3, comprising 5% to 8% of MM, could benefit from specifically designed trials, including experimental approaches that aim to overcome disease resistance.

3. True or False? A combination of

2. True. The Chronic Lymphocyt-

ic Leukemia Research Consortium designed a Phase II study evaluating 7 cycles of lenalidomide and rituximab that were administered to 2 independent, age-specific strata of treatmentnaive patients. The overall response rate (ORR) in arm A (age <60 y) was 95%, with 20% achieving a complete response (CR) and 20% a nodular partial response. The ORR in arm B (age >60 y) was 79%, with 10% of patients achieving a CR, including one CR with incomplete hematologic recovery. Despite differences in pretreatment characteristics and response to therapy, median

James DF, Werner L, Brown JR, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014;32(19):2067-2073, PMID: 24868031.

3. True. In this retrospective study,

patient-level data from the Intergroupe Francophone du Myélome 2005-01 trial (N=482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from 3 other trials. This model allows identification of a subgroup of patients presenting with severe disease, despite the use of the latest and

Moreau P, Cavo M, Sonneveld P, et al. Combination of international scoring system 3, high lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related death. J Clin Oncol. 2014;32(20):2173-2180, PMID: 24888806.

4. False. The NMDP facilitated near-

ly 6,000 transplants in 2012 compared with 1,500 a decade ago. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stemcell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339, PMID: 25054717.

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

5. False. The likelihood of finding 9. True. The approval was based on a a 6/6 HLA-matched cord unit is much lower than the likelihood of finding an 8/8 HLA-matched unrelated adult donor in the NMDP registry. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stemcell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339, PMID: 25054717.

6. True.

Currently, antigen-level matching at HLA-A and HLA-B and high-resolution matching at HLADRB1, with selection of units with 4/6 to 6/6 HLA matching and a minimum cell dose of 2.5Ă&#x2014;107/kg of body weight, is standard practice. Future clinical practice may be affected by recent reports suggesting that matching at the HLA-C locus and high-resolution matching at all HLA loci lowers transplant-related mortality. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stemcell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339, PMID: 25054717. Eapen M, Klein JP, Sanz GF, et al. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol. 2011;12(13):1214-1221, PMID: 21982422. Eapen M, Klein JP, Ruggeri A, et al. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014;123(1):133-140, PMID: 24141369.

7. False. Neither elacytarabine nor

any of the 7 alternative treatment regimens (â&#x20AC;&#x153;investigatorsâ&#x20AC;&#x2122; choiceâ&#x20AC;?) provided clinically meaningful benefit to these patients in this international trial. The overall survival (OS) in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for patients with relapsed and refractory AML. Roboz GJ, Rosenblat T, Arellano M, et al. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014;32(18):1919-1926, PMID: 24841975.

True. Approval was based on 2 randomized studies in heavily pretreated patients with relapsed or refractory CLL. High response rates and improved OS were demonstrated by ibrutinib versus ofatumumab (Arzerra, GlaxoSmithKline) and by idelalisib plus rituximab versus rituximab alone. Byrd JC, Brown JR, Oâ&#x20AC;&#x2122;Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213, PMID: 24881631. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997, PMID: 24450857.

single-group, open-label, Phase II study in which 125 patients with indolent nonHodgkin lymphomas (NHL) who had not had a response to rituximab and an alkylating agent or had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. Subtypes of indolent NHL included FL (n=72), small lymphocytic lymphoma (n=28), marginal-zone lymphoma (n=15), and lymphoplasmacytic lymphoma with or without WaldenstrĂśmâ&#x20AC;&#x2122;s macroglobulinemia

(n=10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a CR. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median PFS was 11 months. Gopal AK, Kahl BS, de Vos S, et al. PI3KÎ´ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008, PMID: 24450858.

10.

True. The approval was based on the results of a multicenter, single-arm trial of 120 evaluable patients with PTCL that was refractory or had relapsed after

prior treatment and included patients with baseline platelets <100,000/mcL. Belinostat was administered by IV infusion at a dose of 1,000 mg/m2 once daily on days 1 through 5 of a 21-day cycle. The ORR was 25.8% (95% confidence interval [CI], 18.3%-34.6%). The overall CR and partial response rates were 10.8% and 15.0%, respectively. The median response duration (first date of response to disease progression or death) was 8.4 months (95% CI, 4.5-29.4). FDA. Drugs. Belinostat. www.fda.gov/drugs/ informationondrugs/approveddrugs/ucm403960. htm. Accessed August 14, 2014.

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CLINICAL ONCOLOGY NEWS • SEPTEMBER 2014 • CLINICALONCOLOGY.COM

How I Manage ...

Survivorship Issues After Allogeneic Hematopoietic Cell Transplantation Tarah J. Ballinger, MD Senior Resident Internal Medicine Vanderbilt University Nashville, Tennessee

Bipin N. Savani, MD Professor of Medicine Director, Long Term Transplant Clinic Vanderbilt Ingram Cancer Center Vanderbilt University Nashville, Tennessee

The most common late-onset causes of death after allo-HCT include recurrent disease, chronic graft-versus-host disease (GVHD), infection, cardiovascular and pulmonary complications, and secondary malignancy. Additionally, comorbidities such as chronic pain, fatigue, insomnia, sexual dysfunction, memory loss, mood changes, vision and dental complications, and financial stressors cause significant distress for patients.1 Increasing numbers of long-term survivors, especially those with difficult or no access to a long-term survivorship clinic, return to their local general hematologist or primary care physician ((PCP P) for follow-up. This article will address topics that both transplant and general physicians should be aware of in managing long-term survivors of allo-HCT.

Should allo-HCT recipients receive more rigorous screening for malignancy than the general population? Due to prior conditioning chemotherapy regimens and total body irradiation, allo-HCT survivors are at high risk for a secondary leukemia, post-transplant lymphoproliferative disorder, and new solid tumors, at a 2- to 4-times increased incidence compared with age-matched controls.2,3 Particularly higher incidences exist for secondary oral cancers and thyroid cancers, especially in patients with chronic GVHD or prior irradiation therapy, respectively.4 Late-effects guidelines published in 2012 by the Center for International Blood and Marrow Transplant Research emphasize the importance of regular age-appropriate cancer screening, which should be stressed to both patients and their primary physicians. Additionally, earlier mammography is recommended for women with a history of total body irradiation, starting at age 25 years or 8 years after radiation.5 Regular examination of the oral cavity

llogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for a number of diseases. Advances in transplantation practices and the development of supportive multidisciplinary centers have led to patients living longer after transplant than ever before. The majority of deaths occur within the first 2 years, after which 10-year survival is approximately 80% to 90% and brings with it a number of late effects that can cause significant patient and health care burden.

and thyroid should be performed. Due to their increased incidence of skin cancers, transplant patients should be educated on the importance of sunscreen protection and regular skin examination.6 Ongoing clinical trials seek to determine whether there are particular genetic defects or lifestyle factors that increase the risk for secondary malignancy (eg, NCT00949052 is active and recruiting).

Are there specific long-term infectious disease concerns, and what guidelines exist for preventing and treating infections in long-term survivors of allo-HCT? The risk for infectious complications is highest in the immediate post-transplant period and up to 2 years after transplant. However, susceptibility to infection often persists long term due to delays in immune reconstitution and impaired cellular and humoral immunity, especially in those with chronic GVHD or in patients taking chronic immunosuppressive therapy. Patients should be educated about this lifelong complication and encouraged to seek prompt medical treatment if they have signs of infection, even if white blood cell counts are normal. Patients with chronic GVHD have impaired opsonization and should be treated with antibiotic prophylaxis against encapsulated organisms, in addition to appropriate viral and Pneumocystis pneumonia prophylaxis, for as long as they take immunosuppressive therapy. All transplant patients should be given inactivated vaccines appropriate to their age and medical conditions, whereas live vaccines should be withheld in patients with chronic GVHD and impaired immunity. Varicella can cause fatal disease in transplant patients; therefore, it is recommended that seronegative patients without evidence of GVHD receive the live varicella vaccine (Varivax, Merck). The first dose may be given with the

measles/mumps/rubella vaccine. Of note, all live vaccines should be administered at 2 years post HCT, if it has been more than 1 year since they have received immunosuppressive therapy and at least 5 months since last dose of IVIG/VZIG or most recent plasma transfusion. The zoster vaccine (Zostavax, Merck) has higher viral titers and remains contraindicated. A set of guidelines published in 2009 by multiple international HCT and infectious disease groups provides detailed recommendations and is a good reference when specific situations of question arise.7

Given the increased incidence of organ dysfunction and chronic medical conditions in transplant survivors, how should general medical care and screening differ for these patients? It is difficult to give a general answer to this question because much of the follow-up is specific to an individual patient and the prior treatment they received. Many of the long-term complications of allo-HCT (Figure) are known, but studies have shown that the transplant community does not do a good job monitoring for these conditions.8 Patients with predisposing risk factors are at particularly high risk for metabolic syndrome and cardiovascular disease; therefore, routine screening and management of these conditions is recommended and a heart-healthy lifestyle is stressed to the patients.9 Pulmonary complications range from chronic infections to small airway destruction secondary to chronic GVHD. Initial post-transplant follow-up includes pulmonary function testing, and many experts recommend continuing regular testing for insidious complications, with a low threshold for chest imaging in patients with respiratory complaints. Patients are strictly counseled to abstain from smoking. Chronic GVHD is a major cause of liver dysfunction and, therefore,

patients should be screened with liver function testing at least yearly in patients surviving beyond 3 years post-transplant, and more frequently if clinically indicated. Routine screening for renal failure is recommended because it is common in allo-HCT survivors, especially those who have received calcineurin inhibitors. Skeletal complications include a high risk for osteoporosis; therefore, routine dualenergy x-ray absorptiometry screening should be performed and patients provided with vitamin D and calcium supplementation. The routine use of bisphosphonates is debated, with some studies showing efficacy before and after transplant in patients with osteopenia and with risk for fractures.10 Long-term survivors also are at risk for cataracts, keratoconjunctivitis sicca syndrome, and retinopathy and should, therefore, be evaluated with annual eye exams. Due to a greatly increased risk for oral cancers and dental issues, annual oral exams and dental evaluations are recommended. The long-term prevalence of hypothyroidism is approximately 20% to 40%, making annual thyroid function testing important.11 Because many allo-HCT survivors regularly visit their PCP for routine care, it is important that these physicians are aware of follow-up recommendations. However, patients themselves should take ownership of their care and be counseled on the importance of regular follow-up. Individualized “survivorship care plans,” which include prior treatments and monitoring guidelines, can be developed by HCT physicians and given to the patient and PCP to help facilitate adequate health maintenance.

What issues are particular to patients who suffer from chronic GVHD, and what evidence exists for the best long-term management options for the prevention of chronic GVHD? Chronic GVHD complicates approximately 40% of allo-HCTs and causes significant morbidity, the most common of which covers a spectrum of skin involvement and sclerotic changes; fasciitis or myositis complicated by joint contractures; visual issues; gynecologic complications; hepatitis; oral and intestinal involvement including ulcers, diarrhea, vomiting, and anorexia; and obstructive or restrictive lung disease. In addition to direct complications of active chronic GVHD, patients with this complication are more likely to report additional medical conditions, chronic pain, emotional

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2014 • CLINICALONCOLOGY.COM

distress, and financial hardship than patients with absent or resolved GVHD.12 A diagnosis of chronic GVHD can be made clinically by following diagnostic criteria established by the National Institute of Health, or may require histologic confirmation by biopsy.13 Patients with limited disease may be adequately managed on steroids alone, but patients often require the addition of cyclosporine or tacrolimus. There may be additional roles for rituximab (Rituxan, Genentech), imatinib (Gleevec, Novartis), mycophenolate mofetil, and sirolimus, which have not yet been defined. In a recent Phase II trial, rituximab showed promise in GVHD prophylaxis, and Phase III trials are underway.14 Studies are ongoing to determine the appropriate use of extracorporeal photopheresis and the proteasome inhibitor, bortezomib (Velcade, Millennium), both of which have been shown to be effective in the treatment of chronic GVHD, but indications and guidelines for use are not yet available. Thus far, agents that have been unsuccessful in preventing chronic GVHD include thalidomide (Thalomid, Celgene), IV immunoglobulin, glucocorticoids, and cyclosporine.

How can the psychosocial and psychological issues specific to post-transplant survival be best addressed and managed? Allo-HCT survivors are likely to be burdened financially from their extensive medical needs and are more likely to be unemployed than their peers. In a recent analysis, 80% of long-term survivors reported financial hardship and 3% reported bankruptcy, likely compounded by increasing insurance issues as the time from transplant increases.15 Survivors, especially those without a good social support system, are at significant risk for posttraumatic stress disorder, depression, anxiety, and suicide. Additionally, as a result of prior therapies, radiation, and possible iron overload, HCT survivors often suffer from sexual dysfunction and infertility. This can be a life-altering issue, especially for younger patients. HCT patients should be treated with a team approach designed to preemptively detect these issues and should be plugged in for support from social workers, psychiatrists, and psychologists. Psychological health and sexual function should be specifically queried at regular intervals, with measurement of sex hormone levels and referral to appropriate specialists as needed.

Are there sufficient resources and transplant physicians to care for the growing population of long-term transplant survivors? There are more than 60,000 (combined allogeneic and autologous) HCTs performed each year worldwide. By the year 2030, it is projected that the number of blood and marrow transplant survivors

• Cataracts • Keratorconjunctivitis sicca

• Memory loss • Depression/anxiety • Post-traumatic stress disorder • Dry mouth • Oral cancer

• Thyroid cancer • Hypothyroidism

7. • Coronary artery disease • Congestive heart failure

• Bronchiolitis obliterans (related to GVHD) • Chronic infections

• Liver dysfunction • Hepatitis B and C • Iron overload

• Renal failure

• Infections • Recurrent malignancy • Secondary malignancy

• Osteoporosis • Avascular neurosis

• GVHD • Skin cancer

• Sexual dysfunction • Infertility

Figure. Late effects after allo-HCT. allo-HCT, allogeneic hematopoietic cell transplantation; GVHD, graft-versus-host disease

will increase 5-fold, potentially resulting in 500,000 survivors in the United States alone. In 2009, approximately 1,115 physicians in the U.S. regularly performed HCTs, with an estimated need for this number to double by the year 2020 to meet the increasing demand.16 The majority of centers are performing more transplants despite unchanged numbers of physicians and available resources. It is not feasible that transplant physicians and care teams can provide adequate ongoing attention to all transplant survivors. A possible solution to this disparity in the number of transplants and the availability of ongoing care is the use of longterm follow-up clinics in an umbrella model for all cancer survivors, similar to that proposed by the National Cancer Institute’s Children’s Oncology Group.17 A number of institutions have adopted HCT-specific survivor clinics if resources are available, which provide at least annual multidisciplinary follow-up. This is particularly important for allo-HCT recipients who suffer from chronic GVHD, for which complications are specific and require the involvement of many support services for adequate management. The System Capacity Initiative Physician Workforce Group of the National Marrow Donor Program is working to find solutions for recruiting transplant physicians interested in the field of long-term follow-up. For most patients, a return to their PCP for regular care and screening is appropriate, highlighting further the necessity for PCPs and patients themselves to be aware of the complications and recommendations following transplant.

Future Directions There are extensive data about the varied late-onset complications of transplant

6. Leisenring W, Friedman DL, Flowers ME, et al. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. 2006;24(7):1119-1126, PMID: 16461782.

survivors, with chronic GVHD remaining the most challenging to manage. However, there are inadequate resources and few guidelines for the prevention and monitoring of these complications. It is imperative that resources be focused on better translation of our knowledge into clinical care. It is recommended that all HCT survivors be seen by a blood and marrow transplant center for possible enrollment in ongoing survivorship studies and be provided with guidelines for future management. All health care workers involved in the care of these patients should be aware of the preventable longterm complications of allo-HCT. Our goal should be the establishment of adequate resources for survivor follow-up and close partnership between health care providers to provide the best longterm quality of life for patients who have undergone allo-HCT.

References 1. Savani BN, ed. Blood and Marrow Transplantation Long Term Management: Prevention and Complications. Oxford, UK: John Wiley and Sons; Dec 2013. 2. Rizzo JD, Curtis RE, Socie G, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113(5):1175-1183, PMID: 18971419. 3. Heilmeier B SN, Socie G, van Limit MT, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation—follow up. Blood. 2008;112: abstract 453. 4. Atsuta Y, Suzuki R, Yamashita T, et al. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease. Ann Oncol. 2014;25(2):435-441, PMID: 24399081. 5. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(3):337-341, PMID: 22395764.

Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238, PMID: 19747629.

8. Savani BN, Griffith ML, Jagasia S, et al. How I treat late effects in adults after allogeneic stem cell transplantation. Blood. 2011;117(11):3002-3009, PMID: 21193694. 9. Griffith ML, Savani BN, Boord JB. Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management. Blood. 2010;116(8):1197-1204, PMID: 2043923. 10. McClune BL, Majhail NS. Osteoporosis after stem cell transplantation. Curr Osteoporos Rep. 2013;11:305-310, PMID: 24202854. 11. Sanders JE, Hoffmeister PA, Woolfrey AE, et al. Thyroid function following hematopoietic cell transplantation in children: 30 years’ experience. Blood. 2009;113(2): 306-308, PMID: 18838614. 12. Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006;108(8):2867-2873, PMID: 16788100. 13. Greinix HT, Loddenkemper C, Pavletic SZ, et al. Diagnosis and staging of chronic graft-versus-host disease in the clinical practice. Biol Blood Marrow Transplant. 2011;17(2): 167-175, PMID: 20691801. 14. Cutler C, Kim HT, Bindra B, et al. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood. 2013;122(8): 1510-1517, PMID: 23861248. 15. Khera N, Chang YH, Hashmi S, et al. Financial burden in recipients of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20(9): 1375-1381, PMID: 24867778. 16. Gajewski JL, LeMaistre CF, Silver SM, et al. Impending challenges in the hematopoietic stem cell transplantation physician workforce. Biol Blood Marrow Transplant. 2009;15(12):1493-1501, PMID: 19781658. 17. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol. 2004;22(24): 4979-4990, PMID: 15576413.

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

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