May 2014

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • May 2014 • Vol. 9, No. 5

INSIDE

IMAGES in ONCOLOGY

ASH 2013

Finding the cost of oncology drugs ..................... 8

New Options For TransplantIneligible Myeloma

SOLID TUMORS

Len/Dex recommended as front-line standard

SPECIAL FEATURE

Exercise decreases AI-associated joint pain .......................................... 10 Genetic test may refine prostate cancer prognosis .............................. 16 Fertility drugs do not increase cancer risk ........................................... 19

HEMATOLOGIC DISEASE By the Numbers: Insurance delays and post-transplant survival ....................................21 Imatinib, nilotinib switch deepens molecular response ......... 23

CURRENT PRACTICE Financial value of community oncology underestimated .................. 16 H. Joachim Deeg, MD: How I manage hematopoietic cell transplantation for myeloproliferative neoplasms ...........................20 Clinical Conundrums ....................... 22

New Orleans—The all-oral combination of continuous lenalidomide and low-dose dexamethasone (Rd) has been declared a new standard for first-line therapy of newly diagnosed, transplant-ineligible multiple myeloma (MM). The designation was based on a survival benefit observed over the previous standard of melphalan, prednisone and thalidomide (MPT) in a Phase III trial presented during a plenary session of the 2013 annual meeting of the American Society of Hematology (ASH; abstract 2).

The relationship of continuous Rd to bortezomib (Velcade, Millennium), see MYELOMA, page 15

SABCS 2013

Delaying Aromatase Inhibitor Resistance San Antonio—In a Phase II study, adding dasatinib (Sprycel, BristolMyers Squibb) to letrozole (Femara, Novartis) in patients with postmenopausal metastatic breast cancer doubled progression-free survival (PFS), but had no effect on clinical benefit rate. The results were reported at the recent San Antonio Breast Cancer Symposium (abstract S3-07).

“These findings suggest that dasatinib may inhibit the emergence of acquired resistance to aromatase inhibitor [AI] therapy,” said Devchand see RESISTANCE, E page 7

‘Floating G, a cytologic alphabet soup of leukemic cells?’

For more information see page 3.

Vogl, NY...

For Triple-Negative Breast Cancer Give adjuvant carboplatin after incomplete response to neoadjuvant AC-T

T

wo randomized prospective trials (one German, one American) presented in 2013 show that the addition of carboplatin to induction chemotherapy for hormone receptor–negative and HER2negative breast cancer (“triple negative”) improves the pathologic complete remission (pCR) rate of such therapy.1,2 For this subset of breast cancer patients, pCR is essentially uniformly associated across studies with a very much improved prognosis in terms Steven Vogl, MD of decreased relapse and improved survival rates. In a 2012 FDA-conducted meta-analysis, pCR improved five-year relapse-free survival from 50% to 85%.

The associated survival benefit has a hazard ratio of 0.16.3 These studies follow a series of small Phase II trials showing high pCR rates from cisplatin or carboplatin given alone in this subgroup of patients, some of whom have see CARBOPLATIN, N page 4

RE VIE WS & COMMENTAR IES

Expert Insights From The Ohio State University—The James Maintenance Pemetrexed Boosts Advanced NSCLC Survival ........................ 13 David Carbone, MD, PhD

Pain Persists in Ambulatory Cancer Patients ....................... 14 Robert M. Taylor, MD

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ClinicalOncology.com

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • MAY 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

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

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

Oncology Nursing

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

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

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

Mayo Clinic Rochester, MN

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

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

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

The Mount Sinai Medical Center New York, NY

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

On the Cover

O

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

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

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

University of Alabama Birmingham, AL

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

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

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

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

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

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

Bioethics

University of California, San Diego, CA

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

T

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

William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung g and Head and Neck Cancers Edward S. Kim, MD

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

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, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

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

Lung g Cancer,, Emesis Richard J. Gralla, MD Albert Einstein College of Medicine, New York, NY

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

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

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

3

4

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

CARBOPLATIN

Table 1. Phase II Studies of Neoadjuvant Platinum Compounds

continued from page 1

EDITORIAL BOARD COMMENTARY

Drug Silver, JCO 2010

Steven Vogl, MD

4

Byrski, JCO 20105

Medical Oncologist, New York City

6,a

Rugo, SABCS 2013

Dose 2

pCR Rate, %

Population

Cisplatin

75 mg/m q3wk × 4

22

28 triple-negative patients; 2 with BRCA1 mutation

Cisplatin

75 mg/m2 q3wk × 4

83

12 BRCA11 mutation carriers

Carboplatin

AUC 6 q21d × 4

52 (estimated)

39 triple-negative, locally advanced cancers

AUC, area under the curve; pCR, pathologic complete remission a Carboplatin was given with concurrent veliparib 50 mg orally twice daily and paclitaxel every seven days for 12 cycles, followed by four cycles of cyclophosphamide and doxorubicin (AC). A concurrent, but not strictly randomized, control group of 21 triple-negative cancers had an estimated pCR rate of 26%

by Bayesian probability analysis with paclitaxel every seven days for 12 cycles, followed by four cycles of AC.

BRCA1 mutations. The two randomized trials may be considered a confirmation of the earlier successes reported by Daniel P. Silver, MD, PhD, and Tomasz Byrski, MD, PhD (Table 1).4-6 These studies also follow data showing that both cisplatin and carboplatin are active as single agents in metastatic breast cancer.7,8

Carboplatin Was Too Toxic As Used Or The Partner Drugs Were Nonstandard Unfortunately, neither of these newly analyzed, randomized studies used carboplatin in a way that should be broadly applied. The German Breast Group GeparSixto trial added 18 weekly doses of carboplatin at an area under the curve (AUC) of 1.5 to a backbone of bevacizumab (Avastin, Genentech/Roche), weekly paclitaxel, and weekly non-pegylated liposomal doxorubicin (a preparation called Myocet not available in the United States).1 The carboplatin was given concurrent with the other drugs.

Not only is the Myocet not available, but the use of bevacizumab is not attractive because of its toxicity and lack of activity in terms of improving disease-free survival and overall survival in adjuvant studies. The ultimate goal of neoadjuvant therapy is of course, to prevent relapse and death from breast cancer by suppressing and eradicating occult metastatic disease.

The neoadjuvant CALGB 40603 trial presented by William Sikov, MD, of the Alliance for Clinical Trials in Oncology, concurrently added four doses of carboplatin at AUC 6 every

®

Table 2. Toxicity of Concurrent Carboplatin Regimens Without Carboplatin, %

With Carboplatin, %

Completed entire course

61

52

Febrile neutropenia

6

6

Grade 3 anemia

1

11

Grade 3 hematologic toxicity

7

26

Stopped for toxicity

0

6

Paclitaxel doses >9

88

62

7

12

92

88

4

9

Neuropathy

2

7

Neutropenia

22

56

Thrombocytopenia

4

20

Nausea, vomiting, dehydration

1

5

Febrile neutropenia

7

12

German Breast Group1

CALGB 40603 (Alliance)2

<6 Subsequent AC doses: 4 1-2 Grade 3 toxicities

AC, cyclophosphamide and doxorubicin; Alliance, Alliance for Clinical Trials in Oncology

three weeks to weekly paclitaxel at 80 mg/m2 for 12 weeks given before four doses of cyclophosphamide and doxorubicin (AC) repeated every 14 days.

This is a more conventional regimen, but the toxicity was severe (Table 2).

Grade 3 neurotoxicity increased from 2% to 7% (data are not yet available on reversibility); hematologic toxicity was severe; and many doses of paclitaxel were held because of toxicity. To most patients who experience it, even grade

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2 neurotoxicity is too much.

Table 3 summarizes the increase in pCR rates from the addition of carboplatin in both studies. For the U.S. study, the table gives the pCR rates in primary tumors and nodes, and only for patients not given concurrent bevacizumab (which was a second randomization in this trial). In the U.S. trial, bevacizumab added some additional pCRs, but was judged by Dr. Sikov as too toxic compared with the modest advantages gained.

Obviously, more work needs to be done to define a regimen in which the addition of carboplatin is tolerable and to demonstrate that the extra pCRs attained by adding carboplatin are associated with improved survival—the ultimate measure of efficacy of adjuvant therapy, whether given before or after surgery.

Triple-Negative Breast Cancer Is Not Homogeneous: Negatives Are Poor Definers It remains unsatisfactory to define a group of patients and tumors by what they are not—it makes much more sense to identify them by what they are. Many such classifications for breast cancer are in development. However, none of them is widely available; we have no consensus on which classification to use; and we have no data to tell us how to treat each group defined in these systems.

We do not even know the BRCA1 mutation status of the patients with triple-negative breast cancer in the U.S. see CARBOPLATIN, N page 6

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

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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

6

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CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

CARBOPLATIN

More on Bone Agents and Early Breast Cancer Survival

What are your thoughts?

New data support the importance of vitamin D

continued from page 4

and German trials—this simple testing should be mandated in trials treating this patient population. We will learn some of this information soon: The German Breast Group will present BRCA mutation data from the GeparSixto trial at ASCO 2014 in June, and the Alliance plans to soon analyze germline mutation status for the patients and gene expression profiles for the tumors entered in CALGB 40603.

Estrogen Receptor, Progesterone Receptor and HER2 Remain the Classifying Criteria for 2014 In 2014, we are stuck with employing clinical classifications based on hormone receptors and HER2. For the moment, we should appreciate how useful these have become, and how much progress we have made using them, rather than dwell on our desire for classifications and therapy based on mutations in DNA repair enzymes, gene expression, tumor suppressors and checkpoint regulators.

Classifiers will be developed using these criteria, but may take decades to become reproducible and useful.

In the meantime, those of us responsible for the care of women with highrisk, triple-negative cancers would do well not to ignore the established efficacy of carboplatin.

Use Carboplatin as a Single Agent After AC and T for High-Risk Women With the results of a CALGB study by Marc Citron, MD, in mind, I suggest we use carboplatin as a single agent after both AC and paclitaxel (T).9 In Dr. Citron’s study, sequential adjuvant single agents (A then T then C) were as effective as AC followed by T, despite the treatment taking 50% longer to complete.

Choose Carboplatin Candidates Wisely

I

n the March issue of Clinical Oncology News, I took a cautious position in favor of adjuvant bisphosphonates to prevent bone metastases and death in women with resected early breast cancer who are more than five years after their last menses. In that editorial, I noted that two studies reported that low levels of vitamin D at diagnosis correlate with increased rates of recurrence.

Just after the editorial went to press, Sharif Mohr, PhD, and colleagues from the Naval Health Research Center in San Diego, published a meta-analysis of five studies looking at serum 25-hydroxy vitamin D levels at diagnosis and breast cancer mortality.1 Four of the five studies showed much lower breast cancer death rates for the 20% of women with the highest vitamin D levels compared with the 20% of women with the lowest levels. Considering all five studies, those with the highest vitamin D levels had half the mortality of those with the lowest levels.

This analysis supports my call for studying vitamin D supplementation for early breast cancer. Women with low levels at diagnosis should be randomized to placebo or to vitamin D supplementation to a sufficient level of 25-hydroxy vitamin D (generally thought to be >30 or 33 ng/mL). Vitamin D supplementation when needed may prove more effective than bisphosphonates and denosumab (Xgeva, Amgen), and will certainly be cheaper, more convenient and less toxic.

—S.V. 1. Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res. 2014;34:1163-1166, PMID: 24596354.

should forgo the late addition of sequential carboplatin.

Ample Precedent for Late Switch in Adjuvant Chemotherapy The use of paclitaxel and docetaxel after AC therapy provides ample precedent for the delayed introduction of active chemotherapy in the adjuvant treatment of triple-negative breast cancer. Daniel Hayes, MD, reported a big benefit from adding paclitaxel after AC

in women with triple-negative tumors.10 Sequential AC for four cycles and docetaxel for four cycles was superior to four cycles of TAC in hormone receptor– negative breast cancer (probably mostly triple-negative), and sequential AC for four cycles followed by four cycles of docetaxel was equal to six cycles of TAC for women with triple–negative tumors in a European study.11,12 That more chemotherapy is still effective after 18 weeks of TAC was demonstrated in the recent report of

Key Points Neoadjuvant carboplatin for triple-negatives • It increased pCR in two randomized prospective trials.

• Meta-analysis shows pCR leads to major decrease in relapse and death.

• Concurrent carboplatin was too toxic as given.

• Failure to achieve pCR is the best way to select high-risk women for carboplatin.

• Carboplatin should be offered only to women without prohibitive toxicity from prior chemotherapy.

Prudence dictates that women with moderate or severe neurotoxicity or moderate or severe lingering cytopenias

• Weekly carboplatin schedule for 18 weeks seems preferable.

Table 3. Randomized Trials of Adding Concurrent Carboplatin to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer Control pCR, %

pCR With Carboplatin, %

AUC 1.5 every 7 d for 18 cycles

38

59

AUC 6 every 21 days for 4 cycles

41

54a

Backbone (Control)

Carboplatin

German Breast Group (N=315)

Paclitaxel, liposomal doxorubicin, bevacizumab, all weekly for 18 cycles

Alliance (N=443)

Paclitaxel every 7 d for 12 cycles, followed by AC every 14 d for 4 cycles

AC, cyclophosphamide and doxorubicin; Alliance, Alliance for Clinical Trials in Oncology; AUC, area under the curve; pCR, pathologic complete remission a

pCR rose from 39% to 49% with addition of carboplatin if considering only the subset of women not getting concurrent bevacizumab (50% of controls and carboplatin patients were randomized to receive bevacizumab).

Clinical Oncology News welcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to gmiller@mcmahonmed.com

the German Breast Group’s GeparTrio trial, in which women with early objective response of well-differentiated hormone receptor–positive breast cancer after two cycles of TAC derived benefit—delayed relapse—by adding a seventh and eighth cycle of TAC compared with stopping after six cycles.13

The Best Definition of High Risk Is the Failure To Achieve pCR We can best define very high risk by picking for adjuvant carboplatin those women who fail to achieve pCR after neoadjuvant AC and paclitaxel (the latter now should be given weekly because it is less toxic than everytwo-week treatment, with the same activity).13 They can then receive classic “adjuvant” carboplatin when they have recovered from their surgical procedures.

This has never been done, but makes excellent sense as a bridge program until we have more trial data. A relapse rate of 50% at five years, as reported in the FDA meta-analysis by Dr. Cortazar just published in Lancet, is high enough to justify treatment with another active drug with which we, as oncologists, are very familiar.3 If neoadjuvant chemotherapy was not given and surgery was done first, then I would consider giving carboplatin after dose-dense AC and weekly T for 12 cycles to women with four to nine involved axillary nodes, and urge women with 10 or more involved axillary nodes to take carboplatin.

When Giving ‘Extra’ Chemotherapy, Give It Carefully It is prudent to give late adjuvant carboplatin as a single agent in small weekly doses. This will allow dose modulation for toxicity each week before each small dose and hopefully will avoid a lot of the severe neurotoxicity and myelosuppression that otherwise might occur from a big dose every three weeks. The incrementally higher pCR rate reported by the German Group’s GeparSixto trial compared with the CALGB 40603 (Alliance) trial suggests two possibilities: Weekly doses may be more active than every-three-week doses, and 18 weeks of therapy may be more active than 12 weeks (table 3). Thus, if the patient is tolerating therapy well after

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CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

12 weekly doses, I would favor pushing to 18, while watching carefully every week for developing neurotoxicity.

If we ever have a reproducible genomic definition of women much less likely to develop neurotoxicity from carboplatin based on profiles of single nucleotide polymorphisms, we will then be able to offer the drug with much more assurance that we will not produce crippling toxicity.

Carboplatin Is an Inexpensive, Effective Drug Available Now One would like to have a simple, nontoxic, easily administered and inexpensive curative therapy for these unfortunate women. We would like to define a target, aim at it and solve the problem.

Until this dream is fulfilled, we have to make do with the drugs we have for the patients who need our ministrations now. If we improve the pCR rate by 20% (as found for carboplatin in GeparSixto), the extra 20% of women who get pCR will now likely have the 85% five-year DFS reported by Dr. Cortazar for pCR in his trial, rather than the 50% five-year DFS of women who do not have a pCR.

RESISTANCE continued from page 1

Paul, DO, PhD, a breast oncologist at US Oncology and Rocky Mountain Cancer Centers, Denver.

Dasatinib is an inhibitor of five tyrosine kinase families, including Src. Because several studies have linked high levels of Src activity to breast cancer metastases to bone, investigators set out to test the combination of letrozole and dasatinib as first-line treatment for metastatic breast cancer.

“Src regulates osteoclast-mediated bone turnover,” said Dr. Paul. “Several studies have shown that Src is important in enabling estrogen-receptor crosstalk with the HER2 family and other growth factor-signaling pathways, as well as other steroid hormone receptors, including the androgen receptor, leading to activation of MAP [mitogen-activated protein]

If adding carboplatin actually increases the pCR rate to 50% from 30% for the triple-negative population, then overall DFS at five years goes to 67.5% from 60.5% with a corresponding survival benefit. The benefit will be smaller if the pCR increase is closer to the U.S. value of 13%, or if many women are excluded from carboplatin by toxicity from AC-T. The benefit may prove bigger if late administration of carboplatin as a single agent allows higher cumulative doses to be given, and if this improves efficacy.

This modest benefit of 7% DFS at five years may not be a “home run,” but most oncologists and patients presenting with non-metastatic, triple-negative breast cancer would consider this an incremental gain worth pursuing.

References 1. Von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). J Clin Oncol. 2013;suppl: abstract 1004.

2. Sikov WM, Berry DA, Perou CM, et al.

Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant

weekly paclitaxel (P) followed by dosedense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). Presented at the San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S5-01.

3. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and longterm clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014 Feb 13. [Epub ahead of print], PMID: 24529560.

4. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol.

2010;28:1145-1153, PMID: 20100965.

5. Byrski T, Gronwald J, Huzarski T, et al.

Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375-379, PMID: 20008645.

6. Rugo HS, Olopade O, DeMichele A, et al.

Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Presented at the San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S5-02.

7.

Sledge GW Jr, Loehrer PJ Sr, Roth BJ, Einhorn LH. Cisplatin as first-line therapy for metastatic breast cancer. J Clin Oncol.

1988;6:1811-1814, PMID: 3199166.

8. Martín M, Díaz-Rubio E, Casado A, et al.

‘These findings suggest that dasatinib may inhibit the emergence of acquired resistance to aromatase inhibitor therapy.’

—Devchand Paul, DO, PhD kinase and PI3 [phosphatidylinositide-3] kinase pathways. Ultimately, this will affect transcription, DNA synthesis, proliferation and breast cancer cell survival.”

The trial enrolled 120 hormone receptor–positive, HER2-negative postmenopausal patients with metastatic breast cancer. Patients were randomized in a 1:1 fashion to receive letrozole monotherapy (2.5 mg orally once daily) or letrozole in combination with dasatinib (100 mg orally once daily) as first-line AI treatment.

No prior AI therapy for metastatic breast cancer was allowed, but patients could have received an adjuvant AI more than one year before study entry.

Investigators found no difference in

clinical benefit rate, the study’s primary end point. However, the median PFS was 9.9 months in patients receiving letrozole alone and 20.1 months in patients receiving combination therapy. Dr. Paul said the combination therapy was well tolerated and that dasatinib may decrease the incidence of osteopenia in patients on AIs. “Previous studies have shown that fulvestrant [Faslodex, AstraZeneca] or exemestane combined with dasatinib did not improve progression-free survival following progression on nonsteroidal aromatase inhibitor–pretreated patients compared with fulvestrant or exemestane alone,” said Dr. Paul. “These findings [with] the first-line letrozole–dasatinib

Carboplatin: an active drug in metastatic breast cancer. J Clin Oncol. 1992;10:433-437, PMID: 1740682.

9. Citron ML, Berry DA, Cirrincione C, et al.

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of nodepositive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol.

2003;21:1431-1439, PMID: 12668651.

10. Hayes DF, Thor AD, Dressler LG, et al.

HER2 and response to paclitaxel in nodepositive breast cancer. N Engl J Med. 2007;357:1496-1506, PMID: 17928597.

11. Swain SM, Jeong JH, Geyer CE Jr, et al.

Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010;362:2053-2065, PMID: 20519679.

12. Eiermann W, Pienkowski T, Crown J, et al.

Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol.

2011;29:3877-3884, PMID: 21911726.

13. Budd GT, Barlow WE, Moore HCF, et al.

S0221: comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. J Clin Oncol. 2013;supple: abstract CRA1008.

data suggest that dasatinib may be of benefit mainly in patients receiving initial aromatase inhibitor therapy.”

Stefan Glück, MD, PhD, the clinical director of the Braman Family Breast Cancer Institute at the University of Miami Health System in Florida, said the study was significant, but not yet practice-changing. “We will need confirmation in a Phase III trial and FDA approval, but it has the potential to be positive,” he explained. “We are also testing this principle in our institution and preliminary data are very promising.”

Dr. Paul said his group would be analyzing patient archival breast cancer tissue in an effort to identify biomarkers that could help inform patient selection for future studies of dasatinib in this patient population.

—Kate O’Rourke Drs. Paul and Glück have no relevant disclosures.

by the

numbers Rapid Rituximab Infusion

Mean infusion time

62.4 minutes

R

Infusion reactions (all grades)

0%

Nurse satisfaction (on basis of survey)

100%

Mean reduction in infusion time with rapid vs standard infusion

94 minutes

ituximab infusion times are typically prolonged in order to reduce the risk for infusion reactions. However, this risk is greatest during the initial infusion. Patients who do not develop infusion reactions with initial treatment may be candidates for rapid infusion, reducing treatment times and hospital costs and potentially improving quality of life.

In a study evaluating rapid rituximab infusions presented at the 2013 annual meeting of the American Society of Hematology (abstract 2985), 50 patients were treated with rapid infusion if they did not develop a grade 3 or 4 infusion reaction with an initial standard infusion. The study was led

by Emily Dotson, PharmD, of Ohio State University in Columbus.

The bottom line: Faster infusions used fewer outpatient resources and increased nurses’ satisfaction.

7

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Behind Closed Doors:

Finding the Cost of Oncology Editor’s Note: For the past two years, Clinical Oncology News has asked several experts on oncology drug costs if, and how, we could find out the actual cost of oncology drugs. A flat “no” was the answer that we most often received, because of the secrecy of contracts between pharmaceutical drug distributors and buyers.

It also quickly became clear that how much you paid for a drug typically depended on who you were (patient, private practice, 340B hospital). Clinical Oncology New ws tasked the magazine’s feature reporter, Victoria Stern, with finding out the cost to patients of a major, recently approved drug in oncology, and in the process, with prooviding a window into one of the most contentious debates in cancer care: the cost of drugs.

T

he assignment was an interesting proposition: Find out what a brandname oncology drug costs.

Although the request sounded simple, I knew it would pose a challenge given that a price will change as it moves along the supply chain from manufacturer to patient. I decided to start my price inquiries at the end points of the supply chain to see if I could track how the price of a brand-name drug changes.

I contacted eight manufacturers with recently approved oncology drugs.

Only three of the companies provided pricing information. Bristol-Myers Squibb, for instance, quoted a wholesale list price of $30,000 per infusion for ipilimumab (Yervoy) 3 mg/kg

for four infusions, totaling $120,000, and Seattle Genetics revealed that a course of brentuximab (Adcetris) costs $15,000 per infusion for six to seven infusions, coming to about $97,000 for a full course of treatment.

I wanted, however, to understand treatment costs for an individual patient, not the average patient, so I sought out the drugs’ unit price. Seattle Genetics informed me that brentuximab costs $5,000 per vial, and a quick Internet search revealed that each vial of brentuximab is 50 mg, so the unit price for brentuximab would be $100.

To find the unit price for ipilimumab, I contacted representatives at First Databank, Red Book and Medi-Span, all

of which publish drug prices. Unfortunately, First Databank and Medi-Span charge a fee for pricing information and I never received the Red Book information I requested. Fortunately, the Centers for Medicare & Medicaid Services (CMS) publishes the unit price of drugs every quarter—and the information is free. I downloaded a massive Excel file off the CMS website with pricing data published on Jan. 1, 2014, and scrolled through the data until I found the unit price for ipilimumab ($128.966 per mg) and for brentuximab ($106.856 per mg).

Despite this success, when it came to uncovering what patients pay for oncology drugs, I hit a dead end. I couldn’t

Whether or not this represents a random sampling of patients, the price range was unintelligible. How then could the manufacturer’s estimate be approximately $30,000 per infusion whereas patients were charged anywhere from $23,000 to $205,000?

Figure 1. The flow of funds for physician-administered, branded cancer drug treatments through the “buy and bill” system.

Courtesy of Rene Conti, PhD, and Ernst Berndt, PhD.

There is huge variation in what private oncology practices or hospitals charge patients for drugs. find any resource that compiles this data.

“It’s virtually impossible to find information at the patient level,” said Richard Freeman, PhD, a professor and the vice chair for research in the Department of Pharmacy Practice & Administration at the University of Maryland Eastern Shore School of Pharmacy in Baltimore, and previously the executive director of health policy for AstraZeneca and the director of Strategic Pricing & Pharmacoeconomics for Sanofi.

“One major reason is payers have multiple contracts in place that vary according to how much providers will be reimbursed. Medicare and Medicaid are not required to disclose this information, nor are the private contractors that administer the program.”

Although specific pricing information was scarce, I did find a post on the Melanoma Research Foundation forum by a patient who expressed concern about the cost of her ipilimumab therapy. The patient revealed that, in early 2013, Cleveland Clinic charged her insurance company more than $205,000 for one 336 mg infusion of the drug. A patient responding to the thread said the price for each of her infusions was around $23,000 in July 2012. A third patient chimed in, noting that her insurance company was billed $55,000 for each infusion in December 2012.

Whether or not this result represents a random sampling of patients, the price range was unintelligible. Using CMS’s estimate of $128.966 per mg, a patient’s 336 mg infusion should come to about $43,333. How then could the manufacturer’s estimate be approximately $30,000 per infusion whereas patients were charged anywhere from $23,000 to $205,000?

The Supply Chain Attempting to answer this question revealed the true complexity of drug pricing. First, I needed to understand how prices vary as a drug moves along the supply chain (Figure 1). A manufacturer publishes a catalog or list price for a drug, typically the wholesale acquisition cost (WAC). WAC is not the actual transaction price for a drug because it does not account for rebates or discounts; rather, it is the price at which negotiations with wholesalers often begin.

The wholesaler or distributor may then sell the brand-name drugs to a hospital, a pharmacy or an oncology practice at a modest markup. In some instances, pharmaceutical companies sell directly to hospitals. Hospitals, in particular, may be eligible for steep discounts of 20% to 50% if they qualify for the 340B Drug Pricing Program, a government program that provides major discounts to institutions that serve a high percentage of uninsured, indigent patients. (See “340B: Helping Patients or Enriching Hospitals?” Clinical Oncology News, October 2013).

The final transaction occurs between the physician or the pharmacy and the patient and/or the insurer. Medicare requires providers to collect a 20% coinsurance from patients, and generally reimburses providers for drugs, such as ipilimumab and brentuximab, that are covered under Medicare Part B using a benchmark called average sales price (ASP). ASP is the final net price a manufacturer receives for a drug after deducting all discounts and rebates.

However, the cost to patients may vary significantly. Each commercial health plan establishes its own policies regarding provider reimbursement and a patient’s out-of-pocket costs for specialty drugs. Additionally, there is huge variation in what private oncology practices or hospitals charge patients for drugs.

“For instance, hospitals are able to sharply increase the price of a drug, regardless of what the manufacturer gets or the actual published sales price,” said Adam Fein, PhD, the president of Pembroke Consulting, Inc., and the CEO of Drug Channels Institute in Philadelphia.

Adding to the complexity, WAC and ASP are not the only benchmarks used to track drug prices and determine reimbursement. Other benchmarks include average wholesale price (AWP), a manufacturer’s list price to wholesalers; the average manufacturers price, a retrospectively calculated and proprietary amount, which is the average price a wholesaler pays a manufacturer for a drug, excluding discounts and rebates; Medicaid’s best price, the lowest price a manufacturer receives for a drug; and 340B price.

“Because there’s not a single payer system in the U.S., multiple benchmarks exist and payers have to estimate the cost basis for each covered prescription drug using these various

9

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

‘It was a very nasty business. The nature of the agreement encouraged me to overuse drugs. But I didn’t increase the amount of chemotherapy I gave in order to increase my rebate. You just can’t do that and look at yourself in the mirror.’

—James Stark, MD formulas,” Dr. Freeman said.

Michael Herepath, PhD, a director at Navigant Life Sciences, a consulting firm, and their practice lead on global

pricing and market access, noted that “as there are many different types of pricing benchmark, which benchmark is applied can be a complex subject in itself, made

more so by the fact that certain benchmarks, e.g., AWP, can be calculated in different ways. The effect is that for every link in the supply chain, it is difficult to ensure consistency in the way that prices have been derived.”

Free Market This complexity in price benchmarking, Dr. Herepath explained, is fueled by the fact that “the U.S. is a relatively free price market, where traditionally products have been priced at what the market will bear.” see DRUG COSTS, S page 10

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CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

CURRENT PRACTICE

DRUG COSTS continued from page 9

What all of this translates to, on a practical level, is that different purchasers pay different prices for the same brandname prescription drug.

“For a wholesaler, maybe today the supply is larger and demand has slipped, so a buyer will get a deal. If you’re a large hospital, you may be able to contract for greater discounts or rebates depending on the volume of drugs you buy or prescribe, or if you qualify for 340B discounts,” said Jack Hoadley, PhD, a health policy analyst and a research professor at Georgetown University’s Health Policy Institute in Washington, D.C. Organizations may get larger discounts depending on the volume of drugs that they purchase. Rebates may depend on whether the buyer provides evidence that it has increased the volume of sales or prescriptions of a particular drug. For example, when James Stark, MD, ran a small, private oncology practice in the mid-2000s, he received rebates from his wholesaler, Oncology Supply, based on his volume of prescriptions. Every quarter that he met his target for rebates, the wholesaler would increase his target for the next quarter.

“It was a very nasty business,” Dr. Stark said. “The nature of the agreement encouraged me to overuse drugs. But I didn’t increase the amount of chemotherapy I gave in order to increase my rebate. You just can’t do that and look at yourself in the mirror.”

Rebates also may be provided if a buyer can prove that it has influenced a drug’s market share. For instance, when hospitals purchase drugs directly from manufacturers, they may get significant rebates based on their ability to influence the prescribing patterns of doctors.

American formularies also often will list only one or two products within otherwise large drug classes or provide selected manufacturers with a preferred listing, Steve Morgan, PhD, an assistant professor of health care and epidemiology at the Centre for Health

Services and Policy Researrch at the University off British i i h Columbia, l bi Canada, has written (Healthc ( Policy 2007;3:e121-e140, PMID: 19305747).

The importance of being listed on a formulary becomes even more paramount when the market is saturated with similar drugs. Consider tyrosine kinase inhibitors (TKIs) to treat chronic myelogenous leukemia. The newer TKIs—dasatinib (Sprycel, Bristol-Myers Squibb), nilotinib (Tasigna, Novartis) and bosutinib (Bosulif, Pfizer), which are indicated for sec-

less likeely to offer discounts. For ipillimumab, b a case in i point, i recent data presented at the 2013 European Cancer Congress revealed that a small percentage of patients could live up to 10 years on the drug (abstract LBA 24).

Such odds may be appealing to patients.

In fact, a recent survey found that most cancer patients prefer drugs that offer “hopeful gambles to safe bets” ((Health Aff 2012;31:676-682, PMID: 22492883).

“In other words, patients value drugs that provide some [even slim] odds of

The key here—and what makes it so difficult to truly know the price of a drug at any point along the supply chain—is that these negotiations take place behind closed doors. ond-line treatment in patients who fail imatinib—are priced almost identically.

Bosutinib and dasatinib cost $9,817 per month and nilotinib costs $9,163, and all three show comparable efficacy in randomized controlled trials ((J Clin Oncol 2013;31:3600-3604, PMID: 23650428).

Given these similarities, a hospital may decide to make one drug a preferred product if a manufacturer is willing to provide a discount or rebate.

“For example, if a hospital agrees to provide bosutinib preferentially over the next year, a manufacturer may cut the price from $120,000 to $60,000 [per patient per year],” said Hagop Kantarjian, MD, the chair and a professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.

If a product is unique or offers potential for longer-term survival, it may be priced higher or manufacturers may be

a long survival even if the average survival is low,” said Mireille Jacobson, PhD, an associate professor of economics and public policy, and the director of the Center for Health Care Management and Policy at The Merage School of Business, University of California, Irvine. “Such drugs offer hope, and for patients facing death, there’s a high willingness to pay for these agents.”

Confidential Negotiations The key here—and what makes it so difficult to truly know the price of a drug at any point along the supply chain—is that these negotiations take place behind closed doors. “The actual transaction price is a trade secret,” Dr. Freeman said.

Elaborating on this point, Dr. Herepath noted, “In essence, whichever link in the supply chain we’re considering, we’re talking about commercially confidential and sensitive negotiations.”

Echoing these thoughts, Dr. Jacobson explained that “firms don’t want you to know prices they’re giving their customers. We don’t know what transaction prices are because making that information public changes the nature of future negotiations.”

In fact, pharmaceutical representatives often don’t know the price of the drugs they’re representing. According to Dr. Fein, pharmaceutical companies rightly prohibit sales representatives from discussing pricing and reimbursement to avoid impropriety such as kickbacks or bribes. Additionally, Dr. Hoadley noted, many oncologists don’t know drug prices and some choose not to know, believing that cost should not factor in to their prescribing decisions.

Many patients, too, find themselves in the dark about the costs of their drugs.

In effect, the manufacturer’s list price has little bearing on what a patient will pay because oncology drugs are treated as commodities, and negotiations for drug prices are subject to the same rules and regulations as those for iPods or refrigerators.

Even asking what a brand-name oncology drug costs misses the point because “if we recognize the dynamic nature of the U.S. market, a price will be obsolete the moment it is disclosed,” Dr. Freeman said.

Dr. Freeman’s comment made me think of the Heisenberg Uncertainty Principle, which states that it’s impossible to accurately determine the position and velocity of a particle simultaneously because the act of observing one component alters the nature of the other. Similarly, identifying the price of a drug at any moment fails to take into account the movement and fluctuations of the market because the price during one transaction will not reflect the price during another transaction. Conversely, when you’re too focused on market fluctuations, it’s only possible to estimate the price of a drug.

“The bottom line is you can get glimpses inside the story of how drug prices vary, but never full knowledge,” Dr. Hoadley said.

—Victoria Stern

SABCS 2013

Exercise Decreases AI-Associated Joint Pain San Antonio—Exercise can decrease the joint pain that some women experience while taking aromatase inhibitors (AI), according to results from the HOPE study presented at the San Antonio Breast Cancer Symposium (S3-03).

The results suggest that exercise might improve adherence to AI therapy, as many patients discontinue treatment because of joint problems.

‘While it could be dangerous to compare across studies, the magnitude of the effects of exercise on improving joint pain is stronger than has been observed with other treatments of joint pain.’

—Melinda Irwin, PhD, MPH “This is particularly exciting given the other known benefits of exercise and weight loss for overall health and the possible benefits with regard to

breast cancer outcome,” said Dawn L. Hershman, MD, MS, a co-author of the HOPE study and leader of the Breast Cancer Program at Columbia University

Medical Center in New York City.

The study enrolled 121 women who had been taking an AI for at least six months and were experiencing at least

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

mild arthralgia. To be included, patients had to be able to exercise, but be engaging in less than 90 minutes of exercise per week before study enrollment.

Patients were randomized to usual care for AI symptoms or a yearlong exercise program consisting of weight training and aerobic exercise. The twice-weekly, supervised sessions involved six common strength-training exercises, eight to 12 repetitions for three sets. The aerobic exercise was moderate in intensity and performed 2.5 hours per week; heart rate monitors were worn to determine intensity. Patients in the “usual care” group received written information that recommended physical activity and monthly phone calls to assess adherence to AIs. During the study period, women in the usual-care group increased their level of activity, but not as much as those in the prescribed-exercise group, and only women in the exercise group lost weight (Table).

“The yearlong exercise program resulted in a decrease of joint pain by about 30%,” said Melinda Irwin, PhD, MPH, the lead author and principal investigator of the study, and an associate professor of epidemiology at the Yale School of Public Health, New Haven, Conn. “While it could be dangerous to compare across studies, the magnitude of the effects of exercise on improving joint pain is stronger than has been observed with other treatments of joint pain.” These include glucosamine, vitamin D and acupuncture.

“Our finding of exercise improving a common AI side effect may in turn improve AI adherence, as well as quality of life and breast cancer recurrence and mortality risk,” said Dr. Irwin.

After Dr. Irwin’s presentation, Steven Vogl, MD, an oncologist who practices in White Plains and Bronx, N.Y., pointed out that the age of the women in her trial (i.e., 60) was much younger than many of the “little old ladies” who are getting AI therapy in the community. “Do you have any suggestions what they should do to mimic the benefits that you achieved?” he asked Dr. Irwin.

SEND US YOUR NEWS Clinical Oncology News appreciates news tips and suggestions for coverage from readers.

All submissions will be considered for publication.

Write to managing editor Gabriel Miller at gmiller@mcmahonmed.com

Table. Change in Exercise and Body Weight Baseline to 12-Month Change

Exercise Group

Usual Care

P Value

Change in physical activity, min/wk

158.9

48.9

0.0001

Attendance to strength training

70%

NA

0.0013

Change in weight

–3.0%

0%

0.026

could consider joining a local YMCA especially if the Y offers the free threemonth Livestrong exercise program offered at many Ys across the country. “Patients should do what they can work into their life on a regular basis and what they like, whether it is taking a zumba class, joining a gym or buying a treadmill,” she said.

—Kate O’Rourke

“We did find benefits with only 60 to 90 minutes of exercise per week, not as strong an effect, but an effect, so walking in your neighborhood even at a brisk

pace at moderate intensity can be beneficial,” said Dr. Irwin.

Dr. Hershman said women hoping to improve side effects from AI therapy

Drs. Hershman, Irwin and Vogl have no relevant disclosures.

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11

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

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

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

Toward a Cancer-Free World: The Ohio State University Comprehensive Cancer Center— Arthur G. James Cancer Hospital and Richard J. Solove Research Institute All images courtesy of OSUCCC–James

12

At left, the exterior of the new hospital and, above, a rendering of the hospital’s light-filled lobby. Inset, from top to bottom: Michael Caligiuri, MD, director of the OSUCCC and CEO of the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute; John Byrd, MD, director of Hematology and co-leader of the Leukemia Research Program at the OSUCCC–James.

C

ancer is no longer defined solely by stage and location, but rather by its biologic and genetic make-up. There is no routine cancer—it is different in each person. Working together and using state-of-the-art facilities and technology, clinicians and researchers at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) are speeding the development and delivery of treatments that target the molecules and markers fueling each person’s unique cancer.

As one of only four U.S. cancer centers approved by the National Cancer Institute (NCI) for Phase I and II trials, the OSUCCC–James offers patients the latest cancer treatments—some of which are not offered anywhere else—and is able to take the most innovative research ideas from bench to bedside. For example, John C. Byrd, MD, and his team shepherded the new leukemia drug ibrutinib from the lab to the clinic at the OSUCCC–James, and a recent FDA approval made this groundbreaking treatment available to patients with mantle cell lymphoma and chronic lymphocytic leukemia. Dr. Byrd, the director of the Division of Hematology at the OSUCCC–James, is now leading efforts to

discover additional applications for ibrutinib.

At the OSUCCC–James, more than 300 cancer researchers come together from 12 of the university’s 14 colleges to power a single vision: to create a cancer-free world, one person, one discovery at a time. The OSUCCC–James is the only NCI-designated comprehensive cancer center in central and southern Ohio.

The New James: The 21st-Century Cancer Hospital In December 2014, Ohio State will open the doors of the new Arthur G. James Cancer Hospital and Solove Research Institute, a transformational facility that will foster collaboration and integration of cancer research and clinical cancer care. The new James will be the Midwest’s largest cancer hospital and the third-largest cancer hospital in the United States.

Patients served by this new 21-floor hospital will find themselves at the intersection of research, education and specialized care. Research and education spaces will be located on every floor, enhancing patient care and giving patients early access to new treatments and tools.

A cancer emergency department, the second

in the nation, will ensure that cancer patients are cared for appropriately in medical emergencies, while protecting their compromised immune systems and medical histories. With more than 500 clinical trials open at any time, the OSUCCC–James will use this research hub to continue pioneering the transdisciplinary, multimodality approach to cancer treatment and patient care. Nearly one in three patients diagnosed and treated at the OSUCCC–James is enrolled in a clinical trial.

The OSUCCC–James is one of only 41 NCI-designated comprehensive cancer centers in the United States, and was ranked “exceptional” at its most recent renewal. In addition to the five-year NCI support grant of $23 million, in 2013, the OSUCCC– James received an $11.3 million NCI SPORE (Specialized Programs of Research Excellence) grant for thyroid cancer research, and holds SPORE grants for leukemia and sarcoma. The Ohio State University recently established the Tobacco Center of Regulatory Science with $18.7 million in federal funding.

The OSUCCC–James has distinguished itself in molecular- and genetic-based research and is the nation’s center for research into Lynch syndrome, a cause of hereditary colon and ovarian cancer. A partnership with biopharmaceutical company MedVax Technologies will take a vaccine developed by OSUCCC–James researchers through clinical development to treat HER2-positive cancers, including breast and several others.

The new James Cancer Hospital and Solove Research Institute will enable clinical teams to offer more options to patients, as cancer care evolves from traditional, broad-based therapies to prevention and targeted treatments for each patient’s unique cancer.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Maintenance Pemetrexed Boosts Advanced NSCLC Survival From the Journal of Thoracic Oncology

F

ollow-up analyses of patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) treated with maintenance pemetrexed (Alimta, Eli Lilly) found benefit across all subgroups studied.

In the original PARAMOUNT study ((J Clin Oncol 2013;31:28952902, PMID: 23835707), 939 eligible patients received induction therapy of four 21-day cycles of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, and 539 nonprogressing patients from this group were then randomized 2:1 to receive either maintenance pemetrexed (500 mg/m2) or placebo until

disease progression. A significant benefit was demonstrated in the pemetrexed maintenance group in disease progression (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.490.79; P<0.0001) and overall survival (OS; HR, 0.78; 95% CI, 0.64-0.96; P=0.0195). In the present analysis, Martin Reck, MD, PhD, of the Hospital Grosshansdorf in Germany, and coauthors sought to identify subgroups, based on patient and disease characteristics, that might benefit from pemetrexed maintenance treatment.

Baseline characteristics of patients surviving longer periods were comparable to those surviving shorter periods. OS improved in all pemetrexed

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

T

he study by Reck et al reports the final OS data from the PARAMOUNT trial in first-line, nonsquamous NSCLC, comparing continuation maintenance pemetrexed to placebo in nonprogressing patients after four cycles of cisplatin and pemetrexed induction therapy. This study showed that there was a significantly reduced risk for disease progression (HR, 0.62) and death (HR, 0.78) with pemetrexed. This survival benefit was seen across all of the studied subgroups, and was no different for patients who achieved a best response of stable disease compared with those who had an objective response.

The use of continuation maintenance

therapy has been commonplace in the United States since the reporting of ECOG E4599 (carboplatin and paclitaxel with or without bevacizumab, with maintenance bevacizumab until progression).1 The study proved that this approach can be well tolerated, but it has taken studies such as PARAMOUNT to begin to convince the lung cancer medical oncology community that maintenance chemotherapy could be both effective and well tolerated. Maintenance pemetrexed has achieved that benchmark in the minds of most lung oncologists and has increasingly become standard practice in this setting. There are still pros and cons, however.

subgroups when compared by age, sex, ethnicity, prior smoking status, and tumor histology and stage. Adverse events, including grade 3 or 4 induction toxicities, were not disproportionately seen in patients with shorter OS. The OS of patients who began the maintenance therapy within six days of completion of induction chemotherapy did not differ from those whose maintenance therapy began between seven and 30 days after completion of induction therapy.

No significant difference was seen between OS of placebo patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. However, among patients in

the pemetrexed arm, PS0 patients survived longer than PS1 patients (17.2 vs.

12.9 months; P=0.023). When PS0 and PS1 patients in the pemetrexed arm were compared with those in the placebo arm with similar ECOG PS, OS was better with pemetrexed treatment.

In this report, published in the Journal of Thoracic Oncology (2014;9:201-213; PMID: 24419418), the authors found only ECOG PS as a clinical parameter that identified a subgroup more likely to benefit from pemetrexed maintenance. Future studies that include molecular testing of participants may identify significant OS differences not revealed in this analysis.

The common, chronic low-grade toxicities of the treatment eventually wear on patients so that stretching the intertreatment intervals or late dose reductions are also common.

Despite a significant (although not overwhelming) improvement of progression-free survival and OS, coming into the clinic every three weeks for an infusion affects quality of life by itself, and the common, chronic low-grade toxicities of the treatment eventually wear on patients so that stretching the intertreatment intervals or late dose reductions are also common. Thus, some patients and some oncologists may still reasonably opt out of this approach in individual situations.

Maintenance erlotinib has shown efficacy in all comers, but has little uptake in patients with epidermal growth factor receptor ((EGFR) wildtype tumors, but increasingly in EGFRmutated tumors. The current U.S. Intergroup trial comparing continuation maintenance with bevacizumab

to switch maintenance with pemetrexed or the combination is accruing well, and will potentially provide other options in this setting. There are still no convincing data that maintenance therapy for squamous or especially small cell lung cancer will become standard practice in the near future, and so we await the development of active and tolerated maintenance regimens in those diseases.

Reference 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550, PMID: 17167137.

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

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

ClinicalOncology.com Experts from The Ohio State University provide clinical perspectives on important recently published studies in solid tumor and hematologic malignancies.

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14

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Pain is Prevalent and Persists in Ambulatory Cancer Patients From the Journal of Clinical Oncology

P

ain in ambulatory cancer patients with solid tumors is complex and dynamic, and adequate pain management requires constant monitoring and therapeutic intervention when needed.

The Eastern Cooperative Oncology Group (ECOG) conducted a multicenter study to assess pain symptoms.

Outpatient oncology patients from 38 (six academic and 32 community) centers completed the MD Anderson Symptom Inventory at their initial assessment visit and again four to five weeks later at a follow-up visit.

Participants were asked to rate their pain experience over the previous 24 hours on a scale of 0 to 10. Rankings of 1 to 3 were considered mild, 4 to 5

moderate and 6 to 10 severe; changes of at least 2 points on the scale were considered clinically significant. The solid tumors represented in this study were breast (49.7%), colorectal (23.6%), prostate (10.3%) and lung (16.4%) cancers. In an article published in the Journal of Clinical Oncology (2014:32:312-319, PMID: 24366929), lead author Fengmin Zhao, MS, PhD, of Boston’s Dana-Farber Cancer Institute, and co-authors compared the severity of pain at the two visits. Of 2,761 patients who completed both surveys, 1,298 (47.0%) described some pain at the initial visit. Specifically, 23.5% of patients had mild pain, 10.3% had moderate pain and 13.2% had severe pain initially. At follow-up, 32.2% of this group initially reporting pain had reduced pain,

EXPERT INSIGHT Robert M. Taylor, MD Chief of Staff, The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Division of Palliative Medicine, Department of Internal Medicine Associate Professor of Neurology Associate Professor of Clinical Medicine Center for Palliative Care, The Ohio State University Wexner Medical Center Columbus, Ohio

T

his paper presents a secondary analysis of a very large study of ambulatory solid-tumor cancer patients who reported on pain and other symptoms. The data provide further evidence that pain is a common problem for such patients and that many patients continue to be treated suboptimally for their pain.

Although the study design limits the conclusions that can be drawn,

the data nevertheless are instructive. For example, the fact that almost 10% of patients without pain, or with controlled pain, at an initial visit had poorly controlled moderate to severe pain at a subsequent visit a month later demonstrates that cancer pain is both dynamic and unpredictable. Furthermore, it is concerning that, of patients with pain at the initial visit, only onethird reported a reduction in pain at

19.6% had worse pain and 48.2% had stable pain. In patients who had no pain at the initial visit (n=1,463; 53%), 19.5% had mild pain, 4.9% had moderate pain and 4.0% had severe pain at the follow-up assessment.

The authors found that 54.9% of patients had adequate pain management at both visits; 11.4% of patients had good pain management at enrollment but were undertreated at followup; 10.2% of patients were undertreated at initial visit but had adequate pain management at follow-up; and 11.7% of patients were undertreated at both visits (an additional 11.8% had missing data for one or more visits). Patients who described severe pain at the initial visit were excluded from this analysis (a pain score of 10 cannot increase by 2), as were patients who did not

complete the survey.

Of the patients describing no pain at the initial visit, 28.4% had pain (8.9% either moderate or severe) at followup assessment. Younger age; Hispanic ethnicity; unemployment; severe constipation and other adverse effects of treatment drugs; and care received in a community center were among the factors that affected reported pain levels. Analysis revealed that inadequate pain management, lower baseline pain levels, younger age and poor health status were all significantly associated with increases in pain self-assessments. The authors concluded, “Pain is not only prevalent but also persistent and dynamic,” and recommended frequent assessments in the ambulatory setting and adjustments of pain treatment as needed.

Study patients who were bothered by analgesic side effects, including constipation, were more likely to have inadequate pain control, thus reinforcing the necessity of assuring that constipation and other opioid side effects are adequately managed in patients with cancer-associated pain. follow-up, suggesting that cancer pain remains undertreated. Additionally, study patients who were bothered by analgesic side effects, including constipation, were more likely to have inadequate pain control, thus reinforcing the necessity of assuring that constipation and other opioid side effects are adequately managed in patients with cancer-associated pain.

Because the study was limited in

duration (to one month) and was not designed to prospectively investigate how to optimally manage cancer pain, it can only point us to problems and suggest ideas for addressing them.

This large study strongly suggests that cancer pain remains a widespread and inadequately managed problem.

Dr. Taylor reported no relevant financial disclosures.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

MYELOMA continued from page 1

melphalan and prednisone (VMP), another widely used standard for the same population, has not been established.

In transplant-ineligible MM, both MPT and VMP were established as preferred therapies over melphalan and prednisone (MP), the previous standard, in independent Phase III trials.

The most recent data, from a trial called FIRST, suggests Rd should now replace MPT. In the FIRST trial, the hazard ratio (HR) for progression-free survival (PFS), which was the primary end point, was 0.72 ((P=0.00006) for continuous Rd relative to MPT. The median PFS was extended by more than four months (25.5 vs. 21.2 months).

“The relative advantage of continuous Rd was consistent across subgroups,” said Thierry Facon, MD, the study’s principal investigator and a professor of hematology at the University of Lille, France. Although there also were some relative tolerability advantages for Rd, a second important advantage of Rd relative to MPT was the lower rate of second primary malignancies (0.4% vs. 2.2%).

In the FIRST trial, 1,623 previously untreated patients with MM were randomized to one of three treatment protocols at participating centers in 18 countries including the United States.

In two arms, patients received Rd on the same 28-day schedule (25 mg of lenalidomide on days 1 through 21 plus 40 mg of dexamethasone on days 1, 8, 15, 22 and 28). The difference was that Rd was offered continuously until progression in one arm but stopped after 18 cycles in the other. The third arm of MPT (0.25 mg/kg of melphalan on days 1 to 4; 2 mg/kg prednisone on days 1 to 4; and 200 mg of continuous thalidomide of a 42-day schedule) was administered for 12 cycles.

After a median follow-up of 37 months, the continuous Rd not only provided a PFS advantage relative to MPT but to the 18-cycle Rd (Rd18) protocol, as well (HR, 0.70; P=0.00001). At four years, the overall survival (OS) rates were 59.4% for Rd, 55.7% for Rd18, and 51.4% for MPT. The difference reached statistical significance for continuous Rd relative to MPT (HR, 0.78; P=0.0168) but not for Rd18 relative to MPT (HR, 0.90; P=0.307).

Several but not all safety and tolerability parameters favored continuous Rd over MPT. In addition to the lower rate of second primary malignancies, patients on continuous Rd had a lower rate of grade 3 or higher peripheral neuropathies (5% vs. 15%), neutropenia (28% vs. 45%) and thrombocytopenia (8% vs.

11%). However, grade 3 or higher infections were more common on continuous Rd (29% vs. 17%) even though episodes

of febrile neutropenia were slightly lower (1% vs. 3%). The rate of deep vein thrombosis was slightly higher on continuous Rd than MPT (5% vs. 3%).

Whereas the FIRST trial suggests that continuous Rd should replace MPT, data from other studies presented at the 2013 ASH meeting support the use of VMP, which is also listed as a first-line therapy for treatment-ineligible MM in several guidelines, such as those from the National Comprehensive Cancer Network. In the context of the FIRST trial, data from the three-arm, Phase IIIb community-based UPFRONT study may be the most significant. In this study, no differences in major outcomes, such as PFS and OS, were observed when the doublet of bortezomib plus dexamethasone (VD) was compared with the VMP standard (poster 653).

The data from UPFRONT “indicate the need for patient-adapted therapy,” said lead author Ruben Niesvizky, MD,

these nor the median OS of 53.1, 49.8 and 51.5 months, respectively, differed significantly. However, the highest toxicity rates and the lowest cumulative bortezomib doses were observed in the VTD group, and Dr. Niesvizky suggested this is relevant when adverse events threaten to lead to early discontinuation of treatment.

“VD doublet therapy may be as effective as VTD or VMP triplet therapy in elderly patients with comorbidities when drug exposure and treatmentrelated toxicities are taken into consideration,” Dr. Niesvizky said.

A related conclusion was drawn from new data presented at the 2013 ASH meeting from the VISTA trial, which helped establish VMP as a standard (abstract 1968). This analysis was designed to evaluate the effect of cumulative doses by comparing outcomes between those above and below the cumulative dose of 39 mg/m2. This

The clinical studies of the proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide have been progressing more or less in parallel, so there is room for debate about which agents are the most potent. the director of the Multiple Myeloma Service at NewYork-Presbyterian/Weill Cornell Medical College in New York City. Specifically, given the association between VMP and a higher rate of toxicities relative to VD in UPFRONT, the two-drug regimen may be a better choice for those most vulnerable to side effects that may prevent prolonged treatment.

In UPFRONT, 502 patients were randomized to one of three 21-day, eightcycle induction protocols before initiating maintenance bortezomib. In the VMP arm, 1.3 mg/m2 was administered on days 1, 4, 8 and 11 of every cycle, whereas 0.9 mg/m2 of melphalan and 60 mg/m2 of prednisone were administered on days 1 through 4 of every other cycle. In the VD arm, the bortezomib dose and schedule were the same while a 20-mg dose of dexamethasone was administered on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first four cycles and days 1, 2, 4 and 5 of the last eight cycles. In the third arm of bortezomib, thalidomide and dexamethasone (VTD), the bortezomib and dexamethasone doses and schedules were the same as those of the VD arm but patients also received 100 mg of daily thalidomide throughout all eight cycles. At the end of induction, maintenance bortezomib was offered in a dose of 1.6 mg/m2 on days 1, 8, 15 and 22 of five 35-day cycles in all arms.

The median PFS rates for the VMP, VD and VTD arms after a median of 3.5 years of follow-up were 17.3, 14.7 and 15.4 months, respectively. Neither

analysis, which included data on 340 patients, demonstrated a significant OS advantage (66.3 vs. 46.2 months; HR, 0.533; P<0.0001) for those who received the higher rather than the lower cumulative dose, whether they achieved this by longer treatment duration, more intensive therapy or both.

“Maintaining patients on bortezomib therapy is important to increase the cumulative dose and exposure, thus improving OS,” said Maria-Victoria Mateos, MD, PhD, of University Hospital in Salamanca, Spain, the study’s lead investigator. Noting that toxicity was the main cause of early discontinuation, she recommended that one or more of several strategies should be used to keep patients on therapy, including modifying the dose of bortezomib, modifying the schedule of bortezomib or switching to the subcutaneous formulation of the drug.

In the absence of a head-to-head trial, Dr. Mateos disagreed with the assertion that Rd is the new first-line standard for transplant-ineligible MM. Although it was found more effective than MPT in the FIRST trial, it has not been compared with VMP, which she believes is currently the most effective combination for this population.

However, she did acknowledge that treatment options are expanding for MM and that the best option should be selected “according to the patients’ characteristics and preferences.”

The clinical studies of the proteasome

Plasma cell dyscrasias— multiple myeloma

inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide (Revlimid, Celgene) have been progressing more or less in parallel, so there is room for debate about which agents can be considered the most potent.

There are limited direct comparisons between regimens anchored with bortezomib and those with an immunomodulator such as lenalidomide.

Kenneth C. Anderson, MD, a hematologist at the Dana-Farber Cancer Institute in Boston, who has published on this topic, suggested that the FIRST trial reinforces existing clinical practices.

“In the U.S., the lenalidomide-dexamethasone combination is already established as a platform initial therapy for the addition of other agents, such as proteasome inhibitors,” Dr. Anderson said. He believes that the FIRST study will primarily change the treatment paradigm outside of the United States, where it will likely have the effect of “increasing use of continuous lenalidomide-dexamethasone combinations while decreasing melphalan-based therapies.”

He suggested that the FIRST data still has utility in providing clear evidence that Rd provides an advantage over melphalan, prednisone and thalidomide. According to Dr. Anderson, the key advantages include an “increased response rate and extent, prolonged progression-free and overall survival, and fewer secondary hematologic malignancies.”

—Ted Bosworth Dr. Facon is a member of the board of directors or advisory committee and the speakers’ bureau for Celgene. Dr. Niesvizky reports financial relationships with Celgene, Millennium and Onyx. Dr. Mateos reports financial relationships with Janssen and Millennium. Dr. Anderson reports financial relationships with Acetylon, Celgene, Gilead, OncoPep, Onyx and Sanofi-Aventis.

15

16

GENETICS

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Genetic Test May Refine Prostate Cancer Prognosis A

new genetic assay for prostate cancer can shine more light on the severity of a patient’s disease, with a series of recent studies indicating the test results also could influence treatment choices.

The Prolaris assay, developed by Myriad Genetics, compares the expression of 31 target genes normalized to 15 housekeeping genes to give a cell cycle progression (CCP) score, which rises with increasing risk for aggressive tumors.

This test “has shown the potential to better inform patient and physician decision making, and thus demonstrate clinical utility,” said Neal Shore, MD, an oncologist at Carolina Urologic Research Center in Myrtle Beach, S.C., and an author of a study presented at the 2014 Genitourinary Cancers Symposium in San Francisco (abstract 47).

Dr. Shore and his colleagues analyzed the results of tissue biopsies from more than 1,600 patients with adenocarcinoma. They retrospectively found a normal CCP distribution ranging from –2.9 to 3.1, with each unit increase of the score corresponding to an increase of roughly double in the risk for death or recurrence. A comparison between the patients’ CCP scores and scores from the Gleason test, an evaluation of prostate biopsy tissue via microscope, did not reveal a strong correlation (r=0.35).

Based on CCP scores, more than half of the men in the study would be categorized under different American Urological Association (AUA) risk levels than the Gleason or prostate-specific antigen (PSA) tests predicted, with 27.9% shifting to a less aggressive cancer category and 27.6% moving to a more aggressive prognosis.

“The great value of this assay is its

‘The great value of this assay is its potential to refine prognoses for newly diagnosed patients with traditionally low and intermediate risk.’

—Neal Shore, MD potential to refine prognoses for newly diagnosed patients with traditionally low and intermediate risk,” Dr. Shore said. For patients who have “clear-cut high-risk disease,” however, “they will more likely, but not always, remain with a high-risk classification, although the Prolaris score could offer additional clinical value which might impact ultimate treatment decisions.”

The clinical stage, PSA test and density, Gleason score, number and percent of positive biopsy cores and other currently used clinicopathologic features “do a pretty good job” of characterizing a patient’s risk, particularly when those features are used together in a nomogram, said Ashley Ross, MD, PhD, an assistant professor of urology, oncology and pathology at Johns Hopkins School of Medicine in Baltimore, who was not involved with the Prolaris research.

“Thus, in the context of assessing the risk of newly diagnosed prostate cancer, while the Prolaris test appears to be able to reclassify a subgroup of patients, the percentage of patients that would

be reclassified in a clinically meaningful way—in a way that changes their management—is likely in the 10% to 20% range at best.”

The challenge is “biologic heterogeneity within the spectrum” of patients grouped by the AUA’s stratifications of low, intermediate and high risk, Dr. Shore said.

“What we really need are better markers of malignant potential,” said Michael Brawer, MD, the vice president of medical affairs at Myriad Genetics Laboratories, Salt Lake City, and a co-author of the abstracts.

In a survey of 47 clinicians who ordered the Prolaris test, physicians indicated that the assay had a high influence on treatment selection for 62% of patients (2014 Genitourinary Cancers Symposium; abstract 277). In slightly more than half of 58 cases, clinicians who reassessed their treatment decisions following the CCP test results chose watchful waiting or other conservative options with reduced therapeutic burden.

Dr. Ross said he viewed Myriad’s approach positively but, “with the

currently available data, the use of the Prolaris test appears to have limitations.”

Presented with a patient’s high CCP score, Dr. Ross said he would dissuade that person from surveillance, although he remained unconvinced of the ramifications of a low CCP score. “What I don’t think they’ve shown well—because the populations haven’t been right—if your score is low, then you’re really safe.”

A study published in February in Journal of Urology (2014 Feb 6. [Epub ahead of print], PMID: 24508632) showed that the Prolaris test was a significant risk predictor for biochemical recurrence and metastatic disease in men with prostate cancer. But because the study evaluated patients after prostatectomy, it would not be possible to answer questions regarding active surveillance based on this data, Dr. Ross said.

Another consideration is the cost of the Prolaris test, which was estimated to be $3,400, according to a 2010 press release. Myriad representatives said that the company anticipates Medicare coverage by July 2014; at the current time, private insurance coverage varies.

Ultimately, a clinician should not base a therapeutic decision on an individual test or factor, Dr. Shore said. This genomic assay should not be used alone, but “in conjunction with these accepted parameters to help strengthen our baseline clinical assessment at the time of diagnosis, and thus provide a more informed decision on primary therapy for the newly diagnosed prostate cancer patient.”

—Ben Guarino Dr. Shore has served as a consultant and an advisory board member for Myriad. Dr. Ross reported no financial conflicts of interest.

CURRENT PRACTICE

Financial Value of Community Oncology Underestimated Community oncologists perform well by any number of financial and quality measures Washington—Community oncology practices need to make payors aware of their value in both the cancer care and larger health care systems, according to an expert on reimbursement.

Private payors are searching for new models of reimbursement, looking at other areas of medicine as well as other industries that may seem idiosyncratic to oncology, leaving some community oncologists struggling to find their place within new entities like accountable care organizations, insurance exchanges or other models such as medical homes, Barry Fortner, PhD, the senior vice president of payor strategy

at ION Solutions, a health care management company that works with many community oncology practices nationwide, said.

There is a march toward paying physicians based on a yet-to-be-determined concept of value, he said, and some practices are concerned about their financial viability. But oncology has a strong value proposition because it offers great access and high quality at a lower cost.

“Can we improve? Yes, but the untold story is actually that the predominant delivery system in America of cancer care is a good deal,” Dr. Fortner said.

“Studies are uniformly showing that

community-based care is less expensive [than hospital care].”

While the nation was fixated on the fiscal cliff at the end of 2012, oncologists have been facing their own “survival cliff,” he said. “Community oncology, as defined by privately owned practices, is facing new levels of stress never seen before by the continued downward spiral of drug reimbursement and encroachments on the ability to bill and dispense,” Dr. Fortner said.

But before altering health care delivery, he said, it’s imperative to preserve what is working, such as access to care. A study by the American Society of Clinical

Oncology found that approximately 65% of cancer patients are seen in private practices. Local access to oncologists is especially critical for populations like rural patients, widowed patients and those of lower socioeconomic status, for whom a five- to 15-mile drive can translate into delays in obtaining care, he said.

The criticism that oncologists do whatever they want, treat patients “to the grave,” and provide disparate quality care are unfounded, Dr. Fortner said.

Looking at the literature, the profession is “quite compliant,” and usually complaints of noncompliance translate not see VALUE, E page 18

18

GENETICS

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Assessing Family Cancer History First-degree histories well documented, but there is room for improvement

A

s many as one in 10 new cancer diagnoses are attributable to genetically inherited disease, according to the American Society of Clinical Oncology, and documenting family history of cancer can have a large effect on screening and preventive decisions. In a new study published in the Journal of Clinical Oncology, investigators who reviewed medical records of patients with breast or colorectal cancer found that 79.8% included the cancer history of firstdegree relatives; however, only 64.6% of records documented cancer history of second-degree relatives.

Clinicians should be pleased with the rate at which the cancer history of firstdegree relatives was documented, said Noralane Lindor, MD, a medical geneticist at Mayo Clinic in Scottsdale, Ariz., who was not involved with this research.

“This is a dramatic change from 10 to 15 years ago,” she said.

“These rates are higher than we thought we’d find, but there is room for improvement,” said Marie Wood, MD, co-author of the study and the director of the familial cancer program in the Hematology/Oncology Division at the University of Vermont in Burlington.

By analyzing the records of 10,466 patients diagnosed with breast or colorectal cancer, representing more than 200 cancer centers, the authors were able to determine the rate at which family history of cancer was recorded ((J Clin Oncol

2014;32:824-829, PMID: 24493722). For patients with breast cancer as well as those with colorectal cancer, fewer than half of medical records documented the age of relatives at diagnosis.

“Providers do a good job of documenting first-degree family history,” Dr. Wood said, but are not as completely recording second-degree family history and are “not great” at reporting age. Age at cancer diagnosis is important, she said, as it can indicate hereditary cancer syndromes if

cancer, said Kevin Hughes, MD, codirector of the Avon Comprehensive Breast Evaluation Center and a surgeon at Massachusetts General Hospital in Boston, who helped conduct the study.

The difference may stem in part from a cultural taboo surrounding the discussion of colorectal problems, he said.

“People don’t talk about their colons, usually, at the dinner table.”

The study also evaluated the rates at which doctors referred patients to

‘This paper highlights that we are missing candidates for genetic testing.’

—Marie Wood, MD diagnosis was made at an early age.

The rate at which providers recorded the history of first-degree relatives was significantly higher for patients with breast cancer than for those with colorectal cancer (81.2% vs. 77.4%, respectively; P<0.001); similarly, the records for patients with breast cancer also included history of second-degree relatives at a higher frequency (68.9% vs. 57.3%, respectively; P<0.001).

The difference in rates of family history between colorectal and breast cancer “reflects the knowledge gap between the two diseases,” Dr. Lindor said.

Patients tend to be more forthcoming about breast cancer than colorectal

receive genetic counseling or testing.

For patients with breast cancer, 29.1% were referred, whereas of patients with colorectal cancer, 19.6% were referred for genetic counseling or testing ((P<0.001).

But looking solely at the rates of referral for genetic tests may be deceptive. “It’s the right percentage of the practice,” Dr. Hughes said, “but not the right patients.”

Of the patients who met the criteria for referral, only 52.2% of those with breast cancer were referred for genetic testing or counseling, and 26.4% of individuals with colorectal cancer were referred. “This paper highlights that we are missing candidates for genetic testing,” Dr. Wood said.

Changes to education or infrastructure could have beneficial effects on family history documentation and subsequent referrals, Dr. Wood said. In an accompanying article in the Journal of Clinical Oncology, the study investigators issued a set of guidelines to help providers assess family history ((J Clin Oncol 2014;32:833-840, PMID: 24493721). These recommendations include establishing history for both maternal and paternal first- and second-degree relatives, ethnicity and, for each instance of a relative with cancer, the age at diagnosis and the primary type of cancer. Clinicians should gather this information at the initial visit, the authors said, and reevaluate family history at periodic intervals.

Electronic health records (EHRs) have the potential to improve the documentation of familial risk, Dr. Hughes said, although most EHRs do not currently have a useful family history section.

By giving “just-in-time suggestions,” Dr. Lindor said, EHRs could prompt doctors to ask their patients about family history of cancer.

—Ben Guarino Drs. Lindor and Wood reported no conflicts of interest. Dr. Hughes has received honoraria from Myriad Genetics and is a co-inventor of HughesRiskApps.com, which offers software to assess cancer risk in patients.

CURRENT PRACTICE

VALUE continued from page 16

to overuse of services but underuse— that oncologists are dropping medication doses too soon or underdosing, or not using enough diagnostic tests.

Most practices today follow evidencebased guidelines and the majority have taken up pathways—a movement that emerged from community oncology practices, Dr. Fortner said. And off-label drug use in oncology is “quite low.” Data on oncologist use of 10 chemotherapies in 2010 showed that 70% used the drugs on-label, 14% used them off-label but still followed National Comprehensive Cancer Network (NCCN) guidelines, and 10% who did not follow NCCN guidelines used the medications on an FDA-approved cancer site ((J Clin Oncol

2013;31:1134-1139, PMIID: ‘The untold story is actually that the 23423747). predominant delivery system in Regarding “treatment to the grave,” America of cancer care is a good Cancer Dr. Fortner said data patients seen shows that only a deal. Studies are uniformly showing in private practices minority of patients that community-based care is less are treated near the end of life, and thosse expensive.’ who do receive chem mo—Barry Fortner, PhD therapy 14 days beforee death tend to be patients at high risk for death because of other comorbidities.

Cancer care will continue to increase of targeted therapies and increased effiAnd patient data analyses demonstrate in value over the next decade as patents ciency of care will help, too. that patients across cancer types have for more cancer drugs expire, and generBy making sure that government and similar survival times whether they are ic or biosimilar forms appear on the mar- the health care industry understand the treated in community or hospital prac- ket, Dr. Fortner said. By 2022, virtually necessity of preserving community cantices. He cited studies indicating that all chemotherapy medications approved cer care, Dr. Fortner said that someday community-managed cancer patients by the FDA in the 1990s will turn over, oncologists may be able to look back cost significantly less to the health care so the costs for treating cancer patients at the survival cliff as a “triumphal system than hospital-managed cancer have the potential to plateau or flatten, summit.” patients. he said. In addition, the development —Karen Blum

65%

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

SABCS 2013

Fertility Drugs Do Not Increase Breast Cancer Risk San Antonio—Women who have undergone hormonal treatments for infertility do not have an increased risk for developing breast cancer. This finding comes from a meta-analysis of 19 studies presented at the San Antonio Breast Cancer Symposium (abstract S5-08).

Today, hormonal infertility treatment is commonplace. In recent years, studies have provided conflicting results as to whether hormonal treatments with the fertility drugs clomiphene and gonadotrophins can increase the risk for breast cancer. Some studies have shown that these agents increase cancer risk overall and particularly uterine cancer risk (Am ( J Epidemiol 2009;169:365-375, PMID: 19037008). Other studies have concluded that fertility drugs provide a protective effect against breast and cervical cancers ((Hum Reprod d 2011;26:252-258).

In the current study, investigators from Italy mined medical databases, such as Medline, to identify cohort studies with any type of hormonal infertility treatment that reported breast cancer incidence or cumulative risk compared with a control group.

The control group could be the general population or an internal control group of women who did not receive hormonal infertility treatments. Nineteen studies comprised the analysis.

Overall, of 100,000 women exposed to hormonal treatments between 1960 and 2011, there were 1,498 who developed breast cancer. Overall, these treatments were not associated with an increased risk for breast cancer (relative risk, 1.03; hazard ratio, 1.05-1.40). The findings were consistent in subgroup analyses that took into account length of follow-up (<10 or ≥10 years) and type of control (infertile women or population-based group).

Alessandra Gennari, MD, PhD, a medical oncologist at Galliera Hospital, Genoa, Italy, who presented the study, said the incidence of breast cancer was modestly increased in women who were treated with hormonal infertility treatment before 1980, the year when the in vitro fertilization procedure was introduced into clinical practice. “This [modest increase] was possibly due to different drug use and schedules and, more importantly, longer drug exposure,” she said.

The meta-analysis was limited in that it only included observational studies that were published, did not look at number of cycles or rate of success parity, and did not evaluate other breast cancer risk factors. Nevertheless, Dr. Gennari said women taking fertility drugs can feel reassured.

“Women wishing to undergo hormonal infertility treatments should not be

alarmed about the associated breast cancer risk,” Dr. Gennari said. “The safety of long-term administration of hormones in repeated empirical ovarian stimulations needs to be further explored.”

Virginia Borges, MD, MMSc, the codirector of the Young Women’s Breast Cancer Translational Program at the University of Colorado Cancer Center in Aurora, applauded the research, but

pointed out that the study did not take into account the success of the fertility treatments.

“I would caution that studies looking at this issue must take into account the effect of whether or not it [hormonal fertility treatment] is successful, since we have known that in many large epidemiology studies, such as Lambe et al published in 1994 in The New England

Journal of Medicine, pregnancy at any age is an increased risk factor for the development of breast cancer in the subsequent years following the delivery of the child,” Dr. Borges said (N ( Engl J Med d 1994;331:59, PMID: 8202106).

—Kate O’Rourke Drs. Gennari and Borges reported no relevant disclosures.

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

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

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

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

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

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

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

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

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

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

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

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour

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

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CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

How I Manage ...

Hematopoietic Cell Transplantation for Myeloproliferative Neoplasms M

yeloproliferative neoplasms (MPN), including primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET), represent a broad spectrum of clonal disorders of hematopoiesis. PMF typically presents with peripheral blood cytopenias and splenomegaly associated with various degrees of bone marrow fibrosis; the life expectancy may range from less than a year to more than a decade. PV and ET generally show a considerably more protracted course over decades, but a proportion of patients with these diseases will also develop marrow fibrosis and marrow failure. In addition, some patients will experience transformation to acute myeloid leukemia. Classic treatment options for MPN have included, among others, hydroxyurea and interferon, the objective being control of blood cell counts. Currently, the only treatment modality with proven curative potential is allogeneic hematopoietic cell transplantation (allo-HCT). Typically, transplantation has been carried out when patients showed progressive declines of peripheral blood cell counts or if there was evidence of leukemic transformation.

Results are superior when transplantation is carried out before leukemic transformation occurs.

The identification of mutations in the Janus kinase ((JAK K) 1/2 gene, in almost all patients with PV and in approximately half of patients with PMF or ET, and the development of pharmacologic inhibitors of JAK1/2, has led to some challenging questions, particularly in patients with PMF, which is the focus of this review.

What is the role of JAK inhibitors in patients who are otherwise considered candidates for allo-HCT? Data to provide answers to this question are only beginning to emerge. The major clinical benefit of JAK inhibitors, such as ruxolitinib (Jakafi, Incyte/ Novartis), are a reduction in spleen size in the majority of patients, and an often dramatic relief of symptomatology (night sweats, bone pain and weight loss), presumably related to modification of the abnormal cytokine profile that is prevalent in patients with MPN. There are data to suggest that, in addition, the drug may prolong survival, primarily among patients in the higher-risk categories as determined by the Dynamic International Prognostic Scoring System (DIPSS). There are some recent data in a small cohort of patients suggesting that patients who received JAK1/2 inhibitors before transplantation had a reduced incidence of toxicity.1 Clearly, prospective trials are needed.

Do the JAK inhibitors have a positive or negative effect on subsequent allo-HCT? Investigators from several leading U.S., Canadian and German centers at a recent roundtable discussion concluded that JAK inhibition may well be beneficial in patients considering allo-HCT, precisely because of the two major benefits of the drug: shrinkage of spleen size and normalization of the cytokine

profile.2 Reduced spleen size should be associated with more rapid engraftment of donor cells post-HCT, and a normalized cytokine spectrum might be associated with lessened toxicity in the periand post-transplant period, conceivably attenuating graft-versus-host disease (GVHD). However, these deliberations do not answer the question about the timing of transplantation. A reasonable approach for transplant candidates may be to monitor closely for disease progression while on treatment with JAK1/2 inhibitors and proceed with allo-HCT at the time of significant decline in blood cell counts, increase in blast count, or regrowth of spleen, among other factors. This implies that HLA typing has been carried out and a donor search has been initiated, such that one could proceed with allo-HCT without a significant time delay. It is not clear at present whether this strategy would need to be modified further by the now-recognized high frequency of mutations in the calreticulin receptor gene (CALR), which is found exclusively in patients who do not have mutations in JAK1/2 and MPL1 genes, which, according to non-transplant studies, appears to be associated with a better-than-average prognosis, that is longer survival.3

What are the results of allo-HCT in PMF? Most results of allo-HCT reported to date involve patients who had not received treatment with JAK1/2 inhibitors. Several large series have been

reported from single institutions, as well as from various national registries and the Center for International Bone Marrow Transplantation Research (CIBMTR).

Reports from single institutions indicate that patients transplanted for marrow failure and blood cytopenias

H. Joachim Deeg, MD Member, Clinical Research Division, Fred Hutchinson Cancer Research Center Professor, Division of Medical Oncology, University of Washington School of Medicine Seattle, Washington

(rather than leukemic transformation) have a probability of post-transplant success that directly reflects the DIPSS classification. Our data show a probability of survival in remission beyond 10 years of 80% for patients with lowrisk disease by DIPSS, about 65% for patients with intermediate-1 risk, and

AT A GLANCE • Currently, for primary myelofibrosis, the only treatment modality with proven curative potential is allogeneic hematopoietic cell transplantation.

• Results are superior when transplantation is carried out before leukemic transformation occurs.

• Reports from single institutions indicate that patients transplanted for marrow failure and blood cytopenias have a probability of post-transplant success that directly reflects the DIPSS classification.

• Conditioning intensity for allo-HCT remains a hotly debated issue.

• Whether any of the known mutations and molecular markers has an effect on post-transplant outcome is currently controversial.

• Investigators at the Seattle Cancer Care Alliance reported that reversing the sequence of a classic conditioning regimen of busulfan plus cyclophosphamide, and administering cyclophosphamide first followed by busulfan, has the potential for significantly reducing up-front toxicity.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

approximately 45% for patients with intermediate-2/high-risk disease.4 Similar results have been reported by Markus Ditschkowski, MD, of University Hospital Essen in Essen, Germany.5 The major reason for inferior outcomes in patients with higher-risk disease was not relapse, but rather non-relapse mortality, which occurred in about 20% of patients with DIPSS intermediate-1/ low-risk disease, but in as many as 40% to 45% of patients with intermediate-2/ high-risk disease. Results reported from multi-institutional and registry studies generally show a three-year overall survival and relapse-free survival of about 45%. Whereas some studies, particularly from single institutions, showed no difference in transplant outcome between patients with HLA-identical sibling donors and those with wellmatched unrelated donors, a retrospective CIBMTR analysis showed five-year survival of 56% for HLA-matched siblings and 48% for well-matched unrelated donors; survival was 34% among patients with partially matched donors.4,6

What are some preparative regimen options for allo-HCT in MPN? Conditioning intensity for allo-HCT has remained a hotly debated issue.

There is no controlled prospective study, and generally older patients (60-65 years or older) or those with comorbid conditions have been conditioned with lowintensity regimens: for example, a combination of fludarabine and 2 Gy total body irradiation (TBI) or a combination of busulfan in the range of 8 to 10 mg/kg in combination with fludarabine.7 Some of these studies using reduced-intensity conditioning have yielded very promising results, with survival probabilities of 75%.8 Data with HLA-haploidentical transplants and cord blood for patients with MPN are currently too limited to provide meaningful statistics. Although relapse has occurred only in 10% to 15%

of patients, GVHD is an issue in at least half of the patients, either in its acute or chronic form or both.

Do currently established molecular events influence outcomes of allo-HCT in MPN? Whether any of the known mutations and molecular markers has an impact on post-transplant outcome is currently controversial. There are data suggesting that patients who harbor the JAK1/2 mutation, V617F, have a better prognosis, that is superior survival compared with patients who have wildtype JAK. However, other investigators could not confirm these findings. There are no data so far on the impact of mutations in the CALR gene on post-HCT outcome. However, either marker can be used for post-HCT monitoring for residual or recurrent disease. In fact, the Hamburg team suggested that an increase in the allele burden of V617F JAK2 should trigger intervention in the form of infusion of donor lymphocytes, which at that point was far more effective in inducing remission than the same strategy when hematologic recurrence was evident in PMF.9

What can we expect in the near future?

Ongoing trials addressing, for example, the question of whether pre-transplant treatment with JAK1/2 inhibitors is beneficial in post-transplant outcome, be it relapse, non-relapse toxicity or GVHD, may lead to the incorporation of JAK1/2 inhibitors into the overall HCT program. There will be further refinements in allo-HCT conditioning regimens. Investigators at the Seattle Cancer Care Alliance reported that reversing the sequence of a classic conditioning regimen of busulfan (BU) plus cyclophosphamide (CY), and administering CY first followed by BU, has the potential for significantly reducing upfront toxicity. In fact, in that study, there was no patient death during the first five

months post-HCT.10 Very likely, we will see the application of additional JAK1/2 inhibitors, possibly with different clinical effects, and possibly the development of agents directed at the CALR mutations. It is difficult to predict how the availability of such agents will affect the decision for or against allo-HCT. In all likelihood, the decision process will be more complex. If there are treatment options other than transplantation that lead to long-term responses, clearly alloHCT will be delayed, certainly in older individuals. Very likely, these patients would then present for allo-HCT with more advanced or refractory disease, and possibly with additional comorbidities. We may need to design new monitoring tools. It is also to be expected that immunotherapeutic strategies will become more widely available, targeting the clonal hematopoietic precursor cells. It is also possible that modification of the marrow and spleen microenvironment may alter the disease pathophysiology, and conceivably improve prognosis.

References 1. Jaekel N, Behre G, Behning A, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib.

Bone Marrow Transplant. 2014;49:179-184, PMID: 24292520.

2. Gupta V, Gotlib J, Radich JP, et al. Janus kinase inhibitors and allogeneic stem cell transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2014 Mar 27. [Epub ahead of print], PMID: 24680977.

3. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379-2390, PMID: 24325356.

4. Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation.

Blood. 2012;119:2657-2664, PMID: 22234678.

5. Ditschkowski M, Elmaagacli AH, Trenschel R, et al. Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic

hematopoietic stem cell transplantation for myelofibrosis. Haematologica. 2012;97:15741581, PMID: 22491742.

6. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant.

2010;16:358-367, PMID: 19879949.

7.

Kröger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood.

2009;114:5264-5270, PMID: 19812383.

8. Rondelli D, Barosi G, Bacigalupo A, et al.

Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood. 2005;105:4115-4119, PMID: 15671439.

9. Alchalby H, Badbaran A, Zabelina T, et al.

Impact of JAK2 V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood. 2010;116:3572-3581, PMID: 20489052.

10. Rezvani AR, McCune JS, Storer BE, et al. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes. Biol Blood Marrow Transplant. 2013;19:10331039, PMID: 23583825.

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

Coming Soon Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Disorders

by Nicolaus Kröger, MD University Hospital Hamburg

by the

numbers Private Insurancea, days

Public Insurance, days

P Value

Time to approval 4 for HSCT

0

<0.0001

Approval to 39 actual transplant

65

<0.0001

Total time to transplant

66

<0.001

Insurance Delays and Post-Transplant Survival

T

imeliness is one of the most important aspects of quality care, according to the Institute of Medicine, and a patient’s type of insurance has been suggested as one factor that may affect the ability to obtain timely treatment. With hematopoietic stem cell transplantation (HSCT), long delays may also affect patient outcomes.

In a retrospective review presented at the 2013 annual meeting of the American Society of Hematology (abstract 723) by Fausto Loberiza Jr., MD, of the University of Nebraska Medical Center in Omaha, the effect of insurance approval was evaluated among 559 patients with hematologic malignancies who went on to HSCT (only 1% not treated with HSCT were refused by their insurance company).

The bottom line: Those with private insurance underwent transplant significantly faster, but there was no significant difference in risk for death between slow and fast approval.

48

HSCT, hematopoietic stem cell transplantation a

Patients with private insurance tended to be younger, have higher income, have fewer morbidities, live in an urban area, and were more likely to be white.

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CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

Prepared by

Syed A. Abutalib, MD

Clinical Conundrums NEJM, JCO, Blood and highlights from the annual meeting of the European Society for Blood and Marrow Transplantation showed superior outcomes compared with patients carrying clonal TP53 lesions.

QUESTIONS

1. True or False. In a

study published in Journal of Clinical Oncology (JCO ( ), expression of CC chemokine receptor 4 (CCR4) in peripheral T-cell lymphomas (PTCL) was associated with better outcomes.

5.

True or False.

In a study published in Blood, the JAK1/2 inhibitor ruxolitinib (Jakafi, Incyte/Novartis) produced significant reductions in spleTrue or False. In nomegaly and sympa Phase II open-label, tomatic burden and multicenter study from improved survival in Japan published in JCO, Primum non nocere. patients with myelofimogamulizumab (Poteli- (First, do no harm.) brosis (MF), regardless geo, Amgen) exhibited clinically meaningful antitumor activi- of their JAK2 mutation status. ty in patients with relapsed CCR4-posTrue or False. In the above study itive PTCL and cutaneous T-cell lymphoma (CTCL), with an acceptable published in Blood, the clinical efficacy and survival improvement did not toxicity profile. occur across different molecular subsets True or False. In a study pub- of patients with primary myelofibrosis lished in Blood, a monosomal karyotype (PMF) treated with ruxolitinib. in patients with MDS was the only factor associated with relapse and lower overTrue or False. In a study published all survival (OS) after transplantation. in Blood, investigators found that B cells from chronic graft-versus-host disTrue or False. In chronic lym- ease (cGVHD) patients had significantphocytic leukemia (CLL), patients har- ly increased proliferative responses to boring small TP53 mutated subclones B-cell receptor (BCR) stimulation along

2.

6.

3.

7.

4.

ANSWERS

1. False. CCR4 is a marker for type

2 helper T cells or regulatory T (Treg) cells and is expressed on tumor cells in approximately 30% to 65% of patients with PTCL. CCR4-positive patients— e.g., in the peripheral T-cell lymphoma not otherwise specified (PTCLNOS) subgroup—have a shorter survival time compared with CCR4-negative patients. Furthermore, CCR4 expression increases with advancing disease stage in patients with mycosis fungoides and Sézary syndrome.

Ogura M, Ishida T, Hatake K, et al. Multicenter Phase II study of mogamulizumab (KW-0761), a defucosylated anti-CC chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157-1163, PMID: 24616310.

Jones D, O’Hara C, Kraus MD, et al. Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. Blood.

2000;96:685-690, PMID: 10887135.

Ohshima K, Karube K, Kawano R, et al. Classification of distinct subtypes of peripheral T-cell lymphoma unspecified, identified by chemokine and chemokine receptor expression: analysis of prognosis. Int J Oncol. 2004;25:605613, PMID: 15289861.

with elevated basal levels of the proximal BCR signaling components B cell linker protein and Syk.

8. True or False.

More than 12 months of lymphocytosis during ibrutinib (Imbruvica, Pharmacyclics) therapy correlates with suboptimal response.

9. True or False. PMF patients with

intermediate-2 or high International Prognostic Scoring System (IPSS) risk have shown a survival advantage with ruxolitinib over placebo (COMFORT-I) or best available therapy (COMFORT-II).

10.

True or False. In CLL, the current prognostic and therapeutic approaches will have to be reevaluated with the advent of novel biomarkers and therapeutic compounds.

Highlights from the annual meeting of the European Society for Blood and Marrow Transplant

11.

True or False. Investigators from Hamburg, Germany, showed that following an HLA 10/10 matched transplantation, mismatches in HLA-DRB3 can have immunogenic consequences and

2. True. Mogamulizumab is a defu-

cosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity.

Mogamulizumab 1 mg/kg was administered intravenously once per week for eight weeks to patients with relapsed CCR4-positive PTCL or CTCL. Objective responses (ORs) were noted for 13 of 37 patients (OR, 35%; 95% confidence interval [CI], 20%-53%), including five patients (14%) with complete response.

The total overall response rate is comparable to that of other FDA-approved drugs, such as pralatrexate (Folotyn, Allos) and romidepsin (Istodax,

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

may induce a polyclonal allo-immune response associated with severe GVHD.

12. True

or False. Eculizumab (Soliris, Alexion) treatment for postallogeneic transplantation thrombotic microangiopathy (TMA) seems to have promising efficacy in patients without uncontrolled acute GVHD or infections at time of TMA diagnosis.

13. True or False. Among patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT), a conditioning regimen with anti-thymocyte globulin (ATG) had no effect on rates of developing pulmonary cGVHD.

14.

True or False. The R-DHAP (rituximab [Rituxan, Genentech], dexamethasone, cytarabine and cisplatin) regimen is an effective remission-induction regimen for fludarabine-refractory CLL patients even in those having bulky lymphadenopathy and/or del(17p), enabling a high percentage of patients to proceed to allo-HCT.

Celgene). Given its novel mechanism of action and favorable toxicity profile compared with multiagent cytotoxic chemotherapy, we might expect the use of mogamulizumab in combination with other agents.

Ogura M, Ishida T, Hatake K, et al. Multicenter Phase II study of mogamulizumab (KW-0761), a defucosylated anti-CC chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157-1163, PMID: 24616310.

3. False.

High-risk disease, as defined by the revised IPSS, and monosomal karyotype were independently

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2014 • CLINICALONCOLOGY.COM

ASH 2013

Imatinib, Nilotinib Switch Deepens Molecular Response For Bcr-abl–positive CML patients New Orleans—Even among patients with chronic myeloid leukemia (CML) who achieve a deep molecular response on imatinib (Gleevec, Novartis), switching to nilotinib (Tasigna, Novartis) can further deepen the response when residual disease is detectable, according to 36-month follow-up data from one of several trials conducted under the ENEST clinical trials program.

In the ENESTcmr randomized trial, 22.1% of patients who switched to nilotinib had achieved undetectable Bcr-abl after 24 months compared with 8.7% of those who remained on imatinib.

“Nilotinib can deepen molecular responses in patients with minimal residual disease on long-term imatinib,” said Brian Leber, MD, a clinical hematologist and professor of medicine at McMaster University Medical Centre in Hamilton, Ontario, Canada. Presenting these results at the 2013 annual meeting of the American Society of

Hematology (ASH; abstract 632), Dr. Leber reported that, to date, none of the patients in either arm has progressed, but several patients in the imatinib arm only have had a confirmed loss of complete cytogenetic response in the course of follow-up.

In this study, 207 patients with a molecular response but detectable Bcrabl levels after at least two years on imatinib were randomized to remain on imatinib or switch to nilotinib. Patients on imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable Bcr-abl by 24 months. Three patients did so.

The results are consistent with another ENEST study presented at ASH that found nilotinib more effective than imatinib as first-line therapy in Philadelphia chromosome–positive (Ph+) CML in chronic phase (CML-CP). In this study (ENESTnd, abstract 632), presented by Giuseppe Saglio, MD, the head of

the Division of Hematology at San Luigi University Hospital in Turin, Italy, 846 newly diagnosed Ph+ CML-CP patients were randomized to 300 mg nilotinib twice daily, 400 mg nilotinib twice daily or 400 mg imatinib once daily. At four years, major molecular response rates were 76%, 73% and 56%, respectively ( <0.0001 for both arms of nilotinib vs.

(P imatinib).

For front-line therapy in this population, “nilotinib affords superior effect compared with imatinib, including higher rates of an early molecular response, which is associated with improved longterm outcomes,” Dr. Saglio said.

However, Michael J. Mauro, MD, who leads the Myeloproliferative Disorders Program at Memorial Sloan-Kettering Cancer Center in New York City, said the findings should be considered in the context of other factors.

“In line with benefits seen in trials using nilotinib for patients at diagnosis

with CML, there is a clear benefit for patients switched in adequate, but not ideal, molecular response to imatinib,” Dr. Mauro said. However, “this benefit may be offset by side effects after switching and is directed at the goal of a complete molecular response, which may be a fluctuating end point and tied mainly to potential entry into treatment discontinuation trials.”

Dr. Mauro added, “It is logical that with more time the benefit of deeper molecular responses will be clearer, when long-term outcomes are improved and further data on treatment-free remission surfaces.”

—Ted Bosworth Dr. Saglio reported financial relationships with Ariad, Bristol-Myers Squibb, Celgene and Novartis. Dr. Mauro reported financial relationships with Ariad, Bristol-Myers Squibb, Novartis and Pfizer.

CURRENT PRACTICE

associated with relapse and lower OS after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality.

Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS. Blood.

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

6. False.

A comprehensive mutation analysis to evaluate the effect of 14 PMF-associated mutations on clinical outcomes in 166 patients included in the COMFORT-II trial showed improved survival independent of mutation profile.

Guglielmelli P, Biamonte F, Rotunno G, et al.

Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123:2157-2160, PMID: 24458439.

4. False. Patients harboring small 7. True. This data reveals a mechaTP53-mutated subclones showed the same clinical phenotype and poor survival (hazard ratio, 2.01; P=0.0250) as patients carrying clonal TP53 lesions.

This study provides a proof of principle that very minor leukemia subclones detected at diagnosis are an important driver of the subsequent disease course.

However, this data should be interpreted in the context of type of front-line therapy.

Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123:21392147, PMID:24501221.

5. True. This was observed in two

Phase III studies against placebo (COMFORT-I) and best-available therapy (COMFORT-II).

Guglielmelli P, Biamonte F, Rotunno G, et al.

Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123:2157-2160, PMID: 24458439.

nism underpinning aberrant B-cell activation in cGVHD and suggests that therapeutic inhibition of the involved kinases may benefit these patients.

Allen JL, Tata PV, Fore MS, et al. Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood. 2014;123:2108-2115, PMID: 24532806.

8. False.

Prolonged (>12 months) lymphocytosis during ibrutinib therapy does not indicate a suboptimal response to therapy. The investigators emphasized that treating physicians understand that isolated progression of lymphocytosis, even when persistent for many months, is not a sign of disease progression and should not trigger unnecessary drug discontinuation.

Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014;123:1810-1817, PMID: 24415539.

9. True. Patients with PMF receiving 12. True. ruxolitinib had longer survival.

Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-II cohorts. Blood.

2014;123:1833-1835, PMID: 24443442.

10.

True. For example, the novel substances that target BCR signaling and CLL cell homing could even be beneficial for asymptomatic patients who are usually approached with a watchand-wait strategy. A trial is planned by the German CLL study group, which will test ibrutinib as a first-line treatment in Binet stage A disease. Patients to be treated will be identified with a prognostic score that is based on biomarkers including clinical, genetic and serum parameters.

Bahlo J, Pflug N, Elter T, et al. Proposal of a prognostic score for previously untreated patients with chronic lymphocytic leukemia based on an overall survival analysis of three German CLL Study Group phase III trials. Annual Meeting Abstracts. Blood. 2011;118:2831.

Mertens D, Stilgenbauer S. Prognostic and predictive factors in patients with chronic lymphocytic leukemia: relevant in the era of novel treatment approaches? J Clin Oncol. 2014;32:869-872, PMID: 24516034.

11. True.

Ayuk JF, Zabelina T. Impact of HLA-mismatch on outcome after ATG-containing myeloablative and reduced intensity unrelated donor transplantation. Presented at the Annual Meeting of the European Society for Blood and Marrow Transplantation; March 30-April 2, 2014; Milan, Italy.

Abstract PH-O050.

Prospective trials are needed to evaluate eculizumab therapy in this particularly severe situation.

De Fontbrune S, Galambrun C, Sirvent A, et al. Efficacy of eculizumab in allogeneic stem cell transplantation associated thrombotic microangiopathy: a retrospective study on behalf of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). Presented at the Annual Meeting of the European Society for Blood and Marrow Transplantation; March 30-April 2, 2014; Milan, Italy. Abstract PH-O057.

13. False.

Among patients who underwent allo-HCT, those who received a conditioning regimen with ATG had lower risks for and cumulative incidence rates of developing pulmonary cGVHD. Liao XW, Lin CT, Yao M, et al. Could prophylactic antithymocyte globulin before allogeneic stem cell transplantation reduce risk of pulmonary GVHD in adult patients with acute leukemia? Presented at the Annual Meeting of the European Society for Blood and Marrow Transplantation; March 30-April 2, 2014; Milan, Italy. Abstract PH-O142.

14. True. The relevance of this data

with the availability of effective targeted therapy in CLL requires confirmation.

Van Gelder M, Ghidey W, Cornelissen J, et al.

R-DHAP immune-chemotherapy is an effective remission-induction treatment for fludarabine refractory CLL patients and allows the majority to proceed to allogeneic stem cell transplantation—results of the prospective multicenter HOVON 88 trial. Presented at the Annual Meeting of the European Society for Blood and Marrow Transplantation; March 30-April 2, 2014; Milan, Italy. Abstract PH-O065.

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