Clinical Oncology News by McMahon Group

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • September 2013 • Vol. 8, No. 9

INSIDE SOLID TUMORS Dose-dense regimen refines testicular cancer therapy ...................................... 9 Axilla radiotherapy called new breast cancer standard .................................. 15

CURRENT PRACTICE Maurie Markman, MD: The essential patient perspective ............................. 3 Few oncologists monitor lab quality ..................................... 14 Quality cancer care: No longer just about survival ...................... 14 Clinical Conundrums .......... 16

by the

numbers

Financial Distress In a survey of 164 cancer patients, as a result of cost: Medication 45% | non-adherence due to cost not fill a 27% | Did prescription filled a 25% | Partially prescription less 22% | Took medication than prescribed Source: Journal of Clinical Practice. doi: 10.1200/JOP.2013.000971

IMAGES in ONCOLOGY

Chemo for Smoldering MM? Not Yet!

he report by MariaVi ct o ri a Mateos, MD, PhD, of the University Hospital of Salamanca in Spain, in the Aug. 1, 2013, issue of The New England Journal of Steven Vogl, MD Medicine (NEJM ( M) is both very important and very, very difficult to read quickly.1 The question under study is fashionable: At what point do physicians decide that a condition in asymptomatic patients is life-threatening and deserves treatment as a cancer? see VOGL, NY, Y page 4

“Untitled (Aerial Perspective),” a carcinomatous invasion of bone. For more information see page 8.

ASCO 2013

Affordable Care Act Impact: It’s All in the Details ... and There Are No Details Chicago—With several key provisions of the Affordable Care Act (ACA) set to take Overall Effects of the ACA on Physicians’ Incomes effect on Jan. 1, it is still difficult to preIncreased revenue dict exactly how it will affect the treat• More covered patients due to insurance mandate and Medicaid growth ment of cancer, a panel of policy experts • More covered preventative services such as mammography screenings told oncologists at the 2013 annual meeting of the American Society of Clinical Decreased revenue Oncology (ASCO). • Penalties for failing to comply with quality reporting programs The 900-page act, colloquially known as • Fee-for-service replaced by bundled payments and medical home Obamacare, is dauntingly complex, yet very and shared savings programs little deals specifically with cancer care. “There are really very few oncologyspecific components,” said William C. Penley, MD, a medical In describing the scope of the ACA, Dr. Penley said it is easier oncologist at Tennessee Oncology in Nashville, who has served to follow the themes of the legislation than the specifics, many of on ASCO’s Government Relations Committee and the board of which are likely to be modified, even if the specific regulations the Association of Community Cancer Centers. see AFFORDABLE CARE, E page 13 RE VIE WS & COMMENTAR IES

Expert Insights From Levine Cancer Institute Osteosarcoma Survival Differs by Gender and Age .................... 10 Peter Anderson, MD

Dose-Dense Regimen Does Not Improve R-CHOP for DLBCL .............. 12 Saad Z. Usmani, MD

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • 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 AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

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

Oncology Nursing

Hematologic Malignancies

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

Michele Neskey, MMSc, PA-C

Maura N. Dickler, MD

Harry Erba, MD, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

University of Alabama Birmingham, AL

Gastrointestinal Cancer

Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

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

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

Gastrointestinal Cancer and Sarcoma

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

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 The Mount Sinai Medical Center New York, NY

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

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

On the Cover

Syed A. Abutalib, MD

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 www.behance.net/MarieSicari

Cancer Treatment Centers of America Zion, Illinois

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

Shaji Kumar, MD

Edward Chu, 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

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

Lung g and Head and Neck Cancers Edward S. Kim, MD Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Mission Statement

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

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

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

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

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

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

What Do Patients Think About _____? An essential perspective EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

ere words cannot adequately describe the complexity of modern cancer care. From spectacular advances in our understanding of the fundamental molecular biology of cancer, to novel antineoplastic medications and strategies, to the effect of drug shortages of generic medications, and to the unquestionably worsening and unsustainable cost of providing optimal cancer care, it is reasonable to declare that a clear path forward is incredibly difficult to define. One critical perspective that we have to consider in our ongoing deliberations over the future of cancer care is that of the patient. And although today no responsible authority would actively disagree with the importance of the “patient perspective,” it is essential to acknowledge just how unique this view might be when compared with that of the provider, government regulator or insurance payor. Certain authorities and experts may believe they “know/understand” the patient perspective, and that as a result their opinions can serve as a reliable surrogate for the patient in policy discussions. This should be vigorously challenged.

It shouldn’t come as any surprise that third-party pronouncements on the views of patients are a poor strategy to establish an appreciation of the attitudes of patients, or even to appreciate their basic understanding of a cancer-related topic. For example, a recent report noted major differences in the perception of women with ductal carcinoma in situ about their future risk for developing breast cancer versus the actual population-based risk defined through longterm follow-up studies; a second survey of cancer patients that asked their opinions regarding somatic genomic testing revealed a limited understanding of the reasons for these tests, as well as concerns about the value and risk associated with the strategy.1,2 Furthermore, in weighing the relative clinical importance of “significantly” delaying cancer progression versus improving “overall survival” with any maintenance antineoplastic drug strategy, investigators routinely and appropriately noted the side effects associated with continuing treatment that could be avoided, or at least delayed, if treatment was discontinued at the point of “maximal response” and the patient “observed” until disease progression.3 Why not simply ask patients—either individually or as a large group—what they prefer? After all, they are the ones who will be experiencing the treatmentrelated side effects or disease progression and its associated clinical manifestations. I provide these examples to emphasize the point that it is not appropriate to simply assume we understand the

patient’s perspective or knowledge of a cancer topic without inquiring in a very formal manner, and ensuring an appropriate sample size that represents all of the relevant constituencies. For health care policy, the role of patients will be different from the examples cited above, but should be no less relevant. When determining the societal value associated with the treatment of metastatic cancer, for example, we should not arbitrarily accept the utility of such therapy based solely on a modest extension of the length of life. The question to be asked is how much value do cancer patients ascribe to a particular outcome and what, for example, “would they be willing to pay”—in toxicity and dollars—to achieve this goal? In fact, recently reported data suggest that current assumptions about cancer patients’ perspectives are woefully inaccurate.3,4 In one study, the large majority of patients declared their interest in a treatment strategy that had the “hope,” but absolutely no guarantee, of a major increase in survival.3 This approach was strongly preferred to one where there was much less hope of a very favorable outcome, and in contrast presented a much more certain modest improvement in survival. In a second provocative study, a large sample of cancer patients with metastatic disease revealed a willingness to pay far more for their anticancer care to extend survival than traditionally believed by health care economists.5 These data suggest that some members

of society may be willing to pay more— perhaps through additional insurance premiums—to be provided this benefit, if necessary, at some point for themselves or their family members. These are only a few examples among many that could be provided, but they serve to emphasize the critical importance of including the direct perspective of the patient—not surrogate-defined— in all current and future discussions of strategies to improve cancer outcomes in a more rational and cost-effective health care environment.

References 1. Ruddy KJ, Meyer M, Giobbie-Hurder A, et al. Long-term risk perceptions of women with ductal carcinoma in situ. The Oncologist. 2013;18:362-368, PMID: 23568001. 2. Gray SW, Hicks-Courant K, Lathan CS, et al. Attitudes of patients with cancer about personalized medicine and somatic genetic testing. J Oncol Pract. 2012;329-335, PMID: 23598841. 3. Gerber DE, Schiller JH. Maintenance chemotherapy for advanced non-small-cell lung cancer: new life for an old idea. J Clin Oncol. 2013;31:1009-1020, PMID: 23401441. 4. Lakdawalla DN, Romely JA, Sanchez Y, et al. How cancer patients value hope and the implications for cost-effectiveness assessments of high-cost cancer therapies. Health Aff.f 2012;31:676-682, PMID: 22492883. 5. Seabury SA, Goldman DP, Maclean JD, et al. Patients value metastatic cancer therapy more highly than is typically shown through traditional estimates. Health Aff.f 2012;31:691699, PMID: 22492885.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

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

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VOGL, NY continued from page 1

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

The study, conducted by the Spanish myeloma group PETHEMA (Programa Español de Tratamientos en Hematología), randomized 119 patients with high-risk smoldering multiple myeloma (SMM) to observation or immediate treatment with lenalidomide and a moderate dose of dexamethasone (LenDex). The primary end point was time to “progression to symptomatic disease,” although the most interesting finding was a statistically significant prolongation of overall survival.

Background Physicians at Mayo Clinic recognized in 1980 that some patients whose plasma cell dyscrasias met the criteria for multiple myeloma lived five years without symptoms or treatment.2 They proposed criteria to identify these patients, who could then be spared the marginally effective therapies of the time—primarily melphalan and prednisone—for many years (Table 1). A 2007 paper from Mayo Clinic is the definitive one in the field.3 It reports a cumulative risk for evolution from SMM to overt myeloma of 73% at 15 years. There was obvious heterogeneity among the patients with SMM: The risk for evolution by CRAB (hyperCalcemia, Renal insufficiency, Anemia and Bone lesions) criteria was 10% per year for the first five years, 3% per year for the next five years, and only 1% per year for the following 10 years. This suggests

Table 1. Definition of Smoldering Myeloma Monoclonal immunoglobulin (serum or urine) And either: Serum paraprotein >3 g/dLa, or >10% plasma cells in bone marrowb And none of the CRAB criteria: • hyperCalcemia • Renal insufficiency • Anemia • Bone lesions a Different cutoffs for immunoglobulin A and those with only light chains. b

In the absence of other causes of bone marrow plasmacytosis.

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

that about 50% of the patients are high risk, and the remainder are low or very low risk for evolution to overt myeloma.

PETHEMA Study Results In the study done by the PETHEMA group in Spain and reported by Dr. Mateos, Len-Dex chemotherapy worked—paraprotein response rate of “partial or better” with nine months of Len-Dex induction was 79%, with 17% of patients achieving complete remission characterized by negative immunofixation electrophoreses. Another 11% later achieved 50% paraprotein reduction— the usual criterion for partial response— during lenalidomide “maintenance” after the nine months of Len-Dex induction, making the total response rate 90%. A quick reading of the abstract suggests that immediate treatment is indicated for a “high-risk” subgroup of patients with SMM because it not only markedly delays evolution to “symptomatic” myeloma, but also prolongs survival. That effective therapy against the neoplastic plasma cell clone shrinks the clone and delays the effects of clonal expansion is not at all surprising, and so is of little interest. That ultimate death is allegedly delayed by treatment initiated before the emergence of any CRAB abnormality that traditionally defines the need for treatment in myeloma is big news indeed.

What Is Wrong With the Paper? The paper is written in a theatrical style reminiscent of a Eugene O’Neill play—although not much happens “on stage,” there is a progressive revelation of critical information as the paper pursues its “long day’s journey.” This makes for an entertaining and smooth read, but could also mislead a reader who only skims what would be the relevant section in most manuscripts. For instance, in the methods section, selection of some of the patients is described as based on at least 95% phenotypically aberrant plasma cells. To my aged eyes, trained in interpreting bone marrow aspirations, this implies that they looked strange under the microscope. It is only in a note to Table 1, three pages later, that the paper states, “aberrant plasma cells were detected by means of flow cytometry.” Four pages later, near the end of the discussion section, it finally becomes clear that the group conducting the study developed criteria for risk “locally.” About 40% of the study participants were entered because no less than 95% of their marrow plasma cells were abnormal (shown by senior author Jesús San Miguel, MD, PhD, to represent the monoclonal population) on a four-antibody flow cytometry test developed in Salamanca, Spain.4 This test is used in Europe by research centers and cooperative groups. To my knowledge, it is not available in North

America. It is possible, but not certain, that it can be scaled up to become commercially available. This means that no U.S. group can precisely seek to duplicate this study because the test to define 40% of the subject population is not available here.

End Point of ‘Symptomatic Disease’ Has Little To Do With Symptoms! It is reasonable to seek to prove that treatment while the myeloma is smoldering prevents emergence of the traditional conditions that indicate treatment— the “CRAB” tetrad. Again and again, the authors call myeloma that meets CRAB criteria “symptomatic.” Actually, three of the four “CRAB” criteria are laboratorybased (hypercalcemia, elevated serum creatinine and anemia), and often produce no symptoms if mild. Participants on the observation arm of the study had blood tests every four weeks—nowhere does the paper state what symptoms (e.g., pain, dyspnea, weakness, palpitations) the patients complained of when the myeloma met CRAB criteria. The paper would be more convincing if all, or even a majority, of the worsening “observation” patients had bone pain or fracture at progression. I suspect only a minority had pain. This matters because deferral of pain is almost always a very good thing, but deferral of mild anemia may, by itself, mean very little. Dr. San Miguel thinks this is a confusing quibble (personal communication). Apparently, international myeloma committees term any myeloma meeting the “CRAB” criteria “symptomatic,” even if the patient has no symptoms. Perhaps international myeloma committees should defer to the English language and call myeloma needing therapy “real,” or “serious,” or “overt,” or “threatening.”

Survival Analysis Surprising; However, Numbers Too Small Multiple myeloma has become a

Table 2. Criteria for High-Risk Smoldering Myeloma in the PETHEMA Study Serum paraprotein >3 g/dL and >10% marrow plasmacytosis or one of the above, plus >95% of marrow plasma cells abnormal (presumably monoclonal) on four-antigen flow cytometry, plus depression of the levels of the two classes of antibody not involved in the myeloma (e.g., depressed IgA and IgM for IgG myeloma) Ig, immunoglobulin; PETHEMA, Programa Español de Tratamientos en Hematología

Table 3. Important Parts of the NEJM Manuscript That Are Easy To Miss • 40% of entered high-risk patients are identified solely by a flow cytometry test available only in Spain • “High-risk” patients are indeed very high risk—80% progression to overt myeloma at 48 months • Many of the progressions to “symptomatic” myeloma probably produced no symptoms at progression • Patients progressing to “symptomatic” myeloma did not receive lenalidomide at progression

chronic disease since the availability of new therapies including thalidomide, bortezomib (Velcade, Millennium), lenalidomide (Revlimid, Celgene) and now carfilzomib (Onyx) and pomalidomide (Pomalyst, Celgene). Median survival has gone from two years in the early 1980s to more than seven years. Because of the progressive availability of new agents and combinations, and improvements in supportive care for high-dose melphalan therapy and autologous stem cell rescue, one can assume an even better prognosis for patients diagnosed in 2013. With so much effective therapy available for myeloma meeting the CRAB criteria, one assumes it would take a large study indeed to demonstrate an even longer survival by starting therapy before CRAB criteria are met. Much to my surprise, Dr. Mateos’s paper reports a statistically significant improvement in survival at three years from early Len-Dex treatment—94% versus 80%. The surprising component is how poorly the “high-risk” SMM group did. The 80% three-year survival for this group—which did not initially meet CRAB criteria, but with treatment beginning when these criteria are met—is no better than the survival of Len-Dex patients with overt myeloma in an Eastern Cooperative Oncology Group study led by S. Vincent

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to gmiller@mcmahonmed.com

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Rajkumar, MD, of lenalidomide with low- or high-dose dexamethasone.5 Dr. Rajkumar’s Mayo Clinic group has shown that some patients with SMM have much worse disease than others (as do some patients with overt multiple myeloma). Some of these patients with a poor prognosis can be characterized cytogenetically by the t(4;14) translocation on fluorescence in situ hybridization, or free light-chain ratios greater than 100, or depression of levels of one or both noninvolved immunoglobulins (which the PETHEMA group called “immunoparesis,” or level of the M spike, or extent of plasma cell marrow infiltration). As Dr. Mateos and her colleagues point out, there is no consensus on exactly how to decide which patients with SMM are “high risk.” It does make sense that patients with “high-risk” SMM—especially when the high risk is based on cytogenetic abnormalities—should develop “high-risk” overt myeloma when “CRAB” criteria are met. If this is correct, then it is not so surprising that the early death rate for the “high-risk” SMM patients on observation is so poor, since they presumably go on at a high rate to develop rapidly progressive overt myelomas that are resistant to treatment. Because Dr. Mateos’s study is so small, the survival difference between the arms is based on a difference of only nine deaths: four versus 13. I, for one, needed to be assured that chance did not cause the difference, with more myocardial infarctions and auto accidents in the group initially assigned to observation. This was not the case. The authors

Table 4. Why Standard Practice Has Not Changed • The definition of high-risk smoldering myeloma used depends on a local test of uncertain standardization and limited availability. • The later therapy of patients initially observed was not standardized, and did not include lenalidomide, at least initially. • Quality of life was not measured. • The survival difference depends on a small number of events. • Survival curves are immature; most of the patients on both arms of the study are still alive, so the timing of their deaths could change the conclusions. • If therapy for overt myeloma continues to improve, the benefits from asymptomatic smoldering myeloma therapy may disappear.

thankfully included a listing of each death on the observation arm, but the NEJM editors allowed them to include it only in the online supplementary appendix. Table S1 in the online supplementary appendix shows that all of the observation patients who died did so after progression to overt myeloma, not from unrelated problems before progression, and after treatment for the myeloma, although one of the patients received only melphalan and prednisone without even bortezomib. Three of the deaths were related to complications from therapy, with two of them following

high-dose melphalan, and one death was sudden.

Tolerability and Toxicity Are Key That three of the 13 observed deaths in the deferred treatment arm were treatment-related emphasizes the extent to which the results depend on the details of the treatments given. As the efficacy of treatment for overt disease improves, and as its toxicity improves, the benefits of treatment while the disease smolders would decrease. Because myeloma remains an in-

curable disease, duration and quality of life are the key end points for patients. Quality of life should be totally intact while the disease smolders—essentially by definition—so it will take a lot of really good-quality days later to make up for any of those sacrificed to a toxic therapy for SMM. Lenalidomide with low-dose dexamethasone is minimally toxic for most patients, and thus was a wise choice for the PETHEMA group to study, even though they may have given a little more dexamethasone than Dr. Rajkumar found optimal.5 see VOGL, NY, Y page 6

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VOGL, NY continued from page 5

The Study Was Unbalanced: Observation Patients Did Not Get Lenalidomide at Progression Lenalidomide is a very good drug for myeloma, with little subjective toxicity. It is only in Table S1 online that it becomes clear that many of the patients on observation probably never got lenalidomide therapy. The authors acknowledge this on the last page of the

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

discussion section of their paper, where they report that lenalidomide was not approved as first-line therapy in Spain or the rest of western Europe. As this article goes to press, lenalidomide is still not approved in Europe as part of first-line therapy for myeloma. One could consider the randomization, then, as one comparing early lenalidomide to no lenalidomide. As the survival curves from this study play out, it will be important to analyze all the therapy received by the patients before they die. If indeed many observation patients die without ever

getting lenalidomide, then this reveals an important flaw in the study. Even if most of the observation patients eventually got “modern” therapy with lenalidomide, thalidomide and bortezomib, it is probably important that they get them early. In the VISTA trial, median survival was improved by 13 months if bortezomib was included with melphalan and prednisone as part of initial therapy.6 The VISTA study proved that initial therapy is indeed important for myeloma, with a major survival advantage even if myeloma patients eventually received all the best

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agents. Until the VISTA results became available, many myeloma experts thought that initial use of the most active agents was not necessary, as long as they were eventually employed. Only late in the discussion section of the paper is there mention of the exact treatment at progression for the observation patients—53% “bortezomib-based,” 28% “induction” (this may mean vincristine, adriamycin and dexamethasone, but is unclear) followed by high-dose melphalan, and 19% something else (that probably means melphalan and prednisone, but the authors,

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like Eugene O’Neill, leave some mysteries unrevealed even at the final curtain).

Were the Criteria for Progression Suboptimal Because They Were Too Strict? Most myeloma clinicians would start chemotherapy for a patient with SMM, or at least look hard for new bone lesions, if the hemoglobin dropped from 11.5 to 10.2, the calcium rose from 9.2 to 10.6, or the creatinine rose from 1.1 to 1.8. The criteria the PETHEMA group chose to define as “CRAB” criteria were fairly strict, and may have resulted in

delayed onset of therapy beyond what most of us would tolerate as we follow these patients carefully. I would love to see a table of the criteria for progression in the 44 observation patients who progressed, with their “CRA” values at progression, the month before progression and at entry. With these data, we could judge for ourselves whether vigilant clinicians would have started therapy earlier. Many myeloma patients are elderly and have significant comorbidities. A one- or two-month delay in effective therapy could easily compromise their

survival by many months.

This Is an Important Result and an Important Concept Just as it was important in 1980 for Drs. Kyle and Greipp to report six patients with myeloma who did well for five years without therapy—the first whose myeloma was called “smoldering”—so it is important now to explore therapeutic intervention for those with plasma cell neoplasms and no symptoms but a poor prognosis.4 The wisdom of intervention, as always, depends on the efficacy and toxicity of the

intervention, as well as a careful definition of the disadvantages of deferring therapy until symptoms develop that can then be improved or resolved. This issue will only get more complicated as the prognostic and therapeutic heterogeneity of multiple myeloma becomes more clearly defined. We need more trials of early intervention for higher risk SMM patients, with larger numbers and more power, with sensitive definitions of disease progression and optimal therapy at progression. I, for one, hope the see VOGL, NY, Y page 8

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VOGL, NY continued from page 7

Spaniards’ conclusion proves correct, and that early intervention with tolerable therapy prevents morbidity and defers mortality.

References 1. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for highrisk smoldering multiple myeloma. N Engl J Med. 2013;369:438-447, PMID: 23902483. 2. Kyle RA, Greipp PR. Smoldering multiple

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

myeloma. N Engl J Med. 1980;302:1347-1349, PMID: 7374679. 3. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582-2590, PMID: 17582068. 4. Pérez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood. 2007;110:2586-2592, PMID: 17576818. 5. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose

dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37, PMID: 19853510. 6. San Miguel JF, Schlag R, Khuageva NK, et

al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:448-455, PMID: 23233713.

Want to know how Robert Kyle, MD, who first characterized smoldering multiple myeloma, treats the disease? See Robert Kyle, MD: How I Treat ... Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma in the July 2013 issue of Clinical Oncology News and online at

ClinicalOncology.com

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CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

ASCO 2013

Dose-Dense Regimen Refines Testicular Cancer Therapy Chicago—Using serum tumor markers to identify poor-prognosis germ cell tumor (GCT) patients who are at risk for worse disease and providing them with intensified chemotherapy decreases the risk for disease progression by 34%, according to results of the GETUG-13 study presented at the 2013 annual meeting of the American Society of Clinical Oncology (abstract LBA4500) by Karim Fizazi, MD, PhD, the

chairman of Cancer Medicine at the Institut Gustave Roussy in Villejuif, France. The study results are changing the practice of some, but not all, clinicians. Current standard treatment for poorrisk GCT is four cycles of BEP (bleomycin, etoposide and platinum). Because clinical trials have shown that singleagent paclitaxel, ifosfamide and oxaliplatin can marginally improve outcomes

in these patients, the French clinical trials group GETUG (Groupe d’Etude des Tumeurs Uro-Genital) hypothesized that combining these three drugs with BEP in selected patients with unfavorable response would improve outcomes. Clinicians treated 263 patients with poor-prognosis GCT with one cycle of BEP, and then assessed two tumor markers between days 18 and 21. Patients with

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a favorable marker decline continued on standard therapy. Individuals without a favorable marker decline were randomized to receive the additional standard three cycles of BEP or a dose-dense chemotherapy regimen. This consisted of two cycles of paclitaxel, oxaliplatin, BEP and granulocyte colony-stimulating factor (G-CSF), followed by two cycles of cisplatin, ifosfamide, bleomycin and G-CSF. Although ongoing, the trial was amended to provide G-CSF to the BEP arm and delete oxaliplatin from the last two cycles in the dose-dense regimen. In patients with unfavorable markers, progression-free survival (PFS) at three years was improved in the experimental arm (59% vs. 48%; hazard ratio, 0.66; P=0.05). Overall survival (OS) data is not yet mature. Neurotoxicity of grade 2 or higher was more common in the dose-dense regimen arm (23% vs. 4%), but was mostly reversible at two years. Salvage high-dose therapy and transplant were needed more frequently with standard BEP (16% vs. 6%; P<0.02). Second cancers were similar in both arms. GETUG clinicians and oncologists from the University of Texas MD Anderson Cancer Center in Houston, who also were involved with the GETUG-13 trial, now consider the dose-dense regimen the new standard for patients with poorrisk GCT with unfavorable tumor marker decline after one cycle of BEP. Chong-xian Pan MD, PhD, who leads the Urothelial Carcinoma Initiative at University of California, Davis Comprehensive Cancer Center, said that OS, not PFS, should be used as the primary end point in testicular cancer trials. “If patients have disease progression, but can still be cured by high-dose chemotherapy, then PFS does not mean much,” he said. “This is very common in GCT.” A 2003 study in the Journal of Clinical Oncology supports Dr. Pan’s viewpoint (2003;21:4100-4104, PMID: 14615439). Dr. Pan does not plan to change his practice and pointed out that the dosedense regimen in GETUG-13 used almost all of the active agents clinicians use to fight testicular cancer and thus may limit later treatment options. “Except the full dose and schedule of BEP, other active agents, including ifosfamide, paclitaxel and oxaliplatin, were only given with two cycles,” he said. “If cancer is not treated with full dose and schedule, cancer is more likely to develop resistance to those specific agents and other agents.” —Kate O’Rourke Drs. Fizazi and Pan have no relevant disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.NEWS

Expert Insights From Levine Cancer Institute 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. We hope you find this Reviews & Commentaries section to be a valuable tool.

Osteosarcoma Survival Differs by Gender and Age From the Journal of Clinical Oncology

meta-analysis of records for patients treated for osteosarcoma revealed overall survival (OS) and response to treatment differed between sexes and among age groups. The authors theorized the effects of puberty and variances in age groups are not yet well understood or appreciated by oncologists. The review, led by Marnie Collins of the Peter MacCallum Cancer Centre and Australasian Sarcoma Study Group in Melbourne, Australia, was sponsored by the LIVESTRONG Young

Adult Alliance. Results were published in the Journal of Clinical Oncology (2013:31:2303-2312, PMID: 23669227). The authors identified 24 neoadjuvant chemotherapy clinical trials through PubMed that included 4,838 patients with osteosarcoma. Patient data and outcome information were grouped into three categories as a surrogate for pubertal stage. For females, the age groups were child (0-11 years), adolescent (12-16) and adult (17+); for males, the groups were child (0-12 years), adolescent (13-17) and adult (18+). Tumor location and surgical

intervention had a significant effect on OS. The authors found that females had higher OS ((P=0.005). Ten-year OS for females was 66% compared with 61% for males. The authors also discovered that females more frequently reported grade 3 or 4 thrombocytopenia (63% vs. 53% for males) and mucositis (33% vs. 28% for males) and that these adverse events were linked to an improved OS. A higher rate of chemotherapy-induced tumor necrosis also was associated with a better OS (P ( <0.001), and was achieved more often in females (56% vs. 50% for males) and more often in children

EXPERT INSIGHT Michael Livingston, MD Hematology/Medical Oncology

Jeffrey Kneisl, MD

Peter Anderson, MD

Orthopedic Surgery, Surgical Oncology

Director, Pediatric Hematology/Oncology, Levine Children’s Hospital

Levine Cancer Institute, Carolinas HealthCare System, Charlotte, N.C.

dult oncology and pediatric oncology rarely cross boundaries in the solid tumor world. For those who see and treat patients with sarcoma, this is a common intersection. The recommendations between adult and pediatric cancer viewpoints and practices can vary or not even be defined. Is the drug dose adequate, too much, or too little? Does the toxicity information apply equally to these populations? How much toxicity is acceptable? Will this 35-year-old man respond like a 70-year-old man or like an 18-year-old woman? As the training and education for these two worlds are separate, the clinical practice is many times not, thus leaving a void in helping practitioners make the best decisions for their patients.

But change for the better (or at least the more rational) is coming. Spearheaded by the LIVESTRONG Young Adult Alliance, there has been more focus recently on the underserved demographic between ages 18 and 40. In this regard, this recent metaanalysis by Collins et al is helpful. Using primary data from more than 4,000 patients and after accounting for known prognostic variables, the authors found that females had higher survival rates than males ((P=0.005) and children did better than the adolescent/young adult (AYA) population ( =0.002). Not surprisingly, postsurgi(P cal meta-analysis confirmed chemotherapy-induced necrosis as the strongest predictor of survival. Female sex predicted improved survival, as did

grade 3 to 4 mucositis, suggesting a difference in disease biology and/or pharmacology between the sexes. As with all well-done studies, these data raise as many questions as they answer. At a minimum, the investigators strongly support the routine use of correlative pharmacokinetic data collection. Perhaps, going forward, female sex should be regarded as an upfront stratification parameter for prospective trials (along with tumor location, histology, etc.). Should one give a newly diagnosed 35-year-old man with osteosarcoma dose-escalated therapy and an 18-year-old woman standard-dose therapy? Without prospective data, it would be difficult and potentially dangerous to make that extrapolation. Nevertheless, in

(59%) than in adolescents (54%) or adults (45%). The authors found that response to chemotherapy is different between the sexes and age groups. Observing that clinical trials tend to involve children or adults, the researchers noted that treatment regimens tend to be extrapolated from study results with less attention shown to adolescents, a critical group as chemotherapy becomes more individualized. Better understanding of the effect of sex and stage of puberty in response to pharmacologic efficacy and toxicity may lead to improved overall outcomes.

future prospective studies, it seems a reasonable question to consider in designing trials. At the end of the day, how far will this get us? A little further, but not as far as we would like. There are only so many perturbations/modifications of standard cytotoxic regimens and most of those have been studied over the past several decades. The difference in 10-year OS between males and females in this study was real but modest (6%). We are left with the stubborn 25% to 30% of locoregional osteosarcoma patients we do not cure—a number that, at least in the adult medical oncology/epithelial world, we might be thankful for, but that for children and young adults continues to be disheartening. At Levine Cancer Institute, we have emphasized bringing the worlds of adult and pediatric oncology closer. We have created a transitional clinic where patients who were treated as adolescents will be followed in an adult clinic setting, providing a seamless transition to continued care. This will not only enhance multidisciplinary patient care, but also link adult and pediatric research efforts. Drs. Anderson, Kneisl and Livingston reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

Aflibercept Addition No Help in Metastatic Pancreatic Cancer Regimen From European Journal of Cancer

he addition of aflibercept to gemcitabine as a treatment regimen for patients with metastatic pancreatic cancer has proven futile, prompting an early end to a study designed to demonstrate improved overall survival (OS). Metastatic pancreatic cancer remains a disease with a very poor prognosis; most treatments fail to extend OS. Because vascular endothelial growth factor (VEGF) overexpression is frequent in this disease, it was hypothesized that a VEGF inhibitor

like aflibercept would improve OS when added to the standard treatment of gemcitabine. Earlier trials established that aflibercept was well tolerated and demonstrated anti-tumor activity. The present study ((Eur J Cancer 2013 Apr 30 [Epub ahead of print]; PMID: 23642329), whose lead author was Philippe Rougier, MD, was a placebo-controlled study that was undertaken at 116 sites in 23 countries. Patients were stratified and randomized to treatment arms with gemcitabine (n=270; 1,000 mg/m2 IV weekly for seven out of eight

EXPERT INSIGHT Reza Nazemzadeh, MD Medical Oncology, Gastrointestinal Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

mproving on the activity of singleagent gemcitabine for metastatic pancreatic cancer has proven difficult over the years as multiple agents have been studied in combination with gemcitabine with disappointing results. Although statistically significant, the addition of erlotinib offered limited benefit with a two-week survival advantage, and has not seen wide adoption as an alternative to singleagent gemcitabine. Only recently with the results of the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study from Von Hoff et al using nab-paclitaxel with gemcitabine has there been a notable step forward from single-agent gemcitabine, although with a 1.8-month improvement in OS.1 The FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) regimen is considered by many to be the gold standard first-line therapy, with a 4.3-month improvement in survival compared with gemcitabine alone, but there are real concerns about its tolerability and effect on quality of life.2 VEGF has been considered a worthwhile target in this disease as overexpression has been frequently noted and appears to correlate with tumor biology, although a previous study

investigating the addition of bevacizumab to gemcitabine did not result in OS benefit.3-5 With a potentially better mechanism to specifically target VEGF expression with aflibercept through enhanced binding affinity for VEGFA and VEGF-B, as well as placental growth factor, in the present study Rougier et al conducted a well-designed randomized, double-blind, placebocontrolled test of efficacy in the firstline metastatic setting.6 Although well tolerated, the experimental arm did not show any benefit in OS or PFS with the addition of aflibercept to gemcitabine, and the study was stopped for futility at interim analysis. As expected with VEGF targeting, the grade 3/4 toxicities seen were primarily hypertension, hemorrhagic events, cardiac dysfunction and proteinuria, although the incidence of these was modestly increased. Similar to what has been seen in other tumor types with VEGF blockade, they observed a trend in OS in patients who developed hypertension, although this was seen in both treatment arms.7,8 As the authors postulated, the lack of significant benefit with targeting VEGF may be in part due to the relative hypovascularity of this disease, although this may be an overly simplistic argument.9

weeks, then weekly for three out of four weeks) plus aflibercept (4 mg/kg IV every two weeks) or matching doses of gemcitabine plus placebo (n=271). Median OS in the aflibercept arm was 6.5 months (95% confidence interval [CI], 5.6-7.9) and 7.8 months (95% CI, 6.8-8.6) in the placebo arm. OS rates in the aflibercept arm were 80%, 54%, 34% and 21% at three, six, nine and 12 months; the OS rates for the same periods in the placebo arm were 83%, 63%, 38% and 25%, respectively. Progression-free survival (PFS) rates between the two arms were not

significantly different. Treatment discontinuation in the aflibercept arm due to adverse events (AE) was more frequent than in the placebo arm (23% vs. 12%, respectively), and patients in the aflibercept arm also had a greater incidence of grade 3/4 AEs, chief among them hypertension. Incidence of hypertensive AEs in the aflibercept group was 13% versus 3% in the placebo group. After the interim analysis showed that the addition of aflibercept did not improve OS in patients with metastatic pancreatic cancer, the study was terminated for futility.

Strong arguments could be made to use the more active combination of FOLFIRINOX but … the use of gemcitabine/nab-paclitaxel may be more prudent and could allow better accrual. With three chemotherapy combinations that have shown superior survival, first-line metastatic trials in this disease going forward should clearly include a more active control arm. Strong arguments could be made to use the more active combination of FOLFIRINOX but, considering the difficulties in consistently giving this regimen to patients who often have a relatively poor performance status at presentation, the use of gemcitabine/nab-paclitaxel may be more prudent and could allow better accrual. Pancreatic cancer remains a challenging disease where cytotoxic and targeted therapies have not produced the results desired by patients and investigators. This is largely related to an inadequate understanding of each patient’s unique tumor/disease process and thus inappropriate patient selection with different therapies that could have useful targets. Further study is certainly warranted to delineate specific treatment pathways for individual patients and to identify additional targets.

3. Seo Y, Baba H, Fukuda T, et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer. 2000;88:2239-2245, PMID: 10820344. 4. Itakura J, Ishiwata T, Friess H, et al. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res. 1997;3:1309-1316, PMID: 9815813. 5. Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27:2231–2237, PMID: 19307500. 6. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11393-11398, PMID: 12177445. 7.

Osterlund P, Soveri LM, Isoniemi H, et al. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer. 2011;104:599-604, PMID: 21304526.

References

8. Leighl NB, Raez LE, Besse B, et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac Oncol. 2010;5:1054-1059, PMID: 20593550.

1. Von Hoff DD, Ervin T, Arena FP, et al. Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2013.

9. Philip PA. Development of targeted therapies for pancreatic cancer. Lancet Oncol. 2011;12:206-207, PMID: 21306954.

2. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825, PMID: 21561347.

Dr. Nazemzadeh reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

Dose-Dense Regimen Does Not Improve R-CHOP for DLBCL From The Lancet

verall survival (OS) did not improve in patients with treatment-naive diffuse large B-cell lymphoma (DLBCL) who were treated with a chemotherapy regimen of 14 days (i.e., R-CHOP) compared with those treated with the standard 21-day cycle regimen. For close to four decades, standard therapy for these lymphoma patients has been combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). The chemotherapy

regimen is given in six cycles every 21 days (CHOP-21). High-dose treatments have not persuasively improved outcomes. A 2004 German study, however, suggested that six cycles every 14 days (CHOP-14) showed superior OS in patients aged 60 years or older. The addition of rituximab (Rituxan, Genentech) to the regimen (i.e., R-CHOP) was found to improve cure rates by 10% to 15%. Researchers from the United Kingdom, headed by David Cunningham, MD, sought to compare R-CHOP-14 with R-CHOP-21 to ascertain whether the R-CHOP-14 regimen

EXPERT INSIGHT Omotayo Fasan, MD Hematology/Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

LBCL is the most commonly diagnosed lymphoma in the United States, with about 75% of patients presenting with advanced disease (bulky stage II, stage III or IV) at the time of diagnosis. Although advances have been made using immunohistochemistry and gene expression profiling to better characterize disease biology into two major subtypes (germinal center B-cell and activated B-cell), the landscape of the up-front therapy for DLBCL has not seen any major shifts in the past decade.1 The CHOP2 regimen was established as the standard of care after an intergroup randomized Phase III trial begun in the mid-1980s touted a 30% cure rate. Attempts at improving the efficacy of CHOP have included dose intensity, by increasing the total amount of drug delivered; dose density, by increasing the total amount of drug delivered per unit of time; and adding other agents to CHOP. The German High-Grade Lymphoma Study Group trial NHL-B2 (four-arm study) then demonstrated that CHOP-14 was

Saad Z. Usmani, MD Hematology/ Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

the superior regimen when compared with standard CHOP-21, dose-intense CHOEP-14 (with the addition of etoposide) and CHOEP-21.3 The efficacy of CHOP-21 was further improved in the early 2000s with the addition of the anti-CD20 chimeric monoclonal antibody rituximab (R-CHOP-21) in patients over the age of 60 years by the GELA (Groupe d’Etude des Lymphomes de l’Adulte) trial.4-6 The MInT (MabThera International Trial) Group later confirmed the GELA findings in a younger population of patients with DLBCL who had good prognoses.7 The same group also concluded in the RICOVER 60 trial that six cycles of R-CHOP-14 is superior to six cycles of CHOP-14, but no comparison was made with R-CHOP-21.8 The Phase III study in The Lancet by Cunningham et al compared outcomes between R-CHOP-14 and R-CHOP-21. Based on study findings, it is evident that dose density is not superior to dose intensity for the treatment of newly diagnosed DLBCL patients. The authors had hypothesized that

provided superior OS. The study was published in The Lancett (2013;381:18171826, PMID: 23615461). Patients from 119 centers in the United Kingdom were enrolled and randomly assigned to the R-CHOP-14 (n=540) or R-CHOP-21 (n=540) group. Patients were eligible if they were 18 years of age or older with treatmentnaive bulky stage IA to IV DLBCL. The primary outcome was OS; secondary outcomes were progression-free survival (PFS), toxicity, event-free survival (EFS) and response rate. Of enrolled patients, 91% (489 in

R-CHOP-21 and 494 in R-CHOP-14) completed at least six treatment cycles. Response rates for the two treatments were similar, as were toxicities. The twoyear OS was 80.8% in the R-CHOP-21 group and 82.7% in the R-CHOP-14 group; two-year PFS was 74.8% in the R-CHOP-21 group and 75.4% in the R-CHOP-14 group. Subgroup analyses did not find any factor that significantly favored the 14-day treatment cycle. The authors suggested that the addition of rituximab mitigated any benefit that might be gained by a dose-dense regimen.

increasing the dose density of R-CHOP effectively by 150% would improve outcomes in OS and EFS. Although most of the intended doses of chemotherapy were delivered, as judged by the median total dose received and median dose intensity achieved, it appears the benefit of this combination may have reached its maximum potential with the 21-day schedule. Subgroup analyses were unable to show benefit from the dose-dense approach in any subgroup, especially for patients with poor prognostic factors. The study highlights the fact that dose density does not overcome the poor prognosis conferred by presence of c-MYC mutations, either alone or in combination with BCL2 (double hit) on survival outcomes in DLBCL. Moving forward, it would make sense to investigate the addition of novel drugs, such as proteasome inhibitors, B-cell receptor-signaling modulators and epigenetic modifiers (like EZH2 inhibitors), to the established standard of care (i.e., R-CHOP-21) in order to improve outcomes in the poor-prognosis group of DLBCL patients.

lymphoma. N Engl J Med. 1993;328:10021006, PMID: 7680764.

References 1. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947, PMID: 12075054. 2. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s

3. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood d 2004;104:634641, PMID: 15016643. 4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242, PMID: 11807147. 5. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117-4126, PMID: 15867204. 6. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:31213127, PMID: 16754935. 7.

Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-391, PMID: 16648042.

8. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105-116, PMID: 18226581.

Drs. Fasan and Usmani reported no relevant financial disclosures.

MORE COVERAGE ONLINE Each month Clinical Oncology Newss posts web exclusive Reviews & Commentaries online. Experts from Levine Cancer Institute provide clinical perspectives on important recently published studies in solid tumor and hematologic malignancies.

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CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

AFFORDABLE CARE continued from page 1

survive expected challenges. The ACA was signed into law in March 2010 and has survived many threats, including a key challenge to the law’s constitutionality rebuffed by the U.S. Supreme Court in 2012. Due at least in part to its enormity and complexity, the provisions are being rolled out incrementally, with the last piece not planned for launch until January 2020. The ACA’s most wellknown provisions—mandatory health insurance coverage, the creation of health insurance “exchanges” to buy individual policies, the abolition of penalties for preexisting conditions—are set to begin at the end of this year, yet the far more comprehensive and detailed plans to control costs and improve quality—that is, the regulations that will most affect physicians—will be rolled out primarily in 2015. “Language regarding quality runs all through the legislation along with a great deal of emphasis on establishing value in the context of cost efficiency,” Dr. Penley said. Despite the length of the legislation, the ACA is more like a “framework,” said Steven Stranne, MD, JD, a lawyer with the firm Polsinelli, PC, based in Washington, D.C. Dr. Stranne, whose firm represents professional medical organizations, noted that Congress passed the ACA with the expectation that the federal agencies responsible for implementing the law will work to resolve any gaps, conflicts and ambiguities within the law along the way. As a result, the effort to tease out and concentrate on specific issues within the ACA was likened by Dr. Stranne to “trying to take a drink from a fire

The Patient-Centered Outcomes Research Institute serves as one example. The institute was established when the bill was signed with the mandate to evaluate “relative health outcomes, clinical effectiveness and appropriateness” of treatment options. Although it has been compared to the United Kingdom’s National Institute for Health and Clinical Excellence (NICE), it does not have the power to regulate coverage. As a result, its influence at this point is difficult to gauge. Although only bits and pieces of the ACA appear to be directly relevant to the practice of oncology, some changes can be identified, according to Dr. Penley. One example is that cancer survivors cannot be denied coverage based on their pre-existing cancer diagnosis. Another example, which will become law with provisions scheduled for enactment in January 2014, is that patients who participate in a clinical trial cannot be dropped by their insurer. Of course, efforts to expand access to care have implications for oncology, just as they do for other areas of specialized care. Several studies have suggested that individuals without health insurance who develop cancer have poor outcomes at least in part because of diagnosis at a late stage. Although it is reasonable to expect a cancer diagnosis to be made earlier among those with access to health care, the Medicaid data is mixed, according to several experts, including Dr. Stranne. Several studies show that rates of late cancer diagnosis remain high among patients enrolled in Medicaid, and outcomes are only marginally superior to those without any health care coverage.

Concentrating on specific issues within the Affordable Care Act is like “trying to take a drink from a fire hose.” The ACA does include several provisions to control costs, but Dr. Stranne reported that there has been a significant effort to avoid the word “rationing.” The fear of rationing has been a potent weapon for those who have fought the ACA, including the claim that the ACA would include “death panels” designed to refuse costly care to ill patients. The idea of health care rationing appears to be deeply unpopular even though it remains unclear whether universal access to treatment is afford-

Although only bits and pieces of the Affordable Care Act appear to be directly relevant to the practice of oncology, some changes can be identified: Cancer survivors can no longer be denied coverage based on a pre-existing cancer diagnosis, and those who participate in a clinical trial cannot be dropped by their insurer. hose.” In some cases, multiple interrelated issues are tackled simultaneously, with one solution likely affecting the others. Dr. Stranne acknowledged that it is challenging for individuals to determine “what is worth keeping track of.”

This is not necessarily an indictment of the quality of care under Medicaid; rather, multiple factors may be contributing to delayed diagnoses, inadequate adherence to treatment, and poor outcomes in patients with low incomes.

able. Many provisions in the ACA are designed to “bend the cost curve,” but the effectiveness of some of these measures is difficult to predict. ASCO does not currently have a task force specifically designed to monitor

the ACA, according to Dr. Penley, but other task forces that follow legislation relevant to oncology practice are monitoring its developments. For the community oncologist, there are many implications but few certainties. Only a modest change in the political balance is needed to threaten the very survival of the ACA. In a Kaiser Poll of public opinion reported earlier this year, about 40% of respondents favored the ACA, 40% opposed it, and 20% were unsure or had no opinion. If the ACA survives continued repeal attempts in Congress, modifications are expected. Even if there is no effort to change the intent of the law, some technical corrections appear necessary on the basis of the feasibility of key ACA provisions. “Some politicians are reluctant to consider fixes because they just want the whole thing to be killed,” Dr. Stranne said. —Ted Bosworth Dr. Penley had no relevant disclosures. Dr. Stranne reported an advisory role for ASCO and other professional medical societies.

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CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

ASCO 2013

Few Oncologists Monitor Lab Quality Chicago—Despite the fact that inaccurate results can have an important effect on outcome, only a minority of clinical oncologists monitor the quality of the laboratory that supplies their biomarker assay results. Because of the critical importance of laboratory technique, joint guidelines from the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) call for oncologists to routinely verify the quality of the laboratory that performs the analyses for their patients. Importantly, the process of validating laboratory quality for biomarker analysis should be ongoing because techniques vary for each biomarker. Tests can involve immunochemistry, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), microarray analysis and a variety of other techniques. Sensitivity and specificity vary, and repeat validation studies are often appropriate. “With the ever-increasing role of biomarkers in cancer care, oncologists’ awareness of biomarker testing performance and participation in decision making related to biomarkers are becoming critical,” said Christine Weldon, MBA, an adjunct instructor at the

Feinberg School of Medicine at Northwestern University in Chicago. She presented survey data at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) on physicians’ relationships with their laboratories that included responses from 156 oncologists and 115 pathologists at 57 cancer treatment centers.

Less than one-third of oncologists knew how their institution implemented a new biomarker test. The survey posed 12 questions on an institution’s decision-making process regarding lab quality and accreditation. The survey also generated information about who participated in making the decisions. Oncologists lagged significantly behind pathologists in their awareness of issues affecting the quality of their laboratory’s results. For example, 88% of pathologists, but only 46% of oncologists ((P<0.0001), were aware of whether their institutional laboratory

was CAP-certified. Similarly, 70% of pathologists versus 21% of oncologists ( <0.0001) who treat breast cancer (P were aware of whether their institutional laboratory underwent CAP proficiency evaluation for FISH and HER2 testing. Whereas 60% of pathologists reported always being involved in institutional decision making regarding testing on biomarkers, the proportion of oncologists was 22%. “Less than one-third of oncologists knew whether their institution had a formal organizational review and decision-making process for implementing new biomarker tests,” Ms. Weldon said. It might be suggested that most oncologists do not take a direct interest in laboratory technique for validating biomarkers because it is outside the scope of their expertise, but Ms. Weldon said clinicians still need to be aware of what a negative or positive result means. When critical treatment decisions are based on the presence or absence of a specific biomarker, having some appreciation of the likelihood of a false-negative or falsepositive result is reasonable. “With the increasing importance of biomarkers to select among therapies, clinicians should be aware of the

biomarker testing performance,” Ms. Weldon said. Ideally, oncologists should participate in the process of overseeing laboratory decisions about the techniques used to assay biomarkers and how the quality of the techniques is validated. Michael Morris, MD, a medical oncologist who specializes in the treatment of prostate cancer at Memorial Sloan-Kettering Cancer Center in New York City, agreed that this issue is relevant. In a recent article by Dr. Morris that outlined the characteristics of useful biomarkers in advanced prostate cancer ((Semin Oncol 2013:40:375392, PMID: 23806501), he said there is variability in test results that clinicians should recognize. “Medical oncologists, as stakeholders in biomarker development and in its translation into clinical decisions and patient care, should be familiar with the performance characteristics and laboratory standards that underlie these tests,” Dr. Morris said. —Ted Bosworth Ms. Weldon reported receiving research funding from Abbott Molecular and Genentech. Dr. Morris had no relevant disclosures.

Quality Cancer Care: No Longer Just About Survival Washington—The definition of quality is shifting in today’s rapidly changing field of cancer care and physicians need to step it up when explaining treatment options to patients and helping them achieve their goals, a panel told community oncologists at the

AT A GLANCE Quality Three important factors affecting how oncologists’ care is judged: •

The value of therapies, as opposed to solely survival

•

Patients’ increasing knowledge of practice standards and new research

•

Complexity of new treatment options demanding better communication

Association of Community Cancer Centers’ national meeting. Oncology used to have one measure of quality—survival, said moderator Cliff Goodman, PhD, a senior vice president and principal of The Lewin Group, a health care consulting firm. Now survival is only one of many things physicians are asked to measure. There are a few trends forcing a change in how quality is assessed. “Imperatives to spend wisely have really changed our definitions of quality to one of value,” said Randall Oyer, MD, the medical director of the cancer program at Lancaster General Hospital in Pennsylvania. Additionally, today’s patients are more engaged and empowered, with different expectations. Finally, the complexity of care requires the development of new methods of communication. Baby boomers are now 67 years old, the median age of cancer diagnosis, said Linda House, RN, BSN, the executive vice president of external affairs for the Cancer Support Community of Washington, D.C., a nonprofit organization providing support and education to people affected by cancer. Seventy-seven percent of cancers are diagnosed in people aged 55 and

older, she said: “We’re seeing this swoon of very empowered people who either are or have been making health care decisions on the part of their parents and are now doing so for themselves. We have a real opportunity to engage these decision makers in a different way than we have in previous generations.”

Evolving treatments demand better communication from oncologists. John Fox, MD, the associate vice president of medical affairs for Priority Health, a health plan in Michigan, said there are many measurable factors that affect patient outcomes. “There’s a tremendous amount of information on patients’ understanding of their cancer condition that impacts decisions, including end-of-life treatment,” he said. Despite these clear changes, defining quality isn’t easy in a field like oncology, which has many variables. “We’ve been accustomed for a long time to thinking about cancer as an

acute illness, and now it’s chronic disease management, which none of us in oncology training really expected to happen,” Dr. Oyer said. Data management of quality measures is also critical, Dr. Fox said. And physicians and payors working in partnership need to make sure the right things are being rewarded. “If we want discussions around endof-life care and patient goals and priorities to occur, we have to recognize that’s an important determinant of outcome and we should pay for that,” he said. “We have to recognize that it takes time not only to plan a chemo regimen but equally important, you have a conversation that educates a patient on that regimen and whether or not it’s curative.” Ms. House said she worries that physicians aren’t always transparent in the reasons why they make certain decisions within clinical pathways. More than half of the 3,600 patients in her organization’s patient experience registry reported a treatment decision being made during their first oncologist visit, yet only 15% said they received information to support the choice. But pathways, on balance, are positive

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

ASCO 2013

Axilla Radiotherapy Called New Breast Cancer Standard Chicago—In patients with early-stage invasive breast cancer with a positive sentinel node, axillary radiotherapy (AxRT) provides comparable protection against relapse but a lower risk for lymphedema relative to axillary lymph node dissection (ALND), according to results of a randomized trial with a median follow-up of more than six years. Although the trial was ultimately underpowered because of an unexpectedly low rate of relapse in both arms, the results were still characterized as practice-changing. “Both axillary lymph node dissection and axillary radiotherapy provide excellent and comparable locoregional control in breast cancer patients with positive sentinel nodes, but radiotherapy produces less edema and can be considered the standard,” said lead author Emiel J. Rutgers, MD, PhD, a surgical oncologist at Netherlands Cancer Institute in Amsterdam. In the European Organisation for Research and Treatment of Cancer (EORTC) AMAROS (After Mapping of the Axilla: Radiotherapy Or Surgery) trial, which was presented as a latebreaker at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO), patients with invasive early clinically node-negative breast cancer of less than 5 cm in size (T1,2) were randomized before surgery to receive ALND or AxRT if the sentinel node was positive. Of the 4,806 patients randomized, 1,425 were found to have a positive sentinel node and underwent axillary treatment with the assigned treatment.

Of those patients randomized to ALND or AxRT, 90% also received adjuvant systemic treatment, which was initiated after ALND or AxRT. The primary outcome was recurrence at five years, which occurred in 1.19% of those randomized to AxRT, 0.43% of those randomized to ALND, and 0.8% in patients who were sentinel node– negative. This unexpectedly low number prevented a planned noninferiority analysis. There were no significant differences between the two treatment groups for secondary end points of disease-free survival (P ( =0.18) and overall survival ((P=0.34). The differences in the rates of

and help physicians know what choices are reasonable, according to Dr. Oyer. “I don’t think using pathways necessarily takes out the customization for patient preferences, or social/cultural background. In any industry, standardization improves safety and efficiency,” he said. Pathways were never meant to demand 100% compliance, Dr. Fox said. In his organization, individual oncology practices can determine their preferred regimens but if they have a patient who needs to vary from that regimen for good reason, “that’s fine with us.” Panelists agreed that currently the idea of including the patient voice as part of quality conversations is mostly lip service. “We still fall down on what defines quality and value from the patient perspective in oncology,” Ms. House said. Providers should do distress screening as part of a pathway, within so many days of cancer diagnosis

or making a health care decision, she said. The main causes of patient distress are fatigue, sexual dysfunction, sleep issues, weight loss and worry about the future, she said: “These are things we don’t measure in traditional ways.” Payors are willing to pay for services that support the “triple aim” of patient experience, health outcomes and total cost of care, Dr. Fox said, “but we have to find things that balance all three of those.” Ms. House said her organization has tools patients can use to have conversations with their health care teams about how pathway decisions are made, what the incentives are, how much it will cost patients and their insurance carriers, and what incentives favor one plan versus another. Patients know what they want as long as they’re asked, Dr. Fox said. “We don’t have the infrastructure in place to make sure we engage patients in those

The study may establish a new standard for sentinel lymph node–positive early breast cancer; however, it also raises questions about which patients should undergo biopsy, and of those, who should and should not receive treatment.

Axillary dissection in early breast cancer.

lymphedema, another secondary end point, were significant. Consistent with measures taken at one and three years, the rate of lymphedema at five years was more than twice as high in the ALND arm (28% vs. 13.6%; P<0.0001). When restricted to those with lymphedema requiring therapy, such as lymph drainage or compression sleeves, the rates remained twice as high after ALND relative to AxRT (16.8% vs. 6.6%). The additional secondary outcomes of shoulder function and quality of life (QoL) did not differ significantly. Although AxRT was associated with a nonsignificant trend toward greater restriction of shoulder movement at one year, this difference dissipated. Despite a trend favoring AxRT for a subscale within the QoL instrument (swollen arm) and a trend favoring ALND for another subscale (arm movement), the lower rate of lymphedema after ALND did not translate into a significant overall QoL advantage at any time point. At ASCO, Monica Morrow, MD, the chief of the Breast Surgical Service at Memorial Sloan-Kettering Cancer Center in New York City, questioned the value of routinely providing either therapy. She noted that no additional

positive nodes were detected in 67% of patients in the ALND arm. Assuming that the proportion was similar in the AxRT arm, approximately two-thirds of those receiving axilla treatment “got no benefit but only toxicity,” Dr. Morrow observed. In the context of the Z11 trial ((JAMA 2011;305:569-575, PMID: 21304082)— which showed very low recurrence rates in a similar sentinel node–positive breast cancer population when no additional therapy to the axilla was offered—Dr. Morrow suggested some further selection process is needed. Agreeing with this premise, Dr. Rutgers responded that he would not necessarily recommend a sentinel node biopsy in every patient. If a biopsy is taken, he considers whether therapy of the axilla is needed based on characteristics of the primary tumor and the sentinel lymph node biopsy. If treatment is chosen, he would then offer AxRT as the first-line therapy if radiotherapy to the breast or chest wall is indicated. —Ted Bosworth Drs. Rutgers and Morrow had no relevant relationships to disclose.

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature more coverage of practice-changing studies from the 2013 ASCO Annual Meeting How I Manage: Young Adults with Acute Myeloid Leukemia by Elihu Estey, MD

discussions and hear what’s most important to them, like being able to travel or spend time with family,” he said. Evidence suggests that patients get more care than they want, had they known what the options were, he said. Often, patients get treatments because they think that’s what their families

want, and families want patients to get treatments because they think that’s what the patient wants. “The overall measure of quality from my frame of reference is that we’re providing the care that the patients wanted,” he said. —Karen Blum

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights From NEJM, Blood, JCO and ASCO QUESTIONS

True or False. In a Phase II study published in The New England Journal of Medicine (NEJM), the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Pharmacyclics) demonstrated durable singleagent activity in relapsed/ refractory mantle cell lymphoma (MCL).

high-risk group with poor response to intensified chemotherapy.

cisplatin (DHAP) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) before autologous transplantation.

7. True or False. Autologous stem

True or False. T-ALL accounts for 10% of adult ALL cases and is more frequently observed in women than men.

True or False. The CML8 TWIST5. True or False. On 8. ER trial showed that when imatinib was

behalf of the Study Alliance Leukemia (SAL), an increase of more than 1% in the NPM1 mutation Primum non nocere. True or False. level (%NPM1/ABL1) In a Phase Ib-II multi- (First, do no harm.) was most prognostic center study published in for relapse after chemotherapy and an NEJM, ibrutinib was associated with a increase of more than 10% in the NPM1 high frequency of durable remissions mutation level was most prognostic for in all patients with relapsed/refrac- relapse after allogeneic transplantation tory chronic lymphocytic leukemia in patients with acute myeloid leukemia (CLL), except in patients harboring (AML). 17p deletions.

3. True or False. An analysis of

adult patients with T-cell acute lymphoblastic leukemia (T-ALL) treated in the ECOG 2993 trial showed that integrated genomic profiling identifies a

ANSWERS

1. True. The primary end point of this

study was overall response rate, which was 68% (75 patients), with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib (Velcade, Millennium) had no effect on the response rate. Secondary end points were duration of response, progression-free survival (PFS), overall survival (OS) and safety. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 months to not reached); the estimated median PFS was 13.9 months (95% CI, seven months to not reached); and the median OS at 18 months was 58%. At a daily dose of 560 mg, mild to moderate fatigue, nausea and diarrhea were observed with ibrutinib. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516, PMID: 23782157.

2. False. The responses were inde-

pendent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1

cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory DLBCL who do not respond to salvage regimen.

6. True or False. An international

Phase II study showed promising results with ofatumumab (Arzerra, GlaxoSmithKline) in combination with ifosfamide, carboplatin and etoposide (ICE) or dexamethasone, high-dose cytarabine and

deletion. At 26 months, the estimated PFS was 75% and the rate of OS was 83%. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42, PMID: 23782158.

3. True. Bone marrow lymphoblast

samples from 53 T-ALL patients treated in the ECOG 2993 clinical trial were included in this study. An early, immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes were associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved OS. Importantly, these “high risk” adult T-ALL patients may benefit from new, emerging targeted therapies or alternative chemotherapy approaches. Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, et al. Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood. 2013;122:74-82, PMID: 23687089. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute lymphoblastic leukemia in adults: clinical

stopped in chronic myeloid leukemia (CML) patients with undetectable minimal residual disease (UMRD), greater than 75% remained off treatment without recurrence at five years.

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

c. Mutation in TET2 is not observed in patients with CMML. d. Of 18 genes that were tested in a study by Raphael Itzykson, MD, of the Hopital Avicenne in Bobigny, France, ASXL1 was the only gene mutation that remained independently prognostic in hypomethylating agent–naive and –treated patients with CMML.

True or False. A study published 9. All of the following statements 10. on behalf of the Center for International

about chronic myelomonocytic leukemia (CMML) are correct except: a. CMML is the most aggressive chronic myeloid malignancy, with three-year survival on the order of 20%. b. Diagnosis of CMML requires monocytosis greater than 1×109/L, dysplasia in at least one hematopoietic lineage, and less than 20% myeloblasts and promonocytes in the peripheral blood and bone marrow.

Blood and Marrow Transplant Research (CIBMTR) in Journal of Clinical Oncology reported that allogeneic hematopoietic cell transplantation (allo-HCT) as treatment for acute lymphoblastic leukemia (ALL) and AML, myelodysplastic syndrome (MDS), and Hodgkin and non-Hodgkin lymphomas increased by 45%, from 2,520 to 3,668 patients annually from 1994 to 2005, at centers in the United States and Canada.

features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114:51365145, PMID: 19828704.

that measurement of MRD as defined by mutant NPM1 can identify a group of patients with increased risk for disease recurrence and allows detection of relapse with high sensitivity in individual patients with AML.

4. False. T-ALL accounts for 25% of

adult ALL cases. This disease is three times more frequent in men than women, and typically presents with hematopoietic failure resulting from bone marrow infiltration by an immature lymphoblast with a T-cell immunophenotype and high white blood cell counts. In addition, T-ALL patients frequently show mediastinal masses and leukemic infiltration of the central nervous system at diagnosis. Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, et al. Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood. 2013;122:74-82, PMID: 23687089.

5. True.

SAL retrospectively investigated the prognostic impact of NPM1mutated-based minimal residual disease (MRD) detection from bone marrow for development of relapse by using a newly developed real-time polymerase chain reaction—to detect types A, B and D—based on locked nucleic acid– containing primers in 174 patients, of whom 155 were treated within prospective protocols. These results indicate

Shayegi N, Kramer M, Bornhäuser M, et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood. 2013;122:83-92, PMID: 23656730. Falini B, Mecucci C, Tiacci E, et al. GIMEMA Acute Leukemia Working Party. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254-266, PMID: 15659725.

6. True. The investigators claimed

that because of the selection of a higher percentage of poor-prognosis patients, these results are superior to those obtained with R-ICE (rituximab [Rituxan, Biogen Idec/Genentech], ifosfamide, carboplatin and etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin). The data are encouraging and provide the basis for the ongoing randomized study comparing rituximab with ofatumumab in DHAP regimens. In two prospective randomized studies, CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) and the Canadian Study LY12, only half of the patients underwent ASCT due to an insufficient

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • SEPTEMBER 2013 • CLINICALONCOLOGY.COM

response rate to R-ICE, R-DHAP or R-GDP (rituximab, gemcitabine, dexamethasone and platinum). Moreover, it did not seem that one regimen was clearly superior to the other. Thus, there is a pressing need to improve on current salvage regimens in DLBCL. Matasar MJ, Czuczman MS, Rodriguez MA, et al. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013;122:499506, PMID: 23692856. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30:4462-4469, PMID: 23091101.

PhD, and colleagues from Flinders Medical Centre in Adelaide, Australia, are the first to have reproduced the STIM (Stop Imatinib) trial results in a prospective fashion, with 40 patients with UMRD demonstrated with a qRTPCR assay with a sensitivity of 4.5 log. Eligibility criteria were similar to those in STIM, with a minimum of three years of imatinib and a minimum of two years of UMRD. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study. Blood. 2013;122:515-522, PMID: 23704092.

Apperley JF. TWIST it but don’t spin it. Blood. 2013;122:470-471, PMID: 23886774.

9. C. Mutations in TET2, SRSF2 and

ASXL1 occur at high frequency in CMML compared with other myeloid malignancies including MDS. Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428-2436, PMID: 23690417. Padron E, Abdel-Wahab O. Importance of genetics in the clinical management of chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:23742376, PMID: 23690427. Vardiman JW, Thiele J, Arber DA, et al. The

2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114:937-951, PMID: 19357394.

10.

True. Newer approaches are needed to further improve one-year OS following allo-HCT. Advancements to reduce the burden of graft-versus-host disease and disease relapse after alloHCT are key areas of research. Hahn T, McCarthy PL Jr, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31:2437-2449, PMID: 23715573.

Crump M, Kuruvilla J, Couban S, et al. Gemcitabine, dexamethasone, cisplatin (GDP) compared to dexamethasone, cytarabine, cisplatin (DHAP) chemotherapy prior to autologous stem cell transplantation for relapsed and refractory aggressive lymphomas: final results of the Randomized Phase III NCIC CTG Study LY12. Blood d (ASH Annual Meeting Abstracts). 2012;120(21): Abstract 745.

7. False. ASCT is the standard of care for patients with relapsed/refractory DLBCL who respond to salvage regimens.

Gisselbrecht C. Ofatumumab in diffuse large B cell lymphoma? Blood. 2013;122:469-470, PMID: 23886773.

8. False. The TWISTER trial showed

that when imatinib was stopped in CML patients with UMRD, more than 40% remained off treatment without recurrence at two years. David Ross, MBBS,

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers.

DECEMBER 1014, 2013

SAN ANTONIO TEXAS USA

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

All submissions will be considered for publication. Write to managing editor Gabriel Miller at

gmiller@ mcmahonmed.com

▶ FULL PROGRAM DETAILS &

REGISTRATION AND HOUSING NOW OPEN AT WWW.SABCS.ORG

To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN122”

on Br on B Bre Breast re and Ovarian Cancers Integrating Data, Improving Outcomes Release Date: October 22, 2012

Expiration Date: October 22, 2013

Chair

Faculty

Learning Objectives

Course Format

Stefan Glück, MD, PhD, FRCPS

Ruth O’Regan, MD

1 Identify recent major findings in breast and ovarian cancer research. 2 Describe how recent findings may affect screening, diagnosis, and the use of biomarkers in breast and ovarian cancer. 3 Discuss the implications of recent research for clinical practice in treating breast and ovarian cancer.

Interactive Web-based monograph

Sylvester Professor, Department of Medicine Division of Hematology/Oncology Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

Professor and Vice Chair for Education Department of Hematology/Medical Oncology Chief of Hematology/Medical Oncology Georgia Cancer Center for Excellence Grady Memorial Hospital Director, Hematology Oncology Fellowship Emory University Chair, Louisa and Rand Glenn Family Breast Cancer Research Director, Emory Breast Center Atlanta, Georgia

Robert A. Burger, MD Professor of Medicine and Oncology Professor, Surgical Oncology Section of Gynecologic Oncology Director, Women’s Cancer Center Fox Chase Cancer Center Philadelphia, Pennsylvania

Samer I. Schuman, MD, FACS, FACOG Assistant Professor, Obstetrics and Gynecology Associate Director, Gynecologic Oncology Fellowship Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Intended Audiences Oncologists

Statement of Need Cancer is the second leading cause of death. Among women, breast and ovarian cancers are particularly common and have high mortality rates. Clinical needs have been identified in the management of patients with these conditions, including the difficulty of translating the constant flow of newly presented data into daily physician practice; the quantity of information being released each year is considerably greater than the clinician can readily absorb. To close these gaps, education is needed in reviewing the most important research in breast and ovarian cancers and clarifying how the new findings may improve screening, diagnosis, and treatment.

Estimated Time for Completion 90 minutes

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.5 AMA PRA Category 1 Credits™. s Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% is required to complete this activity successfully. CME certiﬁcates will be issued immediately upon successful completion.

This activity is supported by educational grants from Genentech, Inc.