Clinical Oncology News Digital Edition - August 2012 by McMahon Group

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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • August 2012 • Vol. 7, No. 8

INSIDE SOLID TUMORS Learning from mistakes: Colon cancer research ..... 4 Vaccine against breast cancer recurrence . .......... 11 T-DM1: ‘Important new weapon’ for HER+ breast cancer . . . . . . . . . . . . . . . . . . . . .......... 12 Breast cancer genomes sequenced . . . . . . . . . . . . . . ........ 14 Everolimus fails in gastric cancer setting .... 15 Genome sequencing for cancer risk has ‘a long way to go’ . . . . . . . . . . . . . . . ........ 21

Bendamustine Impressive For Lymphomas

Turning T Cells Back On To Target Tumors

Bendamustine-rituximab combo likely to become standard

Blocking the PD-1/PD-1L interaction produces responses across a number of solid tumors

Chicago—The combination of bendamustine and rituximab (B-R) is superior to CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone) plus rituximab (CHOP-R) for the first-line treatment of indolent lymphomas, according to results of a Phase III trial. Overall survival data are not yet mature, but the B-R regimen is likely to become a standard of care if a survival advantage emerges. see LYMPHOMA, page 7

Is maintenance immunotherapy beneficial? ............................... 24 Three main genomic subtypes of lung adenocarcinoma uncovered . . . . . . . . . . . . . . . ........ 26 HEMATOLOGIC DISEASE Redefining ‘refractory disease’ in CLL . . . . . . ........... 8 FDA approves carfilzomib for refractory multiple myeloma . ......... 14 CURRENT PRACTICE The conflict between ‘fighting the cancer’ and end-of-life care ......... 3 Clinical Conundrums: Focus on ASCO . . . . . ......... 29

Adjuvant Therapy for Breast Cancer Dose-dense AC plus paclitaxel versus TAC: Similar efficacy, different toxicities

see PD-1, 1 page 6

Chicago—The first Phase III trial to pit dose-dense AC (doxorubicin and cyclophosphamide) plus paclitaxel against TAC (docetaxel, doxorubicin and cyclophosphamide) as adjuvant therapy for breast cancer has shown that the two regimens have similar outcomes. The study details the different toxicity profiles and should aid clinicians in their therapy selection. “The toxicity profiles differed with more neuropathy and more EPO [erythropoietin] use in the dose-dense arms and more diarrhea and febrile see ADJUVANT, T page 10

Chicago—Antibodies that target T cells are emerging as one of the most exciting strategies in cancer treatment. The viability of this approach has been demonstrated with ipilimumab (Yervoy, Bristol-Myers Squibb), which targets cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4), but now studies of programmed death (antiPD-1) and programmed death ligand 1 (anti-PD-L1) T cell attacking therapies also are showing a cancer cell. success across cancer types. Data presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) provided compelling proof of concept for therapies that boost anti-tumor T cell responses. The advances in this area are made possible by an increasingly detailed understanding of the molecular steps that regulate T cell activity. Although it has long been

Vogl, NY to FDA: Make sure the abiraterone label allows us to give it to the men who most need it! • Abiraterone is a wonderful drug for castrate-resistant prostate cancer. Steven Vogl, MD • The “label” now restricts use to men with prior exposure to docetaxel chemotherapy. • The strongly positive COU-AA-302 study presented at ASCO 2012 restricted entry to men with no or minimal symptoms. • Unless someone speaks up, insurance companies and prescription plans may be able to use the revised label to refuse payment for abiraterone for men with symptoms, but without prior docetaxel treatment. t has become clear over the past decade that progressive prostate cancer in the absence of testicular androgen is still sensitive to hormone treatment. Like breast

see VOGL, NY, Y page 27

EXPERT COMMENTARIES FROM CLEVELAND CLINIC

Roger Macklis, MD

Adjuvant radiotherapy improves lymph node control in melanoma . . . . . . . . . . ..... 9

Bassam Estfan, MD

Chromosomal instability phenotype predicts colorectal cancer risk ......................... 17

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer 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

Hematologic Malignancies

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

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Michigan Ann Arbor, MI

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

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

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

Charles F. von Gunten, MD

Sara S. Kim, PharmD

University of California, San Diego, CA

The Mount Sinai Medical Center New York, NY

Infection Control

Bioethics

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

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

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD Mayo Clinic Rochester, MN

Paul J. Ford, PhD Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Pharmacy Cindy O’Bryant, PharmD Richard Stone, MD

University of Colorado Cancer Center Denver, CO

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

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD

Gastrointestinal Cancer and Sarcoma

Mercy Medical Center St. Louis, MO

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

Mission Statement

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

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.

Genitourinary y Cancer Ronald M. Bukowski, MD

Steven Vogl, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Medical Oncologist New York, NY

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

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

Steven D. Passik, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

Vanderbilt University Medical Center Nashville, TN

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

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

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

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. 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 • AUGUST 2012

The Paradox of Increased Efficacy and End-of-Life Care This commentary focuses on the complex and often emotionally charged conflict between a patient’s desire to “fight the cancer” and his or her unquestionably valid need to focus on end-of-life issues at some point in time. The necessity for honest, open and thorough discussions between patients and their health care team—which usually includes the oncologist, primary care physicians and nurses—about goals, symptom control, comfort measures and personal non–health-related decision making cannot be overstated. However, it is critical to acknowledge that this is a dynamic process that may be strongly affected by a number of clinical features unique to an individual patient, including the extent of disease, the severity of cancer-related symptoms and therapy-related toxicity and the presence of comorbid conditions. Additionally, discussions and decisions will be influenced by available therapeutic options. For example, the presumed urgency and specific timing of an endof-life discussion with a patient who has just been diagnosed with stage IV malignant melanoma with a BRAF mutation would likely be quite different today compared with two years ago. A similar statement could be made for a patient with a metastatic renal cell cancer presenting in 2011 versus in 2001. In fact, going back a little further in the

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McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

history of oncology, we can compare the discussion Lance Armstrong likely had with his oncologists regarding his outcome with cytotoxic chemotherapy to a similar discussion that Brian Piccolo— the Chicago Bears football player who died from metastatic germ cell cancer in 1970 and whose story is told in the movie Brian’s Song—had g with his physicians three decades earlier.

population with particularly good baseline performance status.1,2 Thus, it should not be surprising that a recent report on the timeliness and use of hospice care among Medicare patients has noted what might otherwise have been considered a paradoxical finding.3 The research specifically covered two time periods, 1992 to 1994 and 2004 to 2006. In the more recent interval, the overall percentage of Medicare patients with pancreatic cancer who used hospice services substantially increased (67.2% vs. 36.2%; P<0.0001), however, there also was an observed increase in

The necessity for an honest, open and thorough discussion between patients and their health care team about treatment goals, symptom control, comfort measures and personal non–health-related decision making cannot be overstated. As therapy for a given malignancy improves, even if only modestly in the setting of a poorly responsive metastatic cancer, it is natural and not unreasonable that patients might wish to try a new approach to prolong survival, improve existing symptoms or delay their time to progression. Consider, for a moment, metastatic pancreatic cancer. Most objective observers would agree that the overall effect of systemic antineoplastic treatment has been quite limited in this very difficult setting. Yet, a number of randomized trials have revealed a statistically significant favorable effect with several therapeutic strategies, including a striking improvement in overall survival with intensive multiagent chemotherapy in a very carefully selected patient

the proportion of patients who received chemotherapy during the last month of their life (16.4% vs. 8.1%; P<0.0001). And with this increase in chemotherapy during the final month of life, the investigators noted a corresponding increase in intensive care unit services (19.6% vs. 15.5%; P<0.0001).3 Not surprisingly, the authors of this particular report consider the delay in using hospice services to be an indicator of less than optimal care. And unfortunately, in some circumstances this interpretation may be accurate. However, in my opinion, it can be argued that these data actually reflect decisions made by patients following discussions with their oncologists about the availability of new treatment options and the likely effect further

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SALES STAFF

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Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

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EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

treatment would have on their condition. And if further treatment is ineffective, or benefit is seen with subsequent tumor progression, then hospice care will be requested. The substantially greater proportion of patients who ultimately used hospice services in the more recent time period supports this basic hypothesis. Finally, it is appropriate to ask the following: Assuming that an open, honest and thorough discussion between a patient and his or her oncologist about the risks and benefits associated with various treatment options—including specific issues like comorbidities and baseline performance status—actually occurred, is there anything wrong with this decision?

References 1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreas cancer. N Engl J Med. 2011;364:1817-1825, PMID: 21561347. 2. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25:1960-1966, PMID: 17452677. 3. Sheffield KM, Boyd CA, Benarrouch-Gampel J, et al. End-of-life care in Medicare beneficiaries dying with pancreatic cancer. Cancer. 2011;117:5003-5012, PMID: 21495020.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

Colon Cancer Research: Time To Learn From Mistakes Experts assess history of failed colon cancer drug development San Francisco—Researchers have struggled to develop new therapies for colon cancer in recent years and, according to several experts who spoke at the 2012 Gastrointestinal Cancers Symposium, it is time to learn from past mistakes. From a failure to completely understand commonly used, previously approved drugs to poor trial design and an oversimplified view of disease pathways, leading investigators from several countries said it’s time to rethink how colon cancer research is conducted.

Researchers were mistaken to believe that what works in the advanced setting will work in the adjuvant setting.

Proof of Action “No tissue, no marker, no trial,” said James Doroshow, MD, the director of Cancer Treatment and Diagnosis at the National Cancer Institute (NCI). He believes a drug should not move beyond early clinical development unless researchers can demonstrate that it hits its target. Researchers have excelled at developing agents with good pharmacokinetic properties, but these drugs often ultimately fail to help patients. “At best we get about one out of 10 agents that move [from Phase I/II trials] forward into Phase III, and many fewer lead to FDA approval,” said Dr. Doroshow. According to Dr. Doroshow, researchers need to focus on agents with an established mechanism of action and finding biomarkers to select patients for therapy. Drugs like cisplatin “went forward and got FDA approval without having any biomarkers to help you understand which patients to treat,” said Dr. Doroshow. “Until very recently, there had been minimal to no evidence that in humans, irinotecan inhibits topoisomerase I in solid tumors.” A unique class of noncamptothecins called indenoisoquinolines is one example of a rigorously tested new agent. These investigational drugs are similar to irinotecan and topotecan in that they inhibit topoisomerase I, but are different in structure and pharmacologic properties. In late 2009, NCI researchers developed an assay to determine topoisomerase I inhibition as well as measure downstream effects, specifically DNA double-strand breaks. In a Phase I trial, these assays demonstrated that indenoisoquinolines inhibited topoisomerase I in five of six patients. “This is among the first evidence ever that a topoisomerase I inhibitor actually inhibits topoisomerase I in tumors,” said Dr. Doroshow. Evaluating drugs in this manner will allow new agents to be tested with a

An adenoma, a precursor lesion to colorectal cancer.

‘We draw these simple-minded pathways but we know that the pathways are much more complex.’ —Channing Der, PhD relatively limited investment in patients. “There is no guarantee that if we hit the target, the drug will be effective,” said Dr. Doroshow. “But if we don’t hit the target, it is unlikely that it will be useful.”

Faulty Dogma According to Alberto Sobrero, MD, head of the Medical Oncology Unit at Ospedale San Martino in Genova, Italy, researchers have made several mistakes in recent adjuvant colorectal cancer clinical trials involving cetuximab (Erbitux, Bristol-Myers Squibb) and bevacizumab (Avastin, Genentech). In the adjuvant setting for colon cancer, two trials with bevacizumab (NSABP [National Surgical Adjuvant Breast and Bowel Project] C-08 and AVANT Adjuvant FOLFOX4 Versus Bevacizumab and FOLFOX4 Versus Bevacizumab, Oxaliplatin, and Capecitabine in Patients With High-Risk Stage II or Stage III Colon Cancer]) and one trial with cetuximab (NO147) showed that these agents did not improve disease-free survival (DFS) or overall survival (OS). According to Dr. Sobrero, researchers were mistaken to believe that what works in the advanced setting will work in the adjuvant setting, as well as to believe that the greater the risk, the greater the benefit. Although some

therapies that have shown benefit in the advanced setting have gone on to demonstrate benefit in the adjuvant setting, even before the cetuximab and bevacizumab studies, trials with FOLFIRI (5-fluorouracil [5-FU], folinic acid and irinotecan) and IFL (5-FU, leucovorin and irinotecan) showed that this dogma didn’t always hold true. “Micrometastases are not the same as macrometastases,” said Dr. Sobrero. “We need specific assays for the adjuvant setting.” An analysis of data from the MOSAIC (Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer) trial and the EORTC (European Organization for Research and Treatment of Cancer) 40983 trial demonstrates that the dogma of “the greater the risk, the greater the benefit” is on shaky ground. In MOSAIC, patients with stage II and III colon cancer received 5-FU and leucovorin (LV5FU2) or FOLFOX4 (LV5FU2 plus oxaliplatin [Eloxatin, Sanofi-aventis]). The absolute fouryear DFS gain for FOLFOX4 increased with the severity of disease: 3.8% for stage II, 7% for stage II N1 and 12% for stage III N2. Given these statistics, one might expect a 15% to 18% absolute gain

in stage IV disease, said Dr. Sobrero, but in the EORTC 40983 study of FOLFOX4 plus surgery versus surgery alone, there was only an 8% gain at three years with the addition of FOLFOX4 (Lancet 2008;371;9617:1007-1016, PMID: 18358928). According to Dr. Sobrero, the bottom line is that researchers should not expect therapies that work in one disease to work in another type of disease that may be quite different. He pointed out several other limitations of the cetuximab and bevacizumab trials. The N0147 trial was conducted with a FOLFOX backbone and studies have shown that other regimens are better companion therapies for cetuximab. In the bevacizumab trials, perhaps the rationale for treating a micrometastatic condition with an anti-angiogenic agent was faulty or perhaps the therapy duration was a problem. The trials showed a benefit for patients while they were on bevacizumab, but this benefit disappeared once patients stopped treatment.

Collaboration Sabine Tejpar, MD, PhD, an associate professor of gastroenterology in the Digestive Oncology Unit at UZ Leuven in Belgium, believes colon cancer research can move forward if researchers collaborate to build large molecularly annotated databases. This is an effort of the pan-European clinical trials. “I encourage everybody to use their paraffin data sets to collect and analyze [genomics], but as you will see in the end, sharing is very important because you run out of power very, very quickly,” said Dr. Tejpar. She pointed out that researchers shouldn’t become “too comfortable” with using a single marker. For example, microsatellite instability (MSI) is an independent prognostic marker in stage II and III colorectal cancer but, said Dr. Tejpar, “are we really sure there are no subgroups in MSI-high that do bad?” In a study presented at the American Society of Clinical Oncology annual meeting in 2010, Delorenzi et al showed that T4 patients with high MSI had a worse prognosis (abstract 3597).

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

Running stratified trials with only one marker such as KRAS or BRAF is not the best route, Dr. Tejpar said. The goal should be to place patients into very tightly defined groups based on rigorous genomic analysis. Dr. Tejpar acknowledged that developing a matrix of biomarkers would most likely “yield a few hits and probably a lot of headaches in trial design.”

Complex Pathways Broadly speaking, colorectal cancer is a more complex disease than researchers admit, said Channing Der, PhD, a professor of pharmacology at the University of North Carolina and a member of the Lineberger Comprehensive Cancer Center, both in Chapel Hill.

‘There is no guarantee that if we hit the target, the drug will be effective.’ —James Doroshow, MD “We cannot simply look at the 40% of colorectal cancers with KRAS mutations as a homogenous disease,” said Dr. Der. “It is quite genetically heterogenous, biologically and chemically.” And although KRAS is a good marker to exclude patients for EGFR receptor monoclonal antibody therapy, clinicians still don’t have a good therapeutic option to treat the 40% of patients who are KRAS mutant. “Ideally, what we would like to do is target RAS directly and unfortunately at this point, we have not succeeded in those efforts,” said Dr. Der. The current focus is on inhibiting downstream signaling of KRAS, the mitogen-activated protein (MAP) kinase pathway that involves three pivotal kinases: RAF, MEK and ERK. “The current thinking is if we can block this pathway, we should be able to successfully cripple RAS in cancer,” said Dr. Der. Unfortunately, researchers are finding that it is not so simple. “Experimental evidence

would suggest that there are at least five total effector pathways—and likely more—that RAS depends on to mediate its oncogenic action,” said Dr. Der. Experiments in his laboratory have shown that the MEK inhibitor selumetinib (AstraZeneca) was ineffective on KRAS-mutant cancer cell lines, despite blocking activation of this pathway. “We draw these simple-minded pathways but we know that the pathways are much more complex,” said Dr. Der. “There are ways in which the pathways can bypass the block at RAF or MEK

and reactivate the ERK pathway.” The other key issue is that the MAP kinase pathway is not the only one that RAS depends on for initiating and maintaining its oncogenic consequences. Researchers need to consider blocking more than one pathway to effectively ablate oncogenic RAS-driven growth. “A cocktail of inhibitors that target these pathways at multiple points is going to be needed, and the cocktail will have to be different depending on the different RAS isoform, the different mutation and the cancer type that we are doing,” said Dr. Der. “It is going

to be much more complicated than we had envisioned.” —Kate O’Rourke Dr. Doroshow had no relevant conflicts of interest. Dr. Sobrero disclosed a consultant or advisory role with Amgen, Bayer, Genomic Health, Merck, Pfizer, Roche and Sanofi, as well as honoraria from Merck, Pfizer, Roche and Sanofi. Dr. Tejpar disclosed a consultant or advisory role with Biothera and Onyx, honoraria from Merck Serono, and research funding from Merck Serono and Pfizer. Dr. Der disclosed honoraria from Bristol-Myers Squibb, Sanofi and AstraZeneca and research funding from GlaxoSmithKline.

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Hematology Course Director Syed A. Abutalib, MD Assistant Director Hematology and BMT Service Cancer Treatment Centers of America Zion, IL

Oncology Course Director Maurie Markman, MD

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

PD-1 continued from page 1

clear that at least some cancers progress because T cells are not performing their anti-tumor function, it is now understood that tumor cells can mediate T cell deactivation. Immune checkpoints, such as CTLA-4 and PD-1, which deliver critical signals to turn off activated T cells in order to protect normal tissue, are co-opted by tumor cells to protect themselves from immune system attack. In the case of PD-1, it is expression of the PD-1 ligand 1 (PD-L1) on the tumor cell surface that triggers the PD-1 pathway of T cell deactivation. “Basically, T cells expressing PD-1 that encounter tumor cells expressing PD-L1 are turned off. Anti-PD-1 antibody blocks this biochemical shield created by the tumors,” said Suzanne Topalian, MD, a professor of surgery and oncology at Johns Hopkins University in Baltimore. Dr. Topalian presented results of a clinical study with BMS-936558, a human monoclonal antibody that blocks PD-1. Another study with an antibody that blocks PD-L1, called BMS-936559, was presented by Scott Tykodi, MD, PhD, an assistant professor of medical oncology at the Fred Hutchinson Cancer Research Center in Seattle. Results of both studies subsequently have been published in The New England Journal of Medicine (2012;366:2443-2454, PMID: 22658127, and 2012;366:24552465, PMID: 22658128). CTLA-4 and PD-1 are members of the same extended family of cell surface immune checkpoints, but they have different properties. Perhaps most significantly, the CTLA-4 checkpoint is important systemically in T cell activation, whereas PD-1 appears to be a more important immune checkpoint for activated T cells that have reached peripheral tissues. Small clinical studies with inhibitors of the PD-1 pathway have been presented previously, but the two studies presented consecutively at ASCO with BMS-936558 and BMS936559 provided longer-term follow-up in larger numbers of patients. In the Phase I study of BMS-936558 (anti-PD-1) presented by Dr. Topalian, 296 patients were enrolled, of whom some have been followed for two or more years. In the study of BMS-936559 (antiPD-L1), presented by Dr. Tykodi, which is ongoing, safety data were available on 207 patients and activity data on 160 patients. Both studies were dose-ranging with infusions every two weeks. The five histologies represented among the patients in the anti-PD-1 study were melanoma, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), colorectal cancer (CRC) and castration-resistant prostate cancer

‘One of the most remarkable findings was the complementary activity of these 2 drugs targeting distinct molecules in the same checkpoint pathway, thereby validating the PD-1/PD-L1 pathway as a target for cancer therapy.’ —Suzanne Topalian, MD (CRPC). Together, NSCLC and melanoma comprised about two-thirds of the total cancers, with CRC and CRPC each constituting less than 10% of the total. Activity was seen in three of the five histologies with objective responses observed in 28% of those with melanoma, 18% of those with NSCLC and 27% of those with RCC. Most intriguing was the duration of response in patients with advanced disease. “Of 31 responders for whom we have more than one year of follow-up data, 20 had disease control lasting at least a year and there have been some responses lasting beyond two years,” Dr. Topalian said. She considered the substantial objective response rate in NSCLC particularly surprising because of the low response rates previously seen with immunotherapies for this cancer. The most common grade 3 or higher adverse events (AEs) were fatigue in 2%, diarrhea in 1%, elevated hepatic enzymes in 1% and pneumonitis in 1%. In all, 14% of patients had at least one

grade 3 or higher AE and 5% discontinued therapy due to an AE. Of those side effects possibly related to modification of immune function, pneumonitis was the most significant, resulting in three deaths. However, low-grade pneumonitis was reversible by stopping therapy or introducing steroids, and Dr. Topalian reported that “we are optimistic that the impact of this toxicity can be reduced” with better risk assessment. Similar results for the anti-PD-L1 agent, BMS-936559, were reported by Dr. Tykodi. The objective response rates in this study, known as CA 201-100, were 10% for NSCLC, 12% for RCC, 17% for melanoma and 6% for ovarian cancer. Overall, these rates were somewhat lower than those in the anti-PD-1 study, but there was a similarly encouraging duration of response. “The objective response rates do not really capture the activity that we observed,” said Dr. Tykodi, who suggested that progression-free survival (PFS) rates at six months were more impressive. For example, 31% of NSCLC patients and

Although it has long been clear that at least some cancers progress because T cells are not performing their anti-tumor function, it is now understood that tumor cells can mediate T cell deactivation. Immune checkpoints, such as CTLA-4 and PD-1, are co-opted by tumor cells to protect themselves from immune system attack.

AT A GLANCE How It Works: Anti-PD-1 Antibody Certain tumor cells can deactivate T cells that normally would seek out and destroy the tumor cells When they’re active, T cells express PD-1—programmed cell death protein 1 Some tumor cells express PD-1’s partner molecule, PD ligand 1, which turns off T cell function Tumor cells expressing PD-L1 have a protective shield against immune attack Anti-PD-1 is a blocking antibody against PD-1 that interrupts this interaction

T-cell.

53% of RCC patients remained progression-free after six months. As in the antiPD-1 study, the overall tolerability of the agent was good, with only 9% of patients having a grade 3 or higher AE. Neither study, which included doses up to 10 mg/ kg, reached the maximum tolerated dose of the study agent. “One of the most remarkable findings was the complementary activity of these 2 drugs targeting distinct molecules in the same checkpoint pathway, thereby validating the PD-1/PD-L1 pathway as a target for cancer therapy,” Dr. Topalian said. In patients with advanced disease, anti-PD-1 and anti-PD-L1 antibodies provide an “exciting degree of clinical activity,” said James Allison, PhD, the director of the Ludwig Center for Cancer Immunotherapy at Memorial SloanKettering Cancer Center, in New York City. In discussing these data at ASCO, Dr. Allison agreed that this approach appears active in a variety of histologies and is well tolerated. He cautioned that if PD-L1 is required for activity, patients who have tumors or tumor types that do not express the protein may not respond. However, Dr. Allison indicated that PD-1, like CTLA-4, appears to be a viable target. Moreover, he said that the benefits might be extended with biomarkers that identify the best candidates for this therapy. Ultimately, combination strategies that target two immune checkpoints, or coadministration of vaccines that further enhance the effect, may provide the most effective treatment. Meanwhile, controlled single-agent trials are planned to bring forward agents that inhibit the PD-1/PD-L1 pathway. —Ted Bosworth Dr. Topalian has been a consultant or advisor to Amplimmune and Bristol-Myers Squibb and has received research funding from Bristol-Myers Squibb. Dr. Tykodi has received research funding from Bristol-Myers Squibb.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2012

LYMPHOMA continued from page 1

“Bendamustine-rituximab is not only less toxic but more effective than CHOPR,” said Mathias J. Rummel, MD, the head of hematology at Justus-Liebig University-Hospital in Giessen, Germany, and the study’s lead author. Dr. Rummel said the relative benefit was similar for most histologic subtypes, including follicular lymphoma and mantle cell lymphoma (MCL). Among the indolent lymphomas analyzed, the exception was marginal zone lymphoma, for which the relative benefit did not reach statistical significance. In this study, presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3), 549 previously untreated patients with indolent lymphomas and MCL were randomized to a standard CHOP-R regimen (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1 and prednisone 100 mg on days 1-5 with rituximab 375 mg/m2 on day 1) or to bendamustine (Treanda, Cephalon) in a dose of 90 mg/ m2 on days 1 and 2 with the same dose and schedule of rituximab. The B-R regimen was given on a 28-day schedule and CHOP-R on a 21-day schedule, both for a maximum of six cycles. No postinduction maintenance therapy was administered. The study was designed as a noninferiority trial, but the activity favored B-R. After a median of 45 months of follow-up, the median progression-free survival was 69.5 months with B-R and 31.2 months with CHOP-R, generating a 42% reduction in the hazard ratio (HR) of an adverse outcome (HR, 0.58, 95% confidence interval, 0.44–0.74; P<0.00001). The overall survival rates were not significantly different, but a separation in the survival curves after three years of follow-up raises

the potential for a survival advantage over a longer time period. The results also suggested that B-R is less toxic. Many of the most bothersome side effects, such as paresthesias (18 vs. 73 patients; P<0.0001), stomatitis (16 vs. 47 patients; P<0.0001) and infectious complications overall (96 vs. 127 patients; P=0.0025) were significantly and substantially less common on B-R. Although erythema (42 vs. 23 patients; P=0.0122) and cutaneous allergic reactions (40 vs. 15 patients; P=0.0003) were more common with bendamustine, alopecia was rare on the regimen. Rates of second

malignancies were equivalent with one case each—myelodysplastic syndrome in the B-R group and acute myeloid leukemia in the CHOP-R group. At ASCO, Michael Williams, MD, the chief of hematologic malignancies at the University of Virginia Cancer Center in Charlottesville, was reluctant to characterize B-R as the new standard of care in the absence of a survival benefit, but he said, “These results certainly support front-line use.” The activity of bendamustine is encouraging, he said, and ongoing studies, such as one evaluating maintenance rituximab after B-R, may generate

an evolution in the management for indolent lymphoma and MCL patients not eligible for aggressive regimens or stem cell transplantations. —Ted Bosworth Dr. Rummel has received honoraria and research funding from Mundipharma and Roche. Dr. Williams has been a consultant for Celgene, Cephalon, Genentech, TG Therapeutics and has received honoraria from Celgene and Onyx and research funding from Calistoga Pharmaceuticals, Celgene, Cephalon, Genentech, Gilead Sciences, Millennium, Novartis, Onyx and Pharmacyclics.

ONCOLOGYFellow S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

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AT A GLANCE Bendamustine Combined with rituximab as first-line treatment for indolent lymphomas, the drug more than doubled median progression-free survival Overall survival rates were not different in the study; however, a separation in survival at three years suggests potential long-term benefits The drug is currently approved for chronic lymphocytic leukemia and as second-line therapy for indolent B-cell non-Hodgkin’s lymphoma

To obtain educational information for oncology fellows, please visit us online: www.oncologyfellowadvisor.com

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2012

Novel Risk Stratification Scheme Proposed for CLL From Blood

group of chronic lymphocytic leukemia (CLL) experts has proposed redefining the patient risk categories that help define the therapeutic choices in refractory disease. In an article in Blood d (2012;119:41014107, PMID: 22394601), the experts argue that the precise definition of refractory CLL has increased in importance as the variety of treatment options has grown. Diagnostic and therapeutic responses to CLL had been standardized, “motivated by the realization that heterogeneous response … would impede the comparability of treatment results and hold up improvement in clinical care.” The latest published guidelines defined refractory CLL as either no partial

remission (PR) or complete remission (CR), or progression of disease within six months of anti-leukemic therapy. Being refractory to monotherapy with chlorambucil or fludarabine is not the same thing as being refractory following more recent chemoimmunotherapy regimens, such as that of fludarabine, cyclophosphamide and rituximab (FCR). With these firstline treatments, the overall response rate has advanced from 31% to 72% with chlorambucil (CR rate, from 0% to 7%), 59% to 83% with fludarabine (CR rate, 7% to 15%), and 90% to 95% with FCR (CR rate, 44% to 50%). Additionally, the rate of patients who do not respond to first-line treatments has decreased to about 10%, which has lowered accrual of patients for refractory trials and affects salvage strategies.

EXPERT INSIGHT Brian T. Hill, MD, PhD Associate Staff Physician, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, and Assistant Professor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

lthough there are a number of targeted treatments currently being developed for treatment of CLL, including kinase inhibitors such as ibrutinib and CAL-101, these orally available and minimally toxic agents currently are available only through clinical trials. Until these novel drugs are available on a widespread basis, it is important to recognize that the vast majority (>90%) of fit CLL patients requiring treatment will obtain CR or PR with multidrug chemotherapy containing the purine

analog fludarabine in combination with cyclophosphamide and the monoclonal antibody rituximab (FCR).1 The article in Blood, entitled “Risk Categories and Refractory CLL in the Era of Chemoimmunotherapy,” authored by many international CLL experts, offers a timely review of how to risk-stratify these patients. The authors point out that the previous definition of refractory CLL was conceived during an era of much less effective induction treatment regimens.

The authors also noted that patients may have suboptimal or short-lived responses to therapy while still not being categorized as refractory, according to the traditional definition. These patients also have a poor prognosis. The authors propose new risk stratifications for refractory CLL based largely on the predicted effectiveness of FCR or FCR-like treatment. The “highest-risk” category includes “purine analog-refractory” patients with TP53 loss or mutation who have demonstrated a very short (<24 months) response to FCR therapy, with no CR. In these patients, it is unlikely that FCR treatment will generate an acceptable response or prolong survival. Treatment for these patients should rely on drugs with activity in TP53-deleted or mutant cells, investigational drugs from clinical trials or allogeneic stem cell

transplantation (SCT). The next group comprises the “highrisk” patient who, although not qualifying for the highest-risk division, still is likely to relapse early following standard treatment. These patients include those with high β2-microglobulin, unmutated immunoglobulin heavy chain variable region or 11q deletion. These patients, although expected to have a short progression-free survival, would benefit from the addition of rituximab to FC, and also might be appropriate for clinical trials with investigational agents that are combined with FCR (for induction or maintenance). The last risk stratification, “low-risk,” comprises those patients with none of the qualifying criteria in the other groups and no prior treatment. This group would benefit from FCR (or similar) chemotherapy.

Instead of using historical definitions of refractory disease, the authors propose a three-group risk stratification for CLL patients, including highest-risk, highrisk and low-risk. The recommended treatment for the highest-risk group includes enrollment in a clinical trial or treatment with alemtuzumab (with glucocorticoid) in general practice followed by referral for allogeneic SCT or maintenance therapy as part of a clinical trial. It is recommended that highrisk patients be treated with FCR, possibly with an investigational agent as part of a clinical trial, either during induction or subsequent maintenance therapy. Low-risk patients, by contrast, can be treated with FCR or possibly with de-escalation. Commonly used alternatives to FCR include fludarabine and rituximab alone or alternatively bendamustine + rituximab (BR). These lessintensive therapies are appealing particularly for elderly patients or those with comorbidities or “soft” indications

for initiation of therapy, such as fatigue or borderline cytopenias. In short, until newer agents are available, FCR still must be considered the standard of care for most fit CLL patients, particularly those classified with high-risk disease. The Blood d article provides a useful framework to riskstratify CLL, as many low-risk patients may be overly treated with FCR, whereas others (i.e., highest-risk) need alternative therapies.

Reference 1. Hallek M, et al. International Group of Investigators, German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174, PMID: 20888994.

Dr. Hill reports that he is a member of the speaker’s bureau for Teva Pharmaceuticals.

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2012

Adjuvant Radiotherapy Useful in Metastatic Melanoma From The Lancet Oncology

djuvant radiotherapy was found to improve lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma, but who were at high risk for relapse. This multinational, randomized controlled trial, led by Bryan Burmeister, MD, of Brisbane, Australia, and published in The Lancet Oncology (2012;13:589-597, PMID: 22575589),

sought to answer the controversial question of whether radiotherapy in these patients can improve lymphnode field control. A series of older retrospective, nonrandomized studies had unsuccessfully addressed doubts about this approach. The study included 217 eligible patients treated at multiple sites. The patients were randomly assigned to receive either adjuvant radiotherapy of 48 Gy in 20 fractions (n=109) or observation alone. All patients had a high risk for lymph-node field relapse

EXPERT INSIGHT Roger Macklis, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

The editors of The Lancet Oncology y requested that I provide an editorial1 discussing what one should take away of real importance from the trial by Burmeister et al.2 My editorial, paraphrased below, emphasizes that we now finally have good evidence of a real role for radiotherapy to play. If we can understand how to use radiotherapy to control nodal spread and then add that locoregional control measure to improvements in metastatic control using some of the newer biologically based agents, then we will finally see truly significant clinical progress against this disease.

or decades, we have been unable to determine the role of adjuvant radiotherapy in the definitive management of high-risk malignant melanoma.3 However, the recent study by Burmeister and colleagues is a good start. They present an intergroup, randomized trial that finds that adjuvant nodal basin radiotherapy, when used carefully and systematically, significantly improved regional lymphatic control for high-risk patients compared with no further treatment after lymphadenectomy. Overall survival did not differ significantly, unfortunately, but the study did show a significant

improvement in risk for local relapse within the affected nodal basins. Toxic effects were generally mild and manageable. Several new, promising targeted pharmaceuticals and immunomodulating compounds with clear activity against melanoma have been introduced in just the past few years.4 Many of these agents target mutations in the BRAF, RAF, MEK and KIT pathways, such as the inhibitor vemurafenib, which targets the BRAF mutation. Success in early clinical trials resulted in rapid FDA approval for metastatic melanoma.5 It is possible that local-field

based on the number of nodes affected, extranodal spread and maximum size of involved nodes. The primary end point was initial lymph-node field relapse. Median follow-up was 40 months. The study found a significant reduction in risk for lymph-node field relapse among those receiving adjuvant radiotherapy, with 20 relapses in the radiotherapy group compared with 34 in the observation group (hazard ratio [HR], 0.56; P=0.041). Relapse-free survival was

not significantly changed (70 events in the radiotherapy group, 73 in the observation group; HR, 0.91; P=0.56), nor was overall survival (59 vs. 47 deaths; HR, 1.37; P=0.12). The rate of grades 3 and 4 adverse events was similar; however, there were 19 instances of radiation dermatitis. The researchers concluded that adjuvant radiotherapy improves lymph-node field control in high-risk patients, and that this option should be addressed in these patients who have undergone lymphadenectomy.

radiotherapy combined with a targeted pharmaceutical agent could be a successful treatment option. Many preclinical studies exploring similar combinations have been published. For example, Sambade and colleagues6 showed that BRAF-positive cells were radiosensitized after pretreatment with vemurafenib. Postow and colleagues7 reported immunologic analyses of a patient with widespread metastatic melanoma who received both external radiotherapy and ipilimumab. The patient had clear in-field responses and delayed out-of-field responses (i.e., the abscopal effect) to localized radiotherapy. This close analysis of the clinical and immunologic findings for a single patient treated with both radiotherapy and a biologic agent indicated that the radiotherapy appeared to facilitate a sort of auto-immunization process that allowed the patient to show dramatic responses, both in the irradiated area and even in other nonirradiated areas. This fortuitous documentation of the cellular kinetics seen after immunologic â&#x20AC;&#x153;activationâ&#x20AC;? by radiotherapy leading to a body-wide abscopal effect is a major finding and one that likely will lead to many more future improvements as we try to understand exactly how to use each component within the therapeutic melanoma toolbox. Further clinical trials and confirmatory studies need to be conducted before final conclusions can be drawn.

Radiotherapy is unlikely to have a dominant role in melanoma treatment, but we can nonetheless finally assign it a reserved place in the treatment arsenal.

References 1. Macklis R. Finally, a substantial role for radiotherapy in melanoma. Lancet Oncol. 2012;13:561-562, PMID: 22575587. 2. Burmeister BH, et al. Adjuvant radiotherapy versus observation for patients at risk of lymph node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13:589-597, PMID: 22575589. 3. Khan N, et al. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys. 2011;80:645-654, PMID: 21489712. 4. Sekulic A, et al. Malignant melanoma in the 21st century: the emerging molecular landscape. Mayo Clin Proc. 2008;83:825846, PMID: 18613999. 5. Mouawad R, et al. Treatment for metastatic melanoma: old drugs and new strategies. Crit Rev Oncol Hematol. 2010;74:2739, PMID: 19781957. 6. Sambade MJ, et al. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol. 2011;98:394-399, PMID: 21295875. 7. Postow MA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925931, PMID: 22397654.

Dr. Macklis reported no financial disclosures relevant to this study.

Having trouble keeping up with all of the oncology and medical journals that cross your desk? On a monthly basis, Clinical Oncology News highlights key studies from the journals and provides guest clinician perspectives to help you stay up to date. We hope you find this a useful tool.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

ADJUVANT

Table. Three Arms of NSABP-38

continued from page 1

neutropenia in the TAC arm,” said Sandra Swain, MD, the medical director of the Washington Cancer Institute at Medstar Washington Hospital Center in Washington, D.C. She presented the study at the 2012 annual meeting of the American Society of Clinical Oncology (LBA1000). In adjuvant breast cancer treatment, clinicians have a variety of adjuvant regimens to choose from, including dosedense AC followed by paclitaxel (AC-P), an optimal paclitaxel-based regimen, and TAC, an optimal docetaxel-based adjuvant regimen. Until now, AC-P and TAC have never been directly compared in a prospective trial. In the NSABP (National Surgical Adjuvant Breast and Bowel Project)-38 trial, patients with operable, node-positive breast cancer who had no prior therapy received TAC, dose-dense AC-P or dose-dense AC-P plus gemcitabine (Table). Patients were stratified

TAC: docetaxel [T] 75 mg/ /2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3wk ✕ 6 Dose-dense AC➞P: A 60 mg/m2 and C 600 mg/m2 q2wk ✕ 4 followed by P 175 mg/m2 q2wk ✕ 4 Dose-dense AC➞PG: A 60 mg/m2 and C 600 mg/m2 q2wk ✕ 4 ➞ P 175 mg/m2 + gemcitabine 2,000 mg/m2 q2wk ✕ 4

patients were enrolled in each arm. With a median follow-up of 5.3 years, the addition of gemcitabine to AC-P did not improve outcomes. The three arms showed no difference in disease-free and overall survival. Grade 4/5 toxicities were similar, but the TAC arm had fewer grade 3 toxicities than the AC-P arm (36% vs. 41%). Compared with AC-P, TAC patients

‘I’ve always been a TAC user, so I would still probably use that, but I think either one is fine. … I think you need to look at the toxicities.’ —Sandra Swain, MD by number of nodes, hormone receptor status, type of surgery and radiation therapy. All arms received pegfilgrastim or filgrastim; EPO was recommended for patients with hemoglobin less than 11 g/dL. HER2-positive patients were excluded in August 2005 after 1,100 patients had been enrolled. Estrogen receptor–positive patients received hormone therapy for five years after chemotherapy. Approximately 1,600

had a statistically significant greater incidence of grade 3/4 febrile neutropenia (9% vs. 3%; P<0.001), diarrhea (7% vs. 2%; P<0.001) and left ventricular ejection fraction systolic dysfunction (<1% vs. 0), but lower rates of grade 3/4 sensory neuropathy (<1% vs. 7%; P<0.001), allergic reaction (<1% vs. 2%), alanine transaminase (<1% vs. 1%) and rash (<1% vs. 1%). Grade 2 anemia was higher in the AC-P arm than in the TAC

‘Our arguments over superior—if there is such a thing—thirdgeneration regimens are likely to continue.’

AT A GLANCE AC-P vs. TAC Until now, the regimens have never been directly compared in a prospective trial

—Kathy Miller, MD

There were no significant differences in efficacy

arm (24% vs. 12%). “About 50% of patients on the dosedense arms received erythropoietin versus 35% on TAC,” said Dr. Swain. More patients in the dose-dense arms received transfusions (6%) on AC-P than on TAC (4%). There were numerically more cases of leukemias/myelodysplastic syndromes in the dose-dense arms and more deaths on treatment in the TAC arm, although neither was statistically significant. So, how will the results influence clinician choice? “I’ve always been a TAC user, so I would still probably use that, but I think either one is fine,” said Dr. Swain. “I think you need to look at the toxicities. The peripheral neuropathy has always been a big significant issue for me.” Dr. Swain pointed out that EPO is not standard of care at the present time. Kathy Miller, MD, an associate professor at the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, said she believes dose-dense sequential therapies were slightly superior. She pointed out that the TAC arm had “more of the toxicities that are the most potentially life-threatening and the most troublesome to the patients in my clinical practice: neutropenia, granulocytopenic fevers and diarrhea.” She acknowledged there was not a clear winner. “Our arguments over superior—if there is such a thing— third-generation regimens are likely to

The regimens produced different toxicity profiles, with more neutropenia and diarrhea in the TAC arm Disease-free survival has yet to be analyzed for many hormone receptor–positive patients

continue,” she said. Dr. Miller also questioned whether more time was needed for a definitive analysis of the study. “Eighty percent of patients in NSABP-B38 had hormone receptor–positive disease and, for those patients, more than half of the diseasefree survival events are yet to occur, so although statistically it is a definitive analysis, clinically it cannot be so,” she said. —Kate O’Rourke

Dr. Swain disclosed a consultant or advisory role with Genentech, Nektar, Novartis, Roche and Sanofi and research funding from Bristol-Myers Squibb, Novartis, Pfizer, Roche/Genentech and Sanofi. Dr. Miller disclosed a consultant or advisory role with Clovis, Genentech and Nektar, and research funding from Genentech, Geron, Merrimack and Roche.

Everolimus Indication Expanded

he FDA has approved everolimus (Afinitor, Novartis) for advanced hormone receptor–positive, HER2-negative breast cancer in combination with exemestane after recurrence or progression following letrozole or anastrozole. The drug is the first mTOR inhibitor approved for advanced hormone

receptor–positive breast cancer, said Richard Pazdur, MD, the director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. Approval for the drug was based on the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) trial.

In the study, everolimus plus exemestane increased progression-free survival to 7.8 months compared with 3.2 months on exemestane alone. All 724 women in the trial were postmenopausal with advanced hormone receptor–positive breast cancer that had either recurred or progressed following

letrozole or anastrozole. The most common adverse reactions were stomatitis, infections, rash, fatigue, diarrhea and decreased appetite. Full results of the BOLERO-2 trial were published Feb. 9 in The New England Journal of Medicine (2012;366:520529, PMID: 22149876).

New Drugs for Malignancy, An Issue of Hematology/Oncology Clinics of North America Franco Muggia See page 31

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Vaccine Shows Potential To Prevent Breast Cancer Recurrence A

breast cancer vaccine has produced a strong immune response and potentially prevented breast cancer recurrence in a Phase II trial. Senior author Elizabeth Ann Mittendorf, MD, an assistant professor of surgical oncology at the University of Texas MD Anderson Cancer Center in Houston, characterized the vaccine, AE37, as “a small piece of the HER2 [human epidermal growth factor receptor 2] protein with a modification on it so that it is presented well to the immune system. It educates the immune system to recognize the HER2 protein and to eliminate the HER2 protein with the cancer cell.” The vaccine is administered once every three weeks for six vaccinations, with a booster every six months for three years. The study included 201 disease-free breast cancer patients with 103 in the vaccine group and 98 in the control group. Patients had any level of HER2 expression (immunohistochemistry [IHC] scored as 1-3+ or fluorescence in situ hybridization [FISH] >1.2). The vaccine group received AE37 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvantly; the control group received GM-CSF alone. Toxicity was minimal, with 99% of local and systemic toxicities grade 2 or lower. Immune responses were strong and with a median follow-up of 22 months, Kaplan-Meier projections estimated recurrence rates of 10.3% in the vaccine group versus 18% in the control group. The results were presented at the 2012 annual meeting of the American Society of Clinical Oncology in Chicago ((J Clin Oncoll 2012;30[suppl; abstr 2508]). “Women who had node-positive or high-risk node-negative breast cancer and who had completed surgery, chemotherapy and, when indicated, radiation therapy, were randomized to receive either vaccine or placebo,” said Dr. Mittendorf. “At a median follow-up of approximately two years, the recurrence rate for vaccinated patients is 10.3% versus 18% for the controls. That’s a 43% relative risk reduction.” Dr. Mittendorf added, “The vaccine works with low HER2 expression as well as high HER2 expression. … Unlike trastuzumab, which requires that a patient have HER2 overexpression defined as being IHC3+ or amplified on FISH, the vaccine works in patients with any degree of HER2 expression, including those with HER2 1+ or 2+ disease who were told by their clinician that they were HER2-negative.” “This is a very interesting piece of work,” said Jay Brooks, MD, the chief of hematology-oncology at Ochsner Health System in Baton Rouge, La., who was not involved in the study. “Eliciting immune response is important. But how does

it translate to long-term survival? For that we need a prospective randomized Phase III trial. … There has been a long history of tumor vaccines, with no major advances. I’m not trying to sound like a pessimist, just like a realist.” He added, “I would advise a patient of mine to enroll in this research trial, but I don’t think it’s been proven yet.” Based on the data so far, Antigen Express, Inc., the subsidiary of Generex Biotechnology Corporation that holds

the license for AE37, will go to the FDA for an end of Phase II meeting, with the intention of progressing to a Phase III trial, Dr. Mittendorf said. Asked why the vaccine was being tested only against recurrences of breast cancer, Dr. Mittendorf said, “It does have the potential to prevent breast cancer. But the strategy for clinical trials of an entirely preventive vaccine involves tens of thousands of patients and very long followup. … Our strategy is to prevent disease

recurrence.” She added, “It is possible that the vaccine would be protective against other cancers that express the HER2 protein, such as gastric, prostate and ovarian cancers.” —George Ochoa Dr. Mittendorf reported no personal, relevant financial conflicts of interest; however, the trial was funded in part by Antigen Express. Dr. Brooks reported no relevant financial conflicts of interest.

The Greenspan Meeting XXX

November 6-10, 2012, New York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ® New Agents, Clinical Trials, Emerging Developments Tuesday, November 6 Pediatric Oncology Therapeutic Advances in Cancers of Childhood

Saturday, November 10 Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Therapeutic Advances, Treatment Related Complications, Supportive Care, Symptom Management, Targeted Therapies Schedule Nov. 6 Pathways and Pipelines, Careers in Oncology Nov. 7 Hematology, GI, Pediatric Oncology Nov. 8 GYN, Head and Neck, Breast Nov. 9 GU, Lung, Melanoma, OncoTechnology Nov. 10 New Perspectives in Oncology Practice

Conference Highlights Wednesday, November 7 Keynote Speaker Norman Wolmark, MD Thursday, November 8 Ezra M. Greenspan Memorial Lecture José Baselga, MD

Complimentary Breakfasts, Lunches, Dinners

A CME Oncology Conference presented by the The Tisch Cancer Institute of the Mount Sinai School of Medicine and The Chemotherapy Foundation

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

T-DM1 Continues To Impress in Interim Analysis Antibody–drug conjugate an ‘important new weapon’ against HER2+ breast cancer Chicago—In patients with metastatic HER2-positive refractory breast cancer, the combination of trastuzumab (Herceptin, Genentech) and emtansine (DM1) is more effective than capecitabine plus lapatinib (XL) in terms of progressionfree (PFS) and overall survival (OS), according to interim results of a Phase III study. Presented at the 2012 annual meeting of the American Society of Clinical Oncology (abstract LBA1), the results of the EMILIA trial suggest that T-DM1 is more active than XL, which is the only approved combination for refractory HER2-positive breast cancer (Table). “With the EMILIA study, targeted therapy has progressed another step forward in breast cancer therapy and T-DM1 should offer an important therapeutic option in the treatment of HER2-positive metastatic breast cancer,” said Kimberly Blackwell, MD, a professor of medicine and assistant professor in radiation oncology at Duke University Medical Center in

Durham, N.C. Although the interim OS benefit seen with T-DM1 did not meet the prespecified threshold for terminating the trial, the hazard ratio (HR) for the T-DM1 combination relative to XL was highly statistically significant (HR, 0.621; 95% confidence interval [CI], 0.475-0.813; P=0.0005). EMILIA included 978 patients with trastuzumab-refractory, HER2-positive metastatic breast cancer randomized to 3.6 mg/kg T-DM1 administered every three weeks or the combination of 1,000 mg/m2 twice daily capecitabine (Xeloda, Roche) on days 1 to 14 of a three-week schedule along with 1,250 mg of lapatinib (Tykerb, GlaxoSmithKline) daily. The follow-up for this interim analysis was approximately 12 months. In addition to the improvement in OS, PFS was 9.6 months on T-DM1 compared with 6.4 months on XL (HR, 0.64; 95% CI, 0.549-0.771; P<0.0001). The median OS was 23.3 months in the XL group and has not yet been reached in the T-DM1

Table. T-DM1 Versus Capecitabine (X) and Lapatinib (L) in HER2-positive Locally Advanced Or Metastatic Breast Cancer T-DM1

1-year

84.7 (80.76–88.55)

77.0 (72.40–81.50)

2-year

65.4 (58.65–72.15)

47.5 (39.20–55.89)

Objective response, % (95% CI)

43.6 (38.6–48.6)

30.8 (26.3–35.7)

Duration of response in patients with objective response, median months (95% CI)

12.6 (8.38–20.76)

6.5 (5.45–7.16)

Dose reduction, %

16.3

X 53.4 L 27.3

AEs ≥grade 3, %

40.8

57.0

OS, % (95% CI)

‘The EMILIA trial provides convincing evidence that an immunoconjugate targeting HER2 has potent antitumor activity.’ —Louis Weiner, MD

AT A GLANCE T-DM1 The antibody–drug conjugate links trastuzumab with mertansine At one year, T-DM1 had better response and survival rates than capecitabine plus lapatinib (XL) T-DM1 produced higher rates of thrombocytopenia and liver enzyme abnormalities than XL but was generally safer Additional ongoing trials include MARIANNE (Docetaxel/ Trastuzumab vs T-DM1 vs T-DM1 plus Pertuzumab) and TH3RESA (Third-line T-DM1 vs Physician’s Choice of Treatment for HER2+ Metastatic Breast Cancer)

group. Other end points, including objective response rate (43.6% vs. 30.8%) and median duration of response in those who achieved an objective response (12.6 vs. 6.5 months) also favored T-DM1. Although grade 3 or higher thrombocytopenia (12.9% vs. 0.2%) and liver enzyme abnormalities (4.3% vs. 0.8%) were more frequent on T-DM1, grade 3 or higher diarrhea (20.7% vs. 1.6%), palmar-plantar erythrodysesthesia (16.4% vs. 0%) and vomiting (4.5% vs. 0.8%) were more frequent on XL. The overall rate of grade 3 or higher adverse events was 40.8% in the T-DM1 group and 57% in the XL group. Dose reductions were required in 53.4% of those taking capecitabine, 27.3% of those taking lapatinib and 16.3% of

those taking T-DM1. “The EMILIA trial provides convincing evidence that an immunoconjugate targeting HER2 has potent antitumor activity,” said Louis Weiner, MD, the director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, D.C. He characterized T-DM1 as “an important new weapon” for HER2-positive breast cancer and a concept that is likely to be pursued with other types of immunoconjugate agents. —Ted Bosworth Dr. Blackwell has served as an advisor to Genentech. Dr. Weiner has no relevant relationships to disclose.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

‘Genomic History’ of Breast Cancers Reconstructed Mutations of 21 breast cancers identified

esearchers have catalogued all the mutations in the genomes of 21 breast cancers, identified the mutational processes involved in the tumors’ development and deciphered the life history of each cancer. The findings

In the second paper, bioinformatic algorithms were applied to reconstruct the genomic history of the 21 breast can-

‘These mutational patterns … show us that although all breast cancers studied here have a dominant clone, each cancer comprises multiple populations of related clones and that breast cancers are exceedingly complex.’ —Serena Nik-Zainal, MD appear in two reports published online on May 17 in Celll (2012;149:979-993 and 2012;149:994-1007). The researchers sequenced complete genomes of 21 primary breast cancers and matched normal DNA from the same individuals in the first study. A total of 183,916 somatically acquired base substitutions were detected. The researchers identified five distinct mutational signatures, each characterized by a different profile of trinucleotide mutations that contributed on some level to each of the 21 cancers. For the first time, the researchers observed what they called “kataegis”—clusters of mutations in regions of the genome. Kataegis was common, occurring in 13 of 21 breast cancers.

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cers. In the resulting model of breast cancer development, the appearance of the most recent common ancestor—the cell with the full complement of somatic mutations found in all tumor cells—is a key step. This occurs early, with much more time spent driving subclonal diversification and evolution. Eventually, a dominant subclonal lineage emerges, accounting for more than 50% of the cancer cells. When the subclone is sufficiently numerous, the tumor mass becomes clinically detectable. “We have used the entire catalog of somatic mutations in cancers, not just mutations in coding regions, to do a very deep analysis of mutation patterns in 21 breast cancer genomes,” lead investigator Serena Nik-Zainal, MD, a

AT A GLANCE A mutation encoding the NQO1 enzyme makes breast cancer cells harder to treat and more likely to spread. Credit: NCI

clinical research training fellow at the Wellcome Trust Sanger Institute in Cambridge, U.K., told Clinical Oncology News by email. “As a result … we have been able to identify multiple mutational patterns, or mutation signatures, which were not previously appreciable. These mutational patterns tell us something about how the cancers have developed or evolved over time. They bear the imprints of the DNA mutagenic processes as well as the DNA repair mechanisms that have been in operation over the lifetime of the cancer patient. They show us that although all breast cancers studied here have a dominant clone, each cancer comprises multiple populations of related clones and that breast cancers are exceedingly complex.” The research might lead to better methods of characterizing cancers and predicting treatment response. “Treating the single dominant clone in a cancer is probably unlikely to cure a cancer, and we need to develop ways of identifying subclonal populations and

All cancers carry somatic mutations Mutational processes evolve over a cancer’s lifespan, with many emerging late but contributing extensive genetic variation BRCA1/BRCA2 2 breast cancers have a characteristic combination of mutation signatures and a distinctive profile of deletions For the first time, researchers observed what they called “kataegis”—clusters of mutations in regions of the genome learn how to treat them just as effectively,” said Dr. Nik-Zainal. “More work needs to be done to understand the biology behind the processes that drive the occurrence of these mutational signatures, because if we can understand the biology behind these processes, then we are more likely to develop effective therapies for individual people.” —George Ochoa Dr. Nik-Zainal reported no relevant financial conflicts of interest.

HEMATOLOGIC DISEASE

Carfilzomib Approved for Refractory Multiple Myeloma

he FDA has granted approval for carfilzomib (Kyprolis, Onyx Pharmaceuticals) as a third-line treatment for multiple myeloma patients who have already been treated with bortezomib (Velcade, Millennium) and an immunomodulatory therapy. The approval follows a unanimous vote by the Oncologic Drugs Advisory Committee (ODAC) to recommend FDA approval in June. The drug was approved under the FDA’s accelerated approval program, based on clinical data using a surrogate

end point that likely translates into a clinical benefit for patients. The approval study, the 003-A1 trial, included 266 patients. The overall response rate was 22.9% and the median duration of response was 7.8 months. Despite this success, adverse events (AEs) associated with the agent are a serious concern. Serious adverse reactions were reported in 45% of patients; the most common treatment-emergent AEs reported were fatigue (49%) and anemia (46%), and the most common grade 3/4 AE was

thrombocytopenia (29%). Additionally, 37 deaths occurred in Phase II studies of carfilzomib. The most common non–disease-related causes of death were cardiac (five patients), endorgan failure (four patients) and infection (four patients). The full results of the approval trial were published online July 25 in the journal Blood (doi:10. 1182/ blood-2012-05-425934, PMID: 22833546). —Gabriel Miller

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Everolimus Strikes Out in Gastric Cancer Trial Ongoing biomarker analysis may identify responsive subgroup San Francisco—Adding everolimus to best supportive care does not improve survival in patients with advanced gastric cancer, according to a Phase III trial. “The trial was negative. There was no statistically significant difference in overall survival,” said Eric Van Cutsem, MD, PhD, a professor at the University Hospital Gasthuisberg in Leuven, Belgium. He presented the study at the most recent Gastrointestinal Cancers Symposium (LBA3). Everolimus (Afinitor, Novartis) seemed like a good bet for treating stomach cancer because it is an oral mTOR inhibitor and the PI3K/Akt/mTOR pathway is dysregulated in 50% to 60% of cancers. A Phase II study showed everolimus had promising efficacy and acceptable tolerability in patients with previously treated advanced gastric cancer.

‘We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent.’ —David Ilson, MD, PhD The Phase III Granite-1 trial enrolled patients with confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma as long as the majority involved the stomach. Patients were required to have documented progression after one or two lines of previous systemic chemotherapy, Eastern Cooperative Oncology Group performance status 2 or lower, and adequate bone marrow, renal and hepatic function. The trial randomized 656 patients in a 2:1 ratio to everolimus plus best supportive care (BSC) or placebo and BSC. Patients were treated until disease progression or intolerable toxicity. The two arms were well balanced in terms of baseline demographics and disease characteristics. The patients were stratified by region (Asia vs. rest of the world) and the amount of previous systemic chemotherapy; more than half of the patients were from Asia. The median overall survival—the primary end point—was 5.39 months in the everolimus arm and 4.34 months in the placebo arm, a difference that was not statistically significant (hazard ratio [HR], 0.90; P=0.1244). Median progression-free survival, a secondary end point, showed a significant improvement in the everolimus arm (1.68 vs. 1.41 months;

HR, 0.66; P<0.0001). A forest plot analysis did not identify a subgroup that benefited more than others. Dr. Van Cutsem said a biomarker analysis was ongoing. According to David Ilson, MD, PhD, a medical oncologist with the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, in New York City, the large, ambitious Phase III trial was clearly negative, but

“the progression-free survival curve is provocative. “Is there a signal of disease control worthy of further study in this analysis? We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent,” said Dr. Ilson. He cautioned, however, that researchers should not mandate a biomarker up

front in all new studies. “We may miss detection of activity in all patients by mandating biomarkers up front,” said Dr. Ilson. —Kate O’Rourke Dr. Van Cutsem disclosed research funding from Novartis. Dr. David Ilson disclosed research funding from Bayer-Onyx, Roche and Sanofi.

Now Available... Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113” Release Date: October 1, 2011

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Tessa Cigler, MD, MPH

Upon completion of this activity, participants will be better prepared to:

Assistant Professor of Medicine, Weill Cornell Medical Center Attending Physician, NewYork-Presbyterian Hospital New York, New York

Paula D. Ryan, MD, PhD Associate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer Center Philadelphia, Pennsylvania

Target Audience Oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). There are no prerequisites or fees.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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1 Review recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or MBC. 2 Describe a treatment algorithm that reﬂects evidence-based management of advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance. 3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics. 4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

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Method of Participation To receive CME credit, participants should complete the pre-test, read the monograph, and complete the post-test and evaluation either online at www.CMEZone. com (enter keyword MN113). Completed forms also can be faxed to (303) 6485311 or mailed to 5575 S. Sycamore Street, Suite 200, Littleton, CO 80120. CME certiﬁcates will be issued within 6 to 8 weeks upon receipt of completed evaluations. A score of at least 70% is required to complete this activity.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Potential Benefit With Adjuvant Therapy for Stage III CRC in Elderly From the Journal of Clinical Oncology

atients aged 75 years or older with stage III colorectal cancer (CRC) who receive adjuvant chemotherapy may live longer, judging from an extensive review of patient histories. The effect of adjuvant chemotherapy on these older patients has been ill defined because older patients are underrepresented in clinical trials. Although adjuvant chemotherapy in the setting of stage III CRC has been found to heighten the chance for cure, these conclusions have been based

on studies that only minimally have included older patients. This is despite the fact that CRC disproportionately afflicts older individuals. In the present study, published in the Journal of Clinical Oncology (2012 Jun 4. [Epub ahead of print], PMID: 22665536), Hanna Sanoff, MD, and her colleagues culled patient histories from four large data sets to isolate the effect of adjuvant chemotherapy in stage III CRC in older patients. The researchers accumulated 5,489 records of older patients with resected stage III CRC, all of whom were diagnosed between 2004 and 2007

EXPERT INSIGHT Dale Shepard, MD, PhD Staff Physician, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, and Co-Director, Taussig Oncology Program for Seniors

he analysis of the benefits of adjuvant chemotherapy on survival for patients over age 75 years with stage III CRC by Sanoff and her colleagues is an important step toward improved outcomes for this population. Unfortunately, the only data often available to guide therapy for the elderly comes from clinical trials. The MOSAIC1 (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) and

NSABP (National Surgical Adjuvant Breast and Bowel Project Clinical Trials Overview) C-072 studies, whose findings support the use of adjuvant chemotherapy, enrolled less than 5% of patients over age 75, and oncologists may be concerned about treating these patients due to the lack of data. The current analysis used four different databases to assess the benefit of adjuvant chemotherapy in this patient population in actual clinical practice with analysis of outcomes

and survived at least 30 days postsurgery. The four sources of data were the Surveillance, Epidemiology, and End Results cancer registry program that is linked to Medicare claims, the New York State Cancer Registry, the National Comprehensive Cancer Network Outcomes Database and the Cancer Care Outcomes Research and Surveillance Consortium. These databases confirmed that adjuvant therapy declined with age as well as comorbidity. Administration of adjuvant chemotherapy in these patients conferred a survival benefit that was comparable to clinical

trial results that had underrepresented older patients. Additionally, the small benefit credited to oxaliplatin over other chemotherapy regimens also mirrored those of clinical trials in this population in two of the three data sources in which this was examined. The authors concluded this retrospective review had revealed that patients aged 75 years or older with stage III CRC “may anticipate a survival benefit from adjuvant chemotherapy,” and that its use “merits consideration” and discussion with this patient population.

for nearly 5,500 patients. Sanoff et al verified the benefit of adjuvant chemotherapy for these patients. Not surprisingly, findings from the analysis also confirmed that the use of adjuvant chemotherapy declined with age and increasing comorbidity. Although these results may lead to an increased use of adjuvant therapy in older patients, there remain many important questions. The results of this analysis are inherently biased. Although there was no inclusion bias, which often plagues clinical trials in which older patients are excluded due to comorbidity or by not even being offered the trial, the only patients who received adjuvant therapy were those who were considered by their treating oncologists to be fit for treatment. Not surprisingly, the patients considered likely to benefit did. Because this is a retrospective review,

patients were differentiated by age alone. When treating geriatric patients, age is only one consideration. This data does not guide oncologists with any additional factors that may predict either favorable or unfavorable responses to treatment. There may be additional patients who were previously untreated who may benefit from adjuvant therapy. A prospective study incorporating geriatric assessment might help define the optimum therapy for this increasingly large population of patients.

References 1. Andre T, et al. J Clin Oncol. 2009;27:31093116, PMID: 19451431. 2. Kuebler JP, et al. J Clin Oncol. 2007;25:2198-2204, PMID: 17470851.

Dr. Shepard reported no financial disclosures relevant to this study.

Trametinib Improves Survival in Metastatic Melanoma From The New England Journal of Medicine

rametinib improved progressionfree (PFS) and overall survival (OS) in metastatic melanoma. Trametinib (GSK1120212, GlaxoSmithKline) is a selective inhibitor of MEK1 and MEK2 proteins that activate downstream mitogen-activated protein kinases (MAP-K); the MAP-K pathway regulates the proliferation and survival of tumor cells. In earlier studies in mice, trametinib inhibited melanoma tumors with the V600E serine-threonine protein kinase B-RAF (BRAF) mutation;

successful Phase I and II human trials followed. The two most common BRAF mutations, V600E and V600K, are present in 95% of BRAF mutations in all types of cancer. BRAF mutations have been found in about half of all patients with advanced melanoma. Selective BRAF-inhibitor therapy has improved survival in these patients but only been effective short-term. The present open-label, Phase III, international trial ((N Engl J Med 2012;367:107-114, PMID: 22663011), headed by Keith Flaherty, MD, at Harvard Medical School in Boston, tested the efficacy of trametinib compared

with chemotherapy in patients with BRAF-mutated melanoma, with PFS the primary end point and OS the secondary end point. GlaxoSmithKline funded the study. 322 patients with metastatic melanoma with either V600E or V600K BRAF mutations were randomly assigned to receive either trametinib (2 mg orally) once daily or chemotherapy, consisting of either IV dacarbazine (1,000 mg/m2) or paclitaxel (175 mg/m2) every three weeks. Patients in the chemotherapy cohort were permitted to cross over. The median PFS in the trametinib group was 4.8 months and in the

chemotherapy group was 1.5 months (hazard ratio [HR] for disease progression or death in the trametinib group, 0.45; P<0.001). The OS at six months was 81% in the trametinib group and 67% in the chemotherapy group (HR for death, 0.54; P=0.01). Adverse events more frequently associated with trametinib than chemotherapy included rash, diarrhea, peripheral edema and acneiform dermatitis. There were no instances of cutaneous squamous cell carcinomas in the trametinib group. The investigators concluded that trametinib is promising and that further research is needed.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Chromosomal Instability Phenotype a Survival Marker in CRC From the Journal of Clinical Oncology

n stage II and III colorectal cancer (CRC), the chromosomal instability (CIN) phenotype has been found to be a predictive marker of survival by identifying high-risk patients. CIN and microsatellite instability (MSI) are the two known genetic pathways in CRC. CIN cancer occurs following the loss of heterozygosity (LOH) in chromosomes; MSI results from improperly matched repair genes. The MSI phenotype is further classified into “high” and “low” phenotypes; patients with the former phenotype have been found to have a better

prognosis than those with the latter. In the CIN phenotype, the severity of LOH has been found to markedly differ: Some tumors may have LOH in several chromosomes, whereas others may have relatively few. The question, which Toshiaki Watanabe, MD, PhD, and his Tokyo-based colleagues sought to answer, is whether the difference between high-LOH and low-LOH CIN CRC represents a prognostic marker. As reported in the Journal of Clinical Oncology (2012;30:2256-2264, PMID: 22547595), the researchers determined the MSI and LOH characteristics of 845 patients with stage II or III CRC who had undergone curative surgical resection. The LOH ratio was defined

EXPERT INSIGHT Bassam N. Estfan, MD Associate Staff Physician, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, and Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

ancer care is becoming more personalized with improved knowledge of its molecular and genetic characteristics. CRC is no different. In the metastatic setting K-ras status is predictive of response and B-raf is prognostic. Although adjuvant oxaliplatin-based therapy is the standard of

care for stage III colon cancer, adjuvant chemotherapy in stage II remains controversial, and even more so in rectal cancer. Researchers have pursued criteria for selecting patients for adjuvant 5-fluorouracil (5-FU) based on clinical clues (e.g., T stage, perforation, tumor differentiation). Recently,

EXPERT INSIGHT Brian Gastman, MD Staff Physician and Head of the Melanoma Clinic, Cleveland Clinic Dermatology & Plastic Surgery Institute, and Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

or decades, there was no effective treatment for metastatic melanoma, which for the vast majority of patients meant uniform mortality. In 2011, the FDA approved two drugs for this exact scenario, which has greatly enhanced enthusiasm to identify even more effective anti-melanoma

drugs. One of these drugs (the now FDA-approved vemurafenib) targets a mutated protein, BRAF, to block its hyperproliferative capabilities. Vemurafenib, although promising, still only works in a subset of patients, seems to have limited longevity, has significant side effects and tumors can become

as the LOH frequency in chromosomes 2p, 5q, 17p and 18q. Of the analyzed samples, 75 were found to be MSIhigh samples. Of the remainder, 466 were identified as CIN high and 279 were CIN low. CIN-high tumors were defined as having an LOH ratio of 33% or greater; CIN low had an LOH ratio less than 33%. The CIN-high tumors were additionally classified as mild (LOH ratio <75%) or severe (≥75%). Microarray analyses were performed to determine gene signatures and the ability of the CIN phenotype to predict prognosis. The CIN-high cohort had the worst survival ((P<0.001), and the severe subtype of the CIN-high cohort showed

poorer survival than the mild subtype ( <0.001). There was no significant (P difference between CIN-low and MSIhigh survival rates. The CIN phenotype proved to be an independent risk factor for both disease-free (DFS) and overall survival (OS), according to multivariate analysis. Microarray analysis concurred, finding survival was poorer in patients with CIN-high as opposed to CIN-low phenotypes ((P=0.0203). The researchers noted that adjuvant therapy in stage II CRC is controversial. However, “the present study shows that CIN phenotype may be useful in identifying high-risk patients with stage II CRC who might benefit from adjuvant chemotherapy.”

high MSI was found to be associated with favorable prognosis in patients with stage II colon cancer, and even may be a negative predictor of treatment benefit from 5-FU. Watanabe and colleagues further subclassified patients with low MSI and stable microsatellite according to CIN using polymerase chain reaction and gene expression profiling in two different data sets. In their analysis, those with low CIN (<33% LOH) seemed to have a similar prognosis to high MSI, and in a multivariate analysis, CIN status was strongly associated with differences in DFS and OS. Furthermore, those with high CIN could be further classified into mild and severe, prognostically revealing two different populations.

Although clearly establishing the heterogeneity of CRC, these results cannot be used to guide therapy unless proven to be predictive of clinically meaningful outcome benefit. The same can be said for other commercially available prognostic tools. This should be answered through prospectively designed randomized trials with the focus on the predictive and prognostic role of molecular and genetic markers. The magnitude of benefit in original trials is small, and in my mind we may have better luck in identifying those who can be saved from getting toxic chemotherapy, such as the cohort of low CIN in this study.

resistant over time. These features led to a study recently published in The New England Journal of Medicine by Flaherty et al. In this study, the researchers used a new drug that targets further downstream of BRAF, inhibiting substrates of the molecule called MEK, thus the name MEK inhibitor or trametinib. In comparison with chemotherapies in metastatic patients with BRAF mutations, where OS was only 67%, the trametinib group was significantly higher, at 81%. A comparable study published in the same journal in 2011 had similar results with vemurafenib, having an OS at the same time point of 84%. One difference, however, is that unlike trametinib, more than 25% of vemurafenib-treated patients

acquired other types of skin cancers, and many had to have their doses downscaled due to other toxicities. Whether MEK inhibitors can work in combination with BRAF inhibitors or should be used when these latter drugs eventually fail due to tumor resistance currently is under investigation. In short, although the recently FDAapproved drugs and those being studied, such as trametinib, still do not cure the majority of patients, nonetheless patients with melanoma in 2012 are in a much better position than those who suffered from this cancer even just a year or so ago.

Dr. Estfan reported no financial disclosures relevant to this study.

Dr. Gastman reported no financial disclosures relevant to this study.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Vismodegib Reduces Tumor Burden in Nevus Syndrome From The New England Journal of Medicine

ismodegib (Erivedge, GenentechCuris), the recently approved orally administered hedgehog-pathway inhibitor, effectively reduces the basal cell carcinoma (BCC) tumor burden in patients with basal cell nevus syndrome (BCNS). The availability of this drug represents a significant advance in treating this rare disorder. BCNS can cause the eruption of thousands of BCCs on a single patient, with resultant diminished quality of life and frequent scarring surgeries.

The authors of this study, headed by Jean Yang, MD, PhD, of the Children’s Hospital Oakland Research Institute, in California, reasoned that vismodegib’s efficacy against BCCs might translate to efficacy against BCNS. This randomized, double-blind, placebo-controlled multicenter trial was published in The New England Journal of Medicine (2012;366:2180-2188, PMID: 22670904); the research was partially funded by Genentech. The primary end point was reduction in the incidence of new surgically eligible BCCs after three months. The secondary end point was reduction in the

EXPERT INSIGHT Jon G. Meine, MD Staff Physician, Dermatologic Surgery & Cutaneous Oncology, Cleveland Clinic Dermatology and Plastic Surgery Institute

he study by Yang et al is the result of the discovery of the relationship between the hedgehog signaling pathway and the development of BCC in patients with BCNS by Dr. Epstein and colleagues. Patients with BCNS (Gorlin’s) develop innumerable tumors, which lead to significant

morbidity because treatment options are primarily surgical. The development of vismodegib is a breakthrough for modifying the result of a defect in the tumor-suppressor gene that encodes patched 1 (PTCH1), a primary inhibitor of the hedgehog signaling pathway. The majority of sporadic

size of existing BCCs. Patients were assigned in a 2:1 ratio to receive either vismodegib (150 mg per day) or placebo for up to 18 months. Patients were followed for a mean of eight months. The rate of surgically eligible BCCs was lower with vismodegib (two cases per group per year) versus placebo (29 cases; P<0.001). The size of existing BCCs also was reduced compared with baseline (–65% in the vismodegib group vs. –11% in the placebo group). The researchers noted that in some patients in the vismodegib group all such carcinomas clinically regressed,

and no tumors progressed while under treatment with the drug. Residual BCC was not detectable in 83% of biopsied samples removed from sites of clinically regressed BCCs. However, 14 of 26 (54%) patients receiving vismodegib had to discontinue treatment because of adverse events, which most frequently included loss of taste, muscle cramps, and hair and weight loss. The authors concluded that vismodegib reduced the BCC tumor burden in patients with BCNS, and the results “confirm the essential role of the hedgehog pathway in basal-cell carcinomas.”

BCCs (the most common cancer in the United States) have enhanced hedgehog signaling as well. A large study in this patient population would be difficult to achieve. However, this study (N=41) showed a significant halt in the production of new tumors and reduction in the size of “surgically eligible” BCCs present at the onset of the study. One weakness of the study is the relative short time of treatment. The study was stopped because of the significant improvement in patients receiving vismodegib compared with the placebo group. Of patients receiving vismodegib, 54% stopped taking the drug due to adverse side effects including taste disturbances, muscle cramps, hair loss and weight loss. Also of note is that

surgically eligible BCCs that responded to therapy recurred within months of stopping treatment. Overall, this study confirms that vismodegib is successful in stopping the growth of BCC in patients with BCNS. This is an exciting advance for patients who until now have had few options other than surgical excision and destructive treatments: a molecularly targeted drug that helps to correct a missing tumor suppressor in patients with a genetic disease. Future studies will hopefully investigate the optimum duration of treatment and further define the patient population who will benefit from this therapy. Dr. Meine reports no financial disclosures relevant to this study.

Adjuvant Radiochemotherapy for Gastric Cancer Confirmed From the Journal of Clinical Oncology

he benefit of adjuvant radiochemotherapy (RCT) following curative gastric cancer resection was first demonstrated in the Intergroup 0116 study, a Southwest Oncology Group– directed effort that when first published had a median of four years’ follow-up (N ( Engl J Med d 2001;345:725730, PMID: 11547741). The present study looks again at the results, now with more than 10 years’ median follow-up, and finds that its original

conclusions have been confirmed. The randomized Phase III study, published in the Journal of Clinical Oncology (2012;30:2327-2333, PMID: 22585691), included 559 patients, 277 of whom were assigned to observation and 282 to RCT. Patients enrolled in the study had a moderate risk for locoregional failure (LRF) following surgery and had primaries of T3 or greater and/or node-positive gastric cancer. Eligibility criteria included R0 resection of adenocarcinoma of the stomach or gastroesophageal

junction, performance status of 0 to 2 and adequate medical condition and laboratory findings. Chemotherapy consisted of leucovorin and 5-fluorouracil (5-FU) delivered before, during and after radiotherapy, which was targeted to all LRF sites up to 45 Gy. Overall survival (OS) and relapsefree survival (RFS) rates both improved with postoperative RCT. The hazard ratio (HR) for OS was 1.32 ((P =0.0046) and RFS was 1.51 ( <0.001). The overall and locore(P gional relapse rates were substantially

reduced in those receiving adjuvant RCT. The researchers described the treatment benefit as robust, with one exception: Patients with diffuse histology did not exhibit a significant treatment effect. Also of note, second malignancies were noted in 21 patients who had received the RCT regimen versus eight patients in the observation cohort ((P=0.21). The researchers concluded that the toxicities and second malignancies “appear acceptable, given the magnitude of RFS and OS improvement.”

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ AUGUST 2012

Neoadjuvant Chemoradiotherapy for Esophageal Cancer From The New England Journal of Medicine

n the largest such trial to date, preoperative chemoradiotherapy (CRT) improved survival rates in patients with potentially curable esophageal or esophagogastric junction (EGJ) cancer. Members of the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) Group had earlier published a Phase II trial in which neoadjuvant CRT consisted of weekly administration of carboplatin-paclitaxel with concurrent radiotherapy, with encouraging results ((Br

paclitaxel, at 50 mg/m2 of body surface area, for five weeks; together with concurrent radiotherapy, at 41.4 Gy in 23 fractions, administered five days per week. Surgery followed the completion of the regimen. There were 366 patients included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous cell carcinoma and seven (2%) had large cell undifferentiated carcinoma. Of these, 177 were assigned to the C+S group, with the rest receiving surgery alone. Complete resection with no tumor within 1 mm of resected margins (R0) was achieved in 92% of patients in

the C+S group and 69% in the surgery group ((P<0.001). Pathologic complete response was achieved in 47 of 161 patients (29%) who underwent resection after the course of CRT. Median overall survival (OS) was 49.4 months in the C+S group and 24 months in the surgery group. OS was significantly enhanced in the C+S group (hazard ratio, 0.657; P=0.003). Postoperative complications were similar in both groups, as was in-hospital mortality. Adverse hematologic and nonhematologic events were acceptable. Patients with squamous cell carcinoma and adenocarcinoma both benefited from the neoadjuvant CRT.

rates at three years for patients treated with surgery alone range from 5% to 30%. Various perioperative treatment approaches have been explored in an attempt to improve on these

disappointing results. Several studies have investigated the utility of preoperative CRT. These studies have clearly demonstrated evidence for pathologic downstaging with subsequent improvements in the likelihood of achieving a complete resection and local disease control. However, a survival benefit has been more difficult to demonstrate. Several of these trials have been hampered by poor accrual and criticized for having relatively poor outcomes in the surgical control arms. The CROSS trial is the largest study to date comparing preoperative CRT to surgery alone, demonstrating a clear and robust survival advantage in favor

of the former approach. Although this trial is not necessarily practice changing, it does solidify tri-modality therapy as a standard of care in the management of patients with locally advanced esophageal cancer. At the same time, this study provides a potentially less toxic and evidence-based alternative to cisplatin and 5-fluorouracil. Further randomized trials incorporating clinically relevant biomarkers will be required to define the optimum chemotherapy regimen in the preoperative management of this disease.

day) and leucovorin (20 mg/m2 per day) for five days, followed by 4,500 cGy (180 cGy per day), with modified doses of 5-FU and leucovorin on the first four and the last three days of radiotherapy. Additionally, further chemotherapy was given one month after the completion of radiotherapy. This consisted of two, five-day cycles of 5-FU (425 mg/m2 per day) plus leucovorin (20 mg/m2 per day) given one month apart. After a 10-year median followup, the updated results confirm the persistence of benefit from adjuvant RCT, with statistically significant improvements in both OS and RFS. The authors demonstrate a lack of interaction between extent of lymph node dissection (D strata) and therapy. This addresses the prior criticisms of the trial and confirms that RCT is beneficial in this setting regardless of the extent of

lymph node dissection. Thus, this approach remains the confirmed standard in North America. Caveats include the possibility that other biological factors may affect these tumors arising in other parts of the world. Additionally, diffuse histology patients may not benefit, although this needs confirmation in prospective trials addressing this particular group. In addition to reporting outcomes related to survival, the longer followup also allowed for reporting of second malignancies in long-term survivors. There were no statistically significant differences in second malignancies between the two arms. However, the number of cancers in the irradiated arm was numerically greater, possibly related to the longer survival in the chemoradiation arm and a resulting bias. Additionally, primaries such as laryngeal and bladder cancersâ&#x20AC;&#x201D;known

to be related to environmental factors such as smokingâ&#x20AC;&#x201D;were seen and these predisposing factors were not reported. A closer look reveals that many tumors originate at a significant distance from the radiation field and do not satisfy the definition of second primary cancers (SPC) induced by radiation. Although this analysis of SPC is of limited value in determining the actual contribution from radiation or chemotherapy due to the aforementioned limitations, it is still of concern and serves as a basis for discussion of longterm side effects with patients. It is important to note that the survival benefit outweighs the risk for SPC and this study again confirms that RCT improves outcomes in these patients in North America.

J Cancer 2006;94:1389-1394, PMID: 16670722). Based on this study, the CROSS Group decided to initiate a Phase III multicenter, randomized controlled study that compared neoadjuvant CRT followed by surgery with surgery alone. Enrollment was limited to patients with potentially curable esophageal or EGJ cancer. Results were published in The New England Journal of Medicine (2012:366:20742084, PMID: 22646630). The chemoradiotherapy plus surgery (C+S) regimen consisted of weekly administration of carboplatin, with doses titrated to an area under the curve of 2 mg/mL per minute; and

EXPERT INSIGHT Michael McNamara, MD Associate Staff Physician, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute

utcomes of patients with locally advanced esophageal cancer treated with surgery alone have been poor. The median survival of these patients rarely exceeds 18 months. OS

EXPERT INSIGHT May AbdelWahab, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute

he recent update of the landmark Intergroup 0116 study continues to support the use of adjuvant RCT in gastric cancer after curative resection. The Phase III study, originally reported in 2001, randomized patients with resected adenocarcinoma of the stomach or gastroesophageal junction to observation versus RCT. The adjuvant RCT consisted of 5-FU (425 mg/m2 per

Dr. McNamara reported no financial disclosures relevant to this study.

Dr. Abdel-Wahab reported no financial disclosures relevant to this study.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

K-ras Mutation Type May Render Chemo Useless Affects rectal cancer patients with codon 13 mutations; study is ‘intriguing’ albeit initial Orlando, Fla.—For the first time, researchers have shown that a specific type of K-ras gene mutation, located on codon 13, appears to be associated with far worse outcomes following neoadjuvant chemoradiation therapy (CRT) for rectal cancer than other K-ras mutations. The results suggest that patients with K-ras codon 13 mutations are resistant to neoadjuvant CRT for rectal cancer and cannot achieve a pathologic complete response (pCR). Other K-ras mutations also may reduce the chance of achieving pCR compared with wild-type K-ras, but only codon 13 mutations appear to show no chance of pCR. Previous studies have shown that K-ras mutations in codons 12 and 13 appear to play a major role in the progression of colorectal cancer. They also are considered potential biomarkers in lung cancer, but the clinical relevance of these mutations remains unclear. Although the findings are still preliminary, it’s hoped that codon 13 and other molecular markers will one day be used to guide therapy, said lead author Marjun Duldulao, MD, a surgery research fellow and general surgery resident at City of Hope Cancer Center, Duarte, Calif. “If we can validate these findings with future studies, and indeed codon 13 mutations do not have complete

pathologic response to chemoradiation, that would change the paradigm. We could select patients for chemoradiation by their tumors,” said Dr. Duldulao. “No one has broken through yet to take molecular markers to the next step but that would certainly be the hope. With more patients, more studies, perhaps we can use these genetic markers to determine treatment for patients.” He presented the findings at the 2012 annual meeting of the Society for Surgical Oncology. Investigators studied 148 patients with stage II or III rectal cancers who were enrolled in a multicenter prospective clinical trial. All patients underwent preoperative therapy of 5-fluorouracil (5-FU) plus radiation therapy, with FOLFOX (oxaliplatin, 5-FU and leucovorin) when appropriate, followed by surgery six weeks later. DNA was extracted from the pretreatment tumor biopsies and genotyping of K-ras was completed by polymerase chain reaction and direct sequencing. Overall, 60 patients (40.5%) were found to have a K-ras mutation. Of these, 66.7% of mutations occurred in codon 12 (n=40), 20% in codon 13 (n=12), 8.3% in codon 61 (n=5) and 5% in other locations (n=3). Patients with K-ras codon 13 mutations did not respond to CRT compared with patients without K-ras mutations

( =0.037). None of the 20 patients with (P codon 13 mutations had a pCR. For all other K-ras mutations, a minority of patients had a pCR, with rates ranging from 17.5% for patients with codon 12 to 20% for patients with codon 61. The study did not have enough patients for the findings to be conclusive, the researchers caution. “We need bigger studies with more patients,” said Dr. Duldulao. Still, experts called the findings “intriguing,” saying the results suggest that patients may one day undergo investigations to determine codon location prior to treatment. “It’s an impressive original investigation,” said Thomas Weber, MD, a professor of surgery at State University of New York Downstate Medical Center and chief of surgery at the Department of Veterans Affairs, New York Harbor Healthcare System in New York City. “This study will focus attention on the biology of tumors with the codon 13 mutations and should attract support for larger studies in the future,” he said. Patients with wild-type mutations had much better outcomes following neoadjuvant CRT than patients with K-ras mutations, with a 33% pCR rate compared with 13.5%, according to the study. Codon 13 mutations were strongly associated with TP53 gene mutation;

75% of patients with codon 13 mutations had TP53 comutation. Other K-ras mutations had a lower rate of comutation of 38%. The comutation may result in further aggressive tumor behavior, said investigators. Previous studies have shown that patients with colorectal cancer and K-ras mutations in codon 13 have more aggressive disease, frequently associated with local and distant metastases at first diagnosis, than patients with codon 12 mutations (Anticancer ( Drugs 2011;22:913-918, PMID: 21795973). The patients included in Dr. Duldulao’s study were originally enrolled in the TIMING trial, a study published last year that looked at the optimal timing of surgery after CRT for patients with advanced rectal cancer ((Ann Surg 2011:254:97-102, PMID: 21494121). The results suggest that intensive neoadjuvant CRT, followed by additional chemotherapy and holding off on surgery for up to 11 weeks, may result in a modest increase in pCR without increasing complications in patients undergoing total mesorectal excision for locally advanced rectal cancer. —Christina Frangou Dr. Duldulao disclosed no financial relationships.

CURRENT PRACTICE

Undisclosed Supplement Use Poses Threat to Cancer Patients Orlando, Fla.—Almost one-third of cancer patients taking supplements did not have them listed on their medication history or had only a partial list of what they were taking, according to a study presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA; poster T05). “It is very important that we specifically ask patients whether they are taking supplements,” said Christan Thomas, PharmD, who led the study when she was a pharmacy student at Gatton College of Pharmacy at East Tennessee State University in Johnson City. “Consumers need to disclose supplement use to their pharmacists so they can manage those interactions and side effects.” In 2011, researchers at the Regional Cancer Center in Johnson City interviewed 99 cancer patients who had been seen at the center and explicitly asked them about supplement use. They then compared these results with the drug information in the patient charts. The researchers found that 27% of patients

taking supplements either had no supplements listed on their medication histories or had only a partial list. The most commonly reported supplements were a multivitamin (54%), vitamin B12 (22%), potassium (22%), fish oil (20%), iron (17%), calcium plus vitamin D (17%), vitamin D alone (14%) and calcium alone (8%). Other supplements included red yeast rice and vitamin E. No potential chemotherapy–supplement interactions were specifically identified in the study population, but several supplements reportedly taken by patients have been shown to have adverse effects in cancer patients, the researchers noted. If taken in high doses, fish oil, for example, can reduce platelet aggregation and increase risk for bleeding. Calcium and iron can cause constipation, which is often already a problem with cancer patients on opioids. Red yeast rice and vitamin E can increase liver enzymes and cause fatigue and weakness.

Dr. Thomas believes that although a reminder to ask about supplements was at the top of the patient history form, nurses or other health care professionals just forgot to ask and patients didn’t connect the dots. “I think a lot of patients don’t consider supplements to be drugs because they are natural and you can get them over the counter,” said Dr. Thomas.

A More Holistic Approach Cathy Rosenbaum, PharmD, MBA, RPh, a clinical effectiveness and safety officer at Bethesda North Hospital in Cincinnati, said that disclosure of supplement use to health care professionals is not the only problem: Overuse of supplements, without the advice and consent of a physician, also is a concern. A better approach to achieving holistic health, she noted, would be to adopt an optimal nutrition plan that embraces the use of locally grown, organic whole foods—“as much as one can afford,” noted Dr. Rosenbaum, who also is the

founder and CEO of Rx Integrative Solutions, a private consulting practice in holistic medicine located in Cincinnati. “For cancer patients trying to use vitamins, minerals and protein supplements who are having difficulty eating due to side effects from chemotherapy, nutrition in the form of a smoothie might be a more appropriate solution,” she added. According to the National Center for Health Statistics, more than half of all Americans use some kind of vitamin or supplement ((NCHS Data Brieff 2011;61:18, PMID: 21592424). A recent study of cancer patients in the Veterans Administration medical system found that 25% of patients who were using supplements did not tell their physicians about them ((J Altern Complement Med d 2004;10:560564, PMID: 15253863). —Kate O’Rourke Drs. Thomas and Rosenbaum reported no relevant financial conflicts of interest.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • AUGUST 2012

‘A Long Way To Go’: Genome Sequencing and Cancer Risk T

he ability to scan an individual’s DNA and determine the precise risk he or she has for developing a given disease is still far closer to science fiction than fact. A recently published analysis showed that most people would test negative for the genetic underpinnings of many common diseases—including several types of cancer—even when they actually have at least one of the diseases (Sci Transl Med 2012 Apr 2. [Epub ahead of print]). “A fortune-teller with this crystal ball would soon go out of business,” lead investigator Bert Vogelstein, MD, a professor of oncology at Johns Hopkins Kimmel Cancer Center in Baltimore, said at the American Association for Cancer Research’s 2012 annual meeting, where he released results of the study. However, there also was good news: Based on studies of genotyping and disease risk in monozygotic twins, the analysis indicated that more than 90% of people would test positive for a clinically meaningful genetic susceptibility to at least one disease, allowing them to take preventive health and lifestyle measures. The results underscore the complex nature of disease development. “I thought it was quite a good paper, in that they formalize something we knew informally before—that in cancers and most other prevalent diseases, genetics alone is a minor component,” said Tom Curran, PhD, the deputy scientific director at The Children’s Hospital of Philadelphia Research Institute and the associate director of translational genomics at the University of Pennsylvania in Philadelphia. “Moving forward, one would like to take full advantage of personal genome sequencing, including sequencing of methylation patterns in conjunction with analyses of other components of the epigenome that form the interface between the genome and the environment.” The paper was an ambitious genetic and mathematical analysis of information from 53,666 monozygotic twin pairs. Dr. Vogelstein’s team gathered the data from registries in the United States, Finland, Denmark, Norway and Sweden. They calculated the greatest theoretical ability of whole genome sequencing to determine risk for 27 diseases, including cancers and autoimmune and cardiovascular diseases. More than 50% of patients who had one of the 13 diseases would not test positive on a genetic assay. Among the cancers included in the analysis, prostate cancer was the least likely to produce a negative genetic test result, with about 53% of individuals with this disease testing genetically negative. The best result was for coronary heart disease in men, with just over 90% of men with this condition

likely to test positive for it. Alzheimer’s disease, thyroid autoimmunity and type 1 diabetes also were associated with high percentages of positive testing. The researchers also found that the maximum fraction of individuals with or without each disease who would receive a positive test for that disease—indicating a clinically meaningful risk—was very low. Among the cancers, prostate cancer had the highest percentage of positive test results, at about 7%. Leukemia had

the lowest, at around 1%. Risk for coronary heart disease death was associated with the highest percentage, at approximately 81%. Overall, the investigators determined that more than 95% of men and more than 90% of women would receive at least one positive test result, assuming risk alleles are distributed in real life in a way that would produce maximum sensitivity for testing. Dr. Curran said that prediction of

disease development has “a long way to go. We expect there will be successes along the way with individual rare diseases. I don’t think there’s going to be a big, blinding flash of insight—it is more likely that the knowledge is going to accrue incrementally.” —Rosemary Frei, MSc Drs. Vogelstein and Curran do not have any conflicts of interest to disclose.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Phased Ipilimumab Therapy Improves PFS in NSCLC From the Journal of Clinical Oncology

he phased administration of ipilimumab, administered following the combination of paclitaxel and carboplatin, improved progression-free survival (PFS) and immune-related PFS (irPFS) as first-line treatment for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). An international team of researchers, headed by Thomas Lynch, MD, of the Yale Cancer Center in New Haven, Conn., sought to improve on survival rates in patients with advanced NSCLC generated by platinum-based chemotherapy regimens. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation; because ipilimumab (Yervoy; Bristol-Myers

Squibb) blocks the binding of CTLA-4 to its ligands, the team decided to add it to a standard paclitaxel-carboplatin regimen, and compare the results with those of the paclitaxel-carboplatin regimen with placebo, which served as the control. Additionally, the administration of ipilimumab was accomplished either concurrently; together with paclitaxel-carboplatin; or in a phased regimen, in which the paclitaxel-carboplatin combination was given first, followed by ipilimumab. The results of this randomized, double-blind, international multicenter Phase II study were published in the Journal of Clinical Oncology (2012;30:2046-2054, PMID: 22547592). The study included 204 chemotherapy-naive patients with NSCLC who were assigned on a 1:1:1

EXPERT INSIGHT Patrick C. Ma, MD, MSc Director, Aerodigestive Oncology Translational Research, Cleveland Clinic Taussig Cancer Institute, and Assistant Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

n recent years, there have been a number of key advances in therapeutics for patients with advanced NSCLC. The emergence of a new and more tolerable generation of chemotherapeutics with pemetrexed marked the beginning of the era of histologydriven personalized therapy and maintenance chemotherapy. Needless to say, the approval of the anti-vascular endothelial growth factor bevacizumab for anti-angiogenic therapy; the epidermal growth factor receptor antagonist tyrosine kinase inhibitor (TKI) erlotinib; and most recently the TKI crizotinib to inhibit oncogenic fusion EML4-ALK, all bore witness to

a translational breakthrough in cancer-targeted therapy. Nonetheless, the advance in immunotherapeutic approach to lung cancer has been trailing behind. The recent report by Thomas Lynch, MD, and his colleagues met its primary end point of improved irPFS for phased ipilimumab, an anti–CTLA-4 antibody, when combined with paclitaxel-carboplatin as front-line therapy versus the control—but it did not for concurrent ipilimumab. Phased ipilimumab also improved PFS, according to the modified World Health Organization criteria. Overall rates of grade 3/4 immune-related adverse

basis to receive either the concurrent ipilimumab regimen (i.e., four doses of ipilimumab plus paclitaxel-carboplatin followed by two doses of placebo plus paclitaxel-carboplatin); the phased ipilimumab regimen (i.e., two doses of placebo plus paclitaxel-carboplatin followed by four doses of ipilimumab plus paclitaxel-carboplatin); or the control regimen (i.e., six doses of placebo plus paclitaxel-carboplatin). Doses were ipilimumab 10 mg/kg; paclitaxel 175 mg/m2; and carboplatin, area under the curve 6. IV induction treatment was administered every three weeks for as many as 18 weeks; maintenance therapy was either ipilimumab or placebo every 12 weeks. The primary end point of improved irPFS was met for phased ipilimumab versus the control regimen (hazard

ratio [HR], 0.72; P=0.05). Concurrent ipilimumab administration did not meet this end point. PFS also was improved with the phased ipilimumab regimen (HR, 0.69; P=0.02). The median irPFS was 5.7 months for phased ipilimumab, 5.5 months for concurrent ipilimumab and 4.6 months for the control regimen. The median PFS was 5.1, 4.1 and 4.2 months, respectively. The best overall response rate (BORR) was 32%, 21% and 14%, respectively. The best immune-related BORR was 32%, 21% and 18%, respectively. The median overall survival (OS) was 12.2, 9.7 and 8.3 months, respectively. The investigators concluded that the phased administration of ipilimumab following paclitaxel-carboplatin administration warrants further investigation in patients with NSCLC.

events were better in phased ipilimumab than in concurrent ipilimumab therapy. No death was reported in phased therapy, whereas both the concurrent therapy and the control arms each had one treatment-related death. These are very interesting results that certainly warrant further clinical and translational investigations to gain better insight into the mechanism of action and the role of tumor-infiltrating immune cells in affecting therapy outcome. One obvious question to ask is how would ipilimumab (phased) ultimately measure up against bevacizumab (concurrent) when combined with platinum-paclitaxel in front-line advanced NSCLC therapy? As pointed out by the authors, the reported median OS of 12.2 months for the phased ipilimumab arm is comparable with that previously reported for the carboplatin-paclitaxel-bevacizumab combination regimen of 12.3 months. Of note, the former is the result of a Phase II study, whereas the latter is the outcome of a Phase III registration trial study. It will be interesting to see

how the results of a Phase III study of the anti–CTL-4 immunotherapeutic strategy would pan out eventually. Of particular interest also is that, although bevacizumab is being used preferentially in non-squamous histology, ipilimumab (phased) in the present trial appears to show improved efficacy for “squamous” histology, and not for its non-squamous counterpart. If proven to be valid, the two treatment strategies ultimately may be complementary for use to benefit all patients with NSCLC. Although ipilimumab use in melanoma first made the national spotlight at the plenary session of the American Society of Clinical Oncology meeting in 2011, it has now quickly demonstrated promise in NSCLC, which also is highly welcome. It is anticipated that more significant strides in immunotherapy will be made in upcoming years to treat NSCLC, a disease that has not typically been regarded as truly amenable to immunotherapy in the past. Dr. Ma reported no financial disclosures relevant to this study.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

In SCLC, Cranial Irradiation Benefits Incomplete Responders From Clinical Lung Cancer

atients with limited-stage (LS) small-cell lung cancer (SCLC) who have had an incomplete response (IR) following chemotherapy and chest radiotherapy nonetheless benefit from prophylactic cranial irradiation (PCI), a Canadian retrospective study has found. Brain metastasis is not uncommon in patients with SCLC, even among those achieving a complete response (CR) following chest therapy. The suggestion in some studies, which appeared more than a decade ago, that PCI might be effective in patients

with a CR has meant that they have had the option to receive this therapy; for those with an IR, however, that has generally not been the case. The present study (Clin Lung Cancer 2012 June 4. [Epub ahead of print], PMID: 22673624), by Patricia Tai, MD, and colleagues from the province of Saskatchewan in Canada, revisited the question of whether this cohort of patients might receive some benefit. This population-based study looked at patient records from 1981 to 2007 and found 289 CR and IR patients with SCLC who were treated with chest radiotherapy and chemotherapy, with (n=177, 61.2%) or without PCI. Typical radiotherapy doses were

EXPERT INSIGHT John Greskovich Jr., MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, and Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

CLC accounts for approximately 15% of all lung cancers in the United States, for an estimated 33,000 cases per year, and is strongly correlated with tobacco use. Compared with nonsmall cell lung cancer (NSCLC), SCLC has a more rapid doubling time, higher growth fraction and earlier development of distant metastasis, including a high rate of metastasis to the brain. The brain is considered a “sanctuary site” for SCLC cells, and brain relapses commonly are seen in more than 50% of cases despite the use of systemic chemotherapy with or without chest radiation therapy. Brain metastases from SCLC are not adequately controlled by chemotherapy due to the presence of the blood–brain barrier, which prevents achievement of a tumoricidal

dose in the central nervous system. PCI is the delivery of whole-brain radiation in moderate doses to lessen the risk for brain recurrence of SCLC. There is category 1 evidence supporting the use of PCI from the completion of prospective randomized trials (PRT) showing PCI’s role in decreasing the incidence of brain metastasis in both LS and extensive-stage (ES) SCLC patients achieving either a partial response (PR) or CR to therapy.1 Most PRTs did not have sufficient statistical power to detect a significant survival benefit for PCI. But a meta-analysis published in The New England Journal of Medicine (NEJM) in 1999 of seven PRTs using individual patient data (N=987 patients) showed PCI significantly improved three-year OS by 5.4%

2,500 or 3,000 cGY in 10 fractions over two weeks or 3,000 cGY in 15 fractions over three weeks. For the group as a whole, PCI conferred a significant overall survival (OS) and cause-specific survival (CSS) benefit ((P=0.0011 and 0.0005, respectively). There was a significant difference in time to symptoms of first recurrence with PCI (16.9 months) versus without (13.2 months; P=0.0006), and there was a significant delay in symptoms of first recurrence in the brain (with PCI, 20.7 months; without PCI, 10.6 months; P<0.0001). Also of note, among the cohort with a CR, the first metastatic site was the brain in 12.5% who received PCI and 45.5% who did

not (P ( =0.02), and in the 93 patients who constituted the IR cohort, the findings were similarly divergent: 6.1% in those receiving PCI and 27.6% in those who did not ((P=0.05). The symptom-free period before brain metastasis was significantly longer in those with IR, from 8.9 months for those without PCI to 18.5 months among those with PCI ( =0.03). However, in patients with IR, (P PCI did not confer either an OS or CSS benefit ((P=0.32 and 0.39, respectively). The researchers, noting the improved quality of life that is conferred by delaying the burden of metastases to the brain, concluded that their study provides support for using PCI in patients with IR.

(from 15.3% to 20.7%; P<0.01) in LS or ES SCLC patients achieving a CR to initial therapy.2 Furthermore, the occurrence of brain failure at three years decreased from 58.6% to 33.3%. The article by Tai et al evaluating PCI’s effectiveness in a population study of all LS SCLC patients treated in Saskatchewan province from 1981 to 2007 supports the benefit of PCI in improving survival in patients achieving a CR and decreasing risk for brain recurrence and improving symptomfree progression-free survival in all patients responding to therapy. In ES SCLC patients, a PRT of PCI versus no PCI from the European Organisation for Research and Treatment of Cancer published in NEJM in 2007 in 286 patients who had any response to chemotherapy revealed PCI decreased one-year symptomatic brain metastasis from 40.4% to 14.6% ( <0.001) and doubled one-year OS (P from 13.3% to 27.1% ((P=0.003).3 No difference in cognitive or emotional function was noted on quality-of-life testing. Excess late neurologic sequelae have not been reported in studies when PCI is delivered after the completion of chemotherapy and the dose per fraction is kept at 3 Gy or lower. Current recommended

dose-fractionation schemes for PCI are 25 Gy in 10 fractions or 30 Gy in 15 fractions. Following recommended dosefractionation schemes and allowing at least three weeks between completion of chemotherapy and start of PCI achieves an improved therapeutic ratio by decreasing brain failures, improving OS, and limiting neurotoxicity. That said, PCI should be avoided in patients with significant baseline-impaired mental function or poor performance status (Eastern Cooperative Oncology Group 3/4) due to the possibility of worsening quality of life.

References 1. National Comprehensive Cancer Network (NCCN) Guidelines. Small cell lung cancer version 2:2012. www.NCCN.org. 2. Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476484, PMID: 10441603. 3. Slotman B, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357:664-672, PMID: 17699816.

Dr. Greskovich reported no financial disclosures relevant to this study.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

Is Maintenance Immunotherapy Beneficial? Italian study suggests immunotherapy improves survival; U.S. experts point to study flaws Chicago—Maintenance immunotherapy has a favorable effect on five-year overall survival (OS) rates for the treatment of advanced cancers, according to the results of an Italian study. The levels of natural killer cells also were increased by the treatment, vascular endothelial growth factor (VEGF) levels were decreased significantly and the cost of treating colorectal cancer (CRC) was 82% lower compared with the estimated cost of bevacizumab (Avastin, Genentech) treatment.

Eastern Cooperative Oncology Group (ECOG) performance status 0; 35% had status 1; and 3% had status 2. The main primary disease sites were breast, lung, ovary, colon/rectum and stomach. The main metastatic sites were liver, lung, abdomen, bone and lymph nodes. Twenty-six percent had two or more metastatic sites. After five years, the natural killer cell level rose from an average of 309 to 579/ mm3, whereas the VEGF level fell from 520 to 150 ng/mL. These were the primary end points. Two secondary end points were the cost of IL-2 and RA compared with bevacizumab and the adverse event (AE) profile. AEs were mild and only one patient had an AE (urticaria) severe enough to cause withdrawal from the study. The other secondary end points included the five-year OS rate compared with the SEER data for the most commonly treated metastatic cancers. The OS rates were significantly lower

“The best way to use immunotherapy is in this setting— that of minimal residual disease after chemotherapy.” —Francesco Recchia, MD

The investigators compared the results from a five-year trial of maintenance immunotherapy in 500 patients with stage IV cancer, who had benefited from chemotherapy with data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database. They found maintenance immunotherapy with interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) provided significant benefits in lung and breast cancers and CRC, as well as in renal cell carcinoma. The study was presented as a poster at the American Association for Cancer Research 2012 annual meeting (abstract 5366). Suresh Ramalingam, MD, the director of Medical Oncology at Winship Cancer Institute at Emory University in Atlanta, said that the study has significant limitations. The study included only patients who benefited from chemotherapy, and “this group in general tends to do well compared with those who do not respond to chemotherapy,” Dr. Ramalingam said. Furthermore, the researchers compared the outcomes with historical data rather than using a control arm in the trial, and they also studied individuals who had a variety of cancers. Additionally, the researchers’ claim that there is an 82% reduction in cost for CRC treatment “is based on a number of assumptions including the fact that VEGF levels are correlated with clinical benefit with anti-angiogenic

The natural killer cell has punctured and destroyed a larger tumor cell. (Inset) Two natural killer cells attack a cancer cell.

‘‘The The best best way way to to use use immunotherapy immunotherapy is is iin n this this setting—that setting—that of of minimal minimal residual residual d isease a fter c hemotherapy.” disease after chemotherapy.” —Francesco — —F Fra ranc ranc nce essc co oR Recchia, ec e cc ch hia ia, M MD D

agents—and this has not been proven,” added Dr. Ramalingam. He believes, however, that the study provides support for other promising research that targets the immune system in prostate cancer and melanoma. In the study, the treatment schedule started with one year of repeated cycles of self-administered subcutaneous IL-2 at 1.8×106 IU and oral RA at

0.5 mg/kg for five days a week for two consecutive cycles of three weeks, with a one-week rest in between. Treatment was continued over the next year for one week every month and in the following three years for one week every other month. Fifty-two percent of the patients were women and at baseline the average age was 63 years. Sixty-two percent had

in colorectal, lung and breast cancers, as well as in renal cell carcinoma, compared with the study population. “The best way to use immunotherapy is in this setting—that of minimal residual disease after chemotherapy,” lead investigator Francesco Recchia, MD, the director of oncology at the Civilian Hospital in Avezzano, Italy, told Clinical Oncology News. “You can destroy the cells that are left after chemotherapy with the immune system, or at least you can have long-term control of the proliferation of the cells.” —Rosemary Frei, MSc Dr. Ramalingam has been a member of Genentech’s scientific advisory board. Dr. Recchia did not disclose any conflicts of interest.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Subtypes of Lung Adenocarcinoma Uncovered Three distinct patterns of gene expression influence clinical phenotype, response to therapy

ung adenocarcinoma intrinsic molecular subtypes correlate with grossly distinctive genomic alterations and patient response to therapy, according to a new study ((PLoS ONE 7:e36530. doi:10.1371/journal.pone.0036530).

“The squamoid subtype has the least distinctive patterns in relationship to oncogenes,” senior author D. Neil Hayes, MD, MPH, an associate professor of medicine at the University of North Carolina at Chapel Hill, said in an interview.

‘This study suggests that even though lung cancer is complex, the number of predominant patterns is relatively small.’ —D. Neil Hayes, MD, MPH The subtypes—bronchioid, magnoid and squamoid—represent the main naturally occurring patterns of lung adenocarcinoma gene expression, encompassing different functional pathways and patient outcomes, the investigators reported. “The study is still preliminary, not practice-changing in an imminent way, but very, very interesting,” H. Jack West, MD, the medical director of thoracic oncology at the Swedish Cancer Institute, in Seattle, who was not affiliated with the study, told Clinical Oncology News. “It could be an early step toward fundamentally changing how we view and approach lung cancer.” The researchers used published cohorts to detect genomic alterations co-occurring with the molecular subtypes. To provide independent validation, they assayed the tumors of a novel cohort of patients with lung adenocarcinoma (N=116). They found that the subtypes had significant differences in gene sequence mutations, chromosomal instability, regional DNA copy number, DNA methylation and integrated alterations. For example, bronchioid had the greatest EGFR mutation frequency, whereas magnoid had the greatest mutation frequencies in TP53, KRAS and STK11.

“We expect to find characteristic mutations of the squamoid subtype.” Clinical phenotypes differed between the subtypes. For example, bronchioid was characterized by patients who were female and nonsmoking and who presented with early-stage cancer. High smoking exposure and late-stage presentation were common in magnoid and squamoid, and magnoid had a high prevalence of male patients. Patient outcomes also varied between the subtypes. Bronchioid had the best outcome in patient overall survival (Figure), and may have the greatest sensitivity to EGFR inhibitors, whereas magnoid cancers responded best to chemotherapy. “A striking result in the paper is that all of the benefit of chemotherapy was limited to the magnoid subtype,” said Dr. Hayes. The study findings are not ready for clinical application, Dr. Hayes said. “The subtypes have no clinical diagnostic assay. There may be a theoretical benefit for patients in the future.” Dr. West agreed. “In the next three to five years it could lead to a change in how we practice, but not next week.” He added, “I would like to see this replicated in larger settings, and applied prospectively.”

‘[This] could be an early step toward fundamentally changing how we view and approach lung cancer.’ —H. Jack West, MD

AT A GLANCE Three molecular subtypes represent the naturally occurring gene expression patterns of lung adenocarcinoma

Lung adenocarcinoma at 40x magnification.

Dr. Hayes suggested that the study had achieved an advance. “Before the current study, the etiology of subtypes was unknown. … This study suggests that even though lung cancer is complex, the number of predominant patterns is relatively small.” Dr. West said, “Subtypes are like colors. If you jumble them together, you get muddy brown—mediocre results. If you distinguish them and identify and

observe the differences between the colors, it has the potential to do a better job of optimizing our results for patients by honing our care for the tumors of individual patients.” —George Ochoa Dr. West reported no relevant financial disclosures. Dr. Hayes disclosed a patent pending on gene sets related to tumor subtypes.

100

Overall Survival, %

40 Bronchioid Squamoid Magnoid

Years After Surgery

The subtypes produced different clinical phenotypes of disease There is no clinical assay yet, but the findings could direct treatment within five years

Figure. Overall survival among three primary molecular subtypes of lung adenocarcinoma.1 1. Data drawn from five published cohorts assayed for gene expression and including survival follow-up; N = 807.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2012

VOGL, NY continued from page 1

cancer following castration in premenopausal women or after estrogen in the postmenopausal setting, upsetting the hormonal milieu of hormone-dependent tumor cells can produce waves of tumor apoptosis and major benefits for our patients.

prednisone, median survival improved from 10.9 to 14.8 months, median time to PSA progression from 6.6 to 10.2 months and median time to radiographic progression from 3.6 to 5.6 months; PSA response improved from 6% to 29%, partial response by RECIST criteria from 3% to 14%, and pain was improved more often on the abiraterone arm. Toxicity from abiraterone was mild and rarely more than that of prednisone alone.

Insurance companies have been allowed to restrict prescribing of obviously effective drugs according to marketing restrictions imposed on pharmaceutical companies by the FDA. Over the past 30 years, small series have reported occasional minor benefits with ketoconazole, anti-androgens like flutamide and bicalutamide, megesterol, high-dose estrogen and estramustine in the setting of castrate levels of testosterone. Abiraterone and enzalutamide represent the first of what hopefully will be a progressively more effective wave of hormone treatments for prostate cancer. Abiraterone works by blocking the enzyme cytochrome P450 (CYP)-17, which converts adrenally produced precursors to androgen in the tumor and in other tissues. In a Phase I/II study restricted to men without prior chemotherapy treatment, abiraterone (Zytiga, Janssen) produced a greater than 50% drop in serum prostatespecific antigen (PSA) in 67% of patients and 38% of patients (nine of 24) with measurable disease achieved Response Evaluation Criteria in Solid Tumors (RECIST) partial response. Median time to PSA progression was 229 days for all patients, 253 days for those with greater than 50% drop in PSA, and 393 days for those with greater than 90% drop in PSA.1 Toxicity was mild and largely restricted to effects of mineralocorticoid excess produced by the adrenocorticotropic hormone (ACTH) induced in the pituitary to compensate for adrenal blockade. Administration of low doses of prednisone blocks the ACTH secretion, and that is how the drug is given in the United States today. In a Phase II trial restricted to men who had prior docetaxel chemotherapy, 51% of 47 patients entered had PSA declines of greater than 50%, 27% (eight of 30 patients) had partial responses of measurable disease by RECIST criteria, and median time to PSA progression for the entire cohort was 169 days.2 The Phase III trial that led to the drug’s approval in the United States and Europe compared abiraterone plus prednisone with prednisone alone in a population of men with castration-resistant prostate cancer who all had undergone prior docetaxel chemotherapy. With about 1,200 men in the trial, and two-thirds assigned to abiraterone plus low-dose

The obvious conclusion to be drawn from these results is that abiraterone is an excellent drug for metastatic prostate cancer in men with castration-resistant disease. In accordance with the trial’s eligibility, the FDA restricted marketing of the drug to men who would have been eligible for the trial (i.e., those with prior docetaxel treatment). Alas, insurance companies and prescription plans decided not to pay for the drug unless the prescribing physician attests that the patient has had prior treatment with docetaxel. This seems a silly restriction except on the moderate chance that patients who get the relatively toxic docetaxel first will either die or deteriorate sufficiently so as to preclude further therapy before they can get the safe, oral, nontoxic drug abiraterone, which costs insurance $5,000 per month—much more than docetaxel, which is now available as a generic. Those in oncology who treat hormone receptor–positive breast cancer have developed a policy of giving successive hormone therapies as long as it appears they have some chance of benefiting the patient, and switching to the more toxic chemotherapy, which rarely produces prolonged responses, only after failure of all reasonable hormonal manipulations. There is no reason not to apply the same paradigm to metastatic prostate cancer, except that insurance companies have

it proves the remarkable efficacy of abiraterone plus prednisone over prednisone alone in men with metastatic prostate cancer without prior docetaxel exposure. Overall survival curves split at 15 months and were separated by about 20% at 30 months (projected with partial follow-up). Abiraterone plus prednisone proved impressively superior for multiple end points (Table). Dr. Ryan did not say why eligibility in COU-AA-302 was restricted to men with no symptoms or with such mild symptoms that they did not require narcotics. There may have been an ethical consideration in that the standard therapy for symptomatic men is docetaxel and if they were included, then the comparator would have to be docetaxel,

Steven Vogl, MD Medical Oncologist, New York City

targets for drug marketing than medical oncologists, although this may just be hubris on my part. Many oncologists—myself included— are comfortable following asymptomatic men with metastatic prostate cancer on little or no anticancer treatment for years at a time, even if the PSA level

Table. Results of the COU-AA-302 Trial Presented at ASCO 2012 Abiraterone Plus Prednisone

Prednisone Alone

PSA response

62%

24%

RECIST response in measurabledisease patients

35%

16%

>14 months

8 months

Median time to: Radiographic progression PSA progression

11.1 months

5.6 months

Start of chemotherapy

25.2 months

16.8 months

Opiate initiation

Not reached

23.7 months

Deterioration in performance status

12.3 months

10.9 months

PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors

not the relatively ineffective prednisone alone. There may have been a design consideration by the company: Abiraterone plus prednisone versus prednisone alone is a “slam dunk,” a guaranteed positive trial designed to win approval by the FDA. Abiraterone plus prednisone might not prove superior to docetaxel by some major end points, and overall survival might be identical if crossover to abiraterone were allowed for docetaxel patients.

There is no medical reason to restrict use of abiraterone in men who have not had prior docetaxel to those with no symptoms— it clearly worked in symptomatic men with prior docetaxel use. been allowed to restrict prescribing of obviously effective drugs according to marketing restrictions imposed on pharmaceutical companies by the FDA. The presentation at ASCO 2012 by Charles Ryan, MD, an associate clinical professor of hematology/oncology at the University of California, San Francisco, of the results of the COU-AA-302 trial should have solved the problem because

EDITORIAL BOARD COMMENTARY

I wonder if there was a marketing consideration by Janssen to allow the company to eventually market abiraterone primarily to urologists, who as a group are more comfortable treating asymptomatic men, rather than to medical oncologists, who generally get involved when symptoms, especially bone pain and soft tissue masses, develop. I suspect that urologists as a group are easier

is rising, provided the patient can deal with this psychologically. The MRC PR03 trial of early versus late androgen ablation for asymptomatic metastatic prostate cancer ultimately showed no significant survival advantage with early androgen ablation while the patient lacked symptoms.3 There is no medical reason to restrict use of abiraterone in men who have not had prior treatment with docetaxel to those with no symptoms; it clearly worked in symptomatic men with prior exposure to docetaxel. Abiraterone is an effective drug, much less toxic than docetaxel, and oncologists and urologists see VOGL, NY, Y page 28

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

SOLID TUMORS

VOGL, NY continued from page 27

should be allowed to give it to symptomatic patients who need it and patients’ insurance plans should pay for it. One could argue that abiraterone should be proven equal to docetaxel before it is given to symptomatic men. Yet primary androgen ablation for symptomatic prostate cancer (by castration or pituitary suppression) has never been subjected to this test! Because both androgen ablation and abiraterone are much less toxic than docetaxel, I think it unreasonable to request that these nontoxic, effective

CLINICAL ONCOLOGY NEWS • AUGUST 2012

therapies prove themselves equal or superior to toxic palliative chemotherapy. Minimally toxic hormone therapies, even if only moderately effective—and androgen ablation and abiraterone are very effective—are almost always better palliation than toxic chemotherapy. Patients with prostate cancer need a representative at the table when Janssen and the FDA negotiate the label for abiraterone in men without prior exposure to docetaxel. Either the label should read that the indication for abiraterone is metastatic prostate cancer requiring treatment, or it should have a stipulation that any marketing restriction on Janssen regarding symptom

status of the patient should not be interpreted by the insurance industry as a restriction on the use of the drug in asymptomatic men. An alternative long-term solution would be to force insurance companies by statute to look “beyond the label” with properly constituted panels of experts. The FDA was never designed, and certainly has not been supported in terms of budget, to be an agency that decides medical practice. It is charged only with granting marketing permission and approving marketing claims that may be made by the pharmaceutical industry. That indications on FDA labels have become standards of practice to the insurance industry (since they come

free and are public) is only yet another example of the dysfunction of the American health care system.

References 1. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-3748, PMID: 19470933. 2. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-1495, PMID: 20159823. 3. Kirk D. Timing and choice of androgen ablation. Prostate Cancer Prostatic Dis. 2004;7:217-222, PMID: 15278095.

Article and Review Reprints Reprints of Clinical Oncology News articles and reviews are available. Call Julianna Dawson at (212) 957-5300 x271. Reprints can be ordered in black & white or 4-color.

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CLINICAL ONCOLOGY NEWS • AUGUST 2012

Clinical Conundrums

Prepared by

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

Focus on ASCO 2012: Part I

QUESTIONS

1. True or False. Antibody-directed

stimulation of programmed cell death protein-1 (PD-1) or its ligand (PD-L1) can overcome immune resistance and mediate tumor regression.

2. True or False. In the study pre-

sented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) by Suzanne L. Topalian, MD, of Johns Hopkins University School of Medicine in Baltimore, the fully humanized antibody against PD-1 protein, BMS936558, produced tumor shrinkage in approximately one-fourth of studied cancer patients, with response rates of 28% in melanoma, 27% in renal cancer and 18% in non-small cell lung cancer.

3. True or False. In the study pre-

sented by Dr. Topalian, the fully humanized antibody against PD-1 protein, BMS936558, caused combined grade 3 and 4 toxicity in approximately 45% of treated patients.

4. True or False. The Study Group

Indolent Lymphomas (StiL) NHL1 trial demonstrated a progression-free survival (PFS) benefit and improved tolerability with bendamustine and rituximab (B-R) combination when compared with CHOP-R (cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab) combination, in elderly patients with mantle cell lymphoma (MCL) and in all studied patients with previously untreated indolent lymphomas.

5. True or False. Olanzapine (Zyprexa, Eli Lilly), an FDA-approved antipsychotic

ANSWERS

1. False. Antibody-directed blockade

of PD-1, a T-cell co-inhibitory receptor or its ligand (PD-L1) can overcome immune resistance with resultant tumor regression. Currently, about five PD-1 immune checkpoint-blocking compounds are undergoing different phases of trials. Topalian SL, Brahmer JR, Hodi FS, et al. AntiPD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA2509. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454, PMID: 22658127. Brahmer JR, Tykodi SS, Chow LQ, et al.

medication, effectively controlled chemotherapy-induced nausea and vomiting (CINV) in patients who failed to respond to guideline-recommended antiemetic therapy in a Phase III trial.

6. True or False. Primary care physi-

12.

True or False. HER2 receptor does not interact directly with the growthfactor ligand.

cians (PCPs) are well aware of the late side effects of cancer therapies among cancer survivors.

13. True or False. Unlike asymptom-

7. True or False. Early results of the

international Phase III EMILIA (A Randomized, Multicenter, Phase III OpenLabel Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy) trial demonstrated that trastuzumab emtansine (T-DM1), the antibody-drug conjugate linking trastuzumab (Herceptin, Genentech) to a cytotoxic agent, delayed disease progression by 9.6 months compared with 6.4 months with the standard second-line therapy of capecitabine (Xeloda, Roche) and lapatinib (Tykerb, GlaxoSmithKline) among all patient age groups with advanced HER2-overexpressing breast cancer.

8. True or False. In luminal-type

9. True or False. Administration of abi-

raterone acetate (Zytiga, Janssen) in combination with leuprolide and prednisone prior to radical prostatectomy achieved pathologic complete response or near complete response in one-third of men with high-risk, localized prostate cancer.

10. True or False. A randomized

Phase III trial of adjuvant chemotherapy with PCV (procarbazine [Matulane, Sigma Tau], lomustine [CeeNU, BristolMyers Squibb], and vincristine) following standard radiation therapy delayed disease progression but did not increase overall survival (OS) in patients with anaplastic oligodendroglial tumors (AOD).

breast cancer, massively parallel sequencing (MPS) demonstrated that mutations in GATA3 were associated with greater suppression of proliferation with aromatase inhibitor (AI) treatment, suggesting that mutGATA3 might predict endocrine response.

mide-bortezomib-dexamethasone produces rapid and complete hematologic response in patients with light chain (AL) amyloidosis.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465, PMID: 22658128.

at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA2509.

2. True. A subanalysis of these data

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454, PMID: 22658127.

hinted that the PD-L1 protein might serve as a biomarker of response. More than one-third of patients expressing PD-L1 responded to this antibody, whereas responses were not observed among patients lacking PD-L1 expression. No responses were observed in patients with colorectal or castrationresistant prostate cancer. Correct patient selection will be the key in ongoing (NCT01354431 and NCT01358721) and future trials. Topalian SL, Brahmer JR, Hodi FS, et al. AntiPD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. Presented

11. True or False. Cyclophospha-

3. False. Drug-related grade 3 or 4

toxic effects occurred in 14% of patients who received the anti–PD-1 antibody, suggesting that therapy can be delivered safely in an outpatient setting. Among adverse events (AEs) of special interest, pneumonitis (3%) was observed, with findings ranging from isolated radiographic abnormalities to progressive, diffuse infiltrates associated with clinical symptoms in a small number of patients. Only 5% of patients discontinued treatment due to AEs.

atic follicular lymphoma or smoldering multiple myeloma, patients with smoldering Waldenström macroglobulinemia (SWM) should be treated at diagnosis to prevent the development of hyperviscosity-related effects.

14. True or False. John Leonard,

MD, and colleagues at Weill Cornell Medical College, New York City, elegantly combined functional imaging using fluorothymidine–positron emission tomography (FLT-PET) and immunohistochemistry to provide important information about target inhibition and the effects this inhibition has on proliferation and metabolism in patients with relapsed mantle cell lymphoma using the novel cyclin-dependent kinase (cdk) inhibitor PD0332991.

15. True or False. Aristeidis Chaid-

os, MD, PhD, and colleagues at Imperial College London demonstrated that higher doses of CD4− invariant natural killer T (iNKT) cells in peripheral blood stem cell grafts are associated with protection from acute graft-versus-host disease (aGVHD).

Topalian SL, Brahmer JR, Hodi FS, et al. AntiPD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA2509. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454, PMID: 22658127.

False. The StiL NHL1 study was a multicenter, randomized, Phase III study that compared B-R and CHOPR as first-line treatment in indolent lymphomas and MCL. The PFS benefit with B-R was maintained in all indolent histologic subtypes except marginal-zone lymphoma. The OS did not For answers see CONUNDRUMS, S page 30

CURRENT PRACTICE

CONUNDRUMS continued from page 29

differ between the treatment arms. Of note, patients were allowed to cross over upon disease progression. More patients received salvage treatment with B-R than with CHOP-R, and more received transplantation after CHOP-R. Rummel MR, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent and mantle cell lymphomas: updated results from the StiL NHL1 study. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 3.

5. True. The double-blind, random-

ized controlled Phase III trial enrolled 205 chemotherapy-naive patients who were treated with highly emetogenic chemotherapy. All patients were given standard guideline-recommended antiemetic therapy. Of the 205 patients, 80 developed breakthrough CINV and were randomly assigned to 72 hours of treatment with either oral olanzapine at 10 mg per day or oral metoclopramide at 10 mg per day (three times a day for three days). During 72 hours of monitoring, 71% patients in the olanzapine arm and 32% patients in the metoclopramide (P ( <0.001) arm had no vomiting, respectively. Navari RM, Nagy CK, Gray SE, et al. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 9064.

6. False. A study led by Larissa Nekh-

lyudov, MD, an associate professor at Harvard Medical School in Boston, concluded that oncologists often identified the main late side effect of cancer drugs whereas PCPs did not. These findings emphasize that in the transition of patients from oncology to primary care settings, PCPs should be informed about the late effects of cancer treatments so that they may be better prepared to recognize and address these rather important issues among cancer survivors. Nekhlyudov L, Aziz N, Lerro CC, Virgo K. Oncologists’ and primary care providers’ awareness of late effects of cancer treatment: implications for survivorship care. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 6008.

CLINICAL ONCOLOGY NEWS • AUGUST 2012

7. False. Only women ≥65 years old on

the T-DM1 arm did not achieve superior PFS compared with standard treatment. Blackwell KL, Miles D, Gianni L, et al. Primary results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract LBA1.

8. True. This study, led by Mat-

thew James Ellis, MD, the chief of breast oncology at Washington University in St. Louis, also revealed that a TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates, whereas loss-of-function mutations in MAP3K1 are associated with PAM50 lumA status, low proliferation rates, and low-grade histology. Prospective clinical trials based on these findings will require comprehensive genomesequencing approaches and large-scale investigations. Ellis MJ, Ding L, Shen D, et al. Whole genome sequencing to characterize luminal-type breast cancer. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 503.

randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 2.

11. True. In two independent ret-

rospective studies, Mikhael et al and Venner et al reported unprecedentedly high hematologic response rates, 94% and 81%, including complete response in 71% and 42%, respectively, to the combination of cyclophosphamide-bortezomib-dexamethasone in patients with either naive or relapsed AL amyloidosis. The availability of this powerful regimen opens new perspectives in the treatment of AL amyloidosis and raises several challenging questions that should be addressed through controlled, prospective trials. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012;119:4391-4394, PMID: 22331188. Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood. 2012;119:4387-4390, PMID: 22331187.

12. True. The HER2 receptor func9. True. The results of this Phase II tions by a ligand-independent dimeriza-

study led by Mary-Ellen Taplin, MD, of Harvard Medical School and the DanaFarber Cancer Institute in Boston, are impressive, but larger randomized trials are needed to validate these findings. Taplin M-E, Montgomery RB, Logothetis C, et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): results of a randomized phase II study. Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 4521.

10. False. AOD tumors account for

about 5% to 10% of malignant brain tumors. Although a survival difference was not observed in 2006 when results were first reported, long-term followup showed median OS of 42 months in the PCV-plus-radiotherapy arm versus 31 months in the radiotherapyalone arm. In patients with the 1p/19q codeletion, median OS has not yet been reached in the PCV-plus-radiotherapy arm and is 112 months in the radiotherapy-alone arm. Van Den Bent M, Hoang-Xuan K, Brandes AA, et al. Long-term follow-up results of EORTC 26951: a

tion mechanism that primes HER2 for associations with both itself and other HER kinase family members. In HER2amplified breast cancers, the overabundance of membrane HER2 further potentiates this ligand-independent mechanism, resulting in “addiction” to HER2 signaling for tumor cell survival. In particular, overexpression of HER2 results in increased HER2 homo- and hetero-dimer formation and augmented signaling through intracellular cascades such as the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Cortés J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. 2012;30:1594-1600, PMID: 22393084.

13. False.

Patients with SWM should be followed carefully and not treated until “symptomatic” Waldenström macroglobulinemia develops. The definition of SWM is poorly defined, but clinically includes having

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a serum monoclonal IgM protein ≥3 g/dL and/or at least 10% bone marrow lymphoplasmacytic infiltration without evidence of end-organ damage (anemia, constitutional symptoms, hyperviscosity, lymphadenopathy or hepatosplenomegaly). Robert A. Kyle, et al. Progression in smoldering Waldenström macroglobulinemia: longterm results. Blood. 2012;119:4462-4466, PMID: 22451426.

14. True. PD0332991 is a pyridopy-

rimidine with high selectivity for cdk4, producing G1 arrest in preclinical studies and dephosphorylation of Rb at known cdk4-specific phosphorylation sites. To evaluate changes in cell proliferation, the investigators performed FLT-PET and for assessment of metabolism they performed fluorodeoxyglucose-PET, both before and during the third week of daily administration of study drug. Tissue biopsies were obtained at baseline and on day 21 of cycle 1 and assessed using immunohistochemistry for total Rb protein, phospho-Rb, and cell proliferation using Ki-67. This study demonstrates the potential power of combining functional imaging evaluating cell proliferation with tissue biomarker changes in drug development. Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119:4597-4607, PMID: 22383795. Crump M. Hitting the target in MCL. Blood. 2012;119:4580-4581, PMID: 22596168.

15. True. Natural killer (NK) T cells

are present in about one in 1,000 T cells contained in a hematopoietic progenitor cell graft. In multivariate analysis, CD4− iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade 2 to 4 aGVHD in patients receiving CD4− iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively ((P=0.0008); low CD4− iNKT-cell dose was associated with a relative risk for grade 2 to 4 aGVHD of 4.27 ( =0.0023; 95% confidence interval, 1.68(P 10.85). This effect to infuse purified CD4− iNKT-cell could be further explored for prevention or to treat aGVHD. Chaidos A, Patterson S, Szydlo R, et al. Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Blood. 2012;119:5030-5036, PMID: 22371885.

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David Lyden; Danny R. Welch; Bethan Psaila April 25, 2011 This text covers the processes underlying cancer metastasis and the clinical treatment of metastatic disease. More than a compendium of laboratory research articles, the internationally renowned authors of this volume have summarized the state-of-the-art research in the metastasis field.

Central Nervous System Malignancies, An Issue of Hematology/Oncology Clinics of North America

Jill Lacy September 11, 2012 This issue of Hematology/Oncology Clinics of North America a includes topics such as neoplastic meningitis and epidural metastases, management of brain metastases, meningiomas/nerve sheath tumors/pituitary tumors, medulloblastoma/primitive neuroectodermal tumor and germ cell tumors, primary CNS lymphoma, anaplastic gliomas, low grade gliomas and glioblastoma multiforme.

Diagnostic Imaging: Musculoskeletal: Non-Traumatic Disease

B.J. Manaster; Cheryl A. Petersilge; Catherine C. Roberts; Christopher J. Hanrahan; Sandra Moore March 26, 2012 With more than 300 diagnoses, thousands of images, illustrations and graphics, this reference guides practicing radiologists through the intricac es of cies o musculoskeletal uscu os e eta diseases. d seases

Gynecologic Oncology: Clinical Practice & Surgical Atlas

Beth Karlan; Robert Bristow; Andrew Li June 22, 2012 This book brings together a skill-sharpening reference and full-color atlas to deliver an unmatched introduction to the field. As the most comprehensive, evidence-based gynecologic oncology resource available, this all-in-one resource offers high-yield coverage of the discipline’s underlying principles and proven management strategies.

New Drugs for Malignancy, An Issue of Hematology/ Oncology Clinics of North America

Franco Muggia June 28, 2012 Topics in this issue include targeting IGF-1R, tyrosine kinase inhibitors in lung cancer, targeting mTOR, targeting hedgehog, mitotic inhibitors, topoisomerase I inhibitors, and new strategies and drugs inhibiting folate pathways.

Outcomes Research in Surgical Oncology, An Issue of Surgical Oncology Clinics

Clifford Ko June 20, 2012 In this issue of Surgical Oncology Clinics of North America, guest editor Clifford Ko, MD, has assembled the top experts concerning outcomes research in oncology.

Surgical Oncology

David Bartlett; Pragatheeshwar Thirunavukarasu; Matthew D. Neal May 4, 2012 Surgical Oncology y is a full-color text that incorporates the basic tenets of surgical practice with the innovations of modern technology in an evidence-based fashion.The goal of the book is to present the opinions of experts in the field alongside an analytical and unbiased review of the evidence. Each chapter contains not only a summary of the relevant data,, but also presents p succinctlyy a list of landmark studies. CO0812

ÂŠ 2012 Novartis

February 2012

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