Clinical Oncology News Digital Edition - July 2012 by McMahon Group

Hematology/Oncology

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Independent News on Advances in Cancer Care CLINICALONCOLOGY.COM • July 2012 • Vol. 7, No. 7

SOLID TUMORS Roundtable discussion: watchful waiting for rectal cancer . . . . . . . . . . ..... 20 Radium-223 on the ‘fast track’ for prostate cancer . . . . . ..... 24 Controversy continues to surround PSA screening . . . . . . . . . . . . . . . . .... 26 Fish and colorectal cancer risk . . . . . . . . . . . . . . .... 29

Dex Use Vindicated For Cancer-related Fatigue

Erlotinib Falls Short As Second-Line Therapy

Chicago—Dexamethasone can reduce cancer-related fatigue in patients with advanced cancer, according to a double-blind, randomized placebocontrolled trial. The study, presented at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 9002), is the first randomized trial to show that dexamethasone can be effective for this indication. “Steroids are commonly used [for cancer-related fatigue], but there have

For wild-type EGFR lung cancer

HEMATOLOGIC DISEASE Advisory panel recommends carfilzomib for FDA approval . . . . . . . . . . . . . . . . ....... 6 DNMT3A mutations important for AML . ..... 15 Research Report: ‘Chemobrain’ in Children . . . . . . . . . . . . . . . . . ...... 16 CURRENT PRACTICE Pertuzumab approved for metastatic breast cancer . . . . . . . . . . . . . . . . . . . . ....... 6 Clinical Conundrums . . . . . . . . . . ..... 29

see FATIGUE, E page 11

A During the past 4.5 years:

241 392

community oncology clinics have closed

practices have entered into a contractual relationship with a hospital or have been acquired by a hospital

132

practices merged with or have been acquired by a corporate entity other than a hospital

442

practices or oncology groups have reported struggling financially

SEE FULL REPORT...

Access at clinicaloncology.com

s second-line therapy, docetaxel improves progression-free survival (PFS) by one month compared with erlotinib in non-small cell lung cancer (NSCLC) patients who have wild-type epidermal growth factor receptor (EGFR) tumors. This news comes from an interim analysis of the TAILOR (TArceva Italian Lung Optimization) trial. Erlotinib (Tarceva, OSI/Genentech), docetaxel and pemetrexed (Alimta, Eli Lilly) are included in the National Comprehensive Cancer Network guidelines for this patient population. Because it is standard procedure to give pemetrexed in the firstline setting, doctors often are choosing between erlotinib and docetaxel for patients who want more chemotherapy. “TAILOR does not support the use of erlotinib over docetaxel in patients with EGFR

By the NUMBERS

EDUCATIONAL REVIEW Recent Advances and Emerging Therapies In the Systemic Treatment Of Metastatic Melanoma

Erlotinib bound to epidermal growth factor receptor..

Following largest-ever municipal bankruptcy, county threatens oncology unit closure ............................. 8

see ERLOTINIB, B page 28

From the Community Oncology Alliance Practice Impact Report

INSIDE

‘Clinical Biomarkers’ in Optimal Cancer Management

ver the past decade, molecular biomarkers have rightly been emphasized as highly relevant in defining the most beneficial strategies for individual cancer patients. However, in the rush to define molecular subsets of patients, Maurie it is possible that we have lost Markman, MD sight of the relevance of “clinical biomarkers” in directing therapy.

Today, oncologists caring for women with breast cancer fully appreciate the importance of estrogen and progesterone receptor expression and the over-expression of HER2 in optimizing disease management. Epidermal growth factor receptor (EGFR) mutations now define a population of patients with non-small cell lung cancer who may benefit from tyrosine see BIOMARKERS, S page 5

EXPERT COMMENTARIES FROM CLEVELAND CLINIC

Treatment of rare advanced adrenocortical carcinomas . . . . . . . . . . .... 13 Robert Dreicer, MD, MS

Three or four drugs for induction in symptomatic multiple myeloma? ............... 19 Frederic Reu, MD

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JULY 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

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

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

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

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

Pharmacy Shaji Kumar, MD

Edward Chu, MD

Mayo Clinic Rochester, MN

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

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Oncology Nursing

Hematologic Malignancies

Andrew Seidman, MD

Cathy Eng, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Cindy O’Bryant, PharmD

Rhonda M. Gold, RN, MSN

University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Sara S. Kim, PharmD

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

The Mount Sinai Medical Center New York, NY

Community Oncology John W. Finnie, MD

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

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

Mercy Medical Center St. Louis, MO

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

Steven Vogl, MD Medical Oncologist New York, NY

Mission Statement

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 Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer

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

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Lung, g, and Head and Neck Cancers

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

Edward S. Kim, MD

Joseph V. Pergolizzi Jr., MD

University of Texas, MD Anderson Cancer Center Houston, TX

Johns Hopkins University School of Medicine Baltimore, MD

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

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

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

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.

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CLINICAL ONCOLOGY NEWS • JULY 2012

BIOMARKERS continued from page 1

kinase inhibitors, while a KRAS mutation identifies individual colorectal tumors unlikely to respond to anti-EGFR antibody therapy. More recently, BRAF mutations have been recognized as highly prognostic in metastatic melanoma. The future of oncology increasingly will be characterized by discoveries of

cooperative group Phase III randomized trial, which was halted early based on prospectively defined interim results, revealed an unprecedented improvement in progression-free survival (PFS) with the 12-month maintenance regimen compared with a “control arm” of three monthly treatments with an identical paclitaxel program (median PFS, 28 vs. 21 months; P=0.0023). My intent, however, is to emphasize the toxicity of this approach, not the

discussion of subsequent neurotoxic antineoplastic therapy should include this “clinical biomarker.” Conversely, for an individual who has achieved a similar response to the primary platinum-taxane treatment program through six or more cycles without any neurologic symptoms, the risk for developing a serious neuropathy with additional maintenance paclitaxel may be less. Perhaps most importantly, maintenance paclitaxel reasonably could be

‘In our enthusiasm to discover unique targets among individual patients it is important that we not forget the value of clinical biomarkers that may assist in optimizing our care.’ clinically relevant molecular biomarkers that define subsets of patients who should, and should not, receive particular antineoplastic agents. These discoveries promise to dramatically alter the “standard” paradigm of antineoplastic drug management. Although enthusiasm for these developments is appropriate, the truly meaningful role that particular clinical factors may play as highly relevant “biomarkers” has potentially been lost. Consider, for example, the utility of single-agent, three-hour infusional paclitaxel delivered as a maintenance strategy—monthly for 12 months—in women with advanced epithelial ovarian cancer who have achieved a clinically defined complete response following primary platinum plus paclitaxel chemotherapy.1 A National Cancer Institute–sponsored ®

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

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

develop, rather than based solely on a rising serum tumor marker, may be more rational. Alternatively, an equally active, non-myelosuppressive agent may be the treatment of choice. In our enthusiasm to discover unique targets among individual patients it is important that we not forget the value of clinical biomarkers that may assist in optimizing our care.

efficacy. Continuing paclitaxel for 12 months produced no increase in serious adverse events (AEs) compared with the “control arm,” with the exception of reversible alopecia and the development of clinically relevant peripheral neuropathy (grade 2/3: 23% vs. 15%).1 When weighing potential benefits against the harm associated with paclitaxel maintenance, an individual patient’s current neurotoxic AEs during primary chemotherapy may serve as a highly relevant biomarker to assist in the decision-making process. For the patient who has developed, or is in the process of developing, neuropathic symptoms (e.g., numbness and/or tingling in the hands and/or feet), it can be anticipated that continuing paclitaxel would likely exacerbate these symptoms, perhaps substantially. In fact, any

initiated under careful observation with a decision made later on the total number of courses to be delivered. Again, the point is that a patient’s documented ability or inability to successfully tolerate platinum-taxane–based therapy can critically inform subsequent decision making for that specific individual. In other settings, it can be argued that a patient’s prior toxicity profile— for example, modest versus severe bone marrow suppression following initial standard chemotherapy—can assist in future management, including specific drug choices, their doses and schedules and even when a particular secondline treatment may be initiated during the course of the illness. In a patient whose bone marrow reserve is marginal, for example, delaying a known marrowsuppressive treatment until symptoms

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1. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003; 21:2460-2465.

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Sarcoma Awareness Month

uly is Sarcoma Awareness Month, dedicated to increasing research efforts and public awareness of the more than 50 subtypes of sarcoma. The American Cancer Society estimates that about 11,280 new soft tissue sarcomas will be diagnosed this year and 3,900 Americans will likely die of the disease. According to the Sarcoma Alliance, in November 2007, 20 advocates met at the Connective Tissue Oncology Society annual meeting in Seattle to build cooperation among sarcoma non-profit organizations and designate July as Sarcoma Awareness Month. For more information on Sarcoma Awareness Month events and fundraising efforts, visit the Sarcoma Foundation of America at www.curesarcoma.org or the Sarcoma Alliance at www.sarcomaalliance.org.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2012

Pertuzumab Approved for HER2+ Metastatic Breast Cancer Cell growth production issues could affect supply

he FDA has approved pertuzumab (Perjeta, Genentech) for the treatment of HER2-positive, late-stage metastatic breast cancer. The drug is specifically aimed at HER2-positive patients who have not previously undergone anti-HER2 therapy or chemotherapy. Pertuzumab has been approved for use in combination with trastuzumab (Herceptin, Genentech), another anti-HER2 therapy, and docetaxel. Pertuzumab targets the HER2 receptor; however, according to Genentech, pertuzumab is believed to work in a way that complements trastuzumab, as the two medicines target different regions on the HER2 receptor. Approval from the FDA was based on data from the Phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial demonstrating that patients treated with a combination of pertuzumab, trastuzumab and docetaxel had six months greater progression-free survival (PFS) than patients given trastuzumab and docetaxel chemotherapy.

At the time, lead investigator José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center in Boston, called CLEOPATRA “the most positive trial in the history of patients with HER2-positive advanced disease and for that matter in patients with advanced breast cancer.” Because of production issues that potentially could affect the long-term supply of pertuzumab, the FDA limited

its approval to drug product that has not been affected by those issues. Plans are under way at Genentech to mitigate the effect on patients of any potential shortage of the drug. Patrick Yang, PhD, head of Pharma Global Technical Operations at Genentech, said that a cell growth issue in the production process might affect future supplies of the medicine, but that the company currently expects to meet

AT A GLANCE Pertuzumab Extends PFS six months when combined with trastuzumab and docetaxel Common adverse reactions (>30%) include diarrhea, alopecia, neutropenia, nausea, fatigue, rash and peripheral neuropathy Increases risk for left ventricular dysfunction, including congestive heart failure and decreases in left ventricular ejection fraction

The structure of HER-2 and pertuzumab

demand for the drug. Pertuzumab comes with a boxed warning because the use of the drug during pregnancy can result in embryofetal death and birth defects. Common side effects include a decrease in infection-fighting white blood cells, nerve damage and heart problems. The American Cancer Society estimates that in 2011 more than 230,000 women were diagnosed with breast cancer and 40,000 died from the disease. HER2-positive breast cancer is a particularly aggressive form of the disease and affects approximately 20% of patients.

FDA Advisory Panel Recommends Carfilzomib Advisers to the FDA unanimously recommended that carfilzomib (Kyprolis, Onyx Pharmaceuticals) be approved for the treatment of patients with relapsed and refractory multiple myeloma. The recommendation comes despite serious concerns about severe toxicities, including deaths that may be associated with the drug. The Oncologic Drugs Advisory Committee (ODAC) voted 11-0, with one abstention, that the benefits outweigh the risks for patients who have multiple myeloma that has continued to progress despite at least two prior types of therapy, a proteasome inhibitor and an immunomodulatory agent.

The advisory panel was reviewing Onyx Pharmaceuticals’ new drug application for carfilzomib on an accelerated approval basis. Although the FDA does not have to follow the panel’s advice, the agency typically does, and a final decision from the FDA is expected by July 27. ODAC’s recommendation did not

come without significant concerns about toxicities and deaths associated with the use of carfilzomib, a tetrapeptide epoxyketone that irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. Prior to the meeting, documents with background material were given to the ODAC showing multiple deaths

associated with carfilzomib, as well as cardiac, respiratory and hepatic toxicities. Some deaths occurred three days after the patients’ last dose of the medication, according to the background information provided to the FDA. The new drug is seen as a last chance for patients with relapsed and refractory disease. “I do think this drug is beneficial to this patient population given the limited therapeutic options available,” said Michael E. Menefee, MD, an assistant professor of hematology and oncology at Mayo Clinic in Jacksonville, Fla., according to Reuters.

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CLINICAL ONCOLOGY NEWS • JUNE 2012

Hospital Threatens To Shutter Oncology Unit An insolvent Alabama county leaves its indigent cancer patients feeling uncertain “Right now I am fighting for my life,” said Tiajuana Hall, 48, who has been a cancer patient at Cooper Green Mercy Hospital in Birmingham, Ala., for three years. Cooper Green—the only county hospital in the Birmingham Metro area—announced in April that it was going to close its Oncology Department, and as a result countless patients, doctors and nurses have been scrambling to understand how they might be affected. Ms. Hall, who is in the last stage of breast and liver cancer, relies on the treatments she receives once a week at Cooper Green. “This is unfair. How could they do this to patients who

really need this care?” The decision to close Cooper Green’s oncology unit has been controversial in the Birmingham community, and that controversy—particularly among municipal and county leaders—has led to uncertainty. Over the past eight weeks, local elected officials and hospital administrators have both reversed their decision to close the oncology unit as well as aired the possibility of closing Cooper Green Hospital in its entirety. The controversy began when Cooper Green Mercy Hospital administrators—charged with providing care for the indigent in Jefferson County—came

Closing of Community Cancer Centers Across the U.S. Becoming a Trend

he closing of Cooper Green’s oncology unit is one indicator of a much larger trend among oncology practices and particularly community oncology practices—restructuring due to financial pressures. “The alarming trend is not that hospital departments are closing, but that community cancer centers are closing. What is really happening is that community cancer centers—that are efficient and affordable—are closing in large part because of Medicare reimbursements being below the cost of treatment,” said Melissa Veselovsky, the director of patient advocacy at the Ironwood Cancer & Research Centers in Chandler, Ariz. According to an April 2012 report by the Community Oncology Alliance (COA), over the past 4.5 years, 1,254 cancer care clinics or practices have been impacted in some way as a result of financial pressures. In total, 241 clinics or practices have closed; 392 practices have come under a hospital agreement or have been purchased by one; 132 practices have merged or have been acquired by a hospital; 442 practices reported they are struggling financially; and 47 said they have sent their patients elsewhere for treatment at some point. And the trend is increasing. There also has been a 20% increase in the number of community oncology practices that have been affected in the past 12 months. During this time period, there was a 21% increase in cancer clinic closures and a 24% increase in practices entering into an agreement with a hospital or being purchased by a hospital, according to the COA report. The report also states that “Medicare is the largest payer of cancer care … and has substantial market clout in influencing private payers.” The majority of oncology clinics and practices that have been restructured are clustered in a wide band running from the Rust Belt south to the Gulf of Mexico. The irony is that many of these community cancer care centers offer more efficient care than their outpatient hospital counterparts. The COA commissioned Avalere Health to compare the average total costs of cancer care in an outpatient hospital department with the same care in a private physician office setting. The study was funded by Amgen and Millennium Pharmaceuticals and looked at the cost of care for more than 22,000 patients receiving chemotherapy and 19,000 patients undergoing radiation treatments. Published in March, the study found that after risk adjustment, treatment for patients receiving chemotherapy in a hospital outpatient department costs on average 24% more than treatment received in a physician’s office. Between 2008 and 2010, the average cost of care for patients in these plans receiving chemotherapy in a hospital outpatient setting was approximately $35,000 versus $28,200 for those receiving treatment in a physician’s office. Moreover, office-managed chemotherapy had lower costs regardless of the length of the treatment episode. And the value increased as the length of treatments increased. For patients receiving a full 12 months of chemotherapy, hospital outpatient care cost 53% more than in the physician office-based setting. The findings mirror a report done in 2011 by McKesson Specialty Health and commissioned by US Oncology, which also found that patients pay about 10% more for treatment in a hospital outpatient setting. “If hospitals are closing the doors of their cancer centers and community cancer centers can’t afford to stay open either, then what happens to cancer care?” asked Ms. Veselovsky. “According the American Cancer Society, 77% of all cancers are diagnosed over the age of 55. With so many baby-boomers reaching Medicare age and Medicare underpaying, what will this mean for cancer care? It is happening in real time—right before our very eyes.”

under fire from county commissioners for mismanaging hospital finances. Ordered to cut their budget by Jefferson County commissioners, Cooper Green hospital leaders made a $6.7 million annual reduction in spending to stabilize finances, according to reports in The Birmingham News. The

transitional phase was completed. “Without knowing how long the transitional phase will be, I have no future plans as to what I will be doing for work after this is all settled. Until everything is finally decided, I need to take care of the patients who need my care,” said Ms. McQueen. “I have

‘Without knowing how long the transitional phase will be, I have no future plans as to what I will be doing for work after this is all settled.’ —Sharon McQueen, RN reductions included 89 layoffs as well as shutting down the Oncology Department, which provided care for 40 cancer patients. Yet, these cuts may not be enough. In recent weeks, county commissioners have debated closing not just the Oncology Department but also the entire hospital. Hospital leaders have said Jefferson County needs to pay between $3.5 million and $9 million in overdue bills in order for Cooper Green to stay open. The county commission recently gave the hospital $3.6 million, but even that may not be enough to keep the doors from closing. The hospital’s financial problems are the result of more than mismanagement by hospital administrators alone, however. The initial decision to cut back Cooper Green Mercy Hospital’s budget came four months after Jefferson County declared bankruptcy last November. With more than $4 billion in total debt, the Chapter 9 filing by Jefferson County was the largest county bankruptcy in U.S. history. As a result, cancer patients at Cooper Green now find themselves without a clear treatment option. “The hospital told us that [the last week of April] would be our last one at the clinic. They have not told us where we are being transferred to but I will be following my doctor to [Princeton Baptist Medical Center],” Ms. Hall said when asked if the hospital has told patients how and where to continue their care. Hospital officials have previously said that the Oncology Department would remain open until all patients were successfully transferred. “It has been a stressful time here,” said Sharon McQueen, RN, an oncology nurse at Cooper Green. Ms. McQueen explained that the department was told that as of April 13, 2012, it would no longer be accepting new patients but should continue serving existing patients until a

thought about leaving but then what would happen to the patients? Who is going to take care of these people if we [nurses and doctors] all leave and they close the hospital?” Although hospital and county leaders are adamant that the hospital—which opened in 1972 and has been funded by a state trust since 1990—remain open, it’s not clear that the hospital can withstand the financial pressures. Cooper Green CEO and medical director Sandral Hullett, MD, MPH, told the The Birmingham News, “We’re dealing with people who come to us because they need us … One of the special things about Cooper Green is that we can offer people more than primary care. Cooper Green has an obligation to patients. The county has an obligation to the patients … I really want to save the hospital. I want the patients to have good care.” “We are trying to figure out the best way to manage the care of our indigent population,” Tony Petelos, the Jefferson County manager, said. “There will definitely be major changes, but we are not set on what those changes will be.” Mr. Petelos is adamant, however, that “the hospital is not closing. As of right now the hospital will be open to all patients who are in need … it is the commissioners who have the last decision on making the call about whether or not the hospital is closing. Right now I do not feel that it is of the best interest for Jefferson County to close the doors of Cooper Green.” The problems facing Cooper Green and its oncology unit are the result of local issues; however, taken as a whole, financial pressures of one kind or another are an increasingly common problem at oncology clinics across the country (Figure). “It is usually a financial decision that makes an oncology department shut down; no one wants to shut it down— it just becomes too expensive to run,”

CURRENT PRACTICE

Clinics closed Practices struggling financially

From “Community Oncology Practice Impact Report: The Changing Landscape of Cancer Care.” April 4, 2012. Community Oncology Alliance. http://communityoncology.org/.

CLINICAL ONCOLOGY NEWS • JULY 2012

Practices sending patients elsewhere Hospital agreement/purchase Merged/Acquired by a corporate entity other than a hospital

Figure. Oncology practices restructuring within the last 4.5 years as a result of financial pressures. said Melissa Veselovsky, the director of patient advocacy at the Ironwood Cancer & Research Centers in Chandler, Ariz. “When reimbursements drop, foundations fail to renew grants for essential programs, patients lose insurance coverage, states cut Medicaid programs and drug costs increase, there is often no other choice.” Because Cooper Green’s oncology unit is hospital-based, its likely closing does not fit the larger trend of community oncology practices being absorbed into hospitals. However, it may be the harbinger of a new trend in practice closings. “Typically, hospital-based oncology departments are not closing. In fact, private practicing community centers are closing and being absorbed by hospitals, making the patients pay for medical oncology care that is 30% higher than it would cost in a community-based cancer center,” said Ms. Mueller, referring to a recent study done by Avalere Health, a health care research and consulting firm. The study highlighted the

fact that treatment in a community cancer center is less expensive than similar treatment at a hospital-based outpatient treatment center.

B Baptist Medical Center also serve the ccommunity. However, UAB and Cooper Green have not come to a formal agreement on h ccare for the cancer patients who would be cut loose if Cooper Green were to b cclose its oncology unit. “There is concern in the community aas Cooper Green was viewed as a safetty net for indigent patients,” said Boris Pasche, MD, PhD, the director of hemaP ttology/oncology at UAB. “We believe tthe care of indigent patients is a Jeffferson County issue and we are williing to work with other health care provviders in the area to make sure patients rreceive the best care where it is most aappropriate for them. Like most major aacademic medical centers, UAB sees a large share of nonpaying patients. We are focused on providing the best W oncology care to all patients.” o The probable closing at Cooper Green aalso would affect medical training proggrams. “If the [oncology] program closes permanently, some [UAB] medical education programs will be affected,” said Dr. Pasche. UAB previously has used Cooper Green for on-site training and the uni-

‘We have people in our community who don’t have a voice … people who are uninsured and underinsured, who cannot be taken care of at any other hospital in this city.’ —Katisha Vance, MD

However, Ms. Mueller worries that the probable closing at Cooper Green could be a sign of worse things to come. “If hospitals are closing the doors of their cancer centers and community cancer centers can’t afford to stay open either, then what happens to cancer care?” Cooper Green is not the only medical center available to Birmingham patients. The University of Alabama at Birmingham (UAB) and Princeton

versity may have to look elsewhere. Katisha Vance, MD, an oncologist who worked at Cooper Green and also a physician at Princeton Baptist Medical Center, told The Birmingham News, “We have people in our community who don’t have a voice … people who are uninsured and underinsured, who cannot be taken care of at any other hospital in this city.” Since March, several bills in the Alabama State Senate have proposed the

creation of a five-member health care authority that would buy Cooper Green from Jefferson County and have the power to convert it to an outpatient clinic. As part of the deal, the commission would transfer the county’s indigent care fund, which collects $43 million a year from county sales tax, to the newly appointed authority. Jefferson County Commission President David Carrington has said that he is “not against a health care authority for the hospital and thinks Cooper Green will continue to exist.” Cooper Green has been a delicate topic among many county and state lawmakers because of the financial, cultural and social implications of providing social services in a city that serves as the historical center of the Civil Rights Movement. With more than 650,000 residents and the state’s largest city and economic center in Birmingham, Jefferson County contains some of the richest neighborhoods in the state as well as areas of severe poverty and urban blight. Administrators at The American Cancer Society Joe Lee Smith Hope Lodge, which is about an eight-minute drive from Cooper Green, would not comment on the situation at the hospital due to the politics surrounding the issue; similarly, a spokesman at UAB declined to comment officially on what role the university medical center might play in assuming care for the indigent cancer patients who would no longer be seen at Cooper Green. Meanwhile, many in the community are fighting to keep Cooper Green open. Through a Facebook group dedicated to the “Save Cooper Green Mercy Hospital” movement, one community member, Toni Peoples, tells the story of how when she had nowhere else to go, Cooper Green welcomed her with open arms. “I am so thankful that they were there … I am very proud to say I go to Cooper Green for my health care needs.” —Gabrielle N. Rosen

Article & 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 • JULY 2012

A New First-line Option for Advanced Lung Cancer Afatinib improved PFS but toxicities appear higher than first-generation inhibitors Chicago—The oral agent afatinib (Boehringer Ingelheim) will likely be approved for the first-line setting of patients with advanced lung adenocarcinoma who have an epidermal growth factor receptor (EGFR) mutation, based on results from a Phase III trial. Afatinib, a second-generation EGFR inhibitor, improved progression-free survival (PFS) by four months compared with chemotherapy in this patient population, according to results from the LUX-Lung-3 trial. The study was reported at the American Society of Clinical Oncology annual meeting (abstract LBA7500). “I think it is clear that this study establishes afatinib as another proven option for the first-line treatment of EGFR mutation-positive patients, alongside gefitinib and erlotinib [Tarceva, OSI/Genentech],” said Benjamin Solomon, MBBS, PhD, a medical oncologist at Peter MacCallum Cancer Center in Melbourne, Victoria, Australia, who was not involved in the study. Both erlotinib and gefitinib are first-generation EGFR inhibitors, and although gefitinib (Iressa, AstraZeneca) was pulled from the U.S. market in 2005 over concerns about efficacy, the drug has remained a therapeutic option in other countries. The new study randomized patients with EGFR-mutant stage IIIB/IV lung adenocarcinoma to afatinib (n=230) or cisplatin plus pemetrexed (Alimta, Eli Lilly; n=115). The median PFS was 11.1 months in patients who received afatinib and 6.9 months in patients who received chemotherapy (hazard ratio, 0.58; P=0.0004), and this difference was even greater in individuals with the common mutation Del119/L858R (13.6 vs. 6.9 months; P<0.0001). The study is the first EGFR inhibitor lung cancer study “to use cisplatinpemetrexed, what we recognize as the most effective doublet in nonsquamous histology, as the comparator arm,” said Dr. Solomon. Although the trial design gives the drug credibility, the use of afatinib is not without a cost. “There was frequent occurrence of diarrhea, rash, stomatitis and paronychia. Although we don’t have a study to directly compare toxicities in afatinib with first-generation EGFR inhibitors, the impression is the rates here are certainly higher than those seen with the first-generation inhibitors,” said Dr. Solomon. Afatinib caused a number of grade 3 toxicities (Table); the only grade 4 toxicity was stomatitis/mucositis (0.4%). These toxicities, however, were manageable. “Despite these toxicities, it is important to note that the rate of

Table. Comparison of Adverse Events Afatinib

Cisplatin-Pemetrexed

All Grades, %

Grade 3, %

All Grades, %

Grade 3, %

Diarrhea

95.2

14.4

15.3

Rash/acne

89.1

16.2

6.3

Stomatitis/mucositis 72.1

8.3

15.3

0.9

Paronychia

56.8

11.4

Dry skin

29.3

0.4

1.8

discontinuation because of treatmentrelated toxicities was similar between the afatinib arm and the cisplatin-pemetrexed arm,” said Thomas Lynch Jr., MD, the director of the Yale Cancer Center in New Haven, Conn., who was not involved with the study. Trials are needed to examine how afatinib stacks up against erlotinib and gefitinib, and one such study is under way. LUX-Lung-7 is currently randomizing patients with EGFR mutations to afatinib or gefitinib. —Kate O’Rourke

‘It is clear that this study establishes afatinib as another proven option for the first-line treatment of EGFR mutation-positive patients, alongside gefitinib and erlotinib.’ —Benjamin Solomon, MBBS, PhD

Dr. Lynch disclosed employment and stock ownership at Infinity and a consultancy at Boehringer Ingelheim, Merck and SuperGen. Dr. Solomon disclosed a consultant or advisory role with AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer and Roche.

In a normal cell, the ErbB receptors sit on the surface awaiting activation by a growth factor ligand like TGF- or EGF. When a growth factor binds to a receptor, dimerization is triggered with adjacent receptors, which ultimately creates a signaling pathway. This pathway produces signals that facilitate normal cellular processes like cell proliferation and migration.

However, ErbB receptor tyrosine kinases are often over-expressed on cancer cell surfaces. This increased number leads to a state of continuous signaling—“constitutive activation”—that causes a higher rate of cell division.

Unregulated cell growth

Afatinib is different from first– generation TKIs, which only acted against EGFR, because it acts irreversibly against the entire ErbB family.

Figure. Afatinib’s mechanism of action. Afatinib is a tyrosine kinase inhibitor (TKI) against the ErbB family of four structurally related receptor tyrosine kinases—epidermal growth factor receptor (EGFR), HER2, HER3 and HER4.

Image coutesy of Boehringer Ingelheim

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2012

FATIGUE continued from page 1

not been rigorous, randomized controlled trials with cancer-related fatigue as the primary end point,” said Debra Barton, PhD, RN, an associate professor of oncology at Mayo Clinic in Rochester, Minn., who was not involved with the study. She said the study bolstered the use of dexamethasone, an inexpensive therapy, for cancer-related fatigue. The rationale behind dexamethasone is that it can decrease inflammation, which has been linked to cancerrelated fatigue. There is controversy, however, regarding whether the benefits of dexamethasone on cancer-related fatigue arise from a euphoric psychological effect or from a real physical effect. In the study, patients were randomized to 4 mg of oral dexamethasone or a placebo, both given twice daily for 14 days. At the ASCO meeting, researchers presented data analysis for 43 patients who received dexamethasone and 41 patients who received placebo. The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale, a well-validated scale for measuring fatigue, was used to evaluate outcomes. The primary end point—a change in FACIT-F subscale scores from baseline to day 15—was improved in patients who received dexamethasone (mean improvement, 9.0 vs. 3.1; P=0.008). Dexamethasone also improved both fatigue outcomes at day 8 and the total FACIT score, a measure of quality of life, at day 15 (18.16 vs. 7.87; P=0.030). The study also suggested that physical, rather than psychological, changes were driving the drug’s benefit. Dexamethasone significantly improved the physical component of the FACIT score (average improvement, 5.25 vs. 1.32; P=0.002). Sriram Yennu, MD, an assistant professor of palliative care and rehabilitation medicine at the University of Texas MD Anderson Cancer Center in Houston, who presented the study, said the rapid action of dexamethasone is key.

AT A GLANCE Dexamethasone effectively reduced cancer-related fatigue in a well-designed trial The study was limited by a short, two-week follow-up As many as 30% of oncologists already prescribe steroids for cancer patients at the end of life

‘I have used dexamethasone for patients who are even in the early phase of treatment for lung cancer.’

—Marianna Koczywas, MD

There were no differences in side effects in the two study arms, but the long-term side effects and benefits of dexamethasone cannot be ascertained from the trial because of the treatment duration used in the protocol, according to Dr. Barton. “It is likely that the most appropriate role for dexamethasone and fatigue is in advanced cancer for

short periods of time,” said Dr. Barton. Marianna Koczywas, MD, a thoracic oncologist at City of Hope in Duarte, Calif., said studies have shown that 30% of oncologists prescribe steroids for cancer patients at the end of life. She prescribes dexamethasone for many of her cancer patients and has used them for three months and longer in some

patients without adverse effects. “I have used dexamethasone for patients who are even in the early phase of treatment for lung cancer, when they present with symptoms of anorexia, weight loss and fatigue,” said Dr. Koczywas. “I am glad to see this study, because I am hoping that many more oncologists will use steroids for cancer patients at the end of life, to improve quality of life.” —Kate O’Rourke Drs. Barton, Yennu and Koczywas have no relevant disclosures.

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CLINICAL ONCOLOGY NEWS • JULY 2012

Pathologic Stage Indicator of Long-Term Outcome in Rectal Cancer From the Journal of Clinical Oncology

athologic response to preoperative chemotherapy is a marker in locally advanced rectal cancer that correlates with recurrence-free surivival as well as metastasis and local recurrence rates, a team of researchers from the University of Texas MD Anderson Cancer Center in Houston reported in the May 20 issue of the Journal of Clinical Oncology (2012;30:1770-1776, PMID: 22493423). The researchers, led by In Ja Park, identified and retrospectively reviewed 725 patients diagnosed with locally

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

he primary treatment for patients with locally advanced rectal cancer is surgical resection with total mesorectal excision and preoperative CRT.1 However, the varying degree of tumor response seen after preoperative

advanced rectal carcinoma (defined as cT3-4 or cN+ by endorectal ultrasonography, computed tomography scan or magnetic resonance imaging) who were treated at MD Anderson Cancer Center between 1993 and 2008. Patients were given preoperative CRT (median radiation dose was 50.4 Gy with concurrent chemotherapy) and underwent radical resection. The authors compared recurrence-free survival, distant metastasis and local recurrence rates among those patients who had complete (18.1% of the study group), intermediate (29.0%) or poor (53.0%) response by using Kaplan-Meier survival analysis and multivariate Cox proportional

hazard regression. They found that complete versus intermediate versus poor tumor response was associated with higher five-year recurrence-free survival rates and lower five-year distant metastasis and local recurrence rates. For example, five-year recurrence-free survival was 90.5% among patients with complete response compared with 78.7% among those with intermediate response and 58.5% among those with poor response (P ( <0.001). The five-year distant metastasis rates were 7.0%, 10.1% and 26.5%, respectively ( <0.001). Similarly, the five-year local (P recurrence rates were 0%, 1.4% and

4.4%, respectively ((P=0.002). Overall, those patients who had complete response following radical resection had excellent outcomes (compared with those with intermediate or poor response) and thus may be eligible for organ-preserving strategies. However, the authors noted that outcomes following these approaches will need to be compared with those achieved with radical resection. Based on these findings, the authors concluded that the pathologic stage in these patients is “an early response indicator for long-term outcomes that provides better prognostication than does the clinical stage.”

CRT has led some groups to explore organ-sparing techniques in patients with complete clinical responses, with promising results.2 The current study by Park et al is a retrospective review of 725 patients diagnosed with rectal carcinoma. Tumor response was classified as complete (ypT0N0), intermediate (ypT1-2N0) or poor (ypT3-4 or N+) in 18.1%, 29.0% and 53.0% of patients, respectively. The study provides a much-needed benchmark to compare outcomes of organ conservation studies and to counsel patients on expected outcomes based on response to chemoradiation. Poor response to CRT may indicate the need for new

treatment strategies, whereas complete response may lead to consideration of organ-sparing options on study. The importance of pathologic stage as a determinant of cancer survival is highlighted and can aid in the discussion with patients. Furthermore, the study has the advantage of being from a single institution compared with reports that used pooled data from several institutions. This avoids the added inherent biases related to varying treatment techniques, criteria for patient selection and pathologic interpretation between institutions. The main drawbacks of the study are its retrospective nature and the long study period (15 years), since

changes in treatment methods may have occurred—even if radiation doses and types of chemotherapy used were reportedly similar.

References 1. Kapiteljn E, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638-646, PMID: 11547717. 2. Habr-Gama A, et al. Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg. g 2006;10:1319-1329, PMID: 17175450.

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

Stratifying Risk for Invasive Urothelial Bladder Cancer From the International Journal of Radiation Oncology, Biology, Physics

team of researchers from the University of Pennsylvania in Philadelphia—made up of radiation oncologists, urologists and epidemiologists—has proposed a novel method for assessing risk for developing locoregional failures following radical cystectomy and pelvic lymph node dissection (with or without chemotherapy) in the treatment of patients with invasive urothelial bladder carcinoma. In a study published online April 27 by the International Journal of Radiation Oncology, Biology, Physics (2012 Apr 27. [Epub ahead of print], PMID: 22543204), the researchers, led by Brian C. Baumann, AB, prospectively followed 442 patients with urothelial bladder carcinoma who were treated at university-affiliated hospital centers

with radical cystectomy plus pelvic lymph node dissection (with or without chemotherapy), using routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI) to identify locoregional failures. Of the patients included in this study, all of whom were treated between 1990 and 2008, 130 (29%) received chemotherapy. The authors defined locoregional failures as any pelvic failure detected before or within three months of distant failure, and used competing risk analyses to identify factors predicting increased risk for locoregional failures among study patients. Following univariate analysis, the authors found that a number of factors were reliable predictors of locoregional failures, including a pathologic stage at the time of cystectomy of pT3 or higher, the removal of fewer than 10 benign or malignant nodes, the presence of

positive margins and/or nodes following surgery, the presence of hydronephrosis, lymphovascular invasion and mixed histology. Additionally, they determined that node density was marginally predictive, but that the use of chemotherapy, number of positive nodes and type of surgical diversion, as well as the patient’s age, gender, race, smoking history and body mass index were not. On multivariate analysis, only a pathologic stage of pT3 or higher and the removal of fewer than 10 nodes were significant independent predictors of locoregional failures, with hazard ratios of 3.17 and 2.37, respectively (P ( <0.01). Their analysis identified three patient subgroups whose locoregional failure risks varied significantly: low-risk (pathologic stage at cystectomy of pT2 or lower), intermediate-risk (pathologic stage at cystectomy of pT3 or

Invasive urothelial bladder carcinomas

higher and at least 10 nodes removed), and high-risk (pathologic stage at cystectomy of pT3 or higher and fewer than 10 nodes removed). These stratified groups had five-year locoregional failure rates of 8%, 23%, and 42%, respectively ((P<0.01). Risk stratification, the authors wrote, provides “a simple rubric to identify patients most at risk for pelvic recurrence who are most likely to benefit from adjuvant local-regional radiation therapy.”

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

Mitotane Regimens Compared in Adrenocortical Carcinoma From The New England Journal of Medicine

Two regimens were studied as firstline therapy for the treatment of advanced adrenocortical carcinoma. The combination of mitotane (Lysodren) plus etoposide (Vepesid), doxorubicin and cisplatin (Platin) achieved “significantly better” results, based on two key outcome measures, than the combination of mitotane and streptozocin (Zanosar). However, neither regimen used in this study (mitotane-EDP vs. mitotane-streptozocin) offered significant improvement in overall survival (OS) compared with others that have been studied previously. In this study published June 7 in

The New England Journal of Medicine (2012;366:2189-2197; PMID: 22551107), a team of researchers from Germany, Italy and France—the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study group—randomly assigned 304 patients with advanced adrenocortical carcinoma to receive either mitotane plus a combination of etoposide (100 mg/m2 of body surface area on days 2-4), doxorubicin (40 mg/m2 on day 1) and cisplatin (40 mg/m2 on days 3 and 4) every four weeks; or mitotane plus streptozocin (1 g on days 1-5 in cycle 1; then 2 g on day 1 in subsequent cycles) every three weeks for a minimum of one cycle. Patients experiencing disease

progression alternated regimens as second-line therapy. The study’s primary end point was OS. The researchers, led by Martin Fassnacht, MD, found that patients in the mitotane-EDP group had a significantly higher response rate (23.2%) than those in the mitotane-streptozocin group (9.2%; P<0.001). Those receiving mitotane-EDP also experienced a longer median progressionfree survival (PFS) than those in the mitotane-streptozocin group (5.0 vs. 2.1 months; P<0.001). However, perhaps most importantly, OS was similar between the two groups—14.8 months in the mitotane-EDP group and 12.0 months in the mitotane-streptozocin group ((P=0.07).

Among the 185 patients who received the alternative regimen as second-line therapy, PFS was 5.6 months in the mitotane-EDP group and 2.2 months in the mitotane-streptozocin group. Of note, patients who did not receive the alternative second-line therapy had better OS with first-line mitotane-EDP (17.1 months) than with mitotane-streptozocin (4.7 months). Overall, the authors reported that rates of serious adverse events were similar between the two treatment groups. Quality-of-life scores also were similar between the two groups, although the authors acknowledged that participant compliance in answering the questionnaires was only approximately 50%.

mitotane-streptozocin recipients were alive without disease progression at 12 months (26.1% vs. 7.2%). Therapy was tolerable but not benign: Five deaths were attributed to therapy-related complications. While the investigators are to be commended for completing this international Phase III trial in this rare disease, the outcome in my mind suggests that it’s time to move away from standard chemotherapy agents in this disease. Optimal management for these patients include enrollment on Phase II trials (if available) or consideration of Phase I therapy.

treatment of bladder cancer because, as the authors state, the radiotherapy techniques available today, such as intensity-modulated radiation therapy, should offer the potential to reduce the side-effect profile. This new risk stratification should allow us to apply EBRT more intelligently so that the risk–benefit ratio is well balanced.

dvanced adrenocortical carcinoma is extremely rare, occurring in one to two individuals per million each year, but it is highly aggressive and resistant to systemic therapy. Conventional chemotherapy agents have demonstrated limited utility in

the small number of prospective trials devoted to this rare disease. The only approved treatment for advanced disease is the adrenolytic agent mitotane, or o,p´-DDD, an analogue of the insecticide DDT. Recently, an international consortium conducted a

randomized, controlled, open-label, multicenter, parallel-group, Phase III trial to compare two different chemotherapy regimens plus mitotane. A total of 304 adults enrolled during a five-year period with locally advanced or metastatic disease not amenable to surgical resection. The protocol allowed patients to cross over to the alternate regimen for second-line therapy at disease progression. The primary outcome was OS; secondary outcomes included PFS and objective response rate. The OS was similar between mitotane-EDP recipients and mitotane-streptozocin recipients (14.8 and 12.0 months, respectively). More mitotane-EDP recipients than

EXPERT INSIGHT

bladder cancer based on a detailed reassessment of the natural history of surgically treated bladder cancer patients. Recent clinical trials in muscle-invasive bladder cancer have taught us that although chemotherapy plays an important role, it still results in a five-year disease-free survival of about 50% and local failure rates greater than 20%. The authors rightfully argue that improvement is needed. They have provided a series of three risk categories based on pretreatment characteristics and pathologic examination of

the cystectomy specimen in an effort to define those patients with muscleinvasive bladder cancer who would be likely to benefit from adjuvant radiation. In their study, they were able to break patients into three groups with local failure rates of 8%, 23% and 42%, respectively. This is very valuable information because it helps focus efforts aimed at improving local control using what has in the past proven itself to be a very toxic modality: external beam radiotherapy (EBRT). The time is right to reconsider EBRT in the adjuvant

EXPERT INSIGHT Robert Dreicer, MD, MS Department Chair, Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Jay P. Ciezki, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute

his paper does a very good job of defining the potential use of newer radiotherapy techniques in

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

Dr. Ciezki discloses that he is on the editorial board of the International Journal of Radiation Oncology, Biology, Physics (www.redjournal.org), the journal that published this study.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

Stereotactic Ablative Radiotherapy Rivals Surgery for NSCLC From the International Journal of Radiation Oncology, Biology, Physics

atients with potentially operable stage I non-small cell lung cancer (NSCLC) who undergo stereotactic ablative radiotherapy (SABR) have comparable long-term outcomes to those who opt for surgical resection, the current standard of care, a recent study has revealed. Led by Frank J. Lagerwaard, MD, PhD, and a team of researchers from VU University Medical Center in Amsterdam, the study, which was published in the May issue of the International Journal of Radiation Oncology, Biology, Physics (2012;83:348-353, PMID: 22104360), was designed to assess the safety and efficacy of stereotactic ablative radiotherapy among patients in The Netherlands who underwent treatment between 2003 and 2010. At present, approximately

two-thirds of patients with early-stage NSCLC in the country undergo lobectomy. Patients with synchronous lung tumors (or other malignancies), prior high-dose radiotherapy/pneumonectomy, chronic obstructive pulmonary disease (with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease [GOLD] classification), a performance score of ≥3, and any other comorbidity precluding surgery were excluded from the study. In all, 177 patients were included in the final analysis (101 men and 76 women) from a total of 706 patients who underwent the procedure at the VU University Medical Center during the study period; 60% of the patients were stage T1 at the time of treatment and 40% were stage T2. Median age of the study population was 76 years. Depending on tumor size and location, a SABR dose of 60 Gy was delivered on

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

he standard of care for early-stage lung cancer is surgical resection. For the many patients whose medical comorbidities preclude surgery, stereotactic body, or ablative, radiotherapy (SBRT or SABR) has emerged as a novel radiation modality with significant applications to this inoperable population. Retrospective and prospective studies published in the past decade have established the feasibility, safety and efficacy of SBRT in these patients using a variety of dose regimens and technologies. To date, lung SBRT results demonstrate

excellent local control with very little acute toxicity and suggest improved OS compared with historical controls of fractionated radiotherapy. SBRT is now considered by many to be the standard of care for the early-stage inoperable lung cancer patient.1 An early and provocative report by Onishi et al. in 2004 signaled possibly using SBRT in potentially operable patients.2 In this retrospective study, 85 of the 245 analyzed patients were considered medically operable. Remarkably, the three-year OS for this subset of patients was around 85%, with

an outpatient basis using a risk-adapted scheme in three, five or eight fractions. Patients were monitored at three, six and 12 months, and yearly thereafter, using computed tomography. After a median follow-up of 31.5 months, median overall survival (OS) following SABR was 61.5 months. Oneand three-year OS rates were 94.7% and 84.7%, respectively. Using the Thorascore predictive model established by Falcoz et al ((J Thorac Cardiovasc Surg 2007;133:325-332, PMID: 17258556), the authors determined that the 30-day mortality rate for the study population had they undergone lobectomy would have been 2.6% compared with 0% for SABR. Local control rates at one and three years were 98% and 93%, respectively, and regional and distant failure rates were both 9.7% at three years. Finally, SABR had a favorable safety profile within the study population.

Grade 3 or higher toxicities were rare, with the most common, radiation pneumonitis and rib fractures, reported in 2% and 3% of study patients, respectively. As the authors note, the local control and survival rates reported in this study are comparable to those found with surgical resection. However, the authors also acknowledge that the median age and Charlson comorbidity score of 2.0 among patients included in this analysis were higher than those typically found in studies assessing lobectomy. At issue as well is that some two-thirds of the patients included in this study did not have histopathologic confirmation of their diagnosis prior to treatment with SABR. However, the authors point to the fact that OS rates at three years were similar—96% and 81%, respectively—among patients with and without histologic diagnosis ( =0.39). (P

minimal toxicity, and was comparable to surgical results for equivalent-stage patients. Now, a review by Lagerwaard and colleagues presents the largest retrospective series of potentially operable patients published to date in the literature. This is a high-quality report in keeping with the excellent standards that have come to be associated with the Dutch group. Using dose regimens previously described and chosen by tumor location and size, they found that three-year survival for 177 patients was 84.7%, with a local control rate of 93% and a <5% rate of grade 3 or higher treatment-related toxicity. Of particular note was their finding of no 30-day mortality following SBRT, compared with the predicted 30-day surgical mortality of 2.6% calculated from a recognized predictive model (Thoracoscore). The Dutch have been among the leaders in defining the parameters for SBRT and their current results lend support for further investigating the role of SBRT in patients who could be considered surgical candidates. In

that regard, a recently opened joint American College of Surgeons Oncology Group/Radiation Therapy Oncology Group (ACOSOG/RTOG)–sponsored randomized Phase III trial of limited surgical resection compared with SBRT in high-risk operable patients will ultimately answer the question of the appropriateness of SBRT as a treatment option for potentially operable patients.

References 1. Videtic GM, Stephans KL. The role of stereotactic body radiotherapy in the management of non-small cell lung cancer: an emerging standard for the medically inoperable patient? Curr Oncol Rep. 2010;12:235-241, PMID: 20446066. 2. Onishi H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer. 2004;101:1623-1631, PMID: 15378503.

Dr. Videtic 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.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2012

Routine DNMT3A Mutation Analysis Proposed for AML From Blood

esearchers have found significant DNMT3A mutations in patients with acute myeloid leukemia (AML) and suggested a prominent role for DNMT3A mutation analysis in AML diagnosis and management. In a study published online April 5 in Blood d (2012 Apr 5. [Epub ahead of print], PMID: 22490330), Ana FT Ribeiro and colleagues analyzed the

prevalence of DNMT3A, its prognostic effect and its interaction with other molecular markers in 415 newly diagnosed AML patients, all of whom were younger than 60 years. The authors identified DNMT3A mutations in 96 of the 415 (23.1%) study participants. The AML patients with DNMT3A mutations were older and had higher white blood cell and platelet counts than those with DNMT3A-wild-type AML. The median follow-up was 115.7

months. Using univariable Cox regression analysis, the authors found that DNMT3A-mutant patients have significantly worse overall survival (OS; 11.9 vs. 24.0 months; P=0.022) and relapse-free survival (RFS; P=0.005) than those with DNMT3A-wild-type AML. The difference in overall survival was independent of a number of NPM1, FLT3 or CEBPA mutations, and independent of patient age, cytogenetic risk and white blood cell count as well. There was no significant

difference in complete remission rate (88.5% vs. 79.3%) between the two groups in the study population. The authors also discovered that DNMT3A mutations had a negative effect on prognosis following multivariable analysis, based on OS ( =0.003) and RFS ((P<0.001). (P The authors believe that mutant DNMT3A has a prognostic effect in AML and propose DNMT3A mutation analysis in routine molecular diagnostics for AML.

EXPERT INSIGHT Yogen Saunthararajah, MD Staff Physician, Department of Translational Hematology and Oncology Research, and The Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute

deally, a diagnosis or classification should describe a discrete pathobiologic entity with a predictable response to therapy. Although incorporation of cytogenetics has assisted in this effort in AML, more than 40% of AML cases have normal cytogenetics and substantially variable outcomes. Acknowledging mutations is thus also logical. Ribeiro et al underscore that in addition to mutations in genes such as FLT3, DNMT3A mutations are relevant: DNMT3A-mutated intermediate-risk AML treated on protocols built around cytarabine-idarubicin had a significantly worse prognosis. What then is the best treatment for these patients? Like Polycomb mutations, DNMT3A mutations may favor lineage-restriction (perhaps a malignant strategy to enhance MYC activity) but render the clone more vulnerable to treatments that relieve aberrant epigenetic repression of late-differentiation genes.1,2 Could treatment built around hypomethylating agents, alternatives to conventional cytotoxics, be a better option? This is a question worth addressing in future clinical trials.

References 1. Saunthararajah Y, Maciejewski J. Polycomb segment myeloid malignancies. Blood. 2012;119:1097-1098, PMID: 22308277. 2. Metzeler KH, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012;26:1106-1107, PMID: 22124213.

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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.

Jointly sponsored by

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.

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

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.

Supported by an educational grant from

Distributed via

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

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113”

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2012

Research Report: ‘Chemobrain’ in Children Research on neurocognitive issues in pediatric cancer from the annual meeting of the International Neuropsychological Society

ancer is the leading cause of death by disease among U.S. children between infancy and age 15, with approximately 11,000 new cases appearing in this age group each year. Leukemias and brain and other central nervous system (CNS) tumors will account for more than half of these. Although the incidence of invasive cancer in children has increased slightly over the last 30 years, the combined five-year survival rate for all childhood cancers has improved from less

than 50% before the 1970s to 80% today, meaning that not only are more children receiving chemotherapy, but they are living longer after their treatments. Post-chemotherapy cognitive impairment—“chemobrain” for short—is difficult to study and what is known about it has been learned largely from adult populations. These reports highlight the small, but growing, body of research on post-chemotherapy cognitive impairment among children and young adults.

Dex During Childhood Impairs Long-term Cognition Potent steroid likely affects regulation of the HPA axis Montreal—Survivors of pediatric acute lymphoblastic leukemia (ALL) who were treated with dexamethasone are at greater risk for impaired cognition and increased stress response than those who were given prednisone, according to research presented at the annual North American meeting of the International Neuropsychological Society. “Dexamethasone gets into the central nervous system easier with higher penetrance,” said Kevin Krull, PhD, the study’s principal investigator and an associate faculty member in the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital in Memphis, Tenn. “We think that dexamethasone treatment is interfering with the natural development of the ability to regulate and control the HPA [hypothalamicpituitary-adrenal] axis.” Dr. Krull and colleagues randomly chose 37 adults from a cohort treated with only chemotherapy, either a combination of high-dose intravenous methotrexate and repeated cycles of prednisone (n=21) or high-dose intravenous methotrexate and repeated cycles of dexamethasone (n=16). The patients in the study underwent neurocognitive evaluations, brain imaging, physical exams and blood chemistry testing, including serum cortisol before and after a dexamethasone suppression test. Patients who were given dexamethasone during treatment had a mean age of 8.8 years at diagnosis and were evaluated at a mean age of 25, while patients given prednisone were aged 11.2 and 24.6 years, respectively. There were no differences in gender, current age or cumulative, high-dose methotrexate exposure between groups. Patients exposed to dexamethasone

had lower vocabulary, reading, mathematics, verbal memory and cognitive flexibility results as well as poorer emotional regulation than those who received prednisone ((P<0.05 for all). These outcomes were associated with decreased volume of the hippocampus

with their counterparts given prednisone, and that dexamethasone-treated patients had less cortisol suppression than prednisone-treated patients. Systolic blood pressure also was associated with decreased cortical thickness in the frontal and parietal brain regions.

‘If we can show these changes in a larger population, it would be tremendously meaningful.’ —ZoAnn Dreyer, MD and decreased cortical thickness in the frontal and parietal brain areas. The negative impact on cognition associated with chemotherapy for pediatric ALL typically is observed about five years after therapy and is not a unique finding, but there are few studies looking at the late effects of therapy, according to Dr. Krull. “If they have memory problems now [in their 20s], they may be at risk for early-onset dementia and early aging decline,” said Dr. Krull. The clinical implication, Dr. Krull said, is that physicians “can perhaps try to catch that and try to minimize that.” They found no difference in basal cortisol, but observed that survivors who received dexamethasone therapy had elevated systolic blood pressure compared

“[Dexamethasone therapy] has impacted how well they respond to and regulate stress,” said Dr. Krull, commenting on the elevated systolic blood pressure and reduced cortisol suppression. “The question is what can we do to help modulate stress.” Modulating stress can be achieved through a behavioral intervention or pharmacological intervention, he noted. ZoAnn Dreyer, MD, a pediatric hematologist/oncologist at Texas Children’s Cancer Center in Houston, described the study as important because it relates to an ongoing question about the use of different types of steroids in therapy and the impact that these choices ultimately have on various neurocognitive parameters.

AT A GLANCE Pediatric acute lymphoblastic leukemia patients given dexamethasone over prednisone have significantly poorer neurocognitive outcomes 15 years after treatment Dexamethasone may inhibit the development of aspects of the neuroendocrine system responsible for controlling reactions to stress

A model of the dexamethasone molecule

There has been a trend away from the use of dexamethasone at some pediatric centers, particularly in older children, because of its association with the development of avascular necrosis of bone, noted Dr. Dreyer. Although a study involving 37 patients will not alter current treatment protocols for pediatric patients with leukemia, it should cause clinicians to reflect on the long-term effects of current treatments, said Dr. Dreyer. “If we can show these changes in a larger population, it would be tremendously meaningful,” Dr. Dreyer said. “If these findings hold up in a larger population, it might change the direction of what we do. We are constantly looking at ways to make therapy as effective yet safer in the long term.” She added that it was interesting that the investigators correlated neuropsychological outcomes with neuro-imaging and noted that she was surprised by the difference in systolic blood pressure between the two patient groups. Dr. Krull is currently analyzing data from a much larger study of adults who received various therapies when they had leukemia in childhood, including dexamethasone, prednisone and intracranial radiation. Patients in this larger study did not undergo brain imaging, he noted. —Louise Gagnon Drs. Krull and Dreyer had no disclosures.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2012

Chemotherapy Effect on Child Cognition Quick, Significant Learning and memory affected within hours of single treatment Montreal—Chemotherapy affects a child’s cognition with 72 hours of administration, according to research presented at the annual North American meeting of the International Neuropsychological Society. Although there are many studies on the effects on cognition in adult survivors of pediatric cancers, few studies have examined the immediate effects of therapy in children with cancer while they undergo treatment. “We were seeing observable effects on cognition,” said Ava Dorfman, PhD, a fellow at the Neurological Institute at the Cleveland Clinic in Ohio. “Within three days of getting chemotherapy, [pediatric patients] had a decline in verbal learning and memory.” The study involved 19 children and young people—11 males and eight females—who had been treated at the Children’s Hospital at Montefiore Medical Center in Bronx, N.Y. They had mixed diagnoses, with 11 acute

‘There was a specific effect of chemotherapy on a specific domain of cognitive function. It was reproducible and specific, and it was consistent with the symptoms that patients complained of.’

lymphoblastic leukemia cases, four osteosarcoma cases, three non-Hodgkin’s lymphoma cases and one case of malignant fibrous histiocytoma. The mean age of the study participants was 12.8 years (range, 6-21 years) with a mean 10.2 months since diagnosis. The patients were administered chemotherapy as appropriate for their diagnosis, with chemotherapy

including prophylactic intrathecal methotrexate (12-15 mg, dosed according to age), IV methotrexate (5,00012,000 mg/m2) or both. The participants underwent a battery of cognitive tests within 24 hours prior to chemotherapy administration and then within 24 to 72 hours after a single treatment. On the Rey Auditory Verbal Learning

Test, which measures verbal learning and memory, there was a statistically significant decrease in scores, ranging from 12 to 21 points. Dr. Dorfman said that early cognitive remediation, possibly in the form of academic intervention during the treatment phase, may help reduce memory deficits. see EFFECTS, S page 18

Clinical Oncology News wants to publish you! Cash prizes! National literary exposure! A voice in the marketplace of ideas!

—Peter Cole, MD

AT A GLANCE Children and adolescents suffer verbal learning and memory declines within 72 hours of receiving chemotherapy It is unknown whether they recover from cognitive adverse effects In the small study, all participants received methotrexate; however, they also received a variety of other agents

As part of the Clinical Oncology News inaugural writer’s contest, from now until July 30 the magazine will be accepting essays on the topic

‘Change in Medical Oncology or Hematology/Oncology’. Essays can relate to the topic in any way the author sees fit — how medicine has changed for the worse, how it should be changed for the better, or simply a reflection on the process of change itself. Essays will be judged on their eloquence and persuasiveness and should be a maximum of 3,500 words. Winners will be announced in the August issue. First place will receive $1000, second place $500 and third place $250. All will receive recognition and prominent placement in Clinical Oncology News. Submissions should be emailed as a Word document to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

Primary Inflammatory Breast Cancer Regimen Effective From The Lancet Oncology

n patients with primary HER2-positive inflammatory breast cancer (IBC), neoadjuvant treatment with a regimen of bevacizumab (Avastin, Genentech/Roche), trastuzumab (Herceptin, Genentech) and other chemotherapy is effective and well tolerated. IBC accounts for about 5% of all cases and is an especially aggressive form of locally advanced breast cancer. It often is diagnosed in younger women and metastases are more common than with other types of breast cancer. Survival rates at five years are about 40%, a marked improvement in recent years, but the prognosis tends to be worse than other locally advanced breast cancers. Overexpression of HER2 is found in 15% to 25%

EXPERT INSIGHT Halle Moore, MD Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute

espite advances in systemic chemotherapy and targeted therapy, outcomes for individuals with IBC remain unacceptably poor. In the BEVERLY-2 study, Pierga et al evaluated the use of bevacizumab in addition to trastuzumab and chemotherapy in the neoadjuvant treatment of HER2/neuoverexpressing nonmetastatic IBC. In this multicenter study that enrolled 52

EFFECTS continued from page 17

The study, however, is limited by its sample size and the variety of therapies administered, said study investigator Peter Cole, MD, a pediatric oncologist at The Children’s Hospital at Montefiore Medical Center and an associate professor of pediatrics at Albert Einstein College of Medicine of Yeshiva University in Bronx, N.Y. “We always use a combination [of therapies] to decrease resistance,” said Dr. Cole in an interview, stressing that the adverse cognitive effect cannot be definitively attributed to methotrexate

of patients with breast cancer and is associated with aggressive disease. The introduction of HER2-targeting trastuzumab has improved prognoses in these diseases, and its use with various neoadjuvant chemotherapy regimens has been assessed, including in IBC, with good results. IBC is highly vascularized because of high expression of angiogenic factors like vascular endothelial growth factor (VEGF), a mediator of angiogenesis that also is involved in tumor cell growth. Bevacizumab is a VEGF-targeting monoclonal antibody that has shown neoadjuvant activity in IBC. The French authors of the current study (named BEVERLY-2 [Neoadjuvant Bevacizumab, Trastuzumab, and Chemotherapy for Primary Inflammatory HER2-Positive Breast Cancer]), led by Jean-Yves Pierga, MD, wanted

to assess the safety and efficacy of a preoperative regimen of bevacizumab, trastuzumab and chemotherapy in patients with primary HER2-positive IBC. The results of this Phase II, multicenter, open-label, single-arm, noncomparative trial appeared in The Lancet Oncology (2012;13:375-384, PMID: 22377126). Roche provided funding. Fifty-two patients with histologically confirmed HER2-positive nonmetastatic IBC were treated with fluorouracil (5-FU), epirubicin, cyclophosphamide and bevacizumab (for four three-week cycles), and then docetaxel, bevacizumab and trastuzumab (for an additional four cycles). Patients then underwent surgery, followed by a round of adjuvant radiotherapy, trastuzumab and bevacizumab. The primary end points were pathologic complete response (pCR)

and adverse events (AEs). Of the 52 patients, 42 (81%) received all eight cycles of therapy. Forty-nine (94%) underwent surgery. Following neoadjuvant therapy, 33 (63.5%) patients achieved pCR. The most frequent AEs were asthenia and nausea (for both, 69%), followed by grade 3/4 neutropenia (48%). The authors concluded that “neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated” in this population of previously untreated patients. They noted that longterm toxicity and effect on survival need to be assessed through followup and that Phase III data would be needed to confirm this approach as a treatment strategy.

patients, an impressive 63.5% pCR rate was observed following four cycles of 5-FU, epirubicin, cyclophosphamide plus bevacizumab followed by an additional four cycles of docetaxel, trastuzumab and bevacizumab. Due to the Phase II nature of the BEVERLY-2 study, it is impossible to judge to what extent bevacizumab contributed to the high response rate observed. The pCR rate, which includes absence of invasive disease in the breast and axilla, does compare favorably with those observed in other studies of similar patients receiving trastuzumabcontaining neoadjuvant chemotherapy regimens without bevacizumab. In the NOAH (NeOAdjuvant Herceptin) trial, a 38% pCR rate was observed among 117 patients with HER/neu-overexpressing locally advanced breast cancer or IBC who received trastuzumab along with

chemotherapy that included doxorubicin, paclitaxel, cyclophosphamide, methotrexate and 5-FU.1 In a retrospective review of inflammatory breast cancer patients treated at M.D. Anderson Cancer Center with trastuzumab and various taxane and/or anthracycline containing neoadjuvant regimens, a 62.5% pCR rate was observed among 16 patients.2 In multiple randomized studies in various disease stages, the addition of trastuzumab to chemotherapy has resulted not only in improved response rates but also to prolongation of survival for patients with breast cancer. In the setting of metastatic breast cancer, improvements in response rates observed with the inclusion of bevacizumab have not yet translated into meaningful improvements in survival. Whether there will be a role for the

routine use of bevacizumab in the treatment of nonmetastatic breast cancer will depend on longer-term results of randomized studies.

because other therapies also were used. “That complicates the picture if you want to know what is causing side effects.” A future study will aim for homogeneity in terms of the treatment protocol and diagnoses of disease, said Dr. Cole. The study also did not assess if children recovered after treatment. “We saw a significant decline, but we never measured the recovery,” said Dr. Cole, adding that a future study will likely measure patients after they have completed a full cycle of chemotherapy to see if cognition is restored or not. Despite the shortcomings, the study did find a statistically significant and clinically meaningful difference on a

particular cognitive domain after a single chemotherapy treatment. “There was not a global slowing of how their brains work,” said Dr. Cole. “There was a specific effect of chemotherapy on a specific domain of cognitive function. It was reproducible and specific, and it was consistent with the symptoms that patients complained of.” ZoAnn Dreyer, MD, an associate professor of pediatric hematology-oncology at Baylor College of Medicine, and the medical director of the Long-Term Survivor Clinic at Texas Children’s Hospital in Houston, said the study was important because testing was conducted before and after treatment. “They did pretreatment and post-

References 1. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomized controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-384, PMID: 20113825. 2. Dawood S, Gong Y, Broglio K, et al. Trastuzumab in primary inflammatory breast cancer (IBC): high pathologic response rates and improved outcome. Breast J. 2010 Jul 6. [Epub ahead of print]. PMID: 20626396. Dr. Moore reports no financial disclosures relevant to this study.

treatment [testing], which adds a lot of validity to the study,” said Dr. Dreyer. “There does appear to be learning differences, compared with pretesting, immediately after treatment. What we don’t know is if these effects will be lasting complications or whether they are just moments in time. A very good thing to do would be to look at them six months after they have finished their treatment and get a measure at another point in time.” —Louise Gagnon

Drs. Dorfman, Cole and Dreyer have no disclosures.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2012

Four-Drug Myeloma Regimen Adds Toxicity, Not Efficacy From Blood

four-drug combination regimen for previously untreated multiple myeloma (MM), which included bortezomib (Takeda/Millennium), dexamethasone (Decadron), lenalidomide (Revlimid, Celgene) and cyclophosphamide (Cytoxan), showed no clear efficacy advantages over three-drug regimens featuring bortezomib (V), dexamethasone (D) and either lenalidomide (R) or cyclophosphamide (C). The so-called EVOLUTION trial, the results of which were published in the May 10 issue of the journal Blood (2012;119:4375-4382, PMID: 22422823), compared a trio of three-drug regimens that had demonstrated efficacy as firstline therapy for MM in other studies

to the comparatively novel four-drug approach. The study, led by Shaji Kumar, MD, of Mayo Clinic in Rochester, Minn., involved researchers from multiple cancer centers across the United States, and was supported with research funding from Janssen Global Services and Millennium Pharmaceuticals. For this Phase II clinical trial, 140 previously untreated patients with MM were randomized to receive VDCR: bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) and dexamethasone (40 mg on days 1, 8 and 15) with cyclophosphamide (500 mg/m2 on days 1 and 8) and lenalidomide (15 mg on days 1-14); VDC: bortezomib and dexamethasone with cyclophosphamide; VDR: bortezomib and dexamethasone with lenalidomide (25 mg on days 1-14); or VDCmod: bortezomib and dexamethasone

EXPERT INSIGHT Frederic J. Reu, MD Associate Staff Physician Department of Hematologic Oncology & Blood Disorders Cleveland Clinic Taussig Cancer Institute, and Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

hree or four drugs for induction of symptomatic MM? This Phase II randomized exploration by Shaji Kumar, MD, and colleagues suggests that an AE limit may be reached without added myeloma control when two promising bortezomib-based triplets (VDR and VDC) are combined to the quadruplet VDCR. Although all tested combinations reached excellent rates, depths, and durations of responses, neurotoxicity in all treatment arms was

substantial and at least one severe drugrelated AE was seen in 60% to 79%. Maximizing outcome while minimizing cost to quality of life may require more than the suggested consideration of alternative bortezomib administration schedules (weekly) and routes (subcutaneous) in future studies. Taking the heterogeneity of MM with long remissions to doublets in a substantial proportion of patients into account,1 a staged addition of drugs to a starting doublet, if monthly

with a modified dose of cyclophosphamide (500 mg/m2 on days 1, 8 and 15). All regimens were administered in three-week cycles for a maximum of eight cycles, and were followed by maintenance therapy with bortezomib (1.3 mg/m2 on days 1, 8, 15 and 22) for four six-week cycles. All patients were assessed for partial response (PR), complete response (CR) and progression-free survival (PFS). Median follow-up for the overall trial was 20 months (median followup for VDCR, 20 months; VDR, 20 months; VDC, 22 months; and VDCmod, 15 months). The median number of cycles administered for all treatment arms was six. All of the regimens were highly active and well tolerated; common adverse events (AEs) included hematologic toxicities, peripheral

neuropathy, fatigue and gastrointestinal disturbances. At follow-up, PR was seen in 58% of the patients in the VDCR treatment arm, 51% in the VDR arm, 41% in the VDC arm, and 53% in the VDC-mod group. CR rates were 25%, 24%, 22% and 47%, respectively. One-year PFS was 86%, 83%, 93% and 100%, respectively. Based on the one-year PFS data, the authors concluded that the four-drug VDCR regimen offered no clinical efficacy advantages over the three-drug approaches and increased morbidity, particularly hematologic toxicity. The researchers concluded that the VDR and VDC-mod arms had better toxicity profiles, “showed significant activity with high rates of deep responses,” and “warrant further evaluation in a Phase III setting.”

response end points are not met, should save many from added toxicity but still provide close to universal disease control. It might further help delay development of resistance to novel drugs, a situation with a dismal outlook.2 Future trials with sufficient power and follow-up to detect survival differences should compare such strategies with fixed regimens like the ones presented here. A Phase III randomized controlled trial by the Southwest Oncology Group that recently completed accrual compares two (RD) to three (VRD) drugs. Unless this should demonstrate survival advantage with three drugs, two remain a reasonable option for the up-front treatment of MM. A recent retrospective analysis from Moffitt Cancer Center suggests that for most patients, upfront doublets and triplets containing bortezomib or lenalidomide yield similar survival outcomes, but contrary to

common belief less might even be better in the subgroup with cytogenetically high-risk MM.3

References 1. Kumar SK, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118:1585-1592, PMID: 22009602. 2. Kumar SK, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study. Leukemia. 2012;26:1153, PMID: 22569269. 3. Baz R, et al. Outcomes analysis of doublets of novel agents with corticosteroids versus regimens with 3 or more agents for multiple myeloma (MM): A retrospective analysis. Blood d (ASH Annual Meeting Abstracts). 2011;118; abstract 1878.

Crizotinib Shows Activity in Pediatric Cancers C

rizotinib (Xalkori, Pfizer), indicated for the treatment of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive, has shown evidence of activity against three pediatric cancers also driven by ALK K gene abnormalities. The cancers are anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor and neuroblastoma. The results of the Phase I study by Yael P. Mosse, MD, an assistant professor of pediatrics at Children’s Hospital of Philadelphia at the University of Pennsylvania, were presented at the American Society

of Clinical Oncology (abstract 9500). Seventy pediatric patients (median age 9.9 years; range 1.1-21.3 years) with refractory solid tumors and ALCL were enrolled in the study. Crizotinib, an oral targeted drug, was administered twice daily, with six dose levels evaluated. When possible, patients’ cancers were tested for ALK abnormalities, although this was not a requirement for enrollment. Of patients with ALCL, seven of eight (88%) had a complete response (CR). Of patients with neuroblastoma, two of 27 had a CR, and eight had no

disease progression. Of neuroblastoma patients with a proven ALK K abnormality, two of eight had a CR. One patient with an inflammatory myofibroblastic tumor had a partial response, as did one with NSCLC. Dose-limiting toxicity included grade 3 dizziness, grade 5 intra-tumoral hemorrhage, grade 4 liver enzyme elevation and grade 4 neutropenia. In their abstract, the researchers concluded: “Inhibition of ALK in pediatric [patients] with ALK-driven tumors occurs with minimal toxicity and is associated with objective

Dr. Reu disclosed that he receives funding from Celgene.

antitumor activity.” In an email to Clinical Oncology News, lead researcher Dr. Mosse said: “In many ways, this trial is setting a new paradigm of treating pathways rather than tumors, and [of ] allowing collaborations across tumor types. Cancer is an assortment of diseases with distinct genetic profiles, and this study allows us to leverage the genetics across pediatric and adult tumors.” —George Ochoa Dr. Mosse reported research funding from Pfizer.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

On the Spot with Colleen Hutchinson

Watch and Wait for Rectal Cancer

his month features the Clinical Oncology News debut of “On the Spot with Colleen Hutchinson,” a column dedicated to keeping readers informed of the critical aspects of current debates and providing unparalleled access to the thought leaders whose clinical practice and academic research help shape the issues themselves. You’ve heard these experts at the podium, you’ve read their journal articles, but you’ve never heard them be candid like this. Once you’ve read what they have to say, look at your own practice and see how their arguments measure up. Whether you agree or disagree, we’d love you to share your opinion with us. This month’s column centers on innovative approaches to rectal cancer and highlights topics at the intersection of colorectal surgery and colorectal oncology—inclusive of neoadjuvant therapy, transanal endoscopic microsurgery, watch and wait, and what the rectal cancer patient deserves to know. Given the choice to agree, disagree or be on the fence, some of our finest oncologists

and surgeons lay bare their opinions. All of these areas were debated at the Eighth International Rectal Cancer Consensus Conference at Lankenau Medical Center in September. At that meeting, the formation of the new Multidisciplinary International Rectal Cancer Society was announced and we have a message from its founders: The last decade has given witness to a sea change in the management of the rectal cancer patient. As new approaches evolve, each apparent discovery brings with it new and unexpected questions. Proper consideration of these questions and the formulation of personalized patient care guidelines aimed at providing the highest quality of life while maximizing cure demand a multidisciplinary approach by dedicated experts. Clinical Oncology News, by providing a forum for airing some of the many penetrating issues with commentary by the experts, offers an opportunity to sensitize and enlighten the readership of the need to remain alert to evolving data that shift

treatment paradigms. The members of the recently organized Multidisciplinary International Rectal Cancer Society (MIRCS) wish to express their appreciation to the editors of Clinical Oncology News for permitting this timely and important dialogue. Where would we be without the thought leaders who operate, innovate and educate in their own treatment centers and across the globe? Thank you to this month’s contributors for their candid beliefs, opinions and observations, and for the time it took to share them. A special thank you to Gerald Marks, MD, a pioneer in colorectal cancer care and a beacon of innovation and patient advocacy whose distinguished career continues today. As readers, meeting attendees and clinicians deeply involved in everyday patient care, what do you want to hear key opinion leaders in clinical oncology discuss beyond the podium? Let me know at colleen@ cmhadvisors.com. —Colleen Hutchinson

P ARTICIPANTS Theodore Saclarides, MD, is director of the Division of Colorectal Surgery at Loyola University Health System, and professor of surgery at Loyola University Chicago Stritch School of Medicine Chicago, Ill.

John H. Marks, MD, is chief of the Section of Colorectal Surgery of Main Line Health and program director for the Fellowship in Minimally Invasive Surgery and Rectal Cancer Management at Lankenau Medical Center, Wynnewood, Pa.

Richard M. Goldberg, MD, is Klotz Family Professor of Medicine and physician in chief of the Arthur G. James Cancer Hospital at the Wexner Ohio State Medical Center and associate director of the OSU Comprehensive Cancer Center. Dr. Goldberg is a gastrointestinal medical oncologist mainly focused on treatment and research in colorectal cancer.

Gerald Marks, MD, is professor of surgery and colorectal surgeon at Lankenau Medical Center, Wynnewood, Pa.

Angelita Habr-Gama, MD, is professor of surgery, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.

Rodrigo Perez, MD, is professor of surgery, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.

Tim Nguyen, MD, is a gastrointestinal medical oncologist at the Cleveland Clinic in Weston, Fla.

Conor P. Delaney, MD, is chief of the Division of Colorectal Surgery, surgical director of the Digestive Health Institute, vice chairman of the Department of Surgery at University Hospitals Case Medical Center, and professor of surgery and director of the Center for Surgery and Simulation at Case Western Reserve University in Cleveland, Ohio Albert S. DeNittis, MD, is clinical associate professor at Lankenau Institute for Medical Research, and chief of radiation oncology at Lankenau Medical Center, Wynnewood, Pa.

Brad Champagne, MD, is associate professor of surgery in the Division of Colorectal Surgery at Case Western Reserve Medical Center and University Hospitals of Cleveland, and program director for the Accreditation Council for Graduate Medical Education Colorectal Residency and surgical director of the Community Center of Excellence, Digestive Health Institute.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

Statement

Patients deserving radical rectal resection should always be informed of the laparoscopic option.

Dr. Goldberg: The current ACOSOG (American College of Surgeons Oncology Group) trial is evaluating the relative risks and benefits of laparoscopic versus open rectal surgery. In the COST (Clinical Outcomes of Surgical Therapy) trial run by the ACOSOG and the North Central Cancer Treatment Group (NCCTG) in the 1990s (N ( Engl J Med d 2004;350:2050-2059, PMID: 15141043), this technique was proven to be both safe and effective for colon cancer resection. A cautious approach to the integration of this technique in patients who are not enrolled in clinical trials is prudent until data becomes available from the studies under way.

Dr. Champagne: I disagree. For colon cancer, however, they should always be informed.

Dr. Saclarides: Patients should be informed about laparoscopy, and included in the discussion should be the fact that a prospective, randomized, nationwide multi-institutional trial is under way in the United States to determine its efficacy compared with open surgery. Until these data are available, the surgeon should do his or her best operation that follows the basic principles of obtaining negative margins and doing the level-appropriate mesorectal excision for lymph node clearance.

Dr. Nguyen: Agree. In a retrospective study, disease-free and overall survival seem to be comparable with open surgery but with less postoperative complications and shorter hospital stay.

Dr. Delaney: I agree that laparoscopy almost always should be discussed for radical rectal cancer surgery. Although there are some patients who are not candidates because of morbid obesity, multiple prior operations or requirements for multivisceral resection, the majority of patients are candidates for a laparoscopic approach. Many randomized controlled trials and meta-analyses have clearly shown that patients with colon cancer have better outcomes with laparoscopy—at least equivalent oncological outcomes, with lower complication rates, less pain and earlier recovery. Fewer studies have been performed for rectal cancer, but these studies now include several randomized trials and many large comparative series by experienced surgeons. Not surprisingly, laparoscopy has again shown equivalent oncological

‘Knowing the variability of methods and incisions used for laparoscopy, and especially laparoscopy for rectal cancer, it is no surprise that short-term benefits have been called into question.’ —Conor Delaney, MD

outcomes to open surgery. Short-term benefits for rectal cancer have been similar to colon surgery. Knowing the variability of methods and incisions used for laparoscopy, and especially laparoscopy for rectal cancer, it is no surprise that short-term benefits have been called into question. I think surgeons and patients need to remember that an operation is not laparoscopic simply because it is called laparoscopic. For rectal cancer surgery, specimen extraction sites—the largest incision—have been as large as Pfannenstiel or lower midline incisions for laparoscopic-assisted surgery, or as small as transanal or transostomy site extraction. In my own practice, most patients with rectal cancer have the specimen removed through the ileostomy site, and go home on acetaminophen for analgesia, with three other 5-mm port sites. I believe these outcomes and potential for recovery need to be discussed with patients who have rectal cancer.

Dr. J. Marks: On the fence. For colon cancer I would give an unqualified “agree”! The data are overwhelming in favor of laparoscopy. In fact, if open surgery was somehow the new procedure it would never be allowed to be adopted, based on all the studies. For rectal cancer, there are very promising individual and specialized center data, but this hasn’t been validated yet in a prospective randomized trial. The ACOSOG Z6501 trial is under way and should address this issue. With a personal experience of more than 300 laparoscopic transanal endoscopic microsurgery (TEM) resections and a local recurrence rate of less than 5%, I am confident of what the outcome will be, and I believe it will favor the laparoscopic approach.

Drs. Habr-Gama and Perez:

Dr. G. Marks: Agree, with hesitancy. Just as colon cancer is effectively and advantageously managed laparoscopically, it appears that surgery for rectal cancer may enjoy the same benefits. Although I am inclined to say that patients should be informed of the option as a matter of informed consent, we probably are not there yet because the conclusive data are not in hand.

Statement

Local excision without neoadjuvant therapy should be the standard for T1 rectal cancer.

Drs. Habr-Gama and Perez: No! Standard treatment for T1 rectal cancer should be total mesorectal excision. Local excision should be considered an alternative treatment strategy, particularly for frail patients unable to undergo major abdominal surgery or for those who refuse abdominal perineal excision when this treatment is the primary surgical alternative. There is hope that neoadjuvant chemoradiotherapy (CRT) followed by local excision will be a valid and appropriate treatment strategy in the future for these patients.

Dr. Champagne: I agree as long as there are no high-risk features and the risk for recurrence is well explained to the patient who would otherwise tolerate a formal resection. The patient can then make an educated decision about surveillance or more surgery.

Dr. G. Marks: Disagree. A treatment failure for a T1 cancer in my mind is unpardonable, and the reported local failure rates for local excision alone are unacceptably high. Radical resection with sphincter preservation or full-thickness local excision (FTLE) after neoadjuvant CRT is preferable.

Dr. Goldberg: In the hands of expert surgeons and with compulsory visual follow-up, the outcomes for local excision with T1 lesions are excellent and avoid the need for more aggressive therapy and the potential long-term complications of radiation or more extensive surgery. It is critical to scope patients regularly to permit early detection and definitive management of local recurrence.

Definitely!

Dr. DeNittis: Agree. Surgical ability, however, plays a role here. Laparoscopic resections are limited by the number of surgeons who can perform them. If not performed properly, the patient can be at risk for increased recurrence rates with increased local quality-of-life issues.

Dr. J. Marks: Disagree. The results to date, from major centers, show failure rates anywhere from 5% to 19% with T1 cancers treated by local excision alone. This is unacceptable for a group of patients who should have the best results, and the local recurrence rate for unfavorable cancers at our institution and other places is only 3%. For selected cancers (SM1 or very small foci of cancers), as with medically compromised patients, it is an excellent option. see ROUNDTABLE, E page 22

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

ROUNDTABLE continued from page 21

Dr. Nguyen: Agree. For T1 disease, local control and survival are not improved by addition of neoadjuvant CRT.

Dr. DeNittis: Disagree. Due to the high local failure rates and possibility of lymph node metastases, I don’t know why one wouldn’t consider neoadjuvant therapy. It seems we have a chance here to cure this subgroup of patients but offer them suboptimal therapy. If neoadjuvant CRT is not considered, then radical resection should be performed. In our experience with high-dose radiation to 5,580 cGy prior to surgery, patients do extremely well.

‘Selective TEM/FTLE is an acceptable option in the downstaged rectal cancer.’

‘There are tumors that respond slowly and the patience to wait for that response is very important. We are finding that some patients can be long-term survivors with local surgery alone.’ —Albert S. DeNittis, MD as well as systemic imaging, should be a part of any post-procedure surveillance plan.

Drs. Habr-Gama and Perez: Despite this treatment strategy sounding appropriate, long-term oncological outcomes are yet unavailable. Considering that the risk for nodal metastases is closely related to final pathologic ypT status, TEM/FTLE may be acceptable for ypT0 and ypT1.

Statement

Selective TEM/FTLE is acceptable for the downstaged distal rectal cancer.

Dr. G. Marks: Agree. Selective TEM/FTLE is an acceptable option in the downstaged rectal cancer, particularly when the surgeon cannot technically offer sphincter preservation. Secondary determinants come into play and radical restorative resection for the young, fit patient offers a statistical advantage. Reading between the lines, the issue of the timing of surgical decision making is the pivotal point. The state of the cancer after neoadjuvant therapy and a suitable interval should determine the surgical decision.

Dr. Goldberg: Most patients should be enrolled in trials to help to better define the relative outcomes of these approaches compared with standard abdominal perineal resection or low anterior resection. In selected cases where patients refuse definitive surgery or are too high-risk medically for surgery due to comorbid medical conditions, this approach can be considered with careful review of the risks and benefits. Compulsory screening for local recurrence,

Dr. J. Marks: Agree. This is an excellent option, especially when the other alternative is an abdominoperineal resection (APR). Pathologic ypT3 or node-positive disease should be followed then by a radical resection. The decision should be based on the characteristics of the cancer after therapy. The lesion should be nonulcerated and less than 4 cm. All of the mural induration with a 1-cm margin must be excised. Using this approach, we have had a 4% local recurrence, but longer follow-up is needed.

Dr. Champagne: Disagree. This may become standard in the next decade as we become more adept at determining which tumors are amenable to this approach. However, for now, it is only acceptable in patients who cannot tolerate formal resection.

Statement

—Gerald Marks, MD Dr. Saclarides: This statement may apply for most T1 rectal cancers; however, the surgeon needs to review the slides with a pathologist who has a dedicated interest in gastrointestinal cancers. If there is deep penetration into the submucosa, or the lesion is poorly differentiated or has lymphovascular invasion, then radical surgery is probably preferable. If local excision is chosen, the patient must be informed about recurrence rates of about 10% and should undergo close periodic follow-up so that recurrences can be salvaged.

lesion on TEM/FTLE is not equal to no residual disease in the lymph node or mesorectum.

Dr. Saclarides: Even if downstaging has occurred with neoadjuvant therapy, radical surgery is still the surgical option of choice because residual cancer may be present in endoscopically normal areas far removed from the post-treatment scar or ulcer. TEM/FTLE in this setting is an option, however, for elderly patients, patients with comorbid conditions that render radical surgery risky or for patients who absolutely refuse to have a stoma for life.

‘The challenge remaining for all local therapy is to predict which rectal cancers will have lymph node involvement. Armed with this knowledge, I would advocate TEM much more aggressively, but unfortunately we are still grappling with this issue.’ —John Marks, MD

Dr. DeNittis: Agree. Determining the type of surgery on a patient-by-patient basis in this subgroup of downstaged patients is critical. The timing of the type of surgical procedure should be eight to 10 weeks post-therapy. There are tumors that respond slowly and the patience to wait for that response is very important. We are finding that some patients can be long-term survivors with local surgery alone.

Dr. Nguyen: On the fence. Although a few retrospective studies suggest TEM/FTLE is safe for T3 downstaged to T0 to T1 after neoadjuvant CRT, no randomized study has been conducted to answer this question. Having a complete responder of the rectal

Selective TEM/FTLE for the down-staged rectal cancer should not be limited to the distal rectum.

Dr. Saclarides: My response is the same as for the preceding statement. TEM, however, does provide longer reach and improved access to lesions in the mid and upper rectum.

Dr. G. Marks: Agree. TEM in the hands of the proficient surgeon permits safe sphincter-preserving FTLE for cancers in the mid and upper rectum when general and local factors indicate the advisability of FTLE.

Drs. Habr-Gama and Perez: Selective TEM/ FTLE for the downstaged rectal cancer should be limited to the distal rectum.

Dr. J. Marks: Agree. TEM gives the ability to extend local excision into the proximal rectum. With pathologic complete response rates ranging up to 30%, this approach offers an excellent option. Of course, the challenge remaining for all local therapy is to predict which rectal cancers will have lymph node involvement. Armed with this knowledge, I would advocate TEM much more aggressively, but unfortunately we are still grappling with this issue.

Dr. Goldberg: If the experienced surgeon is confident that higher rectal tumors can be excised transanally and pathologic review is favorable for clear margins, this approach can be considered in tumors that are not in the distal rectum and that have been downstaged by preoperative neoadjuvant therapy. This is not a standard approach at this time, however.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

‘TEM for the downstaged rectal cancer can be performed for mid and upper rectal cancers.’ —Tim Nguyen, MD

Dr. DeNittis: Agree. When selecting the patient appropriately, FTLE is an excellent option for the mid to upper rectum, provided the surgeon has the proper technical expertise and is fully knowledgeable from the oncologic standpoint.

Dr. Nguyen: Agree, TEM for the downstaged rectal cancer can be performed for mid and upper rectal cancers.

Statement

Watchful waiting for the complete responder should be restricted to institutional review board (IRB)-approved study programs.

Dr. Saclarides: This statement is absolutely true and the patient should be informed that watchful waiting is not the standard of care in the United States.

Drs. Habr-Gama and Perez: Watchful waiting should be restricted to centers with expertise in rectal cancer management and multidisciplinary settings.

Dr. Goldberg: It is clear that complete response is a favorable predictor for a good long-term outcome. In practice, it is sometimes necessary due to patient preference or risk of definitive surgery to individualize care. Restricting this to research patients in unusual circumstances does not seem reasonable, provided the patient is informed of risks and followup is individualized to fit the circumstances.

Dr. Champagne: It also can be considered in elderly high-risk patients as long as they are compliant with aggressive surveillance.

Dr. J. Marks: Agree! This is a very exciting development and has real promise. That said, there is still a great deal to learn in its applicability. The major concern that I have is that this is being inappropriately applied to patients who are significant operative challenges. There is mucosal regression, but still a sizable cancer left in the wall and these patients are just being followed. We have seen too many patients who have had their treatment inappropriately delayed, with persistent, unrecognized cancer. I think this would be minimized if this was only done under protocol.

Dr. G. Marks: Agree. Following the published results of watchful waiting for the complete responder by the Habr-Gama group, there was a rush to embrace this revolutionary concept. I fear that this is driven by surgeons unable or disinclined to perform sphincter-preservation surgery for low-lying lesions. Recognizing the complete responder with any degree of certainty requires exceptional experience and advanced knowledge of the appearance of the neoadjuvant-treated rectal cancer. Accordingly, watchful waiting should be limited to IRB-approved study programs in centers with high volume.

Dr. DeNittis: Agree. Although there appears to be data supporting this approach, it certainly is not the standard of care. Clinical trials will ensure the proper similarities in patient selection and treatment techniques.

Dr. Nguyen: Agree. We do not yet have the modality that can evaluate with reasonable certainty a clinical complete response that correlates with pathologic complete response.

Statement

Surgical decision making should always await tumor assessment following neoadjuvant therapy and a suitable interval.

Dr. Champagne: Disagree. There are many cases when the appropriate surgical procedure (APR vs. colo-anal) can be determined after the office visit and pelvic magnetic resonance imaging. However, there also are some patients who are “borderline” and their ultimate fate can be better assessed after neoadjuvant therapy.

Dr. J. Marks: Agree. This is the only way the patient and surgeon can enjoy the full benefit of tumor downstaging. Although I would never advocate a minimal margin for a mid to upper rectal cancer after treatment, in the distal rectum, where sphincter preservation hangs in the balance, the advantages to this approach are obvious. Using this mindset, many centers, including our own, have been able to show a decrease in permanent colostomy rate from 25% to 40% to 10% or less.

Dr. Goldberg: Tumor assessment is critical to developing the proper strategy for managing patients after neoadjuvant therapy.

Dr. G. Marks: Agree emphatically. A small body of latecomers to neoadjuvant therapy, perhaps borrowing a page from the treatment of head and neck cancers, advocated that the selection of the surgical procedure be determined by the original presentation

of the tumor rather than after neoadjuvant therapy. Nothing speaks so loudly as the strikingly improved results of local or radical sphincter-preserving surgery following neoadjuvant therapy where otherwise APR would be indicated.

Dr. Saclarides: This statement is false for most patients who have acceptable operative risks. The decision as to which operation is best for such patients should be based on pretreatment tumor size, location and distance from the anus. Until more data are available, the decision should not be based on how much downstaging occurs with radiation and chemotherapy.

Drs. Habr-Gama and Perez: Definitely.

Dr. DeNittis: Agree. There is a significant amount of new evidence to suggest that surgical decision making should be based on the neoadjuvant tumor response and not the pretreatment staging. The response may be predictive of outcome and patientby-patient decision making is crucial. The patient who would otherwise be considered only a candidate for APR would frequently be considered for low anterior resection.

Dr. Nguyen: Agree. Regression of a large tumor that would have required an APR can be evident in four to 12 weeks following neoadjuvant therapy, possibly allowing for conversion to sphincter-sparing surgery.

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

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2012

-emitting Nuclide Targets Bone Metastases Fast-tracked by FDA for difficult-to-treat metastatic prostate cancer San Francisco–Clinical oncologists soon may have a new treatment for patients with metastatic castrationresistant prostate cancer (CRPC), based on results of a randomized, Phase III multinational study. The novel radiation-emitting agent, radium-223 chloride (Ra-223; Alpharadin, Algeta), targets bone metastases with high-energy α-particles. In results presented first at the 2012 Genitourinary Cancers Symposium and later at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO), Ra-223 improved survival and delayed cancer-related bone problems in men with CRPC. The study agent is the first α-particle– emitting drug that been shown to improve survival in metastatic CRPC. In August 2011, the FDA granted the agent Fast Track review status; in June, following updated results presented at ASCO, the company announced that it plans to seek marketing approval in the United States in the second half of this year. “As recently as two years ago, we had very few options for patients with this particularly difficult form of advanced prostate cancer,” said lead author A.

14.0

11.2

months

Osteoblast Newly formed bone

Ra-223

Osteoblast

Radium-223 deposition

Placebo

Figure. Overall survival. Oliver Sartor, MD, a professor of cancer research at Tulane University School of Medicine in New Orleans. “Now we have a handful. But Radium-223 is the first treatment to both reduce adverse skeletal-related events (SREs) and improve survival, making this a particularly promising therapeutic option.” Prostate cancer is considered castration-resistant when growth continues despite extremely low levels of testosterone. In the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) trial, 922 patients with

‘Radium-223 is the first treatment to both reduce adverse skeletal-related events and improve survival, making this a particularly promising therapeutic option.’ —A. Oliver Sartor, MD

Table. Adverse Events With Radium-223 Chloride in Patients With Metastatic Castration-Resistant Prostate Cancer Patients Reporting AEs

Ra-223 (N=509a)

Placebo (N=253a)

All grade AEs, N (%)

450 (88)

237 (94)

Grade 3 or 4 AEs, N (%)

257 (51)

150 (59)

Serious AEs, N (%)

220 (43)

139 (55)

Discontinued due to AEs, N (%)

68 (13)

51 (20)

AE, adverse event; Ra-223, Radium-223 a

Bone marrow

Tumor cells

Patients who received 1 injection or more.

Ra-223 accumulates in new bone growth in and around bone metastases and emits alpha particles that irradiate adjacent cells to a depth of two to 10 cell diameters, resulting in DNA breaks and highly localized tumor cell killing.

progressive CRPC with bone metastases were randomized in a 2:1 ratio to receive Ra-223 plus best supportive care (BSC) or placebo and BSC. BSC included antibiotics, analgesics, radiation therapy for pain from bone metastases and corticosteroids. In an interim analysis of 805 patients presented at ASCO-GU (abstract 8), Ra-223 significantly improved median overall survival compared with placebo (14 vs. 11.2 mo; two-sided P=0.00185; hazard ratio [HR], 0.695; 95% confidence interval [CI], 0.552-0.875). As a result, the trial was discontinued early. Additionally, the time to the first SRE—bone fracture, spinal cord compression, external beam radiation to bone or bone surgery—was significantly delayed (median time to SRE 13.6 vs. 8.4 months, respectively; P=0.00046; HR, 0.610; 95% CI, 0.461-0.807). In follow-up data presented at the 2012 ASCO meeting in Chicago (abstract 4551), the proportion of patients whose Eastern Cooperative Oncology Group (ECOG) performance status (PS) deteriorated two or more points was less among patients given Ra-223 than those given placebo at both weeks 12 and 24 (4% vs. 9% and 7% vs. 12%, respectively). The time for patients’ ECOG PS to deteriorate two

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or more points also was significantly extended in the Ra-223 group compared with the placebo group (P ( =0.003; HR, 0.62; 95% CI, 0.46-0.85). “These findings will help us to increasingly individualize advanced prostate cancer treatment, with a novel agent that can extend our patients’ lives,” said Dr. Sartor. Further research is planned to examine the effectiveness of combining Ra-223 with other drugs. Dr. Sartor said studies are needed to determine whether Ra-223 is effective in combination with newly available immunotherapies, hormonal therapies and chemotherapy. Additionally, other investigators already have begun testing Ra-223 in patients with breast cancer who have bone metastases. Plans also are under way for clinical studies of Ra-223 in other cancers. “The majority of patients were postdocetaxel. This group of people has not often been included in previous trials,” said Dr. Sartor. “All in all, it is an extremely well-tolerated therapy. We believe this novel α-pharmaceutical may provide a new standard of care for prostate cancer.” —John Schieszer Dr. Sartor serves as a consultant for Algeta.

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Intercontinental Controversy: PSA Screening Largest screening trial to date demonstrates 21% risk reduction

massive European study is feeding the controversy over when and how to use prostate-specific antigen (PSA) testing to detect prostate cancer. In an update to previously published data from the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, PSA-based screening reduced mortality from prostate cancer—but at a high cost in overdiagnosis and overtreatment ((N Engl J Med 2012;366:981-990).

Schröder, MD, PhD, a professor of urology at Erasmus University Medical Center in Rotterdam, The Netherlands, said the argument in favor of screening is “strengthened by the new data.” However, “the data have to be balanced against clear disadvantages—overdiagnosis and overtreatment.” Mark S. Litwin, MD, MPH, a professor of urology and public health and the chair of urology at the University of California, Los Angeles, told Clinical Oncol-

‘This is the definitive answer we’ve been waiting for: The more screening we do, the more likely we are to prevent prostate cancer, but the human cost is simply too great.’ —Mark Litwin, MD, MPH The trial is important because of its long follow-up—a median of 11 years— and its size. The ERSPC trial includes 182,160 men aged 50 to 74 years from eight European countries, with a predefined core age group of 162,388 men between the ages of 55 and 69 years. The men were randomly assigned to receive PSA-based screening or no screening. The primary outcome was mortality from prostate cancer. At 11 years, there was a 21% (P ( =0.001) relative reduction in risk for death from prostate cancer in the screening group and a 29% risk reduction after adjustment for noncompliance ((P=0.001). The absolute risk reduction was 1.07 deaths per 1,000 men at a median follow-up of 11 years. At 11 years, 1,055 men have to be invited for screening, and 37 cancers need to be detected, to prevent one death from prostate cancer. The study’s lead author, Fritz H.

ogy News: “This is the definitive answer we’ve been waiting for: The more screening we do, the more likely we are to prevent prostate cancer, but the human cost is simply too great.” “It’s an excellent study, done at a wide array of sites in Europe,” Gerald Andriole, MD, the Robert K. Royce distinguished professor and chief of urologic surgery at Washington University School of Medicine in St. Louis, said in an interview. However, “there are questions of whether it would apply to the United States,” he added. Among the issues Dr. Andriole cited with the European study: “If

Prostate cancer cells.

by the

numbers PSA screening over 11 years 182,160| 1,055| 37|

Men included in the ERSPC trial Men needed to invite for screening to prevent one death Cancers needed to detect to prevent one death

From the European Randomized Study of Screening for Prostate Cancer (ERSPC).

you were randomized to screening, you were likely to be seen at a major hospital or university; if not, generally the man was seen at a community hospital … The type of treatment differed between those screened and not screened.” In contrast, Dr. Andriole said that the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening) trial, for which he is principal investigator, is “more applicable to men in the United States” than the ERSPC. In the PLCO, he said, the prevailing “community standard of care” was applied to men in both arms—annual screening and usual care, which can include opportunistic screening. The PLCO found that the rate of death from prostate cancer did not differ significantly between the two study groups ((N Engl J Med d 2009;360:1310-1319, PMID: 19297565). A recent follow-up study also found no evidence of a mortality benefit with organized annual screening (J ( Natl Cancer Inst 2012;104:125132, PMID: 22228146). “Medical care in all the countries in the ERSPC trial is very different from the United States. The PLCO trial results are far, far more relevant to the United States,” Anthony B. Miller, MD, a professor emeritus at the Dalla Lana School of Public Health at the University of Toronto in Ontario, Canada, and a co-investigator in the PLCO trial, told Clinical Oncology News by email.

AT A GLANCE ERSPC PSA Screening Trial PSA screening reduced the relative risk for prostate cancer death by 21% Trial served as a major source for the U.S. Preventive Services Task Force recommendation against PSA screening There are potential differences in the treatment groups based on where they were seen—community or academic centers The PLCO trial is more applicable to U.S. patient populations

of advice the task force gave clinicians. Dr. Litwin said of the draft recommendation: “There’s no way to disagree with that. The controversy is how to implement it.” “While I can see why the USPSTF came to its conclusion,” Dr. Andriole commented, “the way this has been

‘If you were randomized to screening, you were likely to be seen at a major hospital or university; if not, generally the man was seen at a community hospital. … The type of treatment differed between those screened and not screened.’ —Gerald Andriole, MD

In this context, the 2011 draft recommendation of the U.S. Preventive Services Task Force (USPSTF), recommending against mass PSA-based screening for prostate cancer, is relevant. Dr. Miller advised following the recommendations because “they seem the most appropriate at the present time.” Dr. Schröder said, “I agree at the end with the USPSTF conclusions, but not their way of handling it,” citing the lack

portrayed in the press does more harm than good. There are subsets of men who will benefit from screening, men at above average risk for prostate cancer.” He suggested “risk-based screening—before you screen, identify risk.” —George Ochoa Drs. Litwin and Schröder reported no relevant financial disclosures. Drs. Andriole and Miller reported none aside from their involvement in the PLCO trial.

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ERLOTINIB continued from page 1

wild-type,” said Marina Chiara Garassino, MD, an oncologist at Fatebenefratelli and Ophthalmic Hospital in Milan, who presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). “Docetaxel significantly improves progression-free survival, response rate and disease-control rate over erlotinib.” Other researchers not involved with the study agreed, but pointed out that what the study really showed was that second-line therapies for this patient population, those with wild-type EGFR, perform dismally. Steven Vogl, MD, a medical oncologist in New York City, drove this point home in a questionand-answer session following the presentation. “Docetaxel is a poor drug and erlotinib is a terrible drug for these [unmutated EGFR, second-line systemic therapy] patients. We shouldn’t give them erlotinib anymore,” he said. “Do you agree?” Dr. Garassino concurred. “If we know something does not work and is toxic to boot, then we should not give it,” Dr. Vogl told Clinical Oncology News. “It is hard enough to be dying, but worse to be dying with

toxicity with little chance of benefit.” He said he wouldn’t give docetaxel to this patient population either unless the patient really wanted chemotherapy. “[Docetaxel] is toxic and rarely makes

ratio, 0.69; P=0.014). Response rate was higher in patients receiving docetaxel (13.9% vs. 2.2%; P=0.004). The benefit of docetaxel was seen in all subgroups, including KRAS wild-type patients.

‘If we know something does not work and is toxic to boot, then we should not give it. It is hard enough to be dying, but worse to be dying with toxicity with little chance of benefit.’ —Steven Vogl, MD symptoms better,” he said. The academic TAILOR trial enrolled patients with EGFR wild-type advanced/recurrent NSCLC who had received previous therapy with a platinum-based doublet. Patients had an Eastern Cooperative Oncology Group status of 2. At ASCO, researchers presented an intention-to-treat analysis of 219 patients who were randomized to receive docetaxel (n=110) or erlotinib (n=109) (abstract LBA7501). Because data for the primary end point of overall survival are immature, the investigators presented interim PFS data. The median PFS by investigator review was 3.4 months in patients receiving docetaxel and 2.4 months in patients receiving erlotinib (hazard

Patients who received erlotinib more frequently experienced dermatologic toxicities (14% vs. 0%), whereas patients receiving docetaxel had more frequent neutropenia (27% vs. 1%), neurologic toxicity (15% vs. 8%) and alopecia (29% vs. 2%). The proportion of patients who experienced at least one serious adverse event was similar in the two arms (14.4% vs. 13.1%). TAILOR is the only prospective head-to-head trial comparing erlotinib with docetaxel in wild-type EGFR patients. The PFS hazard ratio seen in this study, however, is consistent with retrospective subgroup analyses of the TAILOR, TITAN (Trial of Induction TPF in Advanced Head & Neck Cancer) and INTEREST (IRESSA NSCLC

AT A GLANCE Because pemetrexed usually is first-line therapy, secondline choice usually is between erlotinib and docetaxel Docetaxel improved PFS by one month over erlotinib Erlotinib resulted in dermatologic toxicities much more frequently Overall, second-line outcomes are poor regardless of drug choice

Trial Evaluating Response and Survival against Taxotere) trials. These trials also showed that chemotherapy is favored over an EGFR tyrosine kinase inhibitor as second-line therapy for NSCLC patients with wild-type EGFR tumors. —Kate O’Rourke Dr. Garassino disclosed a relationship with Eli Lilly. Dr. Vogl had no relevant disclosures.

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Clinical Conundrums

Prepared by

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

Spotlight on selected articles from the Journal of Clinical Oncologyy and Blood

QUESTIONS

1. True or False.

Data from the SOLTI-0701 trial suggest a potential role for the combination of sorafenib plus capecitabine in patients with HER2negative advanced breast cancer and have previously received anthracycline and/or taxane therapy.

2. True or False. A pharmacogenet-

ic study from the North American Children’s Oncology Group (COG) showed that a polymorphism in the CBR3 gene predicted risk for cardiomyopathy in children exposed to high doses of anthracyclines (>250 mg/m2).

3. True or False. The addition of bev-

acizumab to docetaxel and prednisone (CALGB 90401) improved overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) and was associated with greater toxicity.

4. True or False. In PDX-010 (Study

of Pralatrexate in Patients With Relapsed or Refractory Cutaneous T-cell Lymphoma) trial, pralatrexate (Folotyn, Allos Therapeutics) at 15 mg/m2 per week for three of four weeks showed high activity with acceptable toxicity in patients with relapsed and refractory cutaneous T-cell lymphoma (CTCL).

5. True or False. According to a study

by Gunter von Minckwitz, MD, and the German Breast Group, it is inappropriate to use pathologic complete remission (pCR) as the primary end point in neoadjuvant trials using cytotoxic

chemotherapy in patients who present with luminal A subtype (estrogen receptor [ER]-positive and/or progesterone receptor-positive, HER2-negative, grade 1 or 2) breast cancer.

chemotherapy based on the neoadjuvant therapy for breast cancer has resulted in clinically meaningful improvements in outcomes.

shows that carboplatin-based regimens appear to be equally effective in terms of OS, PFS and objective response rate when compared with cisplatin-based combinations for the first-line therapy of small cell lung cancer (SCLC), differing only in their toxicity profiles.

7. True or False. In a recent retro-

13. True or False. Javier Cortés, MD,

6. True or False. Modification of

spective analysis, the five-year recurrence-free survival rates were 90.5% and only 58.5% for pCR and poor responders, respectively, among patients receiving neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

10. True or False. The incorpora8. True or False. In advanced mel- tion of fluorouridine triphosphate into

anoma, the presence of circulating T cells reactive against antigens Melan-A or NY-ESO-1 has no prognostic effect on survival.

True or False. In the NORDIC VII (5-Fluorouracil [5-FU]/Folinate/Oxaliplatin [Eloxatin] [FLOX Regimen] Given Continuously or Intermittently, in Combination With Cetuximab [Erbitux] in First-Line Treatment of Metastatic Colorectal Cancer) trial, patients with KRAS-mutated cancers demonstrated a trend toward improvement in PFS with the addition of an EGFR monoclonal antibody (mAb) to an oxaliplatin-based chemotherapy backbone.

RNA appears to be the most important mechanism of action for 5-FU as infusion time is prolonged, whereas inhibition of thymidylate synthase (TS) becomes more important when 5-FU is administered as a bolus infusion.

11. True or False. Inhibition of the

BRAF kinase with vemurafenib (PLX0602) induces rapid fluorodeoxyglucose– positron emission tomography (FDGPET) responses in patients with BRAFmutant melanoma and always predicts subsequent tumor regression.

12. True or False. The COCIS Meta-

Analysis of Individual Patient Data

and colleagues demonstrate the value of persistent HER2 blockade by reporting a PFS of 17.4 weeks after combined treatment with the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in patients with evidence of disease progression while receiving either of the two agents alone.

14.

True or False. Anas Younes, MD; Yvette Kasamon, MD; and colleagues took advantage of the CD-20 expression in classical Hodgkin’s lymphoma (cHL) and presented Phase III data adding rituximab to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) in patients with advanced cHL.

15. True or False. CyBorD (cyclo-

phosphamide, bortezomib, dexamethasone) combination therapy produces rapid and complete hematologic response in patients with light chain (AL) amyloidosis. for answers see CONUNDRUMS, S page 30

Fish Consumption Linked to Lower Colorectal Cancer Risk Fish consumption may reduce the risk for colorectal cancer, according to a systematic review and meta-analysis published April 17 in the American Journal of Medicine. To be included in the meta-analysis, a study had to have a case–control or cohort study design, have fresh fish consumption as its exposure of interest, report the number of colorectal cancer cases and controls and report the relative risks or odds ratios (ORs) with their corresponding 95% confidence interval (CI) for highest versus lowest level of fish intake. Forty-one publications from 1990 to 2011 were ultimately included, 22 of them prospective cohort studies and the remaining 19 case–control studies. The

summary ORs among all studies showed a significant reduction in colorectal cancer risk in populations with high fish intake (summary OR, 0.88; 95% CI, 0.80-0.95). The evidence suggested that fish consumption may reduce the risk for colorectal cancer by as much as 12%. The protective effect of fish consumption is more pronounced in rectal cancer (summary OR, 0.79; 95% CI, 0.65-0.97) than in colon cancer (summary OR, 0.96; 95% CI, 0.81-1.14), the researchers found. An author, Jie Liang, MD, PhD, from

State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases at the Fourth Military Medical University in Xi’an, China, told Clinical Oncology News by email: “This meta-

The evidence suggested that fish consumption may reduce colorectal cancer risk by as much as 12%. analysis was conducted of currently available epidemiologic studies on the association between consumption of fish and colorectal cancer. … And it is

the first [study] to investigate the relationships between fish consumption and colon or rectal cancer separately, which might provide better suggestions [for] colorectal cancer prevention.” Study limitations include lack of information as to the kind of fish consumed or manner of preparation. Confirmation in a large randomized clinical trial is needed, the authors wrote. —George Ochoa

Dr. Liang disclosed that this study was partially sponsored by the National Natural Science Foundation of China and a Foundation for the Author of National Excellent Doctoral Dissertation of PR China.

CURRENT PRACTICE

CONUNDRUMS

1. True.

continued from page 29

The Phase III study (NCT01234337) will definitively ascertain the efficacy and safety of this combination. Dosing modifications and more aggressive supportive care will be implemented to improve the management of hand–foot skin reaction/hand–foot syndrome (HFSR/HFS) and other toxicities. Baselga J, Segalla JG, Roché H, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30:14841491, PMID: 22412143.

2. False. The North American COG

pharmacogenetic study determined that a CBR3 polymorphism predicted risk for cardiomyopathy in children exposed to low to moderate doses of anthracyclines (<250 mg/m2), although exposure to high doses of anthracyclines (>250 mg/ m2) was associated with increased risk for cardiomyopathy in spite of CBR3 genotype. Blanco JD, Sun CL, Landier W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl-reductase genes—a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:1415–1421, PMID: 22124095.

3. False. Despite an improvement in

PFS and overall response rate (ORR), the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC.

CLINICAL ONCOLOGY NEWS • JULY 2012

5. True. Neoadjuvant trials that are

testing classic cytotoxic drugs with pCR as the primary end point should be encouraged to enroll patients with ER-negative or highly proliferative tumors, given that these are the patients for whom pCR has demonstrated prognostic value. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796-1804, PMID: 22508812. Schott AF, Hayes DF. Defining the benefits of neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30:1747-1749, PMID: 22508810.

6. False. At present, knowing the

response to neoadjuvant therapy does not result in a modification of therapy. Limitations to reliably defining pCR remain challenging. The findings reported by Dr. von Minckwitz should allow for the development of a uniform definition of pCR and subsequently may result in a response-stratified treatment approach. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796-1804, PMID: 22508812.

7. True. The treatment response to

neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlates with long-term outcomes. These data provide guidance through response-stratified oncologic benchmarks for comparing novel treatment strategies.

Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30:1534-1540, PMID: 22454414.

Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30:1770-1776, PMID: 22493423.

4. True. Based on the results of

reactive T cells contributed independently to prognosis and predicted survival better than American Joint Committee on Cancer (AJCC) C M (metastasis) category staging in patients with distant metastasis. This study also provides a rationale for refining vaccination and T-cell transfer strategies by targeting Melan-A and NY-ESO-1 tumor-associated antigens.

the PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma [PTCL]) study, pralatrexate received accelerated approval from the FDA for patients with relapsed or refractory PTCL at a dose of 30 mg/ m2 weekly by IV push for six of seven weeks. The PDX-010 trial attempted to identify a similarly effective CTCL regimen with pralatrexate but with a lower dose and different schedule in order to minimize the adverse-effect profile for continuous long-term use. Further studies are needed to confirm the reassuring outcomes achieved in the PDX010 trial prior to implication of this modified dose and schedule into routine clinical practice. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189, PMID: 21245435. Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119:4115-4122, PMID: 22394596.

8. False. Melan-A– and NY-ESO-1–

Weide B, Zelba H, Derhovanessian E, et al. Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis. J Clin Oncol. 2012;30:1835-1841, PMID: 22529253.

9. True. An excellent editorial by Drs.

Axel Grothey and Heinz-Josef Lenz that accompanied the NORDIC trial publication said the results “add another layer of confusion to the already complex and somewhat inconsistent results on the use of EGFR mAbs in colorectal cancer. The challenge and obligation is to make sense of the NORDIC results and place them into the larger context of the EGFR mAbs–chemotherapy interaction in colorectal cancer.” Tveit KM, Guren T, Glimelius B, et al. Phase III Trial of Cetuximab With Continuous or

Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in FirstLine Treatment of Metastatic Colorectal Cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:17551762, PMID: 22473155. Grothey A, Lenz HJ. Explaining the unexplainable: EGFR antibodies in colorectal cancer. J Clin Oncol. 2012;30:1735-1737, PMID: 22473160.

10.

False. Incorporating fluorouridine triphosphate into RNA appears to be the most important mechanism of action for 5-FU bolus schedules, whereas inhibition of TS becomes more important as the infusion time is prolonged. Studies have demonstrated EGFR inhibitors can reduce TS expression levels, which have an inverse relationship to FU efficacy in colorectal cancer. This could make infusional FU, as opposed to bolus FU, the preferred fluoropyrimidine backbone for EGFR mAbs. Harstrick A, Gonzales A, Schleucher N, et al. Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance. Anticancer Drugs. 1998;9:625-634, PMID: 9773807. Grothey A, Lenz HJ. Explaining the unexplainable: EGFR antibodies in colorectal cancer. J Clin Oncol. 2012;30:1735-1737, PMID: 22473160. Skvortsov S, Sarg B, Lindner H, et al. Cetuximab inhibits thymidylate synthase in colorectal cells expressing epidermal growth factor receptor. Proteomics Clin Appl. 2008;2:908-914, PMID: 21136888. Bijnsdorp IV, Kruyt FA, Fukushima M, et al. Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010;101:440-447, PMID: 19886911.

11. False. Strikingly, 100% of patients

(n=27) treated with vemurafenib obtained an FDG-PET response at day 15 in a study reported by Grant McArthur, MB, PhD, and his colleagues. The inhibition of FDG uptake may be a robust marker of the pathway inhibition of glucose uptake and possibly cell proliferation; however, a reduction of glucose uptake is insufficient to induce high levels of cell death that lead to morphologic regression. Additional data on FDG-PET changes in patients with melanoma who are treated with vemurafenib, including serial studies that are timed to coincide with radiologic assessments, are needed before FDG-PET may be proposed as the primary indicator of anticancer activity. McArthur GA, Puzanov I, Amaravadi R, et al. Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J Clin Oncol. 2012;30:1628-1634, PMID: 22454415. Millward MJ. Early [18F]Fluorodeoxyglucosepositron emission tomography responses in metastatic melanoma: what do they mean? J Clin Oncol. 2012;10:1581-1583, PMID: 22454416.

12. True. On the basis of their COCIS

meta-analysis, the authors noted that the choice of the platinum compound for first-line treatment of patients with SCLC in clinical practice should be individualized. A definitive conclusion for patients with limited-disease SCLC cannot be drawn from this analysis.

Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS Meta-Analysis of Individual Patient Data. J Clin Oncol. 2012;30:1692-1698, PMID: 22473169.

13.

True. Pertuzumab has some activity (objective response rate [ORR], 3.4%) in patients with HER2-positive breast cancer that has progressed during therapy with trastuzumab, but the combination of pertuzumab and trastuzumab seems to be more active (ORR, 17.6%) than monotherapy. This noteworthy observation suggests that the traditional oncologic paradigm— in which most drugs are used only once and discontinued permanently at the first sign of progression—may require modification in the era of targeted therapy. 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;30:15941600, PMID: 22393084.

14. False. Both trials were Phase II,

not Phase III. Approximately 20% to 30% of cHL cells express the B-cell antigen, CD20. The results of these two independent trials were compared with historical controls for response and toxicity analysis and were similar to what one might have expected without the addition of rituximab. Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119:4129-4132, PMID: 22343727. Younes A, Oki Y, McLaughlin P, et al. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood. 2012;119:4123-4128, PMID: 22371887. Küppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9:15-27, PMID: 19078975.

15. True. In two independent retro-

spective studies, Joseph R. Mikhael, MD, and his colleagues and Christopher P. Venner, MD, and his colleagues reported unprecedentedly high hematologic response rates, 94% and 81%, including complete response rates of 71% and 42%, respectively, to the combination of CyBorD in patients with either naive or relapsed AL amyloidosis. The availability of this powerful regimen opens new perspectives in the care 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 progressionfree survival. Blood. 2012;119:4387-4390, PMID: 22331188.

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Recent Advances and Emerging Therapies In the Systemic Treatment of

Metastatic Melanoma JEFFREY T. YORIO, MD Fellow, Hematology and Oncology

KEVIN B. KIM, MD Associate Professor Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

elanoma, the malignant transformation of melanocytes, most commonly occurs in the skin but also may arise from the mucosal surfaces or in the choroid of the eyes. Melanoma is the fifth and

sixth most common cancer in men and women, respectively, in the United States.1 In 2012, more than 76,000 people will be diagnosed with malignant melanoma, and more than 9,000 people will die from the disease nationally.1

Although surgery offers a great cure rate for patients with early-stage melanoma, those who have either metastatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4 Dacarbazine remains the only cytotoxic chemotherapy that is FDA-approved for the treatment of metastatic melanoma. However, dacarbazine has modest clinical efficacy, with a response rate of only about 10%.2,4-6 The FDA also has approved high-dose interleukin-2 (IL-2) for the treatment of advanced melanoma because of the

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

agent’s ability to induce a durable response. Unfortunately, this response is observed in only a small subset of patients, and IL-2 is associated with significant toxicities, such as capillary leak syndrome, that frequently require intensive monitoring in a dedicated unit or intensive care facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine, paclitaxel, carmustine, and lomustine (CeeNu, BristolMyers Squibb)—are commonly used off-label to treat melanoma, but none of these agents or their various combinations have been found to offer a survival advantage over dacarbazine alone.9 Clearly, more active and

C L I N I C A L O N C O L O G Y N E W S • J U LY 2 0 1 2

less toxic drugs are needed for patients with advanced melanoma. In this article, we review recent advances and emerging therapeutic approaches in the systemic treatment of metastatic melanoma.

Newly Approved Drugs For Late-Stage Melanoma IPILIMUMAB Immunotherapy has been used to treat melanoma for decades. Cancer cells, such as those that make up melanoma, have tumor-associated antigens that can be recognized by T cells. This recognition leads to a host response that targets the tumor cells.10 The standard immunotherapy, high-dose IL-2, enhances this response but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively sought to identify and develop more effective immunologic agents with better safety profiles. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells. T-cell activation begins when the T-cell receptor binds to an antigen presented by a major histocompatibility complex on antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7 (CD80/CD86) found on antigen-presenting cells, leading to T-cell proliferation and IL-2 production. As T cells become activated, CTLA-4 is upregulated to the cell surface, where it competes successfully with CD28 for B7 to halt further cell proliferation in a self-regulatory mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7 molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and IL-2 production.13,14 Ultimately, this can help increase the immune response to cancer cells. Initial clinical studies revealed that ipilimumab could be a promising new therapy for metastatic melanoma.15,16 A Phase I/II trial of ipilimumab (â&#x2030;¤10 mg/kg every 3 weeks) in 23 patients with metastatic melanoma demonstrated a disease control rate of 39%, with at least 2 patients experiencing a durable response of longer than 21 months.15 These encouraging results led to several Phase III trials of ipilimumab in patients with metastatic melanoma (Table 1).17,18 In the first Phase III study of ipilimumab, 676 previously treated patients with unresectable stage III or IV melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab with a glycoprotein 100 (gp100) peptide vaccine (n=403), ipilimumab alone (n=137), or the gp100 peptide vaccine alone (n=136).17 Ipilimumab was given at a dose of 3 mg/kg every 3 weeks for 4 doses. The median OS of patients who received ipilimumab alone (10.1 months) was significantly longer than that of patients who received the gp100 vaccine alone (6.4 months; hazard ratio [HR], 0.66; P=0.003).

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the FDAâ&#x20AC;&#x2122;s approval of the drug for the treatment of metastatic melanoma in March 2011. In the second Phase III study of ipilimumab, 502 treatment-naive patients with metastatic melanoma were randomized to receive dacarbazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses. During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS duration of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacarbazine alone (P=0.006). As with other immune-stimulating agents, ipilimumab induces immune-related adverse events (AEs). In the first Phase III trial, the most common immune-related AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diarrhea and colitis was seen in 5% of the patients. The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen in 21% and 17%, respectively. Endocrine immune-related AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon. Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive highdose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-Îą antibody, has been used with some success to treat patients who are unresponsive to high-dose steroids. The use of highdose IV corticosteroids also has been suggested for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies.

Table 1. Clinical Data From Positive Phase III Studies of Melanoma N

Treatment Setting

Primary End Point Results

Hazard Ratio (95% CI)

gp100 vaccine

136

Second-line

OS, 6.4 mo

Reference

Ipilimumab

137

OS, 10.1 mo

0.66 (0.51-0.87)

0.003

Ipilimumab + gp100 vaccine

403

OS, 10.0 mo

0.68 (0.55-0.85)

<0.001

OS, 9.1 mo

Reference

OS, 11.2 mo

0.72 (0.59-0.87)

OSa

Reference

Trial and Regimen

P Value

NCT00094653

NCT00324155 Dacarbazine + placebo

252

Dacarbazine + ipilimumab

250

First-line

<0.001

NCT01006980 Dacarbazine

338

Vemurafenib

337

Dacarbazine Vemurafenib

First-line; V600E BRAF mutation

0.37 (0.26-0.55)

338

PFS, 1.6 mo

Reference

337

PFS, 5.3 mo

0.26 (0.20-0.33)

First-line; V600E BRAF mutation

PFS, 2.7 mo

Reference

PFS, 5.1 mo

0.30 (0.18-0.51)

â&#x2030;¤1 prior systemic therapy; V600E BRAF mutation

PFS, 1.5 mo

Reference

PFS, 4.8 mo

0.45 (0.33-0.63)

<0.001

NCT01227889 (BREAK-3) Dacarbazine

Dabrafenib

187

<0.0001

NCT01245062 (METRIC) Chemotherapyb

108

Trametinib

214

<0.001

CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival a b

Inadequate number of patients in follow-up to provide reliable estimates of the survival curve Dacarbazine or paclitaxel

VEMURAFENIB The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, which codes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most BRAF mutations are the result of a single nucleotide substitution in which valine is replaced by glutamic acid at codon 600 (V600E) of exon 15, leading to the constitutive activation of the MEK protein and ERKs, which are essential to melanoma cell proliferation. Melanoma cells with the BRAF mutation do not require Ras activation to proliferate, indicating that the BRAF mutation is a driving force behind melanoma cell growth. To inhibit the Raf/MEK/ERK pathway, researchers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth factor receptor (VEGFR). However, 2 Phase II trials of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additionally, the presence of the BRAF mutation was not correlated with

response.21,22 Similarly, 2 large randomized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional clinical benefit in patients with metastatic melanoma.23,24 Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the mutated Raf kinase. One of these new drugs, PLX4032 (later named vemurafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A first-in-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melanoma harboring a BRAF mutation were then enrolled in the dose-extension cohort and received vemurafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, a large Phase II study of vemurafenib was conducted in 132 previously treated patients who had metastatic melanoma harboring a V600E BRAF

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Cell membrane receptor

PI3K

Ras

PTEN AKT

Raf MEK 1/2

mTOR

ERK 1/2

IF4E

Cyclin D1

Transcription factors

p70

MMP-2

Tumor cell survival, proliferation, invasion

Nucleus

Figure. Commonly activated signal transduction pathways in melanoma. ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin

mutation.27 The ORR, which was validated by an independent review committee, was 53%, with a median PFS duration of 6.8 months, thus confirming the promising results of the Phase I study. A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacarbazine in treatment-naive patients with metastatic melanoma harboring a V600E BRAF mutation (Table 1).5 Six hundred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of the interim analysis so that patients in the dacarbazine arm could receive vemurafenib. Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent

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of patients experienced grade 2 or 3 photosensitivity reactions, but the use of sunblock helped prevent the blistering typically observed in grade 3 reactions. Eighteen percent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoacanthomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs. These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrated that the binding of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actually leads to transactivation of adenosine triphosphate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated when vemurafenib binds to wild-type BRAF.28,29 Based on the statistically significant improvement in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic melanoma harboring a V600E

Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma Trial and Regimen

Primary End Point

V600E BRAF mutation

PFS

340

First-line

V600E/K BRAF mutation

694

First-line

C-Kit (juxtamembrane)

200

First-line

Any

700

Treatment Setting

Mutation Criteria

First-line

NCT01584648 Dabrafenib (GSK2118436) plus trametinib (GSK1120212) versus dacarbazine NCT01597908 Dabrafenib plus trametinib versus vemurafenib (Zelboraf, Roche) NCT01280565 Masitinib versus dacarbazine NCT01515189 Ipilimumab (3 mg/kg) versus ipilimumab (10 mg/kg) OS, overall survival; PFS, progression-free survival

BRAF mutation. However, despite the high response rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed.

Emerging Targeted Therapies SELECTIVE RAF INHIBITORS The successful development of vemurafenib has generated great interest in the clinical evaluation of selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent, dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, investigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic melanoma harboring a V600 BRAF mutation and received at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33 Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melanoma harboring a V600E/K BRAF mutation.34 Of these 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks.

The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin. Recently, a Phase III study (NCT01227889) was conducted to compare the PFS associated with dabrafenib to that associated with dacarbazine in treatment-naive patients with V600E BRAF-mutated melanoma. The results demonstrated that patients who received dabrafenib had a significantly longer median PFS over dacarbazine (6.7 vs. 2.9 months, respectively; HR, 0.35, 95% confidence interval [CI], 0.20-0.61).35 The ORR also was superior in the dabrafenib arm (50% vs. 6%). The OS data are not available because the study was not designed to compare the OS, and the follow-up thus far is too short for OS evaluation. Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly.

MEK INHIBITORS Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstream of BRAF kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but also by kinase-activating NRAS mutations or other upstream aberrations, such as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway. The results of clinical trials of first-generation MEK inhibitors were disappointing. For example, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein occlusion, which resulted in the discontinuation of their

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development. 36,37 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibitor of MEK1/2. Although in vitro studies revealed that melanoma cell lines containing a BRAF mutation were particularly sensitive to selumetinib,38,39 a randomized Phase II study showed that the drug had no clinical benefit over temozolomide in chemotherapy-naive patients with metastatic melanoma.40 The differences in the median PFS duration (78 vs 80 days) and ORR (5.8% vs 9.4%) between the patients who received selumetinib and those who received temozolomide, respectively, were not statistically significant, and the response rates among patients with melanoma containing a BRAF mutation in each group were both the same, at 11%. Clinical outcomes with the next-generation, hydrogen sulfate (Hyd-sulfate) formulation of selumetinib, which has better oral bioavailability than does the original crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hydsulfate selumetinib to be 75 mg twice daily.41 In a separate Phase I study of combination regimens containing Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF mutation had a higher clinical response rate and longer median time to progression than did those without a BRAF mutation, suggesting that BRAF mutation is a positive predictive factor for Hyd-sulfate selumetinib.42 A randomized Phase II study comparing dacarbazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatment-naive patients with BRAF-mutated melanoma (NCT00936221) recently completed patient accrual, and the results of this study are highly anticipated. Another potent, highly selective, nonâ&#x20AC;&#x201C;ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212, GlaxoSmithKline). Although a Phase I study revealed the MTD of trametinib to be 3 mg per day, 2 mg per day was chosen as the recommended dose for future studies on the basis of pharmacokinetic, clinical activity, and safety data.43 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with metastatic melanoma harboring a V600 BRAF mutation are encouraging.44 In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a V600E BRAF mutation and 75% had M1c disease), 14 (25%) had a confirmed response, and the median PFS duration was 4 months (CI, 3.5-5.6 months). However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mechanisms

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of resistance to BRAF inhibitors also might confer resistance to MEK inhibitors. The results of an open-label randomized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacarbazine or paclitaxel in patients with metastatic melanoma harboring a V600 BRAF mutation was recently announced (Table 1). The trametinib arm had a statistically significant improvement in all 3 clinical parameters (RR, PFS and OS).45 The median PFS was 4.8 months for the trametinib arm compared with 1.4 months for the chemotherapy arm (HR, 0.44; CI, 0.310.64; P<0.0001). In addition, a HR for OS was 0.54 (CI, 0.32-0.92) with a P value of 0.0136, favoring the trametinib arm. Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech). The common AEs of MEK inhibitors include skin rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.36,37,40,41,43,44 Visual disturbances, such as blurry vision or flashing lights, are common but generally mild. Serious ocular toxicity, including central serous retinopathy and retinal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomatic and is reversible upon discontinuation of the drugs.

COMBINATION STRATEGIES USING TARGETED THERAPIES Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced melanoma harboring a BRAF mutation, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisition of activating NRAS mutations,46 acquisition of activating MEK mutations,47 upregulation of upstream receptor kinases,48 upregulation of CRAF kinase,49 induction of splicing variants of BRAF kinase,50 increased Cot expression,51 and activation of PI3K/AKT signaling pathways.52,53 Loss of BRAF mutations and the development of secondary mutations to the drug-binding domain of BRAF kinase have not been observed at the time of drug resistance, however.46,48 A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was re-upregulated at the time of

disease progression in a subset of patients.54 This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associated with resistance to the Raf inhibitors and can, at least partially, bypass the inhibition of the BRAF mutations. In vitro studies have shown that the addition of a MEK inhibitor can delay the development of drug resistance to a selective Raf inhibitor.47 On the basis of these encouraging findings, a Phase I study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma. The clinical data generated from the studyâ&#x20AC;&#x2122;s interim analysis are promising.55,56 Given at the recommended doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diarrhea, and fatigue.55 Skin toxicity, including the development of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxically activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who had metastatic melanoma containing a V600E/K/D BRAF mutation and who had never received a BRAF inhibitor, 43 (66%) had objective responses, including 5 (8%) CRs.55 Of the 26 patients who previously had been treated with a selective Raf inhibitor, 5 (19%) had partial responses.56 The updated results of the Phase II study showed that median PFS was 10.8 months among 24 BRAF inhibitor-naive patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily.57

KIT INHIBITORS Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precursors,58,59 and KITâ&#x20AC;&#x2122;s frequent expression in melanoma specimens59,60 led investigators to conduct 3 studies evaluating the use of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.61-63 Imatinib had minimal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug. Interest in KIT-targeted therapy in melanoma was renewed when Curtin et al showed that KIT mutation and/or amplification is more common in certain subtypes of melanoma than in others.64 In their analysis of 102 primary melanomas, they used a comparative genomic hybridization assay and found KIT mutations and/or increased copy numbers of KIT in 36% of acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chronically sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have

melanoma harboring KIT mutations.65-68 Additionally, the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma harboring a KIT mutation had a clinical response to the drug.69 However, none of 10 patients with KIT amplification without a mutation had a response. In another Phase II study of imatinib in 43 patients with metastatic melanoma harboring a KIT mutation or amplification, 10 (23%) patients had an overall clinical response, and 9 of the 10 responders had a KIT mutation in exon 11 or 13.70 In a separate Phase II study of imatinib in a similar population, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.71 The response rate among patients who had mutations affecting recurrent hotspots of the KIT gene or a higher KIT mutant-to-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these features was 0% (P=0.05), suggesting that the presence of a functionally relevant KIT mutation is required for imatinib or other KIT inhibitors to have clinical benefit.

Emerging Immunotherapies ANTI-PD1 ANTIBODY Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and is involved in T-cell regulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the antigen-presenting cells found in tumors), PD1 suppresses T-cell effector function. Tumoral PD-L1 expression has been associated with negative prognosis in cancer patients.72,73 MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, thereby reactivating T-cell function.74 In a Phase I dose-escalating study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well tolerated with only one serious AE (colitis).75 Of the 39 patients in the study, 3 patients, including one with metastatic melanoma, had a clinical response to MDX-1106. Another Phase I study evaluated the safety profile of a biweekly dosing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.76 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nausea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the preliminary response evaluation, 6 (38%) of 16 patients had objective responses; among these patients, 3 patients with metastatic melanoma had a partial response. The clinical investigation of MDX-1106 is ongoing.

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ADOPTIVE T-CELL THERAPY In the mid-1980s, Rosenberg et al found that tumorinfiltrating lymphocytes (TILs) isolated from murine sarcomas and colon adenocarcinomas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of metastatic tumors.77 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a single dose of cyclophosphamide.78 Other researchers found that when the adoptive transfer of TILs and IL-2 infusion were preceded by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endogenous regulatory cells and lymphocytes competing with the transferred TILs for growth-promoting homeostatic cytokines, 6 of 13 patients had a clinical response.79 Notably, this approach resulted in the persistent clonal repopulation of T cells, which proliferated in vivo and traveled to tumor sites in these patients. In an expanded Phase II study conducted by the same group of investigators, lympho-depleting chemotherapy followed by TIL transfer and high-dose IL-2 infusion elicited a response rate of 51% among 35 patients with metastatic melanoma.80 When TIL transfer and IL-2 infusion were preceded by myeloablative chemoradiation (lympho-depleting chemotherapy plus 2 or 12 Gy of total-body irradiation), clinical activity of the regimen was even better, with response rates of 52% and 72%, respectively.81 Of 20 patients who had CRs in these trials of adoptive TIL transfer, only 1 patient’s disease has relapsed. The other patients continue to have CRs 3 to 7 years following the completion of the treatment.81,82 In another study, CD4-positive T-cell clones targeting the DPB1*0401-restricted epitope of a peptide derived from NY-ESO-1 were isolated from the peripheral blood mononuclear cells of patients with metastatic melanoma and expanded in vitro, and the antigen-specific CD4-positive T cells were infused back into the patient.83 One patient had a complete resolution of lung and nodal metastases that was accompanied by the persistent presence of the NYESO-1–specific CD4-positive T cells and lasted for at least 2 years. This finding suggests that the adoptive transfer of antigen-specific CD4-positive T cells may be used to treat advanced melanoma.

Conclusion After a long drought in the development of successful therapies, recent advances in targeted therapy and immunotherapy have set a new standard of treatment for metastatic melanoma. However, the arrival of ipilimumab and vemurafenib in the clinic has generated more questions and challenges. For example, it is not clear which of these agents, ipilimumab or vemurafenib, should be offered first in patients with metastatic disease, especially in those with limited or slowly

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progressing metastatic lesions; in addition, the optimal sequencing of high-dose IL-2 with these agents remains unknown. Whether a Raf inhibitor should be added to subsequent therapy following the failure of BRAF inhibition is also unclear. The optimal combination of targeted drugs and/or immunotherapeutic agents will need to be determined to maximize their clinical benefit in patients with metastatic melanoma. We hope that these important questions soon will be addressed with rationally designed clinical studies.

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