July 2014 by McMahon Group

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • July 2014 • Vol. 9, No. 7

INSIDE CURRENT PRACTICE ACCC presenters recommend aligning treatments with patient priorities ................... 6 Model puts price tag on Medicare lung cancer screening ................................. 9 HEMATOLOGIC DISEASE Sagar Lonial, MD: How I manage autologous transplantation in multiple myeloma .................................. 18

by the

numbers

How do the new melanoma therapies compare? Drug Regimen

Response Median Rate, % OS, mo

Ipilimumab 3 mg/kg q3wk × 4

10.1

10.9

Vemurafenib 48.4 960 mg bid

13.6

Dacarbazine 5.4 1,000 mg/m2

9.7

Dabrafenib 150 mg bid

NEJM M 2011;364:2507-2516; NEJM M 2010;363: 711-723; Lancett 2012;380(9839):358-365

For full story, see

clinicaloncology.com

IMAGES in ONCOLOGY

Negative ALTTO Trial Shakes Up Breast Ca Research Chicago—Negative results from the Phase III ALTTO trial have put the kibosh on using dual anti-HER2 therapy with lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) in the adjuvant breast cancer setting. The study results also have undermined the use of smaller neoadjuvant breast cancer trials to identify therapies that will work in the adjuvant setting. “This is a serious disappointment, not just for the investigators, but for the entire field [of breast cancer],” said George Sledge Jr., MD, a professor of medicine and the chief of the Division of Oncology at Stanford University School of Medicine, in California. He was not involved with ALTTO but served as the discussant for the study (abstract LBA4) when it was presented at the recent annual meeting of the American Society see SHAKE-UP, P page 8

Twitter Hits and Impressions Double At #ASCO14

For more information, see page 7.

Vogl, NY...

CHAARTED Trial Should Cause Sea Change in Rx! For every man with newly diagnosed metastatic prostate ca, ask: “should he get docetaxel now?”

Chicago—Last month, oncologists were a-twitter about the American Society of Clinical Oncology’s annual meeting—#ASCO14 for those conversant in Twitter parlance. According to numbers from Symplur, a U.S. firm specializing in health care social media analytics, tweets from the meeting hit 38,056 this year, greatly outstripping the 14,634 sent out see TWITTER HITS, S page 6

‘Untitled’; this Sezary Cell seems to be erupting in the blood smear.

major change has just taken place in the approach to metastatic prostate cancer. For the first time, aggressive, early intervention has had a major effect on both survival and time to disease progression. Based on the ECOG-ACRIG study presented at the 2014 annual meeting of the American Society of Clinical Oncology by Christopher Sweeney, docetaxel given concurrently with initiation of androgen-deprivation therapy (ADT) prolongs median survival by 14 months and increases Steven Vogl, MD 5-year survival by 22%, with the curves separating progressively with increasing follow-up.1 For high-volume disease (visceral metastases or at least four bone metastases, with at least one metastasis in appendicular skeleton), median overall survival increased by an even more impressive 17 months. Additionally, median time to symptoms or radiographic progression increased by 13 months for the entire population. see VOGL, NY Y page 8

RE VIE WS & COMMENTAR IES

Expert Insights From The Ohio State University—The James Inverse relationship between adenomas detected and later cancer ................ 13 Peter P. Stanich, MD

Survival benefit from panitumumab in wildtype KRAS S metastatic CRC ............................... 14 Richard Goldberg, MD

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

Resources Can Help Answer Questions on ACA Plans Arlington, Va.—The open enrollment period for Affordable Care Act (ACA) marketplace insurance plans has ended for 2014, but there remains a tremendous need for education and outreach for enrollees, experts said during the annual meeting of the Association of Community Cancer Centers (ACCC). As people start to use their coverage, questions may emerge about health insurance terms and how to navigate the system, said Sarah Lueck, a senior policy

analyst at the Center on Budget and Policy Priorities, a Washington, D.C.-based nonprofit research organization. The ACA brought several benefits for cancer patients, said Michelle JohnstonFleece, the director of state initiatives at the Cancer Support Community Cancer Policy Institute, in Washington, D.C., including a huge coverage expansion, the outlawing of preexisting condition exclusions and the availability of subsidies to make care plans more affordable. But,

she said, a number of challenges remain, including the ability to get adequate information to compare coverage for cancer-related services. In the future, patients are likely to be more cost-sensitive, Ms. JohnstonFleece said, and providers are more likely to receive questions about costs of care, such as what health care services are covered, and what the copays or coinsurance will be for prescription drugs. Patients can access resources for help,

the panelists said. The website www. healthcare.gov explains the basics of plans. The site localhelp.healthcare.gov directs people to their state exchanges and available resources. Additionally, the ACCC and 18 other organizations partnered to produce a Cancer Insurance Checklist (www.cancerinsurancechecklist.org), an English- and Spanish-language guide to help cancer patients evaluate marketplace insurance plans. —Karen Blum

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McMahon Publishing is a 42-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2014 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

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Treatments Should Align With Patient Priorities Arlington, Va.—If cancer patients better understood their disease stage and treatment options, they would make smarter—potentially less-expensive— choices, a panel of experts said during a discussion on cancer value and costs at the annual meeting of the Association of Community Cancer Centers. For patients, the term “value” has different meanings depending on their decade of life, their family’s financial circumstances and geographic location,

Conversations about cost are complicated; they should not necessarily occur during a patient’s initial visit, but they are essential. —Paul Celano, MD said Nancy Davenport-Ennis, a two-time breast cancer survivor and founder of the National Patient Advocate Foundation, in Hampton, Va. “What we’re seeing more and more are patients who want to have

an open dialogue with physicians,” she said. They want to know their available treatment options, “but, just as immediately, they want to know, ‘How am I going to pay for this, and what is the value of my

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life going to be if I agree to this therapy?’” In determining value for patients, physicians need to think about clinical benefits, toxicity of treatment and costs, said Paul Celano, MD, a medical oncologist at Greater Baltimore Medical Center, in Towson, Md. But “those are really broad categories, and before you get into any of them you really need to sit down with the patient and family,” he said. Conversations about cost are complicated; they should not necessarily occur during a patient’s initial visit, but they are essential, he said. The oncology community needs “to ensure [that] patients understand what their treatment options are, and that the care meets their personal goals and preferences, especially in the metastatic setting,” said John Fox, MD, the associate vice president of medical affairs at Priority Health, a health plan in Michigan. He cited a 2012 study showing that 81% of patients receiving chemotherapy for metastatic colorectal cancer and 69% of patients receiving chemotherapy for metastatic lung cancer thought they were getting curative treatment (http://www.nejm.org/doi/ pdf/10.1056/NEJMoa1204410). Often, he added, patients get chemotherapy because that’s what their doctor told them they should do, “when, in fact, they might have been perfectly happy with other alternatives that were less expensive and less toxic.” Treatments should be aligned with patients’ priorities and preferences, he said. “If we’re investing $100,000 to prolong somebody’s life by two months, but that’s not what the patient wanted—if the trade-offs of life prolongation were offset by side effects and hospital time—then that’s a waste.” The costs of cancer care have risen exponentially in the last decade, said Dr. Celano, citing data from the American Society of Clinical Oncology showing that monthly costs of cancer care grew from $100 in 1980, to $10,000 today. “I don’t think anyone thinks that the survival advantage, progression-free survival or clinical benefit has increased by that degree.” For certain individuals with chronic myelogenous leukemia, multiple myeloma or certain forms of breast and lung cancer, costs “are extremely justifiable” but still considerable, he added, noting that oncologists are presented with “an explosion of new therapies” that they are obligated to discuss with patients, so patients can make a fully informed decision. The current reimbursement system focuses on tests, procedures, hospitalizations and equipment, Dr. Celano added. “Where we really fall down is in the conversations we need to [have] with patients. … If we had better conversations, our patients would ... make better choices, and probably less-expensive choices.” —Karen Blum

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Prostate Cancer

Charles F. von Gunten, MD, PhD

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

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

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

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

Oncology Nursing

Hematologic Malignancies Breast Cancer

Bioethics

University of California San Diego, CA

Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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

Harry Erba, MD, PhD

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

University of Alabama Birmingham, AL

Pharmacy Shaji Kumar, MD Mayo Clinic Rochester, MN

Cindy O’Bryant, PharmD

Matt Brow

University of Colorado Cancer Center Denver, CO

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

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

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

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

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

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

Gynecologic y g Cancer

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

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

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

Syed A. Abutalib, MD

On the Cover

Cancer Treatment Centers of America Zion, Illinois

ur cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art photography project focuses on imagery of human disease. Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology. Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigm shift occurring in medicine toward the inclusion of holistic approaches and the role of creative arts in the healing process. If you are interested in purchasing this piece or other work from her collection, Dr. Sicari may be reached at imageryMD@ gmail.com. This piece may be viewed at Johnson & Johnson World Headquarters in New Brunswick NJ until August 1, 2014. Her collection may be viewed at www.behance.net/MarieSicari

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

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

Editorial Philosophy

Vanderbilt University Medical Center Nashville, TN

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Joseph V. Pergolizzi Jr., MD

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

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

The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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

Sara S. Kim, PharmD

Richard Stone, MD

Steven D. Passik, PhD

Johns Hopkins University School of Medicine Baltimore, MD

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

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

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

Support Website Helps Cancer Patients Connect Arlington, Va.—In a scene familiar to many parents, oncologist Charles Weaver, MD, was with his sons in the family homework room a few years ago when he noticed his older son checking Facebook instead of working. As Dr. Weaver started to scold him, his younger son commented that it would be great if there were a “Facebook” for people with cancer to support each other. Dr. Weaver liked this idea. His older son had survived a sarcoma, and because they live in a small town (Ketchum, Idaho), he didn’t have people to talk to about his cancer. In a presentation at the annual meeting of the Association of Community Cancer Centers, Dr. Weaver, CEO of Omni Health Media, explained how shortly after his son suggested the idea of a “Facebook” for cancer patients,

he went to his information technology department to inquire if they could set up a HIPAA-compliant social media Web application where cancer patients could interact and support each other. Thus, he said, CancerConnect.com, the first social media application designed for cancer patients, was born. Free for patients, the application has more than 10,000 pages of information about different cancers, including health and wellness tips and a drug dictionary. The site also houses various support groups, educational videos and links to archived Web chats with cancer experts. More than 150,000 patients access it each month. The social media application and content also can be licensed to hospitals and cancer programs to enhance their own websites and allow cancer patients

to become part of a local social community. About a dozen cancer programs, including Memorial Sloan-Kettering Cancer Center, in New York City; DanaFarber Cancer Institute, in Boston; and Roswell Park Cancer Institute, in Buffalo, N.Y., use the service. Some patients are not “support group people,” and others with rare cancers are unlikely to have support groups, said Faith Addiss, a nurse and patient education facilitator at Roswell Park, the first institution to use the service. The site also has been helpful for caregivers and family members, who have a dedicated space to discuss their fears. “It’s an excellent tool both for information and for support,” Ms. Addiss said. “It increases feelings of empowerment, and when patients are more empowered, they better engage with

their physicians.” Dana-Farber started with just a small community of CancerConnect users, and it was so successful that some participants started meeting in person, said Caren Cummings, the institute’s director of interactive communications. More than 900 of Dana-Farber’s patients are now enrolled. Some of the institute’s content is available only for its own patients, whereas other information, such as discussions about some rare cancers, is made available publicly. One woman newly diagnosed with breast cancer was wondering what to do about losing her eyebrows, noted Ms. Cummings. “Within the first hour, she got 35 responses from people. It’s a wonderful, helpful resource.”

TWITTER HITS

many tweets were produced and how many people were involved, climbed to more than 135 million, again doubling 2013’s numbers. What were tweeters tweeting about?

They shared the top findings from the meeting, opined on major issues and highlighted smaller studies and posters that would have been overlooked. In keeping with Twitter traditions, they

also discussed day-to-day non-oncology issues, such as how to eat a Chicago hot dog while wearing a white shirt.

continued from page 1

at the 2013 convention. “Impressions,” a metric that Symplur uses to assess how

—Karen Blum

—Christina Frangou

Here’s our roundup of top oncology-related tweets from #ASCO14. @fischmd (Michael Fisch, MD, oncologist and palliative care physician at the University of Texas MD Anderson Cancer Center, Houston):

#ASCO14 themes: immunotherapy, value, obesity, learning healthcare, systems biology, social media, genomics, exercise, palliative care Emanuel at #ASCO14: The median income in US is $51,371. One of our cancer drugs wipes out the median income of a household. #costsofcare @ProfJohnCrown (oncologist, Dublin, Ireland):

Amazing to think that biggest treatment story of #ASCO14 was chemotherapy. Benefit of docetaxel in metastatic prostate. @rsm2800 (Robert S. Miller, MD, breast cancer oncologist at Johns Hopkins University School of Medicine, Baltimore):

Most amazing slide of the day: Dr. Venook showing median OS of met colorectal ca of 9 mos in 1992 vs 29+ mos in this trial #ASCO14 #research

@DrAttai (breast surgeon and the president-elect of American Society of Breast Surgeons):

@TedOkonCOA (Ted Okon, executive director, Community Oncology Alliance, Washington D.C.):

For those watching at home you’re hearing so much about obesity, exercise, alcohol, smoking because these factors so important #ASCO14

Running/meeting at #ASCO14 so fast/ much that no time to tweet! Great advances in cancer treatment but how do we pay for them?

@cancerassassin1 (Emil Lou, MD, PhD, gastrointestinal oncologist): @NYCDoc29 (hematologist/oncologist):

#1 thing I learned at #ASCO14: we have more technology than ever to test tumors but need more knowledge how to effectively apply this info. @Cleveland Clinic (quoting Dr. Hudis):

“Obesity is on its way to replacing tobacco as the number one preventable/modifiable cause of cancer.” - @cliffordhudis

“@RxPertise: Many doctors at #ASCO14 say no major, routine impact from the ACA #healthcarereform” I disagree as a private practice Doc!

@drsam (Samuel Blackman, MD, pediatric oncologist):

@cliffordhudis (Clifford A. Hudis, MD, FACP, the chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, and outgoing ASCO president):

“5 years ago, a Tuesday morning session on immunotherapy would have 20 people attending.” Today, SRO [standing room only]. #ASCO14

“Price is what you pay. Value is what you get.” @ASCO must define #value in #cancer care & pursue it. #ASCO14

Clinical Oncology News TWEETS!

Follow us @ClinOncNews And send your Twitter handle to managing editor Sarah Tilyou at smtilyou@mcmahonmed.com so we can follow you.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

Model Puts Price Tag on Medicare Lung Ca CT Screening Chicago—If Medicare follows the recommendation of the United States Preventive Services Task Force (USPSTF) to screen patients at high risk for lung cancer using computed tomography (CT), the price tag would be a $3 per month premium increase per Medicare member, but the percentage of cancers found at a localized stage in those patients would double, according to a mathematical modeling study presented at the American Society of Clinical Oncology (ASCO) annual meeting (abstract 6501). “We hope our findings can inform the ongoing debates about coverage,” said investigator Joshua Roth, PhD, MHA, a postdoctoral research fellow from the Fred Hutchinson Cancer Research Center, in Seattle. Presenting the data at a premeeting press conference, Dr. Roth said that he and his colleagues used data from the NLST (National Lung Screening Trial), the Surveillance, Epidemiology and End Results Program and peer-reviewed literature to create a forecasting model to project outcomes with low-dose CT screening versus without. The model assumes a gradual diffusion of CT screening into clinical practice based on a previous study of the diffusion of breast cancer screening (Cancer Causes Controll 2005;16:701-712). It estimates that an additional 20% of high-risk patients will be offered screening each year. “This is intended to reflect the reality that if screening is implemented, the health care system will need to gradually build screening infrastructure and personnel,” said Dr. Roth, adding that it also accounts for the fact that not all of the high-risk patients who are offered screening will opt to receive it. Over five years, screening would result in 54,900 more lung cancer diagnoses, 11.2 million more CT scans, 2 million false-positives, $5.6 billion more in CT imaging expenditures, $1.1 billion more in diagnostic workup expenditures and $2.6 billion more in cancer care expenditures. The model also estimates an increase in lung cancers that would be detected at a localized stage (32% vs. 15%). In 2011, investigators from the NLST concluded that with 6.5 years of followup, the use of CT reduced lung cancer mortality by 20% compared with chest x-ray in patients at high risk for developing lung cancer. That randomized trial involved 53,454 individuals aged 55 to 73 with a 30 pack-year history of smoking who were still smoking or had quit within 15 years. In 2013, the USPTF recommended CT screening for healthy individuals aged 55 to 80 with the same smoking history as the population in the NLST trial. Medicare is expected to release a draft decision on coverage for this screening in November; however, in April, the Centers

for Medicare & Medicaid Services (CMS) national coverage determination panel voted against coverage, due to uncertainty about the effect of screening outside of

a clinical trial setting. Clifford Hudis, MD, ASCO president and chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City, pointed out that Dr. Roth’s study was just what it claimed to be—a model. He said ASCO’s guidelines support, and even slightly expand, the USPTF recommendations on screening. Edward Kim, MD, the chair of solid tumor oncology and investigational

therapeutics at the Levine Cancer Institute at Carolinas HealthCare System, in Charlotte, N.C., said he supports the USPTF recommendation for screening. “The recent CMS ruling was very disappointing,” said Dr. Kim. “I would think that if you are diagnosing [lung cancer] earlier, then one is saving money.” —Kate O’Rourke Drs. Roth, Kim and Hudis reported no relevant financial conflicts of interest.

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CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

continued from page 1

14 Months More Life Is a Huge Benefit

The control group in this trial, called CHAARTED (ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer), was not an “outlier.” The median survival observed for the control group in CHAARTED was 44 months, which is similar to the 48-month median observed in the control groups in the Medical Research Council’s (MRC) trial of immediate versus delayed ADT (PRO3 trial)2 and the control group of the Southwest Oncology Group trial that compared continuous with intermittent androgen ablation.3 Of the men entered in the trial, 70% were asymptomatic (performance status [PS] 0), only 1.5% were PS 2, 65% had high-volume disease, 68% had tumors with Gleason scores of 8 to 10, and the median prostate-specific antigen (PSA) level at entry was 56. Prior therapy was prostatectomy in 20%, irradiation in 7%, adjuvant ADT in 5%; most of the men presented with de novo metastatic disease.

Heretofore, metastatic prostate cancer was considered an indolent disease that should be treated cautiously with therapy that minimized toxicity as much as possible. Early ADT in asymptomatic patients produced no significant improvement over the median survival of 4 years in the U.K. MRC PRO3 trial.2 Therefore, many of us did not treat men without symptoms from their metastatic prostate cancer, sparing them the fatigue, weakness, osteoporosis and sexual impairment brought on by ADT. We reserved docetaxel and cabazitaxel (Jevtana, Sanofi) for successive treatments if the patient relapsed after initial ADT. Each of these was associated with an approximately 3-month prolongation of survival. More recently, abiraterone (Zytiga, Janssen), enzalutamide (Xtandi, Astellas) and radium-223 also produce 3- to 5-month prolongations of median survival when they are given as successive single agents. These improvements pale beside the 14-month improvement in median duration of life resulting from giving docetaxel concurrently with initial

SHAKE-UP

ADT. Every man with metastatic prostate cancer should get docetaxel before he dies; CHAARTED data argue strongly for giving it early.

It may be that giving docetaxel early to largely asymptomatic men works better because the men are generally in better shape and can tolerate more drug with less toxicity. It may be that ADT works better if docetaxel is on board to kill otherwise enlarging populations of androgen-independent cancer cells. It may be that cancer cells that are marginally sensitive to either treatment are made more sensitive by the other treatment. These possibilities may prove easy to sort out in model systems but very difficult to sort out in sick humans.

What Treatment Paradigm Must Change Immediately Any man presenting with high-volume metastatic prostate cancer should be encouraged to accept six doses of docetaxel concurrently with the start of his ADT, with the promise that his life

Table. Disease-Free Survival Rates in ALTTO Trial Hazard Ratio

P Value

P Value Required For Significance

0.84

0.048

≤0.025

0.96

0.610

≤0.025

Treatment

4-y DFS, %

Trastuzumab

Concurrent lapatinib + trastuzumab Trastuzumab followed by lapatinib

ALTTO, O, Adjuvant djuva t Lapatinib apat b And/Or d/O O Trastuzumab astu u ab Treatment eat e t Opt Optimisation; sat o ; DFS, S,, d disease-free sease ee su survival v va

“It is difficult to mount any enthusiasm for combined blockade of HER2 in the adjuvant setting, at least with the combination used here,” said Dr. Sledge.

Research Approach Called Into Question The trial results also have broader implications for drug research. The FDA can grant accelerated approval for a medication based on a surrogate end point that is likely to predict improvements in overall and disease-free survival. Two years ago, an FDA draft guidance suggested that pCR could be used as a surrogate end point for neoadjuvant breast cancer therapies, based on studies including a Cochrane analysis (Cochrane Database Syst Rev 2007;2:CD005002). Allowing pCR to be used as an end point for approval would allow new drugs to get to patients years before the completion of large, cumbersome trials requiring thousands of patients. “ALTTO requires us to rethink our approach to the development of new

Steven Vogl, MD Medical Oncologist, New York City

Why Does Early Docetaxel Add So Much?

continued from page 1

of Clinical Oncology (ASCO). Clinicians had high hopes for ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation), given that a year ago, researchers from the Phase III NeoALTTO trial reported that adding lapatinib to trastuzumab doubled pathologic complete response (pCR) in the setting of neoadjuvant treatment of patients with HER2-positive breast cancer. The ALTTO trial enrolled 8,381 women with HER2-positive, early-stage breast cancer. Patients underwent surgery and then received chemotherapy plus one year of treatment with trastuzumab alone, lapatinib alone, trastuzumab followed by lapatinib, or concurrent trastuzumab and lapatinib. The trial began in June 2007, and the lapatinib-alone arm was terminated early, in August 2011, due to futility. At the ASCO meeting, investigator Martine Piccart-Gebhart, MD, PhD, an associate professor of oncology at Université Libre de Bruxelles and the head of the Department of Medicine at the Jules Bordet Institute in Brussels, Belgium, reported that patients treated with both HER2-targeted agents had no benefit related to disease-free survival at a median follow-up of 4.5 years (Table). Additionally, compared with trastuzumab alone, the combination was associated with higher rates of diarrhea (75% vs. 20%), rash (55% vs. 20%) and hepatobiliary adverse events (23% vs. 16%).

EDITORIAL BOARD COMMENTARY

drugs for early-stage breast cancer,” Dr. Sledge said. “ALTTO represented a reasonable test of the hypothesis that improvements in pCR rates are associated with improved disease-free survival. These hopes have now been dashed.” A recent meta-analysis of 12 breast cancer trials also has concluded that pCR rate does not predict event-free or overall survival ((Lancett 2014 Feb 13. pii: S01406736[13]62422-8. Epub ahead of print]. In September 2013, pertuzumab (Perjeta, Genentech) became the first breast cancer drug to be granted accelerated approval by the FDA for a neoadjuvant treatment indication based on data showing an improvement in pCR. Dr. Sledge said the ALTTO trial raises the question of whether pertuzumab should have been approved for that indication on that basis. He said, “We currently lack convincing evidence that differences in pCR rates in smaller neoadjuvant trials predict the outcome of larger adjuvant trials.” The Breast International Group (BIG) is coordinating the confirmatory trial

will almost certainly be a lot longer and probably better for much longer because of the 18 weeks of “up-front” docetaxel. Men with low-volume disease had a 37% decrease in hazard rate of death that was similar to that of men with high-volume disease. The difference was not significant in this subgroup because of a lower rate of death and because of their smaller numbers in the trial. Based on the CHAARTED data, men with low-volume metastatic disease, especially those with pain from the prostate cancer, should consider immediate docetaxel with their initial ADT. Men whose tumors had Gleason scores less than 8 actually seemed to benefit more from early docetaxel than those with more poorly differentiated tumors

(APHINITY) for this accelerated approval of pertuzumab, but the final results are not expected until 2023. In the meantime, Maura Dickler, MD, an associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City, said the results of ALTTO will not dissuade her from using pertuzumab. “The results of ALTTO were very disappointing and remind us that pCR is a prognostic marker but not yet predictive of response to a specific drug,” Dr. Dickler told Clinical Oncology News. “However, the CLEOPATRA trial in the metastatic setting demonstrated a significant improvement in PFS that has never been seen with lapatinib. I think many of us believe pertuzumab is more efficacious and better tolerated than lapatinib, and the improved tolerance lends to a higher delivery of drug. Therefore, I remain optimistic that APHINITY may be a positive trial, and I will continue to prescribe pertuzumab in the FDA-approved and [National Comprehensiver Cancer Network]-recommended fashion.” —Kate O’Rourke Dr. Sledge reported relationships with Genentech/Roche, Seattle Genetics and Symphogen. Dr. Piccart-Gebhart reported relationships with Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Genentech/Roche, Sanofi, Symphogen, Synthon and Verastem. Dr. Dickler reported a relationship with Genentech.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

something else before the prostate cancer kills them. The CHAARTED trial investigators reported that 17% of the deaths in the trial participants were felt to be unrelated to the prostate cancer. Alas, we still are not curing any of these men. We await the quality-of-life data from CHAARTED to find out how much better, in addition to how much more numerous, their remaining days became.

based on a greater relative reduction in the hazard ratio of dying. These men also should consider early docetaxel with their ADT.

Data Necessitate Patient Discussion Now and Clinical Trials Soon One could interpret the CHAARTED trial as showing that combining docetaxel with effective hormonal therapy has big survival advantages for the patient. This implies that our current population of men with castration-resistant prostate cancer starting enzalutamide or abiraterone should start these agents together with docetaxel if they have not had docetaxel before. This interpretation also might imply that men who did well for a year or more after a course of docetaxel given with initial ADT but then relapsed might benefit from more docetaxel given with continued ADT plus one of these new active hormonal therapies for metastatic prostate cancer. One could interpret the CHAARTED trial as showing that effective chemotherapy adds to effective hormonal therapy for metastatic prostate cancer. By this interpretation, one should consider adding cabazitaxel—an effective taxane that is not cross-resistant with docetaxel—to second- or third-line hormonal therapy. These interpretations, attractive though they seem, should be immediately tested in clinical trials based on the CHAARTED findings.

What Do We Need To Learn? At the moment, we have a very crude understanding of whom to treat with early docetaxel added to ADT, of when to start therapy in the course of known prostate cancer that has not been cured,

Figure. ECOG-ACRIG CHAARTED trial design.

What Will Happen Now?

ACRIG, American College of Radiology Imaging Group; ADT, androgen deprivation therapy; CHAARTED, ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer; ECOG, Eastern Cooperative Oncology Group

One hopes that every man with newly diagnosed metastatic prostate cancer now will have a careful discussion of the advantages and disadvantages of immediate docetaxel in addition to ADT with a physician well versed in the toxicities of the drug and the details of its administration. Most urologists are not equipped to do this. One also hopes that large urology groups that have sought vertical integration in the past by buying and staffing radiation therapy centers, will not now build infusion centers and hire medical oncologists to administer docetaxel on the demand of the urologist, thus maintaining “control” of the patient and the income stream derived from the care of his metastatic prostate cancer.

of when to stop docetaxel (the choice of six 3-week cycles was arbitrary), and of when to switch to second-line therapy in the absence of symptoms. These, too, are appropriate subjects for study. We clearly have not learned that early docetaxel is beneficial to men who have detectable PSA in the serum after local therapy for prostate cancer and no detectable metastases. Many of these men live decades, and we have no data to support the idea that docetaxel given before radiographic documentation of metastases promotes their quality or duration of life.

How Important Are These Findings? The CHAARTED findings are very important, and may serve as an example for studies in the other common, hormonally driven cancer of adults: breast cancer. The model for those treating hormonally sensitive tumors in patients with metastatic breast or prostate cancers, has been to minimize toxicity and “string out” therapies one at a time for as long as possible. I am unaware of any data that adding chemotherapy to initial hormone therapy for metastatic breast

cancer prolongs life. I am unaware of any large, completed studies specifically looking at this question. Perhaps these should be undertaken, or perhaps ADT is so much more effective than ovarian ablation, tamoxifen or aromatase inhibitors that the latter three are an insufficient base on which to add concurrent chemotherapy. Metastatic prostate cancer has always been considered more sensitive to initial hormone therapy than metastatic breast cancer. Perhaps now we should consider prostate cancer more sensitive to all systemic therapy than breast cancer.

What CHAARTED Has Not Achieved There is no hint from the data presented that even a small fraction of men in the trial have been cured, or that the survival curve is “flattening,” indicating a decrease in the hazard rate for death and the presence of some men who may be cured. The use of early docetaxel represents a refinement and improvement in the palliative therapy of what still is a uniformly lethal disease; the only patients spared death from prostate cancer are those who die of

References 1. Sweeney C, Chen YH, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(18 suppl): Abstract LBA2. 2. Kirk D. Timing and choice of androgen ablation. Prostate Cancer Prostatic Dis. 2004;7:217-222, PMID: 15278095. 3. Hussain M, Tangen CM, Berry DL. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-1325, PMID: 23550669.

Heavy Antibiotic Use Tied to Higher Colorectal Ca Risk Chicago—Certain antibiotics are associated with an increased risk for colorectal cancer, according to a case–control study involving roughly 100,000 patients. Antibiotics may reduce overall bacterial diversity, which can have substantial consequences on the functional stability of microbiota in the colon. “The study suggests that long-term and repeated antibiotic exposure might increase colorectal cancer [CRC] risk,” said investigator Ben Boursi, MD, a medical oncologist from the Integrated Cancer Prevention Center at Tel Aviv Sourasky Medical Center, in Israel. Dr. Boursi’s group presented its findings at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 1599). The researchers evaluated the association between the type, timing, cumulative duration and intensity of antibiotic

exposure and CRC risk, using data from the Health Improvement Network database with information on 11.7 million patients in the United Kingdom and follow-up for as long as 18 years. The investigators identified cases of CRC, excluding patients with a known family history of CRC or inflammatory bowel disease and those who were diagnosed with CRC before the age of 40 years. Patients were matched with up to four controls based on age, sex, practice site and duration of follow-up. Dr. Boursi and his colleagues controlled for known risk factors for CRC, including obesity, diabetes, smoking and alcohol consumption, as well as previous screening colonoscopies. The risk for developing CRC was increased by 6% in patients first exposed to penicillin more than one year before diagnosis (P ( =0.002) and remained

statistically significant for patients who used penicillin more than 10 years before a diagnosis of cancer, with an odds ratio (OR) of 1.11. The risk increased significantly with the number of exposures to penicillin, with ORs ranging from 1.10 for one to five courses, to 1.2 for more than 10 courses ((P<0.0001). The adjusted risk increase associated with each additional antibiotic course per year was 4% on average ((P=0.008). “This is the first study that has looked at whether or not, from an epidemiological standpoint, there is an association between antibiotic use, which is a very common exposure in the population, and colorectal cancer,” said co-investigator Yu-Xiao Yang, MD, an assistant professor of medicine and epidemiology at the University of Pennsylvania’s Perelman School of Medicine, in Philadelphia. “Certain bacteria ... might

promote a pro-inflammatory environment,” Dr. Yang said. “Others may alter or generate toxins that might potentially be carcinogenic or might transform certain dietary or intestinal content into carcinogenic components. ... Looking at what are more biologically plausible effects of antibiotics on colorectal cancer risk, we should be looking at longerterm exposure, or exposure in the more distant past.” Richard Peek, MD, the director of the Division of Gastroenterology at Vanderbilt University Medical Center, in Nashville, Tenn., who was not involved with the study, called the research significant, noting that it adds to the growing body of literature supporting the role of the microbiota on diseases that develop within the gastrointestinal tract. — Kate O’Rourke

REVIEWS & COMMENTARIES

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Expert Insights From The Ohio State University Comprehensive Cancer Center Each month, Clinical Oncology Newss summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care. This month we continue with The Ohio State University Comprehensive Cancer Center. We hope you find this Reviews & Commentaries section, both here and with additional commentaries on our website (at ClinicalOncology.com), to be a valuable tool.

Panitumumab Proves Noninferior to Cetuximab in KRAS S mCRC From Lancet Oncology

atients with chemotherapy-refractory metastatic colorectal cancer (mCRC) achieved similar outcomes whether they were treated with panitumumab (Vectibix, Amgen) or cetuximab (Erbitux, ImClone). Cetuximab, a chimeric immunoglobulin (Ig)G1 antibody, is an effective third-line treatment for patients with wild-type (WT) KRAS mCRC, and panitumumab is a fully human IgG2 antibody. Investigators from several international sites assessed KRAS tumor status in patients with metastatic

adenocarcinoma of the colon or rectum who had disease progression after previous treatment ((Lancet Oncol 2014;15:569-579, PMID: 24739896). Patients with confirmed mCRC and WT KRAS exon 2 tumor status were randomly allocated to receive either panitumumab (6 mg/kg IV on day 1 of a 14-day cycle; n=499) or cetuximab (initial dose 400 mg/m2 IV followed by 250 mg/m2 IV on day 1 of a sevenday cycle; n=500). Treatment continued until disease progression, intolerability or withdrawal of consent. The median duration of treatment was 14.3 weeks (interquartile range

EXPERT INSIGHT Tanios Bekaii-Saab, MD Gastrointestinal Oncology Section Chief and Associate Professor The Ohio State University Comprehensive Cancer Center– Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Columbus, Ohio

SPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in patients with chemotherapy-refractory wild-type [WT] KRAS exon 2 mCRC) demonstrated that panitumumab is noninferior to cetuximab and that these agents provide similar survival benefits in these patients. Median progression-free survival and overall response rates were similar with both agents. Toxicity profiles were expected and predictable for both agents, with more infusion reactions in patients taking cetuximab but more hypomagnesemia in

patients taking panitumumab. Interestingly, the incidence of rash was similar between the groups. Panitumumab was conditionally approved based on the initial results of a Phase III randomized study that suggested an improvement in the mean progression-free survival versus best supportive care in patients with refractory mCRC. Cetuximab was approved based on a median OS benefit versus best supportive care in a similar patient population. ASPECCT, the first study to compare the two monoclonal antibodies

formula [IQR], 6.1-29.3) for panitumumab and 14.1 weeks (IQR, 6.0-29.0) for cetuximab. The primary end point was overall survival (OS) assessed for noninferiority. At the time of the analysis, 383 patients in the panitumumab group (77%) and 393 in the cetuximab group (78%) had died. Median OS was 10.4 months (95% confidence interval [CI], 9.4-11.6) in the panitumumab group and 10 months (9.3-11.0) in the cetuximab group (hazard ratio [HR], 0.97; 95% CI, 0.84-1.11). Incidence of treatment-related adverse events (AEs) was similar: 485 panitumumab-treated patients (98%)

and 494 cetuximab-treated patients (98%) reported an AE of any grade. Fifty cetuximab-treated patients (10%) and 29 panitumumab-treated patients (6%) had fatal AEs. Fourteen patients in the panitumumab group (3%) and 63 in the cetuximab group (13%) reported infusion reactions. Lead author Timothy J. Price, MBBS, and his colleagues concluded that panitumumab is noninferior (Z ( score, –3.19; P=0.0007) and provides survival benefits that are similar to those of cetuximab. Differences in dosing schedules and infusion reactions may influence physician choice.

The choice of which anti-EGFR therapy is to be used in clinical practice perhaps now will rely on the small but meaningful differences (including geographic differences) in the rate of grades 3 and 4 infusion reactions and differences in dose scheduling. head to head, helps confirm the presence of similar efficacy and toxicity profiles. This study helped support the recent approval of the combination of panitumumab with FOLFOX (fluorouracil, leucovorin and oxaliplatin) in patients with mCRC, which was also based on results from PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) (see page 14). The choice of which anti-EGFR therapy to use in clinical practice perhaps

now will rely on the small but meaningful differences (including geographic differences) in the rate of grades 3 and 4 infusion reactions and differences in dose scheduling. Overall, this study provides additional confidence that the data on the benefit of panitumumab or cetuximab in the treatment of patients with WT KRAS tumors remain consistent across lines of therapy. Dr. Bekaii-Saab reported no relevant financial conflicts of interest.

REVIEWS & COMMENTARIES

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Inverse Relationship Between Adenomas Detected and Later Ca From The New England Journal of Medicine

he adenoma detection rate (ADR) has been proposed as a physician quality benchmark, with recommended rates of 15% or more for women and 25% or more for men undergoing colonoscopy. A new study published in The New England Journal of Medicine (2014;370:1298-1306, PMID: 24693890) indicates that, perhaps, those recommended rates should be higher. During the study, researchers from

Kaiser Permanente Northern California gathered data from more than 314,000 colonoscopies performed between 1998 and 2010. The data were eligible for inclusion in the study if the physician had performed more than 300 procedures. Patients with less than six months of followup data were not included. Additionally, if cancer was detected within six months of the baseline colonoscopy, it was determined to be diagnostic and removed from final analysis. The study’s lead author, Douglas A. Corley, MD, PhD, and his co-

EXPERT INSIGHT Peter P. Stanich, MD Assistant Professor Division of Gastroenterology, Hepatology & Nutrition Director, Section of Hereditary Polyposis and Colon Neoplasia The Ohio State University Comprehensive Cancer Center– Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Ohio State University Wexner Medical Center Columbus, Ohio

s we continue to build evidence that colonoscopy with polypectomy reduces CRC incidence and, even more importantly, reduces mortality from CRC, the focus will turn to ways to enhance the effectiveness of the procedure.1 This recently published work by Corley et al seems poised to be a landmark study as this shift occurs. Through the analysis of multiple endoscopists performing colonoscopies in a large health system, they are able to demonstrate an inverse linear relationship between ADRs and interval CRC occurrences. The findings are summarized in a simple, eye-opening statistic: Every 1% increase in adenoma detection is

associated with a 3% decrease in the risk for interval colon cancer. This is convincing evidence that adequate adenoma detection and removal is a key variable in the effectiveness of colonoscopy as a cancer prevention tool. This is likely to have a major effect on practice guidelines discussing quality metrics for screening and surveillance colonoscopy. Current guidelines recommend that endoscopists should be maintaining minimum ADRs of at least 25% in men and 15% in women undergoing first-time screening examinations.2 Based on Corley et al’s results, the expectations could reasonably be higher. The top two quintiles of physicians,

investigators found more than 264,000 colonoscopies performed by 136 gastroenterologists that were eligible for analysis. Of these, 712 cases of interval colorectal adenocarcinoma were identified, of which 255 were advanced-stage cancer. There were 147 deaths from these interval CRCs. The investigators found that the median interval between the colonoscopy and subsequent cancer diagnosis was 39 months. ADRs for physicians ranged from 7.4% to 52.5% (9.7%-60.5% for men and 3.9%-45.9% for women). The

risks for development of CRC according to quintiles of ADRs, from lowest to highest, were 9.8, 8.6, 8.0, 7.0 and 4.8 cases per 10,000 person-years of follow-up. The risk for receiving a diagnosis of an interval cancer was 0.52 (95% confidence interval [CI], 0.390.69) for patients of physicians in the highest quintile compared with those of physicians in the lowest quintile. Dr. Corley and his co-investigators found that when the ADR was modeled as a continuous variable, each 1% increase in detection predicted a 3% decrease in interval cancer risk.

The findings are summarized in a simple, eye-opening statistic: Every 1% increase in adenoma detection is associated with a 3% decrease in the risk for interval colon cancer. which included those with ADRs greater than 28.4%, had significant reductions in interval cancer and CRC mortality, and consideration should be given to making this rate the national benchmark. The findings of this study also highlight the importance of measuring real-time performance characteristics of individual endoscopists in clinical practice. This allows for the implementation of interventions to increase polyp detection as needed to reach these goals and improve patient care. Future work will be needed to determine additional variables to further quantify high-quality colonoscopy and subsequently incorporate them into quality improvement programs. Other factors of interest may include the sessile serrated ADR—especially given their typical proximal location,

which was the most common site for interval colon cancers in this study— and measures of completeness of polyp resection.

References 1. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and longterm prevention of colorectal-cancer deaths. N Engl J Med. 2012;366:687-696; PMID: 22356322. 2. Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. MultiSociety Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97:1296-1308, PMID: 12094842.

Dr. Stanich reported no relevant financial conflicts of interest.

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

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REVIEWS & COMMENTARIES

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Survival Benefit From Panitumumab in Wild-type KRAS S mCRC From Annals of Oncology

atients with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) had extended progressionfree survival (PFS) following a regimen of panitumumab (Vectibix, Amgen) plus FOLFOX4 (i.e., leucovorin, fluorouracil and oxaliplatin) compared with those treated with FOLFOX4 alone. Objective response rates were higher, and a trend toward improved overall survival (OS) was noted. Finalized data collected 30 months after the enrollment of the last patient in PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to

determine Efficacy) were analyzed, with results published in Annals of Oncologyy (2014 Apr 8. [Epub ahead of print], PMID: 24718886). In this international, multisite Phase III study, 1,183 patients with previously untreated mCRC were randomized to receive panitumumab plus FOLFOX4 (arm 1) or FOLFOX4 alone (arm 2). Preliminary results led to the further investigation of patients based on KRAS status. Jean-Yves Douillard, MD, PhD, and his co-investigators confirmed that mCRC patients with mutated (MT) KRAS mCRC had better results when treated with FOLFOX4 without the addition of panitumumab. Patients with WT KRAS mCRC had

EXPERT INSIGHT Richard Goldberg, MD Physician-in-Chief and Gastrointestinal Medical Oncologist The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Columbus, Ohio

he PRIME study demonstrated that panitumumab plus FOLFOX4 significantly improved PFS (the primary end point of the study) versus FOLFOX4 as first-line treatment for WT KRAS mCRC. In this study, 656 patients proved to have WT KRAS tumors as the trial began, which was before there was recognition of the importance of K-RAS mutations as a marker of panitumumab resistance. In the prior report of this study, the median PFS for patients with WT KRAS mCRC was 10.0 months on the panitumumab arm and 8.6 months on the FOLFOX-alone arm ((P=0.01). OS favored the panitumumab arm at 23.9 versus 19.7 months, but OS was not

statistically different in the original analysis ((P=0.17). This updated analysis, done after all patients had a minimum of 30 months of follow-up, confirms the incremental benefit of panitumumab with FOLFOX (23.8 months) over FOLFOX (19.4 months) alone ((P=0.03). The objective response rate was 57% with panitumumab and 48% without it ((P=0.02). No unexpected toxicity patterns were observed. Patients in the panitumumab arm had more skin rash, diarrhea, fatigue, mucositis and electrolyte disturbances. The updated analysis also confirmed the detrimental effect on study end points when patients whose tumors

improved PFS and OS in arm 1 compared with those treated in arm 2. In these patients, median PFS was 10 months (95% confidence interval [CI], 9.3-11.4 months) in arm 1 versus 8.6 months (95% CI, 7.5-9.5 months) in arm 2; the hazard ratio (HR) was 0.80 (95% CI, 0.67-0.95; P=0.01). Median OS was 23.9 months (95% CI, 20.3-27.7 months) in arm 1 versus 19.7 months (95% CI, 17.6-22.7 months) in arm 2; HR was 0.88 (95% CI, 0.73-1.06; P=0.17). The updated final analysis of median OS confirmed these numbers. Results for patients with MT KRAS mCRC favored the administration of FOLFOX 4 alone. In the final analysis of these patients, median OS was 15.5 months (95% CI, 13.1-17.6 months) in

arm 1 and 19.2 months (95% CI, 16.2-21.5 months) in arm 2; HR was 1.16 (95% CI, 0.94-1.41; P=0.16). Quality-of-life surveys revealed no statistically significant or clinically meaningful difference between the two study arms. Adverse events were consistent with earlier reports: Patients treated with panitumumab reported higher rates of skin toxicity, diarrhea and hypokalemia. Patients with WT KRAS mCRC who reported grades 2 to 4 skin toxicities (rash, acneiform dermatitis, pruritus, dry skin, skin fissures or erythema) had longer PFS and OS as well as overall response rates, suggesting development of skin toxicity is an early clinical indicator of the panitumumab regimen’s efficacy.

Because crossover to an EGFR-targeted monoclonal antibody after progression on FOLFOX was permitted, potential survival differences may be attenuated related to panitumumab. harbor a K-RAS mutation are treated with monoclonal antibodies that target the epidermal growth factor receptor (EGFR). Also, as previously noted, the presence and severity of skin rash correlated with outcomes. More exuberant acneiform rash was associated with treatment benefit, as was diarrhea and hypomagnesemia. Allergic reactions were observed in 1% of patients taking panitumumab. Quality of life did not differ between patients by study arm. This updated analysis confirms the value of adding panitumumab to FOLFOX in the first-line treatment of patients whose tumors are determined to be WT KRAS. Because crossover to an EGFRtargeted monoclonal antibody after progression on FOLFOX was permitted, potential survival differences may

be attenuated related to panitumumab. PRIME also confirms that patients whose tumors are K-RAS mutated should not be treated with panitumumab because they appear to be harmed by the addition of panitumumab to FOLFOX. No new toxicity issues were observed, although the exuberance of skin and gastrointestinal toxicities as well as electrolyte deficiencies appears to correlate with benefit. This confirmatory report provides additional confidence that the data on the benefit of panitumumab in the treatment of patients with WT KRAS tumors has remained consistent now that the study is fully mature. Dr. Goldberg reported no relevant financial conflicts of interest.

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HEMATOLOGIC DISEASE

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Ibrutinib Improves OS Over Previous Standard in CLL Chicago—Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK), is being characterized as a significant treatment advance for patients with relapsed or refractory chronic lymphoid leukemia (CLL), based on the results of a Phase III trial presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Although the primary end point of the trial, which compared ibrutinib (Imbruvica, Pharmacyclics) with the monoclonal antibody ofatumumab (Arzerra, GlaxoSmithKline), was progression-free survival (PFS), ibrutinib demonstrated an overall survival (OS) advantage and achieved a remission rate at one year that was substantially greater than that achieved with previous options. The nearly 80% of patients in remission at one year was “about twice as many as we would expect with any of the standard regimens,” according to John C. Byrd, MD, the director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center, in Columbus. Referring to regimens that include rituximab (Rituxan, Genentech) with or without chemotherapy, Dr. Byrd stressed that the advantage of ibrutinib “was observed across all subgroups evaluated, including patients resistant to chemoimmunotherapy and those with a chromosome

17p13.1 deletion.” The Phase III trial, called RESONATE, was presented as a late breaker at the ASCO meeting and simultaneously published by The New England Journal of Medicine online (May 31). The RESONATE investigators randomized 391 patients with CLL or small lymphocytic lymphoma (median age, 67 years) who had received at least one prior therapy and were considered inappropriate candidates for purine analog treatment. Ibrutinib (420 mg once daily) was given until progression. IV ofatumumab was administered for up to 24 weeks at an initial dose of 300 mg at week 1, followed by a dose of 2,000 mg weekly for seven weeks and then every four weeks for 16 weeks. Crossover to ibrutinib was permitted at progression. After a median follow-up of 9.4 months, the median PFS was 8.1 months in the ofatumumab group and it has not yet been reached in the ibrutinib group, producing a hazard ratio (HR) of 0.22 in favor of ibrutinib ((P<0.001). The HR for death favoring ibrutinib was 0.43 (P ( =0.005). When the data were stratified by a large number of subgroups, including those with prior treatment regimens, chromosome 17p13.1 or 11q22.3 deletions, or bulky disease, the relative advantage of ibrutinib over ofatumumab was similar. Overall, 57% of ibrutinib-treated

patients and 47% of the ofatumumabtreated patients had at least one adverse event (AE) of grade 3 or higher, and the most common grade 3 or higher AE in both groups was neutropenia. The most

an assistant professor of medicine at the University of Chicago Comprehensive Cancer Center. Asked to serve as an expert on behalf of ASCO, she called an oral targeted therapy a “paradigm shift”

‘There will be a lot of interest in evaluating whether these agents can be used in the front-line setting, particularly in older CLL patients.’ —Olatoyosi Odenike, MBBS common AE of any grade with ibrutinib was diarrhea, which occurred in 48% of patients (4% grade 3 or higher). Other common AEs in patients taking ibrutinib included fatigue (28%), nausea (26%), pyrexia (24%) and anemia (23%); most AEs were of mild or moderate severity. “The side effects are relatively manageable,” Dr. Byrd reported. He noted that many common AEs, such as diarrhea, typically lessen in severity or resolve over extended therapy. Dr. Byrd noted anecdotally that these AEs did not represent a significant burden for most patients. Due to the high rate of response in a group with few effective options, the data from the ibrutinib trial can be characterized as practice-changing, according to Olatoyosi Odenike, MBBS,

for refractory CLL. Although ibrutinib is not thought at this point to be curative, it could be one of a sequence of targeted therapies employed to keep CLL controlled indefinitely, particularly in older patients who are less tolerant of cytotoxic chemotherapy regimens. “The data show that BTK signaling is a highly effective target, and there are other inhibitors of this pathway that also show promise,” Dr. Odenike said. “There will be a lot of interest in evaluating whether these agents can be used in the front-line setting, particularly in older CLL patients.” —Ted Bosworth Dr. Byrd reported receiving research funding from Pharmacyclics, which also provided support for this trial. Dr. Odenike reported no relevant financial conflicts of interest.

Does the Medicare Data Dump Do More Harm Than Good? I

n an effort to make the U.S. health care system more transparent, affordable and accountable, in April the Centers for Medicare & Medicaid Services (CMS) released an unprecedented amount of privacy-protected data on services and procedures provided to Medicare beneficiaries by physicians and other medical professionals. The database, known as the Carrier Standard Analytic File, contains information on more than 880,000 distinct health care providers who collectively received $77 billion in Medicare payments in 2012 under the Medicare Part B Fee-For-Service program (go.cms.gov/1pdgAHE). It includes all physician claims that Medicare paid directly. Consumer advocates seeking to more thoroughly comprehend health care spending and physician practices, and to identify any inappropriate uses of service, embraced the disclosure, which had been blocked for more than 30 years by court decisions. However, numerous medical organizations, such as the Association of

Community Cancer Centers, contend that the release lacks true transparency and does a disservice to the public. The

explain the complexity of some payment systems and the value of provided services. Both organizations are frus-

‘Let’s pretend that they did have my data right, they didn’t give it in any context. ... You can’t even tell if a physician’s practice is 20% or 80% Medicare.’ —Jeffrey Ward, MD organization said that the information only states physician billing and doesn’t reveal the entire story about the many steps taken to treat patients with cancer. “Unlike many other specialties, cancer treatment involves very costly anticancer drugs,” it said in a press release. “A large proportion of the money that is billed to Medicare is immediately returned to drug manufacturers and distributors to pay for high-cost cancer treatments, including chemotherapy, biologics and other needed medications.” The American Society of Clinical Oncology (ASCO) also took issue with the release, and seconds that it doesn’t

trated that CMS didn’t give oncologists the opportunity to examine the information before it was made public. Jeffrey Ward, MD, immediate past chair of ASCO’s Clinical Practice Committee and a community oncologist, said that when he examined his own data he recognized many inaccuracies, such as how many times he administered chemotherapy and billed patients. “So let’s pretend that they did have my data right, they didn’t give it in any context,” Dr. Ward said. “You can’t compare a physician who’s in private practice with one in a hospital setting, but this release didn’t give any background

to interpret the data. You can’t even tell if a physician’s practice is 20% or 80% Medicare. And unless you can understand the way that billing works, you’ll be left with the assumption that a physician is making a certain amount when that’s not the reality.” Dr. Ward also noted that different medical specialties have a lot of discrepancies in overhead. For example, it’s impossible to compare an oncologist with a psychologist who just needs a room and a couch. In the field of oncology, a substantial proportion of Medicare reimbursement goes toward expensive drugs and machines, and a highly skilled staff essential to care for terminally ill patients. “This information is going to wind up creating a barrier to trust between patients and physicians, and will be used against doctors in business negotiations,” Dr. Ward said. “It will also lead to innocent physicians being accused of fraud and having their names tainted forever.” —Paul Bufano

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CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Hematology and bone marrow transplant highlights from ASCO—Part I stage IA-IIA CTCL, SHP-141, a novel topical skin-restricted histone deacetylase inhibitor (HDAC-i), demonstrated clinical objective response (OR).

QUESTIONS

1. True or False? Dif-

fuse large B-cell lymphoma (DLBCL): Investigators from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource reported to have developed a better cell of origin defining immunohistochemistry (IHC) algorithm than the Hans algorithm to predict overall survival (OS) and event-free survival in patients with DLBCL.

4. True

or False? B-cell non-Hodgkin lymphoma (NHL): In a Phase I study, ublituximab (UTX), a novel monoclonal antibody Primum non nocere. targeting a unique epit(First, do no harm.) ope on the CD20 antigen, resulted in an overall response rate (ORR) of 41% in relapsed and refractory B-cell True or False? Refractory Hodgkin lymphoma patients previously exposed to lymphoma (HL): In a Phase I/II study, rituximab. continuous lenalidomide with low-dose protracted bendamustine (LEBEN) was not active in patients with refractory HL. True or False? Refractory HL: The combination of sirolimus and vorinostat True or False? Cutaneous T-cell is well tolerated with encouraging activlymphoma (CTCL): In a Phase Ib mul- ity in very heavily pretreated patients ticenter, double-blind, placebo-con- with HL who are refractory to standard trolled randomized trial in patients with therapies.

ANSWERS

1. True. The algorithm needs to be

further studied in a larger population and compared with the gold standard, gene expression profiling (GEP). Cell of origin is felt to be one of the most important predictors of outcome to therapy, with better outcome in germinal center B cell-like (GCB) subtypes compared with non-GCB. GEP is not widely available. Therefore, IHC algorithms have been developed as a surrogate for GEP in determining cell of origin. Nadiminti K, Nasr M, Mott SC, et al. A novel immunohistochemistry (IHC) algorithm for assigning cell of origin status in diffuse large B-cell lymphoma (DLBCL) that better predicts survival as compared to the Hans algorithm. J Clin Oncol. 2014;32(5 suppl): abstract e19537.

2. False. Continuous LEBEN was

very active and well tolerated in patients with highly refractory HL. Enrollment continues (NTC01412307), and updated

results with correlative data were presented at the 2014 ASCO meeting. Corazzelli G, Saggese M, Pavone V, et al. A phase 1/2 study of lenalidomide and bendamustine (LEBEN) in chemorefractory Hodgkin lymphoma. J Clin Oncol. 2014;32(5 suppl): abstract 8566.

3. True. No dose-limiting toxicity,

early discontinuations, serious adverse events (AEs) or systemic AEs were recorded (NCT01433731). Time to OR was as early as day 7 of therapy. This is the first skin-optimized topical HDACi with evidence of early clinical activity and without systemic toxicity. According to the investigators, SHP-141 may address an important unmet medical need in early-stage CTCL by feasibly offering clinical benefits of a HDAC-i without safety concerns. Kim YH, Krathen M, Duvic M, et al. A Phase 1b study in cutaneous T-cell lymphoma (CTCL) with the novel topically applied skin-restricted histone deacteylase inhibitor (HDAC-i) SHP-141. J Clin Oncol. 2014;32(5 suppl): abstract 8525.

6. True or False? Advanced follicu-

lar lymphoma (FL): The 5-year update of the FOLL05 study, with mature data on progression-free survival (PFS), confirmed that R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has the best efficacy profile compared with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) and R-FM (rituximab, fludarabine, and mitoxantrone) for the initial treatment of patients with advanced FL.

7. True

or False? Relapsed and refractory multiple myeloma (MM): Daratumumab (DARA; HuMax-CD38), a human immunoglobulin G1k monoclonal antibody, effectively mediates destruction of CD40-expressing malignant plasma cells.

8. True or False?

Relapsed and refractory MM: The MM-003 intentto-treat analysis showed a significant increase in median PFS and OS for highdose dexamethasone versus pomalidomide plus low-dose dexamethasone.

4. True. Single-agent therapy with

UTX was well tolerated and active in rituximab-exposed patients. Studies are ongoing with UTX in combination with novel targeted agents (PI3K-δ and BTK inhibitors). O’Connor OA, Deng C, Amengual JE, et al. A phase I trial of ublituximab (TG-1101), a novel glycoengineered anti-CD20 monoclonal antibody (mAb) in B-cell non-Hodgkin lymphoma patients with prior exposure to rituximab. J Clin Oncol. 2014;32(5 suppl): abstract 8524.

5. True. Investigators enrolled 28

patients (median age 34 years, median of 6 prior therapies—including autoHCT [n=23] and auto- and allogeneic HCT [n=6]) for dose escalation (n=1), a recommended Phase II dose (n=19) or a registered off-label dose (n=8) with the combination of sirolimus and vorinostat. According to Cheson 2007 criteria, the ORR was 57%, with 9 patients showing a complete response (CR; 32%) and 7 a partial response (PR; 25%). At the median follow-up of 5.4 months, the

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

9. True or False? Autologous hema-

topoietic cell transplant (auto-HCT) in MM: In an abstract from the University of Texas MD Anderson Cancer Center and Baylor College of Medicine, both in Houston, investigators reported that dialysis-dependent renal failure should not be an exclusion to autoHCT in patients with MM.

10. True or False? Primary plas-

ma cell leukemia: (pPCL): Investigators from Mayo Clinic, in Rochester, Minn., analyzed the Surveillance, Epidemiology, and End Results database for trends in survival of patients with pPCL (ICD-O: 9733) over the period from 1973 to 2010, and they found absolutely no survival improvement during this period.

median PFS has not been reached. Also, given successful induction of remissions, 5 patients (18%) were referred for allogeneic stem cell transplant. Major grade 3/4 treatment-related toxicities included grade 3 thrombocytopenia in 9 patients (32%), grade 4 thrombocytopenia in 8 (29%), grade 3 anemia in 4 (14%), and grade 3 transaminitis in 3 (11%). Janku F, Oki Y, Falchook GS, et al. Activity of the mTOR inhibitor sirolimus and HDAC inhibitor vorinostat in heavily pretreated refractory Hodgkin lymphoma patients. J Clin Oncol. 2014;32(5 suppl): abstract 8508.

6. True. The final results of FOLL05

study for the initial therapy of advanced stage (II-IV) FL recently were reported, with a median follow-up of 34 months. This trial showed that R-CHOP and R-FM were superior to R-CVP with respect to 3-year time to treatment failure, the primary study end point, and that R-CHOP had a better risk–benefit ratio compared with R-FM. During

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

Write to managing editor Sarah Tilyou at smtilyou@mcmahonmed.com

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ASCO 2014, the investigators presented 5-year follow-up analysis of PFS of the 504 patients included in the study. Luminari S, Dondi A, Marcheselli L, et al. Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma. J Clin Oncol. 2014;32(5 suppl): abstract 8530.

7. False. DARA mediates destruction

of CD38-expressing malignant plasma cells. Investigators evaluated safety, pharmacokinetics (PK), and efficacy of DARA plus lenalidomide plus dexamethasone (LEN/DEX) in patients with relapsed or refractory MM. The most frequently occurring AEs (>40% patients) were neutropenia and diarrhea; 17 were ≥grade 3 with 70% hematologic (neutropenia, thrombocytopenia, anemia). The maximum tolerated dose was not reached. The PK profile of DARA plus LEN/DEX was similar to that of DARA alone, suggesting that LEN/DEX does not affect the DARA PK profile. Available efficacy data from 11 patients demonstrated marked decrease in M-protein in all patients; 8 of 11 patients achieved a PR or better, 5 of 11 a very good partial response (VGPR), and 2 of 11 had minimal responses. The median time to response was 4.1 weeks (range, 2.1-4.3 weeks). Plesner T, Arkenau H-T, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. J Clin Oncol. 2014;32(5 suppl): abstract 8533.

8. False. The MM-003 intent-to-

treat analysis showed a significant increase in median PFS and OS for pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone. Unadjusted median OS in MM-003 was 12.7 and 8.1 months in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups, respectively. After adjusting for crossover, the difference in median OS in the 2 groups was 7 months (12.7 vs 5.7 months). The median OS in the pomalidomide plus low-dose dexamethasone arm was, therefore, more than double that in the high-dose dexamethasone arm. Morgan GJ, San Miguel J, Dhanasiri S, et al. Pomalidomide plus low-dose dexamethasone (POM plus LoDEX) versus high-dose dexamethasone (HiDEX) for relapsed or refractory multiple myeloma (RRMM): overall survival (OS) results of MM-003 after adjustment for crossover. J Clin Oncol. 2014;32(5 suppl): abstract 8593.

9. True. Investigators retrospective-

ly reviewed 2,091 patients who underwent auto-HCT from July 2000 to June 2012, and found 24 patients (1.1%) who were dependent on dialysis (21 on hemodialysis and 3 on peritoneal dialysis). Median duration of dialysis before auto-HCT was 235 days (range, 1-1,481 days). Four patients had high-risk

cytogenetics. The melphalan dose was 200 mg/m2 in 58% of patients and less than 200 mg/m2 in the remaining 42%. The median collected CD34-positive cell count was 4.35×106/kg. All patients engrafted. Treatment-related mortality at 100 days and 6 months were each 0%. The incidence of grade II/IV nonhematologic toxicity was similar across different melphalan doses. The ORR was 92% (CR, 25%; VGPR, 29.2%; PR, 37.5%). Two patients had stable disease. Only 3 patients (12.5%) became dialysis-independent after transplant. The median follow-up is 6.7 years. At the time of

last follow-up, 13 of the 24 patients had died. The median PFS and OS were 1.9 years and 3.8 years, respectively. In univariate analysis, high-risk cytogenetics was a significant predictor of poor PFS ( 0.04) and OS ((P<0.009). A multivar(P= iate analysis was not performed due to the small sample size. El Fakih RO, Nieto Y, Fox PS, et al. Autologous stem cell transplantation in dialysis-dependent myeloma patients. J Clin Oncol. 2014;32(5 suppl): abstract 8601.

10.

False. Only diagnosis between 2006 and 2010 was associated with a

better OS (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; P=0.0018, with reference to the 1973 to 1995 period). The median OS based on periods of diagnosis of 1973 to 1995, 1996 to 2002, 2003 to 2005, and 2006 to 2010 were 9, 9, 8, and 19 months, respectively (P ( =0.002). According to the investigators, these results suggest that since 2006, the use of novel agents in the treatment of pPCL has had a positive effect. Gonsalves WI, Rajkumar V, Go RS, et al. Trends in survival of patients with primary plasma cell leukemia: a population-based analysis from 1973 to 2010. J Clin Oncol. 2014;32(5 suppl): abstract 8608.

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Evolving Role of Autologous Transplantation in Multiple Myeloma

igh-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) was the first treatment to improve overall survival (OS) for patients with multiple myeloma (MM) over that seen with oral melphalan and prednisone. Although these observations were made before the availability of novel agents, auto-HCT remains a viable option in the majority of patients with MM. This article discusses several important aspects of auto-HCT for patients with MM.

In the modern era, which group of MM patients does not benefit from front-line auto-HCT? This is a tough question because many ongoing trials are best suited to answer this with specific biologic subtypes based on fluorescence in situ hybridization and DNA-sequencing data at the time of diagnosis. The most comprehensive study that may be able to answer this question is the IFM/DFCI (Francophone Myeloma Intergroup/Dana-Farber Cancer Institute) clinical trial, in which patients receive three cycles of lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium), and dexamethasone (RVD) and hematopoietic progenitor cell (HPC)

Ongoing Important Clinical Trials in Patients With Newly Diagnosed MM BMT CTN Protocol 1304/DFCI 10-106. A randomized Phase III study comparing conventional dose treatment using RVD with HDT and peripheral stem cell transplant in the initial management of myeloma in patients up to age 65 years. E1A11 (ENDURANCE). A randomized Phase III trial of bortezomib, lenalidomide and dexamethasone (VRD) versus carfilzomib, lenalidomide and dexamethasone (CRD) followed by limited or indefinite-duration lenalidomide maintenance in patients with newly diagnosed symptomatic MM.

collection, followed by randomization to either early or delayed auto-HCT with RVD consolidation. This trial does have a stratification based on risk, and will give us insights into which patients may benefit from one strategy over another. There is some discussion that, perhaps, patients with high-risk MM do not benefit as much from auto-HCT; however, there are data from European groups suggesting that high-risk patients actually may gain additional benefit from tandem auto-HCT.1 These conflicting data sets confuse the management of patients on a moment-tomoment basis. Our group recently published on a series of high-risk patients who were induced with RVD, followed by auto-HCT, and then placed on RVD maintenance for 3 years.2,3 These patients were all high-risk, with more than one-fourth having del 17p. In our analysis, the median progressionfree survival and OS were far superior to what is reported in many other large clinical trials, suggesting that for the high-risk cohort, aggressive maintenance is needed to maintain remission. The Spanish Myeloma Group has shown that high-risk patients may achieve conventional complete remission (CR) at a rate similar to standardrisk patients, yet they fail to achieve minimal residual disease (MRD) negativity.4 This lack of MRD negativity may contribute to early and rapid relapse, especially when no maintenance therapy is planned. Auto-HCT, even among high-risk patients, continues to be one way that patients can be induced to achieve an MRD-negative state (Figure). Compared with consolidation using melphalan, prednisone and lenalidomide, auto-HCT

Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University Atlanta, Georgia

(even using modern induction therapy) improves progression-free survival after consolidation, without a significant improvement in overall response rate, due to an improvement in depth of response (a high fraction of patients achieving MRD negativity).5

Currently, which group of MM patients derives the most benefit from front-line auto-HCT? This question also is awaiting data from randomized trials. However, careful review of older data sets may help to answer this question. For instance, data from European groups suggest that many centers have a 10% to 15% tail on the OS curve, suggesting that some patients may be cured simply with the use of alkylating agents. An update from the PETHEMA group suggests the presence of a tail on the OS curve,6 as does a series of patients from the Arkansas group, where there are more than 15% of patients from total therapy 1 (induction with vincristine, doxorubicin, dexamethasone, tandem auto-HCT with melphalan 200 mg/m2 and interferon maintenance) who are in continuous CR more than 10 years after completion of therapy.7 Based on these long-term follow-up reports and others from large cooperative groups, it appears there is a group of standard-risk patients who could be potentially cured with frontline auto-HCT. Although this may not be a large cohort of patients, the recent and soon-to-be-available new agents may serve to increase the number of patients in this cure group, and it is possible that the use of early auto-HCT may render these patients MRD-negative, thereby increasing their chances of achieving a cure.

With more effective front-line therapies, should patients with less than very good partial response (VGPR) following first auto-HCT still be considered for second auto-HCT? Even in a time when more than 95% of patients achieve a major response following induction therapy alone, there are some patients who do not appear to be sufficiently sensitive to the use of proteasome inhibitors or immunomodulatory drugs (IMiDs). These patients tend not to have a proliferative myeloma but instead have a disease in which the plasma cells simply are resistant to death. These patients can be sensitive to alkylators given in high doses, and, specifically, to highdose melphalan. If a patient has a deeper response following the first auto-HCT but fails to achieve a VGPR, a second auto-HCT would be a reasonable consideration, especially because the patient did not appear to be particularly sensitive to either IMiDs or proteasome inhibitors (presuming RVD was used initially). Outside of this specific type of case, the use of second tandem auto-HCT is limited because most patients will achieve a major response with induction therapy alone, reducing the potential benefit from a second tandem auto-HCT.

Which group of patients requires mobilization chemotherapy to facilitate HPC collection? Cyclophosphamide- or chemotherapy-based mobilization is useful when patients have received extensive cycles of induction before referral to a transplant center. Cyclophosphamide-based mobilization also has the advantage of potentially shortening the number of days of collection due to a more rapid mobilization effect. However, the use of chemomobilization carries with it the risk for complications, such as bleeding or infections, during the period of aplasia, although these events occur rarely. In general, growth factor mobilization or growth factors plus plerixafor (Mozobil, Sanofi)8 have significantly reduced the need for chemomobilization. In our practice, patients who have received more than six cycles of lenalidomidebased induction may be mobilized more effectively with chemotherapy.9 However, the collection failure rate for patients who receive RVD-based induction for four cycles followed by growth factor

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CLINICAL ONCOLOGY NEWS • JULY 2014 • CLINICALONCOLOGY.COM

2. Nooka AK, Kaufman JL, Behera M, et al. Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials. Cancer. 2013;119(3):4119-4128, PMID: 24005889. 3. Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28(3):690-693, PMID: 24220275.

Bortezomib Lenalidomide Combinations New drugs Antibodies

4. Paiva B, Gutierrez NC, Rosinol L, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687-691, PMID: 22128143. 5. Boccadaro M, Cavallo F, Gay FM, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients. J Clin Oncol. 2013;15(suppl):abstract 8509. 6. Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118(3):529-534, PMID: 21482708.

Figure. Getting to MRD: New definitions for CR. CR, complete response; MRD, minimal residual disease

mobilization is very low, suggesting that chemotherapy is not needed for most patients who are referred early in their induction course for HPC collection.

With the use of more effective front-line therapies, how is the success of auto-HCT measured for patients who have achieved CR before the procedure? The use of serum and urine proteins for the treatment and management of patients with MM has provided clinicians with a convenient method for assessment of disease burden, but because we are now achieving lower levels of disease burden as a consequence of more effective therapies, we need to further refine the response criteria to allow for adequate assessment of response depth. As an example of this, the use of multiparameter flow cytometry represents a method to evaluate levels of MRD that are significantly lower than what is observed with a conventional CR.10 Beyond that, sequencing technology may allow assessment of a level 1 log lower (less disease burden) than with multiparameter flow cytometry and is being evaluated in ongoing clinical studies.11 However, relying solely on the use of marrow-based assessment has the potential to miss bone-based disease that may not be represented in the marrow. For this reason, newer response criteria likely will emerge combining MRD assessment with radiologic testing12 to confirm that patients are truly without disease when we declare them a CR. These lower levels of disease burden will demonstrate the improved benefit over the current criteria of conventional CR with each successive antimyeloma treatment.

Future Prospects The use of auto-HCT represents one of the many therapeutic options clinicians have to improve the OS of patients with MM. Its use can extend to patients well over the age of 70, presuming the patient is fit, and it can be used to improve depth of response, even in an era when we use multiple novel agents as part of the induction process. The ultimate utility of this process will depend largely on data from randomized clinical trials, but it is important to keep in mind that even in trials that have been presented to date,

the use of auto-HCT continues to demonstrate benefit over conventional consolidation alone. It is important as we seek to maximize OS, and even seek the cure for myeloma, that suitable patients are referred to a transplant center early in their disease course to allow for HPC collection.

References 1. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase European III studies. Blood. 2013;122(21):Abstract 767.

AT A GLANCE • In MM, lack of MRD negativity may contribute to early and rapid relapse. • Front-line auto-HCT has a role, even in patients with high-risk disease. • In the modern era of more effective front-line therapies, patients with less than VGPR following first auto-HCT still can be considered for second auto-HCT. • Cyclophosphamide- or chemotherapy-based mobilization is useful when patients have received extensive cycles of induction before referral to a transplant center. • Patients with MM should be referred early during the course of induction therapy to transplant centers. • In the modern era of more effective therapies for patients with MM, we need to further refine our current response criteria. • Newly diagnosed patients with MM should be encouraged to participate in well-designed clinical trials.

Barlogie B. High-dose therapy and innovative approaches to treatment of multiple myeloma. Semin Hematol. 2001; 38(2 suppl 3):21-27, PMID: 11309705.

8. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720-5726, PMID: 19363221. 9. Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009;23(10):1904-1912, PMID: 19554029. 10. Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023, PMID: 18669875. 11. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20): 3073-3079, PMID: 24646471. 12. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118(23):5989-5995, PMID: 21900189.

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

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