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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • May 2013 • Vol. 8, No. 5

INSIDE

by the

numbers: sequestration

NEW Column How I Manage ... Chronic Myeloid Leukemia ................................ 9

On April 1, the federal government began implementing its sequestration policy, including cuts to Medicare payments.

CURRENT PRACTICE

Previous cancer drug Medicare payments: Average Sales Price + 6%

Vogl, NY...: “Screen, Baby, Screen” ........................ 21

New payment formula: Average Sales Price + 4.3%

The Tumor Board: A large mass at the small bowel mesentery .............................. 24

Percent drop in payments: 28% Community cancer clinics reporting in a survey that they will be forced to change the way Medicare patients are treated as a result: 72%

Maurie Markman, MD: Does ‘X’ cause cancer? .................................... 26 Clinical Conundrums ......................... 27

FORMORE, MORE,see see FOR By the Numbers: Sequestration ............................... 10

“Bubblehead,” a creation of clustered pancreatic adenocarcinoma cells. For more info, see page 8.

EDUCATIONAL REVIEW

The single biggest question facing community oncology today

Guide to Colorectal Cancer Therapeutic Regimens 2013 3 Pocket Guide ...... insert after page 8

Will You Merge or Won’t You? T

here are two kinds of community oncology practices today, says Patrick Cobb, MD, of St. Vincent Frontier Cancer Center in Billings, Mont.: those that have aligned with a hospital or health system, and those that are thinking about it. As of December 2012, Dr. Cobb’s practice is one of the former. “That’s when we officially signed a contract with St. Vincent’s Healthcare to transition us from a private practice clinic to a hospital-based clinic,” Dr. Cobb says. “We couldn’t see any other way that we’d be able to continue to practice given the current economic environment.” Over the last four-and-a-half years, according to an April 2012 Community Oncology Practice Impact report from the Community Oncology Alliance (COA), 241 community oncology clinics have closed altogether; 132 either have merged with or have been acquired by another practice or a corporate entity (like McKesson’s 2010 purchase of US Oncology); and 392 practices either see PRESSURE, E page 11

Four Trends Driving Oncology Practice Consolidation 1. The Medicare Modernization Act of 2003 reducing medication reimbursement rates to the Average Sales Price + 6% 2. Uncertainty raised by “patches” to the Sustainable Growth Rate (SGR) formula for Medicare spending 3. Uncertainty concerning the long-term impact of health care reform 4. An aging oncology workforce

RE VIE WS & COMMENTAR IES

Expert Insights From Mayo Clinic Percutaneous cryoablation eases metastatic bone pain ............................ 14 Scott Okuno, MD

Single-dose radiation effective for cutaneous T-cell lymphoma ............. 17 William Wong, MD

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD

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

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

Oncology Nursing Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Hematologic Malignancies

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

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

Michele Neskey, MMSc, PA-C

Maura N. Dickler, MD

Harry Erba, MD, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

University of Alabama Birmingham, AL

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

Richard Stone, MD

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

Gastrointestinal Cancer and Sarcoma

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

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

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

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

On the Cover

Syed A. Abutalib, MD

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

Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

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

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Edward Chu, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Policy and Management

Pharmacy

Shaji Kumar, MD Mayo Clinic Rochester, MN

Cathy Eng, MD

Bioethics

University of California, San Diego, CA

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

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

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

Steven Vogl, MD Medical Oncologist New York, NY

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

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

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

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

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

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

Mission Statement

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

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

How I Manage ...

Chronic Myeloid Leukemia T

Jerald Radich, MD he tyrosine kinase inhibClinical Research itors (TKIs) have irreDivision vocably changed the care of Fred Hutchinson Cancer Research Center chronic myeloid leukemia Seattle, Washington (CML) patients, dramatically changing the natural history of this disease.1-4 With multiple TKIs available, we now have an “embarrassment of riches” in treatment options. Below are some common questions and clinically relevant answers regarding treatment.

Which TKI do I start in patients with chronic-phase CML? The choices are imatinib (Gleevec, Novartis) and the more potent secondgeneration TKIs nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, BristolMyers Squibb). Here are some basic considerations for selecting therapy: A. What are the treatment goals? For instance, with a patient in his or her 70s, it may be appropriate to extend survival without concern for potential serious toxicities. For someone much younger, it may be to achieve “deeper responses” with counseling about management of concurrent side effects in order to allow discontinuation of a particular TKI (see fourth question). B. There should be avid evaluation of preexisting comorbidities. It may not be best to prescribe dasatinib or nilotinib, respectively, to a patient with cardiopulmonary problems and vascular disease. C. It is important to consider the chronic-phase disease status at the time of diagnosis. Is the patient low or high Sokal (or Hasford) risk? If the patient seems to be on the verge of transition to accelerated

or blast phase, there may be reason to start therapy with a more potent TKI. D. A physician’s personal experience and comfort level managing various side effects of a specific TKI remain crucial in the decision-making process (Table). All things being equal, the secondgeneration TKIs do yield superior progression-free survival (PFS) compared with imatinib. Three separate randomized clinical trials showed that nilotinib or dasatinib yielded more frequent complete cytogenetic remissions (CCyR) and major molecular responses (MMR) by 12 months, as well as fewer progressions to accelerated or blast phase, compared with imatinib.1-3 To date, however, no randomized trial has shown a benefit in overall survival (OS) with use of nilotinib or dasatinib over imatinib.

When do I consider switching to a different TKI? The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have established online treatment recommendations, which include guidelines for monitoring and

Table. Considerations in Selection of TKI Therapy for Chronic Myeloid Leukemia TKI

Advantages

Disadvantages

Imatinib

Long-term data available; less expensive

Lower rates of CCyR compared with second-generation TKIs; fluid retention; musculoskeletal aches and pains

Dasatinib

10% higher CCyR compared with imatinib; ~2 times higher rates of MMR

Pleural effusion; pulmonary arterial hypertension; thrombocytopenia; hemorrhage

Nilotinib

>10% higher CCyR compared with imatinib; ~2 times higher rates of MMR

Cumbersome dosing schedule; skin rash; pancreatitis; QT prolongation; dyslipidemia/ hyperglycemia; peripheral artery disease

CCyR, complete e cytogenetic remission; MMR, major molec molecular cular response; TKI, tyrosine kinase inhibitor

robust treatment outcome end points.6,7 Fortunately, the NCCN and ELN guidelines are quite similar. Patients should have at least a bone marrow minor cytogenetic response or a peripheral blood BCRABL level of less than 10% by three to six months; and by 12 months, all patients should achieve a CCyR. Failure to achieve established milestones, or recurrence of disease after reaching these goals, is considered a failure of the TKI therapy, and warrants changing therapy to a different TKI. Fluorescence in situ hybridization testing for BCR-ABL should only be done at diagnosis for those patients who have inaspirable bone marrow, or for monitoring in the rare circumstance when peripheral blood for polymerase chain reaction testing is not available.

How do I make a decision about an alternative TKI? This is an even more complicated question. There are now four second-generation TKIs approved for resistant chronic-phase CML—nilotinib, dasatinib, bosutinib (Bosulif, Pfizer) and ponatinib (Iclusig, Ariad). If you have started a patient on imatinib, it makes sense to switch to a second-generation TKI; if a patient needs to switch from initial therapy with a second-generation therapy, then switching to another TKI is justified; but in general, changing to a less potent TKI, that is, imatinib, is probably not the best option.

How do I select a second-generation drug for resistant disease? The same criterion for picking initial therapy applies here as well. Consider the specific side-effect profile, the co-morbidities of the patient and your comfort level with a given TKI. However, an additional important consideration is the presence of ABL point mutations, which confer resistance in about 50% of cases presenting with relapsed CML. There are hundreds of possible point mutations, but the most common have had in vitro testing performed and ample literature exists showing which particular mutation is sensitive to which TKI. Ponatinib is unique among these agents, as it is the only TKI that is effective in patients with the T315I mutation. Moreover, ponatinib seems to be effective across the entire range of known ABL mutations. Time will tell if it becomes the first choice for resistant disease.

How do I manage TKI intolerance? When there was only imatinib, there were complicated schemes to try to keep patients on the drug in the face of side

AT A GLANCE To date, no randomized trial has shown a benefit in overall survival with nilotinib or dasatinib over imatinib. Patients should have at least a bone marrow minor cytogenetic response or a peripheral blood BCR-ABL level of <10% by 3-6 months; and by 12 months, all patients should achieve a CCyR. Until questions about discontinuation are fully answered, no patient should have their TKI discontinued outside the context of a clinical trial.

effects. Now that we have a total of five FDA-approved TKIs, the better course in patients with any toxicity that results in drug discontinuation or reduction is to simply switch TKIs. Fortunately, the available agents appear to be “cross-tolerant”; that is, if a patient has a particular side effect on one TKI, he or she is relatively unlikely to have it on another TKI. This phenomenon is likely a product of genetic polymorphism and the different spectrum of kinases being targeted. Since CML often is diagnosed with a relative absence of symptoms, patients actually may feel worse taking a TKI than they did before they were diagnosed. This is a recipe for poor adherence, and several studies have demonstrated a shockingly poor compliance with the scheduled dosing of these TKIs. This is especially problematic because adherence is strongly associated with the ability to achieve important end points such as MMR and complete molecular response (CMR; see next question).8

Are we ready to discontinue therapy safely after achievement of a specific milestone? It was first thought that patients would need to stay on TKIs forever, because in vitro work showed that the putative CML stem cell survived in the presence of BCR-ABL inhibition. However, several studies have shown that approximately 40% of patients who are in CMR can discontinue TKI therapy successfully, and stay in CMR for several years.9 Most patients relapse within six months after discontinuation, and so far, all patients have responded when rechallenged with a TKI, although not all patients have returned to CMR. There are many things we don’t know see CML, page 10

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

CML continued from page 9

about treatment discontinuation, and these are the subjects of several ongoing and future studies. Can we predict who can be discontinued safely? How long should someone be in CMR before discontinuation, and is the effect the same for all the TKIs? In the cases that relapse, has the absence of TKI inhibition allowed rare clones to begin the process of ABLindependent progression? Until these questions are answered, no patient should have his or her TKI discontinued outside the context of a

clinical trial. Lastly, I would like to mention two global ongoing studies in newly diagnosed patients with CML in chronic phase: the new, global EPIC (Ponatinib in Newly Diagnosed Chronic-Phase CML) trial, which mirrors the schema of the DASISION, ENESTnd and BELA trials; and the ENESTnd (A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive [Ph+] Chronic Myelogenous Leukemia in Chronic Phase) trial, testing the achievement of CMR from MMR by switching from imatinib to nilotinib. However, current data using dasatinib or nilotinib has not demonstrated improved OS with the achievement of MMR.

Series Editor

References 1. N Engl J Med. 2010;362:2251-2259, PMID: 20525993. 2. N Engl J Med. 2010;362:2260-2270, PMID: 20525995.

Syed Abutalib, MD Assistant Director, Hematology and Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Ill.

3. Lancet Oncol. 2011;12:841-851, PMID: 21856226.

Coming soon

4. Blood. 2012;120:3898-3905, PMID: 22915637.

How I Manage: MGUS & Smoldering Multiple Myeloma

5. J Clin Oncol. 2009;27:6041-6051, PMID: 19884523.

by Robert Kyle, MD

6. J Natl Compr Canc Netw. 2009;7:984-1023, PMID: 19878641. 7.

Best Pract Res Clin Haematol. 2009;22:331341, PMID: 19959084.

8. Blood. 2009;113:5401-5411, PMID: 19349618. 9.

How I Manage: Primary Mediastinal Large B-Cell Lymphoma by John Sweetenham, MD

Lancet Oncol. 2010;11:1029-1035, PMID: 20965785.

by the

numbers: sequestration L

ast month, mandatory sequestration took effect, reducing discretionary spending across the United States federal budget. Below are the estimated budget cuts in fiscal year 2013 to agencies within the Department of Health and Human Services. This was provided by Matt Brow, the vice president of Public Policy & Reimbursement Strategy for McKesson Specialty Health.

Estimated Department of Health and Human Services Cuts From Sequestration for FY2013 Centers for Medicare & Medicaid Services

NIH

Administration for Children and Families

Health Resources and Services Administration

Centers for Disease Control and Prevention

$605M

$490M M

FDA

Substance Abuse and Mental Health Departmental Administration Services Mgmt. On Aging Administration

Office of Inspector General

Program Support Center

$5M

$11,855M M $2,529M M $1,532M M

$319M

$275M

$168M

$122M

Sources: OMB Report Pursuant to the Sequestration Transparency Act of 2012; McKesson Specialty Health; American Society of Clinical Oncology; “National Medicare Sequestration Survey,” Community Oncology Alliance, March 2013.

McMahon Publishing is a 41-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© 2013 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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PRESSURE continued from page 1

have a hospital agreement or have been purchased by a hospital. Of course, it’s been nearly a year since that report was issued, meaning the numbers undoubtedly are much higher today. Economic pressures on community oncologists are driving more and more practices to take this step. Before 2008, about 85% of all oncology care was delivered by independent practitioners in a community setting. By 2012, that figure was about 65% ((Am J Manag Care 2012;18:SP98-SP, PMID: 22693989). “Between 2011 and 2012 alone, we saw a 40% increase in the number of practices that were merging with or being acquired by hospitals,” says Ted Okon, COA Executive Director. Four major drivers appear to be behind the consolidation trend: the Medicare Modernization Act of 2003, fully implemented in 2005, which has reduced reimbursement rates for medications to the current Average Sales Price (ASP) + 6%; continued uncertainty about “patches” to the Sustainable Growth Rate (SGR) formula for Medicare spending on physician services; uncertainty concerning the long-term impact of health care reform; and the graying of the oncology workforce. “Well over 50% of oncologists in community practice are over the age of 50,” said Mr. Okon. “Frankly, they see the prospect of less medicine and more bureaucracy, along with much more financial pressure and uncertainty, and they’re getting tired of it. I was on the phone with a community oncologist for an hour this morning, talking about all of these changes. He’s another one who’s seriously considering hospital acquisition [of his practice].” The burden of economic pressures like ASP+6% and the SGR circus falls particularly heavily on oncology, Mr. Okon adds. “As all this is going on, we also have the fact that we’ve seen an escalation in the price of new oncology therapies coming out, and unlike most other areas of medicine, the model of cancer care delivery links the drugs and the services. You have practices that need to maintain inventory of drugs that are growing more expensive. So, when you add ratcheting down of reimbursements to uncertainty about the SGR, practices basically do not have the ability to do a five-year or threeyear strategic plan. In fact, most oncology practices have pretty much ripped up their strategic plans and said, ‘we’re going month to month.’” Add to this the fact that oncology is a very high-dollar, high-risk proposition for a private practice compared with, say, family medicine or OB/GYN, and you have a perfect storm of economic

pressure. “We function like mini-hospital facilities, providing chemotherapy, radiation, ancillary services, and the imaging that’s critical not only in diagnosing but in ongoing monitoring of treatment,” Mr. Okon said. “Oncology is in a unique situation.” Tulsa-based Oklahoma Oncology so far has held fast against the forces driving many of its counterparts to merge with hospitals. But it hasn’t been easy, said Joseph Lynch, MD, who has been with the practice for more than two decades. “Over the past two years, we’ve lost 30% of our patients to hospital-based care,

because we can’t afford to treat them in our offices—such as Medicaid patients, those on Medicare only, and several patients with certain local insurance plans,” he explains. “With the amount that some of these payers would cover for drugs, we were under water. I don’t mind giving my time for free, but I can’t buy people’s drugs for them.” That quandary has led to a decline in quality of care for some of his former patients, Dr. Lynch says. “We already know that the cost of care in the hospital setting is higher, and there are more copays for the patient,” he says. “And

as hospital outpatient centers become more crowded, they’re experiencing errors that are not within the purview of the physicians writing orders. I’ve seen a patient for whom I had written chemo orders, and I didn’t find out until three weeks later that they weren’t given one of their drugs. The patient was ready for the next cycle, and one of the nurses picked up the fact that the patient hadn’t received [cyclophosphamide] in the previous cycle.” Mr. Okon hopes that, as payers and the federal government begin to understand see PRESSURE, E page 12

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PRESSURE continued from page 11

what they may be losing with the shuttering of private oncology practices, the pendulum may be swinging the other way. “After a big wave of consolidation, with hospitals in land rushes trying to grab up all providers, I think we are seeing that payers out there are beginning to realize that this trend is increasing costs without delivering commensurate quality,” he said. “Rather than improving efficiency, all this consolidation is

just giving more leverage to larger entities that are demanding increased payments, and driving up costs.” Instead of joining with hospitals, some community practices are looking for other ways to combine forces and strengthen their bottom line. For example, last year, competing Columbus, Ohio, practices Zangmeister and Columbus Oncology joined together to form one 21-physician practice, a deal that allowed them to cut costs while remaining independent from the two hospital systems where their physicians practice, Mt. Carmel Health and OhioHealth, both of

which have been putting more specialty practices on their employment rosters in recent years. COA has been working to develop a national strategy that would help private practices survive as independent entities. “We’re in the final stages of putting together an oncology medical home payment model that would be utilized by CMS [Centers for Medicare & Medicaid Services],” says Dr. Lynch, who serves on COA’s national board. “It’s quality-driven and focused on milestones. It would codify what we do right now and provide CMS and private payers with the quality

and value measures that we know we have; over time, there would be more cost sharing, and benefits from that.” Dr. Lynch says that the new model may be the only thing that can keep community oncology viable. “With sequestration, this plan would stop the mandatory decline to ASP+4%, which would put the vast majority of practices out of business. We should be able to roll out this model to CMS within the next few months, and within the year we’ll know whether it’s going to be funded.” (Read more about oncology and medical homes on the COA’s

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website at http://www.communityoncology.org/site/medical-home-aco.htm.) Some early-adopting community oncology practices already have blazed trails on the medical home frontier. In 2010, Consultants in Medical Oncology and Hematology (CMOH), near Philadelphia, became the first oncology practice recognized by the National Committee for Quality Assurance as a level III patient-centered medical home, or PCMH. “The aggregated economic savings to CMOH’s payers is estimated to be in the range of $1 million per physician per year. The magnitude of the savings

is a reflection of the cost of caring for a concentrated population of clinically vulnerable, older, chronically ill patients with multiple comorbid conditions and unique psychosocial needs,” CMOH physician John D. Sprandio, MD, wrote in an article in the May 2012 issue of the American Journal of Managed Care. Another oncology-focused PCMH pioneer is Cancer and Hematology Centers (CHC) in western Michigan. “There are several components we’re focused on,” said Stuart Genschaw, the practice’s executive director. “One is not new: it’s clinical pathways, although

we’re using a more advanced set of pathways involving new resources that are coming out related to companion diagnostics and molecular markers.” CHC has had great success incorporating advanced care planning into early meetings with all of its patients. “We have a psychologist and a master’s-prepared social worker who meet with every patient going under active treatment,” Mr. Genschaw says. In that way, the practice is fortunate because a large local payer reimburses for that service for the majority of its patients—something many payers do not. “We’re now

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tracking that and will document the benefit that it brings to our patients.” The third component, says Mr. Genschaw, involves educating the practice’s patients that CHC is now, for all matters, their “medical home.” He says, “We know we can do a better job keeping our patients out of the hospital and out of the [emergency room]. They need to understand that now that they have cancer, we’re the first one to call with any medical issue, not their primary care doctor. We have 24-hour phone triage, so that if someone calls at 3 a.m. with vomiting and diarrhea, the nurse will go through the appropriate pathway, guide them through what to do to prevent dehydration, and set them up for labs at 7 a.m.” Mr. Genschaw also is pushing for oral oncolytics to remain the dispensing purview of community oncologists. “Payers should pay physicians for that as they would pay a specialty pharmacy,” he says. “It’s still chemotherapy that the patients are receiving, and the questions that they have will go back to the oncology nurse or physician, not to the specialty pharmacy. That’s how we can best serve patients on orals. Many practices have embraced in-office dispensing, and I think that should be encouraged rather than having the drugs picked up at Walgreens or shipped to the patient’s house.” Mr. Genschaw believes that payers are starting to recognize the importance of community oncology practices. “Even the Blues in Michigan are starting to recognize that they want us to survive as independents,” he says. “Numerous studies are demonstrating that the cost of care goes up in a hospital setting—about 16% for Medicare and double or triple that for private payers. And I think those practices that sold out early are going to end up regretting it.” Although the transition to a hospital-based practice hasn’t changed much for Dr. Cobb clinically, and has taken him and his colleagues out of the business of billing and collections so that they can focus more on their patients, he acknowledges that he does have regrets. “In private practice, we provided stateof-the-art care for a lot of people and kept them out of the hospital at a lower cost, but payers didn’t see the value in it. That’s our biggest regret.” Conceptually, he says, the medical home model is a very reasonable approach. “It tries to align the incentives for keeping people out of the hospital and in the outpatient setting,” Dr. Cobb says. “The challenge is that payers have to be willing to pay for it, and there has to be enough of an economic incentive for private practices to implement it. If they aren’t reasonably assured that this model is going to work and they’ll have a return on their investment, it’ll be hard to get off the ground.” —Gina Shaw

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Expert Insights From the Mayo Clinic Cancer Center Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a notable cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care. We hope you find this Reviews & Commentaries section to be a valuable tool.

Percutaneous Cryoablation Eases Metastatic Bone Pain From Cancer

ercutaneous cryoablation has been found to be safe and effective for palliation of bone pain due to metastatic disease. Additionally, the palliative effect proved durable. Sixty-one patients with moderate to severe pain from tumors involving or abutting bone were enrolled at Mayo Clinic and seven other institutions in a single-arm study. Patients had previously been treated with radiation therapy (RT), chemotherapy, surgery and/or analgesic medicine, were considered to be poor candidates for conventional therapy or had refused

standard therapies. Patients were eligible for this trial if they reported pain at 4 or higher on a scale of 0 to 10 over the prior 24 hours based on the Brief Pain Inventory-Short Form. All patients who had participated in standard therapies had completed the treatments more than three weeks before enrollment. The tumors ranged from 1 to 11 cm in diameter; more than half of the primary tumors were lung (31%) or renal (20%). Using computed tomography (CT) alone (n=51), ultrasound (n=2) or a combination of ultrasound and CT (n=8) to guide placement, cryoprobes were introduced through a skin nick. Most

EXPERT INSIGHT Scott Okuno, MD Consultant, Department of Medical Oncology, and Professor of Oncology, Mayo Clinic, Rochester, MN

he article by Callstrom et al is a prospective, multi-institutional study demonstrating the safety and efficacy of cryoablation of bony metastatic disease for decreasing the pain scores of patients with solid tumors. Patients with advanced cancers often have symptomatic bone metastases that have failed other local therapies such as surgery and RT. Additionally, systemic options to control pain with chemotherapy and/or opioids are not

adequate. There is a need for more effective palliative options. In this study, Callstrom et al reported on the use of cryotherapy for symptomatic bone metastasis and followed patients for 24 weeks assessing their pain scores and narcotic use. They treated 61 patients with a variety of solid tumors. The average pain score decreased over the length of the study, with 67% having a decrease of 2 or more in their pain score. There were

patients were treated in a single session. The average treatment time was 129 minutes (range 50–210), and involved a freeze/passive thaw/freeze cycle. One of the benefits of cryoablation is that the ice ball formed by the probe can be tracked with imaging devices. A study coordinator interviewed patients before and after treatment, inquiring about pain levels and use of analgesics. Before cryoablation, the mean score for worst pain in a 24-hour period was 7.1 out of 10. At one, four, eight and 24 weeks after therapy, the mean scores for worst pain were 5.1, 4.0, 3.6 and 1.4 out of 10, respectively ((P<0.0001). Use of pain medication

decreased and quality of life also improved. Average pain scores, the mean of which was 4.7 before therapy, improved as well, reducing to 3.5, 2.6, 2.1 and 0.9 at weeks 1 ((P<0.0003), 4 (all remaining, P<0.0001), 8, and 24, respectively. There was one major complication reported: osteomyelitis at the site of ablation. Results appeared recently in Cancer (2013;119:1033-1041, PMID: 23065947). Matthew R. Callstrom, MD, PhD, of the Department of Diagnostic Radiology, Mayo Clinic, and his colleagues concluded that image-guided cryoablation is a safe and effective palliative treatment for bone cancer pain.

‘Like any good study, we are left with more questions than answers, which will stimulate future research.’ patients (14%) who had recurrent pain that was equal to or greater than baseline. Only one patient had a complication (infection). Where does cryoablation of bone fit into the armamentarium of palliative options? This study demonstrates that it is a safe and useful option for patients with symptomatic bony metastasis with solid tumors where a percutaneous approach is reasonable. But like any good study, we are left with more questions than answers, which will stimulate future research. Is cryoablation “better” than radiofrequency for bone lesions? What is the most cost-effective way to treat bone

metastasis? When should we use cryoablation versus RT (in this study only 62% of patients received prior RT)? Does cryoablation work on hematologic bone metastases (this study only treated solid tumors)? Are there certain solid tumor histologies where cryoablation is most or least effective (this study had 20 different histologies)? What is the best bone location for cryoablation (in this study 77% of lesions were in the rib or iliac/ischium/public bone)? Clearly more work for all of us to do. Dr. Okuno reported no relevant financial disclosures.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Sequential Arsenic Trioxide Effective for Relapsed APL From Blood

clinical trial has found that sequential treatment combining arsenic trioxide (ATO) and autologous hematopoietic cell transplantation (HCT) is effective for patients with acute promyelocytic leukemia (APL) who have suffered relapse following conventional therapy. Patients with newly diagnosed APL treated with a combination of all-trans retinoic acid (ATRA) and chemotherapy generally experience long-term complete remission (CR), but approximately 20% of these patients relapse. ATO monotherapy has been relatively successful in

treating these patients. In an article published in Blood (2013 Feb 14. [Epub ahead of print], PMID: 23412094), Masamitsu Yanada, MD, of Fujita Health University School of Medicine in Toyoake, Japan, and his colleagues from the Japanese Adult Leukemia Study Group (JALSG) undertook a prospective trial, with active enrollment between 2005 and 2009, of APL patients with at least one relapse after standard treatment. Thirty-five patients, aged 20 to 64 years (median age 46), were enrolled in this Phase II study to evaluate the efficacy and feasibility of a sequential treatment of ATO followed by autologous HCT for patients with relapsed

EXPERT INSIGHT Mark Litzow, MD Consultant, The Department of Hematology, and Professor of Medicine, Mayo Clinic, Rochester, MN

he treatment of APL is a modern success story in the management of the hematologic malignancies. The use of ATRA, ATO, and anthracycline chemotherapy has transformed this disease from one of the poorest prognostic subsets of acute myeloid leukemia to one that has the highest success rate. Patients with low- and intermediate-risk APL can now be cured in more than 90% of cases. However, some patients may still relapse, particularly if they are in the high-risk subset, and alternative approaches to therapy are needed for these relapsed patients. Yanada and his colleagues from Japan report a small Phase II study evaluating the feasibility and benefit

of a sequential treatment where adult patients with hematologic or molecular relapse of APL received induction and consolidation therapy with ATO followed by AraC as a mobilizing agent to collect PBSCs. This was followed by autologous HCT. This study is the first to systematically evaluate this sequential treatment approach. The results demonstrate the safety and feasibility of this approach in most patients. Impressive results were achieved, with an estimated five-year OS of 77%. Multiple studies in the past have demonstrated that ATO is the best treatment option for patients with relapsed APL. In patients who achieve molecular negativity after

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APL. Twenty-six patients had hematologic relapse and nine patients had molecular relapse. The study protocol required a daily infusion of 0.15 mg/kg of ATO for 60 days or until CR. After CR, patients received two additional courses of ATO for consolidation, followed by chemotherapy, consisting of an intrathecal injection of methotrexate, high-dose cytarabine (AraC) and corticosteroids in preparation for a peripheral blood stem cell (PBSC) harvest and transplant. The sequential ATO treatment induced molecular remission in a majority of patients, and only three of the 35 patients initially enrolled were taken off the protocol for adverse

events related to the study. Twentyfive patients completed the consolidation and proceeded to PBSC harvest; 23 underwent autologous HCT. Although three suffered post-transplant relapse, there was no case of transplant-related mortality. With a median follow-up of 4.9 years, the five-year event-free survival was 65% and overall survival (OS) was 77%. The probability of failure-free survival had been estimated to be 59% at five years. These findings demonstrate the efficacy and feasibility of a sequential treatment combining ATO and autologous HCT for the small group of patients with relapsed APL after conventional therapy.

‘This study has immediate applicability to clinical practice and easily can be implemented at centers familiar with the treatment of APL.’ ATO reinduction chemotherapy, it appears that autologous HCT can provide a high rate of long-term survival with low treatment-related mortality. There are few reports of patients who have received ATO and then gone on to autologous HCT. Thus, the report by Yanada et al is an important contribution to confirm that this sequential approach to therapy in patients with relapsed APL is effective. This study has immediate applicability to clinical practice and easily can be implemented at centers familiar with the treatment of APL and either perform autologous HCT at the center or can refer patients to centers that do autologous HCT. ATO is approved for the treatment of relapsed APL. Autologous HCT in this setting is accepted in clinical practice and should be reimbursable in most

instances by third-party payers. A drawback of this study is the relatively small number of patients who were treated. Also, this was a single-arm study. Ideally, to prove the benefit of the addition of autologous HCT to ATO therapy, it would be best to perform a randomized trial of patients who receive ATO alone in repeated cycles versus those who achieve a remission with ATO and then proceed to autologous HCT. However, practically speaking, it is unlikely that such a trial would be feasible. The study by Yanada et al, then, is an important contribution to the literature, which helps support the feasibility and efficacy of this sequential treatment approach in patients with relapsed APL. Dr. Litzow reported no relevant financial disclosures.

Radiation Oncology in Palliative Cancer Care Stephen Lutz (Editor), Edward Chow (Editor), Peter Hoskin (Editor) See page 32

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Pazopanib for Metastatic Renal Cell Carcinoma? Possibly…. From the European Journal of Cancer

n international clinical trial reported that overall survival (OS) was not significantly different for patients with metastatic renal cell carcinoma (RCC) treated with pazopanib versus placebo. However, further analysis suggested that there may indeed be some benefit. The development of novel therapies targeting tumor angiogenesis has changed the treatment of patients with RCC. Pazopanib, an angiogenesis inhibitor, was employed in a Phase III trial that enrolled 435 treatmentnaive or cytokine-pretreated patients between 2006 and 2007 who were

randomized (2:1) to receive oral pazopanib (800 mg daily) or placebo. An earlier pivotal report on this trial ((J Clin Oncol 2010;28:1061–1068, PMID: 20100962), which was instrumental in gaining regulatory approval for pazopanib, found that the drug significantly improved progressionfree survival (PFS) versus placebo in patients with advanced and/or metastatic RCC (median 9.2 vs. 4.2 months; hazard ratio [HR], 0.46; P<0.0001). The present report, published recently in the European Journal of Cancer (2013;49:1287-1296, PMID: 23321547), offered additional analysis of the earlier clinical trial. By May 2010, 290 deaths had been

EXPERT INSIGHT Roxana Dronca, MD Senior Associate Consultant, Department of Oncology, and Assistant Professor of Medicine, Mayo Clinic, Rochester, MN

number of targeted therapies are currently FDA-approved or are being developed for treatment of metastatic RCC. Pazopanib is an oral agent that inhibits tyrosine kinases (TKs) associated with the vascular endothelial growth factor receptors 1, 2 or 3, platelet-derived growth factor receptors α or β, and stem cell factor receptor c-Kit. The FDA approved pazopanib in 2009 for patients with previously untreated advanced RCC and for patients who had progressed on cytokine therapy. Approval was based on the randomized Phase III study (VEG105192; NCT00334282) that demonstrated a statistically significant increase in PFS with pazopanib compared with placebo, with improvement in PFS seen in both untreated patients and in those who had received cytokine therapy ((J Clin Oncol 2010;28:1061-1068, PMID: 20100962). At the interim analysis, the primary end point (PFS) was met; however, the OS data were immature. In the final analysis of the VEG105192 trial, published by Sternberg and colleagues in the European Journal of Cancer, there was a nonsignificant

improvement in OS for pazopanib compared with placebo-treated patients (22.9 vs. 20.5 months; HR, 0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=0.224). The results of this study highlight a number of relevant issues in today’s rapidly changing treatment landscape. With the increased availability of novel therapies with promising clinical activity for patients with advanced malignancies, there appears to have been a rise in the number of studies that allow patients in the control arm to “crossover” and receive the experimental therapy after disease progression. Allowing such crossover is typically employed for patients’ benefit and not for formally comparing the outcome of interest. With more than half of the patients randomly assigned to the control arm receiving pazopanib upon progression via a parallel open-label extension study (VEF107769), the lack of consistent findings between PFS and OS could have been ascribed to this high rate of crossover, as well as employment of subsequent anticancer therapies after progression (66% of patients

reported, clinical cut-off was reached, and treatment and OS comparisons between the two arms commenced. In the placebo arm 100 patients (69%) died: 93 from RCC, three from serious adverse events (SAEs) while receiving placebo, two from other diseases and two from SAEs during the extension phase of the study. In the pazopanib group, 190 patients died (66%): 169 from RCC, 11 from SAEs while receiving pazopanib, one from an SAE after enrolling in the extension study as an exemption, and nine for other reasons. These results did not show a significant OS benefit with pazopanib treatment. Median OS was not statistically significant: 22.9 months in the

pazopanib group versus 20.5 months in the placebo arm. Cora Sternberg, MD, from the Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, and her co-authors suggested that a high crossover rate confounded the actual benefit to treatment by pazopanib. Patients with disease progression were permitted to receive open-label pazopanib. Patients in both arms of the study reported extensive use of other anticancer treatments. The authors reported that using statistical models that take these factors into account adjusts the results and suggests a benefit with the pazopanib treatment.

‘For malignancies such as RCC, for which sequential therapies with incremental clinical and survival benefit are continuously being developed, demonstrating an OS benefit becomes increasingly difficult.’ in the placebo arm vs. 30% in the pazopanib arm). In order to correct the treatment effect estimate from the intent-to-treat (ITT) analysis for bias introduced by crossover, the authors conducted post hoc exploratory analyses using inverse probability of censor weighting (IPCW) and rank-preserving structural failure time methodologies. These are two similar and previously used approaches to adjust for selective crossover in oncology. Interestingly, although the effect size was similar with the two methods, with an approximately 50% decrease in mortality with pazopanib, only IPCW analysis produced statistically significant results (HR, 0.504; 95% CI, 0.3150.762; two-sided P=0.002). In terms of safety, the AE profile at the final analysis was similar to that previously reported and there were no new safety signals or changes in the type, severity or frequency of AEs. OS remains the gold standard for oncology clinical trials and is considered by the FDA as the most reliable and preferred cancer end point to assess clinical benefit. Yet, there is no statistical standard on how to best analyze OS. The traditional methods of ITT

and per-protocol analysis rely on the assumption that randomization balances the study groups; however, this may not be true if patients crossover to the experimental drug or receive subsequent anticancer therapies after progression. For malignancies such as RCC, for which sequential therapies with incremental clinical and survival benefit are continuously being developed, demonstrating an OS benefit becomes increasingly difficult. Moreover, as recruitment for oncology clinical trials has become increasingly challenging and the number of promising agents has risen, more clinical trials allow unplanned crossover to experimental therapies, underscoring the need for revisiting our statistical methods for OS analysis. Pazopanib remains an active targeted agent with an acceptable safety profile in the first-line treatment of patients with advanced or metastatic RCC. Although no significant difference in OS was observed, this study highlights the importance of interpreting trial results in the appropriate clinical context. Dr. Dronca reported no relevant financial disclosures.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Single-Dose Radiation Effective for Cutaneous T-Cell Lymphoma From International Journal of Radiation Oncology, Biology, Physics

ingle-dose radiation therapy (RT) has proved as effective as multifractionated RT for patients with cutaneous T-cell lymphoma (CTCL). Tarita O. Thomas, MD, PhD, from Northwestern University’s Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues studied the charts of 58 patients (35 men, 23 women) presenting 270 individual lesions, whose disease was refractory to topical or other systemic treatment. These patients were given a single fraction

of palliative RT by the same radiation oncologist between 1991 and 2011. Results were reported in the International Journal of Radiation Oncology, Biology, Physics (2013;85:747-753, PMID: 22818412). Patient and tumor characteristics were compared, as was radiation dosage. The majority of the treatments (97%) were treated with 700 to 900 cGy. Lesions were treated with either electrons or photons. Among the 58 patients with CTCL, 47 had mycosis fungoides (MF); four had MF and lymphomatoid papulosis; three had cutaneous gamma/delta T-cell lymphoma;

EXPERT INSIGHT William Wong, MD Consultant, Department of Radiation Oncology, and Associate Professor of Radiation Oncology, Mayo Clinic Arizona

atients with CTCL who are refractory to topical and/or systemic therapy usually require repeated courses of palliative radiation. Most commonly used radiation regimens involve 20 to 30 Gy in 10 fractions. This study reviewed the records of 58 patients and the treatment outcome of 270 lesions. It showed that a single fraction of 700 cGy or more was highly effective in achieving local control of disease at a lower cost. In the study, several characteristics

of CTCL were associated with a lower local control rate, including large-cell transformation and tumor morphology, as well as lesions in lower extremities. This information is helpful in selecting patients for the single-fraction approach. Patients in this study were treated between 1991 and 2011. The authors did not describe whether planning computed tomography (CT) scan was available or used for patients with tumor stage disease. For tumor stage lesions, clinical

two had Sézary syndrome; one had MF and Sézary syndrome; and one had small/medium-sized pleomorphic T-cell lymphoma. The patients ranged in age from 24 to 97 years. The response to treatment was assessed as complete response (CR), a 100% reduction in lesion size (n=255); partial response (PR), a greater than 50% but less than 100% reduction in lesion size (n=10); and no response, a reduction in lesion size of less than 50% (n=1). There was an additional classification of PR CR, after a second singlefraction treatment completed the 100% reduction of the lesion (n=4).

Researchers found that 70% of the PR group had lesions located on a lower extremity. They speculated that these may have been more aggressive lesions, or that tumor hypoxia, due to peripheral artery disease, may have played a role in the response to radiation. The authors compared the singleversus a 10-fraction treatment, and calculated that the cost, in dollars as well as patient comfort and convenience, was significantly reduced using a single-fraction treatment. These results suggest the need for additional studies to determine an optimal RT regimen for refractory CTCL.

‘I do not feel that a randomized study comparing 3,000 cGy per 10 fractions to a single fraction of 700 cGy is needed in order to convince clinicians to use a large single fraction of radiation for palliative treatment in appropriately selected patients with CTCL.’ set-up and treatment planning could underestimate the extent of disease and potentially contribute to the lower local control rate that was observed. Planning CT scan would be helpful to determine the depth and lateral extension of the tumor lesions and reduce the chance of inadequate dose coverage. The result of this study is consistent with another published report using 800 cGy per two fractions. The excellent local control rate shown in this study is highly relevant and encouraging. I do

not feel that a randomized study comparing 3,000 cGy per 10 fractions to a single fraction of 700 cGy is needed in order to convince clinicians to use a large single fraction of radiation for palliative treatment in appropriately selected patients with CTCL. This regimen would be more convenient for patients, many of whom are debilitated, at a significantly lower cost. Dr. Wong reported no relevant financial disclosures.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Recurrence Examined After Negative Sentinel Lymph Node Biopsy From JAMA Surgery

review of recurrence and survival rates of patients whose melanoma had recurred despite having received a negative sentinel lymph node biopsy (SLNBx) identified certain characteristics, such as older age and male sex, which increased the risk for recurrence. Edward L. Jones, MD, and coauthors from the University of Colorado, Denver, reviewed results from 619 patients who had undergone successful SLNBx at the University of Colorado between 1996 and 2008. Results were published in JAMA Surgery

(2013 Jan 16:1-6. doi: 10.1001/jamasurg.2013.1335. [Epub ahead of print], PMID: 23325294). Of this group, 104 had a positive result and were excluded from the study. The remaining group (n=515) had an initial negative result, including five patients who were treated twice for two separate lesions, resulting in a study cohort of 520 patients. Median follow-up was 61 months (range, 1-154 months). The authors identified 83 (16.0%) patients who originally had a negative SLNBx result but later had a recurrence of disease. The recurrence group was chiefly older (mean age, 56.8 vs. 48.6 years; P<0.001),

EXPERT INSIGHT James Jakub, MD Consultant in General and Gastroenterological Surgery, and Associate Professor of Medicine, Mayo Clinic, Rochester, MN

LNBx is not the panacea, but this manuscript supports its current role in clinical practice: specifically, offering SLNBx to appropriately selected patients with melanoma, and observing the vast majority of nodenegative patients. A negative SLNBx is not intended to guarantee cure, but in general this population has an excellent prognosis (91% five-year overall survival [OS] in this study), and the procedure is reliable with few in-basin recurrences. Jones et al reviewed their incidence and patterns of recurrence in patients with a negative SLNBx. Their study is limited by its retrospective design but is strengthened by its long follow-up, which is more than adequate to detect this event. Their population represents a relatively low-risk group (median Breslow, 1.4 mm) and thus has a low incidence of occult regional nodal involvement (16.8%). Nodal status is a powerful prognostic marker, as reflected in this series with a five-year OS probability of 91% for patients with a negative SLNBx. Of SLNBx-negative patients, 16% suffered a recurrence, with one-fourth

of these in the same basin. H&N SLNBx has, in general, a higher FNR and failed mapping. We cannot tell from this series if the H&N cases primarily explain their high incidence of failed mapping (6.2%) nor of the 35 recurrences in the 110 H&N negative SLNBx patients that recurred, how many were in-basin events. Not surprisingly, poor prognostic markers were associated with a higher incidence of regional nodal recurrence. This potentially reflects the fact that the FNR is the same regardless of Breslow thickness and ulceration and that the prevalence of the disease changes with more aggressive lesions. FNR can result from the surgeon not identifying and removing the correct SLN (as suggested by fewer SLNs harvested in the recurrence group in this study) or the disease not being identified pathologically despite the correct lymph node being removed. Simply stated, the harder one searches for occult disease the more frequently it will be found. The pathologic evaluation of the lymph nodes in this study evolved over time (as it has in most centers) and it would

male (75.9%; P<0.001) and had deeper than average lesions (mean Breslow thickness, 2.7 vs. 1.8 mm; P<0.01). The most likely site of recurrence was the head and neck (H&N) region (42.2%; P<0.001). Ulceration in primary lesions was more likely present in those with recurrent disease (32.5% vs. 13.5%; P<0.001). These results confirm older studies that examined rates of melanoma recurrence. In this group, 40 of the 83 patients with recurrence died (48.2%). The new tumors were reported at the original local (19 patients), in-transit (12 patients), regional (21 patients) and distant (26 patients) sites.

Only 21 of the 520 patients with a negative SLNBx experienced a recurrence in the sampled draining nodal basin, yielding a false-negative rate (FNR) of 4%, which is consistent with earlier studies. The incidence and prevalence of melanoma are increasing. Although five-year survival continues to improve (93% in 2012 vs. 82% in 1975), clinicians still rely on SLNBx results as the primary predictor for survival. The authors noted that greater understanding about sampling techniques and other factors likely to affect recurrence may influence treatment and affect follow-up strategies.

‘This study adds to the body of evidence in melanoma that in patients with micrometastasis, removing this small-volume disease before it becomes clinically evident improves survival.’ be interesting to see if the authors’ FNR (in-basin recurrence) was influenced by this practice change and decreased with time—although this study is likely underpowered to determine this. The FNR with negative SLNBx was historically described based on histologic confirmation (SLNBx followed by complete lymph node dissection). Because the procedure has been shown to be reliable, a complete lymph node dissection is no longer offered to the SLNBx-negative group. As a result, this study looked at clinical recurrence as a surrogate marker. Unlike in breast cancer, where leaving behind occult micrometastatic disease most often does nott result in clinical presentation of regional nodal recurrence, melanoma is much less forgiving, and almost all nodal metastasis will show itself in relatively short order. Therefore, despite this group of patients not having a complete lymph node dissection and pathologic confirmation of the FNR, we can be fairly confident the majority of nodal disease surgically left behind recurred, and this provides a good sense of the true FNR. Because you cannot miss disease in patients who do not have it, the FNR is based only on those with disease (positive nodal disease in this series), not

the entire cohort. As a result, the FNR is calculated as false-negatives divided by the sum of the true-positives and false-negatives. For this series, despite the in-basin recurrence rate being a very respectable 4%, the FNR as calculated above equals 16.8% (21 false-negatives/104 true-positives + 21 false-negatives). Even if the FNR is constant, the in-basin recurrence rate will fluctuate by the prevalence of disease. Two extreme examples demonstrate this point: If the incidence of nodal disease in the lowest risk group was zero, you could open and close the surgical field without ever removing a lymph node and have no in-basin failures. If the prevalence was 100%, the in-basin failure rate would be 16.8% in this series. I agree with the invited editorial that accompanied the article, by Jan Wong, MD, of East Carolina University in Greenville, NC, that this study adds to the body of evidence in melanoma that in patients with micrometastasis, removing this small-volume disease before it becomes clinically evident improves survival. Dr. Jakub reported no relevant financial disclosures.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Circulating Tumor Cells Useful Biomarker of Neuroendocrine Tumors From the Journal of Clinical Oncology

esearchers have shown that circulating tumor cells (CTCs) are a useful prognostic biomarker for overall survival (OS) and progression-free survival (PFS) in patients with neuroendocrine neoplasms (NENs). With advances in the treatment of NENs, defining prognosis has become a more pressing concern. Currently, tumor grade is the standard method, but the heterogeneity of the tumor is not well represented by a small biopsy sample. Similarly, over time, the tumor will evolve, and this cannot be reflected by biopsy. Another possible

prognostic marker for NENs is chromogranin A (CgA), an acid glycoprotein, but it is not specific to NENs. In the present study, Mohid S. Khan, MD, of the Royal Free Hospital, London, and his colleagues sought to find an inexpensive, minimally invasive test that would provide a reliable prognosis for PFS and OS in patients diagnosed with NENs. Patients with measurable metastatic NENs (N=175) were recruited between 2009 and 2011. All had liver metastases. The majority had grade 1 or 2 tumors, and 102 of them previously had received anticancer therapy. Patients had been diagnosed a median

EXPERT INSIGHT Michaela Banck, MD Consultant, Department of Medical Oncology, Mayo Clinic, Rochester, MN

TCs are currently under investigation for prognostication and prediction of therapeutic efficacy in multiple tumors, including breast, prostate and colon cancer.1 Khan et al presented the first study to investigate the prognostic value of CTC in metastatic NENs.2 NENs are a heterogeneous group of malignancies that can arise from neuroendocrine cells of the bronchopulmonary system as well as the entire gastrointestinal tract, including the pancreas, duodenum, small bowel, colon and rectum. A common denominator for all types is that in the metastatic state, the tumors are incurable and systemic therapies, with the exception of that for pancreatic NENs, have not been shown to increase OS. The most widely used and recognized features to predict biological behavior of NEN include histologic grading, markers of proliferation (mitotic counts of Ki67 index), organ site and tumor staging, as reflected in the 2010 World Health Organization classification of NENs. Kahn et al proposed the addition of the presence of at least one

CTC per 7.5 mL blood to the list of poor prognostic features in metastatic NEN. The study was small considering that it used a highly heterogeneous population of NENs (175 patients divided between a 90-patient training set and an 85-patient validation set from across five different types of NENs). The assay used for detection of CTC, the CellSearch system, was FDA-approved for the detection of CTC in breast cancer in 2004 and, later, for prostate and colon cancers. Although it remains to be seen whether detection of CTC with this specific method will be added to the routinely performed clinical evaluation of patients with NEN in the near future, this study clearly has imminent implications beyond the determination of prognosis for NEN. CTC might provide information about tumor grade beyond that obtained from a single biopsy. It becomes increasingly evident that tumors consist of heterogeneous populations of malignant cells and that a single biopsy might not reflect the whole spectrum of tumor grades present in a given individual.

of 26 months (range, 1-134 months) before the sampling. Median followup after CTC testing was 12.6 months (range, 5-28 months). The study was broken into two cohorts. The first group of 90 patients was used as a training set to determine an optimal prognostic CTC threshold. Of the patients, 51% had no CTCs, and 49% had at least one. After comparing the CTC numbers (which ranged from 0 to 3,731) with tumor grades, tumor burden, Eastern Cooperative Oncology Group performance status (ECOG PS) and baseline CgA (≤120, >120), and patient OS and PFS data, the presence of at least one CTC per 7.5 mL of blood was associated

with worse PFS and OS (hazard ratios, 6.6 and 8.0, respectively; P<0.001). The identical tests were performed in a second validation set of 85 patients. The authors noted in their report, which appeared in the Journal of Clinical Oncology (2013;31:365372, PMID: 23248251), that although longer follow-up periods may refine results, initial analysis indicates that the presence of at least one CTC per 7.5 mL in patients diagnosed with NENs was consistently a reliable indicator of disease progression in both the validation sets. The researchers concluded that use of this test can result in more informed patient management.

‘Circulating tumor cells might provide information about tumor grade beyond that obtained from a single biopsy.’ Studies in patients with breast cancer have shown that CTCs mirror the population of different tumor cell clones present in a given patient and therefore could represent an alternative to repeated invasive biopsies.3 However, whether such mirroring also can be found in NENs remains to be demonstrated. CTCs also are candidate predictive biomarkers of therapeutic responses. The Southwest Oncology Group 0500 trial, for example, investigates whether treatment decisions can be made based on blood levels of tumor cells in women with metastatic breast cancer receiving chemotherapy.4 The vision is to identify patients who are failing a given therapy at an early stage and switch to a more effective treatment as quickly as possible. In pancreatic NEN, two drugs, sunitinib and everolimus, increase timeto-tumor progression, but there is currently no way to predict response or to decide at an early stage during treatment whether or not a patient benefits from the treatment, which is often associated with significant side effects. Whether a simple blood draw analyzing the number of CTCs at an early point during treatment could predict efficacy or resistance toward these drugs

remains to be determined. Additionally, CTCs’ promise not only lies in simply counting their numbers. Technologies allowing single-cell DNA and RNA sequencing,3 for example, and determination of copy number variations of cancer genes are currently being developed. In summary, this study by Khan et al is an exciting first step toward harnessing the power of “liquid biopsies” for patients with NENs. Dr. Banck reported no relevant financial disclosures.

References 1. Balic M, Williams A, Lin H, et al. Circulating tumor cells: from bench to bedside. Annu Rev Med. 2013;64:31-44, PMID: 23092385. 2. Khan MS, Kirkwood A, Tsigani T, et al. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J Clin Oncol. 2013;31:365-372, PMID: 23248251. 3. Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580-584, PMID: 23372014. 4. Southwest Oncology Group. http://swog. org/visitors/newsletters/20090805/ s0500.htm. Accessed April 18, 2013.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Computed Tomographic Colonography Good First-Line Dx Test From the Lancet

he use of computed tomographic colonography (CTC) on patients with symptoms of colorectal cancer (CRC) generated more follow-up tests than colonoscopy, but the overall costs between the two modalities were similar in a recent study. Researchers concluded that more widespread adoption of CTC is justified as long as adequate training and best practices are adopted. Symptomatic men and women over the age of 55 years were enrolled in a comparison study based in the United Kingdom in which patients were randomized (1:2) to receive either CTC or colonoscopy. Common complaints

included a change in bowel habits and rectal bleeding. Wendy Atkin, PhD, of the Imperial College of London, and her co-authors reported the rates of additional colonic investigative studies following CTC or colonoscopy. Results were published recently in the Lancet (2013;381:1194-1202, PMID: 23414650). In all, 533 patients consented to the study and were randomly assigned to receive CTC; 1,047 patients received colonoscopy. Of the CTC group, 160 (30.0%) were referred for additional colonic investigation; 86 patients (8.2%) in the colonoscopy group were similarly referred. The authors found that referrals in 83 (15.6%) patients receiving

EXPERT INSIGHT Joel Fletcher, MD Consultant, Department of Radiology, Mayo Clinic, Rochester, MN

he Lancett recently reported results of a prospective, randomized study of CTC versus colonoscopy for patients with symptoms suggestive of CRC. Prior studies from the United States, including the National CT Colonography Trial, have shown that in asymptomatic screening populations, the sensitivity of CTC for large polyps and cancers is similar to colonoscopy.1 However, to better understand the costeffectiveness of CTC, it is important to understand the acceptance of CTC, the diagnostic yield for advanced neoplasia and the number of downstream tests it generates compared with colonoscopy. The primary aim of this U.K. multicenter study was to look at the number of downstream tests generated by CTC compared with colonoscopy, with secondary aims to compare diagnostic yield and complication rates. More downstream tests would be anticipated for CTC because all colorectal polyps and cancers should be removed or biopsied at subsequent endoscopy, whereas colonoscopy will generate additional tests only after incomplete or inadequate examination. The study was undertaken in 21 U.K. teaching and general hospitals with

patients referred by their family physician. Patients had symptoms suggestive of CRC. A colonoscopy or barium enema was ordered per usual practice in the U.K., and participating patients were randomized to receive either CTC or colonoscopy/barium enema. Results of the CTC versus barium enema study are reported in a companion article. CTC was performed according to established techniques, except that exams could be performed on older scanners than those recommended by the American College of Radiology practice guidelines,2 and oral tagging (to diminish false-positives due to stool) was not routinely given. Unlike the National CT Colonography Trial, participating radiologists did not have to pass a proficiency test, but rather those with less experience attended a two-day instructional course. Investigators found that the number of downstream tests generated by CTC was much more than that generated by colonoscopy (30% vs. 8.2%). Reasons for downstream tests following CTC included suspected large polyps or cancer (16%), small colorectal polyps (9%), inadequate exams (3%) and extracolonic findings (10%). Eleven percent

CTC were made to confirm CRC or because of a large (≥10 mm) polyp; among those receiving colonoscopy, these referrals numbered 12 (1.1%). For polyps less than 10 mm in size, the patients receiving CTC had 49 (9.2%) referrals; among the patients having colonoscopies, there was only one (0.1%) referral. Referrals due to clinical uncertainty were made in 28 (5.3%) patients from the CTC group and 73 (7%) from the colonoscopy group. The clinical uncertainty was largely from an inadequate examination caused by cutting the original test short due to patient discomfort. In this study, adverse effects were rare in both groups. The cost difference

was insignificant when the higher price of the colonoscopy was compared with the price for CTC plus the additional tests that were ordered more frequently. The researchers noted, “Neither method shows clear superiority in terms of cost-effectiveness for detecting colonic lesions.” CTC is less invasive than colonoscopy and is an appropriate first-line diagnostic tool for patients who present with symptoms of CRC. The authors noted that establishing best-practice techniques may decrease the number of patients referred for follow-up testing and would lead to increased physician comfort in using CTC for cancer diagnosis.

‘This multicenter U.K. study shows that CTC detects advanced neoplasia with similar yield to colonoscopy in symptomatic patients, but will generate more downstream exams.’ of colonoscopies were incomplete, with only 7% of these patients referred for subsequent testing, but only 1% of colonoscopy patients needed a further test to confirm a suspected polyp or cancer. Overall, additional diagnostic testing of the colon was performed three times more often in the CTC arm. About onethird of downstream endoscopies after CTC were for large polyps and cancers, but it is unclear how often additional investigation was for polypectomy and biopsy of smaller polyps, or was performed due to a false-positive finding. Importantly, the detection rates of CTC and colonoscopy for colorectal polyps and cancer were similar. Additionally, complications in each study arm were rare. In the companion article involving randomization with barium enema, investigators found that CTC performs better than barium enema, and in earlier published work in their cohort, found that CTC was preferred over colonoscopy. In summary, this multicenter U.K. study shows that CTC detects advanced neoplasia with similar yield to colonoscopy in symptomatic patients, but will generate more downstream exams. Unlike prior U.S. studies in asymptomatic screening populations, this U.K. study examined a symptomatic patient population, did not use fecal

tagging in CTC to minimize false-positive results and did not require radiologist proficiency testing. Although this study will inform the cost-effectiveness analysis comparing CTC and colonoscopy in symptomatic patients, it does not address compliance with colorectal screening recommendations or costeffective comparisons in asymptomatic screening patients. Apart from the wider public policy debate, however, the implications for patient care are clearer: Patients with worrisome symptoms for CRC should be encouraged to undergo colonoscopy. If a patient is unwilling to undergo colonoscopy, a physician can feel comfortable asking if the patient will undergo CTC instead. The patient might just say, “Yes.” Dr. Fletcher reported not relevant financial disclosures

References 1. Johnson CD, Herman BA, Chen MH, et al. The National CT Colonography Trial: assessment of accuracy in participants 65 years of age and older. Radiology. 2012;263:401-408, PMID: 22361006. 2. American College of Radiology. ACR practice guideline for the performance of computed tomography (CT) colonography in adults, 2009. http://www.acr.org/~/media/ ACR/Documents/PGTS/guidelines/CT_ Colonography.pdf.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Vogl, NY...

For High Risk of Lung Cancer: “Screen, Baby, Screen” NEJM article gives new formula for risk calculation EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

he Feb. 21 issue of The New England Journal of Medicine (NEJM) contained a complicated article, chock full of statistical calculations, to demonstrate a new, improved calculator of risk for developing lung cancer. The new tool was based on lung cancer incidence in the control group in a negative study of postanterior chest radiographic screening for lung cancer called the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.1 In this model, which is available free online as a Microsoft Excel spreadsheet (www. brocku.ca/cancerpredictionresearch), risk is defined based on age, body mass index, degree of education, the presence or absence of chronic obstructive pulmonary disease, the presence or absence of a personal history of cancer, a family history of lung cancer, race (ethnicity), whether the subject continues to smoke, average number of cigarettes smoked per day, years of smoking and

years since quitting smoking. The first author, Martin Tammemagi, PhD, of Brock University in St. Catharines, Ontario, Canada, tells me he is developing an iPhone app to calculate the six-year risk for lung cancer using his model. He chose the six-year risk as his end point because he wanted to apply the model to the published data from the National Lung Screening Trial (NLST), and compare screening selection using the model with the entry criteria of the NLST in the PLCO population. The NEJM M article shows that his model is the winner, having allowed the detection of more cancers. The article, being mainly statistical and mathematical, is hard reading for clinical oncologists. Regardless, the point is that sophisticated models are available to estimate lung cancer risk for individuals, and we can use them to select whom to screen. The large survival benefit from screening in the NLST trial (see summary box below) suggests that cigarette smokers should now fall into three classes: those whose risk is clearly high enough to justify screening (risk similar to the subjects entered into the NLST); those whose risk is very low and for whom screening is very unlikely to discover many curable, asymptomatic cancers because they are unlikely to occur at all; and those in between in whom it is

We know the benefits of screening outweigh the risks in populations of risk similar to the NLST population because of the large and almost immediate survival benefit!

Summary of National Lung Screening Trial Published in 2011 26,725 subjects per arm assigned to postanterior chest radiographs or three annual low-dose chest CT scans. Eligibility: age 55-74; >30 pack-years tobacco exposure; if stopped smoking it had to be <15 years before entry. Findings: • 7% reduction in death from any cause for screened subjects; • about 40% of the excess deaths in unscreened subjects were not assigned to lung cancer as the cause; • 20% reduction in deaths attributed to lung cancer as the cause; • 4% of lung cancers in screened population were detected between screens, suggesting that more frequent screening might help. Limitations: One-third of cancers in the screened population were detected after screening stopped; 50% of these were beyond stage IA at diagnosis versus 20% detected during screening.

still reasonable to study whether or not screening helps. We know the benefits of screening outweigh the risks—summarized below—in populations of risk similar to the NLST population because of the large and almost immediate survival benefit! This benefit clearly exceeds any short-term risks for the population studied, and probably far exceeds any longterm risks for the population, although this needs to be demonstrated. In 2013, the issue is not how to find the most lung cancers at reasonable monetary cost—the task Dr. Tammemagi set for himself—but rather how best to define a population for whom we can be confident that the benefits of screening—detection of small cancers that have not yet metastasized and that can be cured by resection—outweigh the risks and toxicities. For the moment, until a better model is available, I suggest that we use Dr. Tammemagi’s model, rather than NLST entry criteria, to define that population based on lung cancer risk.

How To Define the Risk of the NLST Population Looking at the curves in Figure 1 of the NLST paper, the control group developed about 900 cases of lung cancer in six years.2 If one deletes the initial rapid rise in cases from initial screening chest radiographs that detected pre-existing cancers in the control group in the first few months (about 100 cases), then the incidence of lung cancer is about 800 cases among about 26,000 subjects, a six-year incidence of 3.1%. Dr. Tammemagi was unable to provide me with a risk profile of the NLST cohort, so for the moment I would suggest immediate screening in any smoker or ex-smoker with a six-year calculated “Tammemagi risk” of 1.5% or higher—half the actual six-year incidence in the NLST control group screened with chest radiographs from the NEJM M graph. If I knew the risk profile of the NLST population (the risk of each quintile), I would favor screening anyone with a risk above that of the lowest 20% (quintile) of NLST patients, which is an arbitrary but reasonable cutoff. I suspect that the subjects included in NLST probably vary a lot in annual risk of lung cancer. It seems likely that screening all risk levels represented in NLST would be too broad, whereas including only the highest 50% might be too restrictive and exclude many who benefit from screening. I chose 80% as a compromise. Certainly, other cut points are reasonable.

Details and Limitations of the Tammemagi Model Dr. Tammemagi’s calculator reflects some of the complex influences on the incidence of lung cancer. As an ex-smoker ages, his risk for developing lung cancer increases with increasing age, but decreases as time from exposure to tobacco lengthens. Dr. Tammemagi has not formally analyzed the model for which effect predominates, but in trying out different scenarios in the model, it seems that the increasing risk for developing lung cancer with increasing age either just balances or overcomes the reduction in risk from more years of smoking cessation. Unfortunately, the “incidence of lung cancer” on which Dr. Tammemagi’s model is based is heterogeneous. Some of the lung cancers in the PLCO control group were discovered based on symptoms of locally advanced disease or metastatic disease. Some of these advanced cancers were small, “curable” lung cancers several years earlier, which is when one would hope to detect them in a screening program. Therefore, the absolute level of risk for finding a lung cancer on a screening CT [computed tomography] scan at any given age estimated by the model is falsely low, because detectable small cancers were only counted years later, when they were large and incurable. Small peripheral lung cancers are almost always asymptomatic. This means risk levels will be higher in a CT screened population, because these cancers will be found earlier, elevating the annual risk early on. The risks will rise annually, especially in those who continue to smoke, as more and more small cancers develop and are discovered. By contrast, I suspect a large number of cancers in the PLCO control group were found incidentally outside of a formal lung cancer screening program because of findings on chest radiography or CT scans done for some other reason. A busy thoracic surgeon in New York estimates that 80% of his patients with operable lung cancer have their masses found incidentally, a process I suggest should be termed “unplanned screening.” For instance, most adults in New York presenting to emergency departments with abdominal pain get CT scans of the abdomen and pelvis that include the lower halves of both lungs. Similarly, many patients with shortness of breath, chest pain, tachycardia or mild hypoxia presenting to emergency departments get CT angiograms of the chest looking for pulmonary emboli. see VOGL, NY, Y page 22

CURRENT PRACTICE

VOGL, NY continued from page 21

Any lung masses found on these studies should receive thorough evaluations.

The Relevant Risk To Determine Is That of Developing a Small, Curable Non-Small Cell Lung Cancer! In deciding whose risk is sufficiently high to justify the costs and risks of screening CT scans and nodule evaluation, what we really need to know is

CLINICAL ONCOLOGY NEWS • APRIL 2013 • CLINICALONCOLOGY.NEWS

the risk of carrying a small, but detectable, “non-small cell” cancer curable by resection or stereotactic radiation. The risk of carrying a large, rapidly growing imminently lethal cancer is not relevant, nor is the risk of developing a “small cell anaplastic” cancer or a small cancer with metastases, because we can do little about these. Similarly, the risk of carrying a cancer invading the large vessels, the mediastinum, the carina or the spine is not relevant to decisions on screening. Happily, we do have a large available series of subjects in which we can determine risk factors for developing a small,

resectable non-small cell lung cancer: the CT-screened cohort in the NLST, 26,000 strong, with one prevalence and two incidence scans for each subject. I suggest Dr. Tammemagi use this cohort to create a risk model for the end point of developing a small, resectable nonsmall cell lung cancer. These characteristics predict a high likelihood of cure by resection or high-dose local irradiation. I suggest that any current or former smoker with a risk for carrying such a nodule above the 20th percentile of the NLST population be screened annually. Subjects below this risk level may well

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enter it as they age, especially if they continue to smoke, so the decision not to screen will need to be revisited annually. Expert panels have convened and cautiously recommend CT screening for lung cancer because of fear that the risks are not all worked out.3,4 These positions have emphasized the large unknowns over the very important known factor: In NLST, annual lowdose chest CT scans produced a 7% reduction in all-cause mortality that begins within two years of screening initiation and continues to grow as long as screening is being done (only two years in the NLST). The excellent review by Memorial Sloan-Kettering Cancer Center pulmonologist Peter Bach, MD, et al cites two negative screening studies (DANTE and DLCST) as failing to corroborate the benefits of CT screening even in terms of lung cancer mortality (much less all-cause mortality), but each study is tiny compared with NLST, with a small fraction of the number of events in NLST to provide statistical power, and each has barely half the follow-up duration of NLST. It may be that these studies included patients at lower risk for developing lung cancer than NLST, making it harder to demonstrate an advantage for CT screening. It would be wonderful if Dr. Tammemagi applied his model to the populations in all three studies so we could compare them in terms of their risk distribution. He writes that he would be pleased to do so if he can get the necessary data (personal communication). Despite the large reduction in overall mortality, committees of experts are concerned with risks from radiation and risks from biopsies and evaluation of the discovered lung nodules, most of which proved not to be cancers. Again, I argue that if these risks were important, then we would not have observed the huge benefit in overall mortality in the first few years, when all of the toxicities of evaluating suspicious lung lesions would have occurred. Late induction of cancers by the screening x-rays may take years to develop, and cannot yet be estimated. That is why screening chest CT scans should always employ a low-dose technique, and why screened cohorts— in NLST, other studies or outside of any study—should be followed long-term for radiation-induced cancers. One should be cautious applying the NLST results to lower-risk populations, in which the benefits will be diluted by more subjects who can only derive toxicity because their risk for developing lung cancer is so low. One should, of course, avoid sloppy work and dangerous procedures in the evaluation of lesions detected by CT screening. Since most of the subjects will never develop lung cancer, it would be a pity to kill or severely injure someone looking for a lung cancer he will never have!

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • APRIL 2013 • CLINICALONCOLOGY.COM

Suggestions for Study: Those Whose Risk Is Comparable to That of the NLST Population: The Group That Should Definitely Be Screened Now The obvious first question is the frequency of screening. This is harder to study than it sounds, since the usual algorithm for a positive CT scan in NLST (a nodule >4 mm, found in about 25% of subjects on the first CT) is a repeat chest CT scan in three months—essentially another screen. In my experience, this is often followed by other CT scans at intervals of less than one year. Thus, if one were to attempt randomization to screens at frequencies less than or greater than one year, a large proportion of each group would actually have very frequent scanning, making the comparison difficult by making the groups similar to one another. By contrast, it would be simple to randomize those with a negative initial screen to follow-up screens at twoyear intervals rather than one year. I believe that this should be done, but with very close attention to the incidence of advanced cancers in the group assigned to less frequent screening, with the datamonitoring committee not waiting for a mortality difference to close the study if a greater number of advanced cancers are found among those assigned to less frequent screening. It would also be simple and valuable to randomize those with positive or suspicious screens to more aggressive versus less aggressive algorithms of evaluation, based on their patterns of tumor growth and change in radiographic density. How to evaluate a positive screen was not addressed in NLST, and data were not collected on how this was done. Data on cost, toxicity and complications should be collected as well as stage of cancers detected and mortality. Finally, we need to study how best to treat small, screen-detected cancers. The obvious options are lobectomy, wedge resection and stereotactic radiation. For appropriate candidates, the latter probably has the lowest morbidity and mortality, and may turn out to be cheaper despite the high cost of radiation equipment and planning, because hospitals, surgeons and operating rooms are not needed.

Suggestions for Study: Those Whose Risk Is Below the Threshold, but More Than Trivial The choice of any threshold for lung cancer screening is arbitrary at this point. For those with a negative initial screen, I think it is reasonable and necessary to compare screening at a lower frequency (every three to four years) with annual screening and also with no planned screening. Screening at lower frequency may still detect many of the more slowly growing cancers while they are still curable. As one applies CT screening to

Points Made in Vogl, NY… Y 2011 Editorial on the First NLST Publication CT screening for lung cancer is now the only cancer screening test shown to affect all-cause mortality. Because only three annual CT scans were done, when the risk continues and climbs for decades, much larger benefits than those observed in NLST are likely if screening continues beyond three annual CT scans—a projected absolute reduction in death of 1.6% after 10 annual screens. Eligibility criteria for NLST were primitive—more sophisticated risk models are available.

The major benefits of CT screening represent the biggest advance in the care of lung cancer since the first pneumonectomy for cancer in 1933.

Workup of positive screens needs to be standardized. Quality in performance and interpretation of CT scans is critical. Low-dose CT scans are relatively cheap—cost is that of two to three cartons of cigarettes!

Points in Current Article Smokers should be divided into three groups based on risk for lung cancer: 1. Those with risk comparable to subjects in NLST: All should be screened. Because survival benefit is quickly apparent and large, the benefits outweigh at least the immediate risks and probably the long-term risks. 2. Those with risk well below that common in NLST: We should study whether to screen and how often to screen in these subjects. 3. Those with quite low risk: Should not be screened until very sensitive and specific tests for lung cancer detection become available. Sorting for these groups should be by sophisticated lung cancer risk models: The best risk model would give the risk for a detectable but curable non-small cell lung cancer. Risk models based on populations with large percentages of patients presenting with symptomatic lung cancers underestimate the incidence of curable cancers at any given age because it may take several years for curable but detectable cancers to become symptomatic. By then they are usually incurable.

populations with a lower risk for developing a cancer, the relative risk for false-positives becomes higher, so the morbidity and occasional deaths from evaluation and treatment become harder to justify, as do the risks for second cancers related to radiation from the CT scans. The goal is to identify the risk level at which these curves cross, and avoid screening in situations in which we do more harm than good. Lung cancer screening tests that involve lower levels of radiation exposure than even low-dose chest CT scans should continue to be developed. These could be imaging tests, or variations on the so far unsuccessful efforts to screen for lung cancer based on sputum cytology, sputum analysis or blood tests.

move in and out of different care settings and institutions. My preference for the moment would be to leave the decision of when to stop screening very elderly smokers to the compassionate judgment of the treating physician. Should it turn out that CT screening for lung cancer becomes popular for very elderly individuals, perhaps the payers (mainly Medicare and Medicaid) should fund randomized studies, stratified by comorbidity, age and risk for developing lung cancer, that compare CT screening with observation for symptoms. The payers’ obvious interest would be in limiting cost by demonstrating limited benefit.

Do Not Study: When To Stop Screening

Final Thoughts: Screening Is No Substitute for Prevention of Nicotine Addiction and for Smoking Cessation

Studies addressing when to stop screening are superficially attractive, but have never been done in any setting to my knowledge. Beyond the obvious wisdom of not looking for an asymptomatic cancer in very sick patients with heart disease, lung disease, stroke and peripheral vascular disease, studying the continued benefits of lung cancer screening in very elderly populations will prove very difficult in terms of recruitment, definition of comorbidity, consent and followup as progressively frail elderly patients

None of the advantages of screening argues against programs promoting smoking cessation, both in screened and unscreened populations of smokers. There is no reason that smoking cessation efforts should not be coupled with CT screening among smokers; indeed, the concern engendered by the screening process may lead some smokers to stop. Lung cancer was a very rare disease before World War I, when tobacco companies gave our soldiers free cigarettes

in the trenches. Screening programs to detect small lung cancers and prevent early death from these cancers should in no way interfere with programs to prevent the pediatric disease that is tobacco addiction. If effective in preventing nicotine addiction, they should pay off manyfold in longer, healthier lives. CT screening for lung cancer remains the only cancer-screening test that has been shown to reduce all-cause mortality in any population—the demonstration of this benefit is a stellar achievement. The major benefits of CT screening represent the biggest advance in the care of lung cancer since the first pneumonectomy for cancer in 1933 by Evarts Graham, MD, at Washington University in St. Louis. Had screening CT scans been available in the 1950s, perhaps Graham’s own death from lung cancer could have been averted. We should rush to apply it to high-risk smokers in our communities before they develop their incurable lung cancers.

References 1. Tammemägi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med. 2013;368:728-736, PMID: 23425165. 2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409, PMID: 21714641. 3. Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 2012;307:2418-2429, PMID: 22610500. 4. Jaklitsch MT, Jacobson FL, Austin JH, et al. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg. g 2012;144:33-38, PMID: 22710039.

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

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The

CLINICAL ONCOLOGY NEWS • APRIL 2013 • CLINICALONCOLOGY.NEWS

Tumor Board

A Large Mass at the Small Bowel Mesentery Welcome to the May issue of The Tumor Board

his column is timely in that it coincides with the annual American Society of Clinical Oncology (ASCO) annual meeting in Chicago, May 31-June 4. In this issue, Samuel Szomstein, MD, the associate director of the Bariatric and Metabolic Institute at Cleveland Clinic Florida in Weston, Fla., submits the case of a patient diagnosed with a mesenteric mass, after umbilical hernia repair. Our invited oncology expert providing a “second opinion” is Chieh-Lin (Catherine) Fu, MD, the director of the Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic Florida. I hope our readers enjoy this issue. I welcome all opinions

and further comments on this topic. I also greatly welcome and encourage suggestions or submission of cases for future issues. Enjoy!

63-year-old man with a significant medical history of sleep apnea (on continuous positive airway pressure), hyperlipidemia, degenerative disk disease, and obesity with a body mass index (BMI) of 36 kg/m2 was referred to our service due to increasing discomfort from an umbilical hernia. The patient noticed the discomfort for several months. He denied any pain, nausea or vomiting, and had no change in bowel movements. His past surgical history included elbow surgery and a plantar fascia repair at age 58 and tonsillectomy at age 12. His mother had a stroke and his father had Parkinson’s disease and diabetes prior to his death. The patient is married with two children and reportedly was not sexually active. He denied smoking and occasionally drank wine. The patient denied weight loss, malaise or fevers. He also had not noted any blood in his stools or black stools, or any change in bowel habits. His skin was negative for lesions, rash and itching. He claimed not to suffer from prolonged bleeding, easy bruising or any swollen nodes. His medications included simvastatin, metaxalone for pain or muscle spasms (Skelaxin, King) and enteric-coated aspirin. On physical examination, the only finding was an incarcerated umbilical hernia, 2 inches in diameter, with no erythema, and slightly tender to palpation; bowel sounds were present with no changes in bowel habits. The patient also had lower-extremity swelling grade I/VI. In addition to management of the patient’s comorbidities for surgery eligibility, he was sent for electrocardiography (EKG) and chest x-ray (CXR) for suspected heart failure. A preoperative assessment was done and the patient was cleared for surgery, with complete blood count (CBC) and coagulation values within normal limits. His chemistry panel also was normal, except for mild elevated glucose. The EKG and CXR did not reveal any abnormality. The patient underwent open repair of the incarcerated umbilical hernia. A transverse incision was made inferior to the umbilicus. The subcutaneous tissue was divided. The hernia sac was reduced and excised. The incarcerated omentum was transected and the rest was reduced into the abdominal cavity. The defect was closed with PDS sutures and nonabsorbable mesh (8 cm in diameter). The umbilicus was closed and injected with local anesthesia. Ten days postoperatively, the patient arrived for a follow-up visit and complained of discomfort around the incision site, but denied pain. He also complained of clear drainage from the wound for 3 days after his surgery, which had since resolved. He currently had minimal pain and mild tenderness at the site. He had resumed his usual diet and activities and wanted to return to work. The patient denied fever, chills or malaise. From the follow-up exam, a small seroma was suspected with no overt signs of infection warranting drainage. Amoxicillin/clavulanic acid (Augmentin, GlaxoSmithKline) was prescribed secondary to incisional site findings. The patient was instructed to return for evaluation if fever or drainage from the

Conrad Simpfendorfer, MD Editor, The Tumor Board Director, Hepatobiliary & Pancreas Surgery Cleveland Clinic Florida Weston, Florida

wound appeared and was asked to return in two weeks for re-evaluation. Two weeks after the last visit, the patient returned complaining of umbilical pain of 8 on a scale of 0-10, and soreness. The duration of the pain was one week and constant. On physical exam, induration and some erythema at the surgical site were noted. The patient denied fever, chills or drainage. The patient was scheduled for abdominal ultrasound (US) with possible drainage of a suspected seroma and prescribed a second course of antibiotics. US was performed within the mid-abdomen and a complex collection was seen measuring up to 19 cm which was not well characterized. Additionally, when Doppler window was used, an arterial vessel was visualized transversing the collection. In discussion with the patient, it was decided to perform a second imaging evaluation with a computed tomography (CT) scan of the abdomen and pelvis. The abdominal induration was still present, and the eversion of the umbilicus was observed. Axial CT scan of the abdomen and pelvis before and after the administration of intravenous contrast was performed. A large mass was found, located at the small bowel mesentery. There was mild lateral displacement of the pancreatic head because of the large mesenteric mass, with no evidence of pancreatic ductal obstruction or asymmetric atrophy to suggest a primary pancreatic lesion (Figures 1 and 2). The mass also caused a mid-ileal loop to be closely apposed to the intra-abdominal wall, deep to the mesh graft repair without findings to indicate herniation. The latter was suspected to be the cause of the abdominal pain, where the mass pushed the small bowel against the mesh. There also was complete encasement of the superior mesenteric artery (SMA) and its branches, as well as the splenic vein, but with no evidence of occlusion. In addition to the mass finding, a symmetric infiltration of the subcutaneous tissues was noted at the level of the umbilicus extending inferiorly toward the pubis, suggesting infectious or inflammatory cellulitis. The appearance of the mass was suggestive of a lymphoma, although this was less likely due to the lack of significant retractile component. Differential diagnoses included metastatic disease, carcinoid, sclerosing mesenteritis and desmoid tumor.

Figures 1 and 2. CT scans demonstrate large mesenteric mass.

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CLINICAL ONCOLOGY NEWS • APRIL 2013 • CLINICALONCOLOGY.NEWS

Expert Opinion by Dr. Fu

T-guided biopsy of the mass was performed and three, 18-gauge core specimens were obtained. Histologic sections Director, showed malignant large pleomorphic lymDepartment of phoid cells surrounded by numerous small Hematologic lymphocytes, infiltrating the soft tissue. Oncology and Blood Disorders Immunostains revealed the atypical lymCleveland Clinic phoid cells expressed CD20, CD10 and Florida BCL-6, and lacked CD5 and cyclin D-1. CD3 was positive in numerous small unremarkable T-cells. CD21 was positive in a subset of malignant cells. A Ki-67 was positive in 60% of the neoplastic cells. MUM-1 was positive in rare malignant cells. Diffuse large B-cell lymphoma (DLCL) was diagnosed. Fluorescence in situ hybridization (FISH) for the MYC gene was negative. This patient was also sent for full-body fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT scan for staging and treatment strategy. In addition to the metabolically active mesenteric mass, a few additional nonmetabolically active retroperitoneal lymph nodes were noted. No other areas of increased metabolism were found. The patient had bone marrow aspiration and biopsy for staging with no evidence of lymphoma. Lactate dehydrogenase (LDH) was within normal range. DLCL is the most common subtype of non-Hodgkin lymphoma (NHL). Immunosuppression has been associated with the risk for NHL. Obesity also has been associated despite confounding factors.1 Although the 18-gauge core biopsies were adequate for diagnosis in this case, an excisional lymph node biopsy, if accessible, is recommended for morphology and architecture. Immunohistochemical stains, flow cytometry, and FISH for chromosomal translocations are ancillary tools necessary to characterize NHL. A germinal Chieh-Lin (Catherine) Fu, MD

Case Challenge OUESTION FROM MARCH ISSUE

67-year-old man had elective cholecystectomy with intraoperative cholangiogram for an episode of gallstone pancreatitis; during surgery, a thickened area was noted at the fundus that resembled impacted stones. The patient denied fever, chills, jaundice or significant weight loss. There was no significant past medical or surgical history. All preoperative labs were normal, as was a chest x-ray. Surgery was performed uneventfully and the patient was discharged home the next day. The pathology report returned four days later reported: • Invasive moderately differentiated adenocarcinoma of the fundus of the gallbladder, 2.7 cm in greatest dimension, infiltrating the entire thickness of the gallbladder wall and involving the surrounding soft tissue • Focal perineural invasion • No definitive evidence of vascular invasion • Cystic duct margin of resection free of invasive carcinoma • Cystic duct margin of resection involved by highly dysplastic epithelium

center NHL based on the CD10 and Bcl-6 positivity would suggest better prognosis than a post-germinal center. However, the MUM-1 would suggest post-germinal center and may be artifactual. Therefore other additional markers, such as GCET1 and FOXP1, which approximate gene expression profiling may be used for further correlation.2 This patient had stage IIA NHL based on involvement of several nodes on the same side of the diaphragm with extranodal extension infiltrating the mesentery without constitutional symptoms of weight loss, fevers or drenching night sweats. Based on the Revised International Prognostic Index (R-IPI), the prognosis is “good,” with a predicted four-year progression-free survival of 80% and an overall survival of 79%.3 The patient’s age is the only negative variable. Treatment is an anthracycline-based chemotherapy conventionally with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) and rituximab (Rituxan, Genentech).4 In retrospect, the patient’s weight masked the NHL while the incarcerated hernia was still likely the primary source of the abdominal pain.

References 1. Larsson SC, Wolk A. Obesity and risk of non-Hodgkin’s lymphoma: a meta-analysis. Int J Cancer. 2007;121:1564-1570, PMID: 17443495. 2. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphoma. Version 1.2013. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed April 1, 2013. 3. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109:1857-1861, PMID: 17105812. 4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med. 2002;346:235-242, PMID: 11807147.

Reply: Dr. Conrad Simpfendorfer

he patient was diagnosed with gallbladder cancer after laparoscopic cholecystectomy for biliary pancreatitis. The pathology reports a 2.7 cm invasive moderately differentiated adenocarcinoma of the fundus of the gallbladder. The tumor invades the entire thickness of the gallbladder wall and involves the surrounding tissues. The cystic duct margin is free of invasive carcinoma and the cystic duct lymph node is benign. Incidental gallbladder cancer is found in 0.33% of patients undergoing laparoscopic cholecystectomy.¹ The extent of tumor invasion indicated on the pathology report may indicate a need for re-resection. Gallbladder cancer is classified by the American Joint Committee on Cancer (AJCC) TNM staging.² This patient appears to have at least a T2 gallbladder cancer, and we would recommend a completion radical cholecystectomy and portal lymph node dissection. No definitive guidelines exist for imaging prior to surgery, although we recommend either multi-detector contrast-enhanced CT scan or contrast-enhanced magnetic resonance imaging scan. An FDG-PET can be ordered in selected patients suspected of having metastatic disease. Patients with low-stage (Tis or T1a) gallbladder cancers, where the tumor is limited to the lamina propria, can be treated with simple cholecystectomy. Cure rates for these tumors range from 73% to 100% in case series.³ For patients with tumor stage greater than T1a, an extended cholecystectomy is recommended. This requires the resection of at least a 2 cm margin of liver from the gallbladder bed. This patient should be re-explored and have a resection of the gallbladder bed and lymph node dissection. In patients who have had a re-resection of T2 tumors found incidentally at cholecystectomy, residual disease has been noted in 57% of patients. Lymph nodes have been reported to be involved in 31%, and the liver was involved in 10%.4 Re-resection significantly increases the chance of long-term disease-free survival in patients with T2 disease. In many series, five-year survival rates increased from 24%-40% to 80%-100% with re-resection.5

• Cholelithiasis

References

• Benign cystic duct lymph node

Arch Surg. 2009;144:441-447, PMID: 19451486.

American Joint Committee on Cancer Staging Manual, 7th Ed. Springer, New York 2010.

Arch Surg. 1996; 131:981-984, PMID: 8790169.

J Gastrointest Surg. 2007;11:1478-1486, PMID: 17846848.

Ann Surg. 2008;247:104-108, PMID: 18156929.

What would you do?

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

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

ncologists should not be surprised that the public is confused. Scarcely a month goes by when there is not some report suggesting an association between something we do, eat, breathe or touch and an increased risk for the development of cancer.1 Individuals with even a shallow understanding of the limitations of epidemiologic methodology and the use of statistical analysis in this area will likely appreciate the dangers inherent in any claims that a particular observation suggests a cause-and-effect relationship. However, it is uncertain that such understanding characterizes the population at large. It is also well recognized that the results of many such studies are unable to be replicated. Furthermore, results of a subsequently reported “negative” study may have greater difficulty being published in a journal of the same impact factor and almost certainly will generate considerably less interest in the lay press than the initial “positive” association. This concern about suggesting a relationship between some activity and the development of cancer is particularly problematic because this complex

constellation of cancer illnesses generates considerable fear among the public.2 And this fear is likely heightened when there are no known risk factors strongly associated with a particular malignancy or when early detection has not been shown to be an effective strategy to improve the odds for a favorable outcome. Under these conditions, the general public, and specific individuals who believe they are “at risk,” may focus on scientifically questionable reports as a strategy to reduce their own risk for developing the cancer in question. It is reasonable to question whether or not there is any real danger to connecting academic pronouncements in a peer-reviewed manuscript associating “X” cause with “Y” cancer based on a case–control study or a populationbased epidemiologic analysis. Furthermore, even if media reports fail to accurately reflect what the paper actually concluded—unfortunately, very often the situation—and makes a far stronger claim of a possible cause-and-effect relationship than the authors intended, what harm is done? There are several possible answers to this highly relevant question. First, in general, it is likely that these reports do not cause any sustained harm, even if they may cause some confusion. Hopefully, members of an individual patient’s health care team, including primary care providers, will be able to explain the meaning, implications and limitations of reported associations between “X” and cancer “Y” if asked. If questions remain, other resources (e.g., relevant specialists within the local medical community, American

Cancer Society, American Society of Clinical Oncology, other specialty societies) should be available to assist. However, in certain circumstances, claimed associations may be more problematic for a particular individual considering the implications of what has been declared as fact. Consider, for example, the statement that certain chemotherapy agents cause secondary malignancies. In this situation the use of the antineoplastic drugs in question may no longer be employed in routine clinical practice or their schedule may have been substantially changed to reduce or even eliminate the risk.3 Yet, when a paper appears in the literature that describes a relationship like this, the critical fact that the studied strategy is no longer employed in routine clinical practice may not be adequately conveyed in either the paper itself or in media reports. If the outcome among patients is unnecessary fear and an unfortunate decision to stop or not receive clearly documented highly effective therapies, the consequences may be serious, even devastating. In one specific example, it has been suggested that fertility drugs increase a woman’s risk for developing ovarian cancer.4 However, it also is known that infertility itself is associated with a heightened risk for ovarian cancer. Therefore, it is very difficult to differentiate an elevated “baseline” increased risk from any greater risk resulting from the administration of fertility treatments. And if an individual woman with documented infertility issues is an appropriate candidate for fertility drugs, it is possible

that fear resulting from these kinds of reports—which are far from satisfying objective, scientific criteria as definitive— may cause that woman to forgo what for her might be a highly beneficial and lifechanging medical intervention. Of course, it is important to acknowledge here that the public has every right to learn of, and inquire about, the outcomes of research studies that suggest a relationship between any “X” factor and the development of “Y” cancer. But it is essential that the medical and research communities and the lay media make major efforts to clearly explain the objectively valid implications of a study’s findings and the essential limitations of the analysis.

References 1. Schoenfeld JD, Ioannidis JPA. Is everything we eat associated with cancer? A systemic cookbook review. Am J Clin Nutr. 2013;97:127-134, PMID: 23193004. 2. Sontag S. Illness as Metaphor. 1st ed. New York: Farrar, Straus and Giroux; 1978. 3. Kaldor JM, Day NE, Pettersson F, et al. Leukemia following chemotherapy for ovarian cancer. N Engl J Med. 1990;322:1-6, PMID: 2104664. 4. Kurta ML, Moysich KB, Weissfeld JL, et al. Use of fertility drugs and risk of ovarian cancer: results from a U.S.-based casecontrol study. Cancer Epidemiol Biomarkers Prev. 2012;21:1282-1292, PMID: 22707710.

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

gmiller@mcmahonmed.com

Genitourinary Cancers Symposium

Immunotherapy Promising for Kidney Cancer Orlando, Fla.—In patients with aggressive metastatic renal cell carcinoma (RCC), combining the standard therapy of sunitinib (Sutent, Pfizer) with an experimental fully personalized immunotherapy called AGS-003 (Argos Therapeutics) can double expected progression-free survival (PFS) and overall survival. These results come from a Phase II trial presented at the 2013 ASCO Genitourinary Cancers Symposium (abstract 348). “We have encouraging clinical and immunologic responses that have been observed and correlated with prolonged overall survival,” said Robert Figlin, MD, the director of the Division of Hematology/Oncology at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute

in Los Angeles, who presented the study. To produce AGS-003, monocytes are isolated from RCC patients during a single leukapheresis procedure and differentiated into dendritic cells. These cells are loaded with antigen-encoding RNA amplified from the patient’s tumor and injected into the patient. Each production run of AGS-003 generates up to five years of treatment for each patient. The immunotherapy stimulates the proliferation of central and effector memory cytotoxic T lymphocytes for a durable immune response. In the study, 21 patients with newly diagnosed, advanced-stage, unfavorablerisk RCC received one cycle of sunitinib and then five doses of AGS-003 three weeks apart and AGS-003 quarterly

until disease progression. Sunitinib also was given until disease progression. The only adverse events (AEs) that were attributed to AGS-003 were injectionsite erythema, which occurred in 33.3% of patients, and injection-site induration, which occurred in 23.8% of patients. No grade 3/4 AEs were related to the immunotherapy, and there was no evidence of emergent autoimmune disease. The median PFS was 11.2 months, and Dr. Figlin pointed out that the median PFS for patients in a similar population who received sunitinib monotherapy would be approximately six months. The median overall survival of the study patients is 30.2 months, roughly twice that expected in a similar population of patients receiving

sunitinib monotherapy. Investigators are planning the Phase III ADAPT trial to compare AGS-003 plus standard therapy with standard therapy alone in newly diagnosed, advanced RCC. Leonard Gomella, MD, the chair of the Department of Urology at Jefferson University Hospitals in Philadelphia, said the data on AGS-003 was “very encouraging and will need to be confirmed in a larger number of patients.” —Kate O’Rourke Dr. Figlin received research funding from and disclosed a consultant or advisory role with Argos Therapeutics. Dr. Gomella had no relevant disclosures.

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights from ASH, NEJM, Blood and JCO chromosome-negative acute lymphoblastic leukemia (ALL).

QUESTIONS

1. True

or False. A study published in The New England Journal of Medicine by a group at the National Heart, Lung, and Blood Institute in Bethesda, Md., demonstrated the clinical utility of eltrombopag (Promacta, GlaxoSmithKline) in patients with severe aplastic anemia (SAA) who had failed immunosuppressive therapy.

4. True

or False. In a population-based Finnish study, unexpectedly high familial risk was uncovered in patients diagnosed with nodular lymphocytepredominant Hodgkin lymphoma (NLPHL).

2. True or False. Unlike in idiopath-

ic thrombocytopenia purpura (ITP), patients with aplastic anemia (AA) exhibit markedly elevated thrombopoietic (TPO) levels.

True or False. In a multinational Phase II trial, high-dose monotherapy with vincristine sulfate liposome injection (VSLI; Marqibo, Talon) was ineffective and resulted in higher toxicity when compared with a conventional dose of vincristine in adults with relapsed/refractory Philadelphia

ANSWERS

True. The group, led by Cynthia Dunbar, MD, successively enrolled 25 adult patients and initiated eltrombopag at a dose of 50 mg daily and escalated the dose every two weeks by 25 mg if the platelet count remained below 20,000/ mm3, until a maximum daily dose of 150 mg was reached. Of the patients, 44% responded with improved production in at least one cell lineage with minimal toxicity. Of the four patients who had a response of at least eight months, three attained normal bone marrow cellularity. Of 11 patients with a response, seven remained on treatment for 16 months. Interestingly, one patient who stopped treatment after nine weeks because of development of a cataract exhibited a continued response for 16 months. Increase in bone marrow fibrosis was not observed. In their closing remarks, the authors wrote: “Given the uncertainty about the risk of MDS or AML, it would be prudent to monitor patients with AA who receive eltrombopag by performing serial bone marrow biopsies and cytogenetic analysis; treatment should be limited to clinical trials.”

5. True

or False. The Cancer and Leukemia Group B (Alliance) 10502 study demonstrated encouraging results with the addition of bortezomib (Velcade, Millennium) to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine (IDAC) for consolidation in older adults with previously untreated de novo and secondary acute myeloid leukemia (AML).

Primum non nocere. (First, do no harm.)

histology lymphoma is a recognized event in the natural history of follicular lymphoma (FL). b. There is no standard treatment for patients with transformed FL. c. The risk for transformation is approximately 3% per year. d. Diagnosis of TL can be comfortably established with markedly abnormal positron emission tomography (PET) scan in a patient with FL.

7. True or False. On behalf of the

Canadian Blood and Marrow Transplant Group, Diego Villa, MD, MPH, of the British Columbia Cancer Agency in Vancouver, reported that patients undergoing allogeneic hematopoietic cell transplantation (HCT) had better outcomes compared with those treated solely with a rituximab-containing chemotherapy regimen or with consolidation autologous HCT.

True or False. Pomalidomide 6. All of the following statements 8. (Pomalyst, Celgene) induces less neu-

about transformed lymphoma (TL) are correct except: a. Transformation into aggressive-

tropenia and more skin rash than thalidomide and lenalidomide (Revlimid, Celgene), respectively.

The group has initiated multiple clinical trials with up-front eltrombopag: 1) in combination with antithrombocyte globulin and cyclosporine in patients with SAA (NCT01623167), and 2) as a single agent in patients with moderate AA (NCT01328587).

Ballmaier M, Germeshausen M, Krukemeier S, et al. Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia. Ann N Y Acad Sci. 2003;996:17-25, PMID: 12799278.

Olnes MJ, Scheinberg P, Calvo KR , et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-19, PMID: 22762314. Becker PS. A New ripple for MPL: eltrombopag for aplastic anemia. The Hematologist. MarchApril 2013. www.hematology.org.

2. True. Previous observations sug-

gest that stimulation of c-Mpl–signaling pathways may overcome depletion of hematopoietic stem and progenitor cells in AA, hence the rationale for a trial with eltrombopag in refractory AA. Humans with congenital amegakaryocytic thrombocytopenia and familial AA, respectively, develop multilineage marrow failure and have a defect in the myeloproliferative leukemia virus ((MPL) gene. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068-4071, PMID: 8639762.

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

Walne AJ, Dokal A, Plagnol V, et al. Exome sequencing identifies MPL as a causative gene in familial aplastic anemia. Haematologica. 2012;97:524-528, PMID: 22180433.

3. False. High-dose VSLI monother-

apy resulted in meaningful clinical outcomes, including durable responses and bridging to HCT in adults with advanced Ph-negative B- and T-cell ALL. Sixtyfive adults with two or more relapses or those whose disease had progressed after two or more therapies were treated in this pivotal Phase II, multinational trial. Eligible patients had at least one prior complete remission (CR) with a leukemia-free interval of at least 90 days. IV VSLI, 2.25 mg/m2, without dose capping, was administered weekly until response, progression, toxicity or pursuit of HCT. The CR/incomplete blood count recovery (CRi) rate was 20%, and overall response rate was 35%. Median CR/CRi duration was 23 weeks (range, five to 66 weeks). The toxicity was manageable and similar to conventional vincristine but with

In a study by Sif Gudbrandsdottir, MD, of Copenhagen University Hospital Roskilde in Roskilde, Denmark, and colleagues, adult patients with newly diagnosed primary ITP had higher sustained responses with the combination of rituximab and dexamethsone compared with dexamethasone alone.

10. According to data published on

behalf of the Center for International Blood and Marrow Transplant Research (CIBMTR), which of the following donors for older (age ≥50 years) hematopoietic transplant recipients with leukemia, myelodysplastic syndromes (MDS) and non-Hodgkin lymphoma (NHL) with good Karnofsky performance status (KPS) should be selected: a. Older (≥50 years) matched-sibling donor (MSD) b. Younger (<50 years) matched-unrelated donor (MUD)

delivery of large, otherwise unachievable, individual and cumulative doses of regular vincristine. Phase III studies in frontline adult ALL and frontline aggressive NHL, predicated on the current study and the successful combination of VSLI with other chemotherapies and rituximab in other Phase II studies, are currently enrolling patients. O’Brien S, Schiller G, Lister J, et al. Highdose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013;31:676-683, PMID: 23169518. Rodriguez MA, Dang N, Fayad L, et al. Phase II study of sphingosomal vincristine in CHOP +/− rituximab for patients with aggressive non-Hodgkin’s lymphoma (NHL): promising 3 year followup results in elderly patients. Blood d (ASH Annual Meeting Abstracts). 2005;106:943. Ashcroft A, Kaplan L, Damon L, et al. Sphingosomal vincristine plus rituximab for treatment of large B-cell lymphoma. Blood d (ASH Annual Meeting Abstracts). 2003;102:1454.

True. The findings of first-degree relatives of patients with NLPHL of approximately 19-fold higher risk (95% confidence interval [CI], 8.8-36) is a call for studies to scrutinize the reasons behind this observation. The see CONUNDRUMS, S page 28

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CLINICAL ONCOLOGY NEWS • MAY 2013 • CLINICALONCOLOGY.COM

CONUNDRUMS continued from page 27

registry-based standardized incidence ratio for classical Hodgkin lymphoma was 5.3 (95% CI, 3.0-8.8) and 1.9 for NHL (95% CI, 1.3-2.6). Saarinen S, Pukkala E, Vahteristo P, et al. High familial risk in nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2013;31:938-943, PMID: 23284040.

5. True. Ninety-five adults between

the ages of 60 and 75 years (median age 67 years) with previously untreated AML (including patients with therapy-related and previous MDS) were analyzed. The frequency of CR was 65%, and 4% achieved incomplete platelet recovery. These results are better than historical controls and may be a result of adding bortezomib. Patients who achieved CR received up to two courses of IDAC consolidation chemotherapy with days 1 to 5 of bortezomib. Further testing of this regimen is planned. Attar EC, Johnson JL, Amrein PC, et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol. 2013:31:923-929, PMID: 23129738.

D. In all cases of progression (or sometimes at diagnosis) after an initial diagnosis of FL—especially if there is a high clinical suspicion of transformation based on the clinical findings (rapidly growing bulky disease, poor performance status and/or B symptoms) and laboratory findings (very high lactate

dehydrogenase)—a biopsy should be obtained. As transformation can be focal, a PET scan may help determine the optimal site (“hottest area”) to biopsy, but only in cases with high clinical suspicion of transformation (reviewed by Bernstein et al). Villa D, Crump M, Panzerella T, et al. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian Blood and Marrow Transplant Group. J Clin Oncol. 2013;31:1164-1171, PMID: 23401459. Bastion Y, Sebban C, Berger F, et al. Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol. 1997;15:1587-1594, PMID: 9193357. Bernstein SH, Burack WR. The incidence, natural history, biology, and treatment of transformed lymphomas. Hematology Am Soc Hematol Educ Program. 2009:532-541, PMID: 20008238.

7. False. Patients undergoing autolo-

gous HCT (56%) had better outcomes than those treated with rituximab-containing chemotherapy alone (31%). Patients treated with allogeneic HCT (13%) did not have improved outcomes compared with patients treated with rituximab-containing chemotherapy, and the HCT was associated with clinically significant toxicity. In multivariate analysis, patients treated with autologous HCT had improved overall survival compared with those who received rituximab-containing chemotherapy (hazard ratio, 0.13; 95% CI, 0.05-0.34; P<0.001). Villa D, Crump M, Panzerella T, et al. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian Blood and Marrow Transplant Group. J Clin Oncol. 2013;31:1164-1171, PMID: 23401459.

False: Pomalidomide induces less asthenia and neuropathy than thalidomide. It is more likely to induce neutropenia than thalidomide. There are subsets of patients with multiple myeloma who are sensitive to the myelosuppressive effects of lenalidomide and have trouble tolerating even very low doses. These patients often do well with pomalidomide, suggesting there are fewer myelosuppressive effects with pomalidomide compared with lenalidomide. Skin rash is commonly seen with lenalidomide but rarely observed with pomalidomide. Richardson PG, Siegel D, Baz R, et al. Phase I study of pomalidomide MTD, safety and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121:1961-1967, PMID: 23243282.

9. True. Adult patients from nine hos-

pitals in Denmark (N=133), were randomly assigned to receive either dexamethasone 40 mg per day for four days (n=71) or in combination with rituximab 375 mg/m2 weekly for four weeks (n=62). The median follow-up was 922 days. The primary end point of sustained response, defined as platelets at least 50×109/L at six months’ follow-up, was reached in 58% of patients in the combination arm versus 37% in the dexamethasone-alone group ((P=0.02). There was longer time to relapse ((P=0.03) and longer time to rescue treatment (P ( =0.007) in the rituximab plus dexamethasone group. However, there was an increased incidence of grade 3/4 adverse events in the rituximab plus dexamethasone group (P ( =0.04). Presently, the American Society of Hematology guidelines offer a

grade 2C recommendation for rituximab as a second-line option. Gudbrandsdottir S, Birgens HS, Frederiksen H, et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood. 2013;121:1976-1981, PMID: 23293082. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidencebased practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-4207, PMID: 21325604. Rao VK. ITP: hematology’s Cosette from Les Misérables. Blood. 2013;121:1928-1930, PMID: 23493768.

10. A. The question addressed in this

retrospective analysis was whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD <50 years) rather than an older HLA-matched sibling (MSD ≥50 years) in leukemia/MDS/NHL patients aged 50 years or older. When selecting a donor for patients who are at least 50 years old with KPS of 90 or 100, priority should be given to an MSD younger than 67 years rather than to a younger-aged MUD. Similarly, for patients with lower KPS (≤80) and/or when the donor is aged 67 or older, lower acute and chronic graftversus-host disease rates after MSD compared with MUD transplantation favor an MSD when such a donor is available. Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood. 2013;121:2567-2573, PMID: 23361908.

Mohammed S. Aziz, MD, assisted in preparing this manuscript.

by the

numbers: personalized medicine 32%

of individuals interviewed were unaware that tests were available to help determine if certain cancer treatments might work in particular individuals and not others. Broken down by cancer type, 74% of mCRC patients, 80% of NSCLC patients, and 90% of breast cancer patients believed their tumor could be tested to help their doctor decide which treatment to give.

Getting Personal

recent international survey of 811 patients diagnosed with cancer in the last five years has unearthed some surprising findings about the personalized medicine revolution. The survey, conducted via telephone, included cancer patients in Argentina, of individuals China, France, Germany, Italy, Spain and were willing to the United Kingdom. Patients had lateundergo repeat biopsies to stage breast cancer, non-small cell lung receive a drug that might work better for them. cancer (NSCLC) or metastatic colorectal cancer (mCRC). The results were presented at the annual meeting of individuals of the European Society for were willing Medical Oncology (poster 1382). to delay treatment if this

69%

66%

helped clinicians select the most effective drug.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Please send comments to managing editor Gabriel Miller at gmiller @mcmahonmed.com

Another Successful Year For the McMahon Group

2012

to recognize the best of an outstanding group of empployees. Now into its ﬁfth decade, the company continues to publish best-read medical newspapers and must-view meddical websites covering several clinical areas, and also creates medical education platforms for physicians, nurses andd pharmacists. All of which proves yet again that a company pow powered wered by talented people will necessarily generate su success. uccess

Here is a review of the winners of the 2012 employee awards: MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

Each year employees are asked to select two outstanding mem mbers representing these diverse departments. The first winner was DIANE LODISE, who is both the director of facilities managemeent, overseeing the facilities owned by the company, and the conveentions coordinator, planning the many details of our extensive convenntion coverage.

The second winner was HYON NG KWON, the company’s development manager for IT, for his continuuing efforts in improving the company’s digital presence.

MAX GRAPHICS PERSON OF THE YEAR

MOST IMPROVED SALESPERSON OF THE YEAR

BLAKE DENNIS was recognized for her excellence as art directtor for Anesthesiology News as well as her graphic design of a varietyy of special projects. Blake is dedicated to creating the most visually appeaaling projects possible.

BRIAN HIGGINSON, publicatioon director for Gastroenterology & Endoscopy News, was recogniized for the increase in that publication’s sales in 2012, which in part ledd to one of its most profitable years ever. His dedication to his clients’ needs and understanding of their products ensure his continued success in sales.

ASSOCIATE/SENIOR/PROJECTS EDITOR OF THE YEAR

MANAGING EDITOR OF THE YEAR

Editorial director of the special projects division, division KATHERINE REIDER was recognized for her contributions as an editor and for providingg leadership and direction to the members of the department. Her diplomacy skills and focus on process have helped ensure that projects are devveloped with the highest level of accuracy and in a timely manner. Katherinee also was recognized for her 10 years of service at McMahon.

GEORGE OCHOA was voted editor ed of the year for his efforts and dedication to McMahon Groupp through his exemplary writing and editing. His stories appear in every McMahon Group publication and on every website and provide the manaaging editors with articles that exemplify editorial excellence.

SALES ACHIEVEMENT AWARD

SALESPERSON OF THE YEAR

The publication director for General Surgery News, MICHAEL ENRIGHT, T was selected for this award in recognition of his strong commitment to his clients and his innovative thinking to create unique marketing platforms, which included the publication’s first international edition as well as the initiation of a website video arcade.

For an unprecedented seventhh year in a row, RICHARD TUORTO earned the salesperson of the year aw ward. Unlike the other awards, which are decided by peer votes, this aw ward is presented to the individual who brings in the most revenue in the calendar year. Richard manages the Anesthesiology News and Painn Medicine News teams as senior group publication director.

THE MCMAHON GROUP PERSON OF THE YEAR

PARTNERS’ AWARD

The top award each year is for the person of the year, which gooes to the employee who goes above and beyond the call throughout thee year. JEANNIE MOYER, associate director of human resources, received the honor this year. Jeannie oversees personnel and works tirelessly to provide the best possible atmosphere for employees each day. She is integral to helping McMahon Group continue to grow every year.

From time to time, the partner--owners of the company recognize the contributions of those who havee had a significant effect on the company’s success through the years. The 22012 award was given to WARD BYRNE, who served as publication director foor Anesthesiology Newss for several years, starting in the early 1990s. He w was responsible for the excellent growth of that newspaper, which today dominates the market. Ward eventually left McMahon Group to start what would be ann 11-year career working at a medical education company, after which he returneed to his true love — teaching. Today, Ward teaches special education in thee New Jersey school system.

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Cancer: The Outlaw Cell: Third Edition

Richard LaFond May 16, 2012 This book is a collection of 25 focused chapters written by leading researchers at the forefront of cancer research. Authors present the current state of knowledge in chapters on the role of heredity, cancer and telomeres, tumor resistance and microRNAs in the pathogenesis of cancer, and map out areas of future research and advancement.

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Colorectal Cancer

Daniel Swinson; Matthew Seymour October 12, 2012 This book summarizes the epidemiology and risk factors for developing colorectal cancer and the basic biology of the disease. The evidence governing approaches in diagnosis and oncological management, both surgical and nonsurgical, of the primary tumor is also covered. Providing perspectives from the different disciplines involved, this pocketbook will serve as an invaluable reference for all health care professionals involved in the management of patients with colorectal cancer.

Gynecologic Oncology: Clinical Practice & Surgical Atlas

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

Handbook of Gastrointestinal Cancer

Janusz Jankowski; Ernest Hawk December 26, 2012 Residents/trainees and specialists in gastroenterology, oncology and surgery, as well as GI/cancer nurses and other health professionals will welcome this accessible guide to the diagnosis and clinical management e t of o all a forms o s of o GI G cancer. ca ce

Radiation Oncology in Palliative Cancer Care

Stephen Lutz; Edward Chow; Peter Hoskin April 22, 2013 This palliative radiation therapy reference and textbook provides a template for the end-of-life care of patients who require intervention by radiation oncologists as well as hospice and palliative medicine professionals working together.

RNA and Cancer

Jane Y. Wu April 1, 2013 This book reviews recent progress in selected areas of RNA processing relevant to cancer development and therapy. It examines the coupling between transcription and splicing. It describes cancer-associated aberrant RNAs, new methodology for their detection and the functional impact on expression of important genes, including oncogenes and tumor suppressor genes. Further topics include the role of microRNAs in cancer and the possible involvement of the perinucleolar compartment.

The Hippo Signaling Pathway and Cancer

Moshe Oren; Yael Aylon April 30, 2013 The Hippo signaling pathway is rapidly gaining recognition as an important player in organ size control and tumorigenesis. Hippo signaling is not solely involved in regulating “classic” tumor characteristics such as cell prolifera-tion, survival and growth, but is also diversely involved in cell-autonomous and non–cell-autonomous differentiation, migration and organ size control. This volume presents virtually all aspects of tumor biology.

The Tumor Immunoenvironment

Michael R. Shurin; Viktor Umansky; Anatoli Malyguine May 1, 2013 Interaction between malignant cells and their surrounding tissue plays a crucial role in tumor growth, invasiveness and spreading to the distant organs. New findings provide evidence of a principal importance of the immune cells for controlling this interaction and orchestrating multiple events in the tumor microenvironment. CO0513