Page 1

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • March 2013 • Vol. 8, No. 3


NEW Column The Tumor Board: Is laparoscopic distal pancreatectomy the new ‘gold standard’? ................ 10


Gastrointestinal Cancers Symposium Colorectal subtypes: Ready for prime time? ...... 13

ESMO Debate: Should neoadjuvant data be used to accelerate drug approval? ................... 20 Multi-targeted TKI promising second-line neuroendocrine option ...................................... 24 Stage III colorectal cancer: Adding cetuximab gives no benefit .............................. 24

HEMATOLOGIC DISEASE Phase III data supports bendamustine in NHL and MCL ................................... 4 Rituximab Improves B-Cell Lymphoma Survival ............ 16

CURRENT PRACTICE Maurie Markman, MD: Diagnostic imaging: A double-edged sword ...... 3 FDA drug actions ............... 26 Clinical Conundrums ......... 29

“Blossom Tree,” an alternate view of mucinous carcinoma.

Vogl, NY...

Cyclophosphamide Prices Skyrocket Causes and effects


n October 2012, my office manager announced that I can no lo nger gi ve IV cyclophosphamide to Medicare patients because I will lose about $100 Steven Vogl, MD on every 500 mg given. For a large lymphoma patient, this can add up to a loss of $400 for each dose of R-CHOP chemotherapy given, far more than I get paid for caring for this patient. Medicare rules forbid me from billing the patient as a result of see VOGL, NY, Y page 5

‘We Prevent Complications, Rather Than Chase Them’ Medical home model begins to change community oncology practice


oday, oncology practices interested in becoming oncology medical homes (OMHs) are lucky in one respect: They don’t have to reinvent the wheel. They can seek advice from existing OMHs and oncology management consultant groups. So, what is involved in transforming a clinic? There isn’t one formula, but several common themes emerged when Clinical Oncology News talked to experts about what it takes to create an OMH, a patient-focused system that delivers quality, coordinated and efficient cancer care. Key aspects include the use of team-based care, streamlined electronic medical records, software that allows tracking of physician compliance with pathways and prompting for real-time evidencebased decision making, and a telephone triage system. At the foundation, the transition see MEDICAL HOME, E page 8


Expert Insights From Mayo Clinic Cancer Center Bevacizumab effective, tolerable in older CRC patients .................. 18 Axel Grothey, MD

Cabozantinib promising for castration-resistant prostate cancer ...... 19 Manish Kohli, MD





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 the 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 towards 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

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


Shaji Kumar, MD Mayo Clinic Rochester, MN

Cathy Eng, MD


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 University of Texas, MD Anderson Cancer Center Houston, TX

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.



Diagnostic Imaging in Oncology

A (Potential) Double-Edged Sword EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia


he potential harm resulting from overexposure to ionizing radiation as a result of our substantial increase in diagnostic imaging strategies is among the most complex health-related discussions within our society.1-3 There are a number of components of this dilemma that increase the difficulty of developing an objective and rational consensus regarding these strategies. First, the dangers associated with radiation have been well known to the public for more than 60 years, beginning with the decision to drop atomic bombs on Japan to hasten the end of World War II and continuing through the “Cold War” era and into the present in frequent national discussions regarding the wisdom of building and/or maintaining nuclear power plants. Furthermore, any discussion of the risk factors for common and less serious skin cancers (e.g., localized basal cell carcinoma) or potentially far more deadly conditions (e.g., malignant melanoma) includes the major role of exposure to natural radiation from the sun. ®

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.

Second, any discussion of the concept of relative risk—including the well-established potential for radiation-associated malignant disease—versus benefit either at the societal level or for the individual patient is fraught with hazard as that theoretical ratio (“risk/benefit”) actually relates to a population of patients or members of society and not to a particular patient or individual. Finally, this issue is made even more complex as we increasingly understand that this theoretical risk is clearly cumulative in nature. As a result, it may not be this particular test (e.g., a computed tomography [CT] scan to evaluate nonspecific but persistent abdominal pain lasting for two weeks) that is worrisome, but rather the multiple procedures performed over many years or decades in a single individual that are of greatest concern. In fact, each individual imaging procedure performed over this extended period of time may have been medically justified, but adding up the total radiation exposure over time may lead one to question whether several or even many procedures could have been avoided. Thus, when attempting to answer the question of the potential benefit-versus-risk of a single routine (e.g., chest radiograph, mammogram, CT scan of the abdomen/pelvis) or more innovative (e.g., CT/PET [positron emission tomography] scan) imaging procedure, the answer may be less than satisfactory in terms of objective data relevant to that patient. The issues associated with

radiographic imaging present an even more unique challenge in oncology. In addition to the general issues noted above, there are questions of how frequently radiographic imaging should be undertaken to detect the presence, confirm the absence or document the progression of a malignancy. In addition, as our imaging strategies improve in both sensitivity and specificity, and the effectiveness of “earlier intervention” as a result of “earlier detection” is confirmed through the conduct of appropriately designed clinical investigations, it is virtually certain these diagnostic approaches will be employed increasingly in routine oncologic care. This includes a likely increase in both overall utilization and more frequent use in individual patients. Several strategies can potentially reduce concerns about the radiographic risks associated with increased use of diagnostic imaging. First, it is critical that the utility of any suggested need for increased radiation exposure be unequivocally documented through well-designed clinical studies. Second, considerable effort should be undertaken by those involved in the diagnostic imaging field to develop paradigms that maximize the opportunity to obtain useful clinical data while minimizing the radiation exposure required in the generation of such data. Finally, despite the recognized benefits associated with the information obtained from procedures that expose patients to forms of radiation (both external and



Kevin Horty, Group Publication Editor

Julianna Dawson, Publication Director

Gabriel Miller, Managing Editor

David Nathanson, Account Manager

Sarah Tilyou, Senior Editor


James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

internal), it will be important for research efforts to continue exploring diagnostic strategies that are not dependent on such exposure (e.g., ultrasound). It also will be important for oncologists to have a clearer understanding of the potential risks associated with obtaining particular types of imaging (e.g., CT scan vs. CT/PET scan) in different settings (e.g., adjuvant therapy with anticipated longterm survival vs. metastatic disease with expected shorter survival) and the impact of cumulative exposures over time. This will be relevant for both the individual decisions that physicians are called on to make when ordering diagnostic or screening radiographic studies, as well as for discussions they (hopefully) will be having with their own patients about the relative risks and benefits of these procedures.

References 1. Brenner DJ, Hall EJ. Computed tomography–an increasing source of radiation exposure. N Engl J Med. 2007; 357:2277-2284, PMID: 18046031. 2. Linet MS, Slovis TL, Miller DL, et al. Cancer risks associated with external radiation from diagnostic imaging procedures. Ca Cancer J Clin. 2012; 62:75-100, PMID: 22307864. 3. Smith-Bindman R, Miglioretti DL, Johnson E, et al. Use of diagnostic imaging studies and associated radiation exposure for patients enrolled in large integrated health care systems, 1996-2010. JAMA. 2012;307:2400-2409, PMID: 22692172.

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

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations

Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

If you missed any recent issues of Clinical Oncology News, visit





Bendamustine Efficacy in NHL and MCL Confirmed Phase III data supports clinical use following StiL NHL 1 trial Atlanta—Results from BRIGHT (Bendamustine Rituximab Investigational Non-Hodgkin’s Trial) support the use of bendamustine (Treanda, Cephalon) plus rituximab (BR) in the first-line treatment of advanced indolent nonHodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL). The Phase III trial found that BR was noninferior to the standards of care, R-CVP (rituximab, cyclophosphamide, vincristine and prednisone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). BR also caused less alopecia and neuropathy. Ian Flinn, MD, PhD, the director of the Hematologic Malignancies Research Program at the Sarah Cannon Research Institute in Nashville, Tenn., presented the results at the annual meeting of the American Society of Hematology (ASH; abstract 902). According to Joshua Brody, MD, an assistant professor of hematology and medical oncology at Mount Sinai School of Medicine in New York City, who was not involved in the research, BRIGHT “is extremely important” and confirms results of the German Study Group Indolent Lymphomas (StiL) NHL 1 trial. “The STiL study, presented by Dr. Mathias Rummel at ASH 2009 and updated at ASCO [American Society of Clinical Oncology] 2012, was the first large, randomized study to show that BR is at least as effective or possibly better than the R-CHOP regimen and apparently better tolerated in some important ways. The use of R-B [BR] increased significantly in 2010 after that data was presented, although that study has yet to be published in a peer-reviewed journal for more thorough review,” Dr. Brody said. “Personally, our clinical practice changed at that time to incorporate R-B for the majority of our patients who might have previously received R-CHOP or R-CVP, and we have been generally happy with the results.” Jennifer Brown, MD, PhD, an attending physician with the Chronic

Table 1. Comparison of Adverse Events of Any Grade Nausea

BR, %


BR, %

R-CVP, %















Febrile neutropenia





Opportunistic infections





Peripheral neuropathy










Peripheral sensory neuropathy















BR, bendamustine plus rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CVP, R CVP, rituximab, cyclophospham cyclophosphamide, mide, vincristi vincristine ine and prednisone

Table 2. Comparison of Grade ≥3 Adverse Events BR, %


BR, %

R-CVP, %

Any event















Drug hypersensitivity





Any infections





Peripheral neuropathy





Respiratory/thoracic disorders





White blood cell count





Absolute neutrophil count





Lymphocyte count





BR, bendamustine plus rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CVP, R CVP, rituximab, cyclophosphamid cyclophosphamide, de, vincristine e and prednisone

Lymphocytic Leukemia & Lymphoma Program at the Dana-Farber Cancer Institute in Boston, who also was not involved with BRIGHT, agreed. “This study adds to the evidence suggesting BR is a very effective regimen in MCL and indolent lymphomas, probably as good and possibly more effective

than our older standard therapies,” she said. She doesn’t use BR for all of her patients, but her group is moving that way. “I think many people are using BR unless the person has very bulky disease that might suggest occult transformation, in which case we would use R-CHOP,” she said. “BR often tends to

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication. Write to managing editor Gabriel Miller at

The study adds weight to the argument that bendamustine plus rituximab is as good, and possibly better, than older standard therapies. be better tolerated.” BRIGHT included treatment-naive patients with indolent NHL or MCL, who were 18 years or older and satisfied a need-to-treat criteria. Patients had CD20-positive disease, an Eastern Cooperative Oncology Group status of 0 to 2, and Ann Arbor stage of no less than 11. Patients were preassigned for randomization to either R-CHOP/ BR or R-CVP/BR. The evaluable analysis included 213 patients who received BR and 206 patients who received R-CHOP or R-CVP. The complete remission rate was 31% in the bendamustine arm compared with 25% in the R-CHOP/R-CVP arm, with a noninferiority P-value of 0.0225. The P-value for determining superiority did not reach statistical significance ( =0.1269). The partial response rate (P was 65% in the bendamustine arm and 66% in the standard therapy arm. BR was associated with a higher incidence of nausea and vomiting, pyrexia, chills, drug hypersensitivity, decreased appetite, rash and pruritis (Tables 1 and 2). R-CHOP and R-CVP were associated with a higher incidence of constipation, paresthesia, peripheral neuropathy and alopecia. R-CHOP was associated with a higher incidence of febrile neutropenia and mucosal inflammation. —Kate O’Rourke Dr. Flinn disclosed research funding from Teva Pharmaceuticals. Drs. Brown and Brody have no relevant disclosures.



VOGL, NY continued from page 1 

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

inadequate Medicare payments. Since my office can seek other sources to pay for the cyclophosphamide, what she said is not strictly true. However, every time I plan on giving cyclophosphamide, I precipitate a crisis search for some way to pay for the drug that will not bankrupt my practice. The history of the wholesale price of cyclophosphamide to one of my distributors is shown in the Table. The price rose ninefold in three years. It seems clear that manufacturing costs for this generic drug did not increase at this rate. Only one company markets the drug in the United States—Baxter Laboratories. The drug that is marketed here is manufactured in Halle, Germany. Baxter justifies the price increases based on the costs of making the drug, maintaining a stable supply and maintaining quality throughout the manufacturing process. Compared with the very, very high prices of new arrivals on the oncology drug market—increases that Hagop Kantarjian, MD, the director of the Leukemia Service at the University of Texas MD Anderson Cancer Center has called “obscene”—even the inflated price of cyclophosphamide is low. Compared with marginally effective drugs like eribulin (Halaven, Eisai), ixabepilone (Ixempra, Bristol-Myers Squibb), regorafenib (Stivarga, Bayer) and pralatrexed (Folotyn, Allos Therapeutics), IV cyclophosphamide at $220 per 500 mg is a bargain. The price itself, then, is

Table. The Wholesale Price of IV Cyclophosphamide (500 mg) January 2010 and before


February 2010


June 2010


February 2011


July 2011


January 2012


October 2012


not the issue, but the rapid rise and its effects are big issues. Cyclophosphamide given intravenously has a special place in the oncology armamentarium that makes it especially difficult to substitute for it. It is an essential drug in the adjuvant treatment of resected breast cancer. Because it causes little or no acute leukemia at conventional doses, it is preferred over drugs like melphalan and thiotepa. Huge studies have demonstrated that two-drug combinations containing cyclophosphamide are more effective than those without it.

Similarly, curative therapy for diffuse large B-cell lymphoma and Burkitt’s lymphoma depends on intravenous cyclophosphamide backbones in complicated regimens. No other drug can be substituted in terms of either safety or efficacy.

Monopoly and Its Consequences With a ninefold increase in price for cyclophosphamide, it is unclear why other generic drug manufacturers have not entered the market, broken the monopoly and undercut Baxter’s price.

The FDA tells me that there is no regulatory reason that only Baxter can market IV cyclophosphamide. Following a change in Medicare laws, Medicare now pays for physician-administered medication based on a number called “average sales price” (ASP), which is calculated from the actual money collected six months earlier for the drug. Medicare pays 106% of this number. This means that every time the price of a drug rises, adjusted reimbursement to physicians lags by six months. This matters very see VOGL, NY, Y page 6 

Visit Late-breaking akin k News Links to O Other ther Therapeutic Areas Fr CME Free

Medical Educa Education tion Archives hii Most Popular Articles & R d Reader eader Co Comments e ts Tabbed Navigati Navigation ion ion

Opti mize d for wide scr disp een lays Educati Educational ucational c onal R i Reviews





VOGL, NY continued from page 5 

little for drugs that cost $1 or $2, or drugs whose prices rise by 1% to 2% at a time. Rises in price of 80% for even modestly expensive drugs lead to prohibitive losses that practices cannot tolerate if they intend to survive and pay their employees. It is possible that Baxter found itself in a monopoly, decided it could and should raise the price, and did so progressively on the assumption that a gradual rise

in price every few months would cause less market disruption and less fuss than a huge price rise of 900% at once. A Baxter spokesman denies that the slow but large price increase was designed to manipulate where patients get their chemotherapy, to shift who pays for the drug, or to shift the cost to a payer who pays more. I wondered if Baxter would make more money if patients were sent to pharmacies to buy their IV cyclophosphamide using their prescription plans. Because of deductibles, copays and the “doughnut hole,” this will increase

patient costs significantly. Many drugs are a lot more expensive for Medicare Part D prescription plans than for physicians. It turns out that IV cyclophosphamide is not one of these, at least in 2013. Baxter charges retail pharmacies and Medicare part D prescription plans approximately the same as it charges physicians via their wholesalers.

Many Hospitals Profit on Drugs While Physicians Lose! It also turns out that hospitals serving poor or uninsured populations— which now comprise one-third of all

U.S. hospitals according to a recent New York Times article—by law get a discount of 20% to 50% on cancer therapeutics in a program called 340B.1 Because this discount applies to all patients treated at the hospital, hospitals in the 340B program now make a tidy profit on giving chemotherapy drugs, a profit that grows with the cost of the drugs. According to The New York Times, about $6.9 billion worth of drugs now moves annually through the program. A money-losing oncology practice could instantly become a profit center if taken over by a 340B

we are


On your phone Wherever you are Catch up on the latest news stories

It’s easy! Use your mobile device’s browser to go to Bookmark us on your homescreen

When you see this application icon you are good to go!

Scan this code with your smartphone to visit Clinical Oncology News mobile Web site. Bookmark the site on your device to read Clinical Oncology News on the go.



hospital, provided it gives a sufficient quantity of expensive drugs discounted under the 340B program. In one of my more paranoid moments, it occurred to me that an unscrupulous hospital or group of hospitals might have sought to manipulate the way the price of cyclophosphamide was increased so that reimbursement to physician offices is always well below cost. If the resulting loss drives the physician practice to sell out to the hospital—very cheaply, since the practice is losing money—the hospital wins. If the physician struggles on,

Regulatory actions to encourage a free market for injectable generic drugs at prices sufficiently high to ensure several sources of supply would go a long way toward resolving the recurring drug shortages that have plagued medical oncology in the past several years. maintaining his practice, but sends his patients to the hospital to receive chemotherapy, the hospital wins because of its 340B discount. Large hospitals could have significant influence on Baxter because they are the major customers for its large line of intravenous solutions and tubing, as

well as needles and syringes. The curious pattern of large stepwise increases in the price of intravenous cyclophosphamide that benefits 340B hospitals justifies an investigation by the Federal Trade Commission, as should the continued Baxter monopoly on intravenous cyclophosphamide, which

in Your Inbox

... to receive the monthly e-newsletter from


Register for free @ Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded website links that give you instant access to additional information as well as unique search features and printing capabilities. Each installment contains brief summaries of the most important articles from the current issue and breaking news ahead of print.

presumably is now very profitable.

Unintended Consequences for Sick Patients Medicine, unfortunately, is quite difficult. Every patient encounter is illuminated by that patient’s ultimate mortality. If the patient is very ill with a disseminated lymphoma of a type that can be cured if treatment is carefully, quickly and appropriately administered, it is a pity that the efforts of the physician and his office have to be diverted to dealing with cost and reimbursement issues, especially for a relatively cheap drug like IV cyclophosphamide. It is no help that many insurance companies take several days to confirm reimbursement policies even when the patient is acutely ill. Skeptics will argue that unscrupulous physicians, in the past, chose chemotherapy regimens to maximize their profits. That this probably occurred is no reason to now divert the attention of conscientious physicians away from the care of sick patients.

What Can Be Done? Given the paralysis in Congress, it is futile to suggest changing the ASP + 6% Medicare reimbursement formula now in place. Encouraging another generic drug manufacturer to enter the U.S. IV cyclophosphamide market or allowing imports from abroad would end the Baxter monopoly and presumably lower or at least stabilize prices. Indeed, regulatory actions to encourage a free market for injectable generic drugs at prices sufficiently high to ensure several sources of supply would go a long way toward resolving the recurring drug shortages that have plagued medical oncology in the past several years.

Reference 1. Pollack A. Drug industry sees abuse in discount program. The New York Times. February 13, 2013:B1.

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




MEDICAL HOME continued from page 1 

involves a culture change. “Oncology payments and thus most of medical oncology care is focused on volumes of treatment. We have moved to several capitation models, as well as our modified fee-for-service medical oncology home pilot with Anthem Blue Cross. We are now dedicated to improving patients’ health, not giving treatments,” said Linda Bosserman, MD, the president of Wilshire Oncology Medical Group, who leads the group’s OMH in La Verne, Calif. “There has to be a culture change, and it means two big things. You have to engage and you have to reengineer. You have to fully engage every staff member at every level and re-engineer what their job is to be a team that delivers much better care, in and outside the clinic. You have to re-engineer your payer system and re-engineer how your patients interact with you.”


where the real cost savings lie. “There is going to be a limited amount of savings in pathways,” said Barbara McAneny, MD, chief executive officer of New Mexico Oncology Hematology Consultants (NMOH), an OMH with four centers in New Mexico. “When you start out, you can identify people who are doing wild stuff and rope them in, but then there is no more to get. The real savings is keeping patients out of the hospital and out of the ERs [emergency rooms].” This is where the telephone triage systems come in. “Our telephone triage service has really been embraced by our patients,” said John Sprandio, MD, the lead physician at Consultants in Medical Oncology and Hematology (CMOH), which has four offices in suburban Pennsylvania. “When we first started measuring data in 2006, we had about 1,600 clinical phone calls that were symptomrelated. Last year, we had about 4,600.” CMOH is the only oncology practice to receive recognition from the National Committee for Quality Assurance

The focus in the medical home model is on treatment pathways as well as anticipating and preventing the symptoms that ultimately put patients in the hospital or the ER. The culture shift involves an aggressive personal medicine approach aimed at anticipating symptoms and preventing them. “We now engage a patient’s kids or spouse or we will put their pills in a pill box or we will call them every day,” said Dr. Bosserman. “If we think the patient needs more support, we will figure out how they can get the support.” Patient education is emphasized, especially in end-of-life care. “The way our health care is organized right now is [doctors] are actively encouraged to treat, even when it is clear that those treatments are futile,” said Dr. Bosserman. Patients with metastatic disease need to be educated that sometimes the best treatment is palliative relief of symptoms and that this can sometimes extend life, she said. Another common theme is the use of pathways. Wilshire physicians meet monthly to evaluate the best of the National Comprehensive Cancer Network guidelines and program their computers to prompt doctors toward them. “Every month, we have meetings with the physicians, nurses and administrative staff, so everybody is on board delivering this quality product,” said Dr. Bosserman. “However, this is not a cookbook. We track warranted variations.” For example, avoiding a chemotherapy that causes peripheral neuropathy in a piano player is a warranted variation that a physician can note in a medical record. Pathways are one of the quality measures many insurers look for, but it’s not

(NCQA) as a level III patient-centered medical home. “Our model, based on the NCQA PCMH [primary care medical home] standards, has attracted national attention from payers, providers and patients,” said Dr. Sprandio. Oncology nurses man the telephone triage lines in most OMH practices and field symptom calls from patients. In some practices, calls are redirected to an answering service after hours with an on-call nurse or physician fielding patient questions. On-call staff can access the practice’s EMR remotely, allowing them to follow the same symptom management algorithms used by nurses during office hours. “Do not have your phone answered by ‘if this is a medical emergency, hang up and call 911,’ because people do it. Then you have someone in the ER for something that you could have quite easily managed in the office,” said Dr. McAneny. “The key is to provide aggressive management of cancer and its treatments, so that we can prevent complications rather than chase them. We can have people come to us, instead of going to emergency departments.” She points out that conditions such as neutropenia or a stable pulmonary embolus is better treated for less money in an oncology office. This takes extra effort from physicians. “It requires physician work. It requires that physicians are willing to see patients the same day,” said Dr. McAneny. If a patient has an event in the middle of the night, NMOH doctors will get out of bed

Table. Oncology Medical Home Quality and Value Measures Developed by the Community Oncology Alliance Patient Care Measures % of cancer patients who received a treatment plan prior to the administration of chemotherapy. % of cancer patients with documented clinical or pathologic staging prior to initiation of first course of treatment. % of chemotherapy treatments that have adhered to NCCN guidelines and pathways. % of cancer patients undergoing treatment with a chemotherapy regimen with a ≥20% risk for developing neutropenia and also received granulocyte colony-stimulating/white cell growth factor. Antiemetic drugs given appropriately with highly emetogenic chemotherapy treatments. Resource Utilization # of ER visits per chemotherapy patient per year. # of hospital admissions per chemotherapy patient per year. Survivorship % of cancer patients who received a survivorship plan within a defined period of days after completion of chemotherapy. % of chemotherapy patients who received psychosocial screening and received measurable interventions as a result of the psycho/social screening. Survival rates of stage I-IV breast cancer patients. Survival rates of stage I-IV colorectal cancer patients. Survival rates of stage I-IV non-small cell lung cancer patients. End of Life % of patients who have stage IV disease and have end-of-life care discussions documented. % of patient deaths where the patient died in an acute care setting. Average number of days on hospice care (home or inpatient) at time of death. A measurement of chemotherapy given near end of life. ER,, e emergency e ge cy room; oo ; NCCN, CC , National at o a Comprehensive Co p e e s ve Cancer Ca ce Network etwo

to direct admit them to a hospital. “It is just part of what you have to do,” said Dr. McAneny. “When you admit to a hospitalist who doesn’t know your patient, you have all of the transition-of-care issues, but also, the hospital isn’t part of your system and doesn’t know that, for example, when you get somebody with neutropenic fever stabilized, you can complete their therapy in your office.” Alternatively, Dr. Bosserman reported that Wilshire oncologists partner with other specialists and hospitalist teams at each of the 12 regional hospitals they serve. Hospitalists and ER doctors actively work with oncologists to participate in cost-effective management, discussing management strategies during evaluations, admissions and discharge. If a patient is admitted, Wilshire oncologists work actively with hospitalists to set goals and oversee care plans that minimize unnecessary workups and minimize hospital stays. “We function as a team with the oncologist as quarterback for the cancer patients,” said Dr. Bosserman. Although physicians have more responsibilities in some areas of the OMH model, they can achieve significant

efficiencies. Minimizing irrelevant activities for physicians is essential. “We have minimized a lot of the tedious data collection that physicians are often engaged in. We increased the efficiency of documentation and communication,” said Dr. Sprandio. His practice uses seasoned oncology nurses and 5.6 full-time equivalents (FTE) per physician compared with the national average of 8.3 FTE. “We developed a medical home enabling software overlay that has allowed us to integrate our workflow with delivery of care, documentation and meaningful use requirements,” said Dr. Sprandio. With the efficient and streamlined used of EMRs and their software overlay, called Iris, CMOH patient navigators have become stewards who ensure that all ordered tests are conducted, treatment plans followed and nothing slips through the cracks. The patient navigator also is critical in the outcome measurement process. Dr. Sprandio has illustrated that documenting reductions in hospital stays, ER visits and other health care costs is essential for insurers to consider paying for the new model. “We have one active contract and we



are anticipating two additional contracts, one national payer and one local payer,” said Dr. Sprandio, who added that insurers agree to consider proposed payment reform after confirming their data and the practice’s commitment to standardizing the process of care. CMOH has lowered ER visits by 68%, hospital admissions per chemotherapy patient per year by 51% and hospital length of stay for admitted patients by 21%. The practice also noted a 22% overall reduction in outpatient visits per hematology and oncology patient per year and a 12% reduction in outpatient visits per patient per year in the chemotherapy subpopulation. Savings to CMOH payers is estimated to be in the range of $1 million per physician per year (Am ( J Manag Care 2012;18[5 Spec No. 2]:SP98SP, PMID: 22693989). Dr. Sprandio said that his group was able to complete this practice transformation through innovation, without formal outside funding. This is not true for all practices. Anthem Blue Cross increased its fee-forservice payment rates to cover the estimated care planning, management and coordination work for Wilshire Oncology’s OMH pilot, which launched in August 2011. The pilot has been extended to August 2014. In summer 2012, Dr. McAneny’s company Innovative Business Solutions received a $19.7 million grant from the Centers for Medicare & Medicaid Services to test the NMOH medical home model in seven oncology practices across the country. Dr. Sprandio said that practices seeking to become an OMH should study the NCQA’s PCMH standards; the NCQA patient-centered specialty practice standards are expected to be published this month. He pointed out that practices also could seek guidance from a growing number of consultants. These include Oncology Management Services in Drexel Hill, Pa., the team of professionals assembled by Dr. Sprandio to facilitate the transformation of other practices to an OMH. “Oncology practices should be able to transition much more quickly than we did,” said Dr. Sprandio. Additional tools are being developed. In January, the Community Oncology Alliance (COA) launched a website brimming with resources for practices aiming to become OMHs ( The site is a byproduct of COA’s Oncology Medical Home Steering and Implementation Committee, which includes providers, payers, administrators, patients, nurses, pharmacists and cancer care advocates. The committee has released a list of quality and value measures for OMHs (Table). “What we are trying to do is put the common glue together, by getting people to agree what the measures of quality and value are,” said Ted Okon, MBA, executive director of the Washington D.C.-based COA.

‘Our model, based on the NCQA PCMH standards, has attracted national attention from payers, providers and patients.’

efficient cancer care. … It is what oncology practices do right now. It’s just that they haven’t gone to the next level and nobody has really been measuring it.”

—John Sprandio, MD —Kate O’Rourke

He said more resources will be added to the site and that an implementation team has been canvasing the hardware, software and different processes that OMHs are using. The aim is to create a self-assessment that practices can use to determine what they need to change to become a medical home.

According to Mr. Okon, cancer centers need to change to OMHs to survive and prosper. “The government has pushed the ball down the hill and it is rolling and gaining more moss or snow depending on the season, and it is rolling toward having [medical practices] prove that they are providing high-quality,


Dr. McAneny is CEO of Innovative Business Solutions. Dr. Sprandio disclosed a financial interest in CMOH and Oncology Management Services and active engagement with the NCQA in the development of the Patient-Centered Specialty Practice recognition program. Dr. Bosserman and Mr. Okon have no relevant disclosures.

Now Available... in Non-Hodgkin’s Lymphoma

Evolving Treatment Paradigms To participate in this FREE CME activity, log on to and enter keyword “MM111” Release Date: August 22, 2012

Expiration Date: August 22, 2013


Learning Objectives

Julie M. Vose, MD, MBA

Review optimal therapy for the management of newly diagnosed and relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), taking into consideration the heterogeneity of patient and tumor characteristics.

Neumann M. and Mildred E. Harris Professor Chief, Division of Hematology/Oncology Professor of Medicine

1 Identify the most recent data pertaining to emerging single and combination therapies for the treatment of relapsed/refractory NHL.

Nebraska Medical Center Omaha, Nebraska


John P. Leonard, MD

2 Explain the most significant new data on consolidation and maintenance strategies in NHL.


3 Describe current and emerging prognostic clinical and molecular markers to aid in treatment decision making for NHL.

Professor of Medicine

Intended Audiences

Weill Medical College of Cornell University

The intended audiences for this educational activity are hematologists, community oncologists, oncology nurses, pharmacists, and other hematology/oncology health care professionals. These professionals constitute the core audience for this initiative as they direct treatment for patients with NHL.

Clinical Director, Center for Lymphoma and

NewYork-Presbyterian Hospital New York, New York

Jonathan W. Friedberg, MD Professor of Medicine and Oncology Chief, Hematology/Oncology Division James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York

challenges for clinicians, who must stay abreast of the new data and be prepared to incorporate emerging therapeutic strategies into their practice.

Course Format Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

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

Statement of Need

Method of Preparation

The incidence of NHL is increasing steadily, and new therapeutic strategies are needed; FL remains incurable, and 30% to 40% of patients with DLBCL still die from their disease. The abundance of ongoing research into therapeutic strategies for these conditions presents opportunities for improved patient outcomes as well as

To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% (in 3 attempts) is required to complete this activity successfully. CME certificates will be issued immediately upon successful completion.

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

This activity is supported by educational grants from Genentec

To participate in this FREE CME activity, log on to and enter keyword “MM111”






Tumor Board

Pancreatic Cancer: Is Laparoscopic Distal Pancreatectomy the New ‘Gold Standard’? Welcome to the inaugural edition of The Tumor Board


his column aims to present readers with challenging cases and/or provide alternative treatment options related to oncology and surgical oncology that are both timely and worthy of discussion. In addition to my commentary, the cases and/or alternative treatment options will be presented to other experts in related fields for “second opinions” regarding evaluation and treatment. This first issue focuses on laparoscopy for distal pancreatectomy. I am very honored to have R. Matthew Walsh, MD, chairman of the Department of General Surgery at Cleveland Clinic Foundation in Cleveland, Ohio, kick off this first issue by providing an expert “second opinion.” I hope readers enjoy the column and benefit from the timely discussions and multiple opinions presented as they relate to oncologic challenges and alternative—and

sometimes controversial—treatments. The focus is on discussion and I hope to hear from readers with their opinions and comments on topics presented in each column. I also greatly welcome and encourage suggestions or case submissions for future issues. Enjoy! Conrad Simpfendorfer, MD Editor, The Tumor Board Hepato-pancreato-biliary and Transplant Surgeon Cleveland Clinic Weston, Florida

Case 1


66-year-old woman presents with a mass in the tail of the pancreas, discovered during evaluation for changes in bowel movement. Computed tomography (CT) scan reports a 2.6-cm hypodense lesion in the tail of the pancreas (Figure 1). A follow-up magnetic resonance imaging (MRI) scan reports a 3μ2.3-cm heterogeneous mass in the tail of the pancreas. There is no evidence of distant metastasis. An endoscopic ultrasound (EUS) reported a 3.5-cm heterogeneous mass in the distal body of the pancreas. The mass abuts the splenic artery and vein. Fine-needle aspiration (FNA) of the mass reported a cystic neoplasm with papillary architecture. CA 19-9 level is greater than 3 U/mL.

Figure 1.

Case 2


n 84-year-old healthy man presents with a mass in the tail of the pancreas, discovered during evaluation for abdominal pain. CT scan reports a 5.2-cm complex mass in the tail of the pancreas (Figure 2). The mass is reported to have cystic and solid components. No evidence of distant metastasis is noted. The patient denies any history of pancreatitis. CA 19-9 level is 84 U/mL.

Figure 2.



Case Challenge

Dr. Simpfendorfer’s Commentary How would you treat these two patients?


would advocate treating these patients based on the presumed pathology. The first patient would appear to have an asymptomatic lesion, and the description of the EUS findings is difficult to interpret. The MRI is not presented, and the CT is of poor quality on one image. I am suspicious that the lesion is a serous cystadenoma that can appear incidentally as a “mass lesion” because the size of the cysts may be quite small. The other major diagnostic consideration would be a solid pseudopapillary neoplasm. I would review the imaging and FNA result, including cytology, in more depth before determining the exact approach. The second patient is more concerning for a pancreatic neoplasm. The description of pain is nonspecific, and I would question the patient more closely on the symptoms, which in general can help guide the workup. The presence of a mass component is an indication for resection, and, for this patient, I would advise a distal pancreatectomy with splenectomy.

Would you perform open or laparoscopic pancreatectomy?


he operative approach should be guided by disease extent and presumed diagnosis, as well as surgeon experience. It is unclear whether the patient in the first case requires resection, but the patient in the second case should have a distal pancreatectomy with splenectomy, both due to the location of the lesion and presumed carcinoma diagnosis. He is a suitable candidate for a laparoscopic resection provided the surgeon has adequate experience. This patient appears to be quite thin and some of the advantages of a min- Resection of pancreatic body with automatic suturing device imally invasive approach may not be realized.


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. No significant past medical or surgical history. All preoperative labs were normal, as was 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 is identified

Is tissue diagnosis necessary before a planned surgery?

• No definitive evidence of vascular invasion


• Cystic duct margin of resection is free of invasive carcinoma

he patient in the first case has already undergone FNA, which should be reviewed for the cytologic features. “Papillary architecture” is an uncharacteristic cytologic feature that would need to be reviewed with an experienced pancreatic cytopathologist. The patient presented in the second case has radiographic features of a mass component, which would be an independent indication for resection.

• Cystic duct margin of resection is involved by highly dysplastic epithelium • Cholelithiasis

‘Second Opinion’:

• Benign cystic duct lymph node

Expert Opinion by R. Matthew Walsh, MD

What would you do?


dvances in instrument technology and surgeon experience R. Matthew Walsh have made laparoscopic surgery the standard technique for Chair, General Surgery several abdominal surgical procedures. Minimally invasive surCleveland Clinic gery for the pancreas has been undertaken with more caution. Cleveland, OH Recently, laparoscopic distal pancreatectomy (LDP) has gained popularity. Studies comparing open distal pancreatectomy (OPD) and LDP have reported advantages with minimally invasive surgery, including reduced postoperative pain, faster recovery, decreased wound complications, less intraoperative blood loss and fewer postoperative complications.1,2 A meta-analysis comparing LDP with OPD concluded that lower blood loss and reduced hospital length of stay were associated with the laparoscopic approach. LDP also was associated with a lower risk for overall postoperative complications and wound infection.3 A multicenter analysis comparing LDP with OPD for the treatment of adenocarcinoma of the pancreas reported similar short- and long-term oncologic outcomes between the two groups, suggesting that LDP is an acceptable approach for resection of pancreatic ductal carcinoma of the left pancreas.4

References 1. 1. Belli G, Fantni C, D’Agostino A, et al. Laparoscopic and open surgical treatment of left-sided pancreatic lesions: clinical outcomes and cost-effectiveness analysis. Surg Endosc. 2012;26:1830-1836, PMID: 22258300. 2. 2. Kooby D, Kneuertz P, Patel S, et al. Laparoscopic distal pancreatectomy: trends and lessons learned through an 11-year experience. J Am Coll Surg. g 2012;215:167-176, PMID: 22632910. 3. 3. Wolfgang C, Venkat R, Edil B, et al. Laparoscopic distal pancreatectomy is associated with significantly less overall morbidity compared to the open technique: A systematic review and Meta-analysis. Ann Surg. g 2012;255:1048-1059, PMID: 22511003. 4. 4. Kooby D, Hawkins W, Schmidt C, et al. A Multicenter analysis of distal pancreatectomy for adenocarcinoma: is laparoscopic resection appropriate? J Am Coll Surg. g 2010;210:779-787, PMID: 20421049.

Have comments or feedback on The Tumor Board? Would you like to suggest a case for an upcoming column? Email managing editor Gabriel Miller at





Vol. 3, Issue 3




We highlight the work of fellowship director Timothy Gilligan, MD. 4 FELLOWSHIP TRAINING

Experts discuss what to expect in 6 the first year of fellowship. FELLOWSHIP TRAINING

Communication skills are crucial for oncology fellows.



is brought to you as a professional courtesy. This content is selected and controlled by McMahon Publishing and is funded by Lilly USA.

For the latest oncology fellow–related information, please visit


Mentor Memos

Survey Says

Physician Finance

Top-Tier Centerss Share Tips


ospitals in the United States are anx xious to be included in the annual US News and World Rep port’s list of top hospitals. To make the 2011 to 2012 cut, cancer centers had to treat at least 254 inpatients with h highlevel expertise in 2007, 2008, and 2009 9.1 The following are the top 10 cancer centerss in US News and World Report, in ascending orrder of quality: University of Texas MD Anderson n Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), Johns Hopkins (JH), Mayo Clinic, Dana Farber Cancer Institute/Brig gham & Women’s Cancer Center, University of Washington Cancer Center in Seattle e, Massachusetts General Hospital, UCSF F Medical Center, Cleveland Clinic, and d Ronald Reagan UCLA Medical Center.1 Oncology Fellow Advisor spoke witth Daniel Spratt, radiation oncology trainee at Memorial Sloan-Kettering (No. 2 on the

Top-Tier page 5

Master Work–Life Balance


raining to be an oncologist can be rough. In the face of long hours, sleep deprivation, and patient suffering, young oncologists may sacrifice hobbies, interests, and even relationships. Many fellows find comfort in reminding themselves that better days are ahead but experts say that they may be setting themselves up for disappointment. Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead to burnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Division of Surgical Oncology at University of Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal wellbeing is not at all successful.” One in 3 oncologists will experience significant career burnout— described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2 Some of its more tragic consequences see, Work–Life page 2

To obtain educational information for oncology fellows, please visit us online:



2013 Gastrointestinal Cancers Symposium

Colorectal Cancer Subtyping: Predicting Outcomes T

he classification of colorectal cancer (CRC) tumors into molecular subtypes could lead to more targeted treatment strategies, according to two studies presented at the 2013 Gastrointestinal Cancers Symposium. “We have developed a diagnostic single-sample predictor that allows the classification of colorectal cancer tumors of different intrinsic molecular subtypes. These subtypes could be clinically relevant as they differ in their underlying biology and clinical outcomes and consequently require different treatment strategies,” said Josep Tabernero, MD, PhD, the director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and lead investigator of one of the studies (abstract 333). Molecular classification systems could be most helpful in managing patients with stage II CRC who have a variable risk for relapse that is hard to predict with current clinical and pathologic factors. The goal of subtyping is not only to identify the patients who need aggressive treatment, but also to pair the right patient with the right drug. Dr. Tabernero and his team used gene expression data taken from 188 patients with CRC (stages I-IV) to develop the classification system, which they subsequently validated in 543 patients (stages II-III). Three distinct molecular patterns were identified: 21.5% of the samples were categorized as subtype A (32 genes), 62% as subtype B (53 genes) and 16.5% as subtype C (102 genes). These subtypes differed according to three biological hallmarks of colorectal tumors: epithelial-to-mesenchymal transition (associated with aggressive tumors); deficiency in mismatch repair genes (associated with genetic alterations); and the rate of cell proliferation—features that are known to independently affect outcomes, according to Dr. Tabernero. “The subtypes were significantly associated with prognosis and significantly correlated with benefit from adjuvant 5-FUbased treatment,” Dr. Tabernero said. Subtype A had a good prognosis regardless of whether chemotherapy was given. Ten-year survival rates were approximately 65% without chemotherapy and 80% with chemotherapy (P ( =0.183). Subtype B had a pronounced benefit from chemotherapy, with 10-year survival rates of approximately 55% without chemotherapy versus 80% with chemotherapy (P ( =0.014). Subtype C, on the other hand, derived no benefit from adjuvant chemotherapy, with 10-year survival rates of approximately 65% without chemotherapy and

‘If these results can be validated, these molecular alteration patterns have the potential to be used as markers to identify which patients should receive aggressive care after surgical resection of both primary and metastatic colorectal cancer and to direct the specific chemotherapeutic agents they should receive.’ —William M. Grady, MD —Willia 50% with chemotherapy (P ( =0.542). The five-year overall survivval difference between types A and B, versus type C, was statistically siggnificant ((P=0.0166). The study findings suggest that these groups would be treated differently: Subtype A would prob bably not require chemo-therapy; subtype B would d receive chemotherapy and d subtype C would require a more aggressive and perhaaps novel treatment. The study researchers plan to evaluate these ssubtypes in patients who have received more current regimens, especially ox xaliplatin. A separate study, presented nted by JoshJosh ua M. Uronis, PhD, of the Duke Institute for Genome Sciences and Policy in Durham, N.C., found that deregulation of oncogenic signaling pathways can be used as a powerful tool to classify patients with CRC into molecular subgroups. The researchers have developed a preliminary set of biomarkers that are prognostic, predictive of treatment response and applicable to patients who have undergone resection for primary or metastatic tumors. The study (abstract 339) took microarray data from 850 patients with primary CRC, based on the activity of 19 oncogenic pathways, and generated patterns of pathway deregulation for each patient’s tumor. A molecular profile of CRC was created that identified six molecular subgroups of colorectal cancer (MSCCs) and found the subgroups differed significantly in their risk for recurrence. For example, although recurrence-free survival approached 100% for MSCC 4, it fell to about 40% for MSCC 3 ((P=0.0004). The model was then applied to a data set of 133 tumor samples of which 94 patients presented with metastatic disease and 34 with primary lesions. Again, the MSCC subgroups differed in recurrence-free survival ((P=0.046), according to Dr. Uronis. The unique patterns of pathway deregulation were translated into gene expression signatures and were used to measure the probability of pathway activation in a panel of cell lines. With this

approach, the model also was predictive of response to various drugs. “We observed that MSCCs demonstrated differential sensitivity to specific targeted agents, such as MSCCs 1, 2 and 3 to inhibition of HER2 by lapatinib and inhibition of the epidermal growth factor receptor by erlotinib,” said Dr. Uronis. “From this we gather that we can make basic predictions using pathway signatures.” The study was validated using a murine model of drug sensitivity that took patient-derived CRC explants and implanted them into mice. This model showed that subgroups with high mammalian target of rapamycin (mTOR) activity were highly sensitive to mTOR inhibitors and those with low mTOR expression were found to be resistant to these drugs. Researchers deduced that the combination of a genomic-based molecular profile of CRC and their preclinical murine model using patientderived CRC explants can be used to develop a clinically relevant prognostic and predictive biomarker of CRC. Representing the American Gastroenterological Association at the symposium, William M. Grady, MD, the associate professor of medicine and chief of the gastroenterology section at the University of Washington Medical Center in Seattle, said, “There has been considerable interest in determining whether molecular alterations in primary colorectal cancer are more accurate prognostic indicators

than a tumorr’s pathologic stage, which is what is cu urrently used.” Focusingg on the study by Dr. Uronis and d his colleagues, Dr. Grady saaid, “They have used a unique approach to idenu tiify molecular alterations th hat are predictive of recurreent cancer, not only for nonmetastatic disease but also m ffor metastatic disease. If tthese results can be validaated, these molecular alteration patterns have the potential to be u used as markers to identify which patieents should receive aggressive care after surgical resection of both primary and m metastatic colorectal cancer and to direct the th specific chemotherapeutic agents they should receive.” Jennifer Tseng, MD, chief of surgical oncology and the co-clinical director for surgery at Beth Israel Deaconess Medical Center and an associate professor at Harvard Medical School in Boston, said, “The work [by Uronis et al] is critical for colorectal care advancement, and symbolic of the new age of cancer care in general. For example, we as surgeons can surgically remove tumors to the best of our oncologic ability, and enable our partners, the pathologists, to stage the tumors and help determine the best treatment. However, currently, there are serious limitations. At the extremes, there is less controversy. There, there is no question that chemotherapy does not [for stage I] or does [for stage III or IV] help the patient, overall. But the vast majority of patients fall into those shades of gray, stage II especially, where we are weighing potentially toxic chemotherapy risks and benefits versus disease recurrence risks and benefits. This type of study helps point us to personalizing cancer care for the individual tumor, and thus the individual patient.” —Caroline Helwick Drs. Uronis and Tseng have no relevant relationships to disclose. Dr. Tabernero has received research funding from Agendia; Dr. Grady previously reported that he has served as a consultant or advisory board member for General Electric, Illumina and Myriad.




Expert Insights From Mayo Clinic Cancer Center Each month, Clinical Oncology News highlights key studies from the most important journals and provides perspectives from guest clinicians at a top cancer center. Every four months, Clinical Oncology News features clinicians from a different U.S. center. This month we introduce Mayo Clinic Cancer Center, who will be providing expert commentaries in the next four issues of Clinical Oncology News. We hope you find our Reviews & Commentaries section a valuable tool.

Mayo Clinic Cancer Center:

Continuing a Tradition of Excellence

Images and text provided by Mayo Clinic Cancer Center


Mayo Clinic Cancer Center has sites in Arizona, Florida and Minnesota.

Mayo Clinic Cancer Center is home to more than 400 physicians and scientists who collaborate across the full spectrum of cancer research and are dedicated to understanding the biology of cancer; to discovering new ways to predict, prevent, diagnose and treat cancer; and to transforming the quality of life for cancer patients today and in the future. More than 135,000 cancer patients receive treatment each year at Mayo Clinic Cancer Center’s three campuses—in Scottsdale/Phoenix, Ariz., Jacksonville, Fla., and Rochester, Minn.

Cancer Patient Care Mayo Clinic’s philosophy of patient care, laid out more than 100 years ago, emphasizes developing medicine as a cooperative science, with the clinician and the laboratory scientist uniting for the good of the patient. That philosophy, still relevant today, enables Mayo Clinic physicians and researchers to form productive collaborations across cancer programs and specialties. Their collective knowledge enhances the potential for breakthroughs in cancer research and treatment.

Mayo Clinic Cancer Center is one of 67 U.S. medical centers to be named National Cancer Institute (NCI) cancer centers. Mayo Clinic has held this NCI designation since 1973, following the creation of the Cancer Centers Branch of the NCI in 1971. Mayo Clinic Cancer Center also has met even more rigorous standards for designation by the NCI as a comprehensive cancer center. These standards include the following: • Basic laboratory research • Participation in high-priority NCI clinical studies • Applied and clinical research • Cancer prevention and control programs • Education and training of health care professionals • Public information services • Community service and outreach Mayo Clinic Cancer Center receives more than $140 million in competitive peer-review grants, including the NCI’s highly sought Specialized Programs of Research Excellence (SPORE) grants. The Cancer Center has five NCI SPORE grants and two SPORE grants that are shared with other institutions. These

SPORE grants support research in brain cancer, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lymphoma and multiple myeloma. Mayo Clinic Cancer Center has 10 major cancer research programs that translate scientific discoveries in the laboratory into leading-edge treatments and therapies for patients. These programs benefit from the crucial infrastructure and scientific support of 15 shared resources, all of which further basic, clinical and population sciences research.

Cancer Clinical Trials Mayo Clinic Cancer Center is a leader in translating knowledge gained from cancer research into better patient care. Patients have access to hundreds of clinical trials led by Mayo Clinic scientists. Trials are also available through the Cancer Prevention Network, a clinical trial study group whose administration and research is based at Mayo Clinic. Still more trials are available through cooperative research agreements with the NCI, the Alliance for Clinical Trials in Oncology and other clinical trial groups.



Pathogenesis of Serous Cancers Tied to Fallopian Tubes From The European Journal of Cancer


new study lends support to the hypothesis that the fallopian tubes are a primary site of pelvic high-grade serous cancer. The study was designed to test the theory by estimating the prevalence of occult cancers found in ovaries or fallopian tubes in a consecutive series of women who were either BRCA carriers or were BRCA-negative high-risk patients. Tissue samples were prospectively collected from asymptomatic, screennegative, high-risk women between January 2000 and March 2012. The study was undertaken by Welmoed Reitsma, MSc, and colleagues at the University

Medical Center Groningen, in Groningen, the Netherlands. Results were published in the European Journal of Cancer (2013;49:132-141, PMID: 22921157). Of the 360 women who underwent risk-reducing salpingo-oophorectomy (RRSO), 188 were BRCA1 carriers, 115 BRCA2 carriers, and 57 were BRCA-negative, high-risk patients. The median age at surgery was 44 years (range 30-72 years). Patients were excluded from the study if the RRSO was part of their breast cancer therapy or if they had previous ovarian/tubal cancer. Gynecologic pathologists aware of the patients’ BRCA status reviewed the specimens. All tissue with positive

EXPERT INSIGHT Andrea Wahner Hendrickson, MD Consultant, Department of Medical Oncology, and Assistant Professor of Medicine, Mayo Clinic


he current publication by Reitsma et al is the latest article in the rapidly evolving field of ovarian cancer pathogenesis. Over the past several years, paradigm-shifting insights have emerged regarding the origin of serous ovarian cancer. Approximately 50% of malignant ovarian cancers are serous. These cancers, which tend to be aggressive high-grade tumors that rapidly spread through the peritoneal cavity, make up the majority of ovarian cancers seen in BRCA1/2 mutation carriers.1 In a 2001 study, Piek et al first reported epithelial dysplasia within the fallopian tubes of six of 12 BRCA1/2 mutation carriers undergoing a risk-reducing bilateral salpingo-oophorectomy (RRBSO) when the surgical specimens were examined by thin sectioning.2 In 2006, Medieros et al conducted a similar study of 13 BRCA1/2 carriers undergoing RRBSO and established a technique termed sectioning and extensively examining the fimbria (SEE-FIM) to evaluate the fallopian tubes in their entirety at 2- to 3-mm intervals.3 This group discovered that 38% of these women had STIC in the fimbria/distal fallopian tube but none had carcinoma in the ovaries. Since that publication, several studies have confirmed these findings, providing mounting evidence that serous cancer of the ovary may indeed stem from the distal fallopian tube and may better be termed

serous tumors of the pelvis. The present report by Reitsma et al is the largest prospective study evaluating the incidence of occult invasive and noninvasive carcinoma using the SEE-FIM method in RRBSO specimens of asymptomatic BRCA1/2 carriers and other women at high risk for ovarian cancer. This study revealed four occult invasive cancers, four noninvasive STIC lesions and 23 cases of atypical hyperplasia. Each of these types of lesions provides the opportunity to gain new insight into the origin of serous tumors of the pelvis. With four serous cancers, this cohort of women had a very low rate of occult cancer (1.1%), slightly lower than documented in prior studies. Possible explanations include the slightly younger median age of women and the requirement for a recent negative pelvic ultrasound and CA-125 before the procedure. Unfortunately, of the four samples that did reveal occult cancers, two did not have the fallopian tube tissue available for assessment of tubal lesions that could have given rise to the invasive cancers, although the other two cases did reveal fallopian tube origins. All four STIC lesions and approximately 74% of the atypical hyperplasia originated in the fallopian tube, with the remaining 25% of the atypical hyperplasias consisting of tubal epithelium on the ovarian surface or within the lining of ovarian epithelial

findings, as well as a sample of normal sections, were reviewed by a second pathologist who had no knowledge of patient information or the previous pathology report. Histomorphologic results included occult invasive cancer in four women: two with fallopian tube and two with ovarian cancers. All were BRCA1 carriers, and all were over the age of 40 years. Four cases of serous intraepithelial carcinomas (STIC) were detected, all in the fallopian tube: one in a BRCA1 carrier (age 60 years); two in BRCA2 carriers (ages 50 and 57) and one in a BRCA-negative high-risk patient (age 56) with an unclassified variant. The pathologists detected

atypical hyperplasia in 23 women: 13 BRCA1, nine BRCA2 and one BRCAnegative. These lesions were either located in the fallopian tube (17 of 23) or most likely derived from the fallopian tube (six of 23), suggesting this as the primary site. These results found the prevalence of cancer to be 1.3% in BRCA carriers, whereas other published reports put the range between 2% and 12%. The present results do lend support to the hypothesis of the fallopian tube as a primary site of pelvic cancer origin, as well as supporting the practice of RRSO before the age of 40 years in high familial-risk women with the BRCA mutation.

inclusion cysts. Unfortunately, the short median follow-up of the women with STIC lesions (one year) makes it difficult to know the subsequent outcome of these women. It is possible that these early lesions might shed malignant cells into the peritoneal cavity even at a preinvasive stage. Due to the small number of STIC lesions discovered and the short follow-up, the long-term implications cannot be assessed from this study. An additional limitation is that a study of this type also requires substantial pathology expertise that may not be available outside of tertiary medical centers. Two specialized pathologists who were aware of the objectives of the trial reviewed all of the specimens. If there was any discrepancy, an independent pathologist who was unaware of the patient history was consulted. Because the STIC lesions and atypical hyperplasia can be quite subtle and the SEE-FIM technique requires more time and extensive pathology experience, similar examination may not be feasible at smaller community-based centers. Although this study is consistent with the hypothesis that serous ovarian cancers originate in the tubes, the low rate of lesions precludes using this trial as definitive evidence of the fallopian tube model or reaching any conclusions regarding the future implications of STIC lesions, or screening practices. However, in combination with prior studies, some potential practice-changing possibilities have been raised. One issue raised is the role of a risk-reducing bilateral salpingectomy (RRBS) in high-risk women who refuse RRBSO. As demonstrated in the Reitsma article, approximately 48% of women with BRCA mutations or who

are otherwise at high risk opt not to undergo an RRBSO. In other investigations, the rate ranges from 30% to 40% as well.4-6 Often the reluctance stems from the consequences of premature menopause, including increased risk for cardiovascular disease, osteoporosis, urogenital atrophy and decreased quality of life. Therefore, there may be a role for an RRBS in women at high risk for a serous pelvic malignancy who are unwilling to undergo a full RRBSO at age 35 to 40 years. It is important to remember that an RRBS would not provide the approximately 50% risk reduction for breast cancer that accompanies estrogen withdrawal,7 although prophylactic mastectomies often also are considered in these patients. In summary, the report by Reitsma et al provides additional support for the role of the fallopian tube in the pathogenesis of serous “ovarian” cancer. Further studies will be needed to determine the rate of malignancies after identification of STIC lesions, and the implications on screening and risk reduction strategies.

References 1. Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev. 2012;21:134-147, PMID: 22144499. 2. Piek JM, et al. J Pathol. 2001;195:451-456, PMID: 11745677. 3. Medeiros F, et al. Am J Surg Pathol. 2006;30:230-236, PMID: 16434898. 4. Kwon JS, et al. Obstet Gynecol. 2013;121:1424, PMID: 23232752. 5. Friebel TM, et al. Clin Breast Cancer. 2007;7:875-882, PMID: 18269778. 6. Metcalfe KA, et al. Int J Cancer. 2008;122:2017-2022, PMID: 18196574. 7.

Rebbeck TR, et al. J Natl Cancer Inst 2009;101:80-87, PMID: 19141781.

Dr. Wahner Hendrickson reported no relevant financial disclosures.





Addition of Rituximab Increases B-Cell Lymphoma Survival From the Journal of Clinical Oncology


he addition of rituximab to a chlorambucil regimen has improved both event-free survival (EFS) and complete response (CR) rates in a study of patients with B-cell lymphomas of mucosa-associated lymphoid tissue (MALT). Initial chemotherapeutic treatment options for extranodal marginal-zone B-cell lymphomas of MALT have been understudied. There is a preponderance of MALT sited in the stomach, and the eradication of Helicobacter pylori generally has been the sole initial treatment for localized gastric involvement. Surgical and radiotherapeutic options are available

should this fail, but there is no consensus on systemic chemotherapeutic options or how to proceed in the case of multiple or non-gastric sites. Emanuele Zucca, MD, and an international group of colleagues from six countries and at 78 medical centers published their results in the Journal of Clinical Oncology (2013;31:565-572, PMID: 23295789). Patients were enrolled in the International Extranodal Lymphoma Study Group 19 (IELSG-19) Phase III, randomized study (Randomized Trail of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) from January 2003 to October 2005. Patients were admitted with a histologic diagnosis

EXPERT INSIGHT Craig Reeder, MD Consultant, Hematology/Oncology, and Assistant Professor of Medicine, Mayo Clinic


his well-written and well-intentioned randomized controlled trial compared alkylator therapy with chlorambucil versus rituximab and chlorambucil as treatment of extranodal marginal zone (MALT) lymphoma in patients having indications

for systemic therapy. The primary end point of the trial was EFS, and the two groups were well balanced for characteristics. The study once again confirmed an increased depth of response with the combination versus chemotherapy

of CD20-positive MALT lymphoma, either newly diagnosed or relapsed. No prior systemic therapy was allowed, except in order to eradicate H. pylori. After inclusions and exclusions, the patient pool of 227 was randomly assigned (1:1) into two pools. The first received oral chlorambucil 6 mg/m2 daily for six weeks; those responding continued receiving the dosage of chlorambucil for 14 consecutive days in 28-day cycles, for four cycles. The second arm added IV rituximab 375 mg/m2 daily on days 1, 8, 15, 22, 56, 84, 112 and 140. EFS was the primary end point; secondary end points included overall response rates, CRs, response duration, progression-free survival (PFS), overall

survival (OS), and acute and long-term toxicity. Both treatments were well tolerated without unexpected toxicities. At a median follow-up of 62 months, the five-year EFS of patients treated in the rituximab arm was significantly better than those treated with chlorambucil alone (68% vs. 50%; P=0.002). Patients in the rituximab plus chlorambucil arm had a higher CR rate as well (78% vs. 65%; P=0.025). Although PFS improved, it was not statistically significant, and the five-year OS was 89% in both arms. In October 2006, the protocol was amended and reopened with a third arm, consisting of treatment with rituximab alone. This study is still in progress.

alone. Achievement of a CR correlated with improved EFS but not with OS. Numerous trials have shown rituximab plus chemotherapy (R-chemo) to be superior to chemotherapy alone in enhancing time-to-event end points by producing more CRs. R-chemo has become the standard treatment for CD20-positive lymphomas when a chemotherapeutic approach is needed. This trial, like many others, failed to show long-term survival advantage. Indeed it seems EFS and PFS are poor surrogates for OS in low grade/indolent non-Hodgkin lymphoma, in part because of its long natural history and the ability to salvage patients at the

time of relapse. Newer drugs and radioimmunotherapy are adding even more options in the upfront and relapsed setting and will no doubt further obscure our ability to define a treatment that provides a survival advantage. This trial does underscore the excellent outcomes for patients with MALT lymphoma and EFS may be a reasonable objective in a clinical trial. As physicians treating patients, however, we must realize that EFS may not always be the best goal for the individual patient. Dr. Reeder reported no relevant financial disclosures.

Paclitaxel-Carboplatin for Platinum-Resistant Ovarian Cancer From The European Journal of Cancer


o combat the toxicities associated with paclitaxel plus cisplatin therapy in patients with platinum-resistant epithelial ovarian cancer, researchers are experimenting with a new combination—paclitaxel plus carboplatin (Paraplatin, Bristol-Myers Squibb)— and early results are promising. In a study published online in December 2012 by the European Journal of Cancer (2012 Dec 28 [Epub ahead of print], PMID 23276720), researchers identified 108 patients with epithelial

ovarian cancer, of whom 43 were platinum resistant. Treatment consisted of six weekly induction cycles of 90 mg/ m2 of paclitaxel plus area under the curve (AUC) 4 of carboplatin, both administered by one-hour infusion on days 1, 8, 15, 29, 36 and 43. Patients who demonstrated clinical benefit on the study regimen (stable disease, partial response and complete response) continued treatment with six maintenance cycles of 175 mg/m2 of paclitaxel in three-hour infusions plus AUC 6 carboplatin in one-hour infusions administered every three weeks. The study

end points included progression-free survival (PFS), overall survival (OS), response rate (RR) and toxicity. Both the weekly and the threeweekly cycles of the study regimen were well tolerated. Treatment delay (median seven days) was required in 16% of the 633 weekly cycles administered (these occurred mainly after the third or the fourth cycle) and in 29% of the 448 three-weekly cycles. Dose reduction was needed in only 2% and 15% of the cycles, respectively. During the 633 weekly cycles, reported grade 3/4 toxicities included

thrombocytopenia (8%), neutropenia (30%) and febrile neutropenia (0.5%). Among platinum-resistant patients, the RR for the paclitaxel plus carboplatin regimen was 58%. Median PFS and OS were eight and 15 months, respectively. Among platinum-sensitive patients, the RR was 76%, whereas PFS and OS were 13 and 26 months, respectively. Among 13 platinum-resistant patients who were started on weekly paclitaxel plus carboplatin less than six months after progression had significantly shorter PFS (four months) and OS (nine months).



Overdiagnosis of Breast Cancer Found in SEER Data Review 23171096). Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute were used to establish trends in the incidence of early-stage breast cancer (i.e., ductal carcinoma in situ and localized disease) and latestage breast cancer (i.e., both regional and distant disease) between 1976 and 2008. The women in the SEER data analyzed in this study were all at least age 40 years. In order to establish a baseline incidence of diagnosis without benefit of mammography, the authors chose the three-year period from 1976 to 1978.

From The New England Journal of Medicine


f a screening tool has merit, it should detect more cancers at earlier, more treatable stages and, as a result, catch fewer cancers at later stages. Researchers undertook an analysis of mammography screening, in which the incidences of both early- and late-stage breast cancers were reviewed over a span of more than three decades. The report, by Archie Bleyer, MD, and H. Gilbert Welch, MD, MPH, was published in The New England Journal of Medicine (2012;367:1998-2005, PMID:

EXPERT INSIGHT Sandhya Pruthi, MD Consultant, Breast Diagnostic Clinic, and Associate Professor of Medicine, Mayo Clinic


he Bleyer and Welch study has renewed the debate over the value of screening mammography. Its main criticism: Routine mammograms have led to overdiagnosis of breast cancer. The problem is that we simply don’t have sufficient long-term data on

outcomes on the term overdiagnosis. And, we don’t have prospective data to be able to reliably counsel patients. Therefore, it’s important to put the study findings in a broader context for women. The study did not account for additional lifestyle or reproductive risk

EXPERT INSIGHT Paul Haluska, MD, PhD Oncologist, and Associate Professor of Oncology, Assistant Professor of Pharmacology, Mayo Clinic


latinum-based chemotherapy is not only the standard front-line treatment for ovarian cancer, it is disease defining. Indeed, sensitivity to platinum is a powerful prognostic tool, with platinum-resistant patients carrying a poor prognosis. Platinum-resistant ovarian cancer can be defined as cancer that has progressed within six months of prior platinum-based chemotherapy. Although such patients may have a low RR, resistance is not absolute and may be overcome to varying degrees with combination chemotherapy, such

as paclitaxel, or by varying the schedule. This study published by van der Berg et al in the most recent issue of the European Journal of Cancerr investigates weekly induction chemotherapy with paclitaxel (90 mg/m2) and carboplatin (AUC 4) for six cycles, followed by six cycles of every three-weekly paclitaxel (175 mg/m2)/carboplatin (AUC 6). In summary, the authors conclude that given a 58% RR, eight-month PFS and 15-month OS for platinum-resistant patients, the treatment was effective therapy for this patient population.

Screening mammography has doubled the number of cases of early-stage breast cancer detected each year, from 112 to 234 cases per 100,000 women, representing an absolute gain of 122 cases. At the same time, the rate at which women present with late-stage cancer has decreased by 8% (from 102 to 94 cases per 100,000 women). If a constant underlying disease burden is assumed, then only eight of the newly detected 122 additional early cancers would have progressed to a later stage. This implies an excess detection of 114 cases of breast cancer per 100,000 women—a “substantial overdiagnosis.”

The authors estimated that mammography over-detects tumors that would never have progressed to clinical symptoms. In 2008, early-stage breast cancer was overdiagnosed in about 70,000 women. Late-stage survivorship has decreased 28% (from 71 to 51 deaths per 100,000), but this is attributed to a combination of improved treatment and screening mammography, with the former providing, in the authors’ estimation, a significantly larger contribution. The authors concluded that mammography has had only a small effect on the rate of death from breast cancer.

factors that may increase the incidence of breast cancer that are unrelated to screening, such as obesity and women giving birth at an older age. Additionally, it did not account for technological advances, such as the implementation of digital mammography. Much of the data reviewed in the study were based on film-detected mammograms. Breast cancer is the leading cause of death for women in their 40s. We know that women are diagnosed with earlystage breast cancers because of mammography. We also know we are going to save lives and improve prognosis by detecting cancers early, regardless of false-positives, unnecessary mammograms or unnecessary biopsies.

As practitioners, we need to make sure we’re obtaining a thorough and accurate family history to assess for hereditary breast cancer risk and counsel appropriately regarding surveillance and risk reduction options. However, it is just as important to remember that more than 50% of women diagnosed with breast cancer will not have a family history of breast cancer. Additionally, practitioners are encouraged to inform and counsel patients about the benefits, risks and limitations of having a mammogram, and they may be called back for additional mammograms or a biopsy.

Additionally, there were no reported grade 4, nonhematologic toxicities and a low incidence of grade 3 toxicities, leading the authors to conclude that the toxicity profile of the regimen was reasonably tolerable. The seemingly paradoxical sensitivity of platinum-resistant ovarian cancer to platinum is not a new area of investigation. Indeed, the authors draw comparisons to several prior studies, which identify the current study as having the largest platinum-resistant cohort yet investigated. It confirms that longer platinum-free intervals increase sensitivity to platinum therapy and outcomes. Technically, the study was conducted soundly and demonstrated that there is a high RR, including 16% complete responses, in platinum-resistant ovarian cancer. However, this comes at a price—26 weeks worth of chemotherapy, including an initial six weeks of intensive treatment, for approximately 32 weeks of PFS.

Although the nonhematologic toxicities were very reasonable, as expected, grade 3 or worse neutropenia was nearly universal. Thus, a quality-oflife assessment may have been useful to determine if patients themselves felt combination chemotherapy would be worth it to them at this point in the treatment of their disease. As these agents are clinically available for use in ovarian cancer, this work does remind us that platinum combinations are a potential option for patients with platinum-resistant disease. In addition to assessing quality of life, future studies could stand to perform correlative molecular analyses on tumor tissue to identify which patients are most likely to benefit from platinum, such that we could better individualize treatment for this group of patients in dire need of better therapies.

Dr. Pruthi reported no relevant financial disclosures.

Dr. Haluska reported no relevant conflicts of interest.





Bevacizumab Effective, Tolerable in Older CRC Patients From Clinical Colorectal Cancer


irst-line bevacizumab (Avastin, Genentech) plus chemotherapy may be just as safe as chemotherapy alone in older patients with metastatic colorectal cancer (mCRC), a new report has revealed. Although the FDA initially approved the study drug for first-line therapy of mCRC in 2004, its use in this setting— particularly among older patients—has been circumscribed due to the incidence of adverse events (AEs), such as gastrointestinal perforation, thromboembolic

events, hypertension, and wound-healing complications, in some clinical trials. However, before this study, which was published online in December 2012 by the journal Clinical Colorectal Cancerr (2012 Dec 28 [Epub ahead of print], PMID: 23276520), the relative safety of bevacizumab in older patients—particularly those with preexisting medical comorbidities—had not been thoroughly studied. The authors of the study identified 6,821 patients with mCRC aged 65 years and older from the Surveillance, Epidemiology and End Results

EXPERT INSIGHT Axel Grothey, MD Oncologist, and Professor of Oncology, Mayo Clinic


RC ranks second in cancer deaths in the United States with about 51,000 patients expected to succumb to this disease in 2013.1 The majority of patients with CRC are over the age of 65 years at diagnosis, with a median age of 71. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is a key component of standard systemic medical therapy used in the metastatic setting.2 Some of the bevacizumab-related side effects—in particular, the higher rate of arterial thromboembolic events compared with placebo—might limit the use of this drug in elderly patients with clinically relevant comorbidities.3 The analysis presented by Shankaran and colleagues used SEER-Medicare data to get a better understanding of the risk– benefit ratio for bevacizumab as a component of CRC therapy in elderly patients. The study included more than 6,800 patients in the periods 2001 to 2003 and 2005 to 2007, which are before and after the FDA approval of bevacizumab. One of the key findings was that patients over the age of 75 as well as patients with significant comorbidities and prior cerebrovascular disease were much less likely to receive bevacizumab as part of their therapy. In a retrospective, pooled analysis, the rate of AEs was not higher in patients treated with

Joleen M. Hubbard, MD Oncologist, and Assistant Professor of Oncology, Mayo Clinic

bevacizumab compared with patients treated with chemotherapy alone. The study has several limitations that are related to the very structure of the SEER database, which only captures AEs associated with Medicare claims. Thus, the analysis cannot be a substitute for a prospective evaluation of bevacizumab in clinical studies. The key conclusions of the analysis, however, mirror the results obtained in subgroup analyses of large observational cohort studies in CRC, as well as a pooled analysis of randomized trials conducted with bevacizumab.4,5 It appears that if elderly patients are carefully selected based on their clinical status, comorbidities and medical history, bevacizumab can be safely administered in this patient population, producing a similar treatment benefit from this drug to their younger counterparts. The efficacy and tolerability of bevacizumab in elderly patients has been confirmed in an elegant trial presented at the 2013 American Society of Clinical Oncology Gastrointestinal Symposium.6 In this international trial conducted exclusively outside of the United States, 280 patients with mCRC aged 70 years and older (median age 76) were randomized to capecitabine alone or capecitabine plus bevacizumab as first-line therapy. The addition of bevacizumab significantly improved

Program (SEER)-Medicare database and categorized them based on firstline treatment (none, chemotherapy alone, or chemotherapy and bevacizumab). Preexisting conditions known to increase bevacizumab-related risks for AEs were identified in the year before diagnosis. Among the patients selected for study, only 19% received first-line bevacizumab plus chemotherapy; those aged 75 years or older who had a higher comorbidity index or had preexisting cerebrovascular disease were less likely to receive the drug. Among those patients

who did receive first-line bevacizumab, the incidence of AEs was not higher compared with those who received chemotherapy alone (hazard ratio [HR], 0.97). Patients who received first-line chemotherapy without bevacizumab between 2005 and 2007 had the highest AE incidence rate; however, AE incidence rates were comparable between patients receiving first-line chemotherapy between 2001 and 2003 (135 AEs per 100,000 person-days) and patients receiving first-line chemotherapy with bevacizumab between 2005 and 2007 (141 AEs per 100,000 person-days).

It appears that if elderly patients are carefully selected based on their clinical status, comorbidities and medical history, bevacizumab can be safely administered in this patient population. progression-free survival and response rates and led to a remarkable median overall survival of almost 21 months, which rivals results in younger patients. Except for a slight increase in venous and arterial thromboembolic events, no increased side effects were noted with the inclusion of bevacizumab. These results suggest that capecitabine plus bevacizumab could be considered one of the treatment standards for elderly patients with CRC. In the United States, however, most elderly patients receive an oxaliplatin-based combination therapy like FOLFOX (leucovorin, 5-fluorouracil and oxaliplatin) or XELOX (capecitabine plus oxaliplatin) as backbone for the addition of bevacizumab.5 A prospective evaluation of oxaliplatin is still clearly warranted in the context of fluoropyrimidine (capecitabine)-bevacizumab first-line therapy. A trial addressing this very question was initiated by the Intergroup (N0949, NCT01279681), but was unfortunately closed in December 2012 due to poor accrual. In summary, the body of evidence confirms that bevacizumab can be safely and effectively used in elderly patients with CRC using clinical criteria to eliminate patients at higher risk for bevacizumab-related side effects. A fluoropyrimidine alone can be considered as chemotherapy backbone for the addition of bevacizumab in first-line therapy in patients over the age of 70.

References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. Ca Cancer J Clin. 2013;63:11-30, PMID: 23335087. 2. Grothey A, Allegra C. Antiangiogenesis therapy in the treatment of metastatic colorectal cancer. Ther Adv Med Oncol. 2012;4:301-319, PMID: 23118806. 3. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-1239, PMID: 17686822. 4. Cassidy J, Saltz LB, Giantonio BJ, et al. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol. 2010;136:737-743, PMID: 19904559. 5. Kozloff MF, Berlin J, Flynn PJ, et al. Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: results from the BRiTE observational cohort study. Oncology. 2010;78:329-339, PMID: 20733336. 6. Cunningham D, Lang I, Lorusso V, et al. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). ASCO Meeting Abstracts 2013;31:337.

The Mayo Foundation received research funding from Genentech for studies conducted by Drs. Hubbard and Grothey.



Cabozantinib Promising in Castration-Resistant Prostate Cancer From the Journal of Clinical Oncology


he orally bioavailable tyrosine kinase inhibitor cabozantinib (Cometriq, Exelixis) has demonstrated clinical activity in patients with castration-resistant prostate cancer (CRPC) in a Phase II randomized discontinuation trial with an expansion cohort. The FDA has already approved cabozantinib for the treatment of metastatic progressive medullary thyroid cancer. The Phase II trial, the results of which were published in the Feb. 1 issue of the Journal of Clinical

Oncology (2013;31:412-419, PMID: 23169517), enrolled 171 men with CRPC; all patients received open-label treatment with cabozantinib during a 12-week lead-in stage. Initially, those with stable disease at 12 weeks were to be randomly assigned to cabozantinib or placebo; however, the study oversight committee recommended suspension of randomization after enrollment of 122 patients because of “unexpected changes on bone scan and decrease in pain observed during the lead-in stage.” During the leadin stage, 72% of evaluable patients on

EXPERT INSIGHT Manish Kohli, MD Oncologist, and Associate Professor of Oncology, Mayo Clinic


abozantinib (previously known as XL-184) is an oral inhibitor of MET and vascular endothelial growth factor receptor 2, both of which are overexpressed during the emergence of CRPC and both of which also play a critical role in the development of bone metastases. In Phase I trials, cabozantinib has shown broad activity against several tumor types, with acceptable toxicity profiles. The current Phase II study evaluated efficacy of cabozantinib in patients with metastatic CRPC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and had progressed on at least one standard treatment. One of the key features of this study is its novel Phase II randomized “discontinuation” design. This design attempts to maintain the ability to evaluate tumors for response while minimizing exposure to placebo in tumors

with objective regression, while allowing for randomized evaluation where the activity is to prolong progression. In this study, therefore, all patients received an open-label treatment with 100 mg of oral cabozantinib during a 12-week lead-in stage followed by response assessments by Response Evaluation Criteria in Solid Tumors criteria, at which point patients with stable disease were randomly assigned to receive either cabozantinib or placebo. These randomly assigned patients were then observed until they met study-defined progression criteria, at which point treatment assignment was unblinded. Patients were taken off study if they were receiving cabozantinib or were allowed to restart cabozantinib if on placebo. Patients restarted on cabozantinib after first progression on placebo were observed until subsequent progression.

cabozantinib had regression in soft tissue lesions and 68% had improvement on bone scan, including 12% with complete resolution. As a result, in all, 31 patients were randomly assigned to either receive cabozantinib or placebo and 57 patients continued openlabel treatment, whereas an additional 49 eligible patients were enrolled before closure of the cohort (of these, 28 remained on cabozantinib for more than 12 weeks). Among those treated with the study drug for 12 weeks, median progression-free survival (PFS) was 23.9

weeks compared with 5.9 weeks with placebo (P ( <0.001). In 57% of these patients, serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by at least 50%. On retrospective review, bone pain improved in 67% of 116 evaluable patients, with a decrease in narcotic use in 56% of patients. The most common grade 3 adverse events reported during the trial were fatigue (16%), hypertension (12%) and hand-foot syndrome (8%). These resulted in dose reductions in 62% of patients.

Cabozantinib, although not yet ready for “prime-time” use as of yet, promises to be an extremely potent alternative for offering to CRPC patients. The use of this adaptive design had an 80% power to detect a hazard ratio of 0.5 for evaluating efficacy, with the primary end point being PFS from the point of random assignment after completion of the 12-week lead-in period, in those patients who demonstrated initial stable disease at week 12. By the 12-week lead-in period, 55 of the 171 patients enrolled had discontinued the cabozantinib treatments either due to drug toxicity or lack of response. However, the most interesting part of the results of this novel drug design lies elsewhere. After initially enrolling 171 patients for the 12-week lead-in period and after randomizing 122 patients of these to cabozantinib or placebo, the study continuation was suspended on the recommendation of the study oversight committee, as it was felt that unexpectedly positive results on bone scan and decrease in pain observed during the lead-in stage of random assignment made it unethical to continue randomization of patients to placebo

following the lead-in period. In this sense, the trial design and the study results have been successful, as the results demonstrate that the drug is efficacious and so should be pursued vigorously in Phase III trials, which are well under way. Of note, common all-grade adverse events included fatigue, decreased appetite, taste alterations, nausea, diarrhea, weight loss, and hand-foot syndrome in 62% of the study population. Cabozantinib, although not yet ready for “prime-time” use as of yet, promises to be an extremely potent alternative for offering to CRPC patients in the future if these initial efficacy results hold out in on-going Phase III trials. The current need thus lies in encouraging patients to be directed to on-going trails with this drug, if and when the current standard treatments for treating this stage have been exhausted. Dr. Kohli reported no relevant conflicts of interest.





ESMO Debate:

Should Neoadjuvant Data Be Used To Speed Drug Approval? Vienna—Can neoadjuvant breast cancer data be used to accelerate drug development? At the recent annual meeting of the European Society for Medical Oncology, a pro–con argument was conducted in a lively manner meant to incite controversy, convince audience members to change their minds and provide a few laughs in the process. PowerPoint slides even incorporated images of a bullfight with Jose Baselga, MD, PhD, in the arena.

Neoadjuvant Data: The Pro Argument Dr. Baselga, the physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York City, vehemently argued that pathologic complete response (pCR) can be used as a surrogate marker for disease-free survival (DFS) and overall survival (OS). Neoadjuvant trials, he said, provide an efficient trial design for assessing the efficacy of novel therapies.

pCR also was associated with improved OS (OR, 0.24) and was strongly correlated in HER2-positive (OR, 0.09; P=0.02) and triple-negative disease (OR, 0.29; P<0.00001). Additionally, the German Breast Group analyzed the association between tumor response at surgery and long-term outcome in patients with primary breast cancer receiving neoadjuvant anthracycline-taxane–based chemotherapy in seven randomized trials (J ( Clin Oncol 2012;30:1796-17804, PMID: 22508812). pCR was associated with improved DFS in luminal B/HER2 / -negative, HER2positive/nonluminal and triple-negative tumors, but not in luminal A or luminal B/HER2 / -positive breast cancer. “pCR after neoadjuvant chemotherapy is associated with significantly improved disease-free survival and overall survival, particularly for HER2positive and the triple-negatives. pCR should be considered as a surrogate

‘pCR should be considered as a surrogate marker for survival outcomes as new therapies are being evaluated in the neoadjuvant setting.’ —Jose Baselga, MD, PhD They involve smaller sample sizes, faster trials and less money than large Phase III adjuvant trials. Several studies speak to the strengths of pCR as an end point in breast cancer patients, said Dr. Baselga. The NOAH (NeOAdjuvant Herceptin) trial showed that neoadjuvant trastuzumab (Herceptin, Genentech) induced a higher pCR in patients with HER2-positive breast cancer than in those who received chemotherapy only and that this correlated with improved DFS (Lancet ( 2010;375:377-384, PMID: 20113825). In a recent meta-analysis, Dr. Baselga and his colleagues analyzed 30 published studies involving neoadjuvant chemotherapy in breast cancer patients to evaluate the association between pCR and subsequent DFS and OS (Bardia A, et al. AACR Advances in Breast Cancer Research Conference. Oct 2011). The average pCR rate in the sample of 11,206 patients was 22%, with a range of 3% to 27%, and pCR was associated with improved DFS (odds ratio [OR], 0.33; P<0.00001). The OR was 0.37 in HER2-positive patients and 0.20 in triple-negative tumors (P ( <0.00001).

marker for survival outcomes as new therapies are being evaluated in the neoadjuvant setting,” said Dr. Baselga. He added that in patients with estrogen receptor–positive breast cancer, clinicians need to think about using different biomarkers. Ki67 has been shown to be predictive in several clinical trials, including the RAD001 trial. This trial demonstrated that adding everolimus (Afinitor, Novartis) to neoadjuvant letrozole treatment in postmenopausal women with operable ER-positive

‘The fact that we cannot give everolimus in the adjuvant setting is ridiculous. If you have a patient with luminal disease that you know is going to recur with a high chance, we are doing a disservice to the community by not being able to offer it to them.’ —Jose Baselga, MD, PhD breast cancer improved response rate, from 59.1% to 68.1% ((J Clin Oncol 2009;27:2630-2637, PMID: 19380449). “At day 15, a large difference in Ki67 is seen between the everolimus plus letrozole and the placebo plus letrozole arms, which was not seen at baseline,” said Dr. Baselga. He argued that the neoadjuvant data from the RAD001 trial should speed drug approval. “The fact that we cannot give everolimus in the adjuvant setting is ridiculous,” said Dr. Baselga. “If you have a patient with luminal disease that you know is going to recur with a high chance, we are doing a disservice to the community by not being able to offer it to them.” Dr. Baselga pointed out that data from NEOALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimization) was not being allowed to influence clinical practice. Researchers simultaneously launched the ALTTO and NEOALTTO trials to investigate whether dual HER2 blockade with trastuzumab and lapatinib (Tykerb, GlaxoSmithKline) is better than single-agent trastuzumab. The primary end point of NEOALTTO, in which the dual blockade was given in the neoadjuvant setting, was pCR (Lan( cet 2012;379:633-640, PMID: 22257673). “The study accrued very rapidly, and

FDA’s Rationale for Using Pathologic Complete Response as a Surrogate End Point in Neoadjuvant Trials “We believe that use of pCR as an end point to support accelerated approval in high-risk populations in the neoadjuvant setting has the potential to help address unmet need in these populations in a far shorter time frame than would be required via the conventional approach to breast cancer drug development.” From “Guidance for Industry: Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.” U.S. Food and Drug Administration, May 2012.

for over a year and a half now, we have known that combined HER2 blockade induces a dramatic improvement in pathologic complete response,” said Dr. Baselga. Meanwhile, the ALTTO trial being conducted in the adjuvant setting involves 8,000 patients and is not expected to report results for several years. “Do we have any doubt that the outcome [of ALTTO] will be positive? No, we don’t,” said Dr. Baselga. “So, why are we depriving women of receiving dual HER2 blockade, which is clearly the way to go based on NEOALTTO?” Dr. Baselga pointed out that the FDA recently released a draft guidance stating a drug may receive accelerated approval based on a surrogate end point that is reasonably likely to predict clinical benefit, and for neoadjuvant breast cancer treatment, that surrogate could be pCR. “In case you don’t know, we are broke. We don’t have the resources to do 10,000-patient clinical trials. We cannot wait for the results of adjuvant trials that we know are going to be positive,” said Dr. Baselga. “The day that the ALTTO trial is positive, we are going to feel good, but we will also feel very sad and very bad, because we know that trastuzumab and lapatinib is better than trastuzumab, yet how many lives have we lost? Was this necessary? It was totally unnecessary. There is not a single wellconducted neoadjuvant trial that has not been confirmed in the adjuvant setting. There are some that are suboptimal that have never been confirmed, but that is an issue of science.”

Neoadjuvant Data: The Con Argument Ian Tannock, MD, PhD, a professor of medical oncology at Princess Margaret Hospital in Toronto, Canada, argued strongly that neoadjuvant data should not be used to speed drug approval. see NEOADJUVANT, T page 22 


Now Available... on Breast and Ovarian Cancers

Integrating Data, Improving Outcomes To participate in this FREE CME activity, log on to and enter keyword “MN122” Release Date: October 22, 2012


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

Expiration Date: October 22, 2013


Learning Objectives

Course Format

Ruth O’Regan, MD

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

Interactive Web-based monograph

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

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

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

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

Intended Audiences Oncologists

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

Estimated Time for Completion 90 minutes

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

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

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

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

To participate in this FREE CME activity, log on to and enter keyword “MN122”



NEOADJUVANT T continued from page 20 

Companies, he said, need to focus on developing drugs that have a meaningful impact on survival, decrease symptoms and improve quality of life. “We have to recognize that anything else is a surrogate end point, and while surrogate end points might be valuable, they must correlate with those outcomes,” said Dr. Tannock. “What we do not need are drugs that have a trivial impact on survival with a high cost and a high toxicity.” He said he accepted the fact that patients who achieve a pCR in neoadjuvant trials usually have better survival, but that did not get around the main problem of giving a new drug with unknown safety to women. “Even large randomized controlled trials are insufficient to disclose serious toxicities when new agents are prescribed. Nearly 60% of potential fatal adverse events are not in the initial FDA label,” said Dr. Tannock. “I think there are ethical questions about prescribing a new drug to patients after accelerated approval [is granted] based on a small neoadjuvant trial.” He also said that if the confirmatory trial of a drug that has gained accelerated approval is an adjuvant trial, there are ethical concerns about selling a drug to women who can afford it, while


recruiting others to a clinical trial. “Women will perceive benefit because of conditional approval, and they will be reluctant to take part in the clinical trial, so the whole process as proposed by the FDA may be retarded rather than accelerated,” said Dr. Tannock. He pointed to a study in the Journal of Clinical Oncology that provided a statistical argument as to why achieving response may be correlated with improved survival, but that it should not be used to imply cause and effect ((J Clin Oncol 2008:26;3913-3915, PMID: 18711176). One of the arguments put forth in this paper is that it is generally impossible to refute the possibility that response is just a marker that selects the good-prognosis patients, those who would have survived longer even if the therapy has no effect at all. The question is “is the surrogate end point of response reasonably likely to predict overall clinical benefit,” Dr. Tannock said. In the RAD001 trial, everolimus improved response rate, but grade 3/4 toxicities increased from 4% to 23%. “Neoadjuvant trials involving new agents require the new drug to be given to women with a potentially curable disease, [which is] not always a good strategy for potentially toxic new drugs,” said Dr. Tannock. He pointed out that improvements in surrogate end points do not always translate into survival benefits. For example,

‘Make no mistake: A drug that does not improve survival but does add toxicity is not a negative trial. That is a harmful trial.’ —Ian Tannock, MD, PhD

the FDA granted accelerated approval for bevacizumab (Avastin, Genentech) in metastatic breast cancer based on a 5.5-month improvement in PFS in the E2100 trial, but rescinded approval after several studies demonstrated that the drug only modestly improved PFS and did not increase overall survival. “Make no mistake: A drug that does not improve survival but does add toxicity is not a negative trial. That is a harmful trial,” Dr. Tannock said. Although he lamented the fact that few drugs have been approved for breast cancer in the past five years, he said that speeding the approval of subpar drugs was not the answer. “We don’t need a process that increases the approval of marginal drugs,” said Dr. Tannock. According to Dr. Tannock, one of the reasons that good drugs are not being developed is the FDA’s and the European Medicines Agency’s policy of approving any new drug that improves OS or PFS, no matter how small the difference, as long as it is statistically significant. “What this has done is [it has]

The Great Divide in Pain Medicine Access

—Kate O’Rourke Dr. Baselga has served as an advisor or consultant for Exelixis, Merck, Novartis and Roche, and has received grants for clinical research from GlaxoSmithKline. Dr. Tannock disclosed uncompensated consultant or advisory roles for and research funding from Bayer, Eli Lilly, Exelixis, Genentech, Johnson & Johnson and Sanofi.

Figure. Overall morphine consumption.

by the


encouraged Big Pharma to do very large trials to detect trivial differences in outcome that allow drug registration,” said Dr. Tannock. “We don’t need those enormous trials to detect a truly effective drug.” According to Dr. Tannock, the solution to the problem of unwanted marginal drugs is to require value-based pricing as a condition for approval, so that the price of new drugs is related to their effectiveness. Future trials would become smaller and faster because sample size depends on the effect size that a trial is designed to detect or exclude, and companies would be discouraged from developing marginally effective drugs.



United States





t the European Society for Medical Oncology annual meeting, researchers presented preliminary data from the International Collaborative Project to Evaluate the Availability and Accessibility of Opioids for the Management of Cancer Pain. The consortium evaluated opioid drug availability, cost to consumers and barriers that stand in the way of cancer patients trying to obtain these drugs. Data was gathered between December 2010 and July 2012 in 76 countries in Africa, Asia, the Middle East, Latin America, the Caribbean and 19 Indian states. Only 12 countries surveyed provided all seven of the opioid medications considered to be essential for the relief of cancer pain by the International Association for Hospice and Palliative Care: codeine, immediate- and slowrelease morphine, injectable morphine, oral oxycodone, oral methadone, and transdermal fentanyl. In many countries, opioids that were on a formulary were only available occasionally or half the time. Many countries have highly restrictive regulations that limit entitlement of cancer patients to receive prescriptions, limit prescriber privileges, impose restrictive limits on duration of prescription, restrict dispensing, and increase bureaucratic burden of the prescribing and dispensing process. “There is an urgent need for formulary review, improving affordability of medications, improving availability of opioids by better distribution and dispensing, careful examination of multiple drug control policies, and for repeal of excessive restrictions, which are impeding this most fundamental aspect of cancer care,” said Nathan Cherny, MD, head of Cancer Pain and Palliative Medicine, Shaare Zedek Medical Center, Jerusalem, Israel, who presented the survey results.

Worldwide morphine consumption













Mg/capita Based on 2009 and 2010 data from the International Narcotics Control Board.


... to receive the monthly e-newsletter from


Register for free

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded website links that give you instant access to additional information as well as unique search features and printing capabilities. Each installment contains brief summaries of the most important articles from the current issue and breaking news ahead of print.




A Second-Line Option for Neuroendocrine Tumors Multi-targeted TKI pazopanib shows promise in mixed, pretreated patient population Vienna—Pazopanib (Votrient, GlaxoSmithKline) may offer a treatment option for patients with locally advanced or metastatic pancreatic neuroendocrine tumors (pNETs) that have failed treatment with two of the most recently approved drugs for this patient population. This news comes from results of the Phase II PAZONET trial, which were reported at the annual meeting of the European Society for Medical Oncology (abstract 11570). “Pazopanib is the first drug to show clinical activity in patients with neuroendocrine tumors who have failed at least one previous systemic treatment based on mammalian target of rapamycin (mTOR) inhibition or other multitargeted agents,” said Enrique Grande, MD, from the Ramon y Cajal University Hospital in Madrid, Spain, who presented the results on behalf of the Spanish Task Force for NETs. The most recent agents to be approved by the

FDA for pNETs are the vascular endothelial growth factor receptor inhibitor sunitinib (Sutent, Pfizer) and the mTOR inhibitor everolimus (Afinitor, Novartis). Both drugs were approved in 2011 based on progression-free survival data. The new multicenter study included 44 patients with well- and moderately differentiated carcinoid or pancreatic islet cell, locally advanced or metastatic tumors that were not amenable to surgery, radiation or combined modality therapy with curative intent. Patients were treatment naive (21%) or had been treated with an mTOR inhibitor only (24%), a tyrosine kinase inhibitor (TKI) only (36%), or both a TKI and an mTOR inhibitor (24%). All patients had progressive disease within 12 months and the median number of previous systemic treatments was two. Fortytwo patients were evaluable for response. The primary end point was clinical benefit rate, defined as complete response plus partial response plus

Table. Clinical Benefit Rate in NET Patients Receiving Pazopanib Response by RECIST

Patients, %

Complete response


Partial response


Stable disease


Progressive disease


NET, neuroendocrine tumor; RECIST, Response espo se Evaluation va uat o C Criteria te a in So Solid d Tumors u o s

stable disease at six months by Response Evaluation Criteria in Solid Tumors. The clinical benefit rate was 85.7% (Table) and the median progression-free survival was 10 months. Grade 3/4 toxicities included asthenia (19%), diarrhea (10%), hypertension (10%), transaminase

elevation (12%), hyporexia (2%) and hyperglycemia (7%). According to Eric Baudin, MD, PhD, from the Institut de Cancerologie Gustave Roussy in Villejuif, France, an expert on NETs, the study suggests antitumor activity of pazopanib in a mixed population of well-differentiated NETs pretreated with multiple options including a TKI and/or an mTOR inhibitor in 80% of cases. He was encouraged by the safety data. “Sequencing of targeted molecular therapies could be considered an option in future protocols analyzing best sequencing strategy in NETs,” Dr. Baudin said. —Kate O’Rourke Dr. Grande disclosed he is on the advisory boards and has received honoraria from IPSEN Pharma, Novartis Oncology and Pfizer Oncology and has received research support from GSK Oncology. Dr. Baudin disclosed a relationship with HRA, Ipsen, Novartis, Pfizer and Sanofi.

Adding Cetuximab Gives No Benefit in Stage III CRC PETACC8 trial reports negative results Vienna—Adding cetuximab (Erbitux, Merck Serono) to FOLFOX4 does not improve outcomes in patients with resected stage III colorectal cancer (CRC), according to results from the Phase III PETACC8 (Pan-European Trials in Alimentary Tract Cancer) trial, reported at the annual meeting of the European Society for Medical Oncology (LBA4). The trial can be added to the growing list of studies that have shown that CRC therapies that are effective in the metastatic setting are not always successful in early stages of the disease. In PETACC8, patients with fully resected stage III, KRAS wild-type CRC were randomized to receive six months of adjuvant treatment with FOLFOX4, either with or without cetuximab.

Chemical structure of cetuximab.

FOLFOX4 consists of oxaliplatin 85 mg/ m2 administered as a two-hour infusion on day 1; leucovorin (200 mg/m2) administered as a two-hour infusion on days 1 and 2; followed by a loading dose of 5-fluorouracil (5-FU; 400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on days 1 and 2 every two weeks. In an interim analysis of 1,602 patients, Julien Taieb, MD, PhD, from the Georges Pompidou European Hospital-Paris Descartes University in Paris, France, reported no difference in disease-free or overall survival. There were no survival differences in BRAF wild-type patients. A subgroup analysis showed that patients with more aggressive pT4N2 tumors might benefit from cetuximab (hazard ratio, 0.555; P=0.0122). Colon cancer expert Fortunato Ciardiello, MD, PhD, from the Second University of Naples in Italy, offered several possible reasons for the negative results. First, perhaps in unselected, fully resected stage III CRC patients treated for six months with a combination of a fluoropyrimidine and oxaliplatin, “a plateau of efficacy has been reached.” This would explain the negative results of the recent CRC trials investigating either bevacizumab or cetuximab, said

Dr. Ciardiello. A second possibility is that the FOLFOX chemotherapy backbone is not the most appropriate combination for cetuximab. Another potential explanation is that the biology of micrometastases in fully resected stage III CRC patients is different from the biology of metastases in stage IV CRC and, therefore, anti-angiogenic drugs and anti-endothelium growth factor receptor drugs are not effective in the adjuvant setting. This latter hypothesis has been previously suggested to explain the negative results of the AVANT and National Surgical Adjuvant Breast and Bowel Project CO-8 trials, both of which tested bevacizumab, as well as the North Central Cancer Treatment Group-N0147

trial that tested cetuximab. A fourth explanation, said Dr. Ciardiello, is that the KRAS wild-type tumor group is a heterogenous biologic and pathologic group, and thus this group needs to be further divided to find effective therapies. “I strongly encourage the authors to conduct further translational research studies in the PETACC8 KRAS wild-type patients,” said Dr. Ciardiello. —Kate O’Rourke Dr. Taieb disclosed a consultancy/advisory role and honoraria from Merck KGaA. Dr. Ciardiello disclosed honoraria and research funding from Bayer, Merck KGaA and Roche.

Why They’re Not Working


argeted therapies have now failed in a series of advanced colorectal cancer trials. Here are some theories as to why:

• FOLFOX provides a “plateau of efficacy” that targeted therapies cannot improve on in unselected patients • FOLFOX does not pair well with bevacizumab or cetuximab • Micrometastic disease in resected stage III patients is biologically different from metastases in stage IV disease • The KRAS S wild-type tumor group is heterogenous with subgroups of responders and non-responders that have yet to recognized

Education That Matches Your Preferred Learning Style.

The Oncology Education Collaborative helps you identify educational activities in the learning formats YOU prefer. Select from a broad array of activities including live meetings, online programming, podcast downloads, mobile app education, print education, satellite radio broadcasts, and more. Learn more at




FDA Approves Generic Version of Doxil To Ease Shortage O

n Feb. 4, the FDA approved the first generic version of doxorubicin hydrochloride (HCl) liposome injection to ease an ongoing shortage of the cancer drug, the agency announced in a press release. For products on the FDA’s drug shortage list, the agency’s Office of Generic Drugs uses a priority review system to expedite review of generic applications. The newly approved medication is made by Sun Pharma Global FZE, and is the generic equivalent to Doxil (Janssen Products, LP). The drug will be available in 20- and 50-mg vials, according to the press release. Doxorubicin

HCl liposome injection is administered intravenously and indicated, under certain conditions, for ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma, according to the drug’s prescribing information. “The agency is committed to doing everything we can to address drug shortages so that patients can get the medicines they need when they need them,” Capt. Valerie Jensen, RPh, the director of Drug Shortage Staff at the FDA’s Center for Drug Evaluation and Research, said in a statement. “For the past year, the FDA has been working to ensure that supplies of doxorubicin

continue to allow importation of Lipodox. However, once supplies of Sun Pharma’s approved version of the drug are sufficient to meet projected demand, the agency said it expects to reinstate its ban on importing any unapproved doxorubicin HCl liposomal product. Janssen Products, which is the sole U.S.-based supplier of doxorubicin HCl liposome injection, has stated that manufacturing issues are to blame for the ongoing shortages of Doxil. Updates on the drug’s availability can be obtained at http://www.doxilsupply. com/index.html. —George Ochoa

hydrochloride liposome injection were not interrupted.” Part of those efforts by the agency included a decision in February 2012 to allow temporary importation of Lipodox, a branded version of doxorubicin HCl liposome injection that also is produced by Sun Pharma, along with its distributor, Caraco Pharmaceutical Laboratories Ltd. The FDA stressed, however, that Lipodox is not approved for marketing in the United States; the agency used its regulatory enforcement discretion to allow importation of the drug during the Doxil shortage. For the present time, the FDA will

Pomalidomide Approved for Advanced Multiple Myeloma O

n Feb. 8, the FDA approved pomalidomide (Pomalyst, Celgene Corporation) for patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression within 60 days of the last treatment, according to an agency press release. “Treatment for multiple myeloma is tailored to meet individual patient’s needs, and today’s approval provides an additional treatment option for patients who have not responded to other drugs,” Richard Pazdur, MD, director of the Office of

Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. A thalidomide analog, pomalidomide was approved under the FDA’s accelerated approval program and was granted orphan product designation. According to FDA and Celgene press releases, pomalidomide’s safety and effectiveness were evaluated in a Phase II, randomized, open-label trial of 221 patients with relapsed or refractory multiple myeloma. Patients were randomized to pomalidomide alone or pomalidomide with low-dose dexamethasone. In patients

treated with pomalidomide alone, 7.4% achieved objective response rate (ORR). The median duration of response has not yet been reached in this arm. In patients treated with pomalidomide with lowdose dexamethasone, 29.2% achieved ORR; median duration of response was 7.4 months. Approval is based on response rate, according to the Celgene press release. Clinical benefit, such as improvement in symptoms or survival, has not been verified. Pomalidomide carries a boxed warning stating that it is contraindicated

Therapeutic developments: Antibody-drug


n February 22, the FDA approved trastuzumab emtansine (T-DM1, Roche) under the agency’s priority review pathway for women with HER2-positive, metastatic breast cancer (mBC) who have been previously treated with trastuzumab (Herceptin) and a taxane chemotherapy, either separately or in combination. T-DM1 is a novel antibody-drug conjugate—the cytotoxic agent mertansine (DM1) is attached to the antibody trastuzumab using a biochemical link designed by the biotechnology company ImmunoGen. The theory is that an antibody, by targeting surface proteins like HER2 or CD56, will deliver a cytotoxic “payload” directly to cancer cells wherever they may be throughout the body. T-DM1 is only the first in a series of drugs in clinical development using conjugate technology, a concept that stands to have a significant impact on cancer treatments. T-DM1 is already being tested in a Phase II/III study of gastric cancer and Roche has reported that the company has approximately 25 antibody-drug conjugates in their development pipeline alone. The Table highlights a handful of conjugate compounds in development that are using ImmunoGen’s technology.

in pregnancy because it causes severe birth defects or embryo-fetal death; and that it can cause venous thromboembolism. Because of the embryo-fetal risk, pomalidomide is available only through the Pomalyst Risk Evaluation and Mitigation Strategy program. Common adverse reactions include fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain and pyrexia. —Based on FDA and Celgene press releases


Table. Clinical-stage compounds with ImmunoGen’s antibody-drug conjugate technology. ADC Compound

Disease Type

Development Stage


HER2+ breast cancers

Ph III/registration


HER2+ gastric cancers




Diffuse large B-cell lymphoma



Small-cell lung cancer




Multiple myeloma




Ovarian, lung cancers

Ph I



Solid tumors

Ph I



Non-Hodgkin’s lymphoma

Ph I


BAY 94-9343

Solid tumors

Ph I


AMG 595


Ph I


Amgen 2


Ph I





makes all the difference

With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine.

Help and Hope

1-800-813-HOPE (4673)




Breast Ultrasound Best for Evaluating Young Women Single-center study suggests an unlikely change in imaging guidelines


ltrasound should be the primary imaging modality in women aged 30 to 39 years with focal breast signs or symptoms, according to a large study. Adjunct mammography adds little value and should be reserved for certain high-risk cases, such as patients with a highly suspicious lesion on ultrasound, a known gene mutation or a strong family history for the malignancy, according to the study authors ((AJR 2012;199:1169-1177, PMID: 23096195). “We studied women under 40 with palpable breast lumps to see how best to diagnose cancer. This hasn’t been studied carefully,” lead author Constance D. Lehman, MD, PhD, a professor of radiology at the University of Washington in Seattle and the director of imaging for Seattle Cancer Care Alliance, told Clinical Oncology News. “This is the largest study to date of breast ultrasound and adjunct mammography in women 30 to 39 years of age who present with focal breast signs or symptoms of cancer in the United States.” In the retrospective, single-center study, the researchers identified all women in their 30s who underwent ultrasound examination with corresponding mammography between Jan. 1, 2002 and Aug. 31, 2006, for focal breast signs or symptoms. The total cases identified were 1,208 in 954 patients (mean age, 35 years). Outcomes were benign in 1,185 cases (98.1%) and malignant in 23 cases (1.9%). Ultrasound found 22 of the 23 cancers, whereas mammography found 14 of 23. Breast ultrasound proved to have 95.7% sensitivity for cancer detection at the site of focal breast concern, 89.2% specificity, 99.9% negative predictive value (NPV) and 13.2% positive predictive value (PPV). Mammography had a sensitivity of 60.9%, specificity of 94.4%, NPV of 99.2% and PPV of 18.4%. Mammography detected one additional malignancy in an asymptomatic area in

Right breast ultrasound from a 35 year-old patient with bilateral palpable breast masses. The ultrasound documented a 19×14-mm hypoechoic mass. She was found to have metastatic disease to her breast from a lung neuroendocrine carcinoma. Vaughan et al. World Journal of Surgical Oncology 2007

‘It suggests that a change in guidelines and practice is warranted, specifically that ultrasound should be the first “go to” radiologic examination, and that mammography might be largely abandoned for patients in this age group, in this specific clinical scenario.’ —Andrew Seidman, MD a patient who subsequently was found to have a BRCA2 gene mutation. “Before our study, in the United States we were doing mammography first in women ages 30 to 39,” said Dr. Lehman. “We found that best practice is to start with ultrasound. Ultrasound is the better primary tool in these women.” The current American College of Radiology

(ACR) Appropriateness Criteria for women 30 years of age or older with a palpable breast mass recommend mammography as the first imaging modality, followed by ultrasound. Dr. Lehman thinks the criteria should be revised. “ACR is reviewing our data and other available evidence, and considering changes to their guidelines.” Andrew D. Seidman, MD, an attending

physician at Memorial Sloan-Kettering Cancer Center in New York City, who is not associated with the study, commented: “It is an important study because it represents the largest analysis of the utility of ultrasonography and diagnostic mammography in patients between 30 and 39 years of age who present with breast signs or symptoms. It suggests that a change in guidelines and practice is warranted, specifically that ultrasound should be the first ‘go to’ radiologic examination, and that mammography might be largely abandoned for patients in this age group, in this specific clinical scenario.” Regarding the study’s limitations, Dr. Lehman said, “It’s a single-site study. And the ultrasound was performed by radiologists specialized in the use of breast ultrasound.” Dr. Seidman noted these and other limitations, including the study’s retrospective design and its insufficient “special handling” of patient subgroups at higher baseline risk for having breast cancer or ductal carcinoma in situ. Dr. Seidman did not agree, however, that the current ACR Appropriateness Criteria should be revised on the strength of this study. “While it would appear that mammography may indeed add very little to ultrasonography for the woman aged 30 to 39 who presents with breast signs or symptoms, it is hard for me to imagine that under such circumstances, patients and their physicians will forgo mammography. The time of breast pain or a lump is an anxious moment for most women, and a retrospective, single-institution study, no matter how robust, does not seem sufficient to either change guidelines or dissuade patients and their physicians from proceeding with mammography, or even [magnetic resonance imaging], for that matter.” —George Ochoa Drs. Lehman and Seidman reported no relevant financial conflicts of interest.

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



Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights from ASH 2012 and NEJM, Blood and JCO

4. True


1. True or False. In Hodgkin lympho-

ma (HL), 10% to 15% of patients with early-stage and 20% to 30% of those with advanced-stage disease fail to achieve durable remissions, ultimately dying of resistant or recurrent HL.

2. True or False. The German Multi-

center Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) reported that the administration of singleagent blinatumomab (MT103, Micromet) improved relapse-free survival (RFS) in patients with B-cell adult acute lymphoblastic leukemia (ALL) with persistent or recurrent minimal residual disease (MRD).

3. True or False. Tiziano Barbui, MD,

and colleagues at the Research Foundation at Ospedali Riuniti di Bergamo in Italy, reported a hazard ratio (HR) of 1.0 for thrombosis in patients with essential thrombocytosis (ET) who are harboring the JAK2V617F mutation.

by the


or False. Using the new threetiered International Prognostic Score of thrombosis in the essential thrombocythemia (IPSET-thrombosis) model, the risk for thrombosis was 1.03% patients per year in the low-risk group, 2.35% in the intermediate-risk group and 3.56% in the high-risk group.

6. True or False. Chris-

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

5. True or False. On Feb. 8, 2013,

the FDA granted accelerated approval to pomalidomide (Pomalyst, Celgene) for the treatment of patients with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Millennium), and have demonstrated disease progression within 60 days of completion of the last therapy.

tian Gisselbrecht, MD, on behalf of the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study, reported significant improvement in event-free survival (EFS) with rituximab maintenance therapy following autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with relapsed CD20+ diffuse large B-cell lymphoma (DLBCL).

7. Patients with angioimmunoblastic

T-cell lymphoma (AITL) may have all of the following characteristics except: a. hemolytic anemia b. skin rash c. hypergammoglobulinemia d. presence of T-cell receptor gene rearrangements in 100% of the patients

8. True or False. Quantitation of

hematogones at engraftment is useful

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

to predict prognosis of patients treated with allogenic HSCT (allo-HSCT).


True or False. In newly diagnosed MM, IgH translocations are detectable in approximately 20% of patients.

10. True or False. Currently, the

one subgroup of patients with DLBCL who should be considered for alternate initial therapy, outside of a clinical trial, is the subset with a concurrent translocation involving BCL2 and MYC.

11. True or False. Gene expres-

sion profiling (GEP) studies have identified several molecular subtypes within DLBCL with distinct intracellular oncogenic pathways. for answers see CONUNDRUMS, S page 30 

How easy is it for patients and physicians to access newly approved cancer drugs? It depends on what country you live in. At the European Society for Medical Oncology annual meeting, experts discussed access issues. One physician, Heinz Zwierzina, MD, of Innsbruck Medical University in Austria, highlighted the differences in average time delay between marketing approval of cancer drugs and effective market access. Germany, the United States and the United Kingdom came out on top.

Figure. Access to New Drugs Based on data from Ann Oncoll 2007;18 Suppl 3:iii1-iii77.

United States


United Kingdom



0 123


















Belgium 0





Average time delay in days between approval of cancer drugs and market access





CONUNDRUMS continued from page 29 


1. True. There remains an unmet

need for a valid method to predict the completeness of therapeutic response and ultimately patient outcomes in HL. Ideally before treatment, or early in treatment, identifying a patient subset in which continuing standard therapy would be ineffective is preferable in order to institute a more effective therapy to achieve complete response. Positron emission tomography (PET)/computed tomography has yielded highly promising results as a surrogate test for determining tumor chemosensitivity and outcomes. Several ongoing prospective trials are exploring the feasibility of treatment de-escalation strategies in patients with a negative interim PET, as well as therapy escalation in patients with advanced-stage HL who have a positive interim PET result. Gallamini A, Kostakoglu L. Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood. 2012;120:4913-4920, PMID: 22932799. Hutchings M, Mikhaeel NG, Fields PA, et al. Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol. 2005;16:1160-1168, PMID: 15939713.

2. True. In this Phase II study report-

ed on behalf of GMALL, blinatumomab demonstrated excellent activity against MRD in virtually all patients with B-precursor ALL, including patients with Philadelphia chromosome-positive ALL harboring the T315II mutation and older adults. These positive results are being confirmed in the larger ongoing trials. Topp MS, Gökbuget N, Zugmaier G, et al. Longterm follow-up of hematological relapse-free survival in a phase II study of blinatumomab in patients with minimal residual disease (MRD) of B-precursor acute lymphoblastic leukemia (ALL). Blood. 2012;120:5185-5187. PMID: 23024237. Bassan R. Toward victory in adult ALL: blinatumomab joins in. Blood. 2012;120:5094-5095, PMID: 23258898.

3. False. The HR for patients har-

boring JAK2V617F was 2.0, indicating a 100% increase in risk for thrombosis compared with individuals without the JAK2V617F mutation. The HRs for thrombosis for patients aged 60 years or older, those with cardiovascular (CV) risk factors and those with a history of thrombosis were 1.5, 1.6


and 1.9, respectively. In the new threetiered prognostic model for thrombosis in ET, patients aged 60 years or older or those with presence of CV risk factors are assigned 1 point, whereas patients with history of thrombosis or presence of JAK2V617F mutation are assigned 2 points. The low-risk group for thrombosis is defined as a total score of less than 2 points; intermediate risk, 2 points; and high risk, greater than 2 points. The investigators recommend cytoreductive therapy in patients of any age who have a history of thrombosis, or in patients with advanced age with either CV risk factors or JAK2V617F-positive mutational status. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-5133, PMID: 23033268.

4. True. In the two-tiered “conven-

tional” classification, risk for thrombosis was 0.95% patients per year in the lowrisk group and 2.86% patients per year in the high-risk group. Only 48% of previously defined low-risk patients are considered at low risk with the new classification, whereas the remaining 52% are classified as intermediate risk. The majority of patients classified at high risk, according to conventional risk factors, are now reclassified at intermediate (31%) or even at low thrombotic risk by IPSET. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSETthrombosis). Blood. 2012;120:5128-5133, PMID: 23033268.


True. The approval was based on the results of the CC-4047-MM-002 clinical trial, a multicenter, randomized, open-label study in 221 patients with relapsed and refractory MM. The efficacy results demonstrated an overall response rate of 7% in patients treated with pomalidomide alone and 29% in those treated with pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable in the pomalidomide-alone arm and was 7.4 months in the pomalidomide plus lowdose dexamethasone arm. The recommended dose and schedule for pomalidomide is 4 mg taken orally on days 1 to 21 of repeated 28-day cycles until disease progression.

American Society of Hematology. FDA grants accelerated approval to pomalidomide for patients previously treated for multiple myeloma. http:// Accessed February 9, 2013.


False. In total, 477 patients with CD20+ DLBCL who were in their first relapse or were refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by hematopoietic cell rescue. There were 242 patients randomly assigned to either rituximab every two months for one year or observation. After auto-HSCT, 122 patients received rituximab, and 120 patients were observed only. The median followup time was 44 months. The 4-year EFS rates after auto-HSCT were 52% and 53% for the rituximab and observation groups, respectively ((P=0.7). Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20+ diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30:4462-4469, PMID: 23091101.

7. D. AITL is a rare clinicopatholog-

ic entity characterized by an aggressive course and dismal outcome with current therapies. Five-year overall and failurefree survivals are 33% and 18%, respectively. The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer–cell lymphomas. Twenty-two institutions in North America, Europe and the Far East participated in the study. From 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphadenopathy was noted in 76% of patients and 89% had stage III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammoglobulinemia occurred in 13% and 30% of patients, respectively. T-cell receptor gene rearrangement is negative in up to 30% of patients with AITL. Federico M, Rudiger T, Bellei M, et al. Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol. 2013;31:240-246, PMID: 22869878.

8. True. Transient marrow expan-

sion of normal B-cell precursors, termed hematogones, is occasionally observed

after allo-HSCT. In the study by Takahiro Shima, MD, and colleagues, hematogones that comprised greater than 5% of bone marrow mononuclear cells constituted a group of patients with significantly prolonged overall survival and RFS, irrespective of their primary disease or donor cell source following allo-HSCT. Shima T, Miyamoto T, Kikushige Y, et al. Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation. Blood. 2013;121:840-848, PMID: 23233661.

9. False. In newly diagnosed MM,

IgH translocations are detectable in approximately 40% of patients. There is a notable diversity of chromosomal partners involved in IgH translocations. The most frequently involved loci are 11q13 (CCND1) in 15%, 4p16 (FGFR3/ MMSET) in 15% and 16q23 (MAF) in 5% of cases. Other recurrent loci, including 6p21 (CCND3) and 20q11 (MAFB), occur less frequently. Bergsagel PL, Mateos MV, Gutierrez NC, et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood. 2013;121:884-892, PMID: 23165477.

10. True. Patients with dual trans-

locations have a worse outcome and should be considered for alternate therapies. Although it remains unclear which alternate approach will prove beneficial, these patients have a remarkably poor outcome after R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) regimen, with a median survival of less than one year. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:402-409, PMID: 23233611. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452-3459, PMID: 22851565.


True. Despite our improved understanding of the diversity of DLBCL, management strategies remain remarkably uniform. The GEP analysis has paved way for novel clinical trials with agents targeting dominant biologic pathways in molecularly determined DLBCL. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362:1417-1429, PMID: 20393178.


Now Available...

Individualizing Therapy in Metastatic Breast Cancer To participate in this FREE CME activity, log on to and enter keyword “MM112” Release Date: October 22, 2012

Expiration Date: October 22, 2013


Learning Objectives

Linda T. Vahdat, MD

1 Appraise recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or metastatic breast cancer (MBC).

Associate Professor of Clinical Medicine NewYork Presbyterian Hospital Weill Cornell Medical Center New York, New York


Adam Brufsky, MD, PhD Assistant Professor of Medicine University of Pittsburgh School of Medicine Co-Director, Comprehensive Breast Cancer Center Medical Director, Women’s Cancer Center Magee Womens Hospital/UPCI Pittsburgh, Pennsylvania

William J. Gradishar, MD Professor of Medicine Division of Hematology and Medical Oncology Department of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

in integrating this potentially practice-changing data. For these reasons, oncologists require education on clinically relevant recent studies, against a backdrop of evidence- and consensus-based treatment recommendations.

2 Describe a treatment algorithm that reflects evidence-based management of advanced HER2-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

Course Format

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

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

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

Intended Audiences Oncologists

Statement of Need Complexities in the management of MBC are substantial, and the optimal approach to therapy remains unclear. Toxicity, resistance, and hypersensitivity reactions limit the use of cytotoxic drugs in mainstay treatment regimens, and improved therapeutic options are needed for this heterogeneous disease. There are encouraging data on novel treatment approaches, including combinations and sequencing regimens, but clinicians face challenges

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

Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement

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

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, view the program, and complete the post-test and evaluation. A score of at least 75% is required to complete this activity successfully. CME certificates will be issued immediately upon successful completion. This activity is supported by educational grants from Genentech, Inc

To participate in this FREE CME activity, log on to and enter keyword “MM112”













ABC of Breast Diseases

J. Michael Dixon October 8, 2012 This book covers congenital problems, breast infection and mastalgia and addresses the epidemiology, prevention, screening and diagnosis of breast cancer. It outlines the treatment and management options for breast cancer within different groups and includes new chapters on the genetics, prevention and management of high-risk women.

Scan here for our complete catalog of medical books.

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at


Abeloff’s Clinical Oncology: Expert Consult—Online and Print

Martin D. Abeloff; James O. Armitage; John E. Niederhuber; Michael B. Kastan; W. Gillies McKenna May 21, 2008 This respected reference incorporates basic science, pathology, diagnosis, management, outcomes, rehabilitation and prevention—all in one convenient resource—equipping you to overcome your toughest clinical challenges.


Annual Editions: Dying, Death, and Bereavement 13/14

George Dickinson; Michael Leming January 31, 2013 The Annual Editions series is designed to provide convenient access to a wide range of current articles from some of the most respected magazines, newspapers and journals published today.


Atlas of Diagnostic Oncology: Expert Consult—Online and Print: Fourth Edition

Arthur T. Skarin December 23, 2009 This atlas provides the guidance you need to diagnose a full range of neoplastic conditions with greater accuracy for better patient outcomes. An unrivaled collection of more than 2,500 images and drawings—combined with succinct, clinically focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations. a estat o s


Encyclopedia of Radiation Oncology

Jay E. Reiff; Reiner Class; Stephan Mose; Luther W. Brady; Theodore Yaeger April 30, 2013 The aim of this comprehensive encyclopedia is to provide detailed inforr mation on radiation oncology. The wide range of entries is written by leading experts. They will provide basic and clinical scientists in academia, practice and industry with valuable information about the field of radiation oncology.


Manual of Clinical Oncology: Seventh Edition

Dennis A. Casciato May 9, 2012 This guide is a concise pocket manual that incorporates basic science, clinical findings and available technology into the diagnosis and management of cancer. It focuses on information useful for participating in rounds and for making diagnostic and therapeutic decisions at the bedside of cancer patients.


MD Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller April 22, 2011 This book details the personalized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.


Surgical Oncology

David Bartlett; Pragatheeshwar Thirunavukarasu; Matthew D. Neal May 4, 2012 Surgical Oncology y incorporates the basic tenets of surgical practice with the innovations of modern technology in an evidence-based fashion.The book presents the opinions of experts in the field alongside an analytical and unbiased review of the evidence. Each chapter contains not only a summary of the relevant data, but also presents succinctly a list of landmark studies for disease or organ g system. y CO0313

The March 2013 Digital Edition of Clinical Oncology News  

The March 2013 Digital Edition of Clinical Oncology News

The March 2013 Digital Edition of Clinical Oncology News  

The March 2013 Digital Edition of Clinical Oncology News