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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • October 2013 • Vol. 8, No. 10

INSIDE SOLID TUMORS Nintedanib Looks Promising for NSCLC Approval ................................... 10

CURRENT PRACTICE Elihu Estey, MD: How I Manage Acute Myeloid Leukemia in Young Adults .......................... 14 Clinical Conundrums ........................... 16

by the


he growing demand for cancer care, combined with increasingly complex treatments, a shrinking workforce and rising costs, now constitutes “a crisis” for the field, according to a new report from the Institute of Medicine (IOM). Health care experts have been warning that the cancer care system needs improvements. The new report, from one of the most respected organizations in health care policy, effectively pours gasoline on the fire. According to Matthew Farber, the director of provider economics and


Medicare chemotherapy costs: office vs. hospital cost +33% | additional per patientt of giving chemo in the hospital cost +29% | additional per day y of giving chemo in the hospital Patients 13% | receiving

chemo in the hospital setting in 2005

33% | In 2011 Costs based on 2011 data. Source: From studies done by the Moran Company on behalf of The US Oncology Network, Community Oncology Alliance and ION Solutions.


IOM Report Warns Of Impending Cancer Care Crisis

see IOM CRISIS, S page 3

Image courtesy of Science Photo Library

340B: Helping Patients or Enriching Hospitals?

ASCO 2013

Payment Reform: Between a Rock And a Hard Place Chicago—Community oncology practices are facing some tough decisions as they transition out of the fee-for-service reimbursement model. The alternatives, most of which base reimbursement on proof of quality of care, require investment. It’s a Catch-22. “Practices will have to make a strategy decision. Are you going to invest in the structural changes needed to participate in quality-based reimbursement before you have the contracts that will pay you back?” asked John V. Cox, DO, MBA, of Texas Oncology in Dallas. “Or are you going to go out and try to win those contracts and then on the fly try to engage see REFORM, M page 12

Leukemia blood cells.

A once-promising program loses its way, creating perverse financial incentives


ack in 2008, oncologist James J. Stark, MD, faced a tough decision: shut down his small private practice or sell it to Riverside Health System. Out of economic necessity, Dr. Stark chose to sell his practice. Riverside Health, a hospital chain based in Newport News, Va., converted Dr. Stark’s office to an outpatient extension of the hospital, and he went from being a solo practitioner to one of 12 salaried oncologists and 400 doctors. Dr. Stark’s story has become a familiar one. Over the past several years, an increasing number of small oncology practices and community oncology clinics have wrestled with the difficult decision to close their doors or be purchased by a large medical entity. The Community Oncology Alliance (COA), which mapped this changing landscape, revealed that from 2007 to 2013, 288 oncology clinics have closed and 469 have been purchased by or are now affiliated with a hospital. At the same time, the cost of cancer care appears to be rising. After being purchased see 340B, B page 4


Expert Insights From Levine Cancer Institute Crizotinib Improves NSCLC Survival After Platinum Therapy ........................ 7 Edward Kim, MD

Boost After Whole Breast Radiation For Ductal Carcinoma in Situ? ......................... 8 Hadley J. Sharp, 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 University of California, San Diego, CA

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

Oncology Nursing

Hematologic Malignancies

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

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

Mayo Clinic Rochester, MN

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

Richard Stone, MD

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

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

Gastrointestinal Cancer and Sarcoma

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

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

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

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

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

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

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

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

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


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

Steven Vogl, MD Medical Oncologist New York, NY

Editorial Philosophy 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

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

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

Genitourinary y Cancer Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD

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

Policy and Management


Shaji Kumar, MD

Edward Chu, MD

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

Andrew Seidman, MD

Gastrointestinal Cancer


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

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



IOM CRISIS continued from page 1 

public policy at the Association of Community Cancer Centers (ACCC), “none of the problems or solutions listed in the report are incredibly shocking,” but the study “is a call to arms.” The report proposes a conceptual framework for making improvements, outlines 10 goals and issues several recommendations (Table). Tom Smith, MD, one of the report’s authors, and an oncologist and the director of palliative care at John Hopkins’ Sidney Kimmel Comprehensive Cancer Center in Baltimore, says the following recommendations may make the most impact: that patients have written care plans; that clinicians provide detailed information to patients about benefits, risks and costs of treatment; and that any seriously ill patient has access to palliative care alongside usual oncology care. “Palliative care is the home run of American medicine,” Dr. Smith said. “First, people have better symptom management and quality of life. Second, people have fewer hospital days and hospitalizations at the end of life. Third base is people live at least as long, if not longer, with both hospice and palliative care. And fourth, it is care that we can actually afford.” Another important recommendation is removing reimbursement barriers to team-based care. Some insurance companies do not pay for a patient to see more than one physician per day, when oftentimes the ideal is to meet with a team of caregivers. Dr. Smith said new care models may remedy this, including bundled payments, accountable care organizations and oncology patientcentered medical homes. To align clinical trial populations with those most commonly seen in a community clinic, the IOM recommends rewarding companies with a six-month patent extension when they conduct drug trials in older patients or

‘[Cancer] care often is not patient-centered; many patients do not receive palliative care to manage their symptoms and side effects from treatment; and decisions about care often are not based on the latest scientific evidence.’ —Institute of Medicine

Table. IOM Cancer Care Goals Provide patients with understandable information on cancer prognosis, treatment benefits and harms, palliative care, psychosocial support and estimates of total and out-of-pocket costs. Provide end-of-life care consistent with patients’ needs, values and preferences. Ensure members of the cancer care team coordinate with one another and with primary/geriatric and specialist care teams to implement patient care plans and deliver comprehensive, efficient and patient-centered care. Ensure the cancer care team has core competencies. Expand breadth of cancer research data collected on cancer interventions for older adults and individuals with multiple comorbid conditions. Expand the depth of data available for assessing interventions. Develop an ethically sound health care information technology system that can “learn” by enabling real-time analysis of data from cancer patients in a variety of care settings. Develop a national quality-reporting program for cancer care as part of a learning health care system. Reduce disparities in access to cancer care among vulnerable and underserved populations. Improve the affordability of cancer care by leveraging existing efforts to reform payment and eliminate waste.

and it’s a financial loser, so everything is against it,” Dr. Arnold said. “I think if you tell doctors we support it [by having a specific code], the symbolism is really important. It says, ‘this is something from a societal point of view that we want you to do.’” According to Virginia Vaitones, MSW, the president of the ACCC, educating patients about all aspects of chemotherapy treatment takes at least an hour. It is not reimbursable if undertaken by nurses and only partially reimbursable when done by doctors. She thinks having more thorough discussions up front will save money in the long run, and she sees the new codes coming to fruition within the next five years. A precedent for having specialized consultation codes has been set—an existing diabetes management code can be used as an example. Many clinicians hope the report’s focus on patient-centered care will encourage research in this area. Current clinical trials are rarely designed to provide information to a patient who is going to live with treatment-related side effects and long-term sequelae. “The older oncology literature is really focused on things like survival and recurrence,” said Benjamin Smith, MD, an associate professor of radiation oncology at University of Texas MD Anderson Cancer Center in Houston. “Those are helpful, but they don’t tell the whole story of the way a patient experiences an illness.” Dr. Smith, who also is a health services researcher, believes the IOM report will make waves. “I think IOM reports carry quite a bit of weight,” he said. As evidence, he pointed to a 1999 IOM report that concluded the gaps in cancer care need further study. “There has been a dramatic proliferation of cancer-related health services research between the time that report was published and the present day,” he said. “Given there is a historical precedent, I am hopeful that this IOM report will have an impact.”

individuals with multiple comorbidities. This is a tool used to encourage trials in pediatric populations. Another important recommendation is for payers to implement payment models that incentivize discussions about clinical options, cost of care and end-of-life care issues. Robert Arnold, MD, the chief of palliative

care and medical ethics at the University of Pittsburgh School of Medicine, says physicians who have end-of-life care discussions currently bill their time under general counseling Current Procedural Terminology, or CPT, codes. He thinks having specific CPT codes for an end-of-life conversation will help. “It’s an uncomfortable conversation

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340B continued from page 1 

by Riverside Health, Dr. Stark found that insured patients started getting billed at the hospital rate and chemotherapy prices skyrocketed. “A $3,000 chemo event suddenly became a $7,000 chemo event,” he said. The price of chemotherapy drugs also has increased significantly. Over the past decade, monthly costs for new anticancer drugs have more than doubled, from $4,500 to $10,000 ((J Natl Cancer Inst 2009;101:1044-1048, PMID: 19564563). Just last year, the FDA approved three new drugs to treat chronic myelogenous leukemia that came with exorbitant price tags: Ponatinib (Iclusig, Ariad) costs $138,000 annually; omacetaxine (Synribo, Teva) is $28,000 for induction and $14,000 for a maintenance course; and bosutinib (Bosulif, Pfizer) costs $118,000 annually ((Blood d April 2013. [Epub ahead of print]). A possible explanation for these trends is hospitals are increasingly relying on the 340B Drug Pricing Program as a way to generate revenue. In 1992, Congress created the 340B program with the objective of providing uninsured, indigent patients with better access to prescription medicines. As a response to the 1990 Medicaid Drug Rebate Program, the 340B program was designed to cast an even wider net of care, covering poor patients who did not qualify for Medicaid. “Like many programs and ideas, 340B is really important in terms of filling a need so patients who can’t afford care don’t fall through the cracks,” said Ted Okon, the executive director of the COA. “The concept of 340B is critical for cancer care, in particular, given that the cost of treating cancer has been increasing.” The 340B program requires pharmaceutical companies to provide federally funded clinics and public hospitals serving a high percentage of uninsured patients with rebates on prescription drugs delivered in the outpatient setting. Initially, only about 100 facilities in the country qualified for 340B rebates, including public health clinics, community mental health clinics and disproportionate share hospitals. But recently, the number of eligible facilities has ballooned. A snapshot shows that from 2005 to 2011, the number of hospitals participating in the 340B program almost tripled, from 591 to 1,673, comprising one-third of all hospitals in the nation, according to a September 2011 report from the Government Accountability Office (GAO). Notably, the study found that discounts from the 340B program have increased sixfold, from $1 billion in 2003 to $6 billion in 2010. This trend has many worried that the 340B program has strayed from


its original intention to help needy patients, and is creating a loophole through which hospitals can make millions of dollars a year. “Today, we have a very confusing situation,” said Adam J. Fein, PhD, the president of Pembroke Consulting, Inc., and CEO of Drug Channels Institute in Philadelphia. “There are some legitimate entities that really do require additional financial support. However, there are

the patient and insurer at the drug’s full price. The regulation that may have pushed 340B expansion over the edge occurred in April 2010, when HRSA allowed 340B-covered entities to contract with an unlimited number of pharmacies to fill prescriptions, not one pharmacy as the 1996 HRSA regulation stated. As a result, the number of contract pharmacies has increased sevenfold, from 3,785

Under 340B, an institution treating an insured patient in the outpatient setting can acquire a drug at a deeply discounted price and still bill the patient and insurer at the drug’s full price. also many profitable, large, well-funded health systems that are taking advantage of the program by using the funds in ways that can’t be linked in any way to its initial purpose.”

The 340B Transformation Since its inception, 340B has undergone several key changes that have expanded its use. In 1994, the Health Resources and Services Administration (HRSA) allowed outpatient facilities considered integral to a 340B-eligible hospital to participate in the program, where “integral” referred to hospital outpatient services reimbursable under Medicare. In 2003, Congress extended 340B benefits to rural and small urban hospitals serving a certain percentage of indigent patients, and in 2005, children’s hospitals came under the 340B umbrella. By 2010, the Affordable Care Act had extended the scope of the 340B benefits to outpatient settings of cancer hospitals, rural referral cen-

in 2010 to 30,046 in 2013, according to HRSA data. Walgreens dominates this market, contracting with nearly 5,400 340B pharmacies, but other facilities, including The University of California medical centers, have networks of more than 100 contract pharmacies. Today, about one in five pharmacies acts as a contract pharmacy for a 340B entity, Dr. Fein said. Contract pharmacies appear to reap substantial profits from these arrangements. In a recent letter addressed to Walgreens president and CEO Gregory Wasson, Sen. Charles Grassley (R-Iowa) wrote that, according to Walgreens senior 340B inventory and reconciliation analyst Timothy Hong, 340B is “projected to add a minimum of $250 million in incremental revenue over the next 5 years.” Although contract pharmacies may provide substantial value to patients by

‘Expanding the number of 340B-eligible patients with good insurance has become a vehicle for hospitals to boost revenue, make up revenue losses and gain a competitive edge.’ —Rena Conti, PhD ters, sole community hospitals and critical access hospitals. The definition of a 340B patient also has left the program vulnerable to growth. In 1996, HRSA defined an “eligible” individual as someone for whom the hospital maintains records and who receives care from an employee of the hospital. Medicaid-insured patients, with some exceptions, are not eligible for 340B rebates to prevent hospitals from claiming duplicate discounts on drugs through 340B and the Medicaid Drug Rebate Program. However, the definition of patient does not mention the patient’s insurance coverage or ability to pay, which means an institution treating an insured patient in the outpatient setting can acquire the drug at deeply discounted prices and still bill

giving them greater access to prescription drugs, the profits acquired by contract pharmacies through 340B are a far cry from the program’s original intention, said Rena Conti, PhD, an assistant professor of hematology/oncology in the Department of Pediatrics at the University of Chicago. There are also several drivers of 340B growth that are not directly related to the program. In 2003, Congress passed an amendment to Medicare regulations, which took effect in 2005, mandating Medicare to substantially reduce its reimbursement to oncologists for chemotherapy drugs. “I think the 340B phenomenon started when Medicare changed the reimbursement formula for cancer drugs and services,” Mr. Okon said.

“Medicare felt that it was overpaying for these drugs, so reimbursement was reduced to more closely match the drug’s sale price.” This decrease was meant to coincide with an increase in reimbursement for other services, but the new reimbursement system was riddled with problems, leaving many oncology clinics and private practices, such as Dr. Stark’s, without adequate funds to cover basic costs. Before 2005, if a drug cost Dr. Stark $100, Medicare would reimburse him between $120 and $125. With that $20 to $25 difference, he could cover all out-of-pocket expenses, such as $60,000 yearly salaries for his two registered nurses and $4,000 per month for medical supplies, such as needles, intravenous tubing, syringes and gauze pads. But by 2008, reimbursement for drugs had fallen to roughly $106, leaving Dr. Stark unable to afford these baseline costs. In recent years, hospitals also have experienced budget cuts. “Under these increasing pressures, expanding the number of 340B-eligible patients with good insurance has become a vehicle for hospitals to boost revenue, make up revenue losses and gain a competitive edge,” Dr. Conti said.

Repercussions of 340B Expansion The potential to profit from 340B is changing the landscape of cancer care. “The big problem with the program is that eligible hospitals get the drugs at discounted prices and charge patients and insurers the full price,” Dr. Conti said. “This creates incentives for hospitals to find more paying patients to capture the spread.” For instance, Duke University Health System, which boasts a $2.5 billion health system, disclosed earning $292 million in gross profits from 340B patients over the past five years, and 95% of the patients for which the hospital claimed 340B discounts had Medicare, Medicaid or private insurance. To maximize these profits, 340B entities are purchasing community and private oncology practices and then driving patient care into hospital outpatient departments. “What hospitals are doing is acquiring the outpatient oncology practices so they can get more 340B benefits and pocket the profits for all the patients they use,” said Bryan Liang, MD, PhD, JD, a professor of anesthesiology and the director of the San Diego Center for Patient Safety, at the University of California, San Diego. Given that a typical oncologist uses $2.5 million to $4 million of drugs each year, if hospitals increase the number of oncologists under their employ and claim 340B discounts on the outpatient chemotherapy drugs that these



oncologists purchase, hospitals can rake in profits of $1 million or more per oncologist per year. In addition, “with 340B, eligible hospitals are motivated to use the most expensive product to generate the largest profit margin from 340B rebates,” Mr. Okon said. The growing number of 340B discounts also may be motivating pharmaceutical companies to raise their prices. “Pharmaceutical companies manufacturing branded drugs can increase prices to offset the 340B discounts, both on currently available drugs and on drugs they’re launching,” Dr. Conti said. However, Dr. Conti noted, the same is not true for generic manufacturers. “We are seeing treatment regimens shift away from generics toward branded drugs. Many generic manufacturers, which are essentially giving away drugs for close to free in the 340B program, don’t have the same ability to increase prices,” she said. Despite these downsides, one benefit of 340B growth is the potential to treat more indigent, uninsured patients. After being purchased by Riverside Health, Dr. Stark became eligible for 340B. His chemotherapy drug costs fell by 40%, and he could then treat uninsured patients on a routine basis. “Riverside Health told me that if you see a patient without insurance, just treat him; we’ll absorb the loss, and it will keep us in 340B business,” Dr. Stark said. “So, patients with no insurance were sitting in my chemotherapy suite next to patients with good insurance. I was unable to do that regularly in my solo practice because I was not 340B-eligible.” However, it is unclear whether the profits captured by hospitals are actually reducing costs for patients or providing greater access for indigent populations. Two recent studies by Avalere Health and Milliman have documented increased costs associated with chemotherapy administered in the hospital outpatient setting, reporting that Medicare pays $6,500 more per patient and patients pay $650 more out-of-pocket. The Avalere study also found that chemotherapy provided in a hospital outpatient setting costs 24% more, on average, than it does in a physician’s office. In terms of patient access, “I’ve heard too many stories of cancer clinics that have closed, leaving patients to travel huge distances to receive their care,” Mr. Okon said. “Many sick patients just can’t do the travel, and thus don’t get treatment.” However, all 29 340B-covered entities interviewed for the GAO’s 2011 study reported using 340B to benefit patients regardless of the revenue they received through the program. Eligible entities provided free prescription medications, passed 340B rebates to eligible patients

DSH pays wholesaler for pharmacy ❻6 stock (ship-to/bill-to)


Product movement

DSH receives total reimbursement ❽8 (minus contract pharmacy and

Financial flow Contract relationship

vendor fees)) DSH submits replenishment ❹4 purchase order to wholesaler Disproportionate Share Hospital Pharmacy pays total ❼7 reimbursement (minus

Pharmacy submits replenishment ❸3 purchase order to 340B entity

contract pharmacy p y fee)) 340B contract pharmacy splitbilling vendor

5 Wholesaler replenishes pharmacy stock (ship-to/bill-to)


Contract Pharmacy

patient fills script ❶1 atEligible contract pharmacy

Pharmacy is reimbursed based ❷2 on network contract, e.g., Third-party payer

AWP-x% + dispensing p g fee Patient makes co-payment ❷2 per third-party insurance

Figure. Flow of funds and product for 340B contract pharmacy network. AWP, average wholesale price; DSH, disproportionate share hospital Source: Fein AJ. 2012-13 Economic Report on Retail, Mail and Specialty Pharmacies. Drug Channels Institute; January 2013.

and expanded patients’ access to expensive chemotherapy drugs by extending pharmacy hours. The 13 covered entities that generated 340B revenue exceeding drug-related costs used the profits to serve more patients and provide additional services, such as patient education programs. Also emerging from the 340B growth is a new industry of 340B consultants and software vendors seeking to profit from the program. For instance, Dr. Fein explained, after a patient has filled a prescription at a pharmacy and paid for it through insurance, a software company hired by the hospital will pick through the electronic prescription data and identify those for which it is profitable to convert to a 340B claim (Figure). The hospital will buy the prescription from the pharmacy; the pharmacy will turn over its reimbursement from the insurance company for a small fee; and the hospital will replace the inventory that the pharmacy dispensed. “The hospital can then claim a 340B rebate on that prescription even though the insurance company may have already paid full price for it,” Dr. Fein said. “This all happens without the patient, third-party payer or manufacturer knowing.”

Potential Solutions “If left unchecked, the 340B program will continue to grow,” Dr. Liang noted. This growth is projected to reach $12

billion by 2016, according to estimates from the Berkeley Research Group, a consulting firm. Experts have proposed ways to rein in 340B by implementing stricter regulations and greater oversight. For instance, Dr. Fein thinks hospitals

poor and uninsured, or keeping the program at its current scale but passing 340B savings on to patients and insurers. Closer policing of the program is currently under way. HRSA has been conducting regular audits of contract

To maximize these profits, 340B entities are purchasing community and private oncology practices and then driving patient care into hospital outpatient departments. and pharmacies should be required to identify prescriptions being claimed as 340B rebates, to increase transparency. He also proposes creating guidelines that dictate how 340B entities should manage their contract pharmacies, especially those with large networks, as well as regulations that limit which patients and prescriptions are eligible for discounts. Hospitals should disclose how they use 340B profits. “We should have some guidelines as to how indigent patients and true safety net clinics and hospitals should be benefiting from these funds, and more oversight regarding how funds are being spent,” Dr. Fein said. “I doubt Congress intended for 340B to support multimillion-dollar bonuses for hospital executives.” Dr. Conti has proposed either scaling down the program and limiting access to drug discounts to patients who are

pharmacies to make sure prescriptions receiving 340B claims are legitimate, and has launched an initiative to recertify entities in the 340B program to improve program integrity and compliance. Already, more than 270 treatment sites belonging to 85 hospitals have been ejected from the program, according to Krista Pedley, the federal official in charge of the 340B program. “People don’t realize how deadly serious this 340B situation is, especially with cancer care,” Mr. Okon said. “We’ve never had more promise in terms of understanding and treating cancer, but we’ve also never been in a more dangerous position, pricing care out of the market because of programs like 340B. [The] 340B [program] should be protected like a crown jewel, not abused.” —Victoria Stern




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

Preoperative Chemo Improves Gastroesophageal Cancer Outcomes From the European Journal of Cancer


meta-analysis of randomized clinical trial (RCT) results for patients with gastroesophageal cancer revealed a significant benefit from administering chemotherapy before surgical resection. Although surgery is regarded as the most effective treatment modality for locoregionally advanced gastroesophageal adenocarcinoma, there have been conflicting reports about the value of pre- and postoperative chemotherapy.

The authors of this study, led by Ulrich Ronellenfitsch, MD, of the University Medical Center Mannheim in Germany, identified 14 RCTs encompassing 2,422 eligible patients with adenocarcinoma of the stomach, gastroesophageal junction or esophagus. The authors, who published their findings in the European Journal of Cancer (2013;Jun 22. [Epub ahead of print], PMID: 23800671), were also able to obtain supplementary updated individual patient data for 45% of the patients included in this meta-analysis.

EXPERT INSIGHT Jimmy Hwang, MD Chief, Upper GI Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.


he meta-analysis from Ronellenfitsch et al is an interesting report that reviews the benefits from preoperative chemotherapy, with or without radiation, from RCTs. The study does have some methodologic issues. Unfortunately, this analysis was conducted before the data from the very influential CROSS (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study) trial.1 This study of 368 patients was roughly similar to the chemoradiation population evaluated in the present meta-analysis. Similarly, two studies, the OE02 (preoperative cisplatin-fluorouracil [5-FU] in esophageal cancer) studyy2 and the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy; pre- and postoperative epirubicin-cisplatin-5-FU) study,3 together comprise about half of the overall population in this meta-analysis. Although this study aggregates data from all gastroesophageal adenocarcinomas, the individual studies often

Jonathan C. Salo, MD Surgical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

comprised either gastric (about onehalf of the study population) or esophageal cancers (about one-fourth of the study population), and as was noted some of the studies evaluating esophageal cancers included both squamous cell and adenocarcinomas. One of the potential strengths of this study is that in some studies, the authors were able to evaluate individual patient data. Being able to do so in only a portion of the patients in the study limits the power of the authors’ conclusions. The primary conclusion from this meta-analysis is that preoperative chemotherapy, with or without radiation, improves survival by about 20% compared with surgery alone in patients with gastroesophageal adenocarcinomas. Reassuringly, there did not appear to be a significant difference in postoperative outcomes between patients receiving preoperative therapy and those who did not. However, the question of whether

Aggregate RCT information and individual patient data from more than 1,000 study patients demonstrated that overall survival (OS) was better in those patients receiving preoperative chemotherapy. The authors found a sustained survival benefit starting at about 18 months after surgery (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.73-0.89; P<0.0001). They speculated that tumor downstaging and an increased likelihood of complete resection added to the survival advantage over surgery alone. The odds

of a complete resection were about 1.4 times higher in patients pretreated with chemotherapy. The authors found no evidence that chemotherapy before resection jeopardizes perioperative safety. Some of the RCT study data included preoperative radiotherapy. Although there may be an added benefit, analyses of subgroup differences were not statistically significant. The authors concluded that standard care should include chemotherapy before cancer resection.

there is a benefit from the addition of systemic therapy to surgery has largely been resolved. The key questions at this time include: 1) Is preoperative therapy appropriate for all patients— for example, patients with T1 or T2 disease? 2) Is preoperative therapy preferable to postoperative therapy? 3) Should radiation be a part of pre- (or post-) operative therapy? This study cannot address the first question, but clinically—and increasingly, given endoscopic technologies— this is important. Likewise, this study was not intended to answer the question of whether there is a benefit to postoperative therapy, or whether postoperative therapy is similar in efficacy to preoperative therapy. Nonetheless, there are large RCTs and other metaanalyses, including some employing individual patient data, that demonstrate a similar survival benefit (HR, 0.78) as reported by Ronellenfitsch et al.4,5 Therefore, in patients who present with significant bleeding or obstruction, postoperative therapy also may be reasonable. Although the present study did not have the power to demonstrate whether adding radiation to chemotherapy produced a significant benefit, there was a suggestion of improvement (HR, 0.85; but with 95% CI, 0.59-1.22). Additionally, a meta-analysis of five studies6 reported at the 2013 American

Society of Clinical Oncology annual meeting, which included 1,110 patients with resectable gastric cancer and compared adjuvant chemoradiation and adjuvant chemotherapy, found a significant improvement in survival (HR, 0.79; P=0.03). Taken together, these findings support further investigation of the two approaches. Ultimately, the primary shortcomings of this study relate to our ability to use the results from this meta-analysis to influence current therapy. However, in confirming the results from the largest RCTs, it supports our current standard that the optimal potentially curative therapy for gastroesophageal adenocarcinomas is multimodal, requiring surgery and chemotherapy, and potentially radiation.

References 1. N Engl J Med. 2012;366:2074-2084, PMID: 22646630. 2. J Clin Oncol. 2009;27:5062-5067, PMID: 19770374. 3. N Engl J Med. 2006;355:11-20, PMID: 16822992. 4. JAMA. 2010;303:1729-1737, PMID: 20442389. 5. Lancet. 2012;379:315-321, PMID: 22226517. 6. J Clin Oncol. 2013;31(suppl): abstract 4066.

Drs. Hwang and Salo reported no relevant financial disclosures.



Crizotinib Improves NSCLC Survival After Platinum Therapy From The New England Journal of Medicine


atients with previously treated, advanced non-small cell lung cancer (NSCLC) who had chromosomal rearrangements of the anaplastic lymphoma kinase ((ALK K) gene fared better with crizotinib (Xalkori, Pfizer) than those receiving standard cancer chemotherapy. The primary end point of this prospective, Phase III open-label trial was progression-free survival (PFS). Alice T. Shaw, MD, of Massachusetts General Hospital in Boston, was the primary author of this international study, which was reported in The New England Journal of Medicine (2013:368:2385-2394,

PMID: 23724913). In all, 4,967 patients who had previously been treated with one platinumbased regimen and had locally advanced or metastatic lung cancer were screened for rearrangement of the ALK K gene. The screenings identified 347 ALK-positive patients who were randomized into two groups: Patients received either oral crizotinib (250 mg) twice daily or standard IV chemotherapy of pemetrexed (500 mg/m2 of body surface area) or docetaxel (75 mg/m2) every three weeks. Both groups were matched for age (>84% were <65 years old) and sex. The majority had adenocarcinoma of the lung and had never smoked, characteristics consistent with other studies of patients with ALK-positive lung

EXPERT INSIGHT Daniel E. Haggstrom, MD Hematology, Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.


he era of targeted treatment for patients with lung cancer has begun, initially with epidermal growth factor receptor (EGFR) mutations and now with ALK translocations. These mutations constitute approximately 20% of the NSCLC population, and enriched populations can be more than 30%. Not only do patients with tumors harboring these molecular abnormalities have choices in therapy, but oral biologic medications have now been shown to be as or more effective than traditional cytotoxic treatments. How long can this renaissance period continue in lung cancer research? Shaw and colleagues report that an ALK inhibitor (crizotinib) can be more beneficial than chemotherapy in a subset of patients with ALK-positive NSCLC. The improvements were observed in RR, PFS and QoL. The median survival of both groups was more than 20 months, an impressive value considering seven- to eight-month survival times are generally expected from second-line cytotoxic chemotherapy.1 Should our practice patterns now include testing all patients with lung cancer for markers including EGFR and ALK? At Levine Cancer Institute, we recommend testing for these markers

Edward Kim, MD Chair, Department of Solid Tumors and Investigational Therapeutics Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

at diagnosis in all patients with nonsquamous lung cancer. Patients with biomarker-enriched tumors are treated with the appropriate biologic treatments. For those patients who enter our system after diagnosis and treatment, we send the diagnostic sample (if adequate) for ALK testing, or rebiopsy if tissue samples are not adequate. We also are developing a molecular marker platform that will test numerous biomarkers in patients’ tumors. By performing comprehensive marker testing in patients with lung cancer, we will hopefully identify additional tumor abnormalities that can be treated with specific biologic treatments when the responses could be equivalent to, if not better than, standard cytotoxic therapy. In practice, if a druggable target exists and is found, then we need to find an appropriate, specific treatment for those patients. By identifying novel biologic treatments with unique driver mutations, treatment approaches can be more tailored to avoid added toxicities and improve QoL in patients with cancer. In this study, crizotinib, as well as EGFR inhibitors (gefitinib, erlotinib and afatinib), have demonstrated improved QoL without added toxicities

cancers. Study patients were evaluated for PFS, determined by radiologic review, and overall survival (OS), response rates (RR), safety and patientreported quality of life (QoL). PFS was 7.7 months in the crizotinib group and three months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.370.64; P<0.001). Response rates were 65% with crizotinib (95% CI, 58%-72%) and 20% with chemotherapy (95% CI, 14%-26%; P<0.001). At the time of review, median OS was 20.3 months for patients receiving crizotinib and 22.8 for those on standard chemotherapy. There was significant crossover to crizotinib, however: Of the 174 patients

who received chemotherapy, 112 subsequently received crizotinib (64%), which likely influenced OS. In the safety analysis, all events were recorded, and no adjustment was made, despite the longer length of treatment for crizotinib patients (median treatment, 31 vs. 12 weeks). The incidence of treatment-related grade 3 or 4 adverse events (33% in those receiving crizotinib and 32% in those receiving standard chemotherapy) and treatment-related serious adverse events (12% and 14%, respectively) were similar in both groups. Self-reported QoL surveys indicated a significant reduction in disease symptoms and a greater delay in worsening of symptoms in the crizotinib group.

By performing comprehensive marker testing in patients with lung cancer, we will hopefully identify additional tumor abnormalities that can be treated with specific biologic treatments when the responses could be equivalent to, if not better than, standard cytotoxic therapy. in patients with lung cancer.2,3 Assessment of progressive disease also is emerging as an issue in the management of biologic treatments. As many of these therapies are easier to receive and have different or lessened side effects, the bar for when to stop or change treatment in a clinically asymptomatic patient may need to be revisited. In this study, there were almost three times as many patients in the crizotinib arm who were continued on the drug beyond RECIST (Response Evaluation Criteria In Solid Tumors) progression. It is clear that physicians are increasingly more comfortable in continuing well-tolerated treatment in the setting of asymptomatic disease progression. Different assessment methods of progression may need to be developed to better guide clinicians when treating with targeted biologic agents. Studies with crizotinib have noted that central nervous system (CNS) disease has been an early area of disease progression, calling into question the CNS penetration of the drug itself.4 Second-generation ALK inhibitors have better activity in the CNS and may confer better overall disease control with different side-effect profiles. Indeed, even in a small population of patients with ALK-positive

lung cancer, numerous compounds and expanded research efforts continue with the goal of controlling progression and improving QoL. Emphasis on acquiring adequate tissue, early marker testing and implementing matched treatments with molecular targets will serve to extend this exciting time in lung cancer treatment.

References 1. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-2103, PMID: 10811675. 2. Bezjak A, Tu D, Seymour L, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2006;24:3831-3837, PMID: 16921034. 3. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;372:1809-1818, PMID: 19027483. 4. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443-e445, PMID: 21422405.

Drs. Haggstrom and Kim reported no relevant financial disclosures.





Boost After Whole Breast Radiation for Ductal Carcinoma in Situ? From the International Journal of Radiation Oncology, Biology, Physics


Canadian study comparing the effects of additional (so-called boost) radiation to the tumor cavity in the treatment of patients with ductal carcinoma in situ (DCIS) demonstrated no advantage in the development of local recurrence from the addition of the boost radiation to the standard

approach, which consists of breast-conserving surgery and radiation therapy. A team of Canadian researchers analyzed data from patients treated in Ontario between 1994 and 2003. Using a province-wide cancer registry, the authors were able to identify 129,140 patients with invasive breast cancer, DCIS or benign breast disease. The researchers, whose primary author was Eileen Rakovitch, MD,

analyzed a subset of 1,895 patients who received treatment for DCIS that consisted of breast-conserving surgery plus radiation. By abstracting chart information and physician billing data, it was determined that approximately one-third of these patients (n=561) received additional boost radiotherapy to the tumor cavity. Results were published in the International Journal of Radiation Oncology, Biology, Physics


PRACTICAL APPROACHES FOR THE PRACTICING ONCOLOGIST AND HEMATOLOGIST Clinical Trials, New Agents and Regimens Practice-Ready Therapies and Emerging Developments Conference Highlights

(2013:86:491-497, PMID: 23708085). The authors examined the 10-year survival and recurrence rates of the two groups. The local recurrencefree survival (LRFS) rate was 88% for those who received boost radiation and 87% for those who did not ((P=0.27). The invasive LRFS was 94% and 93%, respectively ((P=0.58). The authors also performed multivariate analyses, seeking to identify benefits to certain subgroups. They did not find a reduced risk for recurrence when the additional radiation treatment was performed in younger patients, those with positive margins, high nuclear grade, or presence or absence of necrosis or multifocality. Although there are indications that boost radiation has been useful adjuvant therapy in the treatment of certain invasive breast cancers, in this retrospective population study of patients with DCIS, the predictive benefit was not improved beyond the results achieved with breast-conserving surgery and standard radiotherapy alone. EXPERT INSIGHT


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lthough four randomized controlled trials (RCTs) demonstrated that radiation after lumpectomy for DCIS reduces recurrences by approximately 50%,1-4 adjuvant radiation continues to be controversial in this disease, particularly for favorable cases (i.e., low/intermediate grade, small extent of disease, postmenopausal presentation, wide negative surgical margins). Once the decision to treat is made, the radiation oncologist faces additional challenging treatment decisions: Use whole breast radiation versus partial breast? Conventional fractionation versus hypofractionation? Boost the lumpectomy bed versus no boost? Although the RCT for DCIS incorporated conventional whole breast treatment without a boost, there is much debate regarding the optimal approach in practice. The benefit of a boost for DCIS has been extrapolated from RCTs evaluating invasive carcinoma.5,6 In the boost arm of the EORTC (European



Organisation for Research and Treatment of Cancer) study, local recurrence was decreased by 40%, with younger women deriving the most benefit.7 However, the toxicity of boost radiation also can be appreciated from this trial, as moderate to severe fibrosis was ultimately noted in twice as many patients in the boost arm.7 Other features that consistently relate to higher risks for fibrosis include lower-quadrant (dependent) location, large boost volume and deep lumpectomy bed necessitating photon boost. Nevertheless, the great majority of patients have a good cosmetic outcome and little morbidity to treatment with or without boost. In the absence of RCT data, retrospective studies have been performed to evaluate the effect of boost treatment in DCIS to determine if and when the benefits outweigh toxicities. Unfortunately, these studies have yielded mixed reports. Although at least one small series suggested no local control benefit to boost,8 others have suggested benefit.9,10 Rakovitch et al, seeking to advance our understanding of the value of boost radiation for DCIS, analyzed the largest series of patients to date and identified no local control benefit to boost treatment. The analysis has several strengths, in particular the large number of patients, central review of pathology in most cases, and well-balanced patient and tumor characteristics in the two cohorts. However, as is the case with any retrospective review, there are significant limitations. First, details regarding margin information are lacking, with more than onefourth of cases “unreported” and no specifics regarding width of margin for the remaining patients. Furthermore, the size/extent of DCIS in the group study is not reported. As is evident in the Van Nuys Prognostic Index,11 as well as in the Harvard and ECOG 5194 trials,12 patients are riskstratified in part based on size and width of the margin given the large body of literature identifying these as significant predictors of recurrence. Finally, the heterogeneity of dose/ fractionation employed in this series, and particularly the disparate use of hypofractionation between the two arms, makes it difficult to draw practical conclusions from the findings. Prospective data is needed to definitively determine the impact of boost treatment for DCIS, with careful stratification for known risk factors, and application of nonvariable doses/fractionation to the whole breast prior to boost. Fortunately, two Phase III trials are ongoing, with French

and Trans-Tasman Radiation Oncology Group studies randomizing DCIS patients to boost after whole breast radiation. Until results are known, our policy is to offer whole breast treatment with boost to the majority of patients, excepting only those with the most favorable DCIS presentations in whom the optimal treatment is likely no radiation at all.

References 1. J Clin Oncol. 2006;24:3381-3387, PMID: 16801628.

2. J Clin Oncol. 1998;16:441-452, PMID: 9469327. 3. J Clin Oncol. 2008;26:1247-1252, PMID: 18250350.

8. Neoplasma. 2006;53:507-510, PMID: 17167720. 9. Lancet Oncol. 2006;7:652-656. PMID: 16887482.

4. Lancet. 2003;362:95-102, PMID: 12867108.

10. Int J Radiat Oncol Biol Phys. 2012;82:e153-e158, PMID: 21664063.

5. N Engl J Med. 2001;345:1378-1387, PMID: 11794170.

11. J Natl Cancer Inst Monogr. 2010;2010:193196, PMID: 20956828.

6. J Clin Oncol. 1997;15:963-968, PMID: 9060534. 7.

Eur J Cancer. 2008;44:2587-2599, PMID: 18757193.


12. J Clin Oncol. 2009;27:5319-5324, PMID: 19826126. The authors reported no relevant financial disclosures.

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ASCO 2013

Nintedanib Looks Promising for NSCLC Approval Chicago—Adding nintedanib (Vargatef, Boehringer Ingelheim) to docetaxel in second-line treatment of patients with stage IIIB/IV, locally advanced non-small cell lung adenocarcinoma improves survival by more than two months. This finding comes from a preplanned analysis of Phase III trial data presented by Martin Reck, MD, PhD, head of the Thoracic Oncology

and Clinical Trial Departments at Hospital Grosshansdorf in Grosshansdorf, Germany, at the annual meeting of the American Society of Clinical Oncology (abstract LBA8011). “The drug should be approved,” said Edward Kim, MD, the chair of Solid Tumor Oncology and Investigational Therapeutics at the Levine Cancer Institute in Charlotte, N.C., who was

not involved with the study. Nintedanib is an oral, angiokinase inhibitor that targets vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor. Docetaxel is the current standard of care in second-line NSCLC therapy. The LUME-Lung 1 study enrolled 1,314 patients with stage IIIB/IV, locally

advanced, recurrent NSCLC after firstline therapy. Inclusion criteria were an Eastern Cooperative Oncology Group status of 0 or 1; no prior docetaxel or angiogenesis inhibitors besides bevacizumab; and no active brain metastases, leptomeningeal disease, or cavitary or necrotic tumors. The patients were randomized to receive docetaxel (75 mg/m2 IV day 1,

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21-day cycles) and either placebo or oral nintedanib (200 mg twice daily on days 2 through 21). Baseline characteristics were well balanced in the two arms and represented an unselected population. Approximately 90% of the patients presented with metastatic disease, and less than 5% had been treated with bevacizumab. Overall, nintedanib improved median progression-free survival by about three weeks (3.4 vs. 2.7 months; hazard ratio [HR], 0.79; P=0.0019), but not OS. In a preplanned analysis by histology, however, patients with

lung adenocarcinoma had a significant 2.3-month improvement in median OS (12.6 vs. 10.3 months; HR, 0.83; P=0.0359). Patients receiving nintedanib had higher rates of drug-related adverse events (AEs; 76.4% vs. 68.1%) and drugrelated AEs grade 3 or higher (50.8% vs. 42.0%), but there was no increase in the incidence of AEs leading to discontinuation or serious AEs. The greatest increases in AEs in patients receiving the investigational drug were seen for diarrhea, nausea and transient elevation of alanine transaminase. The incidence of

severe bleeding events or hypertension did not differ between treatment groups. Dr. Kim said many lung cancer researchers are attempting to identify targeted therapy drugs that produce profound responses in very specific populations of patients, similar to what was seen with crizotinib (Xalkori, Pfizer), but most patients do not have driver mutations. “For the large majority of lung cancer patients who don’t have driver mutations that are targetable, we have to rely on systemic chemotherapy,” he said. “If you can add a cytotoxic drug or a biologic to therapy and

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improve survival by over two months, then I think we seriously have to consider these drugs as having real effects and integrate them into our practice.” —Kate O’Rourke Dr. Reck disclosed a consultancy/advisory role with and honoraria from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Pfizer and Roche. Dr. Kim disclosed an advisory role with Boehringer Ingelheim.




REFORM continued from page 1 

your practice to change?” The changes are not trivial, according to Dr. Cox and several other participants in a Community Oncology Town Hall devoted to physician payment reform held at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO). “Ultimately being paid for how much you do will be replaced by being paid for how well you do it,” said Jeffery C.


Ward, MD, a hematologist/oncologist at Swedish Medical Center in Seattle. He is among those who do not necessarily believe this is a bad development. Whether fee-for-service, with its incentive to perform more procedures, has an inherent negative effect on quality of care remains controversial; nevertheless, the opportunity to lower costs with other models is irresistible for health policymakers, and inevitable for practicing physicians. However, any up-front costs incurred by the transition to a new payment system will fall particularly hard on

community practices. Institutional and academic settings have much larger economies of scale and far greater infrastructures; in the community, not only are the initial costs relatively higher and borne directly by the physicians who run the practice, community physicians also have to invest a lot more sweat equity. Even in practices that have some of the needed infrastructure in place, such as sophisticated electronic medical record (EMR) systems, owner-oncologists must be actively involved in pushing through the changes that alter daily

processes—and may not be immediately embraced by other staff—and make bets on how best to allocate resources. “Payment dollars that exist today are bridging us to a future that requires us to take risks,” Dr. Cox said. As an early adopter of a patient-centered specialty practice coordinated by the National Committee for Quality Assurance, Dr. Cox believes that the current efforts of third-party payers to develop systems for reimbursing quality of care are only transitional. “Currently, many oncologists are dealing with very sophisticated contracts

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that acknowledge pathway management and evidence-based care, endof-life management, and other practices that save the payers money, but this is not where we are going,” Dr. Cox said. Rather, these are transitional steps toward programs that will require physicians to accept risk in a vertically integrated care system. Dr. Cox foresees a broader focus on comprehensive care, rather than simply altering pieces of the system. He is not alone. “We began looking at models several years ago that might be applicable to the oncology setting, and we came to the

conclusion, like many folks, that the real cost savings in medicine are not going to come from drugs and the changes in drug reimbursement. The real changes are going to come from the processes in which we deliver care,” said Mark Thompson, MD, a hematologist/oncologist at Mid Ohio Oncology/Hematology Inc., in Columbus, and the president of the Community Oncology Alliance. He also believes that a patient-centered specialty practice, also known as the medical home model, will likely play a role moving forward because of its strengths in coordinating and

integrating care across specialties. Payment reform is at least partly driven by the relentless rise in health care costs as a proportion of gross domestic product (GDP). According to Roscoe F. Morton, MD, an oncologist at Medical Oncology and Hematology Associates of Iowa in Des Moines, this proportion has now reached nearly 18% and is nearly double that of most European countries where quality of care is comparable. By 2021, the projected proportion of the GDP will be 20% at current rates of growth. Much of this rise is driven by drug The bookstore division of













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costs. Oncologists administering these drugs are caught in the crossfire because of a misperception that administration costs, rather than the rising drug purchase costs, account for at least some of the overall cost inflation. It was hoped that standardizing administration costs by reimbursing oncologists for an average sale price plus 6% would reduce the focus on the oncologist as a contributor to rising drug costs; it has not been entirely effective. “As long as we continue in a system in which we are taking a margin on drugs, we become a firewall that is protecting two interested parties. It protects the pharmaceutical industry because it takes the focus off of them and it protects politicians, who can pick on oncologists and ignore the pharmaceutical industry. The only way to change the focus is for us to get out of the middle,” Dr. Ward said. As payers switch from a fee-for-service model to a model that reimburses physicians based on demonstrable quality of care, many physicians will have to function in both worlds. For those with multiple payers using different strategies for reimbursement, it will be necessary to track both services performed and quality-of-care measurements so that each can be provided for reimbursement to the appropriate payer. The upside is that tracking quality of care will likely benefit patients, and clinicians can expect to be rewarded for doing better, rather than just doing more. “Many physicians recognize opportunities to introduce efficiencies into the system. Right now, there is no reward for that. There is an opportunity here to claim some of those savings. Otherwise, the payers define the rules and scoop up any savings,” said Richard A. Deem, the senior vice president for advocacy of the American Medical Association in Chicago. The transition to other forms of payment will not be smooth or short. According to Allen S. Lichter, MD, ASCO’s CEO, “I don’t think any of us would say that we expect there to be zero fee-for-service medicine in the United States five or even 10 years from now. There may always be some fee-for-service, but this does not appear like it will survive as the dominant approach.” He also indicated that a move away from fee-for-service is not necessarily a bad thing if the alternative preserves physician compensation while improving quality of care. “I am proud of the fact that oncologists have been at the table in negotiating change. By staying involved in the discussion, we can help sail the ship into port,” Dr. Lichter said. —Ted Bosworth None of the physicians or other sources for this story reported any relevant conflicts of interest.





How I Manage ...

Acute Myeloid Leukemia in Young Adults A

cute myeloid leukemia (AML) is a genetically heterogeneous disease with marked differences in survival following intensive chemotherapy based on numerous factors including age, comorbid conditions, cytogenetics and molecular abnormalities. Despite advances in prognostic algorithms, therapeutics and supportive care, the majority of patients with AML die from their disease. This article specifically focuses on younger adults—usually defined as those younger than 60 years old—with AML. In this group of patients, high complete remission rates of approximately 70% to 80% are expected; however, most patients ultimately relapse and overall survival (OS) is limited to 40% to 45% at five years.

How do I define “young adults”—biological age or chronological age? Chronological age alone should not be a reason for not offering potentially curative therapy to an older patient because age is not the most important prognostic factor for either treatmentrelated mortality (TRM) or resistance to therapy. Attention should be given to a careful evaluation and documentation of comorbidities. Studies have shown that performance status is a better predictor of TRM than calendar age.

Should adolescents with AML be treated differently? Interestingly, “adolescents and young adults” (AYA), a category comprising patients aged 17 to 21, are now recognized as a distinct group. In particular, AYAs with acute lymphoid leukemia (ALL) seem to fare better when given pediatric rather than adult therapy. Whether the same is true in AML

AT A GLANCE Chronological age alone should not be a reason for not offering potentially curative therapy to an older adult with AML. The goal of therapy in AML should be to achieve a state with no MRD. NK-AML patients in first CR are allocated into one of four prognostic groups. Allogeneic hematopoietic cell transplantation is underused in AML.

remains unclear. However, given the ALL data, patients up to age 30 are now being treated in pediatric ALL studies. The arbitrary nature of both 21 and 30 years suggests again that biological age is more important than chronological age. Currently, the answer is “no” to this question. All adult patients with AML should be risk-stratified and treated according to either National Comprehensive Cancer Network (NCCN)– or European LeukemiaNet (ELN)–based recommendations.

Which induction regimen do I use in AML? This depends on the likelihood the patient’s disease will be resistant to

Elihu Estey, MD Professor of Medicine, Division of Hematology University of Washington Member, Fred Hutchinson Cancer Research Center Seattle, Washington

standard 3+7, for example using a daunorubicin dose of 90 mg/m2 daily + Ara-C (cytarabine) for three cycles. Resistance encompasses both no complete response (CR) and relapse. The goal is not merely to achieve CR but to achieve a state (e.g., before allogeneic transplant or after induction) with no minimal residual disease (MRD), as assessed by flow cytometry or polymerase chain reaction since minimal residual disease (MRD) predicts a higher likelihood of relapse. Other important predictors of relapse are adverse cytogenetics and FLT3/ITD expression. A patient with a complex or monosomal karyotype (MK) may well enter CR with 3+7 but is likely to have a poor

Table. Suggested Treatment Recommendations By Prognostic Groups in Young Adults With de novo AML Induction Therapy

Post-Remission Therapy

Double-mutated CEBPA with NK, t(8:21), inv(16), t(16:16), normal karyotype with NPM+ and FLT3/ITD negative


Repetitive (3-4) cycles with intermediate- or high-dose Ara-C


Normal karyotype without NPM1 and FLT3/ITD OR cytogenetic abnormalities other than unfavorable and MK.





3+7 or allo-HCT clinical trial


Unfavorable cytogenetics Clinical trial allo-HCT; preferwithout MK ably clinical trial involving allo-HCT



Risk Category

Definition of Risk Group


Clinical trial allo-HCT; preferably clinical trial involving allo-HCT

allo-HCT, allogeneic hematopoietic cell transplantation; CEBPA, CCAAT enhancer-binding protein a; FLT, Fms-like tyrosine kinase; ITD, internal tandem duplication; MK, monosomal karyotype; NK, normal karyotype; NPM, nucleophosmin

quality of remission. In such a patient, I would choose an investigational induction regimen rather than 3+7. In contrast, in patients with disease less likely to be resistant to 3+7 (e.g., patients with a normal karyotype), I would choose 3+7 (Table).

What molecular markers other than NPM and FLT3 influence my decisions about postremission therapy in normal karyotype AML (NK-AML)? What about FLT3 allelic burden? In younger patients with AML, normal cytogenetics/intermediate-risk disease comprises more than half of cases. There is significant heterogeneity in the consolidation approach for these patients. In recent years, our understanding of the mechanisms responsible for the development and progression of disease in patients with AML has increased substantially. By characterizing NK-AML on the basis of mutated genes, including Fms-like tyrosine kinase 3 (FLT3 ( gene), nucleophosmin 1 ((NPM1 gene) and CCAAT enhancerbinding protein-α (CEBPA gene), an important prognostic classification has been developed. Currently, NK-AML patients in first CR are allocated into one of four groups: 1. NPM mutated (NPM+) and wildtype for FLT3/ITD; 2. Double CEBPA mutation; 3. Wild type for NPM, FLT3/ITD, and CEBPA; 4. FLT3/ITD-positive (FLT3/ITD+). Patients in groups 1 and 2 are thought, on average, to be at such low risk for relapse that the risk associated with allogeneic hematopoietic cell transplantation (allo-HCT) is not justified. In contrast, the risk for relapse does justify allo-HCT in group 3 and, especially, group 4. Recent data suggests that these guidelines (for group 4) should be modified by FLT3 allelic ratio (AR). In particular, patients with low (1%-24%) or intermediate (25%-50%) ARs have lower relapse rates than patients with a high (>50%) AR. However, the low and intermediate AR groups have higher relapse rates than FLT3 wild-type patients.

How many consolidation cycles are appropriate with and without anticipated allo-HCT? It is generally felt that three consolidation courses—for example, with intermediate- or high-dose Ara-C (HiDAC)—are appropriate. However,



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

Coming soon recent data from the United Kingdom suggests that the answer may depend on the patient’s MRD status after completion of planned consolidation therapy. Patients with no MRD are more likely to benefit from an additional course than patients with MRD. This is reminiscent of previous findings that patients who benefit most from HiDAC are those most sensitive to standard-dose Ara-C, for example those with inv(16) or t(8;21) AML. My answer would not be affected by whether allo-HCT is planned. I would proceed to allo-HCT when available except in a case where the patient has MRD before HCT, in which case, given the high relapse rate in patients receiving allo-HCT with MRD, I would try to eliminate the MRD, often by changing to a different regimen. This of course runs the risk that the new regimen would be unsuccessful and that MRD would turn into frank relapse, further increasing the relapse rate after allo-HCT. The question of whether patients with MRD before allo-HCT should receive further therapy to eliminate the MRD seems worthy of a randomized trial.

How I Manage: Follicular Lymphoma

How I Manage: Maintenance Therapy Following Autologous Transplant in Lymphoma

by Bruce D. Cheson, MD

by Michael R. Bishop, MD

Lombardi Comprehensive Cancer Center

University of Chicago

Is allo-HCT underused in AML? Yes. And too often it is delayed beyond its optimal timing. The US InterGroup (SWOG, CALGB, ECOG) is now conducting a study to determine whether 60% of appropriate candidates (see the second question above) can receive alloHCT in first CR. This certainly seems like a low figure and suggests that alloHCT is underused. Furthermore, this will allow better understanding of the reasons behind low use of allo-HCT and will eventually lead to appropriate application of this curative strategy to more patients with AML.

References 1. Walter RB, Buckley SA, Pagel JM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122:18131821, PMID: 23847197. 2. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 2013;88:318-327, PMID: 23526416. 3. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909-1918, PMID: 18450602. 4. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121:2213-2223, PMID: 23321257.

RESEARCH Advancing the knowledge of gastric cancers.

Creating more precise and effective treatments.

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Prepared by

Clinical Conundrums

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights From NEJM, Blood, JCO and ASCO QUESTIONS

1. True or False. In a study pub-

lished in The New England Journal of Medicine, apixaban (Eliquis; Pfizer, Bristol-Myers Squibb) was noninferior to conventional therapy for the primary end point of symptomatic recurrent venous thromboembolism (VTE) or death related to VTE.

2. True or False. The indications

and drug interactions are similar among the three new oral anticoagulants, apixaban, rivaroxaban (Xarelto, Janssen) and dabigatran (Pradaxa, Boehringer Ingelheim).

3. True or False. In a study pub-

lished in Blood, Francis Mussai, DPhil, of the University of Oxford in the United Kingdom, and his colleagues reported the ability of acute myeloid leukemia (AML) blasts to inhibit the immune system and hematopoiesis through aberrantly high levels of arginase II activity.


1. True. The investigators randomly

assigned 5,400 patients (143 patients with cancer were enrolled) with acute deep vein thrombosis or pulmonary embolism in double-blind fashion to receive apixaban, at a dose of 10 mg twice daily for seven days followed by 5 mg twice daily for six months, or conventional therapy with subcutaneous enoxaparin bridging to warfarin for six months. Symptomatic recurrent VTE or death related to VTE occurred in 2.3% of patients who received apixaban and in 2.7% who received warfarin. The risk for major bleeding favored apixaban; major bleeding occurred in 0.6% of these patients compared with 1.8% of patients who received warfarin. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808, PMID: 23808982. Cushman M. Treating acute venous thromboembolism—shift with care. N Engl J Med. 2013;369:865-866, PMID: 23808983.

2. False.

The interactions differ among the three newly available anticoagulants and may relate to characteristics of the patient such as age, body weight, and presence or absence of kidney disease. Medical professionals should refer to the products’ monograph before prescribing them. Potential interacting drugs, such as inducers or inhibitors of P-glycoprotein and the cytochrome P450 enzyme CYP3A4, should

4. True or False. According to the

2013 European LeukemiaNet recommendations for the management of chronic myeloid leukemia (CML) published in Blood, molecular response4.5 (MR4.5) is defined as either detectable disease with less than 0.0032% BCRABL1 international scale (IS) or undetectable disease in cDNA with greater than 32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1.

5. True or False. According to 2013

European LeukemiaNet recommendations for the management of CML published in Blood, clonal chromosome abnormalities in Philadelphia chromosome–negative (Ph–) cells are a warning of progressive disease only in the case of an aberration in chromosome 8.

6. True or False. In a study pub-

lished in Blood d by Annkristin Heine, MD, from University Hospital Bonn in Germany, and colleagues, ruxolitinib (Jakafi; Incyte Pharmaceuticals,

be taken into consideration. It should be noted that in the United States, rivaroxaban is the only new oral anticoagulant approved by the FDA for the treatment of acute VTE. Cushman M. Treating acute venous thromboembolism—shift with care. N Engl J Med. 2013;369:865-866, PMID: 23808983.


True. This study identified, for the first time, that AML blasts alter the immune microenvironment through enhanced arginine metabolism. The investigators of the study elegantly showed that aberrant arginase II activity contributes to leukemogenesis via suppression of T lymphocyte activity through polarization of monocytes into a suppressive M2-like phenotype and via direct inhibition of hematopoietic activity, which in turn may contribute to pancytopenia and marrow failure observed in AML. Theoretically, the immunosuppressive activity of AML blasts can be modulated through small-molecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. However, several questions remain, according to an accompanying editorial by Guido Marcucci, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, Ohio, including the following: What is the relationship between AML genotypes and plasma arginase activity? Do high levels of arginase activity correlate with the presence of unfavorable AML cytogenetic and molecular features? Are residual

Novartis) therapy in myelofibrosis (MF) significantly reduces bone marrow fibrosis without impairment of dendritic cell (DC) function.


All of the following statements about T-cell large granular lymphocyte leukemia (LGLL) are correct except: a. Rituximab may be a safe and effective therapy in patients with T-cell LGLL accompanying rheumatoid arthritis (RA). b. T-cell LGLL, in some patients with RA, may be a reactive manifestation of chronic autoantigen stimulation rather than a true concomitant malignancy. c. T-cell LGLL is associated with rheumatoid arthritis (RA) in up to 80% of cases.

8. True or False. In a randomized controlled trial (RCT) published in the Journal of Clinical Oncology, Yi-Hsiang Huang, MD, PhD, and colleagues from Taipei Veterans General Hospital in Taipei City, Taiwan, showed that entecavir

blasts in patients receiving hematopoietic cell transplantation still able to produce serum arginases, thereby inhibiting the host immune system and hematopoiesis, and in turn causing disease relapse? Can levels of arginase activity predict treatment failure, and can they be used as surrogate markers for minimal residual disease? Mussai F, De Santo C, Abu-Dayyeh I, et al. Acute myeloid leukaemia creates an arginase-dependent immunosuppressive microenvironment. Blood. 2013;122:749-758, PMID: 23733335. Marcucci G. Arginase-mediated “field” defects in AML. Blood. 2013;122:620-621, PMID: 23908439.

4. True. In CML, molecular response

is best assessed according to the IS as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts, and it is expressed and reported as BCR-ABL1% on a log scale, where 10%, 1%, 0.1%, 0.01%, 0.0032% and 0.001% correspond to a decrease of 1, 2, 3, 4, 4.5, and 5 logs, respectively, below the standard baseline that was used in the IRIS (International Randomized Study of IFN versus STI571) study. The term “complete molecular response” (CMR) should be avoided and substituted with the term “molecularly undetectable leukemia,” with specification of the number of the control gene transcript copies. MR4.0 is defined as either detectable disease with less than 0.01% BCR-ABL1 IS or undetectable disease in cDNA with greater than 10,000 ABL1 transcripts.

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

(ETV) prophylaxis can significantly prevent rituximab-associated hepatitis B virus (HBV) reactivation in patients with lymphoma and resolved hepatitis B infection.

9. True or False. Early referral to

hematopoietic transplantation centers is crucial in the majority of patients with newly diagnosed mature T-cell nonHodgkin lymphoma (NHL).

10. True or False. In a meta-anal-

ysis published in the Journal of Clinical Oncology, a consistent and robust beneficial effect of bortezomib-based (Velcade, Millennium) therapy on postinduction and post-transplantation responses was demonstrated in patients with previously untreated multiple myeloma.

Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872-884, PMID: 23803709.


False. Clonal chromosome abnormalities in Ph– cells, which may develop in up to 5%-10% of responders and in the absence of dysplasia are a warning only in case of chromosome 7 involvement [monosomy 7 and del(7q)]. Furthermore, metaphase karyotyping may reveal additional clonal chromosomal abnormalities in Ph+ cells (CCA/Ph+), a situation referred to as clonal cytogenetic evolution. CCA/Ph+ defines tyrosine kinase inhibitor failure. CCA/Ph+ is associated with shorter overall survival (OS) on second-line imatinib (Gleevec, Novartis) after rIFNα failure but not secondline dasatinib (Sprycel, Bristol-Myers Squibb) or nilotinib (Tasigna, Novartis). Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872-884, PMID: 23803709.

6. False. In an accompanying edito-

rial, Ayalew Tefferi, MD, of Mayo Clinic, wrote that “ruxolitinib therapy in MF conjures limited benefit in terms of reversing bone marrow fibrosis or significantly reducing JAK2 V617F allele burden; its value is mostly limited to relief of constitutional symptoms and reduction in spleen size. Even then, benefit comes at the cost of drug-associated anemia, thrombocytopenia, and cytokine-release syndrome during drug discontinuation.”



Additionally, in this study, ruxolitinibrelated dose-dependent DC dysfunction was demonstrated, which highlights unwanted off-target impaired T-cell activation in MF. The investigators of this study caution that patients should be closely monitored for potential infectious complications and the development of malignancies during protracted therapy with ruxolitinib in MF. On the other hand, this data may set the stage for further testing of ruxolitinib as a novel immunomodulatory drug in patients with a deregulated immune response, including steroid-refractory graft-versus-host disease and sepsis.

Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31:2765-2772, PMID: 23775967.

9. True. Data from the Center for

International Blood and Marrow Transplant Research (CIBMTR), published in the Journal of Clinical Oncology, reinforces that hematopoietic cell transplantation (HCT) should be considered earlier in the overall management of patients with mature T-cell NHL. In this study, a unifying finding was that transplantation was

often offered late in the disease course, with 50% of allogeneic HCT and 30% of autologous HCT patients receiving more than two prior treatment regimens. Such late referral was detrimental; the use of either modality for patients receiving more than two lines of therapy was associated with a threefold increased risk for relapse, fivefold increased risk for overall mortality, and a sevenfold increased risk for non-relapse mortality. Smith SM, Burns LJ, van Besien K, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol. 2013;31:3100-3109, PMID: 23897963.

10. True.

In addition, improved long-term outcomes including progression-free and overall survival, without substantial additional or unrecognized risks, were observed. Sonneveld P, Goldschmidt H, Rosiñol L, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stemcell transplantation in patients with previously untreated multiple myeloma: A meta-analysis of Phase III randomized, controlled trials. J Clin Oncol. 2013;31:3279-3287, PMID: 23897961.

Asia Maqbool, MD, assisted in preparing this manuscript.

Tefferi A. Ruxolitinib targets DCs: for better or worse? Blood. 2013;122:1096-1097, PMID: 23950171. Heine A, Held SA, Daecke SN, et al. The JAKinhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122:1192-1202, PMID: 23770777.

7. C. The paradoxical efficacy of ritux-

imab therapy on a T-cell monoclonal disease suggests that, in some cases, T-cell LGLL may be a reactive manifestation of chronic autoantigen stimulation rather than a true malignancy. Studies are warranted to assess positive results, for the first time, with rituximab therapy in patients with concomitant RA and T-cell LGLL. T-cell LGLL is associated with RA in up to one-third of cases. Cornec D, Devauchelle-Pensec V, Jousse-Joulin S, et al. Long-term remission of T-cell large granular lymphocyte leukemia associated with rheumatoid arthritis after rituximab therapy. Blood. 2013;122:1583-1586, PMID: 23869084.

8. True. The incidence of HBV reac-

tivation in patients with lymphoma and resolved hepatitis B after rituximab-based therapy ranged from as low as 1.5% to as high as 23.8%. This is the first RCT to determine the role of antiviral prophylaxis in CD20+ patients with lymphoma and resolved hepatitis B. Inclusion criteria were serum HBsAg (surface antigen) negativity and anti-HBc (core antigen) positivity, anti-HBs positive or negative, alanine aminotransferase (ALT) less than 2 times the upper limit of normal and bilirubin less than 2 mg/dL. Patients were randomly assigned in a 1:1 ratio to receive either prophylactic or therapeutic ETV 0.5 mg per day. In the ETV prophylactic group, oral treatment was initiated within one week before the first course of chemotherapy. ETV prophylaxis was continued until three months after completing chemotherapy (although investigators recommend longer duration of therapy). In the control group, patients started ETV therapy in the presence of HBV reactivation and HBsAg reverse seroconversion during follow-up. In addition, ETV therapy was initiated in the control group immediately, without waiting for HBsAg reverse seroconversion, if a patient’s HBV viral load was more than 2,000 IU/mL, accompanied by serum ALT more than 100 U/L.

DECEMBER 1014, 2013


This international symposium aims to achieve a balance of clinical, translational, and basic research, providing a forum for interaction, communication, and education for a broad spectrum of researchers, health professionals, and those with a special interest in breast cancer.




In the research of advanced cancers

What if the PD-1 checkpoint pathway played an important role in tumor growth? The programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. However, some tumors exploit this pathway to evade the bodyâ&#x20AC;&#x2122;s protective immune response to cancer1-5 In a normal state, the immune system recognizes tumors and can mount an active antitumor response6,7 Antigen-presenting cell

Step 1:

Tumor releases antigen8 T cells

Through tumor-immune surveillance, activated T cells can eradicate tumor cells from the body 6,7

Step 2:

Antigen-presenting cells activate T cells that proliferate, migrate to, and attack the tumor8


One way that tumors can evade normal immune attack is by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor1,2,5

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack1,2,4,5

PD-1 receptor

By exploiting the PD-1 checkpoint pathway, cancer cells evade the immune response and continue to proliferate1,2,6,8 PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptopic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 2. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 3. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 4. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 5. Dong H, Strome SE, Salomao DR, et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 6. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 7. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at Š2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB01112-02-01 06/13 Printed in USA.

October 2013  
October 2013