March 2015 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • March 2015 • Vol. 10, No. 3

CURRENT PRACTICE Plasma-based biopsies can help guide therapy .............. 4

SOLID TUMORS Vogl, NY: Ultrasound-guided biopsies should be done the same day as imaging whenever possible ...................................... 8 Report from GI Cancers Symposium: What is optimal timing for post-radiation surgery in rectal cancer patients? ..... 12

HEMATOLOGIC DISEASE Pediatric Oncology: Immune therapies promising in acute lymphoblastic leukemia ................................... 14 Jennifer Brown, MD, PhD: How I manage deletion 17p chronic lymphocytic leukemia ................................. 16

by the

numbers 1.0 No family history

2.3 One first-degree relative with CRC

4.3 More than one first-degree relative with CRC 0

Relative risk for CRC. CRC, colorectal cancer Source: National Cancer Institute (based on SEER Program data).

Contralateral Prophylactic Mastectomy Debate

Controversy Swirls Around Rising Rates Of CPM Surgeries San Antonio—For more than a decade, the rate of contralateral prophylactic mastectomy (CPM) has been rising in patients with unilateral breast cancer. At the San Antonio Breast Cancer Symposium (SABCS), clinicians discussed the controversy and some of the drivers behind this trend. CPM rates have skyrocketed in the United States, from an estimated 1.9% in 1998, to 4.5% in 2003 and 11.2% in 2011 ((J Clin Oncol 2007;25[33]:52035209, PMID: 17954711; JAMA Surg see MASTECTOMY, Y page 10

Breast tumor cluster; for women with dense breasts, MRI can add to the sensitivity of mammography; story on page 7.

Prostate Cancer:

Paying for Cancer Care: Part 1

Study Stresses Need To Better Stratify Pts At Intermediate Risk

Something’s Got To Give P

Orlando, Fla.—Patients with intermediate-risk prostate cancer who undergo active surveillance are four times more likely than those with low-risk disease to die of prostate cancer within 15 years, according to a study of 1,000 patients. “More research is needed to better characterize those intermediate-risk patients who can safely be monitored on a surveillance program,” said investigator D. Andrew Loblaw, MD, a radiation oncologist at Sunnybrook Health Sciences Centre, in Toronto, Canada, who presented the study at the 2015 Genitourinary Cancers Symposium (abstract 163). Active surveillance is a globally see INTERMEDIATE RISK, K page 9

hysicians, patients, payors and politicians all want to see reform for the entire U.S. health care system, but nowhere is reform needed more than in the area of cancer care. The rising costs of cancer care today are unsustainable. In this series, Clinical Oncology News takes an in-depth look at the problem, as well as solutions that might help cure what ails health care in America.

The rising costs of health care in the United States are unsustainable. When one considers that the median annual household income for a family of four in the United States is around $52,000 and a family’s annual health care costs, including insurance premiums, were about $23,215 in 2014 (Milliman Research Report May 2014), it is easy to see that individuals cannot afford wellness, let alone a serious illness. Although employers bear the brunt of health care costs in this country because they pay a higher percentage of an employee’s health insurance premiums, families can still expect high contributions and out-of-pocket expenses totaling a median of almost $10,000 a year, just under one-fifth of their annual wages. Nowhere is the cost of care more apparent than in the oncology sector, where annual direct medical costs are expected to increase to more than $173 billion in 2020 from $104 billion in 2006, according to “The State of Cancer Care in America: 2014,” a report see CANCER CARE, E page 6

NEW this month:

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Prostate Cancer by Leonard Gomella, MD Thomas Jefferson University

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

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

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

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

Gastrointestinal Cancer

Paul J. Ford, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

Pharmacy Harry Erba, MD, PhD

Breast Cancer

Michele Neskey, MMSc, PA-C

University of Alabama Birmingham, AL

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Policy and Management

Cindy O’Bryant, PharmD

Mary Lou Bowers, MBA

University of Colorado Cancer Center Denver, CO

Mitchell Cancer Institute Mobile, AL The Pritchard Group Rockville, MD

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

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

Bioethics Joseph P. DeMarco, PhD

Infection Control

Cleveland State University Cleveland, OH

Susan K. Seo, MD

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

Memorial Sloan-Kettering Cancer Center New York, NY

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

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

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

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

Ephraim Casper, MD

Steven Vogl, MD

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

Medical Oncologist New York, NY

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

Michael Enright, Publication Sales menright@mcmahonmed.com McMahon Publishing is a 43-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.

William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

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Lung g Cancer,, Emesis

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

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

Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

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

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

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Circulating Tumor DNA

Plasma-Based Biopsies Can Help Guide Therapy A

new type of blood biopsy tracks the evolving genetic fingerprint of a patient’s cancer by measuring circulating tumor DNA in the plasma. The tool may be particularly beneficial for patients who cannot undergo conventional tissue biopsies. Guardant360, a blood test that measures circulating tumor DNA, is one of nearly a dozen “liquid biopsy” assays now available or in development in the United States. In studies presented at oncology meetings in summer and fall 2014, researchers reported that Guardant360 accurately assesses the genomic profile of a tumor, using 54 clinically actionable genes. Oncologists can use this information to identify tumor-specific genomic alterations that can help drive treatment options. Although such blood biopsies do not provide the details of hundreds of genes that a conventional biopsy can, and circulating tumor DNA is not detectable in about 5% to 15% of patients with advanced cancer, in selected patients genomic sequencing can aid clinical decision making and identify targeted therapies and experimental clinical trials suitable for patients. “I’ve been very impressed with the ability of the Guardant360 to provide rapid information on mutation status of over 50 genes as well as copy number information on several genes,” said Scott Kopetz, MD, PhD, an associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston. “This is information that I’ve used to change the management of metastatic colorectal cancer patients,” added Dr. Kopetz, who has conducted research using Guardant360 and other bloodbased assays but has not received funding from the makers of Guardant360 or other companies that develop similar tests. At MD Anderson, Dr. Kopetz uses the Guardant360 assay for patients with colorectal cancer in whom it is difficult to get tissue. “In these patients, we need to understand their KRAS or NRAS status to make decisions about treatment with monoclonal antibodies. We’ve used Guardant to understand whether patients have developed resistance to these antibodies and should no longer be receiving them.” It also is useful in patients with amplifications of the MET T gene, said Dr. Kopetz. “These are things that occur later in treatment and are not present in the primary tumor. If we just rely on the archival tissue, we would not see this information and would not have been able to get these patients onto clinical trials based on these results.”

University of California, San Francisco Medical Center, doubted the accuracy of the patient’s initial pancreatic cancer diagnosis after the woman was referred to their cancer center. The team used a blood biopsy after a conventional biopsy failed to provide adequate tissue. The results, along with other tests, led to a diagnosis of ovarian cancer. “They started treating the patient [for] ovarian cancer with ... chemotherapy, and after three cycles of treatment the disease became resectable,” said Dr. Talasaz.

Obtaining Liquid Biopsy Results

‘For physicians who are looking to rapidly get results of KRAS, NRAS and BRAF for routine clinical decision making, this provides a very convenient and rapid assay that has been accepted by insurance companies....’ —Scott Kopetz, MD, PhD Validation Studies To date, the assay has been validated in breast, lung, colorectal, skin and prostate cancers. It was formally launched in June 2014 after a series of clinical validation studies were presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). In one of the studies, which was conducted by Guardant (abstract e22041), 86% of 300 patients evaluated had detectable somatic genomic alterations in circulation, and the concordance of tumor biopsy–derived alterations to those in blood was 93% when tumor biopsies were taken concurrently with the blood draw. Another of the studies, conducted at the John Wayne Cancer Institute, in Santa Monica, Calif., looked at the results of circulating tumor DNA analysis in 18 patients with metastatic melanoma (abstract 9018). Again, the circulating tumor DNA mutations detected matched those from paired metastatic tumor tissues resected after the blood draw. The mutations detected included well-known melanoma mutations, BRAF F and TP53, but also mutations that are more rare, such as CDKN2A, NRAS, PTEN, N NOTCHII, EGFR and JAK2. “This is taking next-generation sequencing to a whole new level by looking at blood. Once you’ve identified that a patient has cancer and you start treatment, you still need to follow treatment response. This assay provides that mechanism,” said investigator Dave S.B. Hoon, PhD, the director of the Molecular Oncology Department and Sequencing Center at the John Wayne Cancer

Institute. “Liquid biopsies have been around for decades. Now, it’s taken to a whole new level in terms of how it’s done and the accuracy of it,” he said. Dr. Hoon, who has been investigating the role of circulating tumor cells in melanoma since the 1990s, also serves on the board of Guardant. Another study presented at ASCO (abstract 11093) assessed Guardant360 in patients with metastatic breast cancer. Eighteen women with locally advanced or metastatic breast cancer who failed standard therapies had plasma analyzed for circulating tumor DNA. All women were found to have circulating tumor DNA alterations, including alterations in TP53 (44%), PIK3CA (44%), ALK K (39%) and EGFR (28%). Based on the results, three women were continued on HER2-targeted therapy after circulating tumor DNA confirmed ERBB2 alteration or amplification. Two HER2-negative women were started on HER2-targeted therapy after tests revealed ERBB2 mutations. The test is not designed to diagnose cancer, said AmirAli Talasaz, PhD, Guardant’s president and chief technology officer. It’s intended to monitor the evolution of a tumor over time by measuring 18 actionable cancer-related genes and the “hot” exons of an additional 36 onco-tumor suppressor genes. In one patient, the test corrected a misdiagnosis of pancreatic cancer, according to a poster presented at the 2014 annual meeting of the American Society of Human Genetics (abstract 3422S). The poster authors, from the

When using Guardant360, an oncologist submits two tubes of a patient’s blood, which are sequenced at Guardant’s CLIA-certified laboratory. Analysis identifies genomic alterations and associated treatment options, and a report is generated and reviewed by Guardant’s molecular tumor board before being sent to the oncologist within two weeks. The report does not recommend specific treatments. It quantitatively reports variants found in the blood, saying, for instance, “BRAF V600E mutation at 0.5% level.” The tumor board outlines any association between variants and treatments in publicly reported literature or experimental clinical trials. Dr. Kopetz said blood biopsies using circulating tumor DNA could be particularly helpful for community oncologists. “For physicians who are looking to rapidly get results of KRAS, NRAS and BRAF for routine clinical decision making, this provides a very convenient and rapid assay that has been accepted by insurance companies to allow treatment with cetuximab [Erbitux, Bristol-Myers Squibb] and panitumumab [Vectibix, Amgen],” he said. It also can help physicians who are considering referring patients to academic centers or signing patients up for clinical trials, he said. “This assay has been used to help decide whether or not there are particular therapies that may benefit a patient in a research setting. It may be that oncologists order this to help decide whether a trip out of state may be worthwhile for a patient.” Guardant360 lists at a price of $4,900. Oncologists and Guardant representatives told Clinical Oncology News that insurance companies frequently cover the test in cases where genomic profiling is needed and conventional biopsy is not an option, although the review cycle takes many months. —Christina Frangou

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Adherence to TKIs Is Not Optimal Among CML Patients T

he BCR-ABL tyrosine kinase inhibitors (TKIs) offer a clear advantage to individuals with chronic myeloid leukemia (CML), but that advantage is contingent on strict adherence to the regimens. s. More than one study that looked at a imatinib (Gleevec, Novartis), a first-gen neration TKI, showed that major molecu ular response (MMR) is not achieved when adherence is less than 80% and complette molecular response (CMR) is not achieveed when adherence is less than 90%. “If a patient does not take at least 90% % of the medication as prescribed, they maay not get a complete benefit,” said Kristin R. Anderson, BSc, BSP, ACPR, a clinicaal oncology pharmacist in the Departmen nt of Pharmacy at Foothills Medical Cen ntre, in Calgary, Canada. “Therefore, if our ur patients missed one out of nine doses, they would not be considered adherent— that is a pretty high expectation.” Because the six-year probability of achieving CMR and MMR is associated strongly with adherence, Ms. Anderson and her colleagues studied medication adherence to determine the proportion of CML patients who are at least 90% adherent to their prescribed regimen of imatinib, dasatinib (Sprycel, Bristol-Myers Squibb) or nilotinib (Tasigna, Novartis), as well as to identify subpopulations that are less adherent to these agents. The investigators did a retrospective cross-sectional analysis of 124 patients with CML who were treated at the Tom Baker Cancer Centre, in Calgary ((J Oncol Pharm Practt 2015;21[1]:1925, PMID: 24503243). All of the patients were older than age 18 years, with 95% being between ages 30 and 90 (Table). Most (63%) were men. Ninety percent of patients were taking imatinib, 6% were taking dasatinib and 4% were taking nilotinib. The investigators looked at patients who had been on therapy for at least six months and who already should have refilled their prescriptions at least once. They found that 38 patients (31%) did not adhere to their TKI regimen. At first glance, Ms. Anderson thought that this nonadherence rate was “rather high,” but when she looked at the literature and found that nonadherence rates as high as 46% have been reported, she realized that a “nonadherence rate of 31% is not out of the norm.” Still, she was surprised at some of the individuals who were nonadherent. These included patients who were not taking any other concurrent medications ((P=0.004), patients younger than age 50 years ((P=0.02) and patients taking imatinib ((P=0.01). There was no statistical association between adherence and nonadherence and patient gender, residence, years of treatment, adverse events (AEs) or previous treatment with interferon (7%

Table. Patient Characteristics in TKI Adherence Study Characteristicsa C

Gender G Male M

Female F

Age A

previously received interferon), according to the investigators. Although other studies, such as one by Darkow et al ((Pharmacoeconomics 2007;25[6]:481-496, PMID: 17523753), found that pill burden increased nonadherence, the Calgary study found that the opposite was true. The Calgary researchers theorized that individuals who were taking several medications had developed coping mechanisms that enabled them to remain adherent, or considered themselves sicker, which provided an incentive to remain compliant. “We suggested that patients on other medications may have an established routine or reminders. They may also consider themselves in poorer health, providing incentive to take their medications as prescribed.” The age difference suggests that a patient’s views about disease and about medications can vary over his or her lifetime, according to the investigators, who recommended that adherence-enhancing interventions should “actively engage” those younger than age 50. Additionally, the investigators indicated that the adherence differences among the three TKIs might be attributed to their AE profiles. They noted that overall the agents are associated with similar AEs, but the incidence of specific AEs differs for the three TKIs. Because the United States and Canada have different health care systems, some U.S. clinicians might wonder if these results were germane to U.S. patients with CML. Ryan N. Bookout, PharmD, BCOP, BCPS, a clinical pharmacist at the Moffitt Cancer Center, in Tampa, Fla., said that the findings are very pertinent to the U.S. experience. “The Canadian study does represent what we see in the United States. Adherence, especially in TKI use, is of great importance especially in diseases such as CML, where adherence to a patient’s medication regimen is directly related to clinical outcomes for these patients,” said Dr. Bookout, who did not participate in the study.

He said it was unique for the researchers to look at adherence after the patients had been taking the regimen for some time. “One of the biggest problems in long-term drug therapy for many diseases and especially with CML is that adherence tends to wane in patients as you look longer into therapy,” Dr. Bookout said. The Canadians, however, found no difference in adherence over time. Meir Wetzler, MD, FACP, a professor of medicine and chief of the Leukemia Section at Roswell Park Cancer Institute, in Buffalo, N.Y., said the study had one “main deficiency” because it did not review the role the treatment team and the size of the institution play in increasing adherence. He said that a treatment team that supports the patient could help improve adherence by offering education and support (Clin Lymphoma Myeloma Leuk 2012;12[2]:88-93, PMID: 22154234). Additionally, he said the size of the center was very important, citing a multicenter study that found that the treating physician and the center where the patient was seen played a very important role in adherence with imatinib (Blood ( d 2009;113[22]:5401-5411, PMID: 19349618). “Both of these studies highlight the importance of a large, compared with a small, practice that treats CML patients and the supporting staff in such a practice,” said Dr. Wetzler, who also was not involved with the study. Regardless of the reasons for nonadherence, Dr. Bookout said that the Calgary researchers made good suggestions for improving adherence. “The use of different types of reminders, including medication calendars, telephone reminders and education fitting different age groups as well as socioeconomic levels is very important,” he said, suggesting that the Calgary researchers develop a follow-up study of age-directed interventions. “There are many tools to encourage patients to be adherent to their regimen. Past studies have provided the benefits of

118-30

30-50 3

50-70 5

70-90 7

>90 >

Residence Within Calgary

Outside of Calgary

TKI use Imatinib

111

Dasatinib

Nilotinib

Interferon Previously used

Not previously used

114

Side effects Yes

Length of treatment, y <1

1-3

3-5

5-7

Concurrent medications 0

1-2

3-5

6-9

>10

TKI, tyrosine kinase inhibitor a

Categories may contain <124 patients because of missing data.

increased patient instruction, patient education, telephone follow-up, establishing routines and using prompts like phone alerts,” Ms. Anderson said, adding, “When patients understand that poor adherence is directly linked to poor outcomes, they are likely to increase adherence.” —Marie Rosenthal Ms. Anderson and Dr. Bookout reported no relevant financial relationships. Dr. Wetzler died shortly after being interviewed for this story.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

600 Clinics closed

8% 8% 6% 3%

69%

3% 2%

Laboratory Nonmedical Diagnostic imaging Radiation therapy Infusion Evaluation & Management Drugs

Oncology practices revenue sources. Source: J Oncol Practt 2011;7:2s-15s.

Everything Old Is New Again Investigators at Emory University, in Atlanta, developed an economic model that found that cancer patients and insurers paid about $139,100 for a year of life in 2013. That same benefit in 1995 cost $54,100 ((JAMA 2011;305:2347-2348, PMID: 21642689). No wonder medical expenses are the leading reason that Americans file for bankruptcy.

High Volume Over High Value Although costs to patients are increasing, oncologists are seeing incremental changes that have been eroding their reimbursements, forcing an unprecedented consolidation in the industry

And then there is ASP+6 (average sale price plus 6%), the Medicare drug reimbursement covered under Medicare Part B, which is regulated by Congress. Perhaps one of the oddest payment conventions in health care, ASP+6 is the method used to reimburse physicians for dispensing IV and injectable chemotherapy. Oncology physicians are unusual in that they not only diagnose, treat and manage patients, they also dispense chemotherapy. It wasn’t always this way but changed when the federal government instituted a formula to pay for cancer drugs (average wholesale price + n), which provided oncologists with a profit from dispensing

400

Practices sending patients elsewhere

300

Practices acquired by hospitals

200 100

Practices merged

3/ 1 1/ 12 7/ 1/ 1 11 2 /1 /1 2 3/ 1/ 13 7/ 1/ 1 11 3 /1 /1 3/ 3 1/ 14 7/ 1/ 14

/1 /1

7/ 1

3/ 1

0 /1

by the American Society of Clinical Oncology (ASCO). The average monthly cost of cancer drugs newly approved by the FDA now exceeds $10,000, according to Jennifer L. Malin, MD, PhD, the medical director for oncology at Anthem Inc., the largest forprofit managed health care company in the Blue Cross Blue Shield Association. Furthermore, she said, according to an analysis by medical ethicist Ezekiel Emanuel, of 13 cancer therapies approved in 2012, only one improved survival by more than six months. “For the most part, the new therapies are coming out very expensive, but only some of them are showing that they really make an impact on our patients’ outcomes,” she said, during an ASCO webinar held Dec. 9, 2014.

Practices struggling financially

continued from page 1

500

7/ 1

CANCER CARE

with many private practices either being bought by hospital systems or merging with larger practices, explained Jeffrey Ward, MD, a medical oncologist/hematologist at Swedish Cancer Institute, in Edmonds, Wash. In 2005, 87% of chemotherapy was administered in a physician-owned community oncology practice; by 2011, only 67% of chemotherapy was administered in that setting, with 33% being administered in outpatient hospital settings, according to a May 2013 report by the Moran Group, a health care research and consulting firm in Arlington, Va. Insufficient Medicare reimbursement, exacerbated by the sequester cut to cancer drugs, lower reimbursements and drug margins to private practices than hospitals see (partially because of 340B pricing) are reasons for the move from private practice to hospital-based care, according to a report by the Community Oncology Alliance (COA; “Practice Impact Report,” July 2013). The COA has been following these trends since 2008, and among 1,447 clinics, the 2013 report shows the following: • 544 practices were acquired by hospitals; • 395 practices reported struggling financially; • 313 closed their doors; • 149 practices merged or were acquired by another corporate entity other than a hospital; and • 46 practices were sending Medicare patients somewhere else for treatment. Despite the better reimbursements afforded hospitals, cancer care costs more in the hospital setting than in private practice. The Centers for Medicare & Medicaid Services (CMS) alone pays $6,500 more per patient per year for chemotherapy administered by a hospital, and cancer patients on Medicare pay $650 more when they receive chemotherapy in the hospital outpatient setting instead of from a community oncologist, according to a 2011 report by Milliman, an actuarial consulting firm.

Month

Historical trend in the changing landscape. Source: The Community Oncology Alliance

chemotherapy, and they stopped sending their patients to the hospital. This practice model, also called “buy and bill” used to provide 50% of a community oncology practice’s income ((J Natl Cancer Inst 2001;93[21]:1595-1597; PMID: 11698559). In 2005, the Medicare Modernization Act changed average wholesale price to ASP, which pays for the cost of some, but not all, drugs and greatly decreased the margin on those drugs. ASP+6 has good and bad attributes, according to Dr. Ward. It saved CMS $800 million in the first year alone, he said. ASP+6 has helped keep generic oncology prices down, he added, because it provides an incentive for providers to seek the lowest price for a given drug. Additionally, because there is a six-month lag between price adjustments with ASP+6, manufacturers understand that single-source providers can only tolerate small increases. Although after-market increases for single-source drugs are smaller, introductory pricing for new oncology therapeutics has grown “progressively more insane,” he said. The last 10 drugs introduced to the market cost about $10,000 a month, he added. “We don’t believe that reform is entirely complete until buy and bill is replaced,” Dr. Ward said. “Whether we believe it or not or whether it is true or not, there are plenty of people who believe that ASP+6 pricing incentivizes us to use more drugs and to use more expensive drugs.” Reforming payment for cancer care, especially care that is becoming more molecularly subdivided into thousands of diagnoses compounded by stage and line of therapy, is a complex issue, these experts said. What is needed is a reimbursement model that incentivizes high-value over high-volume care, according to CMS, and most proposals to “fix” the system are centered on changing the fee-for-service model that currently pays for much of health care in this country. “How much more could we be doing for our patients?” asked webinar speaker Kavita Patel, MD. “We would all

rather put our [focus] on our patient’s health outcomes, personal patient satisfaction and the quality of care they receive,” said Dr. Patel, a fellow and the managing director of clinical transformation at the Brookings Institute’s Engelberg Center for Health Care Reform, in Washington D.C. Fee-for-service does not support much of the high-intensity services that the oncology team provides, she said. Care must be coordinated among a broader team than in most other disciplines. The team includes radiation oncology, surgery, internal medicine, pharmacy, nursing, social work and other care coordinators. “We all know that if [we were] given an alternative payment and finance mechanism, we could identify ... some of the things that would improve care,” Dr. Patel said. Under the current fee-for-service system, “it is really challenging” to provide high-value care, she said. Not only do fee-for-service payment models not reimburse for services that focus on improving health outcomes, patient satisfaction and quality of care, according to Dr. Patel, but many third-party payors exclude high-ranking cancer centers from their networks. For instance, Memorial Sloan-Kettering Cancer Center, in New York City, is only included in two of nine exchange plans in the city, she said. Most alternative models revolve around the use of clinical pathways, patient-centered oncology medical homes, oncology accountable care organizations and bundled payments. The next installment of this series will explain these alternatives and highlight programs being developed by hospitals, insurers and CMS. Regardless of which models are chosen, oncologists must have a seat at the table and drive the discussions, according to Dr. Ward, who also chaired the ASCO Payment Reform Workgroup. “If not, I think we will not only end up with a model that as oncologists we will be unhappy with, but also a model that does not work.” —Marie Rosenthal

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CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Study Advocates MRI Plus Mammography for Select Patients San Antonio—For women with dense breasts—who are at a higher risk for developing mammographically occult breast cancer (MOBC)—adding magnetic resonance imaging (MRI) to routine screening can improve on the sensitivity of mammography, according to the results of a study presented at the 2014 San Antonio Breast Cancer Symposium (SABCS). “Women with MOBC present a particular challenge because their cancers aren’t always picked up on conventional imaging,” said Freya Schnabel, MD, who presented the results at the symposium (abstract P1-01-02). “So, even if they’re being meticulous and following up, they might eventually be diagnosed with cancers that are larger and more established than if the conventional imaging had initially worked for them,” said Dr. Schnabel, the director of breast surgery at NYU Langone Medical Center, in New York City.

“Whether it’s with an ultrasound or MRI, it’s time for physicians to adopt a different approach for screening,” said Jean Weigert, MD, a radiologist and the director of breast imaging at the Hospital of Central Connecticut, in New Britain, who led the Connecticut study. Even though MRI will find more cancers than ultrasound because it is extremely sensitive for finding cancers in dense breasts, according to Dr. Weigert, she said she still would advocate

for the use of ultrasound as a place to start. “It’s cheaper, less time-consuming, everybody has it and everybody can do it,” she said. “You simply get more bang for your buck. … I strongly believe that we are at a point of changing the paradigm for this cohort of patients.” Dr. Schnabel said the next step is to begin studying the characteristics of breast tissue in high-risk women, especially those whose risk comes from atypical hyperplasia and genetic

factors. “The underlying mechanism by which dense tissue correlates with an increased risk for malignancy is unclear,” she said. “It comes down to knowing how and why to screen different patients because, ultimately, that’s what’s going to help save lives.” —Paul Bufano Dr. Schnabel reported no relevant financial relationships. Dr. Weigert reported being on the advisory board of Tractus.

Cases in Hyponatremia

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To learn more about mammographically occult breast disease and improve screening for patients with dense breasts, Dr. Schnabel and her colleagues queried the medical center’s breast cancer database for women newly diagnosed with breast cancer from January 2010 to April 2014. Out of 1,781 women (median age, 59 years), 110 (6%) had MOBC and 1,671 (94%) had mammographically evident breast cancer (MEBC). More patients with ductal carcinoma in situ had MEBC (24%) than MOBC (18%), and more women with invasive lobular carcinoma had MOBC (17%) than MEBC (10%). Increased breast density on mammography was associated significantly with MOBC ((P<0.001). “Our study shows increased breast density reduces the sensitivity of mammography, which compromises the ability to detect meaningful findings,” Dr. Schnabel said. “We need to consider the addition of other tests to mammography … for women with dense breasts and other breast cancer risk factors. MRI is one of those additional tests and ultrasound is ... as well.” This notion of supplementary testing is supported by the results of a Connecticut study that stressed that all women with dense breasts who have a negative mammogram should be given an ultrasound as well. The study, also presented at SABCS (abstract S5-01), found that ultrasound identified an additional 3.2 cancers per 1,000 women (see story at bit.ly/1JetKgt).

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Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

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Revise Conventions of Breast Imaging To Put Patients First! EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist New York City

was appalled to learn at the 2014 San Antonio Breast Cancer Symposium that some breast imagers routinely defer diagnostic biopsies for women with positive ultrasounds for days or even weeks. There usually is no good medical reason for this, and it undoubtedly produces days of unnecessary anxiety and fear, since only about 1 in 10 to 20 women referred for biopsy based on ultrasound findings will have a biopsy that is positive for cancer, at least among those with negative mammograms. Deferring biopsies by weeks when the true-positive rate is so low is an unacceptable burden on these women! The subject came up in a presentation by Jean Weigert, MD, a diagnostic radiologist at the Hospital of Central Connecticut, in New Britain, who reported the local experience with ultrasounds mandated by state law for women with dense breasts, who as a group are at increased risk for breast cancer, but for whom mammograms are often difficult to interpret (see story at bit.ly/1JetKgt). The quickest and easiest way to biopsy a breast lesion is to locate it under ultrasound and to use ultrasound to guide positioning of the biopsy needle. The process takes just a few minutes, and the tissue generally is available for interpretation the next day. Indeed, for lesions first visualized by mammography or magnetic resonance imaging (MRI), most radiologists will try to find them on ultrasound to allow application of this simple, quick, inexpensive, and efficient technique. An informal survey of breast imaging centers in the New York metropolitan area indicates that some centers routinely offer same-day biopsies when they can, whereas others routinely make patients wait 2 weeks. Some patients prefer to defer the biopsy, and I see no reason to coerce them into a rushed biopsy they do not want as long as diagnosis of obviously malignant lesions is not deferred by more than 2 weeks. However, for those who do want prompt biopsy, it should be made routinely available. American College of Radiology Imaging Network studies, as cited by Dr. Weigert, show that adding ultrasound to negative mammograms detects another 4.2 cases of breast cancer per 1,000 women per year, 90% of which are in situ or stage 1. Ultrasound always has seemed attractive to me—why not use a technique that makes immediate biopsy

easier for any detected, suspicious lesion. Some biopsy procedures, such as stereotactic biopsy of lesions visualized only on mammography, needle localization of mammographically identified lesions, and MRI-guided biopsies, are sufficiently complex to justify some delay in their scheduling—ultrasoundguided biopsy is not!

The point of this article is not that the United States does a lot of breast imaging based on “shaky science” and inappropriate end points, but that the least we can do for the woman who chooses to have this imaging is to get her through it in the minimum time possible with the least anxiety and disruption to her life that we can manage.

Requires Standby Capacity That Will Not Always Be Used

How Much Is Needed For Same-Day Biopsies?

It seems, however, that the economics of the imaging industry have intervened and led to a process by which the woman is told a suspicious lesion exists, but that she will have to return days later to have it sampled. The excuse given is that breast imaging centers are too busy, and have insufficient staff, space, and funds to maintain a capacity to perform immediate or same-day biopsies. Although these statements undoubtedly have a seed of truth, these same imaging centers have not been too short of funds to first buy digital mammogram equipment, then spend millions of dollars on MRI machines and the magnetically shielded buildings needed to house them, then localization equipment for MRI-guided biopsies, then tomosynthesis equipment.

What resources would be required to do same-day biopsies? A local center in Westchester, N.Y., with 2 radiologists interpreting breast imaging studies, averages 6 biopsies per day, with a lot of variation between busy and quiet periods. Between cleaning the room and sterile preparations and a “time out” to make sure the correct breast is undergoing biopsy in the correct patient, the chief radiologist estimates it takes 45 minutes to perform a single ultrasound-guided biopsy. To make this center able to offer same-day biopsies, probably 90 minutes of room time and staffing would have to be set aside, although this would not always guarantee that a biopsy could be offered the same day as it is recommended. Of course, on some quiet days, the time set aside would be wasted. Another center in New York City routinely does 4 to 7 biopsies per day, but can do up to 9 if needed. Delay of more than 1 day is rare at this center, unless the patient prefers to defer the biopsy.

Breast Imagers Should Compete On Service, not Hardware Our problem is that breast imaging facilities have been allowed, even encouraged, to compete based on ever more complex and expensive imaging hardware, rather than on patient service. I predict that if we can induce 1 major imaging center in a given marketing area to advertise that it routinely offers sameday biopsies for positive ultrasound exams, all the other centers in the area will feel obligated to offer this service to avoid losing business. They should have offered this service from the first. The data underpinning breast imaging for cancer detection are considered shaky by many1 and largely refer to film mammography preventing deaths attributed to breast cancer. It is fairly clear that newer imaging techniques find more cancers. Although finding the extra cancers gratifies the radiologist and offers business to the surgeon, radiotherapist, and medical oncologist, there is no evidence from prospective comparative trials that newer techniques prevent more breast cancer deaths (the end point used in the past for mammography studies). Indeed, the appropriate end point would be a reduction in all-cause mortality among women randomized to screening. The necessary studies to search for reduction in allcause mortality would be very large, very expensive, and very long, so such studies have not been undertaken.

Insurance Issues: A Snag That Can Be Overcome Some insurance companies want to review and examine the ultrasound report before approving an ultrasoundguided biopsy. This seems silly—all such reports will state that the patient has a suspicious lesion that warrants biopsy. One solution would be for the initial ultrasound request to state “ultrasound with biopsy if indicated” and to have insurance companies routinely accept this order. It is absurd to think a company would approve of a cancer screening test and then refuse to allow a simple needle biopsy to establish the presence or likely absence of a cancer. Some payors will not pay for a mammogram if a biopsy is done on the same day! Such policies are a disservice to patients and should be forbidden by state insurance regulators. Advocates should publicize these policies—I doubt they would stand the light of day. They are part of an insurance trick: “make the provider inconvenience the patient if he wants to be paid in full for his services.” These are the tricks that make patients and providers hate insurance companies. Some centers believe the radiologist must obtain a prescription from the ordering physician to proceed with the

biopsy, fearing citation for “self-referral,” and that insurance will not pay unless an outside ordering physician is requesting the biopsy. Because ordering physicians often fail to quickly return phone calls, this can result in days of delay. Some radiologists will not perform elective biopsies if the patient has taken aspirin, nonsteroidal anti-inflammatory drugs, or antiplatelet drugs in the recent past.

Source: Indian J Radiol Imaging. 2009;19(3):242-247.

On the other hand, it is a rare referring physician who would deny a request for an ultrasound-guided biopsy if the radiologist (who, after all, is the expert) recommends it, and especially if it can be done within a few hours. There is no current difficulty regarding self-referral when the radiology department calls the patient back for an annual screening. This issue should be easily addressed with minor regulatory changes. The decision to recommend immediate needle biopsy obviously should be with the radiologist who discovers the suspicious lesion. The insurance coverage and regulatory issues should be resolved easily with suitable public, advocate, press, state insurance department, and legislative pressure.

Same-Day Biopsies May Decrease Prophylactic Mastectomies The anxiety and difficulty associated with breast imaging and biopsy procedures has contributed to the current epidemic of prophylactic mastectomies among relatively low-risk women in the United States. While making ultrasound-guided biopsies and their results more quickly available is not likely to prevent any deaths from breast cancer, it may well decrease the number of needless mastectomies of breasts without serious disease by streamlining the process of breast lesion evaluation. Compared with the capital and labor costs of prophylactic mastectomy and reconstruction, the facility and staffing costs for same-day ultrasound-guided biopsies are a real bargain for society! Same-day biopsies also are a compassionate and moral imperative.

Reference 1. Welch HG, Passow HJ. Quantifying the benefits and harms of screening mammography. JAMA Intern Med. 2014;174(3):448-454, PMID: 24380095.

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INTERMEDIATE RISK continued from page 1

recognized standard approach for patients with low-risk prostate cancer and selected intermediate-risk patients. Patients on active surveillance undergo physical examinations, digital rectal examinations, prostate-specific antigen (PSA) measurements and repeat tumor biopsies. In the new study, investigators analyzed prospectively collected data on 945 patients who were on active surveillance at Sunnybrook Health Sciences Centre between 1995 and 2013. Radiation or surgery was offered to patients who had a PSA doubling time of less than three years, increasing Gleason score or clinical progression. The study population included 213 patients with intermediate-risk cancer and 732 patients with low-risk cancer. Intermediate-risk was defined as a PSA more than 10 ng/mL, Gleason score 7 or clinical stage T2b/2c. Most of the patients in the intermediate-risk group (61.5%) were older than age 70 years. Compared with patients with lowrisk cancer, those with intermediaterisk cancer had a nearly fourfold higher chance of dying of prostate cancer within 15 years (Table). “When we have a patient in front of us with intermediate disease and we are thinking about active surveillance, we often select

patients who have other medical conditions that we think might contribute to a shorter life expectancy,” said Dr. Loblaw. “Despite the selection factors that we use in our clinic for intermediate-risk patients, we are still seeing a greater risk of dying of prostate cancer. We believe more research is needed to better identify the group of patients that may be watched conservatively.” Ashley Ross, MD, PhD, an assistant professor in the Department of Urology,

Oncology, and Pathology at Johns Hopkins School of Medicine, in Baltimore, said he was not surprised that men with intermediate-risk disease do worse on surveillance than men with low-risk disease. He noted that randomized clinical trials have shown that men with intermediate-risk disease have improved survival if they undergo surgery, whereas there is no evidence that surgery improves survival in low-risk patients ((N Engl J Med

Table. Prostate Cancer Survival by Risk Level

Survival

Low-Risk Prostate Cancer

IntermediateRisk Prostate Cancer

P Value

10-y overall survival, %

84.2

67.3

0.0001

15-y overall survival, %

66.7

50.8

0.0001

10-y prostate-specific survival, %

98.3

97.2

0.01

15-y prostate-specific survival, %

96.7

88.5

0.01

2012;367[3]:203-213, PMID: 22808955; N Engl J Med 2014;370[10]:932-942, PMID: 24597866). “Hopefully, a more granular look at the data will help guide us as to whether risk stratification among intermediate-risk men can select patients who are truly safe to undergo disease surveillance,” Dr. Ross said. “It is important to note that the difference in 10-year cancer-specific survival among intermediate-risk men and low-risk men was significant but marginal in this study. This suggests that following some intermediate-risk men who are older and have limited life span may be acceptable.” Charles Ryan, MD, a professor of clinical medicine and urology in the Department of Medicine at the University of California, San Francisco, said the role for active surveillance in intermediate disease is when the patient has a relatively short life expectancy, which can be defined as less than 10 years. “The survival curves separate after 10 years. This is a consistent finding in the active-surveillance literature: Death from prostate cancer occurs as a late event,” Dr. Ryan said. “This study underscores the need to identify further markers of risk. There are genomic and other biomarkers that are being studied.” —Kate O’Rourke Drs. Loblaw, Ross and Ryan reported no relevant financial relationships.

Report From Genitourinary Cancers Symposium

Prostate Cancer Being Diagnosed at Higher Risk ORLANDO, FLA.—In 2011, the U.S. Preventive Services Task Force (USPSTF) recommended against prostatespecific antigen (PSA) testing to screen men for prostate cancer, regardless of a man’s age. Now a new study shows that the proportion of men diagnosed with intermediate- and high-risk prostate cancer increased by nearly 6% between 2011 and 2013. Although the new study, presented at the 2015 Genitourinary Cancers Symposium (abstract 143), does not prove a cause–effect relationship between these recommendations and the diagnosis of higherrisk cancers, “the data indicate that the USPSTF might reconsider their recommendation,” said lead study author Timothy Schultheiss, PhD, a professor and director of radiation physics at City of Hope Medical Center, in Duarte, Calif. The researchers conducted their study using patient data collected from the National Oncology Data Alliance (Elekta), a proprietary database of merged tumor registries from more than 150 hospitals in the United States. In an analysis of data from 87,500 men with prostate cancer, the investigators found that from 2005 to 2011, the proportion of men with prostate cancer and a PSA greater than 10 ng/mL decreased gradually, and between 2011 and 2013, this proportion increased by 3% per year. In men over the age of 74, the increase was 6% per year. A similar trend was identified when the researchers classified patients using the National Comprehensive Cancer Network (NCCN) risk categories, which combine PSA, T-stage and Gleason score. Using the NCCN categories, the percentage of patients presenting with

intermediate- or high-risk cancer decreased from 2005 to 2011, but increased by roughly 3% per year starting in 2011. There was no evidence of a plateau. The authors estimated the trend would translate into an additional 1,400 deaths each year. “If you don’t screen men, when they do show up with prostate cancer, the horse is out of the barn. They are more likely to be at intermediate risk. By missing early disease, you are going to catch it when it is palpable or patients are having symptoms, and it is more difficult to treat,” said Dr. Schultheiss. “We need to be intelligent regarding who we screen and who we treat. We are not suggesting that everyone be screened with PSA, but we are not suggesting that no one be screened either.” He said clinicians should counsel patients regarding the risks and benefits of screening based on their history, risk factors and life expectancy. However, Ashley Ross, MD, PhD, an assistant professor in the Department of Urology, Oncology, and Pathology at Johns Hopkins School of Medicine, in Baltimore, who was not involved with the research, said it is unclear whether identifying men when they have intermediate- rather than low-risk disease would decrease survival, but there is evidence indicating that surgery does not benefit patients with low-risk disease. Pointing out that around the time the USPSTF issued its guidelines, associations such as the American Urological Association also were making recommendations for less PSA testing. Dr. Ross noted that clinical trials, including PIVOT (Prostate cancer Intervention Versus Observation Trial) and a recent Scandinavian study, have shown that surgery does not

benefit men older than 65 years with low-risk cancer. PIVOT provided high-quality level 1 evidence that in patients with low-risk cancer, radical prostatectomy did not significantly reduce all-cause or prostate cancer mortality compared with that in patients who were not treated (N Engl J Med 2012;367[3]:203-213, PMID: 22808955). A Scandinavian trial of watchful waiting versus radical prostatectomy also found that radical prostatectomy did not improve survival in patients with low-risk prostate cancer (N Engl J Med 2014;370[10]:932-942, PMID: 24597866). “You don’t want to diagnose the man who is over [age] 75 with low-risk prostate cancer. These men are often treated aggressively, and that represents overtreatment,” said Dr. Ross, referring to a study published in 2014 (Cancerr 2014;120[23]:3642-3650, PMID: 25042117). “You want to catch them when they have intermediate- or high-risk localized cancer, where treatment might be able to help them. This study indicates that, particularly in older men, there is a shift away from diagnosis of low-risk localized prostate cancer, which is a good thing.” Dr. Ross noted the new study found that the T-stage has remained stable since 2005 and did not report whether the incidence of metastatic presentation was increasing. —Kate O’Rourke

Drs. Schultheiss and Ross reported no relevant financial relationships.

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MASTECTOMY

and an increased risk for surgical complications. Benjamin Anderson, MD, a professor of surgery at the University of Washington and the director of the Seattle Cancer Care Alliance’s Breast Health Clinic, said he believes some women have unrealistic beliefs about how their reconstructions will work, particularly in relation to nipple sensation. “I have often had patients come in and say, ‘no one told me that I would be numb,’” said Dr. Anderson.

continued from page 1

2015;150[1]:9-16, PMID: 25408966). Numerous studies, however, have shown that CPM does not improve survival over unilateral mastectomy or breast-conserving surgery plus radiation. “There is really very little to support the widespread use of CPM, and the increasing trend toward greater use of CPM is perplexing,” said Ismail Jatoi, MD, PhD, from the Division of Surgical Oncology and Endocrine Surgery at the University of Texas Health Science Center, in San Antonio. “Contralateral prophylactic mastectomy is not justified, except in a few instances. For example, it would be justified in patients who harbor the BRCA1/BRCA2 gene [mutation], where the risk of contralateral breast cancer is very high.” In a study of BRCA1/2 mutation carriers, the 10-year survival rate was 89% in women receiving CPM and 71% in women receiving unilateral mastectomy ((P<0.001) ((Breast Cancer Res Treat 2013;140[1]:135-142, PMID: 23784379). But setting aside these high-risk women, most clinicians do not feel evidence supports CPM. “It seems counterintuitive that in an era of minimally invasive surgery, in a time when surgical oncologists are trying to remove only that which they have to, that the women themselves are actively choosing more aggressive surgery, despite the fact that there is no survival benefit,” said Andrea Pusic, MD, an associate professor of plastic and reconstructive surgery at Memorial Sloan-Kettering Cancer Center, in New York City.

The Message Is Not Getting Through Although patients are told that numerous studies show that CPM does not improve survival, this message does not seem to be getting through, according to results of a study by Rosenberg et al surveying 123 women (Ann ( Intern Med 2013;159[6]:373-381, PMID: 24042365). “When we asked women, ‘why did you choose CPM,’ 90% told us improved survival was one of the important reasons,” said Ann Partridge, MD, MPH, a senior physician and the director of the Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute, in Boston, who was involved with the study. According to Dr. Jatoi, a few recent studies have identified an association between CPM and an improvement in breast cancer–specific and overall survival; however, a selection bias is the most likely reason for this finding in women who are not high risk ((Breast Cancer Res Treat 2013;142[3]:465-476, PMID: 24218052; J Natl Cancer Inst 2010;102[6]:401-409, PMID: 20185801). In a recent analysis of almost 500,000

Who Is Choosing CPM?

‘It seems counterintuitive that in an era of minimally invasive surgery, in a time when surgical oncologists are trying to remove only that which they have to, that the women themselves are actively choosing more aggressive surgery, despite the fact that there is no survival benefit.’ —Andrea Pusic, MD patients, CPM was associated with a 16% reduction in breast cancer–specific mortality, a 17% reduction in all-cause mortality, but an even greater reduction, 29%, in noncancer mortality ((Breast Cancer Res Treat 2014;148[2]:389-396, PMID: 25301088). “Obviously CPM should not have any effect on noncancer mortality,” said Dr. Jatoi. “What this suggests is that there is a strong selection bias favoring women who undergo CPM. Women who undergo CPM are perhaps a healthier cohort of women or a cohort of women with better access to health care.” Dr. Jatoi pointed out that the risk for a woman with unilateral breast cancer to develop a cancer in the opposite breast has decreased since 1985, when hormonal therapy became standard. Studies show, however, that women overestimate their risk. The survey by Rosenberg et al showed that the average-risk woman believes she has a 10% chance of developing contralateral

cancer risk because of innumeracy or because they are like a “deer in headlights” after a breast cancer diagnosis. Others, especially very young women, might think the risk estimates do not pertain to them. “Your risk of getting breast cancer is on the order of one in 2,000 if you are [age] 35, or one in 200 if you are 40,” noted Dr. Partridge. But, she added, women who already have had a breast cancer often say, ‘I wasn’t supposed to get breast cancer in the first place, and now you are going to tell me it is not going to happen again. Why wouldn’t it happen again!’ These women often articulate that they feel like they have a target on their back, and they want to do everything they can to get rid of it.” Other women might believe that any risk for developing additional cancer is too much risk. According to Dr. Partridge, one advantage to CPM is the diminished need for surveillance. “This has real value for some women,” she said. Dr. Pusic

‘Women who already have had a breast cancer often say, “I wasn’t supposed to get breast cancer in the first place, and now you are going to tell me it is not going to happen again. Why wouldn’t it happen again!” These women often articulate that they feel like they have a target on their back, and they want to do everything they can to get rid of it.’ —Ann Partridge, MD, MPH breast cancer without CPM within five years of her surgery. This is much higher than the roughly 1% rate identified in the scientific literature (2012 SABCS, abstract 69; Figure). Dr. Partridge said that some women may be unable to comprehend their

agreed. “I have women who are traumatized by the follow-up mammogram emotionally, and they articulate to me on a regular basis, ‘I wish I had the other side off,’” Dr. Pusic said. The downsides of CPM include detrimental sexual and emotional effects,

An analysis of the National Cancer Data Base revealed that the majority of patients who opt for CPM have no major genetic or familial risk factors for contralateral disease (JAMA ( Surgg 2014 May 21. [Epub ahead of print], PMID: 24849045). Women are more likely to choose CPM if they have higher baseline levels of anxiety, have a child, are more worried about recurrence or have genetic testing, regardless of whether the result is positive or negative, said Dr. Partridge. White race, family history of breast cancer, the use of breast reconstruction and the use of magnetic resonance imaging (MRI) also are associated with CPM ((Ann Plast Surg 2014;72[6]:s153-s157, PMID: 24691345). “Women who undergo preoperative MRI have more than a twofold increase in the risk of undergoing removal of the opposite breast,” said Dr. Jatoi. “The reason is that MRI is associated with a higher false-positive rate in the opposite breast, which oftentimes prompts CPM.” CPM has increased dramatically in younger women. In an analysis of 2011 data from a population-based California Cancer Registry, 12.3% of women undergoing treatment for unilateral breast cancer underwent a bilateral mastectomy compared with 2% in 1998; but the rate rose to 33% from the 1998 rate of 3.6% in women younger than age 40 years ((JAMA 2014;312[9]:902-914, PMID: 25182099). Dr. Jatoi said there was an inextricable link between CPM and breast reconstruction, and that perhaps women prefer the better symmetry associated with bilateral mastectomy and reconstruction. Roughly 85% of women undergoing CPM opt for breast reconstruction ((Ann Plast Surgg 2014;72[6]:s153-s157, PMID: 24691345). In the United States, said Dr. Pusic, women are more likely to undergo an implant reconstruction rather than a flap reconstruction, and long-term aesthetic outcomes from an implant reconstruction are better if the surgery is done bilaterally rather than unilaterally. The significant rise in immediate reconstruction rates in the United States correlates closely with a 203% expansion in implant use ((Plast Reconstr Surg 2013;131[1]:15-23, PMID: 23271515). “Unilateral implant reconstruction can be disappointing in the long

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term,” said Dr. Pusic, noting that as the remaining natural breast falls as a woman ages, the implant rises. “It’s very important that women understand expected outcomes with unilateral implant over time. However, excellent aesthetic long-term results can be obtained with unilateral mastectomy and autologous reconstruction, and we are just not seeing women choosing that option.” Although clinicians have believed that an autologous reconstruction has a more difficult recovery, unpublished data, from a 2,000-patient study Dr. Pusic is leading, show that at three months postsurgery, women who undergo autologous reconstruction have less discomfort and morbidity than women who have implant surgery. Lindi Vanderwalde, MD, a general surgeon at Baptist Medical Group, in Memphis, Tenn., pointed out that in a community setting, patients are only offered implant reconstruction. “Microvascular surgery has become limited to academic centers,” she said.

Peace of Mind Is Major Factor According to Dr. Partridge, although aesthetic outcome is a factor in the rising CPM rates, it is not the principal driver. In the survey by Rosenberg et al, 60% of women ranked cosmetic

Risk an average-risk woman believes she has for developing contralateral breast cancer within five years of unilateral mastectomy Risk identified in the scientific literature an average-risk woman has for developing contralateral breast cancer within five years of unilateral mastectomy

Figure. Perception of risk for contralateral breast cancer after unilateral mastectomy vs. actual risk. Based on Ann Intern Med d 2013;159[6]:373-381, PMID: 24042365 and 2012 ASCO Breast Cancer Symposium, abstract 69.

symmetry as extremely important or very important in their decision to have CPM, but the most important reason, noted by 95%, was peace of mind. In another study, 36% of patients cited wanting their breasts to match as a reason for undergoing CPM, but worry about getting another breast cancer was listed by 80% ((Am J Surg 2011;201[5]:615-618, PMID: 21545909). Whatever their reasons for choosing CPM, women appear to be satisfied with their decision. In a survey of women

younger than 40 years of age who underwent CPM, 80% said they were extremely confident in their decision, and 90% said they would definitely choose CPM if deciding again ((Ann Intern Med 2013;159[6]:373-381, PMID: 24042365). Only one-fourth of these women were BRCA1/2 mutation carriers. Regardless of whether patients feel satisfied, however, clinicians need to do more to ensure that CPM risks and benefits are effectively communicated, Dr. Partridge said. Although 80%

‘There is really very little to support the widespread use of CPM, and the increasing trend toward greater use of CPM is perplexing.’ —Ismail Jatoi, MD, PhD of women are speaking to physicians about their reasons for choosing CPM, only 50% say physicians are discussing the reasons not to have the surgery with them, according to the survey by Rosenberg et al. “Recent findings suggest that women are making decisions about surgery based on inaccurate risk perceptions and understanding. Decisions are potentially being made without adequate information or psychosocial support,” said Dr. Partridge. “Clearly there is work to be done.” —Kate O’Rourke Dr. Pusic receives royalties from the Breast-Q (a patient-reported outcome questionnaire) when it is used in industry-sponsored clinical trials. All the other sources reported no relevant financial relationships.

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Rectal Cancer:

What’s Optimal Timing for Surgery After Radiation? San Francisco—Although an interval up to 75 days between radiation and surgery may achieve higher rates of pathologic complete response (pCR), a delay of more than 60 days from radiation to surgical resection decreases overall survival (OS) in patients with rectal cancer, according to data presented at the 2015 Gastrointestinal Cancers Symposium (abstract 510). “In patients with locally advanced rectal cancer, there was a significant difference in complete pathologic response, positive margin status and survival before and after 60 days’ interval between radiation and surgery,” said Jonathan C. Salo, MD, a surgical oncologist at the Levine Cancer Institute at Carolinas Medical Center, in Charlotte, N.C. “A radiation– surgery [R-S] interval of less than 60 days was associated with greater OS than an interval of greater than 60 days.” The optimal timing of surgery relative to the conclusion of neoadjuvant therapy has been ambiguous, according to Dr. Salo, who presented the results of the retrospective study that was led by Ciara R. Huntington, MD, a general surgeon at Carolinas Medical Center. “Other studies have shown that in treatment of locally advanced rectal adenocarcinoma, an increased time interval of six to 12 weeks from the end of radiation therapy to surgery may increase the rate of

pCR,” said Dr. Salo, “but the optimal time interval with respect to survival has not been established. This study evaluated the impact of time delay on overall mortality.” The National Cancer Data Base was queried for patients with adenocarcinoma of the rectum and no evidence of metastasis at diagnosis, who underwent preoperative chemoradiation followed by radical surgical resection from January 2004 through December 2006. The cohort consisted of 6,805 patients, who generally were treated with low anterior resection (57.3%), colonanal reanastomosis (8.4%) or abdominoperineal resection (28.4%). They had a median survival of 66.6 months. Dr. Salo outlined the following findings: • OS was equivalent in groups with R-S interval less than 60 days. • OS was shorter for a R-S interval of more than 60 days compared with less than 60 days (hazard ratio, 1.25). • The pCR rate increased up to 75 days after radiation, and did not increase further thereafter ((P=0.0003). • Positive surgical margins occurred at equivalent rates for all groups of R-S interval less than 60 days. • Positive surgical margin rate increased after 60 days following radiation ( =0.0067). (P “There was a significant relationship between radiation–surgery interval and

Table. pCR Based On R-S Interval RS Interval, days

pCR, %

<30

3.7

31-45

5.7

46-60

7.7

61-75

8.8

75+

pCR, pathologic complete response; R S,, radiation–surgery R-S radiation surgery

complete pathologic response ((P=0.0002),” he emphasized. “Additionally, a radiation– surgery interval of more than 60 days was associated with 20% greater risk for mortality. This effect became more pronounced with increasing intervals; an interval of greater than 75 days was associated with 28% increased risk of mortality, while patients with an interval of less than 60 days saw a survival benefit,” he said. Other significant predictors of survival were age, surgical margins, cormorbidity index, time to discharge after surgery, TMN pathologic staging, surgical volume and patient income ((P<0.05 for all values). Asked to comment on this study during the meeting, Nancy Kemeny, MD, an

attending physician at Memorial SloanKettering Cancer Center and a professor of medicine at Weill Cornell Medical College, both in New York City, noted several limitations: The data could be outdated due to improvements in chemotherapy and surgery; some patientand treatment-related specifics were lacking or not reported; and the overall pCR rate of 6.8% is lower than most current reports (12%-28%). However, Dr. Kemeny added that this large retrospective study “has given support to the concept that a longer interval … from the end of chemoradiation to surgery is necessary to increase the chance of complete response, but waiting more than 60 days decreases overall survival.” Although it may take time to develop a complete response, in the absence of a tumor response, these longer intervals may actually be harmful, she said. “An increased time delay could facilitate local tumor growth and metastasis, enhance fibrosis, and delay the resumption of postoperative chemotherapy,” Dr. Kemeny said, suggesting that the optimal strategy might be “measuring response more frequently.” —Chase Doyle Drs. Salo and Kemeny reported no relevant financial relationships.

Study Finds Wide Variation Among Rectal Cancer Guidelines

ide variation exists in clinical practice guidelines for rectal cancer, according to a recent study from the University of Michigan Comprehensive Cancer Center, in Ann Arbor. The report, published in Cancer, r looked at the clinical practice guidelines for rectal cancer from five top institutions in the United States, Canada and Europe. Researchers evaluated the guidelines—all published in the past six years—with respect to overall quality using a tool that rated them on a percentage scale on six quality domains. The scores ranged from 27% to 90%, suggesting wide variation. The Michigan investigators said the study highlights some important information for physicians who are following such guidelines and underscores the importance of not following guidelines blindly. “The guidelines are of varying quality and they have varying recommendations,” said lead investigator Sandra L. Wong, MD, MS, an associate professor of surgery at the University of Michigan Medical School. “It’s not as easy as just viewing a guideline and following it.” The guidelines from the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom had the overall highest score, whereas those from the European Society for Medical Oncology (ESMO) ranked lowest. All five organizations, which also included the American Society of Colon and Rectal Surgeons (ASCRS), Cancer Care Ontario (CCO) and the National Comprehensive Cancer Network (NCCN), scored highest on the “clarity of presentation” domain. Overall, the lowest scores were in the “applicability” domain. The greatest disparity

existed in the “rigor of development” domain, with NICE scoring 96% and ESMO 17%. Additionally, NICE, ASCRS and CCO included systematic reviews in developing their guidelines, whereas ESMO and NCCN did not. Dr. Wong and her colleagues also assessed 21 common points of care among the guidelines and found that all five guidelines agreed on only eight recommendations for care. Six processes of care were in direct conflict with one another. These included differences in diagnosing and staging, the role of laparoscopic surgery and the duration and methods of aftercare surveillance. Furthermore, the study found that even when guideline panels used the same randomized clinical trials as evidence, they sometimes make different recommendations. For example, when it came to postoperative chemotherapy in patients who received preoperative chemoradiation, recommendations among the guidelines were highly variable, although they cited the same trial. “We found that to be pretty striking,” Dr. Wong said. “If you’re somebody who’s looking at the guidelines trying to figure out what’s the best thing to do for your patient, you can see how that can get very confusing very quickly.” Several factors may account for the discrepancies in recommendations. First, there are, in fact, no global guidelines for creating clinical practice guidelines. Geography also should be taken into account. For example, the study authors point to the differences in practice between North America and Europe in the

use of short-course radiation therapy for moderaterisk rectal cancer patients. The makeup of the panel at each organization also can affect the outcome. Some of the guidelines panels included experts in a single specialty, whereas others encompassed multidisciplinary specialties and patient advocates. Finally, as seen in the example above, panels may interpret evidence differently. Dr. Wong said the study emphasizes the need for physicians to look at guidelines more critically. “Physicians really need to be aware of where they’re getting their data,” she said. “Guidelines are great because on a regular basis they keep you up to date on what’s going on, but you really have to look at the source, and if there’s something that you’re not sure about, you need to not only read what the guideline says but you need to go deeper and look at references and the trials that the recommendations are based on.” Cathy Eng, MD, a specialist in colorectal cancer at the University of Texas MD Anderson Cancer Center, in Houston, agrees. “These guidelines are meant to guide you, but they’re not set in stone,” she said. “The biggest take-home point is that physicians need to look at whichever guidelines they are using a little more in depth and not necessarily presume that one set of guidelines is better than another.” Dr. Eng was not involved with the study. Dr. Wong also said those creating the guidelines should make it clear when expert consensus or opinion enters into the recommendations and be sure to call out any controversy. —Ashley Welch

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Managing Hereditary CRC Syndromes A thorough history, genetic testing and enhanced screening often can forestall advance of disease San Francisco—Close screening and follow-up of patients with genetic predispositions to colorectal cancer syndromes have major implications for the prevention and treatment of these syndromes, according to findings presented at the 2015 Gastrointestinal Cancers Symposium. “Careful follow-up of family members when hereditary colorectal cancer syndromes are found makes the diagnosis cost-effective and can dramatically alter the natural history of the disease,” said C. Richard Boland, MD, the chief of gastroenterology at Baylor University Medical Center, in Dallas. “With colonoscopies and some occasional extra surgery, [clinicians] can turn Lynch syndrome into a fairly ‘boring’ disease—without the big surprise of cancer.” Dr. Boland reported that the first step in evaluating familial clusters is determining whether it is a colonic or intestinal polyposis syndrome or one of the nonpolyposis syndromes. However, such classification is rarely as straightforward as it might sound. “There’s not a simple black line between polyposis and nonpolyposis,” Dr. Boland said.

to cancer; fundic gland polyps, which are not neoplasms although they look like they are to many pathologists; desmoid tumors; as well as other forms of cancer. MAP is caused by mutations in MutYH, a base-excision repair gene (Figure). “Mutations are usually missense,” Dr. Boland elaborated, “and the mutations are dominated by founder mutations.” According to Dr. Boland, the two most common mutations in the MutYH H gene for whites are a very inactive allele and a hypomorphic allele. The interaction between the two accounts for the heterogeneity of the syndrome. “A typical diagnostic strategy [for Europeans] is to look for these two mutations first,” he explained, “and if one of them is found, then … sequence the whole gene looking for the other. However, if it’s not a European, then you probably have to ask for the whole gene to be sequenced,” he added, noting that “with next[generation] techniques, that is probably going to [become] the standard.” Lynch syndrome is autosomal dominant and caused by a germline mutation in one of four DNA mismatch repair genes. “Almost all the tumors have mic-

‘Taking the family history first is critically important … Because there are many “pseudo types” that are not actually Lynch syndrome, you must talk to the patient to help determine this. ... Nothing makes sense until you have family history.’ —Thomas Seufferlein, MD

milder cases of the syndrome, an annual colonoscopy can suffice, according to Dr. Boland. “Treatment has to be individualized based on the patient’s willingness and availability to get follow-up and tolerate some degree of uncertainty in exchange for keeping the colon in place,” he said.

panels. Testing of multiple genes, for example, may uncover sequence variations that suggest a functional change in the gene, but it may not be causing the cancer—or cancer risk—in that patient or family. “We can now sequence many genes that we cannot interpret,” Dr. Boland cautioned.

‘With colonoscopies and some occasional extra surgery, [clinicians] can turn Lynch syndrome into a fairly “boring” disease—without the big surprise of cancer.’ —C. Richard Boland, MD

Familial adenomatous polyposis

MutYH-associated polyposis

MutYH gene 1p34

q APC gene 5q21 q

Figure. Adenomatous polyposis colii and MutYH H genes. Source: http://www.genetics4medics.com/familial-adenomatous-polyposis.html.

Focusing his presentation on two polyposis syndromes—familial adenomatous polyposis (FAP) and MutYHassociated polyposis (MAP)—as well as on the nonpolyposis Lynch syndrome, Dr. Boland explained that “classic polyposis is more than 100 polyps, and in the case of [FAP] and [MAP], they’re all adenomatous polyps.” But, he added, “attenuated forms of FAP and a lot of MAP [cases] have fewer than 100.” With Lynch syndrome, he said, generally patients have “about three polyps by age 30 and about six polyps by age 50, but there are often patients who have more than this.” FAP is caused by inactivating germline mutations in the APC gene (Figure). Noting that APC is a large gene, with 2,843 codons, Dr. Boland said, “Such a big target is an invitation for genetic trouble.” FAP is a systemic disease, with an associated likelihood of periampullary cancer somewhere between 5% and 8%. Patients can develop duodenal adenomas, which are true neoplasms and lead

rosatellite instability (MSI),” he said, “and the tumors show absence of the expression of the mutating gene, so these are always inactivating mutations.” More than two-thirds of the cancers caused by Lynch syndrome occur in the proximal colon, but there’s an increased risk for other tumors, too, including endometrial, gastric and urinary tract tumors.

Treatment Approaches “We treat FAP with a prophylactic colectomy in the late teens or early 20s,” Dr. Boland said. “It’s important for the child to be fully grown to be able to tolerate the surgery … but you want to get the colon out as early as possible.” After the colectomy, it is important to assess “the duodenum for adenomas and cancer and [follow] the germline mutation through the family,” he explained. Even with a colectomy, however, patients are still at risk for pancreatic and gastric cancers. A prophylactic colectomy also is an option for patients with MAP, but in

“For Lynch syndrome, we don’t usually go to a prophylactic colectomy; an annual colonoscopy will do,” Dr. Boland noted. “For women with this disease,” he said, “removal of the uterus and ovaries after childbirth is recommended, especially in Lynch syndrome MSH6 type.” If colon cancer is found in conjunction with Lynch syndrome, however, Dr. Boland suggested a colectomy preserving the rectum, and an ileorectal or ileosigmoid anastomosis. He also noted that patients with Lynch syndrome, and possibly others with MSI, may not respond to 5-fluorouracil–based chemotherapy.

Interpretation Lags Behind Gene Sequencing Despite the obvious advantages of screening, Dr. Boland concluded his presentation by discussing some of the issues concerning diagnostic testing

Asked to comment on the presentation, Thomas Seufferlein, MD, from Ulm University Hospital, in Ulm, Germany, strongly agreed that screening should be performed routinely. “The trouble is,” he said, “it starts with taking proper history of patients, which is not often done or done correctly. … The simple things are those that are usually forgotten. We are prone to say, ‘let’s get this to pathology,’ but taking the family history first is critically important. ... You have to know what you actually want. Because there are many ‘pseudo types’ that are not actually Lynch syndrome, you must talk to the patient to help determine this. ... Nothing makes sense until you have family history.” —Chase Doyle Drs. Boland and Seufferlein reported no relevant financial relationships.

HEMATOLOGIC DISEASE

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Therapies Using Immune Engineering Show Promise for ALL San Francisco—Two strategies that involve immune engineering have produced highly encouraging responses in acute lymphoblastic leukemia (ALL), according to data from separate studies presented at the 2014 annual meeting of the American Society of Hematology (ASH).

Severe cytokine-release syndrome, which could include such manifestations as hypotension, respiratory and renal insufficiency, and coagulopathy, was most common in individuals with a high disease burden during the study. Along with corticosteroids, the interleukin-6 (IL-6) inhibitor tocilizumab

CTL019 attaches to cancer cells

CTL019 cells target CD19-expressing cancer cells, attaching to them and initiating cell death.

In one study, T cells engineered for chimeric antigen receptor (CAR) targeting were used in children with relapsed or refractory disease. In the other, a bispecific monoclonal antibody was used to achieve negative minimal residual disease (MRD) status in adult ALL patients already in hematologic complete remission (CR). The results of both trials were positive and both strategies appear poised for accelerated development, investigators said. In the pediatric study, 36 of 39 children achieved a CR after an induction infusion of modified T cells (abstract 380). Although 10 of the responders have relapsed, 26 of the remissions persisted, with a median follow-up of six months and maximum follow-up of 31 months. No relapse occurred in any patient who remained in remission 12 months after the infusion. The T cells were engineered with a CD19-directed CAR (CTL019, Novartis), which the FDA has given a breakthrough therapy designation. In all responders, these infused cells, called CTL019, have produced CD19+ B-cell aplasia, according to the principal investigator Stephan Grupp, MD, PhD, the director of Translational Research at Children’s Hospital of Philadelphia’s Center for Cancer Research. Early and robust proliferation of CTL019 cells correlated with response. Persistent B-cell aplasia in long-term responders suggests that the CTL019 cells, which are administered one week after lymphodepleting chemotherapy, may remain functional even after they are no longer detectable with flow cytometry, according to Dr. Grupp.

Cancer cell death is initiated

them. There are also a small number of patients who remain in remission for more than one year after receiving this therapy. However, it is also important to emphasize that we still need to exercise some degree of caution since the most dramatic therapeutic responses are associated with potentially life-threatening toxicities,” Dr. Bollard observed. Vikramjit S. Kanwar, MRCP, the chief of the Division of Pediatric Hematology-Oncology at Albany Medical Center, in New York, expressed similar sentiments. “Immune-engineered therapy, such as CAR T-cell therapy, is the latest buzzword in the world of oncology. However, only time will tell whether initial promising results for childhood patients with refractory ALL will translate into improved long-term survival,” Dr. Kanwar said.

Adults With ALL: Blinatumomab

Courtesy: Novartis

(Actemra, Genentech) has proven effective for reversing cytokine-release syndrome in its severe forms. Intravenous immune globulins, administered for B-cell aplasia, have prevented significant infectious complications during the trial. Most of the patients who were still in remission received no therapy after the initial CTL019 infusion. In those who achieved a durable remission, the biggest risk appeared to be a recurrence with cells that no longer expressed CD19. Notably, CTL019 has shown promise in a variety of other hematologic malignancies in which cells express CD19 surface antigen, such as non-Hodgkin lymphoma. Dr. Grupp reported that more than 130 patients have been treated with CTL019, and multicenter trials have been initiated already. Preliminary results with adults and children, including some children who were part of the study presented at the 2014 ASH meeting, were published late last year ((N Engl J Med 2014;371[16]:1507-1517, PMID: 25317870). The early results with CAR therapies targeted at CD19 are considered “extremely exciting,” but Catherine Bollard, MD, the director of the Program for Emerging Technologies in Immune Cell Therapies at Children’s National Hospital, in Washington, D.C., cautioned that there is “still much to understand before this therapy becomes mainstream.” She specifically suggested that the benefit-to-risk ratio is not yet well understood. “The response rates are incredibly good for a high-risk patient population, many of whom have no other therapeutic options available to

In adults who have ALL, another study, called BLAST, tested a different approach with a different goal (abstract 379). In this study, patients already in hematologic remission but with

persistent MRD received blinatumomab (Blinctyo, Amgen), an antibody construct designed to redirect CD3+ T cells to produce lysis in CD19+ B cells. The administration of blinatumomab, which is a licensed construct called a bispecific T-cell engager (BiTE), was undertaken to eliminate MRD. Patients with persistent MRD have a risk for hematologic relapse that is higher than 90%. In BLAST, 116 adult ALL patients in hematologic remission, defined as less than 5% blasts after chemotherapy courses but no prior hematologic cell transplant (HCT), were enrolled in an open-label investigation. Blinatumomab was given by continuous IV infusion in a six-week cycle of four weeks on and two weeks off. The primary end point of the study was negative MRD after one cycle, although patients were permitted up to four cycles of blinatumomab and to receive HCT at any time after the first cycle. (MRD was defined as less than 0.1% ALL cells per sample.) The results were impressive, with 78% of the patients becoming MRD-negative, defined as no detectable ALL with

BiTE® antibodies function as a bridge between T cells and cancer cells. Courtesy: Amgen

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Young Adults With ALL Do Better With Peds Regimens San Francisco—Confirming observational studies, the prospective US Intergroup C10403 study has associated an intensive pediatric regimen for acute lymphoblastic leukemia (ALL) with high rates of event-free (EFS) and overall survival (OS) in adolescents and young adults (AYAs). “An intensive pediatric regimen with the C10403 foundation will serve as the basis for future studies in AYA ALL in the US Intergroup, and this represents a shift in approach,” said the study’s lead investigator Wendy Stock, MD, the director of the Leukemia Program at the University of Chicago Comprehensive Cancer Center. Dr. Stock and her team drew on observations from retrospective data that outcomes were consistently better among adolescents with ALL who were placed on a pediatric treatment protocol rather than one designed for adults. The goal of the C10403 trial was to determine whether pediatric protocols used more broadly in young ALL patients, defined as those younger than age 40 by the National Cancer Institute, were feasible and had the ability to boost key outcomes relative to those observed historically. The investigators based the design on a previous Children’s Oncology Group (COG) trial, ALL 0232, which evaluated newly diagnosed ALL patients up to the age of 30 years. Reporting the results of the C10403 trial at the 2014 annual meeting of the American Society of Hematology (abstract 796), Dr. Stack said 296 evaluable patients received a regimen

amplification by polymerase chain reaction in a central reference laboratory after a single cycle, reported Nicola Gökbuget, MD, the head of the Study Center at Goethe University Hospital, in Frankfurt, Germany. According to Dr. Gökbuget, MRD-negative status was achieved in all subgroups evaluated, including older patients and patients with a high MRD level at entry. A few patients who did not achieve MRD-negative status after the first cycle did so after a subsequent cycle. Flu-like symptoms were common, but most adverse events were grade 2 or lower. Exceptions included grade 3 or higher pyrexia in 7% of patients, tremor in 5% and neutropenia in 16%. To improve tolerability and reduce treatment interruptions, the protocol permitted a dose reduction of blinatumomab after a treatment interruption, but this was not a common occurrence. MRD-negative status in ALL is considered to be the single most important

consisting of a series of courses, beginning with an induction therapy with daunorubicin, vincristine, prednisone, pegaspargase (Oncaspar, Sigma-Tau), methotrexate and cytarabine. It was followed by a seven-drug consolidation regimen, a four-drug interim maintenance regimen, a seven-drug delayed intensification regimen and finally a five-drug prolonged maintenance therapy. Adverse events were common but manageable, and the induction mortality of 2% was identical to the outcome for AYAs treated by pediatricians in one treatment arm of the COG ALL 0232 trial for high-risk children (identical to the 10403 regimen). The median EFS was 59 months and the median OS has not yet been reached. The two-year rates for EFS and OS were 66% and 79%, respectively. For EFS, the two-year rate is nearly double that observed in historical controls. Although this trial excluded

Philadelphia chromosome–positive patients, outcomes were even better in patients without other adverse prognostic markers, such as BCR-ABL1–like signature or CRLF2 overexpression. In the 72% of patients without BCR-ABL1–like expression, which is known to upregulate multiple kinases, EFS at two years was 81%, versus 57% in those with this expression. For those without CRLF2 overexpression, EFS at two years was 79%, versus 43% with overexpression. The investigators found that the ability to achieve a negative minimal residual disease status on day 28 was one of the best predictors of sustained remission. The investigators noted a trend for better outcomes with younger age, but this did not reach significance. Additionally, obese patients, which represented a sizeable minority of those enrolled, appeared to do worse. Studies to evaluate dose adjustments in overweight patients may be appropriate, Dr. Stock

step toward long-term disease control, according to Dr. Gökbuget. “Nearly all patients with persistent or recurrent MRD will relapse despite continued chemotherapy,” she said. In contrast, the

blinatumomab, Ali McBride, PharmD, the clinical coordinator in hematology/oncology at the University of Arizona Cancer Center, in Tucson, considered blinatumomab to be more immediately

The ‘blinatumomab results were impressive, and its measurable response, with a decrease in MRD either in the first or the second cycle, has changed the paradigm of ALL treatments.’ —Ali McBride, PharmD ability to provide sustained MRD-negative status could constitute an important prerequisite for the cure of ALL. “Follow-up of this trial will investigate whether high MRD response rate translates into long-term clinical benefit, such as continued molecular remission and long-term survival,” Dr. Gökbuget reported. Assessing the status and prospects of both therapies, the BiTE construct and

relevant to clinical practice. This agent recently was approved by the FDA, and the data from the 2014 ASH meeting reinforce its role in clinical care. The “blinatumomab results were impressive, and its measurable response, with a decrease in MRD either in the first or the second cycle, has changed the paradigm of ALL treatments,” Dr. McBride said. The data on the BiTE agent, which is a first-in-class therapy, is promising, but

said. In patients with high-risk disease, such as BCR-ABL1–like expression, she expressed interest in testing regimens that include targeted kinase inhibitors or novel targeted antibodies. Ching-Hon Pui, MD, the chair of the Department of Oncology at St. Jude Children’s Research Hospital, in Memphis, Tenn., characterized these results as encouraging. Although the improvement in two-year EFS is an important finding, he suggested that “longer follow-up is needed to determine whether this early finding will translate into improved cure rates.” He also said that it might be useful to consider strategies to counter the hepatotoxicity associated with asparaginase (Erwinaze, Jazz) and glucocorticoids because they are considered important components of the pediatric regimen. “The apparent worse outcome of obese patients in this trial may be related to their underlying hepatic steatosis, which is frequently associated with obesity and increased toxicity and decreased tolerance to treatment with asparaginase and glucocorticoids,” Dr. Pui said. “It would be interesting to test whether treatment of hepatic steatosis at the time of cancer treatment would improve the outcome for obese ALL patients or older patients with comorbidities such as diabetes, prediabetes and hyperlipidemia.” —Ted Bosworth Dr. Stock reported a financial relationship with Sigma-Tau. Dr. Pui reported no relevant financial relationships.

there “will be several noticeable issues to address, the first two being the monitoring and delivery of therapy,” Dr. McBride said. “The continual delivery of this therapy via pump [to] both inpatients and outpatients will lead to numerous administration issues and monitoring parameters that pharmacists and nurses will need to evaluate in the continued delivery of this drug,” he said. “In addition, infusion reactions will need to be monitored during the early delivery of this therapy, which has been associated with an increased release of cytokines.” Finally, Dr. McBride noted that this therapy is likely to be associated with a “hefty price tag,” so many centers will need to evaluate “where this drug falls into payors’ clinical pathways.” —Ted Bosworth Dr. Grupp reported a financial relationship with Novartis. Drs. Gökbuget, Bollard, Kanwar and McBride reported no relevant financial relationships.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

How I Manage ...

Deletion 17p Chronic Lymphocytic Leukemia W

Jennifer R. Brown, MD, PhD Director, CLL Center Department of Medical Oncology Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

ith a number of new therapies becoming available for chronic lymphocytic leukemia (CLL), including ibrutinib (Imbruvica, Pharmacyclics), idelalisib (Zydelig, Gilead), and obinutuzumab (Gazyva, Genentech) in the past 14 months, the future looks bright for effective and better tolerated therapy. However, the highest-risk subgroup of patients with CLL, those with deletion 17p, remains challenging, even with the novel agents, and many key questions about how to manage these patients in the era of novel agents are not yet answered by the available data.

Is there prognostic heterogeneity among patients with deletion 17p CLL? The significant prognostic impact of deletion 17p in CLL was first identified by Dohner and colleagues, who reported that this chromosomal abnormality was associated with a significantly reduced overall survival (OS) of approximately 32 months from diagnosis.1 Many subsequent studies, including prospective randomized trials, have confirmed the strong association of this abnormality with reduced progression-free survival (PFS) and OS.2-4 In

fact, a recent prognostic model based on 1,948 untreated CLL patients, most of whom were evaluated at the time of therapy initiation, found that the hazard ratio (HR) for OS for deletion 17p was 6, and the next most significant factor had a HR of 2.3.5 These poor outcomes are most clearly established for patients with deletion 17p who require therapy or were previously treated. A study from the University of Texas MD Anderson Cancer Center, in Houston, and Mayo Clinic, in Rochester, Minn., looked at outcomes of 99 treatment-naive CLL patients with

AT A GLANCE • A number of factors that are not yet fully understood may influence prognostic heterogeneity in patients with CLL harboring the 17p abnormality. • A mutation in the TP53 gene without deletion 17p is seen in 3% to 11% of patients with CLL at time of first therapy. • It is important to recheck CLL FISH panel prior to initiation of treatment and again at relapse. • The best reported outcomes with standard therapies in deletion 17p have been with high-dose steroid regimens in combination with alemtuzumab. • Following the approvals of ibrutinib and idelalisib, both of these highly active drugs are better options than standard therapy for patients with CLL harboring deletion 17p. • Ibrutinib has received FDA approval for any line therapy in patients with CLL harboring deletion 17p. • Allo-HCT remains the only known curative therapy in patients with CLL.

Ongoing Clinical Trials in 17p CLL ClinicalTrials.gov Identifier

Trial RESONATE-17: Ibrutinib in 17p CLL with 1-4 prior regimens27

NCT01744691

Idelalisib-rituximab in previously untreated 17p CLL

NCT02044822

ABT-199 in previously treated 17p CLL

NCT01889186

C ,c CLL, chronic o c lymphocytic y p ocyt c leukemia eu e a

deletion 17p and found that 67 were asymptomatic at time of identification and were, therefore, followed without therapy.6 Of these patients, 53% required therapy over the next 3 years, most within 18 months, whereas of the 19 who didn’t, only 3 progressed in 70 months. Thus, a subset of recently diagnosed untreated patients with deletion 17p can have more indolent disease, although this is much less true of patients with deletion 17p who have been treated or require treatment. A number of factors that are not yet fully understood may influence this prognostic heterogeneity. The first category of considerations is focused on deletion 17p itself, specifically the frequency of the event per fluorescence in situ hybridization (FISH), and whether mutation of the other TP53 allele is observed. The FISH probe itself has more variability than the other probes used in CLL, such that very low levels of 17p (likely 10%-15% or lower) do not always allow for accurate results.7 Whether or not there is a biologic cutoff for the frequency of 17p that is associated with poor outcome also remains controversial. A 20% cutoff was reported as most predictive in the United Kingdom National Cancer Research Institute (NCRI) LRF4 trial,2 although this cutoff was subsequently revised to 10%.8 The MD Anderson/Mayo Clinic study and a second study examining 294 patients with deletion 17p examined the 17p percentage clone size in quartiles, and both found progressively worse OS in the higher quartiles, although the most predictive single threshold was 25%.6,9 Another not fully understood consideration is whether it matters prognostically if the other TP53 allele is mutated. Studies thus far have suggested that the other allele is mutated in 75% to 85% of patients with deletion 17p3,10,11 making the subgroup without mutation difficult to study. TP53 mutation without deletion 17p is seen in 3% to 11% of patients at time of first therapy3,11 and

the limited data available have suggested that there is no prognostic difference between deletion 17p alone, TP53 mutation alone, and both together,4,11 such that recent studies often analyze these patients together. A recent study using next-generation sequencing (NGS) suggested that TP53 mutation present at very low clone levels (median 2.1% frequency) was associated with an adverse prognosis comparable to that seen at higher clone levels as well as with higher percentage TP53 mutation clones at relapse.12 A number of studies have suggested other disease features that may modify the impact of deletion 17p. For patients at diagnosis, the MD Anderson/Mayo study found that Rai stage 1 or higher disease, unmutated IGHV V and deletion 17p in more than 25% of nuclei all were associated with reduced OS in a multivariable analysis.6 In the German CLL Study Group CLL8 trial, the only predictor of PFS greater than 24 months in deletion 17p patients treated with FCR (fludarabine-cyclophosphamide-rituximab [Rituxan, Genentech]) was a white blood cell count less than 50,000/mcL, and no association with IGHV V status was seen, suggesting that IGHV V may influence time to therapy more than response in this subgroup.3 A recent study confirmed that IGHV V and ZAP70 were associated with time to first therapy in deletion 17p/TP53-mutated patients, whereas genomic complexity, as measured by increasing copy number aberrations, was predictive of OS.13 A recent analysis presented at the 2014 annual meeting of the American Society of Hematology suggested that although complex karyotype was associated with deletion 17p, complex karyotype was more predictive of adverse event– free survival (EFS) and OS than 17p in patients treated with ibrutinib.14 However, 2 prior studies have not found worse outcomes with complex karyotype in the setting of deletion 17p,6,9 so this question remains open.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Outside of a clinical trial, what options are available as frontline therapy for 17p CLL?

with this agent in relapsed/ refractory 17p CLL patients.19 However, the data on untreated deletion 17p patients remain extremely limited. One patient treated in the initial Phase Ib study developed Richter’s transformation and died.20 Four untreated deletion 17p patients were included in a study of ibrutinib with rituximab in high-risk patients; 2 of these patients achieved CR, whereas outcomes were not reported for the other 2.21 Use of ibrutinib in the upfront setting in general does not appear to be associated with any concerning safety signals and, given its high activity in the relapsed setting in deletion 17p, it is an excellent option for therapy in these patients. Idelalisib was approved in the United States in combination with rituximab for relapsed CLL patients who are otherwise candidates for rituximab alone. However, the European Medicines Agency granted a broader indication encompassing any line therapy of CLL with deletion 17p. The up-front data come from 9 patients with deletion 17p treated in a study of idelalisib with rituximab in patients aged 65 years and older. The study showed an ORR of 100% and a CR of 33%.22 With a median follow-up of 24 months, none of the patients had relapsed or died. So, the limited data indicate that idelalisib also is an active agent in this setting. However, care is required using idelalisib in the up-front setting because a higher incidence of transaminitis,

Conventional chemoimmunotherapy typically has significantly reduced benefit in CLL with deletion 17p. For example, the combination of bendamustine (Treanda, Cephalon) and rituximab (BR) was associated with a limited 37.5% overall response rate (ORR) and markedly reduced EFS in patients with deletion 17p.15 FCR was associated with a 68% ORR, but only 5% complete response (CR) and 18% PFS at 3 years.16 The best reported outcomes with standard therapies in deletion 17p have been with high-dose steroid regimens in combination with alemtuzumab. For example, the UK NCRI CLL206 trial examined alemtuzumab 30 mg 3 times per week with methylprednisolone 1 g/ m2 for 5 days every 4 weeks, and reported an ORR of 88%, CR of 65%, median PFS of 18 months, and median OS of 39 months in a previously untreated deletion 17p cohort.17 A similar study of alemtuzumab with high-dose dexamethasone resulted in a 97% ORR, 21% CR, median PFS of 33 months, and median OS greater than 60 months, confirming the activity of these regimens.18 Following the approvals of ibrutinib and idelalisib, both of these highly active drugs are possible options for the initial therapy of CLL patients with deletion 17p. Ibrutinib received FDA approval for any line therapy of deletion 17p CLL, based on the 28-month median PFS seen

diarrhea, and pneumonitis were seen than had previously been reported in relapsed patients.22

Do you repeat a prognostic (FISH) profile before treatment of CLL and if yes, why? I suggest initial prognostic profiling at time of diagnosis because patients with high-risk markers should be monitored more closely, and the results also provide data with which to guide appropriate counseling. It also is important to recheck FISH at the time of treatment because of the above treatment considerations, and because the available evidence suggests that evolution can occur with time, even in the absence of therapy. The initial prospective study on this subject reported a 1.4% rate of newly acquired FISH abnormalities in the first 2 years of follow-up, but 27% at 5 years or more of follow-up; 71% of the patients who showed evolution had been treated in the interim.23 A more recent retrospective study of 294 patients with deletion 17p found that 27% of the patients in whom the deletion was acquired were not treated before that occurred, at a median of 49 months from CLL diagnosis.9 Rechecking FISH before secondor later-line therapy also is extremely important because adverse clonal evolution, particularly involving 17p and 11q deletions, is even more likely to occur after therapy.24 A recent study using NGS to evaluate lower-percentage TP53 clones found that even very low levels

were associated with adverse OS, and that these low-level clones at diagnosis typically became the predominant population at relapse.12

Outside of a clinical trial, how do you select therapy for relapsed and refractory 17p CLL? Ibrutinib and idelalisib with or without rituximab certainly are the primary approved therapies of choice in this setting. The Table shows the reported clinical trial outcomes for each of these agents thus far.21,22,25-31 The ibrutinib data look somewhat better than the idelalisib data, but, in general, ibrutinib-treated patients were less heavily pretreated and healthier than those treated with idelalisib. The most appropriate sequencing of the 2 agents is not clear because very few patients who were treated with both in sequence have been reported. Of 6 patients treated with ibrutinib who had previously received idelalisib, 5 responded, with 4 partial responses (PRs) and 1 PR with lymphocytosis. 25 Whether patients progressing on ibrutinib respond to idelalisib is unclear, however, because they have been excluded from clinical trials. Ibrutinib tends to be used first because of a more favorable toxicity profile, unless it is contraindicated due to anticoagulation or bleeding risks. ABT199 (Genentech/AbbVie) also is a very promising agent in deletion 17p, but it is not yet approved. see HOW I MANAGE, E page 18

Table. Summary of Data With BCR Inhibitors in CLL Median F/U, mo

Patients, N

Median Prior Regimens

Response, %

PFS, %

OS, %

101

ORR 90, CR 6

68.4 at 30 mo

79.9 at 30 mo

46 at 30 mo (median 28.1 mo)

66 at 30 mo

132

ORR 80

86 at 12 mo

ORR 86

79 at 12 mo

11.5

144

PR+PRL 65

79.3 at 12 mo

83.5 at 12 mo

NHLBI, deletion 17p

NR, some untreated

PR 53, PRL 43

85 at 14 mo

Ibrutinib-rituximab

MDACC21

2.5

ORR 95, CR 10% overall

72 in del 17p vs 84 in others

78 in deletion 17p vs 89 in others

Idelalisib

Phase I, deletion 17p or TP53 329

ORR 54

Median 3 mo

Idelalisib-anti-CD20 ab

Phase Ib idelalisib + rituximab or ofatumumab, del 17p or TP5330

ORR 73

Median 20 mo

80 at 24 mo for all patients

Idelalisib-rituximab

115, all31

106

ORR 77

Median 19.4 mo

Not reached

115, deletion 17p or TP53 3

ORR 82

Median 16.6 mo

Not reached

Up-front, elderly, deletion 17p22

ORR 100, CR 33

100 at 24 mo

Drug Ibrutinib

Study and Patient Subgroup 25

Phase Ib/2, all

Phase Ib/2, deletion 17p

RESONATE, no deletion 17p26 RESONATE, deletion 17p

RESONATE-17

CLL, chronic lymphocytic leukemia; CR, complete response rate; F/U, follow-up; MDACC, University of Texas MD Anderson Cancer Center; NHLBI, National Heart, Lung, and Blood Institute; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PRL, partial response with lymphocytosis Based ased on o references e e e ces 21,, 22,, and a d 25-31. 53

HEMATOLOGIC DISEASE

HOW I MANAGE continued from page 17

When do you refer patients with deletion 17p CLL for allogeneic hematopoietic cell transplant? Before the advent of the B-cell receptor (BCR) pathway inhibitors, my goal for all patients with deletion 17p CLL who were adequately young and fit was to achieve remission and plan an allogeneic hematopoietic cell transplant (allo-HCT) once they were in remission, even first remission. This approach was based on the extensive data that, even if they achieve an initial response to therapy, the PFS of deletion 17p patients is very short.2,3,16-18 As we have discussed above, the BCR pathway inhibitors have very significant activity in these patients, and durations of remission longer than we have seen before. However, these remissions are still shorter than those of non–deletion 17p patients; for example, the median PFS of relapsed/refractory deletion 17p CLL patients treated with ibrutinib is 28 months. Furthermore, these patients are more likely to acquire resistance,32 and develop Richter’s transformation, which has been seen commonly among these patients. For example, in the RESONATE-17 trial investigating ibrutinib in patients with deletion 17p CLL who have had 1 to 4 prior regimens, 11 of 20 relapses to date (55%) have been with Richter’s transformation, which is very hard to salvage. In fact, in all of the ibrutinib studies to date, relapsing patients have been very difficult to salvage, and the PFS and OS curves are very similar.26 For this reason, together with the fact that allo-HCT remains the only known curative therapy in CLL, I think it is very important to continue to think seriously about allo-HCT in this setting, particularly in higher-risk patients, who likely include those who are heavily pretreated, have refractory disease, or have complex karyotype.14,19,26 Many of the patients are finding that they feel very well on their oral BCR pathway inhibitor and tend to want to delay transplant, but it is very important to make sure they are aware of the unknown durability of these responses and the risk for fulminant relapse that may not be salvageable. Many of these issues are elegantly discussed in a recent paper on the current role of allo-HCT in CLL given the availability of the newly available novel agents.33

Future Prospects Many important questions remain, particularly for 17p-deleted CLL, for which the efficacy of the novel inhibitors is less than in more indolent CLL. At present, the experience with

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

these agents in front-line deletion 17p CLL is extremely limited, so more work is needed to characterize durability of response and PFS in this setting, as well as to assess the real risk for Richter’s transformation at relapse and our ability to salvage patients who have relapsed. It is likely that combinations of novel agents will be required to sustain durable responses in these patients, and the likely upcoming approval of ABT199 will facilitate some of the most interesting combinations. Although much work remains to be done, the targeted agents are transforming the landscape of CLL, even in patients with 17p-deleted CLL.

References 1. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910-1916, PMID: 11136261. 2. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370(9583):230-239, PMID: 17658394. 3. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):32473254, PMID: 24652989. 4. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28(29):4473-4479, PMID: 20697090. 5. Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49-62, PMID: 24797299. 6. Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114(5):957-964, PMID: 19414856. 7.

Smoley SA, Van Dyke DL, Kay NE, et al. Standardization of fluorescence in situ hybridization studies on chronic lymphocytic leukemia (CLL) blood and marrow cells by the CLL Research Consortium. Cancer Genet Cytogenet. 2010;203(2):141148, PMID: 21156226.

8. Oscier D, Wade R, Davis Z, et al. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica. 2010;95(10):17051712, PMID: 20511662. 9. Delgado J, Espinet B, Oliveira AC, et al. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results. Br J Haematol. 2012;157(1):67-74, PMID: 22224845. 10. Edelmann J, Holzmann K, Miller F, et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood. 2012;120(24):4783-4794, PMID: 23047824. 11. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011;29(16):2223-2229, PMID: 21483000. 12. Rossi D, Khiabanian H, Spina V, et al.

Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123(14):2139-2147, PMID: 24501221. 13. Delgado J, Salaverria I, Baumann T, et al. Genomic complexity and IGHV mutational status are key predictors of outcome of chronic lymphocytic leukemia patients with TP53 disruption. Haematologica. 2014;99(11):e231-e234, PMID: 24997154. 14. Thompson PA, Wierda WG, Ferrajoli A, et al. Complex karyotype, rather than del(17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens. Blood. 2014;124(21): abstract 22. 15. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30(26):3209-3216, PMID: 22869884. 16. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174, PMID: 20888994. 17. Pettitt AR, Jackson R, Carruthers S, et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol. 2012;30(14):1647-1655, PMID: 22493413. 18. Stilgenbauer S, Cymbalista F, Leblond V, et al. Alemtuzumab combined with dexamethasone, followed by alemtuzumab maintenance or allo-SCT in “ultra High-risk” CLL: final results from the CLL2O phase II study. Blood. 2014;124(21): abstract 1991. 19. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42, PMID: 23782158. 20. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58, PMID: 24332241. 21. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10):10901099, PMID: 25150798.

25. O’Brien SM, Furman RR, Coutre S, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol. 2014;32(5 suppl): abstract 7014. 26. Brown JR, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3 RESONATE trial of ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2014;124(21): abstract 3331. 27. O’Brien S, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion: results from the phase II RESONATE-17 trial. Blood. 2014;124(21): abstract 327. 28. Farooqui M, Aue G, Valdez J, et al. Single agent ibrutinib (PCI-32765) achieves equally good and durable responses in chronic lymphocytic leukemia (CLL) patients with and without deletion 17p. Blood. 2013;122: abstract 673. 29. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397, PMID: 24615777. 30. Furman RR, De Vos S, Leonard JP, et al. A phase 1 study of the selective PI3Kд inhibitor idelalisib (GS-1101) in combination with therapeutic anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia. Blood. 2013;122(21): abstract 4180. 31. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (ZYDELIG) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood. 2014;124(21): abstract 330. 32. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294, PMID: 24869598. 33. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014;124(26):3841-3849, PMID: 25301705.

Series Editor

22. O’Brien SM, Lamanna N, Kipps TJ, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kд) д inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol. 2013;31(suppl): abstract 7005.

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

23. Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol. 2006;24(28):46344641, PMID: 17008705.

How I Manage Lower-Risk MDS

24. Stilgenbauer S, Sander S, Bullinger L, et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007;92(9):1242-1245, PMID: 17666364.

Syed Abutalib, MD

Coming Soon

Guillermo Garcia-Manero, MD Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MARCH 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums Updates from FDA, Blood, and JCO Prepared by

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

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

QUESTIONS

2. Panobinostat is a histone deacetylase inhibitor. Which of the following is nott an adverse effect (AE) of this drug? a. Thrombocytopenia b. Hyperkalemia c. Arrhythmia d. Pyrexia

DLBCL and indolent B-cell malignancies, neurologic toxicity was the only troublesome AE. True or false?

5. The SAL-AML 2003 study published

in JCO demonstrated improved relapsefree survival in patients with mutated NPM1 and unmutated FLT3/internal tandem duplication (ITD) and a normal karyotype profile who received allogeneic hematopoietic cell transplantation (allo-HCT) from a sibling donor compared with those who received conventional chemotherapy alone. True or false?

6. According to European LeukemiaNet

(ELN), patients with mutated NPM1 without FLT3/ITD and normal karyotype are assigned to the intermediate-1 prognostic group. True or false?

In the Journal of Clinical Oncolo1. On February 23, 2015, the FDA 3. gy (JCO ( ), a National Institutes of Health 7. Data from randomized controlled granted accelerated approval to panobinostat (Farydak, Novartis) in combination with bortezomib (Velcade, Millennium) and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. True or false?

ANSWERS

1. True. The approval was based on the

results of progression-free survival (PFS) in a subgroup of patients from a randomized, placebo-controlled trial evaluating panobinostat (or placebo) in combination with bortezomib and dexamethasone. The median PFS values were 10.6 and 5.8 months in the panobinostat-containing arm (panobinostat-bortezomib-dexamethasone) and the control arm (placebobortezomib-dexamethasone), respectively (hazard ratio, 0.52; 95% CI, 0.36-0.76). FDA. FDA approves Farydak for treatment of multiple myeloma. http://1.usa.gov/1vDnVbz. Accessed February 24, 2015. ASCO news. Received on February 23, 2015.

2. b. The most common hematologic

abnormalities included thrombocytopenia and neutropenia; the most common chemistry abnormalities were hypophosphatemia and hypokalemia. Electrocardiogram changes, including new T-wave changes and ST-segment depressions, occurred in 64% of patients in the panobinostat-containing arm and 42% in the control arm. Arrhythmias occurred more frequently in patients receiving panobinostat than in those in the control arm (12% vs 5%). The most common AEs in the panobinostat-containing arm were diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting. Panobinostat is approved with a boxed warning about severe and fatal cardiac toxicities and severe diarrhea. FDA. FDA approves Farydak for treatment of multiple myeloma. http://1.usa.gov/1vDnVbz. Accessed February 24, 2015. ASCO news. Received on February 23, 2015.

group reported successful treatment of patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) with anti-CD19 chimeric antigen receptor (CAR) T cells. True or false?

4. In the study using anti-CD19 CAR

T cells to treat chemotherapy-refractory

3. True. Patients received a condition-

ing chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Complete remissions (CRs) were obtained in 4 of 7 evaluable patients; 3 of these 4 CRs are ongoing, with durations ranging from 9 to 22 months. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent b-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540-549, PMID: 25154820.

4. False. The most troublesome toxici-

ties experienced by patients on this protocol were hypotension and neurologic toxicities. The mechanism of the neurologic toxicities is under investigation. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent b-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540-549, PMID: 25154820.

5. True. This trial used a donor versus

no donor random assignment and retrospectively looked at the effects of NPM1 mutation on both relapse and overall survival (OS). OS between the groups was no different, given the ability to provide subsequent therapies to patients in the nodonor arm who experienced progression. Röllig C, Bornhäuser M, Kramer M, et al. Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SALAML 2003 trial. J Clin Oncol. 2015;33(5):403-410, PMID: 25547501.

False. According to ELN, patients with mutated NPM1 without FLT3/ITD

trials show superiority of peripheral blood (PB) grafts over bone marrow (BM) grafts for allo-HCT in the setting of reduced-intensity conditioning (RIC) transplantations for hematologic malignancy. True or false?

8. A Phase II trial published in JCO and normal karyotype are assigned to the favorable prognostic group. The authors of the ELN prognostic validation suggest that allo-HCT should be considered as an option for patients with normal karyotype and mutated NPM1 without FLT3/ITD. The ELN classification has not been evaluated for specific treatment approaches and, therefore, is not shown to be predictive. The question remains open, and the real-world “answer” lies in the hands of the treating physician. Alyea EP. Time to reconsider the role of allogeneic transplantation for patients with acute myeloid leukemia and NPM1 mutation? J Clin Oncol. 2015;33(5):381-382, PMID: 25547505. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474, PMID: 19880497. Röllig C, Bornhäuser M, Thiede C, et al. Longterm prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol. 2011;29(20):2758-2765, PMID: 21632498.

7. False. There have been no random-

ized trials comparing PB with BM grafts in the setting of RIC transplantations for hematologic malignancy. In a recent Center for International Blood and Marrow Transplant Research analysis, survival after allo-HCT of PB and BM grafts are comparable in the setting of nonirradiation RIC regimens for hematologic malignancies. Eapen M, Logan BR, Horowitz MM, et al. Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation. J Clin Oncol. 2015;33(4):364-369, PMID: 25534391.

8. True. The 2-year OS of patients

demonstrated superior outcomes in patients with a non-germinal center B cell (non-GCB) phenotype DLBCL treated with lenalidomide (Revlimid, Celgene) plus R2CHOP (rituximab [Rituxan, Genentech]-cyclophosphamide-doxorubicin-vincristine-prednisone) compared with a historical cohort of patients treated with R-CHOP (rituximab-cyclophosphamide-doxorubicinvincristine-prednisone). True or false?

9. Which of the following tyrosine

kinase inhibitors is paired accurately with its AE ? a. Nilotinib (Tasigna, Novartis) and severe peripheral arterial occlusive disease (PAOD) b. Ponatinib (Iclusig, Ariad) and exanthema c. Bosutinib (Bosulif, Pfizer) and pulmonary hypertension d. Dasatinib (Sprycel, Bristol-Myers Squibb) and pancreatitis

10.

FDA granted orphan drug designation to BGB324 for the treatment of acute myeloid leukemia (AML). True or false? with a non-GCB phenotype treated with R-CHOP was 46%, versus 83% with R2CHOP. The PFS of patients with a nonGCB phenotype treated with R-CHOP was 28%, versus 60% in the R2CHOP group. The median age was 65 years; 70% of patients were older than 60 years and 9% were at least 80 years old. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a Phase II study. J Clin Oncol. 2015;33(3):251-257, PMID: 25135992.

a. Arterial and venous thromboembolic events have been reported in ponatinib-treated patients and diarrhea and exanthema have been reported in bosutinib-treated patients. Dasatinib has been associated with fluid retention, primary pulmonary hypertension and QT prolongation but not pancreatitis. Nilotinib is associated with PAOD as well as increases in pancreatic enzymes, serum bilirubin, and fasting glucose levels. Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125(6):901-906, PMID: 25525119.

10. True. BGB324, a first-in-class,

highly selective small-molecule inhibitor of the Axl receptor tyrosine kinase, blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis. BGB324 is the first compound in BerGenBio’s pipeline to enter clinical trials in AML and non-small cell lung cancer. BerGenBio. BerGenBio receives orphan-drug designation from FDA for BGB324 in the treatment of acute myeloid leukemia. http://bit.ly/1zLQFvd. Accessed February 23, 2015.

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