Feb 2015 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • February 2015 • Vol. 10, No. 2

CURRENT PRACTICE How to document on EMRs to avoid raising the ire of auditors ................

Pediatric Oncology: Using pharmacogenomics to reduce toxicity .................

SOLID TUMORS Report From SABCS: Evidence builds for first-line use of fulvestrant ................................. Vogl, NY comments on the IBIS-1 findings and the role of tamoxifen prevention ..............................

San Francisco—The tyrosine kinase inhibitor (TKI) sorafenib significantly increases event-free survival (EFS) in younger patients with acute myeloid leukemia (AML), according to a multicenter, randomized placebo-controlled trial. When added to standard therapy, sorafenib (Nexavar, Bayer) was associated with an increase in the number and severity of adverse events (AEs), but after three years of follow-up, 56% of those randomized to sorafenib were relapse-free compared with 38% ( =0.017) of those in the placebo arm. (P see AML, page 24

Report From GI Cancers Symposium: TRIBE solidifies a role for FOLFOXIRI plus bevacizumab in advanced CRC .....................

IMAGES in ONCOLOGY

Sorafenib Becomes First TKI To Show Benefit in AML

INSIDE

HEMATOLOGIC DISEASE Eva Domingo Domenech MD

Chronic lymphocytic leukemia (CLL) cells; in pooled data from two Phase III trials of CLL patients, an MRD-negative result predicted durable PFS better than objective response did; story on page 25.

HER2+ Breast Cancer:

Report From the Gastrointestinal Cancers Symposium:

Can We Identify Patients Who Can Skip Trastuzumab?

Study Bolsters Link Between Vitamin D Levels and CRC

San Antonio—Stromal tumor-infiltrating lymphocytes may be useful as a biomarker to identify HER2-positive breast cancer patients who can skip trastuzumab according to a study pre

20 Report From ASH:

Take a bite out of G-CSF acquisition costs* GR ANIX® is an option in shor t-ac ting G-CSF therapy See what’s new inside!

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • February 2015 • Vol. 10, No. 2

CURRENT PRACTICE How to document on EMRs to avoid raising the ire of auditors ................

Pediatric Oncology: Using pharmacogenomics to reduce toxicity .................

Report From GI Cancers Symposium: TRIBE solidifies a role for FOLFOXIRI plus bevacizumab in advanced CRC .....................

IMAGES in ONCOLOGY

Sorafenib Becomes First TKI To Show Benefit in AML

INSIDE

HEMATOLOGIC DISEASE Eva Domingo-Domenech, MD, and Anna Sureda, MD, PhD: How I manage relapsed & refractory HL .................. 20 Report From ASH: MRD negativity predicts efficacy in B-cell malignancies ......................

Clinical Conundrums .......................

Chronic lymphocytic leukemia (CLL) cells; in pooled data from two Phase III trials of CLL patients, an MRD-negative result predicted durable PFS better than objective response did; story on page 25.

HER2+ Breast Cancer:

Report From the Gastrointestinal Cancers Symposium:

Can We Identify Patients Who Can Skip Trastuzumab?

Study Bolsters Link Between Vitamin D Levels and CRC

San Antonio—Stromal tumor-infiltrating lymphocytes may be useful as a biomarker to identify HER2-positive breast cancer patients who can skip trastuzumab, according to a study presented at the San Antonio Breast Cancer Symposium (abstract S1-06). The study also adds to the accumulating evidence that these immune cells are associated with benefit from chemotherapy. In the study, researchers analyzed primary tumor samples obtained from the Phase III NCCTG (North Central Cancer Treatment Group) N9831 trial before patients started treatment. Samples were considered to have high

San Francisco—Higher levels of vitamin D were associated with markedly improved progression-free survival (PFS) and overall survival (OS) in patients receiving treatment for metastatic colorectal cancer (mCRC), according to an analysis of more than 1,000 patients. The findings were presented at the recent Gastrointestinal Cancers Symposium (abstract 507). The study’s lead investigator, Kimmie Ng, MD, MPH, a physician at Dana-Farber Cancer Institute, in Boston, said the research adds to the existing evidence that vitamin D levels have an effect on cancer. Vitamin D is known to inhibit cell proliferation and angiogenesis, induce cell differentiation and apoptosis and have anti-inflammatory effects. “Many of these processes are dysregulated in cancer, which led to the hypothesis that perhaps vitamin D had anticancer activity,” said Dr. Ng. Laboratory data support this hypothesis, with experiments demonstrating that administering vitamin D to mice with intestinal cancer reduces tumor burden. Additionally, a previous prospective cohort study in 304 patients with CRC showed that higher blood levels of vitamin D (25-hydroxyvitamin D) were associated with a significant improvement in OS ((J Clin Oncoll 2008;26[18]:2984-2991, PMID: 18565885).

see TILS, S page 10

see VITAMIN D D, page 16

Essential Oncology™

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • FEBRUARY 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

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

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

No-Nos for EMRs Certain actions raise the ire of the auditor King of Prussia, Pa.—Time-saving methods, such as drop-down menus and copying and pasting text, might seem like a good idea for a busy doctor filling in an electronic medical record (EMR). However, some things just should not be “automated” because bad documentation can result in the denial of payments, according to Cindy C. Parman, CPC, CPC-H, RCC, a principal of Coding Strategies Inc., in Powder Springs, Ga.

At the least, payments can be denied; at the most, the health care worker can be convicted of fraud and fined, or even jailed. In a presentation at the Association of Community Cancer Centers’ 2014 Oncology Reimbursement meeting, Ms. Parman said that using the correct code in an EMR with good documentation equals money, so it behooves physicians and other health care professionals to think before they just copy and paste repetitive information into an EMR. Such actions can trigger the ire of the Office of Inspector General (OIG), which investigates Medicare fraud. At the least, payments can be denied; at the most, the health care worker can be convicted of fraud and fined, or even jailed. “I used to say, ‘if it is not documented, it didn’t happen.’ Now I say, ‘if it is not documented well, I can’t defend it,’” said Ms. Parman, a former auditor for an insurance company. The purpose of the medical record is to document what occurred with a particular patient during a particular encounter, she explained, not to ensure payment. “Physicians should be aware that templates designed to gather select information focused primarily on reimbursement are often insufficient to demonstrate that all coverage and coding requirements have been met,” she warned. Any prebuilt documents, such as electronic form templates, might not accurately reflect what happened to the patient that day. As an auditor, Ms. Parman reviewed a “chart where the patient ‘fell at the nursing home last Thursday’ four months in a row because the doctor just defaulted the note forward.” The program integrity manual from the Centers for Medicare & Medicaid Services (CMS), which explains to auditors where to look for patterns that may result in fraud, waste and

abuse, states that EMRs that “tend to have obvious or nearly identical documentation” should be scrutinized. Copying and pasting information can get health care professionals in trouble, not only because nearly identical documentation appears in one or several charts, but also because information that should not be in the chart can be entered accidentally. “We have to watch actions such as copy and paste. There was a nurse who was working on her resume at lunch. She copied it and accidentally pasted her resume into the patient’s chart,” Ms. Parman said. “Cloning,” using large chunks of text in different charts or repeated in the same chart, can be a problem because medical records that contain cloned material are not really accurately reflecting each patient encounter. Ms. Parman said such cloned areas of text often sound like definitions instead of a recap of the patient encounter, and CMS does not permit them. The OIG puts out a work plan that discusses the areas that it will pursue when reviewing potentially inappropriate payments. Auditors have reported an increased frequency of medical records with identical documentation across services, according to Ms. Parman, yet doctors continue to defend the practice. “I had one doctor say to me: ‘All I treat are breast cancer patients, and they are all pretty much the same’ [when defending the cloning of material in his EMRs],” said Ms. Parman. Every patient has a different medical history, family history, treatment, response, etc., she argued. Another doctor told her: “You make it sound like we should only document exactly what we do.” Yes, she said, document only what you do, and it will keep you out of trouble. Templates are particularly prone to triggering red flags among auditors, based on their heavy reliance on check boxes, drop-down menus and other features that can result in an EMR entry that may not reflect the particulars of a given patient’s evaluation and treatment. CMS discourages the use of such templates, according to Ms. Parman. “CMS doesn’t say you can’t do it, but they kind of hint that if you do, they will audit you and take their money back if they don’t like what you’ve done.” She was reviewing documentation and templates at another physician’s office and one of the doctors told her that his template was different from the rest of the group. When she asked how it was different, he said, “It guarantees a level 5 on everything I do.” His practice might

‘We have to watch actions such as copy and paste. There was a nurse who was working on her resume at lunch. She copied it and accidentally pasted her resume into the patient’s chart.’ —Cindy C. Parman, CPC, CPC-H, RCC consider him a financial asset, because he is getting higher reimbursements, but the OIG would consider that fraud. Not every action a physician takes requires higher reimbursements. It is important to “not just check boxes to bill a code, [but rather to document] what we did for the individual patient,” Ms. Parman said.

Coding Changes Ms. Parman worked with a group that was audited because they overused modifier 59, which basically unbundles a group of services that CMS had bundled. The original intent of modifier 59 was to indicate that a particular service should not be bundled because it was a distinct service that was independent of other services provided that day. The group was a small practice with a freestanding infusion center. Everyone showed up for work on a Monday and they were greeted by a half-dozen auditors. The auditors ended up finding a lot more inaccuracies that they had issues with, “but modifier 59 was what brought them through the door,” Ms. Parman said. CMS still has exclusionary coding that allows unbundling, but it has removed modifier 59 and implemented four different codes to take its place. The new codes are: • XE Separate Encounter: designates a service that is distinct because it occurred during a separate encounter.

• XS Separate Structure: designates a service that is distinct because it was performed on a separate organ/ structure. • XP Separate Practitioner: designates a service that is distinct because it was performed by a different practitioner. • XU Unusual Overlapping Service: designates a service that is distinct because it does not overlap usual components of the main service. CMS explained in a communication transmittal that it will continue to recognize modifier 59; however, it should not be used when a more descriptive modifier is available, and CMS might require a more specific modifier before issuing payment. Ms. Parman suggested that practices should get out of the habit of hard coding modifier 59. She worked with a different group that had used many modifier 59 codes. When she was asked about it, the woman in billing said, “If I pick the one that has a 59 on it, I never get an inquiry, so I always pick the one with a 59.” CMS bundles services because it wants them bundled, cautioned Ms. Parman. “It doesn’t mean you add modifier 59 on it because you want to get paid more.” For more information on CMS policy regarding modifier 59 and how to code for separate or distinct procedural services, visit http://goo.gl/ffUMGa. —Marie Rosenthal

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Pediatric Oncology

Applying Pharmacogenomics Can Help Reduce Toxicity Toronto—Because pharmacogenetic factors influence the effects of pediatric oncologic therapies, genetic information is increasingly being used to help minimize toxicities in pediatric patients with cancer, but some experts urge a cautious approach. “The goal is to identify markers of clinical, diagnostic utility that will prevent severe, adverse events in children,” said Shahrad Rod Rassekh, MD, MHSc, a pediatric oncologist and a clinical assistant professor at British Columbia Children’s Hospital, in Vancouver, British Columbia.

The vast majority of patients with ALL are cured, but about 10% do not achieve a cure, he said. Research suggests that TPMT genotype affects the efficacy of ALL treatment. One study found that patients who were heterozygous for allelic variants of TPMT that conferred reduced enzyme activity had a significantly reduced rate of minimal residual disease positivity compared with patients who carried homozygous wildtype alleles ((JAMA 2005;293[12]:14851489, PMID: 15784872). In another example, Dr. Rassekh and his co-investigators have vali-

‘In a perfect world, we would like to characterize both the tumor and the patient’s susceptibilities and ... vulnerabilities and come up with a personalized combination of chemotherapy that maximizes cure and minimizes toxicity. We are not there yet.’ —Paul Nathan, MD, MSc During a presentation at the 2014 Congress of the International Society of Pediatric Oncology, Dr. Rassekh said that factors such as a child’s size, diet and the presence of concomitant diseases influence how a drug is dosed, and genetic information is yet another factor to consider when making any dose adjustments in pediatric oncology. Dr. Rassekh gave the example of the gene coding for thiopurine S-methyltransferase (TPMT) and its relationship to the treatment of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine.

dated genetic variants in two genes that are predictive of anthracyclineinduced cardiotoxicity. They have put forth a prediction model, taking into account clinical risk factors, to detect patients who are at low versus high risk for developing cardiotoxicity (Pedi( atr Blood Cancer 2013;60[8]:1375-1381, PMID: 23441093). Paul Nathan MD, MSc, the director of the After Care Clinic in the Division of Hematology/Oncology at the Hospital for Sick Children, and an associate professor of pediatrics and health

policy management and evaluation at the University of Toronto, in Canada, said personalized therapy in pediatric oncology aimed at decreasdecreas ing toxicities, although a laudable goal, is not yet ready for prime time. “In a perfect world, we would like to characterize both the tumor and the patient’s susceptibilities and specific vulnerabilities and come up with a personalized combination of chemotherapy that maximizes cure and minimizes toxicity,” said Dr. Nathan, who moderated the keynote session. However, he added, “we are not there yet.” The example of TPMT as a pharmacogenetic marker in the treatment of ALL is a straightforward one, but in the majority of pediatric oncology cases, multiple genes are likely linked to treatment toxicities, which makes it challenging to find strategies to reduce these toxicities, said Dr. Nathan. Moreover, he said, modifying therapy could compromise the potential for curing disease. “People don’t want to damage the possibility of cure by changing doses,” said Dr. Nathan. “People are loath to trade off cure” to reduce late toxic effects. Furthermore, even if patients are identified as being at high risk for developing

toxicity and there is a protective agent available to administer to those patients, that protection might carry its own hazards, noted Dr. Nathan, citing the example of dexrazoxane and its use to prevent cardiotoxicity. “There have been cases in the literature of patients who get [dexrazoxane] and develop secondary cancers, such as leukemias,” said Dr. Nathan, noting that dexrazoxane is not used currently in pediatric oncology in Europe. Despite these concerns, both Drs. Rassekh and Nathan noted that there has been a paradigm shift in pediatric oncology thanks to major strides in treatment. Dr. Nathan said, “The mantra was cure at any cost 30 or 40 years ago because survival was so poor. Now that survival rates are close to 80%, it’s increasingly about the quality of life and what a patient’s life will be like after cure.” This likely will drive continued efforts to uncover pharmacogenetic factors that influence pediatric oncologic treatment. —Louise Gagnon Drs. Rassekh and Nathan reported no relevant financial relationships.

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Avoiding Surgery in Locally Advanced Rectal Cancer Evidence builds for nonsurgical treatment options San Francisco—Many patients with locally advanced rectal cancer (stage II/III) who achieve a clinical complete response (cCR) after neoadjuvant chemoradiation can skip rectal recision without negative outcomes, according to a study presented at the 2014 Gastrointestinal Cancers Symposium (abstract 509). In a cohort of 73 such patients who were treated with a watch-and-wait (WW) strategy, 77% avoided rectal resection, and the local disease control rate, with salvage therapy, was 98%. “For patients with complete response, nonoperative management appears to be a safe and effective treatment strategy and achieves a high rate of rectal preservation,” said lead author Philip Paty, MD, a surgical oncologist at Memorial SloanKettering Cancer Center (MSKCC), in New York City. “Patients managed nonoperatively avoid the risks of major surgery and maintain excellent bowel function.” Locally advanced rectal cancer is the most common presentation of rectal cancer. For the past 10 years in the United States, standard management of this disease has been neoadjuvant chemoradiation to the pelvis, followed by rectal resection, and, in most cases, adjuvant chemotherapy. Because pathologic analyses have revealed that 12% to 38% of patients with stage II/III rectal cancer have a CR after neoadjuvant chemoradiation, clinicians have debated whether surgery is always necessary for this subset of patients. Angelita Habr-Gama, MD, a professor of surgery at University of Sao Paulo School of Medicine, in Brazil, was the first to start evaluating nonoperative, WW management in selected rectal cancer patients. In recent years, a small number of U.S. cancer centers, including MSKCC, the University of Texas MD Anderson Cancer Center, in Houston, and University of Rochester Medical Center, in Rochester, N.Y., have followed suit. In the new study, investigators reviewed the records of all 442 patients with stage I/III rectal cancer who underwent neoadjuvant treatment at MSKCC between 2006 and 2013. They compared outcomes for patients who achieved cCR after neoadjuvant therapy and underwent nonoperative, WW management (n=73) with outcomes of patients who underwent rectal resection and were found to have had a pathologic CR (n=72). Most of the patients in the study had stage II/III disease. Patients undergoing the WW approach were initially followed at three- to four-month intervals by digital rectal and endoscopic examinations, and at six-month intervals by cross-sectional imaging.

‘For patients with complete response, nonoperative management appears to be a safe and effective treatment strategy …. Patients managed nonoperatively avoid the risks of major surgery and maintain excellent bowel function.’ —Philip Paty, MD The median follow-up of all patients in the study was 3.3 years, and the longest follow-up was more than eight years. In the WW cohort, 74% experienced a durable cCR and avoided rectal surgery, and 26% eventually underwent rectal surgery to treat tumor regrowth. Nineteen of the regrowths were detected by endoscopy or physical examination, and three were detected through imaging.

rectal-preserving surgery. “They either had the rectum resected and reconnected, or rectal resection plus permanent colostomy,” Dr. Paty said. “Rectal function can be retained/restored by surgery plus reconnection, albeit [there is] poor quality in many patients. Nonoperative management preserves the rectal organ itself and preserves rectal function (normal or close to normal).”

‘When Dr. Habr-Gama first started doing this, everybody thought she was crazy, although they knew she was asking a question that everybody wanted an answer to. … Ten to 15 years later, the data became impossible to ignore.’ —John Monson, MD “Of the 19 regrowths, all were able to have surgical salvage, and in all cases, the operation was successful in removing the tumor with clear margins,” Dr. Paty said. In 17 of the 19 cases, a full rectal resection was required, but in two of the regrowths, the tumors were small and a local excision was successful in controlling the cancer. Thus, 77% of the entire nonoperative management group had their rectal function preserved. Pelvic recurrence after salvage therapy occurred in one patient for a 98.5% overall local control rate. None of the patients in the cohort who had surgery up front had

The four-year disease-specific survival and overall survival were not significantly different between patients who had surgery up front and those in the WW group. The study adds to evidence from international researchers showing that patients who achieve a cCR after chemoradiation can safely be managed with WW. In the most recent work from Dr. Habr-Gama’s group in Brazil, 70 patients were treated and 47 achieved cCR ((Dis Colon Rectum 2013;56[10]:1109-1117, PMID: 24022527). Of the 47 cCR patients, 72% ultimately avoided surgery and

thus were able to preserve their rectum. In the overall cohort of 70, rectal preservation was achieved in 50%. In a 21-patient study from the Netherlands, with an average follow-up of 25 months, 20 patients remained in cCR after neoadjuvant chemoradiation; one patient developed a local recurrence and was managed with salvage surgery ((J Clin Oncol 2011;29[35]:4633-4640, PMID: 22067400). In the United Kingdom, researchers reported a series of six patients with locally advanced rectal cancer who were successfully managed without surgery (Colorectal Dis 2012;14[5]:567-571, PMID: 21831177). Dr. Paty said that in the MSKCC series and the three international studies, patient and tumor characteristics at presentation were quite heterogeneous, with variable T stage (T1-T4), nodal stage (N0N2) and tumor location (0-12 cm above anal opening). “Smaller tumors have a higher CR rate, but even larger tumors can melt away completely,” he said. John Monson, MD, a professor of surgery and oncology and chief of the Division of Colorectal Surgery at University of Rochester Medical Center, said that although momentum is building for WW management of selected patients with rectal cancer, it is not ready for prime time. There are still unknowns, he said, such as how do you prove that a patient has completely responded. “This needs to be managed in centers of excellence that have expertise in it,” Dr. Monson said. “It requires quite an investment of time and effort on the part of the doctors and on the part of the patient.” Furthermore, patients being treated with this approach need to be reexamined every three months for at least the first three years, he continued. “When Dr. Habr-Gama first started doing this, everybody thought she was crazy, although they knew she was asking a question that everybody wanted an answer to. Everybody had seen these patients,” Dr. Monson said. “Ten to 15 years later, the data became impossible to ignore and innovative centers such as ours said, ‘what about this paper from Brazil,’ and we started evaluating it. This is definitely not ready to be standard of care, but it is ready for a serious scientific evaluation at this point.” A prospective Phase II trial of WW management for locally advanced rectal cancer has recently begun enrolling patients at 20 institutions across the United States. —Kate O’Rourke Drs. Paty and Monson reported no relevant financial relationships.

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cost (WAC AC C) of o alll sho ort rt-a -act -a c in ct ing g GG-CS CSF F pr prod oduc od ucts uc t ts as of November 11, 201 0 3. 3 WAC C rep prese sent se ntss pu nt publ blis bl ishe is he ed ca cata talo log gue gu g e or lisst pr pric ices es and n may not represent acctual tra ansa a tion ac o al pri r ce es. s. Ple leas ase e co con ntac actt yo your urr sup uppl plie er fo forr ac actu tual al pri r ce c s. s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red ductio cttio on in dur urat a io at i n off sev ever ere e ne n utrro openia a vs placebo (1.1 days vs 3.8 8 da d ys, p<0 0.0 000 001) 11 – Ef E fica cacy cy was eva cy valu luat ae at ed d in a m mult mu ltin nat ational, m multice enter, randomized, controlled, Phase III study of chem motherapy-naïve 2 2 1 patien ents tss witth hi hig g -ris gh-r gh iskk br brea east stt cance er receivving do oxorubicin (60 mg/m IV bo olus)/docetaxel (75 mg/m ) » Th he sa safe fe etyy of GR GRA A IX was esta AN ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast ca anccer er,, lu lung ng can nce er, or non-Ho odgkin lympho oma (N NHL)1 » No Now w of offe ferri fe ring ng a new e presentation for self-ad dministration

Indication » GR G AN A IX is a leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients w th non wi onm mye oid malig myel gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant inci in cide dencce of febrile neu utropenia.

Important Safety Information » Sple Sp eni n c ru upture: Splen nic rupture, including fatal cases, can occur following the e administrattion of human granulocyte colo co lony ny-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in pati pa tien e ts who report up pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut u e resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o de d ve elop fever and d lung infiltrates or respiratory disstress after receiving GRANIX, forr ARDS. Discontinue GRANIX in patients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receiving hG G-CSF SFs. Reactions n ca an occurr on initial exp exposure. posure Permanentlyy discontinue GRANIX in patients with serious allergic reac actions. tions D Do o no not administe er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egfilgr g astim. » Use e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in pa patients with sickkle cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in patients with sickle cell disease. Discontinu ue GRANIX in i patients undergoin ng a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss characteriize z d by hyp ypote ensiion o , hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life-thr h eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece c ivve sttanda dard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimullatin ng fa actor o (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibility tha hat GRAN NIX X acts as a grow wth factor for any tumor type, inclu uding myelo oid d malignancies and myelodysplasia, diseasses e for which GRA ANIX is not app proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent ad dvers r e re ea action that occurred in patients treated with GRANIX at the recommended do d se with an incidence of at leastt 1% or gre eat e a er and two ti t mess more frequent than in the placebo group wass bone pain. Please see brief summary of Full Prescribin ng Information on adjacent page.

For more information, visit GRANIXhcp.com. Refe Re fere renc nce: e 1. GRA ANIX® (tbo-filgrastim) Injection Prescribing g Info orm r ation. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

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Report From SABCS:

Evidence Builds for First-Line Use of Fulvestrant San Antonio—Fulvestrant provides a substantial overall survival (OS) benefit over anastrozole in the first-line treatment of postmenopausal women with estrogen receptor (ER)–positive advanced breast cancer, according to the results of a Phase II trial presented at the 2014 San Antonio Breast Cancer Symposium (SABCS). Currently, fulvestrant (Faslodex, AstraZeneca)

is approved for use in the second-line treatment of breast cancer. Investigator John Robertson, MD, who presented results from the trial, called FIRST (Fulvestrant First-line Study Comparing Endocrine Treatments), at the symposium (abstract S6-04), said a Phase III trial currently underway, called FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,iÃ« À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À i [see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

Advanced Breast Cancer), should provide a definitive answer as to whether fulvestrant can be moved to first-line treatment. During the FIRST trial, Dr. Robertson, a professor of surgery at the University of Nottingham Royal Derby Hospital, in Derby, U.K., and his colleagues, randomized roughly 200 postmenopausal patients with ER-positive, advanced cancer to receive either fulvestrant 500

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

mg (days 0, 14 and 28, and every 28 days thereafter) or anastrozole 1 mg daily. The arms were well balanced with respect to disease stage, measurable disease, prior endocrine treatment and prior adjuvant chemotherapy. In terms of the primary end point—the clinical benefit rate—fulvestrant was at least as effective as anastrozole (72.5% vs. 67%; P=0.386). The median time to progression (TTP) was improved in the fulvestrant arm (23.4 vs. 13.1 months; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.47-0.92; P=0.01). The median OS was 54.1 months in the fulvestrant arm and 48.4 months in the anastrozole arm, a 5.7-month difference (HR, 0.70; 95% CI, 0.50-0.98; P=0.041). “The survival benefit seems to correlate with the TTP benefit,” said Dr. Robertson. “The benefit was consistent in all subgroups.” Subgroups were defined by age (64 years or younger or 65 years or older), visceral disease, prior chemotherapy, prior endocrine therapy and measurable disease. Noting that the rate of adverse events was similar to what has been seen in previous trials, he said fulvestrant is a well-tolerated drug. After the study presentation at SABCS, a clinician from the audience questioned whether compliance could explain the outcomes, given that anastrozole is an oral agent and fulvestrant is given as an intramuscular injection. Dr. Robertson replied, “We don’t have data on compliance, but in the metastatic setting, most patients take their drugs.” He added that if patients are less likely to take their oral medications, this would be another “advantage” for fulvestrant. Some clinicians in the United States say they will not make practice changes based on the results from FIRST. Maura Dickler, MD, an associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City, told Clinical Oncology News that she will wait for “results from FALCON before making any major decisions about first-line fulvestrant.” The different costs of these two agents might be a factor considered in the decision-making process. According to a company spokesperson for AstraZeneca, the wholesale acquisition cost (WAC) of a 500-mg injection of fulvestrant is $1,808.63, and the WAC of a 30-day supply of branded anastrozole (Arimidex, AstraZeneca) is $434.10. Anastrozole went off patent in 2010. —Kate O’Rourke Drs. Robertson and Dickler reported financial relationships with AstraZeneca.

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Report From SABCS:

Capecitabine Strikes Out in Older Breast Ca Patients San Antonio—Adjuvant capecitabine does not improve survival in women with early breast cancer receiving the bisphosphonate ibandronate (Boniva, Genentech), according to results from the Phase III ICE trial presented at the San Antonio Breast Cancer Symposium (SABCS; abstract S3-04). The “study failed to show that adjuvant capecitabine improves invasive diseasefree survival [DFS] in patients receiving ibandronate,” said lead investigator Gunter von Minckwitz, MD, the chairman of the German Breast Group in NeuIsenburg, in Germany. “The outcome of elderly patients with moderate- or highrisk early breast cancer receiving ibandronate alone is very favorable, with a disease-free survival of 77% and overall survival [OS] of 88% at five years.” Because the elderly are underrepresented in clinical trials, clinicians often do not have a good idea how effective and tolerable cancer therapies are in patients over the age of 65 years. Capecitabine, a prodrug that is enzymatically converted to fluorouracil (5-FU) in the body, has demonstrated single-agent activity in metastatic breast cancer. Adjuvant bisphosphonates have been shown to increase DFS and OS in postmenopausal patients. In the ICE [Ibandronate with or without Capecitabine in Elderly patients] trial, 1,358 women at least age 65 years with moderate- or high-risk early breast cancer were randomized to ibandronate alone or with capecitabine (Table). In the 80% of patients in the trial who were hormone receptor–positive, anastrozole and/or tamoxifen and/or radiotherapy were started after capecitabine. The median age of women in the trial was 71 years, and the two arms were well balanced with respect to patient and tumor characteristics. Roughly onefourth of patients discontinued ibandronate in each arm, with approximately 3% citing toxicity as the reason. Roughly 17% of patients discontinued capecitabine, 7.8% because of toxicity. Patients receiving capecitabine were more likely to

Table. ICE Trial Design Requirements for Entry • Node-positive disease regardless of additional risk factors, or node-negative disease with ≥1 other risk factor (histologic tumor size ≥2 cm, grade II or III, ER and PR negative) • Charlson Comorbidity Index ≤2 Design Patients stratified by center, nodal status, age and receptor status • Arm 1: Ibandronate 50 mg orally daily or 6 mg IV every 4 wk for 2 y • Arm 2: Ibandronate 50 mg orally daily or 6 mg IV every 4 wk for 2 y + capecitabine 2,000 mg/m2 orally daily on days 1-14 every 3 wk for 6 cycles

‘I suspect that the overall use of adjuvant chemotherapy in older patients, especially hormone receptor– positive patients, has already been falling, and ICE is supportive of that.’ —Clifford Hudis, MD

ER, estrogen receptor; PR, progesterone receptor

‘The outcome of elderly patients with moderate- or high-risk early breast cancer receiving ibandronate alone is very favorable, with a disease-free survival of 77% and overall survival of 88% at five years.’ —Gunter von Minckwitz, MD experience grade 3/4 adverse events (31% vs. 8.7%), with most of the increase due to gastrointestinal and skin problems, especially hand–foot syndrome. At five years of follow-up, patients receiving ibandronate alone showed no statistically significant difference compared with those receiving ibandronate plus capecitabine with respect to the rates of DFS (75% vs. 78.8%; P=0.7010) or OS (87.6% vs. 90.1%; P=0.3816). After Dr. von Minckwitz’s presentation, George Sledge Jr., MD, a professor of medicine and the chief of the Division of Oncology at Stanford University School of Medicine, in California, pointed out that there are now several trials that have been negative for 5-FU–based regimens in early breast cancer, including the National Surgical Adjuvant Breast and Bowel Project (NSABP)-36, also presented at the SABCS meeting (abstract S3-02). NSABP-36 compared six cycles of 5-FU, epirubicin and cyclophosphamide with

four cycles of doxorubicin and cyclophosphamide (AC) in patients with nodenegative breast cancer. “In every case, the fluoropyrimidine arm struck out.” Dr. Sledge questioned whether there is any role for fluoropyrimidine in the adjuvant setting anymore, and Dr. von Minckwitz replied, “Currently, I would say there is no role for using 5-FU or other formulations of this agent in early breast cancer.” He said he would lean toward providing AC or an AC-taxane sequence in elderly women with breast cancer. He pointed out that the Cancer and Leukemia Group B (CALGB) 49907 study showed that OS was slightly better for older patients with early breast cancer when they were treated with standard chemotherapy (either AC or CMF [cyclophosphamide, methotrexate and 5-FU]) rather than capecitabine (90.6% vs. 86.4%; P≤0.02). Other studies have shown an AC or an AC-taxane regimen trumps 5-FU regimens. “A patient

would have to be really unfit before I would not treat her with chemotherapy,” said Dr. von Minckwitz. According to Clifford Hudis, MD, the chief of the Breast Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, there has been a declining use of chemotherapy in the elderly in the United States. Asked about the significance of ICE, Dr. Hudis told Clinical Oncology News that an increasing number of trials have shown that chemotherapy in elderly patients with breast cancer provides little benefit in estrogen receptor– positive patients. In the CALGB 49907 study, he said, standard chemotherapy was shown to be better than capecitabine, but the improvement was driven mostly by patients with triple-negative cancer and estrogen receptor/progesterone receptor–negative cancer. In the estrogen receptor–positive patients, the results looked “no different,” said Dr. Hudis. “I suspect that the overall use of adjuvant chemotherapy in older patients, especially hormone receptor–positive patients, has already been falling, and ICE is supportive of that. In the ICE study, capecitabine [didn’t] add anything,” said Dr. Hudis. ‘There is an increased recognition of the force of competing [causes of ] mortality in older patients.” —Kate O’Rourke Drs. von Minckwitz, Sledge and Hudis reported no relevant financial relationships.

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

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TILS

system, end of story.” If patients have a maximal immune response induced by their tumor, adding trastuzumab has little effect or, in fact, can limit further T-cell function, she said, pointing out that in the small number of patients who appeared to already be at maximal response, there was a nonsignificant trend for worse recurrence-free survival. “If T cells are highly activated, further activation can be a bad thing,” said Dr. Disis. “T cells can become exhausted, undergo deletion or stop functioning entirely.” Jonas Bergh, MD, PhD, a professor and senior physician at the Karolinska Institute, in Stockholm, Sweden, called the study “provocative,” and predicted that “if the results can be reproduced, this will really have [treatment] implications.” Dr. Bergh pointed out that although

continued from page 1

levels of stromal tumor-infiltrating lymphocytes (TILs) if 60% or more of the cells in the sample specimen were immune cells.

‘If T cells are highly activated, further activation can be a bad thing. T cells can become exhausted, undergo deletion or stop functioning entirely.’ —Mary Disis, MD Tumor-infiltrating lymphocytes.

Among 489 women with HER2-positive, early breast cancer who were randomized to chemotherapy alone in the N9831 trial, those with high levels of stromal TILs had an 80% decreased chance of disease recurrence after a median follow-up of 4.4 years. Among 456 patients randomized to chemotherapy and trastuzumab (Herceptin, Genentech), the chance of disease recurrence was the same, regardless of the levels of stromal TILs. “There are two main findings from our study,” said lead author Edith Perez, MD, the deputy director of Mayo Clinic Cancer Center, in the Division of Hematology/Oncology at Mayo Clinic, in Jacksonville, Fla. “First, patients with high levels of tumor-infiltrating immune cells did well with chemotherapy alone. Second, the level of tumorinfiltrating immune cells had no impact on the benefit of adding trastuzumab to chemotherapy.” Dr. Perez pointed out that although the N9831 trial demonstrated that adding trastuzumab to chemotherapy significantly improved recurrence-free

‘These results suggest that levels of tumor-infiltrating immune cells may provide a biomarker to identify patients who might do well without trastuzumab, but we must conduct additional large clinical trials before we can consider changing clinical practice and omitting HER2-targeted therapy … for patients who have high levels of tumor-infiltrating immune cells.’ —Edith Perez, MD and overall survival, some patients did not benefit from trastuzumab and did well with chemotherapy alone. “These results suggest that levels of tumorinfiltrating immune cells may provide a biomarker to identify patients who might do well without trastuzumab, but we must conduct additional large clinical trials before we can consider changing clinical practice and omitting HER2-targeted therapy from the treatment regimens for patients who have high levels of tumor-infiltrating immune cells,” said Dr. Perez. Dr. Perez said she was surprised that high levels of stromal TILs were not associated with increased benefit

from trastuzumab, because a previous study had shown the contrary ((Ann Oncol 2014;25[8]:1544-1550, PMID: 24608200). She acknowledged, however, that the previous study had a smaller number of patients and lower statistical power. The investigators plan to conduct further research to examine whether a particular subtype of immune cells is associated with improved patient outcomes. Mary Disis, MD, a professor in the Division of Oncology at the University of Washington, in Seattle, who was not involved with the research, said the new study shows that “the way trastuzumab works is by stimulating the immune

trastuzumab works by enhancing the immune response, lapatinib (Tykerb, GlaxoSmithKline), another commonly used anti-HER2 agent, does not. He hoped the researchers would compare the association of TILs in patients receiving trastuzumab with those receiving lapatinib. Dr. Perez said she was planning to conduct this comparison, using data from the ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) trial. —Paul Bufano and Kate O’Rourke Drs. Perez, Disis and Bergh reported no relevant financial relationships.

by the

numbers

BCS alone BCS + RT

BCS + RT + chemotherapya

Frequency, %

Mastectomy alone

Mastectomy + chemotherapya

Nonsurgical treatment 10

No treatment 7

6 4

5 1

Mastectomy + RT + chemotherapya

15 10

Mastectomy + RT

7 1

BCS, breast-conserving surgery; RT, radiation therapy a

Early stage (I and II)

Late stage (III and IV)

Female breast cancer treatment patterns by stage, United States 2008.

May include common targeted therapies

Based on American Cancer Society, Surveillance and Health Services Research, 2013 (National Cancer Database, 2008).

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Report from SABCS:

PI3K Inhibitor Pictilisib Trial Disappoints San Antonio—Although the first Phase II trial of a phosphatidylinositol 3-kinase (PI3K) inhibitor in breast cancer missed its primary end point, investigators remain optimistic about the potential for others in the treatment of breast cancer. “I expect the lay public to call [this study] a ‘defeat’ and say that [all] PI3K inhibitors do not work. That would be sad,” said Carlos Arteaga, MD, the director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, in Nashville, Tenn., who was not involved with the study.

xenograft models. The trial enrolled 168 women with ER-positive, advanced or metastatic breast cancer who were resistant to aromatase inhibitors. Patients were randomized to receive 500 mg of fulvestrant with a placebo or fulvestrant plus pictilisib. “When we analyzed data for all women with ER-positive disease, the improvement in progression-free

Table. Comparison of Grade ≥3 AEs Found In >2% of Patients AE

Pictilisib, Placebo, % %

Diarrhea

Nausea

3.4

Rash

Fatigue

Vomiting

Hyperglycemia

AST increased

Colitis

AE, adverse event; AST, aspartate aminotransferase

‘There were very minimal on-target surrogate side effects, which suggests to me that the drug was not strongly inhibiting the PI3K pathway.’ —Carlos Arteaga, MD PI3K/mammalian target of rapamycin (mTOR) signaling has been implicated as a resistance mechanism to anti-estrogen therapies in the in vitro and clinical setting. Between 40% and 45% of estrogen receptor (ER)–positive breast cancers harbor a PI3KCA mutation. In the new trial, presented at the San Antonio Breast Cancer Symposium (SABCS; abstract S2-02), investigators tested the combination of fulvestrant (Faslodex, AstraZeneca) and pictilisib (Genentech), an oral, pan-class I PI3K inhibitor, because they have shown synergy in ER-positive breast cancer

survival was not statistically significant,” said lead author of the study Ian Krop, MD, PhD, the director of clinical research for the Breast Oncology Program at the Dana-Farber Cancer Institute, in Boston. However, he noted that when the investigators included only women with ER/progesterone receptor (PR)–positive breast cancer, “adding pictilisib resulted in a doubling

of progression-free survival, from 3.7 months to 7.4 months, in an exploratory analysis.” The investigators plan to test whether the benefit of pictilisib for women with ER/PR-positive breast cancer holds true for an additional cohort of patients within the study.

Significant Dose Adjustments Needed Gastrointestinal and dermatologic toxicities resulted in significant dose modifications and discontinuations of pictilisib. Patients taking the PI3K see PICTILISIB, B page 17

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

Expiration Date: November 11, 2015

Faculty

Goal

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.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

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

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

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

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

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Vogl, NY: Tamoxifen Chemoprevention After 20 Years...

Lots of Concern Amidst Unexpectedly Prolonged Activity EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist New York City

amoxifen keeps preventing breast cancer 15 years after it has been stopped! This was the major conclusion of IBIS-1 (International Breast Cancer Intervention Study) at a median follow-up of 16 years. Jack Cuzick, PhD, from the Wolfson Institute of Preventive Medicine, in London, presented the results at the 2014 San Antonio Breast Cancer Symposium and published them in Lancet.1 Rather than just delaying the onset of clinical breast cancer, or suppressing the development of breast cancer during its administration, 5 years of oral tamoxifen keeps preventing new breast cancers out to year 20! Based on these newly revealed data, one need treat only 22 asymptomatic healthy “high-risk” women to prevent 1 breast cancer or ductal carcinoma in situ (DCIS) at 20 years. Excluding DCIS (which is not life threatening) and estrogen receptor (ER)–negative breast cancers (which are not prevented by tamoxifen), one need treat only 29 asymptomatic healthy “high-risk” women to prevent one invasive ERpositive breast cancer at 20 years. In IBIS-1, high risk was defined by a positive family history of breast cancer in 95% of the participants. Other ways of saying the same findings: • Five years of tamoxifen decreases breast cancer incidence (including DCIS) from 12.3% to 7.8% at 20 years in high-risk women. • Among women free of breast cancer at 10 years, taking tamoxifen from years 1 to 5 decreases the breast cancer incidence at 20 years from 6.3% to 3.3%. Five years of tamoxifen reduces the incidence of breast cancer by a relative 28% at 10 years and by 31% between years 11 and 20. • Treating 1,000 women with positive family histories with 20 mg of tamoxifen daily during years 1 to 5 prevents 45 breast cancers and cases of DCIS (including 34 invasive ER-positive cancers) out to year 20. The benefit would have been even greater if entry had been forbidden to women who took hormone replacement therapy (HRT) for menopausal symptoms during the trial (these women had only about one-third the benefit of that

enjoyed by those who did not take HRT). These are major and, at least for me, unexpected positive findings. I did not expect the rate of new breast cancers to remain lower 10 to 15 years after tamoxifen had been stopped. I would still have been pleased had the rate just remained equal to that of the placebo patients. Not only was there no “catch-up” of new cancers after tamoxifen was stopped, but there also was a continued suppression of new cancers more than 10 years after cessation of treatment. The biologic explanation for the prolonged benefit remains obscure as well as uncertain. IBIS-1 is unique among breast cancer prevention studies in that the follow-up is so long (thanks, in part, to prolonged funding) and that participants remained “blinded” to their treatment assignment long after treatment was complete, even though the efficacy of 5 years of tamoxifen to prevent breast cancer had been established.

Prevention Is a Necessary, But Not Sufficient, End Point For a Prevention Trial Breast cancer “preventionists” such as Victor Vogel argue that breast cancer is terrible, its treatment is unpleasant and toxic, with short- and long-term side effects, and it can lead to premature death.2 Therefore, preventing breast cancer obviously is a laudable goal in itself, and the prevention of breast cancer obviously is good for the patient. But I, and others, remain skeptical that the benefits of prevention outweigh its risks.2,3 If one treats 1,000 “high-risk” women and prevents 45 of them from getting breast cancer over 20 years, then one must worry about what happened to the 955 who had no benefit because they would not have gotten breast cancer or DCIS anyway, or they got one of these despite the preventive therapy. With this skeptical view, to justify an intervention in healthy and asymptomatic women, one must show that all 1,000 of the treated individuals live longer as a group, live better, or, preferably, both. The problem with proving that tamoxifen-treated women live longer is that the study would have to be very large to detect a survival difference because so few women (even in a cohort selected by family history) ultimately die of breast cancer, and the follow-up would have to be very long to detect any difference. Each of these makes the proposition a very expensive one that no organization or country yet has expressed an interest in supporting. That such a study would be long and expensive does not make the requirement incorrect!

Physicians and patients still should insist on a study showing overall survival (OS) benefit to justify chemoprevention of breast cancer. The problem with proving that tamoxifen-treated, asymptomatic, healthy, high-risk women live better is that most of these women clearly do not live better! Some of this is because of the subjective side effects from tamoxifen, such as hot flashes, vaginal discharge, and dyspareunia. Another component of the impaired quality of life is from less common, but more serious, side effects such as deep vein thrombosis, endometrial cancer, and endometrial sarcoma, which can threaten not only health but also life. It is not obvious how to compare the common, very annoying tamoxifen toxicities suffered for 5 years by most tamoxifentreated women, plus the severe toxicities of tamoxifen for a small number, against the toxic effects of breast cancer diagnosis and treatment among the few breast cancers prevented (for 4.5% of the women treated). I doubt it can be done in a convincing way. That leaves us with a need for a study large enough to detect a survival difference.

IBIS-1 Hints That Tamoxifen Does Not Benefit Long-Term Survival Since we do not have, nor are we ever likely to obtain, survival results from a breast cancer prevention trial statistically powered to look at OS as its primary end point, IBIS-1 is key in evaluating the long-term effects of 5 years of tamoxifen chemoprevention because its treatment assignment code was not broken and there was little or no crossover to tamoxifen from those assigned to placebo. The IBIS-1 results turn out to be worrisome, but they remain far from definitive because they are based on very few events. Just as IBIS-1 is underpowered to show a survival benefit (as are all the other breast cancer chemoprevention trials),4 it is underpowered to show a statistically significant excess of severe toxicities, overall deaths, and cancer deaths among tamoxifen-treated women. Most worrisome (though still far from statistical significance) is that total deaths among tamoxifen-treated women were increased—182 versus 166, with about 3,600 women entered into each arm.1 The overall death rate at 20 years was 5.1% among those taking tamoxifen versus 4.6% among those given placebo, a hazard rate (HR) of 1.1 (95% confidence interval, 0.88-1.34). Most of the excess deaths were during the first 10 years of follow-up. This is an OS effect in the wrong direction! We cannot be certain at all that

tamoxifen really is associated with increased deaths because of the small numbers entered and the small number of events. However, if tamoxifen does lead to more deaths in the proportion noted in IBIS-1, then the apparent benefit of 45 fewer breast cancers among the 1,000 women given tamoxifen while healthy is negated by 5 excess deaths among these women in the first 20 years. The IBIS-1 first author (Jack Cuzick) accepts that the mortality data are “not favorable” but thinks the very small numbers make it “too early” to say that the data are “unfavorable.”5 He noted that the median age of women in the trial is now only 66 years, and that less than 5% have died. With plans to follow this cohort for at least another 10 years to get more mature data, he prefers to describe the data as showing “no mortality benefit at this stage,” rather than noting the small survival decrement. All that he says is true: the number of events is very small and the survival observations very early. The issue, as far as I am concerned, is whether physicians should now urge their patients who are well and at moderate risk of breast cancer (well below that of BRCA-1 and -2 mutation carriers) to take tamoxifen to prevent breast cancer. One could consider primary prevention of coronary disease with statins as an analogy. If the first long-term report of a statin trial in hyperlipidemic subjects without coronary disease showed more deaths in the statin arm, even though fewer patients had myocardial infarctions, would we rush to put healthy people on statins? I suspect not! Because we are good at treating breast cancer (as we are at treating myocardial infarction) but not good at treating death, the information that tamoxifen chemoprevention may lead to more deaths should give us pause, and we should insist on more definitive data that tamoxifen does not cause excess deaths before exposing healthy at-risk women to tamoxifen. Thus, we should consider the 20-year analysis of IBIS-1 very bad news indeed for tamoxifen as chemoprevention, and wait for more data.

Small Numbers of Excess Deaths From Endometrial And Breast Cancers I and others have expressed skepticism of analyses based on alleged cause of death because the assignment of cause of death can be arbitrary and often is wrong.6 That said, IBIS-1 investigators observed 5 excess deaths attributed to breast cancer in this trial among tamoxifen-treated women,

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who also had an excess of 2 ER-negative breast cancers (4 vs 2). It is possible, although not likely (because the numbers are very small), that tamoxifen prevents ER-positive breast cancer, in part, by converting some early precancers to ER negativity. The IBIS-1 investigators also observed 5 excess deaths attributed to endometrial cancer among tamoxifen-treated women; 4 of the deaths occurred in the first 10 years of follow-up.1 This isn’t surprising because the association of tamoxifen therapy with endometrial cancer is well documented. It is a concern because IBIS-1 reports no compensating decrease in breast cancer deaths to justify this obviously toxic chemoprevention.

Counting Women in IBIS-1 With Metastatic Breast Cancer Might Be Reassuring Another way of looking for benefit from chemoprevention that corrects for the efficacy of treatment of incident breast cancers would be to count the number of subjects who develop metastatic breast cancer. Metastatic breast cancer almost always kills the patient, although for some ER-positive cancers it can take a decade or more after metastases are noted to do so. Survival free of metastatic breast cancer as an end point might show some benefit that otherwise would be missed. This would require IBIS-1 investigators to annually query women who developed breast cancer about whether metastases had been diagnosed. On the contrary, if chemoprevention using tamoxifen did not prevent metastatic breast cancer in an adequately powered study, I would be loath to offer it to healthy women unless they had a particular reason to be very eager to prevent even effete breast cancers.

Myth of Informed Discussion: Few Physicians Have the Time, Few Patients the Capacity In our correspondence on this subject, Dr. Cuzick wrote, “we (IBIS investigators) never urge patients to take preventive therapy, but prefer to indicate this is an option worth considering and to provide the case for and against.”5 He expressed worry that my position expressed in this editorial suggests it should not even be discussed. I believe such a discussion is reasonable, but I am concerned that most primary physicians in the United States have neither the expertise nor the interest to have such discussions. If insurance companies were willing to pay $300 for a 1-hour discussion of breast cancer chemoprevention, I have no doubt most primary physicians could acquire the expertise and develop the interest in such discussions. Absent convincing data that chemoprevention makes women live longer or live better, it seems unlikely that insurance companies and

Good News From IBIS-1 • 5 y of tamoxifen keeps on preventing breast cancer out to 20 y from its inception. • The degree of benefit (cases prevented per year) is stable out to 20 y. • Endometrial cancer and venous thrombosis remain problems only during 5 y of therapy. • One need treat only 29 women to prevent 1 invasive estrogen receptor– positive breast cancer.

References 1. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBISI breast cancer prevention trial. Lancet Oncol. 2014 Dec 10 [Epub ahead of print], PMID: 25497694.

Bad News From IBIS-1 • IBIS-1 has no hint of a survival advantage for tamoxifen chemoprevention. • IBIS-1 had a 0.5% increase in overall mortality at 20 y in those given tamoxifen. • Women assigned to tamoxifen had more deaths from breast cancer and endometrial cancer, but these differences are small and far from statistically significant. • IBIS-1 provides no hint that women assigned to tamoxifen chemoprevention lived longer or lived better. More likely, they lived more poorly because of the well-known toxicities of tamoxifen.

government systems will devote major funds to promote it—and justifiably so! The reality of medical practice in the United States is that physicians have very little time with each patient, and that the time assigned to each patient is dedicated more to the computer than the patient. In most patient encounters, the physician looks at the computer more than he looks at the patient, touches the computer more than he touches the patient, and, if one counts “pop-ups” and flash messages, may even listen more to the computer than to the patient. Breast cancer chemoprevention will not be widely adopted without a strong push to get women on therapy and an even stronger one to keep them on therapy. Compliance rates with adjuvant hormonal therapy for resected breast cancer—with its well-established survival benefits—are poor despite physicians’ best efforts.7 Experts already have strongly recommended breast cancer chemoprevention in prestigious journals8 without much uptake in the medical community and without many women starting it. I believe the IBIS-1 data just published argue that the benefits are too uncertain to justify a national or international push to chemoprevention, expensive efforts to foster widespread discussion, and very difficult efforts to sustain therapy among women who choose to start tamoxifen, raloxifene, or exemestane for chemoprevention. Medical expenditures and physician time are limited. In dealing with asymptomatic individuals, emphasis should be put on weight control, smoking cessation, blood pressure control, vaccinations, seat belt use, and reduction

rarely kill when properly treated. If this hypothesis is correct, we can spare tamoxifen chemoprevention for the 955 of 1,000 women who will not benefit from chemoprevention and treat the 45 who would have breast cancers prevented (in the first 20 years) only after they develop breast cancer and clearly need treatment.

of coronary risk factors, not on breast cancer prevention. To prevent cancer deaths, society’s resources would be far better expended on promotion of computed tomography screening of heavy smokers to detect nonmetastatic lung cancer than on promotion of pharmacologic prevention of nonlethal breast cancer among moderate-risk women.

Cautious Conclusion: Avoid Tamoxifen Chemoprevention Until We Have More Data It was obvious early on from tamoxifen adjuvant trials among breast cancer patients who had remaining breasts “at risk” that tamoxifen prevents breast cancer, long before the trials called NSABP P19 and IBIS-1 were undertaken to test tamoxifen chemoprevention. IBIS-1 shows that tamoxifen not only prevents breast cancer but that the prevention effect continues long after the tamoxifen stops,1 something not predicted from tamoxifen adjuvant studies, probably because adjuvant trials generally do not search for long-term contralateral breast cancer prevention. The failure to show a hint of survival benefit, indeed the finding of a small survival detriment, argues that healthy women with positive family histories who are not harboring known deleterious mutations (none of which had been identified when IBIS-1 was undertaken) should not routinely get tamoxifen chemoprevention until we have data that it does more good than harm. It remains possible that tamoxifen prevents only breast cancers that are very easy to treat—those that are easily detected when small (because they grow slowly), and are low grade and sensitive to hormone therapy. These

2. Vogel V, Vogl S. Breast cancer prevention: Vogel vs. Vogl. [Letter to the Editor, with Reply]. Clinical Oncology News. 2011;06:10. http://www.clinicaloncology.com/ViewArticle.aspx?d =Letter%2bTo%2bThe%2bEditor&d_ id=459&i=October+2011&i_id=767&a_ id=19154. Accessed January 23, 2015. 3. Vogl SE. Is it good to prevent breast cancer with exemestane? Clinical Oncology News. 2011;6(7). http://www.clinicaloncology. com/ViewArticle.aspx?d=Vogl%2c+NY&d_ id=556&i=July+2011&i_id=745&a_id=17479. Accessed January 23, 2015. 4.

Cuzick J, Sestak I, Bonanni B, et al. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381(9880):1827-1834, PMID: 23639488.

Cuzick, Jack, personal communication, January 6, 2015.

6. Vogl SE. Vogl, NY, calls for annual lung CT scans now to save lives! Clinical Oncology News. 2011;6(11). http://www. clinicaloncology.com/ViewArticle. aspx?d=Solid+Tumors&d_ id=148&i=October+2011&i_id=767&a_ id=19153. Accessed January 23, 2015. 7. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28(27):4120-4128, PMID: 20585090. 8. Davidson NE, Kensler TW. “MAPping” the course of chemoprevention in breast cancer. N Engl J Med d 2011;364(25):2463-2464, PMID: 21639807. 9. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P1 Study. J Natl Cancer Inst. 1998;90(18): 1371-1388, PMID: 9747868.

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

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Reports From ESMO:

Series of Phase III Trial Results Refute Earlier Findings Negative trials in breast, lung, pancreatic cancers confirm value of this test of benefit Madrid—Five Phase III trials testing potentially practice-changing approaches to cancer control delivered negative results at the 2014 Congress of the European Society for Medical Oncology (ESMO). The results, some of which were presented as late breakers at the Congress, were highly anticipated and each yielded a surprising refutation of a promising hypothesis. The number of failed Phase III trials provides particular reinforcement for the need for multicenter trials, regardless of the promise of clinical data from smaller studies.

HER2-Negative Breast Cancer: RESILIENCE In women with HER2-negative metastatic breast cancer, sorafenib (Nexavar, Bayer) provided a highly significant progression-free survival (PFS) advantage over placebo ((P<0.001) when added to capecitabine in a Phase II trial. In a confirmatory Phase III trial presented at ESMO, called RESLIENCE (abstract LBA8), no such benefit was observed. In fact, there was a trend for worse overall survival (OS) for those who received sorafenib. In this multinational double-blind trial, presented by Jose Baselga, MD, PhD, the physician-in-chief and the chief medical officer at Memorial SloanKettering Cancer Center, in New York City, 537 women with locally advanced or metastatic HER2-negative breast cancer were randomized to receive sorafenib or placebo in combination with capecitabine. Most of the treated cancers were hormone receptor–positive, but about one-third were triplenegative. Almost 60% of the patients had received prior chemotherapy.

The median PFS was 5.5 months in the sorafenib arm and 5.4 months in the placebo arm ((P=0.4). The median OS was 18.9 and 20.3 months, respectively. There were no differences in objective response and most other measures of activity. Grade 3

or higher adverse events (AEs) were more frequent in the sorafenib arm (64.3% vs. 43.5%). Despite the Phase II results and the theoretical benefits from a tyrosine kinase inhibitor (TKI) with both antiangiogenic and antiproliferative effects, RESILIENCE was soundly negative.

Adjuvant Immunotherapy In NSCLC: MAGRIT Trial In patients with completely resected non-small cell lung cancer (NSCLC), a Phase II trial suggested that adjuvant therapy with a vaccine targeting the MAGE-A3 (melanoma-associated anti-

gen-3) protein could delay progression when administered with an immunostimulant. In the Phase II study, a variety of outcomes favored the vaccine, including OS, although none were statistically significant in the relatively small study. In a larger multinational Phase III trial called MAGRIT, the therapy was well tolerated, but there did not appear to be even any trends for clinical benefit after a mean 38 months of follow-up. Characterized as the largest trial ever conducted in NSCLC (N=2,272) and the first to evaluate adjuvant immunotherapy in early NSCLC, the study showed no relative advantage for the recombinant MAGE-A3 immunotherapeutic, even in a careful analysis of subgroups, according to investigator Johan K. Vansteenkiste, MD, of the Respiratory-Oncology Unit at University Hospitals of Leuven, in Belgium. MAGE-A3–positive NSCLC, which is identified in about 35% of patients with resectable NSCLC, was required for trial enrollment. MAGE-A3 is expressed by several cancers besides NSCLC, including melanoma and some hematologic malignancies, and is an attractive target for immunotherapy. Although the therapy was well tolerated, with no difference in grade 3 or higher AEs observed in the two arms of the MAGRIT study, the disappointing results do not encourage further study.

Repeated Course of Gefinitib In NSCLC: IMPRESS Anecdotal experience has suggested that continuation of a TKI beyond disease progression (as defined by RECIST criteria) might provide benefit to patients with NSCLC that is positive for an activating epidermal growth factor receptor ((EGFR) mutation who responded previously to a first-line TKI before developing resistance. New Phase III data from the IMPRESS trial proves otherwise. In the randomized, multinational trial, the PFS was the same (5.4 months) in those randomized to receive the TKI gefinitinb and those given placebo on top of the cisplatin-pemetrexed doublet. The IMPRESS trial randomized 265 patients who had metastatic NSCLC with an activating EGFR mutation at disease progression after first-line gefitinib. There were no differences in objective response. Although the OS analysis is not yet mature, the hazard ratio (HR) in follow-up at the time of analysis suggested a relative disadvantage for the addition of gefitinib (HR, 1.62; P=0.0029). Although there was no additional or unexpected toxicity with the combination, investigator Tony S.K. Mok, MD, a professor of clinical oncology at the Chinese University of Hong Kong, concluded that patients with EGFR mutation–positive NSCLC should receive chemotherapy alone after development of clinical resistance to first-line EGFR TKI treatment.

and did not complicate surgery, but no conclusion could be drawn about its routine use in clinical care.

Adjuvant Therapy in Pancreatic Cancer: CONKO-006 Although a Phase IIb, rather than Phase III trial, CONKO-006 was characterized as the largest clinical trial ever conducted in R1-resected pancreatic cancer. It tested the ability of adjuvant sorafenib plus gemcitabine to improve disease-free survival (DFS) after surgery over adjuvant gemcitabine alone. The DFS difference was one month (9.6 vs. 10.7 months); it was not statistically significant ((P=0.89), and favored gemcitabine alone. Moreover, AEs, including those that were grade 3 or higher, were more common among patients who received sorafenib.

Neoadjuvant Radiation in Locally Advanced NSCLC: SAKK 16/00 Radiation is a common adjuvant therapy in patients with locally advanced NSCLC, but providing radiation with chemotherapy before surgery produced ambiguous results in a multinational Phase III trial called SAKK 16/00. In this trial, which randomized 232 patients at 23 centers, all the patients received three cycles of neoadjuvant cisplatin and docetaxel but were randomized to receive a concomitant boost of radiotherapy delivered in 22 fractions over three weeks. Relative to chemotherapy alone, the addition of radiation increased response rates and the proportion of patients who achieved a complete resection, but it failed to provide a statistically significant improvement in local control, event-free survival or OS, according to Miklos Pless, MD, from the Tumor Center, Kantonsspital Winterthur, in Switzerland. The study showed that chemoradiation is feasible

Despite the theoretical advantage of sorafenib for halting pathways for tumor growth, the lead author of this multinational trial, Marianne Sinn, MD, from the University of Berlin’s Charite Hospital, in Germany, reported no signal of increased benefit and no plans to evaluate this approach further. —Ted Bosworth Drs. Baselga and Sinn reported no relevant financial relationships. Dr. Vansteenkiste reported a financial relationship with GlaxoSmithKline, the sponsor of the MAGRIT study. Dr. Mok reported financial relationships with Amgen, AstraZeneca, AVEO, BioMarin Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eisai, Eli Lilly, Janssen, Merck Serono, Novartis, Pfizer, Roche and Taiho. Dr. Pless reported a financial relationship with Sanofi.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

For Advanced Colorectal Cancer:

TRIBE Solidifies Role for FOLFOXIRI Plus Bevacizumab San Francisco—Updated results from the Phase III TRIBE trial provide support for the use of FOLFOXIRI plus bevacizumab as first-line therapy for patients with metastatic colorectal cancer (mCRC). Compared with the standard treatment of FOLFIRI plus bevacizumab and maintenance therapy, FOLFOXIRI plus bevacizumab and maintenance therapy extended the median overall survival (OS) by roughly four months. “The reduction in the risk of death [was] 20%,” said Chiara Cremolini, MD, a medical oncologist at the Tuscan Tumor Institute in Pisa, Italy. She presented the results of TRIBE at the Gastrointestinal Cancers Symposium (abstract 657), on behalf of the Gruppo Oncologico Nord Ovest (GONO), an Italian cooperative trials group.

‘Looking at the survival curve, the benefit of FOLFOXIRI plus bevacizumab increases over time.’ —Chiara Cremolini, MD Studies have shown that adding bevacizumab (Avastin, Genentech) to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) and FOLFOX (leucovorin, 5-FU, oxaliplatin)—the two most widely used first-line chemotherapy regimens for mCRC—increases OS. A previous Phase III trial, also conducted by GONO, demonstrated that FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) alone improved survival compared with FOLFIRI alone in the first-line treatment of mCRC ((J Clin Oncol 2007;25[13]:16701676, PMID: 17470860). To determine if adding bevacizumab to FOLFOXIRI would add further benefit, the TRIBE investigators randomized 508 patients with unresectable mCRC to receive up to 12 cycles of bevacizumab at a dose of 5 mg/kg, plus either FOLFOXIRI or FOLFIRI. Patients then received maintenance with 5-FU-leucovorin plus bevacizumab until disease progression. The arms were well balanced in terms of factors such as performance status and adjuvant chemotherapy. Previously, TRIBE researchers reported that at a median follow-up of 32.2 months, FOLFOXIRI reduced the risk for progression by 25% (median progression-free survival [PFS], 12.1 vs. 9.7 months; P=0.003) ((N Engl J Med 2014;371[17]:1609-1618, PMID:

‘This regimen is not for everyone, but for the right patient, this is one of the most active regimens with an impressive, almost 25%, survival rate at five years.’ —Smitha Krishnamurthi, MD

25337750). There also was a trend for improved survival. At that time, the investigators reported that patients receiving FOLFOXIRI had a significantly higher incidence of grade 3/4 neurotoxicity, stomatitis, diarrhea and neutropenia. In the updated results presented at the Gastrointestinal Cancers Symposium, see TRIBE, E page 16

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

VITAMIN D

Table. Relationship Between Vitamin D Levels And Survival

continued from page 1

To shed more light on the issue, investigators analyzed pretreatment vitamin D levels and outcomes of patients with mCRC in the CALGB (Cancer and Leukemia Group B)/SWOG (Southwest Oncology Group) 80405 trial in a “preplanned, prospective, observational cohort study,” said Dr. Ng. CALGB/ SWOG 80405 compared three different first-line regimens for newly diagnosed, advanced CRC. All three regimens started with chemotherapy and added bevacizumab (Avastin, Genentech), cetuximab (Erbitux, Bristol-Myers Squibb) or both. The median vitamin D level in the 1,043 patients who had vitamin D information available was 17.2 ng/mL. The recommended healthy range is greater than 20 ng/mL. The investigators organized patient data from lowest to highest levels of vitamin D, and then divided patients into five groups. They discovered that both PFS and OS were significantly improved in patients with higher vitamin D levels (Table). The association persisted across all patient subgroups and after adjusting for multiple prognostic factors. “Patients who had levels in the highest quintile had a median survival of 32.6 months compared with 24.5 months for patients with levels in the lowest quintile,” said Dr. Ng. Older age, black race, lower dietary and supplemental vitamin D intake, higher body mass index, worse general physical condition and lower physical activity were associated with lower vitamin D levels. Patients whose blood specimens were drawn in the winter and spring months also had significantly lower vitamin D levels, as did patients

TRIBE continued from page 15

with a median follow-up of 48.1 months, the FOLFOXIRI arm continued to show a superior PFS (median 12.3 vs. 9.7 months; hazard ratio [HR], 0.77; P=0.006), as well as a statistically significant superior OS (median 29.8 vs. 25.8 months; HR, 0.80; P=0.030). “Looking at the survival curve, the benefit of FOLFOXIRI plus

Quintile (Q)

Vitamin D Level, Range, ng/mL

Vitamin D Level, Median, ng/mL

OS, mo (log rank P=0.01)

PFS, mo (log rank P=0.02)

Q1 (n=208)

2.2-10.8

8.0

24.5

10.1

Q2 (n=209)

10.9-15.4

13.6

30.0

10.9

Q3 (n=208)

15.5-19.2

17.2

28.4

11.4

Q4 (n=201)

19.3-24.0

21.4

27.2

12.7

Q5 (n=208)

24.1-72.7

27.5

32.6

12.2

OS, overall survival; PFS, PFS, progression-free progression free surv survival vival

‘Patients who had levels in the highest quintile had a median survival of 32.6 months compared with 24.5 months for patients with levels in the lowest quintile.’

—Kimmie Ng, MD, MPH

who resided in the northern and northeastern sections of the United States and Canada. These factors have previously been linked to lower vitamin D levels. Few patients reported vitamin D supplement use.

Smitha Krishnamurthi, MD, a CRC expert and medical oncologist at University Hospitals Case Medical Center, in Cleveland, who was not involved with the study, said the study results will be of “great interest” to patients with CRC

bevacizumab increases over time,” said Dr. Cremolini. The estimated five-year OS rate was 24.9% in patients receiving FOLFOXIRI plus bevacizumab compared with 12.4% in patients receiving FOLFIRI plus bevacizumab. The benefit was consistent across all subgroups, including by KRAS or BRAF status and performance status. “This study clearly demonstrates that FOLFOXIRI and bevacizumab is a safe and effective treatment for patients

with advanced colorectal cancer who can tolerate a triple chemotherapy regimen,” said Smitha Krishnamurthi, MD, a CRC expert and medical oncologist at University Hospitals Case Medical Center, Cleveland, who was not involved with the study. Pointing out that 90% of the patients in the trial were asymptomatic at the time of enrollment and patients over the age of 75 years were not eligible, Dr. Krishnamurthi said, “This regimen

‘Vitamin D levels may lead to a slowergrowing tumor or could enhance the effects of chemotherapy.’ —Smitha Krishnamurthi, MD who frequently want to know whether there is anything in addition to chemotherapy that can be done to improve their outcomes. “Vitamin D levels may lead to a slower-growing tumor or could enhance the effects of chemotherapy,” Dr. Krishnamurthi said. According to Dr. Ng, “randomized clinical trials are needed to establish causality,” and a randomized, double-blind, Phase II trial of vitamin D in mCRC is underway. The study is randomizing patients with mCRC to receive FOLFOX (leucovorin, 5-FU, oxaliplatin)-bevacizumab with either 8,000 IU of vitamin D3 daily for two weeks followed by 4,000 IU of vitamin D3 daily, or 400 IU of vitamin D3 daily (the standard amount found in a multivitamin). “I plan to discuss our findings with patients and screen for vitamin D deficiency, since we now know that metastatic patients are frequently deficient,” said Dr. Ng. “Again, it’s too early to recommend vitamin D as a treatment, but since there are standard guidelines to replete to greater than 20 ng/mL for bone health, that is what I do with my patients.” —Kate O’Rourke Drs. Ng and Krishnamurthi reported no relevant financial relationships.

is not for everyone, but for the right patient, this is one of the most active regimens with an impressive, almost 25%, survival rate at five years.” —Kate O’Rourke

Dr. Cremolini reported financial relationships with Bayer and Roche. Dr. Krishnamurthi reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Oncotype DX DCIS Score Receives More Validation San Antonio—Results from a study presented at the San Antonio Breast Cancer Symposium have validated the Oncotype DX DCIS Score in a diverse, general population of individuals with ductal carcinoma in situ (DCIS). “The score is the first multigene biomarker assay in DCIS that can provide individualized estimates of the risk of recurrence in women who are treated by breast-conserving surgery [BCS] alone,” said Eileen Rakovitch, MD, an associate professor of radiation oncology at Sunnybrook Health Sciences Centre, in Toronto, Canada. “This score can help clinicians [help] patients make more informed decisions about their own risks of local recurrence and better understand the potential benefits of treatment.” Most patients with DCIS are treated with BCS followed by radiation, but guidelines recommend that surgery alone may be an option for individuals at low risk for recurrence. “The challenge is that clinical factors and pathologic features of DCIS do not help clinicians reliably identify individuals at low risk for recurrence,” said Dr. Rakovitch. “Some women who are at low risk are overtreated, whereas others at higher risk may not be receiving helpful treatment.” The DCIS score is a panel of 12 genes derived from the Oncotype DX Recurrence Score (Genomic Health). The DCIS score provides individualized estimates of the 10-year risk for local recurrence following treatment by BCS alone. The score is expressed as a variable from 0 to 100 and one of three risk groups: low risk (score below 39), intermediate risk (score 39-54) and high risk (score greater than 55). Previously, this score was validated as a

Table. 10-Year Recurrence Risk by DCIS Score Risk Group High Risk

Intermediate Risk

Low Risk

Invasive local recurrence, %

15.5

20.9

8.0

DCIS local recurrence, %

13.7

14.1

5.4

DCIS, C S, ducta ductal ca carcinoma c o a in ssitu tu

‘This score can help clinicians [help] patients make more informed decisions about their own risks of local recurrence and better understand the potential benefits of treatment.’ —Eileen Rakovitch, MD predictor of local recurrence in the Eastern Cooperative Oncology Group E5194 study ((J Natl Cancer Instt 2013;105[10]:701710, PMID: 23641039). The validation, however, was conducted in a highly selected population of women with DCIS. Women in the trial were required to have

Dr. Rakovitch’s institution has received funding from Genomic Health. Dr. Osborne reported no relevant financial relationships.

‘There was certainly the hope that this would be a somewhat more active agent, but there was enough activity that there is interest in pursuing additional research related to this pathway in breast cancer.’

PICTILISIB continued from page 11

inhibitor experienced significantly more adverse events (AEs) of any grade than individuals receiving only fulvestrant. These included diarrhea (63% vs. 9%), nausea (48% vs. 19%), rash (43% vs. 17%), dysgeusia (35% vs. 0%), fatigue (27% vs. 20%), vomiting (20% vs. 4%) and stomatitis (16% vs. 2%). Several grade 3/4 AEs also were more common in patients taking pictilisib (Table). “There was certainly the hope that this would be a somewhat more active agent, but there was enough activity that there is interest in pursuing additional research related to this pathway in breast cancer,” said co-investigator Eric Winer, MD, the director of the Breast Oncology Center at Dana-Farber

either 1) low/intermediate-grade DCIS, with a tumor size no greater than 2.5 cm, or 2) high-grade DCIS, with a tumor size no greater than 1 cm. Protocol specifications included a minimum negative margin width of at least 3 mm or no tumor on re-excision.

To test the DCIS score in a broader spectrum of DCIS patients, Dr. Rakovitch and her colleagues conducted a population-based cohort study of cases diagnosed with pure DCIS in Ontario from 1994 to 2003 (abstract S5-04). Patients were included if they received BCS alone and had negative resection margins. The 10-year recurrence risk was 12.7% in patients identified as low risk by the score, 27.8% in patients identified as intermediate risk and 33% in patients identified as high risk. The score was useful in predicting both DCIS recurrence and invasive breast cancer recurrence (Table). “Our results show that the score is predictive in a general population of patients with DCIS,” said Dr. Rakovitch. At a press conference, Kent Osborne, MD, the director of the Lester and Sue Smith Breast Cancer Center at Baylor College of Medicine, in Houston, inquired about tamoxifen use in the study cohort. Dr. Rakovitch said that tamoxifen usage in the time period of the study was very uncommon. Dr. Osborne noted that “in an era when tamoxifen is used as a prevention in patients with estrogen receptor–positive DCIS, recurrence rates would be even lower, and, therefore, [the score] provides a greater measure of safety in patients who don’t receive radiation therapy.” In other words, in the era where tamoxifen is used, patients with a low score could have an even lower risk for recurrence. According to Dr. Rakovitch, the DCIS score is the only multigene biomarker assay that has been validated in DCIS to date. —Kate O’Rourke

—Eric Winer, MD

Cancer Center. Dr. Winer pointed out that the PI3K kinase is complex, and its α-subunit is thought to be responsible for most of the important signaling in breast cancer. Agents that more specifically target the α-subunit may be more potent. Buparlisib (Novartis), a PI3K

inhibitor in Phase III trials, looks to be such an agent, he said. Dr. Arteaga said the results presented at SABCS do not support the notion that pictilisib inhibits the PI3K pathway very well. “There were very minimal ontarget surrogate side effects, which suggests to me that the drug was not strongly inhibiting the PI3K pathway,” Dr. Arteaga explained. He would expect a strong inhibitor of this pathway to produce more

hyperglycemia and rash. He also said that he believes that other PI3K inhibitors may work better as anticancer agents. —Kate O’Rourke Dr. Krop reported a financial relationship with Genentech. Dr. Winer reported financial relationships with AstraZeneca, Genentech, GlaxoSmithKline and Pfizer. Dr. Arteaga reported financial relationships with Genentech and Novartis.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Report From ASH:

In DLBCL Responders, No Plus to Radiation After R-CHOP San Antonio—In patients with nonbulky limited-stage diffuse large B-cell lymphoma (DLBCL) who achieve a complete response (CR) after R-CHOP, radiation does not yield any additional significant advantages. according to a randomized Phase III trial. Based on the similarity of outcome in patients with a negative positron emission tomography (PET) scan after four cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone), “radiation should be reserved for the minority of patients who do not reach CR after R-CHOP,” reported Thierry Lamy, MD, PhD, a professor of hematology at the University of Rennes, in France. Presenting the data from the 02-03 trial at the 2014 American Society of

Hematology (ASH; abstract 393) annual meeting, Dr. Lamy provided indirect support for PET monitoring of treatment response in DLBCL, an approach supported by two other studies presented during the same session. The value of a consolidation course of radiation therapy (RT) has been evaluated before. Dr. Lamy cited four studies conducted before the introduction of rituximab (Rituxan, Genentech); however, the results were conflicting. Since R-CHOP became a standard, no definitive study has been conducted in patients with nonbulky DLBCL (tumor size less than 7 cm). The 02-03 trial included patients up to 75 years of age with CD20-positive DLBCL. The median age was 56 years, with 35% of the patients older than age

Tool Can Identify DLBCL Patients At Risk for CNS Involvement SAN FRANCISCO—A tool validated for uncovering patients with diffuse large B-cell lymphoma (DLBCL) who are at high risk for central nervous system (CNS) involvement may have immediate clinical application. CNS relapse remains a major challenge in DLBCL despite the effectiveness of rituximab (Rituxan, Genentech)-based regimens. Early detection may allow more aggressive therapies to modify the adverse effect this has on outcome. “CNS relapse is typically a lethal event with median survival of only three to six months. Strategies are needed to select patients for CNS-directed diagnostic workup,” explained Kerry J. Savage, MD, a researcher in the Department of Medical Oncology at the British Columbia Cancer Agency (BCCA), in Vancouver. Dr. Savage presented data validating a prognostic tool that appears sensitive for this purpose at the 2014 ASH annual meeting (abstract 394). The prognostic model initially was developed by the German High-Grade Non-Hodgkin Lymphoma Study Group and reflects all five International Prognostic Index factors (age >60 years, elevated lactate dehydrogenase, stage ≥3 disease, >1 extranodal sites, and Eastern Cooperative Oncology Group performance status ≥2), as well as evidence of kidney and/or adrenal gland involvement. Already found viable for CNS risk stratification in Germany, the model was further validated by the data presented by Dr. Savage in 1,597 DLBCL patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) at participating centers in the BCCA network. Comparing the risk stratifications and incidence of CNS involvement in the BCCA data set with the previous studies conducted in German patients, Dr. Savage and her colleagues found the results to be “strikingly similar,” she said. In patients identified as high risk with this model, the CNS relapse risk was 12% after a median follow-up of 4.2 years. In the low-risk group, CNS involvement was found in 6.6%. The median time to CNS relapse was 6.7 months, suggesting this event occurs early and reinforcing the value of employing a screening tool at the time of diagnosis. The protocol has immediate potential clinical application, according to Dr. Savage. A relatively simple method of identifying patients at high risk for CNS involvement or relapse, this could be employed to justify diagnostic procedures for early detection of CNS involvement to target front-line therapies. The consistency of the results of screening with this methodology in Germany and British Columbia reinforces its clinical utility. “This analysis validates the German prognostic model,” said Jane N. Winter, MD, a professor of medicine at Northwestern University’s Feinberg School of Medicine, in Chicago. Based on the data, she agreed that this tool “will help to easily identify patients at greatest risk for CNS relapse,” but she also suggested, reiterating a point made by Dr. Savage, that the model may be best employed at the time of diagnosis. She said that “the very short average interval to CNS relapse of 6.7 months demonstrated in the BCCA patient population suggests that imaging and CSF examination at diagnosis may identify disease before it becomes clinically evident.” —Ted Bosworth Dr. Savage reported a financial relationship with Roche. Dr. Winter reported financial relationships with Janssen and Sanofi Oncology.

60 years. Most patients had a modified (according to Miller criteria) International Prognostic Index (IPI) score of 0 (56%) or 1 (37%). Additionally, most (82%) had normal lactate dehydrogenase levels, and only 4% had B symptoms at baseline. All the patients received four or six consecutive cycles of R-CHOP 14 (six cycles of R-CHOP every 14 days plus two cycles of rituximab). Those randomized to radiation therapy (RT) received 2 Gy per day five days per week for four weeks after completing R-CHOP. In patients who did not achieve CR after R-CHOP based on PET scan, two additional cycles of R-CHOP followed by RT were permitted. This therapy was administered to 34 (79%) of the 43 patients with a partial response at the end of R-CHOP, including 12 patients randomized to the no-RT arm. Seven (4%) of the patients in the RT arm refused radiation. Data were presented on 301 evaluable patients who entered before the end of 2013. An intent-to-treat analysis at five years showed that the rate of event-free survival among patients who achieved a CR on PET was 87% in patients who received R-CHOP alone and 91% (P ( =0.13) in those who received RT after R-CHOP. The five-year overall survival (OS) rates of 90% and 95% (P ( =0.32) for the two arms, respectively, also were not significantly different, Dr. Lamy said. Of the 20 relapses, 12 occurred in patients taking R-CHOP alone and eight occurred in the group receiving RT. Despite the persistent numerical advantage of RT with respect to each of these outcomes, he said that they were “absolutely not significant.”

Using PET To Identify Poor Responders These data showed no advantage for RT in patients who achieved a PETconfirmed CR, but two other studies presented at the 2014 ASH meeting focused on the value of PET to identify poor responders to front-line R-CHOP who may be candidates for intensified therapy. In a Phase II trial conducted in Canada, PET was employed to select patients with an insufficient response on R-CHOP to be switched to R-ICE (rituximab with ifosamide, carboplatin and etoposide). In a German study, the value of PET for guiding treatment was evaluated in patients with a variety of lymphomas, not just DLBCL. In the Canadian study (abstract 392), 155 patients with DLBCL who had not received treatment previously were enrolled before their fourth cycle of R-CHOP. Subsequent therapy was directed per the results of PET scanning that was performed and interpreted at a central site. Those with a negative PET result completed R-CHOP,

and those with a positive PET result were switched to four cycles of R-ICE. If a second PET after R-ICE was positive, RT was offered, if feasible. In this study, 88 (59%) were PET-negative and completed R-CHOP, 50 (33%) were PET-positive (48 were initiated on R-ICE), and 12 (9%) were PET-indeterminate. Nine of the 48 patients switched to R-ICE were unable to complete all four cycles due to toxicity and six of these patients returned to R-CHOP. Consistent with previous reports, PETnegative disease was associated with favorable outcomes. OS at four years in this group was 96%. In PET-positive patients, the four-year OS was 73%, whereas those with an indeterminate PET had a four-year OS of 82%. Overall, PET appears to be a useful prognostic tool, but “simply switching patients to an alternative non–cross-resistant chemotherapy regimen does not appear to be sufficient to overcome the inherent resistance in this poor-risk population,” said Laurie H. Sehn, MD, a medical oncologist with the British Columbia Cancer Agency, in Vancouver. The value of R-ICE as an alternative regimen is uncertain on the basis of this study, she said, because “relatively few PET-positive patients converted to a negative PET scan following the switch.” In the German study (abstract 391), called PETAL (Positron Emission Tomography Guided Therapy of Aggressive NonHodgkin’s Lymphomas), an interim PET was performed three weeks after the second cycle of R-CHOP in 853 patients with lymphoma, of whom about 70% had DLBCL. The interim PET was characterized as favorable in 87% of patients and unfavorable in 13%, and the PET scan remained a highly significant predictor of OS in a multivariate analysis that included other prognostic factors, such as IPI score. Switching patients from R-CHOP to a more aggressive regimen, however, did not appear to improve outcomes. “The data suggest that applying strict rules to the performance and interpretation of an interim PET proves highly predictive of outcome,” said Ulrich Dührsen, MD, PhD, a professor of hematology at the University of Essen, in Germany. Although changing to a more aggressive protocol in this series failed to improve outcome in patients with an unfavorable interim PET, Dr. Dührsen said that this is still a viable approach. —Ted Bosworth Dr. Lamy reported no relevant financial relationships. Dr. Sehn reported a financial relationship with Roche. Dr. Dührsen reported financial relationships with Amgen and Roche.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

How I Manage ...

Relapsed/Refractory Hodgkin Lympho H

Eva Domingo-Domenech, MD

Anna Sureda, MD, PhD

Senior Consultant in Hematology Catalan Institute of Oncology Duran i Reynals Hospital Barcelona, Spain

What is the best second-line therapy for relapsed and refractory HL? The best debulking regimen before auto-HCT remains to be defined; there are no published prospective randomized clinical trials comparing the efficacy and toxicity of the different regimens used. The most commonly used regimens—such as DHAP (dexamethasone, cytarabine, and cisplatin),3 ICE (ifosfamide, carboplatin, and etoposide),4 ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin),5 and IGEV (ifosfamide, gemcitabine, and vinorelbine)6—have been shown to be effective in reducing bulky disease, mobilizing hematopoietic stem and progenitor cells into the peripheral blood, and testing chemosensitivity before high-dose chemotherapy. Using these regimens, the trials have reported overall response rates of around 80% and complete remission (CR) rates ranging from 21% to 54%. The German Hodgkin Study Group

odgkin lymphoma (HL), which is diagnosed in 7,000 to 7,500 new patients annually in the United States, is one of the most curable hematologic malignancies. HL displays a bimodal curve in incidence, and most patients are diagnosed in an early stage of the disease. Patients with early-stage HL have an overall survival (OS) greater than 90% with modern therapies,1 whereas the 10-year OS in advanced-stage HL is only approximately 50%.2 The number of patients with relapsed or resistant HL is low, but such patients represent a clinical challenge. The use of high-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) has shown efficacy and safety, and it is now considered the standard of care for patients with chemosensitive and nonlocalized relapse. In this column, we attempt to answer some important questions oncologists face when taking care of patients with relapsed and refractory HL.

(GHSG) developed a sequential highdose regimen that was used before high-dose chemotherapy itself.7 Treatment consisted of 2 cycles of DHAP to reduce tumor burden. Patients achieving a CR or partial remission (PR) went on to receive a high-dose chemotherapy program including high-dose cyclophosphamide (4 g/m2 IV), methotrexate (8 g/m2 IV), vincristine (1.4 mg/m2 IV), and etoposide (2 g/m2 IV). Patients were then autografted using the BEAM (BCNU, etoposide, cytarabine, and melphalan) regimen. The response rate after the final evaluation was 80%. Freedom from treatment failure (FFTF) and OS were 62% and 78%, respectively, for patients with early relapse, and 63% and 79%, respectively, for patients with late relapse. These promising results prompted the GHSG to develop a prospective, randomized Phase III clinical trial that compared the conventional salvage approach (DHAP × 2 cycles followed by auto-HCT) with DHAP plus highdose sequential protocol followed by

AT A GLANCE • The best debulking regimen before auto-HCT remains to be defined. • Allo-HCT basically has been used in patients failing an auto-HCT procedure. • PET scan–positive study at the end of salvage chemotherapy and before auto-HCT has been considered an adverse prognostic factor. • Long-term outcome of allo-HCT will be significantly improved with a more widespread use of brentuximab as a bridge to transplant.

auto-HCT. Interestingly, there were no significant differences with respect to progression-free survival (PFS), FFTF, or OS between the 2 study arms.8 Potential reasons to explain the lack of effectiveness of this more intensive procedure were the higher toxicity of the intensive arm, the increased time to reach the transplantation procedure, as well as inability of a significantly higher percentage of patients in the intensive arm to receive 100% of the expected chemotherapy dose. In the future, the use of brentuximab vedotin (Adcetris, Seattle Genetics) as part of the second-line therapy in combination with the above-mentioned regimens may improve the response rate and the number of CRs, but this remains investigational.

Should all patients with relapsed and refractory HL undergo auto-HCT? Only patients with chemosensitive disease should undergo an auto-HCT. The study published by the Spanish Group for Lymphomas and stem Cell Transplantation (GELTAMO) with 494 autograft HL patients, identified the presence of active disease at transplantation as an adverse prognostic factor for time to treatment failure (TTF) and survival.9 We should attempt to improve the quality of the remissions of the patients undergoing the procedure with more effective salvage protocols or drugs, ie, add brentuximab without added toxicities to improve outcomes. In a recently published series of 15 consecutive patients who had relapsed/refractory HL and fluorodeoxyglucose-positron emission tomography (FDG-PET)–positive disease after platinum-based salvage therapy, treatment with a median of 4 cycles of brentuximab resulted

in normalization of FDG-PET in 53% of the patients,10 thus improving posttransplant outcome.

When do you recommend allogeneic HCT and why? Compared with the number of autologous transplants, few patients with HL have undergone allogeneic (allo)HCT (Figure 1A-1C). Allo-HCT basically has been used in patients failing auto-HCT. Unfortunately, the information we have in this setting is based on Phase II prospective clinical trials that include reduced numbers of patients with short follow-up. Additionally, transplantation procedure methodology has been heterogeneous among different studies, making comparisons impossible. There are no Phase III randomized prospective clinical trials comparing the role of allo-HCT with other therapies. The Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT) has reported the largest retrospective analysis looking at 285 multiply relapsed HL patients.11 Forty-seven patients (17%) were in CR, 123 (43%) had chemosensitive disease, and 115 (40%) had chemoresistant disease. The nonrelapse mortality (NRM) was 12% at 100 days, 20% at 12 months, and 22% at three years; refractory disease was associated with significantly higher NRM. Two-year PFS was 29%, and it was significantly worse for patients with chemoresistant disease ((P<0.001). Development of either acute or chronic graft-versushost disease (GVHD) was associated with lower relapse rate. Anderlini et al reported a series of 40 patients with relapsed/refractory HL undergoing reduced-intensity conditioning (RIC)/allo-HCT from an HLA-

HEMATOLOGIC DISEASE

Percent

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Figure 1A. Evolution of allo-HCT for relapsed/refractory HL over time.

Figure 1B. Myeloablative vs reduced-intensity conditioning regimens in allo-HCT recipients. allo-HCT, allogeneic hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning

Source: Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (personal communication).

identical sibling (n=20) or a matched unrelated donor (n=20).12 Two-year OS and PFS were 64% and 32%, respectively; the 2-year projected risk for disease progression was 55%. There was a trend for the response before allo-HCT to favorably affect PFS ((P=0.07) and disease progression ((P=0.049) but not OS. Partial responders and patients with stable refractory disease did similarly with regard to OS and PFS. Response rate 3 months after alloHCT was 67% in the Spanish experience.13 Forty HL patients with multiply relapsed disease and adverse prognostic factors were treated with IV fludarabine (150 mg/m²) and melphalan (140 mg/m²), with cyclosporine A and methotrexate as GVHD prophylaxis. The 2-year OS and PFS were 48% and 32%, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS and PFS. In vivo T-cell depletion with alemtuzumab (Lemtrada, Genzyme) was the basis of the RIC protocol used by the UK Cooperative Group.14 NRM was 16% at 2 years, and projected 4-year OS and PFS were 56% and 39%, respectively. Finally, the largest Phase II trial including 78 patients with multiply relapsed HL and with adverse prognostic factors has been a joint effort of GELTAMO and the LWP of the EBMT.15 Median follow-up of the whole series was 4 years. NRM was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. Patients who were allografted in CR had a significantly better outcome. PFS was 48% at 1 year and 24% at 4 years; OS was 71% at 1 year and 43% at 4 years. Chronic GVHD was associated with a lower relapse incidence and a better PFS. A more recent investigation of a response-adjusted transplantation algorithm identifies a further potential

strategy for evaluation of allo-HCT in those deemed to be at high risk for failure of auto-HCT. This approach targets intensification to those who have residual FDG-avid disease following salvage therapy.16 Patients were considered for allo-HCT if they failed to obtain CR to salvage therapy, had at least stable disease following most recent salvage therapy, and had an appropriate donor. The 3-year PFS of 68% in this high-risk group was encouraging, with 80% current PFS following donor lymphocyte infusions. Such approaches may require refinement according to the number of lines of salvage and the outcome of prospective studies evaluating maintenance strategies following auto-HCT, and it is recommended that they be evaluated within the context of prospective national studies.

Which conditioning regimen do you prefer before autoand allo-HCT? A wide variety of high-dose chemotherapy regimens have been used with auto-HCT. No prospective clinical trials have been performed, although regimens have been compared retrospectively. High-dose regimens frequently are divided into those that use total body irradiation (TBI) and those that contain only drugs. The use of TBI might be associated with increased pulmonary toxicity, particularly in patients who have received prior mediastinal irradiation. Spanish registry results showed that the use of TBI-containing regimens before auto-HCT was associated with a significantly higher risk for transplant-related mortality,17 largely related to a higher incidence of secondary malignancies after the autologous procedure.

Percent

allo-HCT, allogeneic hematopoietic cell transplantation

Figure 1C. Evolution of cord blood transplants and haploidentical transplants in relapsed/refractory HL over time. CBT, cord blood transplant; Haplo-HCT, haploidentical hematopoietic cell transplant Source: Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (personal communication).

One of the most common high-dose chemotherapy regimens used before auto-HCT is CBV (cyclophosphamide, carmustine, and etoposide), which was developed at the University of Texas MD Anderson Cancer Center, in Houston. The original CBV regimen has been modified and individual institutions have used widely differing schedules. No prospective trials have examined whether variations in the CBV regimen lead to different outcomes, although higher doses of carmustine have been associated with an increased risk for pulmonary toxicity, particularly in patients who have received prior chest irradiation. Another high-dose

chemotherapy regimen is BEAM, which was developed by investigators from London and also has been widely modified. Retrospective analyses have failed to show significant differences in survival when CBV- and BEAM-type regimens were compared.18,19 In the allogeneic scenario, RIC regimens have allowed allo-HCT to be performed more safely, but relapse remains the most common cause of treatment failure. This was supported by the EBMT analysis that showed a 32% relapse rate following myeloablative conditioning compared with 58% with RIC regimens.20 Other studies also have see HOW I MANAGE, E page 22

HEMATOLOGIC DISEASE

HOW I MANAGE continued from page 21

shown a better outcome using more intensive regimens, such as the combination of fludarabine and melphalan12 and the BEAM-alemtuzumab regimen.21 Recently, the LWP of the EBMT retrospectively analyzed long-term outcome of patients with HL undergoing a myeloablative allo-HCT (n=99) versus those receiving a RIC/allo-HCT (n=215) in recent years (S. Stavrik, personal communication; December 2014). With a median follow-up of 34 months, NRM was not significantly different between both groups (11% at 36 months), and the relapse rate was significantly higher in the RIC group (55% vs 40% at 36 months; P=0.05), with a better PFS in the myeloablative group (50% vs 33% at 36 months; P=0.02). No differences in OS were observed.

What are the prognostic implications of PET scanning just prior to auto- and allo-HCT? The role of PET scanning in patients with HL is clearly established at diagnosis and at the end of treatment, but its role after an intensive procedure is not as clear. More recently, a positive PET scan study at the end of salvage chemotherapy and before the auto-HCT also has been considered an adverse prognostic factor. Two studies have added additional information to the prognostic value of FDG-PET. Jabbour published a retrospective study in 211 relapsed/refractory HL patients, in which a pretransplant positive PET/gallium scan was able to predict poor outcome after auto-HCT.22 In 2010, Moskowitz et al reported their experience in a group of 153 HL patients who were prospectively included in transplantation protocols. Functional imaging status before auto-HCT was the only factor that was significant for event-free survival (EFS) and OS by multivariate analysis and it clearly identified poor-risk patients (5-year EFS, 31% and 75% for functional imaging–positive and negative patients, respectively).23 Moskowitz et al recently published a Phase II study using PET scanning after salvage therapy and before autoHCT to stratify treatment.24 Ninetyseven patients with relapsed/refractory HL received 2 cycles of ICE. Patients with a negative scan received a transplant. If the FDG-PET result remained positive, patients received 4 biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin. Patients without evidence of disease progression proceeded to auto-HCT. At a median follow-up of 51 months, EFS analyzed by intent-to-treat and by transplantation was 70% and 79%, respectively.

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Table. Ongoing Clinical Trials ClinicalTrials.gov Identifier

Study Name

Official Name

Sponsor

Status

Phase I/II Feasibility Study Combining Brentuximab Vedotin With Second Line Salvage Chemotherapy (DHAP) in Hodgkin Lymphoma Patients

Phase I/II Feasibility Study Combining Brentuximab Vedotin With Second Line Salvage Chemotherapy (DHAP) in Hodgkin Lymphoma Patients Refractory to First Line Chemotherapy or in First Relapse Who Are Eligible for High Dose Treatment Followed by Autologous Peripheral Blood Stem Cell Transplantation (ASCT)

NCT02280993

Marjolein Spiering (Academisch Medisch Centrum-Universiteit van Amsterdam); Millennium

Recruiting

Brentuximab Vedotin, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma (BV-ICE)

A Phase I/II Trial of Brentuximab Vedotin (BV), Ifosfamide (I), Carboplatin (C), and Etoposide (E) for Patients With Relapsed or Refractory Hodgkin Lymphoma (BV-ICE)

NCT02227199

University of Washington

Currently recruiting

Brentuximab Vedotin in High-Risk CD30+ Lymphoma Post Allogeneic Stem Cell Transplantation (AlloSCT)

Safety and Efficacy of Brentuximab Vedotin Maintenance After Allogeneic Stem Cell Transplantation in High Risk CD30+ Lymphoma (Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma ([ALCL])

NCT02169505

University of Texas MD Anderson Cancer Center

Opens for recruitment March 2015

Patients transplanted with negative FDG-PET before auto-HCT after 1 or 2 programs had an EFS greater than 80%, versus 28.6% for patients with a positive scan ((P<0.001). The implications of a positive PET scan result before allo-HCT are not established. In a prospective study of 80 patients undergoing RIC/allo-HCT, pretransplantation PET scan status had no significant effect on either relapse rate or OS.25

performance status due to the administration of a less toxic salvage therapy and optimized disease control. A better understanding of the impact of conditioning regimens in this setting also will favor a decrease in relapse rate after the procedure. Finally, the widespread use of haploidentical donors as well as the improvement in supportive care after this “new transplant modality” will increase the number of potential candidates for the allogeneic strategy.

Future Prospects

References

Auto-HCT most probably will remain the standard of care for patients in first chemosensitive relapse. Nevertheless, the potential widespread use of PET scan to evaluate disease status after salvage therapy and before auto-HCT will allow us to better define the most appropriate population of patients to undergo transplantation. If the goal is to achieve a PET-negative CR, the combination of new drugs (eg, brentuximab) with salvage protocols eventually will achieve it, thus allowing subsequent improvement in the long-term outcome of patients undergoing auto-HCT (Table). Finally, the impact of maintenance therapy after transplantation of patients with high-risk HL consolidated with an auto-HCT will be elucidated with the final results of the AETHERA trial. Even in the era of the new drugs, alloHCT still should be considered to consolidate response of patients relapsing after auto-HCT. Long-term outcome of allo-HCT will be improved significantly with more widespread use of brentuximab as a bridge to transplant; patients will be allografted with a better

1. Armitage JO. Early stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):653-662, PMID: 20818856. 2. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy in advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327(21):1478-1484, PMID: 1383821. 3. Josting A, Rudolph C, Reiser M, et al. Timeintensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13(10):1628-1635, PMID: 12377653. 4. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97(3):616-623, PMID: 11157476. 5. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol. 1999;10:593595, PMID: 10416011. 6. Santoro A, Magagnoli M, Spina M. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92(1):35-41, PMID: 17229633. 7.

Josting A, Rudolph C, Mapara M, et al. Cologne high-dose sequential

chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann Oncol. 2005;16(1):116-123, PMID: 15598948. 8. Josting A, Mueller H, Borchmann P, et al. Dose intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol. 2010;28(34):5074-5080, PMID: 20975066. 9. Sureda A, Constans M, Iriondo A, et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16(4):625-633, PMID: 15737986. 10. Onishi M, Graf SA, Holmberg L. Brentuximab vedotin administered to platinumrefractory, transplant-naïve Hodgkin lymphoma patients can increase the proportion achieving FDG PET negative status. Hematol Oncol. 2014 Sep 18. [Epub ahead of print], PMID: 25236531. 11. Robinson SP, Sureda A, Canals C, et al. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome. Haematologica. 2009;94(2):230-238, PMID: 19066328. 12. Anderlini P, Saliba R, Acholonu S, et al. Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin’s disease: low transplant-related mortality and impact of intensity of conditioning regimen. Bone Marrow Transplant. 2005;35(10):943-951, PMID: 15806128. 13. Alvarez I, Sureda A, Caballero MD, et al. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006;12(2):172-183, PMID: 16443515. 14. Peggs KS, Hunter A, Chopra R, et al. Clinical evidence of a graft-versus-Hodgkin’s lymphoma effect under reduced-intensity allogeneic transplantation. Lancet. 2005; 365(9475):1934-1941, PMID: 15936420. see HOW I MANAGE, E page 27

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Report From ASH:

Rituximab Maintenance Offers Durable Control in MCL San Francisco—In patients with mantle cell lymphoma (MCL) who achieve a good response after R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin) and autologous hematopoietic stem cell transplant (auto-HCT), rituximab maintenance substantially improves duration of disease control, according to a planned interim analysis from the LyMa Phase III trial. At three years, event-free survival (EFS) climbed from 73.4% in the wait-and-watch arm (WW), to 88.1% in the arm randomized to an injection of rituximab every 2 months. No P value was provided for this interim analysis, but it was reported to be statistically significant.

did not reach at least a partial response (12 patients) were permitted to receive four courses of R-CHOP. Ultimately, 257 patients underwent auto-HCT with a conditioning regimen consisting of rituximab plus BEAM (carmustine, etoposide, cytarabine, melphalan). Of these, 239 (92%) achieved a complete response and were randomized to receive an injection of 375 mg/m2 of rituximab every two

months or to enter the WW control arm. In addition to the advantage for EFS, the primary end point of the study, rituximab maintenance provided an almost identical advantage for progression-free survival (PFS). The estimated PFS rates at four years for rituximab and WW were 80.4% and 61.8% ( =0.0032), respectively. The similar (P EFS rates at three years and four years

(estimated) of follow-up demonstrate the low risk for complications associated with rituximab, such as infections, that are captured with EFS and not PFS. At three years, 85.5% of those in the WW and 93.1% of those in the rituximab maintenance group were still alive. This rate compares favorably see RITUXIMAB, B page 24

makes all the difference

‘Given the tolerability of rituximab maintenance, there is a high likelihood that this strategy will be widely adopted by U.S. physicians.’ —Brad Kahl, MD

In the LyMa protocol, randomization to rituximab maintenance was restricted to patients who achieved at least a partial response to auto-HCT after R-DHAP induction. Most patients did, according to investigator Steven Le Gouill, MD, PhD, the chief of the Lymphoma Research Program at University Hospital, in Nantes, France. Providing the interim results of LyMa at the 2014 annual meeting of the American Society of Hematology (abstract 146), Dr. Le Gouill indicated that the new data build on previous evidence from the same group supporting four-cycle R-DHAP as an effective induction regimen. In the LyMa study, investigators from the Lymphoma Study Association enrolled 299 patients with MCL who were no older than age 65 years (median age, 57 years) and who had not been treated previously into a protocol that began with four cycles of R-DHAP. Those who

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HEMATOLOGIC DISEASE

AML continued from page 1

“This is the first evidence from a randomized trial that a TKI can improve outcome in AML,” reported the trial coordinator Christoph Röllig, MD, a senior physician at University Hospital, in Dresden, Germany. Presenting the results of this trial, called SORAML, at the 2014 annual meeting of the American Society of Hematology (abstract 6), Dr. Röllig said he considered the results encouraging but cautioned that further confirmatory studies or evidence of an overall survival (OS) benefit are needed to declare this regimen to be a new standard. In the study, 276 AML patients under the age of 60 years were randomized at 25 centers to receive 800 mg of sorafenib daily or placebo. All patients received a standard chemotherapy regimen, which consisted of two cycles of daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not respond received a second induction with high-dose cytarabine plus mitoxantrone. Sorafenib was given with the induction regimen (days 10-19 of each cycle), as well as with the consolidation regimen (day 8 until three days before start of next cycle), and as maintenance for 12 months after consolidation. Allogeneic hematopoietic cell transplantation (HCT) was scheduled in intermediate- and high-risk patients with a matched donor after a first complete remission. EFS was the primary end point of the trial. After a median follow-up of 36 months, EFS persisted in 40% of the sorafenib group and 22% of the placebo group. The median EFS was 21 and nine months for the sorafenib and placebo arms, respectively ((P=0.013). Median relapse-free survival (RFS), a secondary end point, was not yet reached in the sorafenib arm and 23 months in the placebo arm

RITUXIMAB continued from page 23

with that seen in previously reported studies in similar populations. Dr. Le Gouill emphasized that a greater than 90% survival in the experimental arm was achieved although patients received neither anthracyclines nor total body irradiation. The final analysis of the primary end point of the study, which is EFS at four years, will not be available until 2016, but Dr. Le Gouill suggested that the data already support this protocol for extended disease control. “The LyMa trial results, to date, demonstrate that rituximab should be used in maintenance therapy after [auto-HCT] and

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

‘This is the first evidence from a randomized trial that a TKI can improve outcome in AML.’ —Christoph Röllig, MD ((P=0.017). A numerical OS S advantage (63% vs. 56% alive at a three years) had not reached staatistical significance at the time of o follow-up (P ( =0.382), althou ugh the curves appear to be separating. When AEs were compared, hand–foot syndrome, fever, rash, liver enzyme elevations an nd bleeding all were signifficantly more common with sorafenib th han with placebo. The most common n grade 3 or higher AEs were fever (40% %), infections (22%) and bleeding (2%). Sorafenib, which inhibits several kinases that are potentially important to the proliferation of AML, is approved for the treatment of advanced renal cell carcinoma, primary liver cancer and thyroid cancer. It was tested previously in older AML patients, but no advantage for EFS in this group was observed ((J Clin Oncol 2013;31[25]:3110-3118, PMID: 23897964). In the prior study and the current study, response was stratified for patients who were positive for FLT3 mutations, which was not a strong predictor of response in either study. In all age groups, AML remains a challenging disease with poor longterm control in those who do not achieve a sustained complete remission after HCT. The identification of a new drug class active in AML is a potential advance, but it remains unclear whether sorafenib or other TKIs that block pathways of tumor cell proliferation can increase rates of cure independent

The need for confirmatory trials is critical. However, these data associate sorafenib with a ‘lasting antileukemic response’ in younger patients with AML. —Courtney D. DiNardo, MD of their ability to slow disease progression. Long-term survival will be followed closely in the SORAML trial. To judge what these data mean for routine practice, Courtney D. DiNardo, MD, an assistant professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston, characterized the need for confirmatory trials as critical. However, she agreed that these data associate sorafenib with a “lasting antileukemic response” in younger patients with AML. They may also change practice if longer SORAML follow-up demonstrates an OS benefit.

Table. Interim EFS and PFS Results From LyMa Trial Outcome Measure

Rituximab Maintenance Arm

Watch and Wait Arm

EFS at 3 y, %

88.1

73.4

Statistically significanta

PFS at 4 y, %

80.4

61.8

P=0.0032

P Value

EFS, event-free survival; PFS, progression-free survival a

The e P va value ue was not ott reported, epo ted, but itt was reported epo ted to be stat statistically st ca y ssignificant. g ca t

provides the rationale for a new standard of care” for older patients with MCL, he said. Asked to comment on the relevance of these data to clinical practice, Brad

Kahl, MD, the Skoronski Chair of Lymphoma Research at the University of Wisconsin School of Medicine and Public Health, in Madison, cautioned that the trial has not yet demonstrated an

However, she is equally intrigued with the underlying mechanism of action and what it may reveal about how to better target AML. “One of the more interesting results to come out of this trial was that no particularly favorable or unique response was seen in the cohort of FLT3-mutated patients,” Dr. DiNardo said. “It suggests that this multikinase inhibitor may be exerting antileukemic effects outside of direct FLT3 inhibition.” —Ted Bosworth Drs. Röllig and. DiNardo reported no relevant financial relationships.

overall survival benefit, but he suggested that the EFS improvement is clinically meaningful. “Given the tolerability of rituximab maintenance, there is a high likelihood that this strategy will be widely adopted by U.S. physicians,” Dr. Kahl said. He characterized LyMa as “the first randomized trial to show clinical benefit for rituximab maintenance in younger mantle cell lymphoma patients who have been treated with an intensive treatment plan.” —Ted Bosworth Dr. Le Gouill reported financial relationships with Celgene, Janssen-Cilag, Mundipharma, Pfizer and Roche. Dr. Kahl reported a financial relationship with Infinity.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Report From ASH:

MRD Negativity Predicts Efficacy in B-Cell Malignancies San Francisco—A negative minimal residual disease (MRD) status in the peripheral blood is not just a prognostic marker, but it might be an excellent tool for judging treatment efficacy for some B-cell malignancies, according to studies evaluating this marker in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

Table. Median PFS in MRD-Negative vs. MRD-Positive Patients PFS, Patients With CR and MRD Negativity, mo

PFS, Patients With CR and MRD Positivity, mo

PFS, Patients with PR and MRD Negativity, mo

69.2

40.4

61.7

C , co CR, complete p ete response; espo se; PR,, partial pa t a response; espo se; MRD,, minimal a residual es dua disease d sease

MRD Negativity Predicts Survival Pooled data from two Phase III trials of patients with CLL showed that an MRD-negative result in the peripheral blood predicted durable progressionfree survival (PFS) better than objective response. “Patients who were MRD-negative but had a partial response [PR] and a single splenomegaly had a statistically significant longer PFS than patients who had a complete response [CR] but remained positive for MRD,” reported investigator Barbara Eichhorst, MD, a research oncologist in the Center of Integrated Oncology at the University of Cologne, in Germany, who presented the CLL trial results at the 2014 annual meeting of the American Society of Hematology (ASH; abstract 23). The prognostic significance of MRD status has long been recognized, but MRD has not been widely employed to measure response to therapy and guide treatment modifications. In the most recent National Cancer Institute guidelines for CLL, published more than six years ago ((Blood 2008;111:5446-5456, PMID: 18216293), negative MRD status was not specifically recommended as an outcome measure in routine care. The new, pooled data suggest that this should be revisited, according to Dr. Eichhorst. She and her colleagues in the German CLL Study Group evaluated the prognostic importance of MRD status in 542 CLL patients in two Phase III trials. The median age of the patients was 61 years. Treatment regimens included fludarabine and cyclophosphamide (FC) with or without rituximab, as well as bendamustine and rituximab. At the time of treatment, fewer than 15% of the patients had Binet stage A disease, about half had stage B disease, and the remainder had stage C disease. On fluorescence in situ hybridization analysis, the most common mutations were del(13q), which was found in 38% of patients and del(11q), found in 25% of patients. Del(17p), which was an exclusion criterion in one of the studies, was found in 1.3% of the patients.

‘Our data demonstrate that achievement and preservation of MRD negativity is the strongest independent predictor of prognosis in MCL patients.’ —Christiane Pott, MD, PhD

‘These data are clear that the MRD result is the single parameter with the strongest correlation with PFS. [Although] other measurable parameters can, in some cases, still be informative, treatment strategies aiming at cure of CLL will most certainly need to work toward achieving MRD-negative CR.’

Department at the University Hospital Schleswig-Holstein, in Kiel, Germany. The prognostic importance of MRD was consistent in those older and younger than age 65 years. Additionally, the degree of MRD positivity did not appear to be important. Even low-level MRD tracked with a reduced PFS. “Our data demonstrate that achievement and preservation of MRD negativity is the strongest independent predictor of prognosis in MCL patients,” Dr. Pott concluded. She told Clinical Oncology News that she believes that MRD status has implications for patient management. “Applying MRD status as a tool for tailored treatment, therapeutic approaches should focus on a maximum MRD response to improve longterm outcome,” Dr. Pott said.

Critical Prognostic Tool

—William Wierda, MD, PhD MRD negativity was found in 81.8% of the 214 patients with a CR and 47.9% of the 328 with a PR, but MRD status was a more consistent predictor of PFS than CR or PR. Median PFS was significantly longer in MRD-negative versus MRD-positive patients in the CR population (69.2 vs. 40.4 months; P<0.0001), but patients who achieved PR and were MRD-negative had a significantly longer PFS than those who were MRD-positive and achieved CR (61.7 vs. 40.4 months; P=0.008). Dr. Eichhorst said that the difference in median PFS between the MRD-negative PR group and the MRD-positive CR group remained significant whether the splenomegaly cutoff values were 12 or 14 cm. These data suggest that “persistence of splenomegaly as the sole abnormality post treatment in MRDnegative patients has no negative influence on PFS,” she said. Calling MRD-negative status a “potent predictor of treatment efficacy regardless of the clinical response assessment,” Dr. Eichhorst concluded that this analysis “supports the use of MRD for response evaluation.”

Implications for Patient Management Similar conclusions about the relevance of MRD status were drawn from an analysis of 406 patients with MCL conducted by the European MCL Network and presented at the ASH meeting (abstract 147). The investigators prospectively monitored the association between MRD status and outcome in patients in remission six months after autologous hematopoietic cell transplantation (auto-HCT). About 40% of these patients were older than age 65 years. The proportions of patients at low, intermediate and high risk on the basis of the modified international prognostic index (MIPI) were 44%, 34% and 22%, respectively. When MRD status was evaluated at intervals over the course of follow-up, MRD-positive status in the peripheral blood was “highly associated with a shorter PFS, and this association was independent of baseline MIPI score, treatment arm or protocol,” reported investigator Christiane Pott, MD, PhD, an oncologist in the Second Medical

Others share the opinion that MRD status is a critical prognostic tool in at least some B-cell hematologic cancers. Contacted for his opinion about MRD, William Wierda, MD, PhD, the medical director of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center, in Houston, agreed that MRD is emerging as the best measure of therapeutic response. “Traditionally, we have used a composite response evaluation, which considers measurable disease in blood, nodes and marrow, but it is relative blunt. These data are clear that the MRD result is the single parameter with the strongest correlation with PFS,” reported Dr. Wierda. Although “other measurable parameters can, in some cases, still be informative, treatment strategies aiming at cure of CLL will most certainly need to work toward achieving MRDnegative CR.” —Ted Bosworth Dr. Eichhorn reported financial relationships with Gilead, GlaxoSmithKline, Janssen, Mundipharma and Roche. Drs. Pott and Wierda reported no relevant financial relationships.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums

profiling of CD34-positive selected peripheral blood cells was able to divide persons with PV into 2 distinct clinical phenotypes.

relapsed or refractory HL who previously were heavily treated.

serves as a checkpoint to limit T-cell– mediated immune responses.

Highlights from NEJM, Blood, JCO, and updates from the FDA

3. True or False? The recently pub-

lished Lugano classification recommends staging positron emission tomographycomputed tomography (PET-CT) scan for lymphoplasmacytic lymphoma (LPL).

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

Prepared by

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

QUESTIONS

1. True or False? The FDA approved

ruxolitinib (Jakafi, Novartis) as firstline therapy for patients with polycythemia vera (PV).

2. True or False? In a study published in NEJM, gene expression

ANSWERS

1. False. Ruxolitinib was approved for

use in patients with PV who have had inadequate response to or cannot tolerate hydroxyurea. RESPONSE was a global, randomized, open-label study conducted at 109 sites. In all, 222 patients with PV who were resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only. The primary end point of the study was the proportion of patients whose hematocrit was controlled without phlebotomy from week 8 through week 32, and whose spleen volume was reduced by at least 35% from baseline, as assessed by imaging at 32 weeks. The results showed that 21% of patients on ruxolitinib had a reduction in the need for a phlebotomy and a reduction in spleen volume, compared with only 1% of patients who received best available therapy. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm425677.htm. Accessed January 23, 2015. Verstovsek S, et al. Results of a prospective, randomized, open-label Phase III study of ruxolitinib in polycythemia vera patients resistant to or intolerant of hydroxyurea: the RESPONSE trial. Presented at: 2014 annual meeting of the American Society of Clinical Oncology (abstract 7026).

True. Investigators analyzed gene expression in CD34-positive peripheral blood cells from 19 patients with PV, using oligonucleotide microarray technology (after correcting for potential confounding by sex, since the phenotypic features of the disease differ between men and women). Nineteen patients with PV were put into 2 groups that did not differ significantly with respect

to age, neutrophil JAK2 V617F allele burden, white blood cell count, platelet count, or clonal dominance. However, they did differ significantly with respect to disease duration; hemoglobin level; frequency of thromboembolic events, palpable splenomegaly, and splenectomy; chemotherapy exposure; leukemic transformation; and survival. These findings might inspire future studies to refine prognostic and therapeutic approaches for persons with PV. Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in polycythemia vera. N Engl J Med. 2014;371(9):808-817, PMID: 25162887.

False. The consensus was that PETCT should be recommended for routine staging of FDG-avid, nodal lymphomas (essentially all histologies except chronic lymphocytic leukemia/small lymphocytic lymphoma, LPL/Waldenström’s macroglobulinemia, mycosis fungoides, and marginal zone NHL, unless there is a suspicion of aggressive transformation) as the gold standard. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068, PMID: 25113753. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):30483058, PMID: 25113771.

4. True. The Ann Arbor classifica-

tion subdivides patients according to the absence (A) or presence (B) of disease-related symptoms. However, these features frequently are neither recorded nor accurate. Moreover, in the International Prognostic Index, Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI 2, Mantle Cell

4. True

or False? According to the Lugano classification, suffixes A (absence of B symptoms) and B (presence of B symptoms) are only required for Hodgkin lymphoma (HL) and not for non-Hodgkin lymphoma (NHL).

6. True or False? The PD-1 pathway 7. True or False? In a study pub-

lished in Blood, BCL2 mutations were not associated with increased risk for transformation and shortened survival in follicular lymphoma (FL).

8. True or False? In a study pub-

lished in Blood, dinaciclib demonstrated single-agent activity in relapsed multiple myeloma (MM).

5. True or False? In a study pub- 9. True or False? The combination of lished in NEJM, nivolumab (Opdivo, Bristol-Myers Squibb) demonstrated substantial therapeutic activity and an acceptable safety profile in patients with

carfilzomib (Kyprolis, Onyx) and thalidomide (Thalomid, Celgene) in previously untreated MM was shown to be unsafe in a Phase II study.

International Prognostic Index, and International Prognostic Score, constitutional symptoms do not confer an unfavorable outcome. Patients with HL need to be assigned the designations A or B because symptoms direct treatment decisions in this disease.

2015;22;372(4):311-319, PMID: 25482239.

Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068, PMID: 25113753.

5. True. In heavily pretreated patients

(N=23) with relapsed or refractory HL, the majority of whom relapsed after autologous hematopoietic cell transplantation and brentuximab (Adcetris, Seattle Genetics) treatment, the use of nivolumab was associated with an overall response rate of 87% and a rate of progression-free survival (PFS) of 86% at 24 weeks. Adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319, PMID: 25482239.

True. PD-1 ligands engage the PD-1 receptor and induce PD-1 signaling and associated T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation. By expressing PD-1 ligands on the cell surface and engaging PD-1 receptor–positive immune effector cells, tumors can co-opt the PD-1 pathway to evade an immune response from the patient. PD-1 ligand overexpression in HL suggests that this disease may have genetically determined vulnerability to PD-1 blockade. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med.

7. False. BCL2 mutations are associ-

ated with increased risk for transformation (hazard ratio, 3.6; 95% confidence interval, 2.0-6.2; P<0.0001) and shortened survival in FL. If these results are replicated, this might serve as the foundation for further studies in FL. In particular, the assessment of BCL2 mutation status along with FLIPI could allow better stratification of FL patients in future clinical trials. Additionally, it might also be reasonable to assess the effects of earlier therapeutic intervention, use agents that bypass the mitochondrial apoptotic pathway, or treat with Bcl-2 antagonists in this subgroup of FL patients. Correia C, Schneider PA, Dai H, et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood. 2015;125(4):658-667, PMID: 25452615.

8. True. Dinaciclib is a novel potent

small molecule inhibitor of cyclindependent kinases (CDK)1, CDK2, CDK5, and CDK9. Overall, 27 evaluable patients were accrued; the median number of prior therapies was 4. The dose level of 50 mg/m2 was determined to be the maximally tolerated dose. The overall confirmed partial response rate (PR) was 3 of 27 (11%), including 1 patient receiving 30 mg/m2 (1 very good PR [VGPR]) and 2 patients receiving 40 mg/m2 (1 VGPR and 1 PR). Additionally, 2 patients at the 50 mg/ m2 dose achieved a minimal response (clinical benefit rate, 19%). Investigators are exploring a clinical trial combining dinaciclib with bortezomib. They believe that the combination may allow patients to derive additional benefit from the proteasome inhibitors by

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2015 • CLINICALONCOLOGY.COM

decreasing the resistance to these agents. Kumar SK, LaPlant B, Chng WJ, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443-448, PMID: 25395429.

HOW I MANAGE continued from page 22

15. Sureda A, Canals C, Arranz R, et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin’s lymphoma. Results of the HDR-ALLO study—a prospective clinical trial by the Grupo Español de Linfomas/trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012;97(2):310-317, PMID: 21993674. 16. Thomson KJ, Kayani I, Ardeshna K, et al. A retrospective-adjusted PET-based transplantation strategy in primary resistant and relapsed Hodgkin lymphoma. Leukemia. 2013;27(6):1419-1422, PMID: 23135356. 17. Sureda A, Arranz R, Iriondo A, et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/trasplante Autologo de Médula Osea Spanish Cooperative Group. J Clin Oncol. 2001;19(5):1395-1404, PMID: 11230484.

9. False. In a multicenter Phase II

study of the European Myeloma Network, the combination of carfilzomib, thalidomide, and dexamethasone (KTd) was active, safe, and well tolerated. Complete response rates after induction and

18. Brice P, Bouabdallah R, Moreau P, et al. Prognostic factors for survival after highdose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s disease; analysis of 280 patients from the French registry. Bone Marrow Transplant. 1997:20(1);21-26, PMID: 9232251. 19. Czyz J, Dziadziusko R, Knopiska-Postuszuy W, et al. Outcome and prognostic factors in advanced Hodgkin’s disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Ann Oncol. 2004;15(8):1222-1230, PMID: 15277262. 20. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26(3):455-462, PMID: 18086796. 21. Faulkner RD, Craddock C, Byrne JL, et al. BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation

consolidation treatment were 25% and 63%, respectively; rates of VGPR or better after induction and consolidation were 68% and 89%, respectively. At a median follow-up of 23 months, the 36-month PFS was 72%.

for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients. Blood. 2004;103(2):428-434, PMID: 12969983. 22. Jabbour E, Hosing C, Ayers G, et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/ refractory Hodgkin lymphoma. Cancer. 2007;109(12):2481-2489, PMID: 12015774. 23. Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116(23):4934-4937, PMID: 20733154. 24. Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665-1670, PMID: 22184409.

Sonneveld P, Asselbergs E, Zweegman S, et al. Phase II study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015;125(3):449-456, PMID: 25398935.

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

Coming Soon How I Manage 17p Chronic Lymphocytic Leukemia Jennifer Brown, MD, PhD Dana-Farber Cancer Institute Boston, Massachusetts

25. Lambert JR, Bomanji JB, Peggs KS, et al. Prognostic role of PET scanning before and after reduced-intensity allogeneic stem cell transplantation for lymphoma. Blood. 2010;115(14):2763-2768, PMID: 20124510.

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