Clinical Oncology News by McMahon Group

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

INSIDE SOLID TUMORS Nab-Pac boosts survival in metastatic pancreatic cancer ...................................... 26 Second-line chemo validated for esophagogastric cancer ...................................... 26 Oncotype colon assay alters physicians’ choices .................................... 27 Highlights from the AACR meeting ..................... 28

HEMATOLOGIC DISEASE

Using preventive drugs to reduce breast cancer risk

n July 8, the American Society of Clinical Oncology (ASCO) issued an updated guideline for using pharmacologic interventions to reduce breast cancer risk in women at increased risk for the disease. The product of a systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012, the clinical practice guideline includes several important changes from the last edition (2009). For tamoxifen and raloxifene (Evista, see ASCO UPDATE, E page 9

How I Manage... Transplant-eligible patients with multiple myeloma: Kenneth Anderson, MD ..... 18 Progress slow in MDS treatment, but options coming ................................... 20 Genomic revolution: Under way and moving fast ............................ 21 Experts disagree on role of transplant in myeloma ................................. 22

CURRENT PRACTICE Maurie Markman, MD: “Data” versus “meaningful data” ............... 9 The value of virtual cancer centers ...................... 17 Clinical Conundrums ......... 29

IMAGES in ONCOLOGY

ASCO Updates Breast Cancer Guidelines

Image courtesy of Science Photo Library

Vogl, NY...

Two Miserable Extra Months: Not Worth Very Much! And not very worthy of pursuit!

ach year sees the approval and marketing of new, ever more expensive drugs that prolong the largely miserable lives of dying cancer patients by one Steven Vogl, MD to three months. Erlotinib (Tarceva, Astellas) was probably the first—prolonging life (median survival) as second- or third-line therapy for non-small cell lung cancer by about two months and for pancreatic cancer by about 12 days. Regorafenib (Stivarga, Bayer) for colon cancer is one of the most recent—prolonging life by six see VOGL, NY, Y page 6

Carcinoma cell, colored transmission electron micrograph (TEM).

Oncologists Fear Misleading CMS Quality Data No fewer than six CMS programs to assess the quality and value of physicians’ work

his winter, oncologist David Eagle, MD, typed his own name into the Centers for Medicare & Medicaid Services (CMS) Physician Compare website and clicked “search.” His name popped up, along with a page of partly erroneous information about his practice. The site lists Dr. Eagle as a hematologic oncologist—a term he’s “never heard before”—who works at one office location and maintains privileges at one hospital in North Carolina. In fact, Dr. Eagle works at two office locations and two hospitals, none of which registered when Dr. Eagle searched within one mile of his practice zip code. It’s this kind of inaccurate reporting that worries doctors about a growing movement for more public reporting of data about doctors. “These [facts on the Physician Compare site] are things that should be easy to figure out. But if CMS can’t get simple data correct, we have to wonder about how they plan to get meaningful information about more complex issues,” said Dr. Eagle, an oncologist at North Carolina’s Lake Norman Oncology, in a phone interview. Dr. Eagle and other oncologists are concerned about the push to amass data about physicians—data that will then be used to shape physician reimbursements and direct patients to health care providers. Broadly speaking, physicians say they support quality improvement programs. Many see ONCOLOGISTS FEAR, R page 10

SPECIAL ASCO 2013 COVERAGE Off-label prescribing: ‘The good, the bad and the ugly’ ........................... 12 A new combo for nausea and vomiting ............................................................. 14 Defining the ideal length of androgen blockade .......................................... 14 Standard of care change for advanced ovarian cancer .............................. 16

For the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy Single-agent TREANDA tripled median PFS Progression-free survival (PFS)* Survival distribution function

1.0 TREANDA (n=153)

0.9

Chlorambucil (n=148)

18 Months

0.8

median PFS

0.7 0.6 0.5 0.4

6 Months

0.3

median PFS

0.2 P<.0001 HR=0.27 (95% CI: 0.17, 0.43)

0.1 0 0

Months

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). HR=hazard ratio. CI=confidence interval.

TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I–IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles. The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. • TREANDA is administered with a convenient dosing schedule – The recommended CLL dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA Please see accompanying brief summary of full Prescribing Information.

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration].] Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions]] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions]] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. •Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2511e (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

November 2012

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

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

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

Oncology Nursing

Hematologic Malignancies

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

Jennifer R. Brown, MD, PhD

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

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

Michele Neskey, MMSc, PA-C

Maura N. Dickler, MD

Harry Erba, MD, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

University of Alabama Birmingham, AL

Mayo Clinic Rochester, MN

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

Richard Stone, MD

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

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

Gastrointestinal Cancer and Sarcoma

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

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

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

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

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

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

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

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

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

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

Steven Vogl, MD Medical Oncologist New York, NY

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

Lung g and Head and Neck Cancers Edward S. Kim, MD

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

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

Genitourinary y Cancer Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD

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

Policy and Management

Pharmacy

Shaji Kumar, MD

Edward Chu, MD

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

Andrew Seidman, MD

Gastrointestinal Cancer

Bioethics

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

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

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

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

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Follow-up: Counterfeit Chemo T

he June and July issues of Clinical Oncology News featured a two-part story on counterfeit cancer drugs entering the U.S. supply chain. The story has been the most-read article at ClinicalOncology.com since it was posted, and since the two-part series was published, the story has continued to unfold. On July 12, Paul Daniel Bottomley was sentenced to six months of house arrest and five years’ probation after he pleaded guilty to misprision of a felony, a charge meaning that he failed to report a felony crime to authorities. Bottomley founded Montana Health Care Solutions in 2008, a facility that featured prominently in Clinical Oncology News’ coverage of the counterfeit drug problem. Although an estimated $6 million in cash and property purchased from the sale of illegal pharmaceuticals was seized from Bottomley during his arrest and prosecution—and although 76 doctors in 22 states contacted the FDA because they may have purchased counterfeit Avastin from Montana Health Care Solutions—Bottomley will not serve time in prison. Bottomley faced up to three years in prison for his role in distributing fraudulent medications, and prosecutors had asked for a one-year prison sentence, to make an example of Bottomley and deter others from distributing illegal, unapproved or misbranded medications. Clinical Oncology News will continue to cover this important issue affecting the cancer care community.

TOP STORIES at ClinicalOncology.com Most-Read Stories

Most-Emailed Stories

Counterfeit Chemo: Part I

Immunotherapy Promising for Kidney Cancer

Scrambling To Deal With Sequestration

Counterfeit Chemo: Part II

Duloxetine Reduces Chemo-Induced Peripheral Neuropathy Pain

Counterfeit Chemo: Part I

A Glimpse of Next-Generation Sequencing

Will You Merge or Won’t You?

Cytarabine Improves Combination Therapy for Mantle Cell Lymphoma

Homoharringtonine Induction Therapy for TreatmentNaive AML

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CURRENT PRACTICE

VOGL, NY continued from page 1

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

weeks at the cost of considerable toxicity and no obvious improvement in the already severely impaired quality of life of the suffering patients.1 Similar data exist for ixabepilone (Ixempra, Bristol-Myers Squibb) and eribulin (Halaven, Eisai) for breast cancer, pazopanib (Votrient, GlaxoSmithKline) for sarcomas, the latter of which provides seven weeks longer median survival and 13 weeks longer progression-free survival based on evaluation with every-sixweek computed tomography. Although these drugs have some obvious benefits, their costs embody many of the most undesirable aspects of U.S. medical care. They are massively overpriced for the benefits they confer, and the cost is borne largely by two overlapping groups: American taxpayers and American consumers. The price is completely dissociated from any significant market pressure. Rather, successive generations of drugs are priced higher and higher each year as the gall of drug companies increases. Indeed, one can fairly confidently guess the year of a drug’s approval by its monthly cost—a cost that relates more to Big Pharma’s estimate of the price ceiling beyond which society would be outraged than to the cost of drug development or the costs of manufacture and marketing. Thus, erlotinib was priced at about $2,400 per month in 2000 and regorafenib at about $9,350 per month in 2012. The level just “below outrage levels” has apparently risen to about $40,000 per month for three-month courses of immune therapies like sipuleucel-T (Provenge, Dendreon) for prostate cancer and ipilimumab (Yervoy, Bristol-Myers Squibb) for melanoma. The high prices paid for drugs that delay progression for very sick patients by only a few months, and the large profits they generate, divert drug company research funds from trials that seek prolonged high-quality remission or cure.

How Did This Come To Be? Big Pharma and its lobbyists—with deep pockets that support many election campaigns—have succeeded in inducing the U.S. Congress and state legislatures to pay the asking price for

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

any approved drug. By law, Medicare Part D prescription plans are forbidden from bargaining over the prices of approved drugs. As a consequence, both American taxpayers and American consumers pay higher prices for drugs than anywhere else in the world. The Medicare prescription plan’s deductible and copay provisions, which are designed to discourage the use of marginally beneficial drugs, have been effectively nullified by the creation of bogus charities and foundations through which Big Pharma pays the copay and deductible to itself, and still makes huge sums by collecting 80% to 95% of the posted price from Medicare and private insurers. At the same time, insurance companies have consolidated, so most are dominant in their market and can pass the increasing cost of drugs through to the purchasers of the insurance as much higher premiums. It seems this leaves enough money for very large salaries and bonuses for upper-echelon executives.

Stakeholders in the Status Quo Drugs companies and venture capital firms have learned the current system, lobbied to modify it to their advantage, adapted to it, and proven themselves capable of prospering in this absurd environment. If society changes the rules, stakeholders will push back to defend their current business models. Any changes will be resisted by political action committees, “Harry and Louise” advertisements, positive and negative political pressure, and public relations campaigns that call value pricing “death panels.”

Should We Pay More for Drugs That Work Better and Help the Sick More? The intuitive answer is yes. Just as one would be willing to pay more for a bigger car, a faster car, a safer car or a more attractive car, one would pay more for a drug that offered many extra years of good life than one that offered an extra few months of poor-quality life just before death. Why do these simple market concepts not apply to medications? The market no longer functions. The very high cost for each dose means that few consumers can afford to pay on their own, regardless of how much they value the benefits of the drug, assuming they have the knowledge and judgment to estimate that value. Either society as a whole, or insurance companies, thus participate in whatever market exists to determine drug pricing. Society has set some rules to allow developers of approved drugs to reap profits from their investment—years of exclusive rights to sell based on the drug’s patent. Eventual expiration of the patent allows price-lowering competition.

While the patent is valid, it is almost impossible to get drug prices on the Internet—these have become closely guarded industrial secrets. Many new, expensive drugs are marketed through a single or a very limited number of “specialty pharmacies.” I do not know for certain why this happens, but I suspect this allows the drug company to charge different prices to different cus-

is getting a discount I cannot obtain. So, we already have many prices for the same drug made by the same manufacturer. These are not dictated by a free market, nor by the extent of the benefit to patients (the ultimate users); rather, manufacturers manipulate the retail price to maximize profits and avoid the appearance of violating government insurance regulations.

The drug approval system in the United States rewards companies for statistically significant, but clinically minor, benefits. tomers, and to maintain discounts given to specific customers, either because of their size or negotiating acumen, and keep them secret from other customers, some of whom may be government or other buyers that forbid discounting below the prices they pay.

Drugs are occupying an ever-bigger chunk of the medical care budget, which already represents about 17% of the U.S. economy. The magnitude of funds being drained from the system for so little return in health, life or function begs for correction.

The Patient Is Not the Purchaser

Bizarre Pay Patterns Dominate for Physicians as Well as Drugs—Both Reflect Economic and Political Clout

Intermediaries separate the beneficiary of insurance from the purchaser of insurance, often the government or an employer, who chooses the limits of the policy. The insurer often chooses the drugs for which it will pay, determines the additional cost to beneficiaries and determines what price it will pay, if any. Some states require insurers to pay for approved drugs for approved indications. This is often astute policy for state lawmakers, although not always the wisest use of limited resources. In contrast, the National Institute for Health and Care Excellence (NICE) in Britain evaluates drugs not only for safety and efficacy, but critically on the benefit as it relates to the cost.

Drug Prices Should Be Based On Benefits to the Patient Because what may be a lifesaving drug for one condition may be a poor drug for another, it makes sense to charge more for the drug in the situation in which it is more valuable to the patient.

Can the Same Drug Have Two Prices? Of course it can! A single drug often has many prices, but we are just not used to having two prices based on the drug’s value; we are used to two or many prices based on the market clout of the purchaser and how this affects the profits of the seller.

Small Purchasers Are at a Big Disadvantage A number of drugs purchased by small practices cannot be obtained for prices at or below reimbursement by Medicare or private insurance companies. If the price I must pay as a solo practitioner with no volume discount is above 106% of average sales price, some other entity

Bizarre drug-pricing patterns have a parallel in the rules governing physicians’ compensation. It makes sense to pay more for better service, better care, more compassion, better availability and better communication. Instead, we have HMOs that automatically pay solo physicians half what they pay for the same service done in a large group or hospital practice with more negotiating clout. The provided service is judged on absurd “bullet points” emphasizing “boilerplate” and easily fabricated and largely irrelevant lists of present or absent symptoms.

It Is Possible To Charge More For Better Drugs and Less for Marginal Ones This already happens, although the charges are varied not by benefit, but by expense to the insurer. Medication insurers already charge much higher copays for expensive, brand-name drugs than for cheap generics. Some very expensive drugs are not covered at all, or are covered under exceptional circumstances known only to the insurer (listed on the computer screens in front of the clerks we are obliged to call for “prior approvals”). A benevolent and wise insurer, one interested in the care of the sick as well as the cost to society, would charge a small copay for erlotinib to a patient with a lung adenocarcinoma with an exon 19 EGFR deletion, where response for about a year could be expected in 75% of treated patients, and a huge copay for thirdline erlotinib in patients with lung cancer with wild-type EGFR, where erlotinib barely has any benefit at all. If the United States had a legislature capable of deliberation based on the see VOGL, NY, Y page 8

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VOGL, NY continued from page 6

needs of the country and its citizens, surely it would replace the current chaotic system—one that produces riches for drug manufacturers, insurance companies and the marketers of both drugs and insurance—with a system that rewards innovation and the development of effective drugs, and with prices somehow tied to both costs and benefits, rather than campaign contributions, access to politicians and skill at smear advertising. The prices paid for very good drugs may have to be very high to compensate for randomized trials with very long follow-up to demonstrate long-term safety and efficacy. Adjuvant therapy for breast cancer is an important example; because rates of death from metastases are already very low for the largest subgroups of patients, any benefits for those few who now still relapse and die must be shown to outweigh toxicity among those who already enjoy long and healthy lives with currently available therapy. In contrast, society would suffer little if the criteria became less stringent for

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The cost of a drug should be based on its benefit to patients in a given disease setting. approving marginal drugs for the very ill near the end of their lives, or for diseases that have few effective treatments available, and thus allow faster and lessexpensive drug development. The FDA has already made major strides in this area. Society should demand lower prices as compensation for the lower development costs for these drugs.

The FDA Already Picks Likely ‘Winner’ Drugs for Expedited Development The FDA already has a program to decide which drugs it will support preferentially for development, to help the drug industry bring them to market sooner. The good drugs are designated as likely filling an “unmet need,” and the really good drugs as “breakthroughs.” If the United States had a single-payer system, with the right to bargain with drug companies on price (as do single

payers in Canada and the United Kingdom), I suggest that the payer would be unwilling to pay much for poor drugs, and would be willing to pay more for drugs that benefit citizens more and for longer periods. Negotiations could include price; patent protection (there is no reason that drug patent protection must be the same for bad drugs as for good ones); price increases if company-sponsored studies discover a new indication that substantially benefits sick members of society, like a major decrease in relapses when given as adjuvant therapy or major activity against a different disease; and higher prices paid for situations in which the benefit is great, such as years of improved survival without disease.

there is no antitrust issue. If there are a small number of private companies acting as negotiators, they need a legislatively mandated negotiating body to shield them from antitrust liability. Wouldn’t it be wonderful if the United States had a Congress that could effectively deal with these issues?

Reference 1. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-312, PMID: 23177514.

What are your thoughts?

The Proposal We need to modify the current system to encourage drug companies to fund studies that seek better and more beneficial uses for their drugs, and discourage studies seeking statistically significant but biologically minor advantages. This would be far easier in the setting of a single payer or a very small number of payers. If the government is the single payer,

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

by the

numbers: Community Practice Closings On June 25, the Community Oncology Alliance released updated results of their Practice Impact Report, which charts the financial status of cancer centers across the U.S. Their last report was released in April 2012; these new figures include changes to practices within the past 15 months. Over the past six years:

288 |

clinics have closed

407 |

practices have reported struggling financially

43 | 469 | 131 |

practices have sent all of their patients elsewhere for treatment practices have been purchased or entered into a hospital agreement practices have merged or been acquired

Relative to the 2012 report:

20% |

increase in clinics closed

20% |

increase in practices purchased or entered into a hospital agreement

Source: Community Oncology Alliance. Community Oncology Practice Impact Report. June 25, 2013.

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Measuring Quality: “Data” Versus “Meaningful Data” EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

ewly diagnosed cancer “Patient A” inquires about the availability of specific information on “Surgical Oncologist B” and “Hospital C.” The request is logical and should be relatively simple to obtain: “What are the five-year survival rates of all patients treated for my type of cancer by ‘Surgical Oncologist B’ at ‘Hospital C’”?

difficult, or realistically not possible, to interpret the meaning of these survival data. How will a patient know if a five-year survival rate of 40%, 70% or 95% is an indicator of good, satisfactory or poor quality in the absence of some benchmark with which to compare? Because of this need for information, it is increasingly likely that patients will request specific survival outcome “data” from more than a single cancer provider, for example, “Surgical Oncologist D, E and F” and/or “Hospital G, H and I.” We’ve now arrived at the core problem behind this understandable and very rational patient request: The well-recognized heterogeneity of biological (histology, relevant driver mutations, inherent drug resistance, growth patterns, etc.) and clinical factors (presence of serious

Biological factors in cancer and unique patient populations make comparing physicians’ quality difficult. Nevertheless, patients are entitled to know. Of course, the likely purpose of this request is to use these “data” in the decision-making process for determining where the patient will obtain treatment. Unfortunately, just as is the case in baseball (or essentially any sport) where knowing your team’s final score (“we scored eight runs”) is of very limited value unless you also know the other team’s score (“but, they scored nine runs”), in the absence of an appropriate comparison population it will be very

ASCO UPDATE continued from page 1

Eli Lilly), the new guideline uses the stronger words “should be discussed as an option” rather than the previous guideline’s “may be offered.” The updated guideline recommends discussion of both tamoxifen and raloxifene as options to reduce the risk for invasive breast cancer, specifically estrogen receptor (ER)-positive breast cancer, in women aged 35 years or older who are at increased risk for breast cancer or who have lobular carcinoma in situ (LCIS). Tamoxifen is recommended in premenopausal and postmenopausal women, whereas raloxifene is recommended only in postmenopausal women. The previous guideline stated that aromatase inhibitors are not recommended

comorbidities, baseline performance status, unique socioeconomic issues) make the legitimacy and utility of any direct comparison between nonrandomized patient populations highly suspect.1 In fact, it was more than 50 years ago that David Karnofsky, MD, noted and reported the relevance of a patient’s pretreatment performance status in substantially impacting survival independent of the stage of a particular disease at presentation and the specific

to lower breast cancer risk outside of the clinical trial setting. In contrast, the new guideline says that the aromatase inhibitor exemestane (Aromasin, Pfizer) should be discussed as an alternative to tamoxifen and/or raloxifene in postmenopausal women. “Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large,” Kala Visvanathan, MBBS, a co-chair of the guideline panel and an associate professor of epidemiology and oncology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in a statement. “For some women, these therapies can reduce the risk for breast cancer by up to 50%.” —George Ochoa

treatment delivered.2 Numerous prospective and retrospective studies conducted since that time have confirmed Dr. Karnofsky’s initial observation.1 I am not suggesting that the survival data provided by an individual oncologist or health care organization is inaccurate or misleading. Although it might be misleading to directly compare fiveyear survival rates between two completely different cancer organizations, a patient has a right to ask for and be provided this information. Why should a request for five-year cancer survival results be any different from a patient asking about a hospital’s Joint Commission certification, or asking about a hospital’s surgical infection rate over the past two years, or the experience of a particular surgeon with robotic surgery? However, at the same time, any survival data provided to a patient must be accompanied by a substantial effort by the medical team to explain the serious limitations of the information, especially if they will be used by the patient to compare with other cancer providers. Again, the point to be made is that the data are not incorrect, but that meaningful comparisons of the quality of care being provided are—with a few notable exceptions—rarely possible. Nevertheless, in this discussion with a patient or his or her family, it is relevant to acknowledge that there are objectively valid indicators related to the process of care that speak indirectly, but quite meaningfully, to the overall quality of care being provided, as well

as highlight the focus of specific providers, hospitals and health care organizations on patient satisfaction and safety (e.g, Hospital Consumer Assessment of Healthcare Providers and Systems [known as HCAHPS], the Joint Commission, The Leapfrog Group and the American Society of Clinical Oncology’s “Quality Oncology Practice Initiative”). While individual patients may ultimately use these “certifications” as they choose the location of their care, in this setting the comparison between practitioners and groups will be based on features within the direct oversight of these individuals or organizations—the process of care, as opposed to factors largely outside of their control: the biology of an individual cancer and the unique clinical factors associated with a patient.

References 1. Markman M. Provider impact on survival outcomes in the management of malignant disease. Curr Oncol Rep. 2013;15:193-196, PMID: 23430700. 2. Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the Karnofsky Performance Status. Cancer. 1980;45:2220-2224, PMID: 7370963.

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

gmiller@mcmahonmed.com

Key Recommendations in the Guideline Update • Tamoxifen (20 mg per day orally for five years) should be discussed as an option to reduce the risk for invasive, estrogen receptor (ER)-positive breast cancer in premenopausal or postmenopausal women. Tamoxifen targets the estrogen receptor in breast tissue, and therefore is only effective for prevention of ER-positive breast cancer. • Raloxifene (60 mg per day orally for five years) also should be discussed as an option to reduce the risk for invasive, ER-positive breast cancer. It targets the estrogen receptor in breast tissue. Its use is limited to postmenopausal women. • Exemestane (25 mg per day orally for five years) should be discussed as an alternative to reduce the risk for invasive, ER-positive breast cancer in postmenopausal women. It is an aromatase inhibitor, a class of drugs that lower the amount of estrogen in postmenopausal women and are given to women with ER-positive breast cancer after surgery to lower the risk for cancer recurrence. Although exemestane is approved for the treatment of breast cancer, the FDA has not yet approved its use in breast cancer prevention. This recommendation is based on encouraging data from a single clinical trial that showed a reduction of up to 70% in overall and ER-positive invasive breast cancer incidence for exemestane compared with placebo over a three-year period. • All three agents should be discussed (including risks and benefits) with women aged 35 years or older without a personal history of breast cancer who are at increased risk for developing invasive breast cancer, based on risk factors such as the woman’s age, race, and medical and reproductive histories.

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ONCOLOGISTS FEAR continued from page 1

societies, including the American Society of Clinical Oncology (ASCO), have developed programs of their own that are designed to improve quality within the specialty. But physicians are apprehensive about government programs that collect and report data without first being validated as quality improvement tools, said Robin T. Zon, MD, a medical oncologist at Michiana Hematology Oncology in Elkhart, Ind. “That’s the concern—do these processes really improve quality? Do these processes improve outcomes? What are the outcomes we’re talking about? Are we talking about quality of life? Are we talking about survival? All of that plus more? Right now, it’s not completely understood,” she said.

What CMS Is Reporting on Oncologists Today, CMS is midway through a multipronged endeavor to gather and report data about physicians. These data will eventually be used to adjust payments for physicians and to direct Medicare patients to the health care providers deemed to offer quality, costeffective service. As it stands now, CMS has at least half a dozen reporting programs partway through implementation, including Physician Compare, the Physician Quality Reporting System, the Electronic Prescribing Incentive Program, the EHR Incentive Program, Quality and Resource Use Reports and the Physician Value-Based Modifier Program. Most of these programs have been reported in depth over the years. Still, it’s worth highlighting a few of the key programs currently ramping up. Physician Compare (www.medicare. gov/find-a-doctor/provider-search. aspx)—the website with the erroneous

information about Dr. Eagle’s practice— was created under the Affordable Care Act (ACA). Right now, Physician Compare reports physicians’ name, gender, addresses and phone number, along with clinical training information, languages spoken, hospital and group affiliations and whether physicians accept Medicare patients. Plans are under way, however, to use the site for “consumer choice and value-based purchasing” beginning around 2015. And, in one of the more contentious changes to the site, CMS will soon add a new Consumer Assessment of Healthcare Providers and Systems (HCAHPS) Survey. The survey will add quality and patient satisfaction scores to each physician’s page.

To date, oncologists have lagged behind other practitioners in PQRS participation. Physicians worry that patient surveys may be inaccurate or unfair. “There’s no way to ensure that the patient surveys accurately represent their experience with a physician,” said Hamidreza Sanatinia, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada in Las Vegas. Patients sometimes see so many physicians that they get names confused, he said. “Or sometimes a family member fills it out as a form and they don’t know the doctor. Maybe a patient leaves the hospital and gets a bill, then gets angry, and they trash their doctor. “I simply don’t know how reliable this reporting is. I don’t know how statistically it’s going to exclude patients who are angry for no reason,” he said.

One of the best-known reporting programs is the Physician Quality Reporting System (PQRS), the Medicare physician quality reporting system started as a voluntary program in 2007. Each year, more physicians have signed on to the program with more than 320,000 eligible health care professionals submitting PQRS data for 2011. That’s up from about 100,000 during the inaugural 2007 reporting period but still 200,000 physicians short of the CMS goal of at least half of all health professionals participating by 2013. This year, for the first time, physicians will be penalized for not participating, although the payment penalties will not take effect until 2015. Experts say the risks of nonparticipation now outweigh any benefits. “A physician’s decision not to participate will be a costly one in the long run,” said Elaine L. Towle, CMPE, the director of consulting services for Oncology Metrics, a division of Altos Services in Boston, during an ASCO-sponsored webinar dedicated to CMS reporting. In an important change for oncologists, CMS added new oncology measures for reporting this year—a development applauded by ASCO and the American Society of Radiation Oncology. Both societies had pushed for oncology measures, hoping to draw more oncologists to the program. So far, oncologists lag behind other practitioners in PQRS participation. According to CMS data, only 22% of eligible radiation oncologists and 30% of hematologists/oncologists successfully participated in the PQRS program in 2010. Still, ASCO representatives remain concerned about the federal government’s capacity to conduct “meaningful quality assessment across the field of medicine.” They’d like to see quality improvement programs like PQRS conducted on a specialty-by-specialty basis. In oncology, ASCO leaders want CMS to use the existing physician-led Quality Oncology Practice Initiative (QOPI) as the oncology quality reporting

mechanism for any new Medicare reimbursement structure. “For any of the models being proposed, we believe that QOPI should serve as the performance measurement program to ensure the highest quality of cancer care possible,” said ASCO Clinical Practice Committee Chair Jeffery Ward, MD, in a statement from ASCO. “Patients deserve patient-centered care that is evidence-based as reflected in QOPI’s performance measures,” he said. Finally, there’s the newest public reporting project from CMS—the Quality Resource Use Report (QRUR). Created as part of the ACA, the QRUR issues confidential feedback reports to physicians based on data collected from PQRS and Medicare claims data. Through these reports, physicians can compare the quality and cost of the care that they provide with that of other physicians in their specialty or region. It’s not easy to calculate exactly what amount of care or cost of care a physician has contributed to a specific patient. The QRUR program attempts to break down that information by categorizing patients into three categories: patients whose care was directed by a physician (when a physician bills for 35% or more of all of a patient’s outpatient Evaluation & Management [E&M] visits); patients whose care they influenced (defined as billing for less than 35% of a patient’s outpatient E&M visits but 20% or more of their professional costs); and patients whose care they contributed to (defined as billing less than 35% of outpatient visits and less than 20% of other total medical costs). Currently, the QRUR is being pilot tested in Iowa, Kansas, Missouri and Nebraska. Within two years, the reports will include a payment modifier. All these programs are leading to what’s called a value-based payment modifier. The modifier will result in differential payments to physicians based on both the quality of care they provide

AT A GLANCE Quality Reporting If you think staying on top of all the practice-changing research in oncology is tough, try staying on top of all the new physician quality reporting programs in medicine. Here are a half-dozen currently being implemented by CMS; try to match the name of the program with its purported goal. (Don’t worry, your reimbursement will not be penalized for wrong answers.) CMS Program 1. Physician Compare 2. Physician Quality Reporting System 3. eRx Program 4. (EHR) Incentive Program 5. Quality and Resource Use Reports 6. Value-Based Payment Modifier Program

What It Does A. Provides confidential information to physicians on the cost and quality of their treatments B. Gives payments for “meaningful use” of certified EHR technology C. Helps Medicare enrollees find and choose a physician D. Combines both cost and quality data in calculating payments for physicians E. Incentivizes physicians to report quality measures F. Rewards successful electronic prescribers Answers: 1:C, 2:E, 3:F, 4:B, 5:A, 6:D

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

and the cost of that care. The modifier will be rolled out to physicians working in groups of 100 or more in 2015, and to all physicians by 2017. The value-based modifier is “still a bit nebulous as it’s a work in progress,” said Dr. Eagle. What is known is that physicians will be branded into four different categories: low cost and high quality; low cost and low quality; high cost and high quality; and high cost and low quality.

What Does It Mean for Physicians? Quality reporting systems are supposed to represent a win–win–win for all involved: Physicians will offer better quality care, patients will receive better treatment and health care costs will decline. However, not everyone is convinced of the programs’ success. Just look at the case with hospitals, said Dr. Eagle. He points to the experience with hospital-ranking reports like Hospital Compare. The information reported on Hospital Compare doesn’t always reflect the reality, he said. What’s more, he said, if you compare hospitals across different ranking sites—say, Hospital Compare versus Health Grades—the reports often conflict. A hospital may be considered top tier on one site but come out near the bottom of another. In a study of ranking systems for Boston-area hospitals, hospitals that ranked first or second by one grading system were often ranked seventh or eighth by other systems

((Health Afff 2008;27:1680-1687, PMID: 18997226). Physicians worry that doctor-reporting systems could give similarly distorted versions of a physician’s performance. “If you’re going to rate physicians and measure our performance, you have to make sure you are doing it the right way. It’s difficult,” said Dr. Eagle.

called Dr. Sanatinia very upset after she received the lexicon-heavy report. “She thought she had lupus because I’d ordered lupus anticoagulant testing, which came back negative. But the description on the lab was so confusing that she thought she had lupus. She was angry with me because she thought I didn’t tell her she had lupus.”

QOPI. They do not have the funds to support more quality reporting programs, especially now that the sequester cuts are in effect. “The majority of oncologists have not joined QOPI or PQRS. Some of these are folks in underserved areas and don’t have the resources, financially or otherwise. And now the sequester is going to

Concerns about quality, accuracy and validity have been tossed around for years. What’s different now is that many new programs are coming at once and financial penalties—not simply rewards—are in place. And most critically, it comes at a time when oncology practices are under tremendous pressure. Concerns about quality, accuracy and validity have been tossed around for years. What’s different now is that many new programs are coming at once and financial penalties—not simply rewards— are in place. And most critically, they come at a time when oncology practices are under tremendous pressure. Dr. Sanatinia said quality reporting just adds to already high stress levels, both for patients and providers. “We care for extremely sick patients at a time when they are overwhelmed with stress and frustration,” he said. “This process should be about making things better for our patients, not worse.” He recounted an experience with one of his patients when she received a report from the Electronic Health Record (EHR) Meaningful Use Incentive program. The 80-year-old patient

He said there are plenty of benefits that could come from quality reporting but the process needs to be proved before it is implemented. The focus needs to be on patients, not on data, he said. “I think a lot of physicians feel that we are doing all this to please agencies rather than take care of the patient. We are spending time collating information, not seeing patients. You can’t help but feel that way,” he said. The smaller community oncology practices feel the stress most acutely, he added. Many lack the financial resources needed to invest in the ever-changing information technology requirements for quality reporting—and there have been many over the past five years. Some practices already poured dollars and efforts into the oncologist-led

have a significant impact on those who have not been able to get to that point one way or another,” said Dr. Zon. Dr. Eagle, the oncologist who discovered wrong information about himself on the Physician Compare website, said many challenges lie ahead as physicians, specialty societies and government agencies figure out how to get meaningful, accurate information from all the data collected. He called on oncologists to educate themselves about quality reporting and be involved in the process. “It’s coming whether we agree with it, like it or not. This will be an important part of health care in future,” he said. “I’d start by checking what Physician Compare says about you. You might be surprised.” —Christina Frangou

by the

numbers: Sequestration’s Real Impact

hroughout the spring, it became clear that community oncology practices would be affected by the mandatory 2% reduction in Medicare payments as a result of the sequester. Sequestration is now four months old and the actual impact on patients is becoming more explicit.

According to a survey of nearly 200 respondents by the Association of Community Cancer Centers:

54% |

reported that chemotherapy infusion services have been impacted

40% |

have changed nutrition or other complementary services

35% |

have referred patients to other sites for care

30% |

have made changes to survivorship programs

30% |

have changed their patient navigation services

15% |

have changed their clinical trial participation

7% |

have delayed treatments due to the sequester

4% |

have begun collecting copays prior to the start of treatment

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Off-Label Drugs: ‘The Good, the Bad and the Ugly’ At ASCO, off-label drug prescribing quantified, then examined

ff-label drug use in oncology is common: Roughly 18% of drug costs in older patients with metastatic cancer are for drugs used off-label. However, the bulk of off-label drugs are recommended in National Comprehensive Cancer Network (NCCN) compendia, and roughly 50% of this latter group will eventually receive FDA approval. “Unapproved use was highest in prostate cancer patients and multiple myeloma,” said Dawn Hershman, MD, MS, an associate professor of medicine and epidemiology at Columbia University Medical Center in New York City, who presented this data at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 6509). Dr. Hershman’s research is part of a recent push to quantify the use of offlabel drugs in cancer patients and their effect on costs. In 1993, Congress required Medicare to cover off-label drug prescriptions when standard medical compendia, such as the NCCN guidelines, supported a drug’s use. Several years ago, a study of self-reported off-label use among 146 oncologists found that 81% had prescribed medications off-label at least once and 93% had discussed offlabel therapy with patients ((J Clin Oncol 2008;26:5994-6000, PMID: 19029413). Compared with community oncologists, academic oncologists were more likely to have ever provided off-label prescriptions (89% vs. 75%; P=0.06) and to

by the

have discussed off-label prescriptions at least once per month (41% vs. 19%; P=0.0004). Academic physicians also were more likely to deny requests for off-label drugs at least once per month (16% vs. 2%; P=0.004).

New Data From ASCO In the new study, Dr. Hershman and her colleagues used the Surveillance, Epidemiology, and End Results Medicare database to identify patients with metastatic cancer who were older than age 65 and received chemotherapy between 1998 and 2007. The investigators focused on cancers of the breast, ovaries, uterus, lung, colon and prostate, as well as myeloma. For each of the 42,634 patients identified, researchers determined the proportion of drug claims that had an FDA-approved indication, an indication based on NCCN compendia guidelines or neither of these. Patients who had chemotherapy more than 30 days before diagnosis were excluded. For each tumor type, the researchers only included a drug if at least four patients had a claim for it. If a patient only had one claim for a drug, the data was excluded from the analysis. Overall, there was little variation over time in terms of prevalence of off-label use. Roughly 45% of the total number of claims was for drugs that were not approved by the FDA. “There was quite a range in terms of

numbers:

Top 10 Most Commonly Prescribed On-patent Anticancer Drugs in 2010 70% | On-label use 30% | Off-label use to an NCCN-supported off14% | Conformed label indication with an FDA-approved cancer site, 10% | Used but an NCCN-unsupported setting

$12 billion | Total spending on these drugs in 2010 $2 billion | Off-label and NCCN-supported $2.5 billion | Off-label and NCCN-unsupported Source: Conti RM. J Clin Oncol. 2013;31:1134-1139, PMID: 23423747.

some cancers where a very small proportion of the claims was for unapproved drugs such as colon cancer [roughly 10%] and other drugs, such as myeloma [roughly 88%], prostate [68%] and lung [68%], where there was a much higher proportion for unapproved drugs,” said Dr. Hershman. The number of different drugs used that were not approved by the FDA or recommended by compendia was much higher in prostate cancer (33 drugs), compared with ovarian cancer (28), breast cancer (20), myeloma (18), uterine cancer (13), colon cancer (eight) and lung cancer (eight). Bevacizumab (Avastin, Genentech) was one of the drugs most commonly used off-label. In a multivariate analysis, race, location and socioeconomic status had no effect on off-label prescribing; unapproved use decreased with increasing

Table. Comparison of Off-Label Use By Tumor Type Receipt of Unapproved Drug Tumor Type

Odds Ratio

Prostate

Referent

Myeloma

0.72

<0.0001

Lung

0.61

<0.0001

Uterus

0.46

<0.0001

Ovary

0.32

<0.0001

Breast

0.31

<0.0001

Colon

0.09

<0.0001

P Value

Off-label drug prescribing is incredibly common among cancer physicians; however, no studies have analyzed the reasons or motivations behind off-label prescribing. age and more than two comorbid conditions. Tumor type was highly influential, with prostate cancer leading the pack in terms of greatest number of offlabel prescriptions (Table). Dr. Hershman hypothesized that the high use of off-label drugs in metastatic prostate cancer and myeloma could be affected by the fact that very few drugs are approved or on compendia for these disease states, and perhaps clinicians were spurred on by encouraging Phase II trial data. In terms of finances, 64% of the drug costs were for FDA-approved drugs, 18% were for drugs that were not FDAapproved but were recommended in compendia, and 18% were for drugs that were not approved or recommended. “Of the about $850 million spent on drugs in this cohort, about $150 million were for compendia [only]-approved indications and $150 million were for unapproved indications,” said Dr. Hershman. About 50% of the drugs in compendia were eventually approved. A recent study by researchers at the University of Chicago and Memorial Sloan-Kettering Cancer Center also evaluated the effect of off-label use on health care costs ((J Clin Oncol 2013;31:11341139, PMID: 23423747). This study used information from IntrinsiQ IntelliDose, a pharmacy software provider maintaining a population-based cohort database of medical oncologists. The investigators analyzed data on the 10 most

commonly prescribed, patent-protected chemotherapy drugs that were administered intravenously in 2010. Thirty percent of these drugs were prescribed offlabel, but roughly half conformed to an NCCN-supported off-label indication. Of the $12 billion spent on these drugs in 2010, $4.5 billion was spent on off-label use, with $2.5 billion spent on drugs not listed in NCCN compendia. The prevalence of off-label use varied significantly, with drugs such as bortezomib (Velcade, Millennium) rarely being prescribed, and others, such as bevacizumab, rituximab (Rituxan, Genentech) and gemcitabine (Gemzar, Eli Lilly), commonly used. Bevacizumab topped the list with $1.942 million being spent on the drug and only $837 million for indications supported by NCCN compendia.

Pros and Cons In a presentation at the ASCO meeting, Monika Krzyzanowska, MD, MPH, an oncologist at Princess Margaret Cancer Center at the University of Toronto, Ontario, Canada, discussed “the good, the bad and the ugly” of off-label prescribing in oncology. The practice can provide early access to drugs supported by evidence from clinical trials, although the drug has not been vetted through the FDA. In patients with rare diseases, it can provide access to medications for which there may not be adequate information or incentives for a

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

company to obtain an approval. Off-label prescribing also allows for innovative uses of a drug. “One may argue that off-label prescribing to try to match a genomic mutation might be one such use,” said Dr. Krzyzanowska. Recently, researchers published positive results on a case that used this very approach. Off-label cetuximab (Erbitux, Bristol-Myers Squibb) and panitumumab (Vectibix, Amgen) plus regorafenib (Stivarga, Bayer) were used in a patient with V600E BRAF-mutant metastatic colon cancer (Cancer Biol Ther 2013;14 [Epub ahead of print], PMID: 23792568). According to Dr. Krzyzanowska, this type of research should be conducted in a way that clinicians can learn from each case study. “There needs to be a way to track the experience in this setting, as, unfortunately, a lot of times such matches are unsuccessful, and the only ones we hear about are the occasional successful ones,” she said. However, not all is positive with offlabel prescribing. In terms of negative effects, studies have shown that offlabel prescribing can hinder accrual to

clinical trials. In an evaluation of 172 clinical trials, time to accrual was slower (41 vs. 22 months; P=0.002) and less efficient (8.8 vs. 22.7 patients per month; P=0.001) when clinicians not involved in the study had the option to prescribe, off-label, the drug being studied ((J Clin Oncol 2010;28:5067-5073, PMID: 20975070). Then there are more morbid downsides. “A lot of the medications that we prescribe for cancer patients come with a significant risk of toxicity and that needs to be taken into consideration,” said Dr. Krzyzanowska. So far, no studies have analyzed the reasons or motivations that physicians prescribe off-label. “Are we prescribing offlabel because perhaps we don’t want to have that end-of-life discussion or perhaps we are worried about litigation,” said Dr. Krzyzanowska. “We don’t have any information on either of these issues.” She said studies are needed to investigate this and other issues, including whether compendia-compliant use is in fact appropriate. In Dr. Hershman’s study, only 50% of compendia drugs

were eventually approved. “The drugs that were not eventually approved by the FDA never did come off the compendia,” said Dr. Hershman. A 2009 study in the Annals of Internal Medicine concluded that many of the compendia used are inconsistent with each other, incomplete and out of date ((Ann Intern Med 2009;150:336-343, PMID: 19221366).

that warrant off-label use. Public awareness initiatives, such as those by the American Cancer Society, can educate patients. At the reimbursement stage, disease pathways have the potential to increase more appropriate off-label use. Closer examination is needed for non–compendium-consistent use, diseases or drugs with high prevalence of

Off-label use is composed of a roughly equal mix of chemotherapies supported by the NCCN compendia and those that are not. Dr. Krzyzanowksa said there are several opportunities for improving off-label use of drugs. “Once a drug becomes available on the market, it then has to be recommended by a physician to a patient, the patient has to accept the recommendation and then the drug has to be reimbursed,” she said. “If we think about solutions, we can think about them at each one of those stages.” Physician education and decisionsupport tools, she said, could help clinicians understand the circumstances

off-label use, expensive drugs and situations where the benefit is likely small but the risk for toxicity substantial, said Dr. Krzyzanowska. “I think we are ready to have some greater scrutiny on offlabel use,” she said. —Kate O’Rourke Dr. Hershman had no relevant disclosures. Dr. Krzyzanowska disclosed a consultancy for Bayer, honoraria from AstraZeneca, Novartis and Sanofi, and research funding from AstraZeneca, Eisai and Novartis.

by the

numbers: The 10 Worst Cancer Charities W

hat are the worst cancer charities in the United States? The Tampa Bay Times and the Center for Investigative Reporting (CIR) answered this question by compiling a list of America’s worst charities—including organizations purported to help children, police, firefighters and the fight against cancer. What makes these 50 charities so bad is that they spend the bulk of the donations they receive—collectively, 69.3%—on paid solicitors, 27.2% on operating the charity and a mere 3.5% on direct cash aid.

The 10 Worst Cancer Charities (ranked by total paid to solicitors over 10 years).

Ten of the 50 worst charities— or 20%—are associated with cancer. Ten of the 50 worst charities—or 20%—have cancer (or, in one case, leukemia) in their titles. Others may claim to be addressing cancer under a more general heading, such as the Optimal Medical Foundation and the National Caregiving Foundation. The most popular theme among charities that are explicitly cancer-related is breast cancer—four have titles containing those words. Children’s cancer is the supposed target of another three, with the remaining three featuring positive words such as America, hope, and national. Despite some efforts, regulators have achieved little to stop the perpetrators behind these charities, according to the Tampa Bay Times and CIR. When confronted with regulatory action in one location, the operators may move to another state and begin again. Indeed, laws and regulations can be their friends. Children’s Cancer Recovery Foundation was able to list some of its fundraising as a charitable program on its taxes, by having the solicitors deliver messages on cancer prevention and survival when they call to ask for donations. —George Ochoa

Ranka

Charity

Total Raised by Solicitors

Total Paid to Solicitors

% to Direct Cash Aid

Cancer Fund of America

$98 million

$80.4 million

0.9

American Breast Cancer Foundation

$80.8 million

$59.8 million

5.3

Breast Cancer Relief Foundation

$63.9 million

$44.8 million

2.2

Children’s Cancer Fund of America

$37.5 million

$29.2 million

5.3

Children’s Cancer Recovery Foundation

$34.7 million

$27.6 million

0.6

National Cancer Coalition

$41.5 million

$14 million

1.0

Woman To Woman Breast Cancer Foundation

$14.5 million

$13.7 million

0.4

Children’s Leukemia Research Association

$9.8 million

$6.8 million

11.1

United Breast Cancer Foundation

$11.6 million

$6.6 million

6.3

Hope Cancer Fund

$1.9 million

$1.6 million

0.5

Rank among the 50 worst charities, based on money spent on fundraising over a decade.

Source: Tam Tampa mpa Bay Times and Center for Investigative Reporting

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

ASCO 2013

A New Combo to Prevent Nausea and Vomiting NEPA—a combination of netupitant and palonosetron—appears promising Chicago—A Phase III study has demonstrated that NEPA (Helsinn), a fixeddose combination of oral netupitant and palonosetron, is superior to oral palonosetron alone in preventing chemotherapy-induced nausea and vomiting (CINV). The study was presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract LB9514). The multinational study randomized 1,455 chemotherapy-naive patients receiving anthracycline-based chemotherapy to receive either NEPA (300 mg of netupitant plus 0.5 mg of palonosetron) or 0.5 mg of palonosetron. Patients received these drugs 60 minutes before receiving chemotherapy. Thirty minutes after chemotherapy, all patients also received dexamethasone: 12 mg if they were receiving NEPA and 20 mg if they were receiving palonosetron. Patients receiving NEPA had improved outcomes in the primary efficacy end point: complete response, no emesis and no rescue medication during the delayed CINV phase, which occurs 25 to 120 hours after chemotherapy (Table). David Ettinger, MD, a professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, who was not involved with the study, said the new

Table. Patient Outcomes Complete Response Rates

NEPA Plus DEX, %

Palonosetron Plus DEX, %

P Value

Delayed (25-120 h)

76.9

69.5

0.001

Acute (0-24 h)

88.4

0.047

Overall (0-120 h)

74.3

66.6

0.001

Overall (no significant nausea)

0.020

DEX, dexamethasone; NEPA, NEPA A, netupitant plus palonosetron palonosetrron

The new combination drug is seen as a step forward, but oncologists would much prefer an IV formulation. trial was “excellent.” However, he pointed out that guidelines from the National Comprehensive Cancer Network classify anthracycline-based chemotherapy as highly emetogenic and the standard of care is the three-drug combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone. Because of this, he would like to see a randomized clinical trial that compares this three-drug

combination with NEPA plus dexamethasone. According to Dr. Ettinger, oncologists are unlikely to use an oral CINV medication. An IV formulation of NEPA, however, would be welcomed. Rudolph Navari, MD, a medical oncologist at the South Bend Clinic of Cancer Care Partners in Mishawaka, Ind., also not affiliated with the new study, agreed. “The company [Helsinn]

developed the oral form because it was technically easier to develop and get to market. The company is developing an IV form, but there are some technical issues. An IV form is preferred by oncologists due to reimbursement issues,” Dr. Navari said. “[In addition], patients would have to come to the clinic with the oral form in hand, because oncologists cannot supply the oral form in their clinic. Patients are not reliable in supplying their own oral medications in a timely fashion.” Dr. Navari characterized the study presented at ASCO as significant. “I believe there will be FDA approval,” he commented. “Netupitant would be the second NK-1 receptor antagonist available [aprepitant was the first]; it has efficacy and no significant toxicity,” said Dr. Navari. “But, there needs to be an IV form.” Paola Bonvicini, a spokesperson for Helsinn, confirmed that the company was developing an IV formulation, but would not divulge any other information about its status. —Kate O’Rourke Dr. Ettinger disclosed a consultancy/ advisory role with Biodesix, Boehringer Ingelheim, Gilead Sciences, Lilly and Roche/ Genentech. Dr. Navari had no relevant disclosures.

ASCO 2013

Defining the Ideal Length of Androgen Blockade With radiation, androgen blockade can be halved, Phase III study suggests Chicago—Men with high-risk prostate cancer will fare just as well whether they receive 18 or 36 months of androgen blockade after radiation therapy, according to a Phase III Canadian study presented at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA4510). Although some clinicians are already changing their practice, others say longer patient follow-up is needed. Thirty-six months of androgen blockade has been the standard of care for high-risk prostate cancer. A shortened therapy schedule would reduce health care costs, as well as minimize a long list of side effects, including the emasculating effects of castration syndrome. In the study, investigators enrolled 630 men with node-negative, high-risk prostate cancer, which was defined as T3-4,

prostate-specific antigen (PSA) greater than 20 ng/mL or Gleason score greater than 7. Patients had to have normal hepatic function, no regional disease, no distant metastases and no previous malignancy. All men received radiation therapy to the prostate and pelvis in tandem with androgen blockade for either 18 or 36 months. Androgen blockade

there was no statistically significant difference in rates of overall survival (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.85-1.56; P=0.366) or disease-specific survival (HR, 1.07; 95% CI, 0.62-1.84; P=0.819). Nor were there differences in biochemical failure, use of a second course of androgen blockade or rates of pelvic node metastases.

Although some clinicians are already changing their practice, others say longer patient follow-up is needed. consisted of bicalutamide 50 mg per day for one month and goserelin (Zoladex, AstraZeneca) 10.8 mg every three months. Patient characteristics were well balanced in the two arms. With a median follow-up of 6.5 years,

According to Anthony D’Amico, MD, PhD, the chair of the Genitourinary Radiation Oncology Division at DanaFarber Cancer Institute in Boston, the trial really had a superiority trial design and was underpowered for a

noninferiority study. There have only been 165 deaths in the trial so far, and this was why the hazard ratio for overall survival had such a wide confidence interval. Biostatisticians at Dana-Farber believe the trial requires 275 deaths to assess noninferiority with 1.35 as the confidence interval upper limit, which is what is needed to rule out at most a 35% increased risk for death when using 18 compared with 36 months of androgen blockade with 95% confidence. Based on current death rates, this won’t happen until the median follow-up is 7.5 years. At this point, Dr. D’Amico said, the only thing that clinicians can really conclude is 36 months is not superior to 18 months, but 18 months may be inferior to 36 months. Before the Canadian study, a European see ANDROGEN, N page 16

To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN122”

on Br on B Bre Breast re and Ovarian Cancers Integrating Data, Improving Outcomes Release Date: October 22, 2012

Expiration Date: October 22, 2013

Chair

Faculty

Learning Objectives

Course Format

Stefan Glück, MD, PhD, FRCPS

Ruth O’Regan, MD

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

Interactive Web-based monograph

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

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

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

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

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

Intended Audiences Oncologists

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

Estimated Time for Completion 90 minutes

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

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

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

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

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

ASCO 2013

CHORUS Trial May Change Ovarian Cancer Treatment Chicago—Neoadjuvant chemotherapy plus surgery and chemotherapy is a viable alternative to the standard treatment of primary surgery plus chemotherapy for the first-line treatment of advanced ovarian cancer, according to results of the CHORUS (Chemotherapy or Upfront Surgery in Ovarian Cancer Patients) trial presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract 5500). The study, conducted by researchers in the United Kingdom and Ireland, is expected to change clinical practice. “Without question, CHORUS should have a major impact on community oncology practice,” said Maurie Markman, MD, the senior vice president of clinical affairs and national director for medical oncology at Cancer Treatment Centers of America in Philadelphia. “This is the second excellent evidence-based, Phase III, randomized clinical trial that has revealed the equivalent survival outcome, with substantially less morbidity, associated with the use of neoadjuvant chemotherapy in a subset of patients with advanced ovarian cancer.” The first was a trial from the European Organization for Research and Treatment of Cancer (EORTC-55971; N Engl J Med 2010;363:943-953, PMID: 20818904). CHORUS was designed as a noninferiority trial. Investigators enrolled 552 patients with clinical International Federation of Gynecology and Obstetrics stage III-IV ovarian cancer. Patients were randomized 1:1 to receive

ANDROGEN continued from page 14

trial had tested a six-month schedule of androgen blockade in a similar group of patients with prostate cancer—six months was inferior to the standard 36 months (N ( Engl J Med d 2009;360:25162527, PMID: 19516032). “For now, for high-risk prostate cancer utilizing standard dose radiation of 70 Gy, 36 months of androgen blockade appears to be too

Table. Comparison of Outcomes in CHORUS Trial Neoadjuvant Chemotherapy Up front

Primary Surgery Up front

Hazard Ratio (CI)

Median PFS

11.7 mo

10.3 mo

0.90 (0.75-1.07)

24.5 mo

22.8 mo

0.87 (0.71-1.05)

Debulked to 0 cm residual disease, %

Mortality within 28 d of surgery, %

0.5

5.6

Grade 3+ chemotherapy toxicity

Grade 3/4 complications, %

Discharge within 14 d post-op, %

CI, confidence interval; OS, overall survival; PFS, PFS, progression progression-free free su survival urvival

The addition of neoadjuvant chemotherapy reduces morbidity for advanced ovarian cancer patients, however, the results only apply to those with a poor prognosis. either the standard treatment of primary surgery plus six cycles of platinumbased chemotherapy, or three cycles of platinum-based therapy before and after the surgery. Baseline characteristics were well balanced in both arms. Only about 30% of patients had a performance status of 0.

Progression-free survival and median overall survival were similar in the two arms (Table). Patients receiving neoadjuvant therapy were more likely to achieve optimal debulking, were less likely to die within 28 days of surgery, and had fewer postoperative complications, except for hemorrhage which was

much in general, six is too little and 18 months of hormonal therapy may be just right, but we need a little more time to tell,” said Dr. D’Amico. Oliver Sartor, MD, a prostate cancer expert and the medical director of Tulane Cancer Center in New Orleans, said Dr. D’Amico was technically correct about the trial being underpowered, but he thought the data was still convincing. “The fact is that the long-term outcome is approximately the same. The results have given me enough comfort to begin

changing practice,” said Dr. Sartor. He began using the 18-month course when the Canadian researchers presented the data at the ASCO Genitourinary Symposium earlier this year. Dr. Sartor expects the study will change the practice of some community oncologists for some patients. “For the patients who may be in the ‘lower,’ higher-risk category, I feel pretty comfortable with 18 months,” said Dr. Sartor. “If, however, somebody has multiple factors that contribute to a high-risk

higher (7% vs. 3%). Many experts, including Gini Fleming, MD, who directs the breast oncology and gynecologic oncology programs at the University of Chicago, point out that EORTC-55971 and CHORUS were conducted in very sick groups of patients, with survival rates much shorter than in most up-front randomized controlled trials in stage III ovarian cancer. For this reason, she said, the findings cannot be generalized to all patients with advanced ovarian cancer; the findings only apply to poor-prognosis patients. “In a population of ovarian cancer patients that are not able to be optimally cytoreduced or have a poor performance status, neoadjuvant chemotherapy appears to be at least as good in terms of overall survival and safer in terms of overall complications,” said Dr. Fleming. Dr. Markman agreed. “The data clearly indicate that it is highly appropriate to consider the use of this [neoadjuvant] approach to the management of ovarian cancer patients presenting with largevolume disease, when it is felt to be difficult to achieve an optimal surgical outcome with primary surgical cytoreduction,” he said. CHORUS was a United Kingdom Medical Research Council trial. —Kate O’Rourke Dr. Markman had no relevant disclosures. Dr. Fleming disclosed a consultancy or advisory role with Sanofi and research funding from Abbott Laboratories, Corcept and Pfizer.

profile, I am continuing to be relatively conservative and [consider] three years for those patients. If a patient has multiple risk factors, such as a Gleason score 8 to 10, and PSA greater than 20, and T3 disease … if you have three of those, I am leaning toward the longer course.” —Kate O’Rourke Dr. D’Amico had no relevant disclosures. Dr. Sartor disclosed a consultancy for Abbvie and Tolmar.

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.

Write to managing editor Gabriel Miller at gmiller@mcmahonmed.com

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Virtual Cancer Centers:

A Panacea for the Rising Costs of Coordinated Care? Washington—In an era when patients, W providers and insurers are demanding increased coordination of cancer care services but the costs of establishing freestanding cancer centers run in the multimillion-dollar range, hospitals and health systems should consider forming “virtual” cancer centers as less capital-intensive alternatives, said presenters at the Association of Community Cancer Centers’ national meeting. For health systems spread out over multiple campuses or cities, “it may be physically impossible, or unrealistic, to centralize or consolidate all cancer care services,” said Matt Sturm, MBA, a senior manager with ECG Management Consultants’ office in Seattle. But, thinking outside the box, such systems can work to establish a virtual cancer center, in which services normally offered by a single cancer center are organized so that patients and providers can easily access them throughout the system, Mr. Sturm said. A virtual center has been working well for Hawaii Pacific Health (HPH), a network of four hospitals and 44 outpatient clinics across six Hawaiian islands, said Kristen Chun, RN, MBA, the executive director of HPH’s oncology service line in Honolulu. HPH offers adult oncology, pediatric oncology and women’s oncology; and, through partnerships with additional health providers, radiation oncology and clinical trials. Most services are based on Oahu, yet there is also a need to provide services to patients living on the neighboring islands. “It’s really important that our network reach out statewide,” Ms. Chun said. “It’s not uncommon to have patients on Kauai be diagnosed with a serious form of cancer that requires radiation therapy and simply opt out of treatment because they have no interest in traveling to Oahu for six-week periods of time. “What we’re interested in doing is letting patients know we have all the components of a one-site building but we share them in the community and provide care where the patient is. That’s the model that is going to be the most successful for us.” Some patients do travel to other islands for care, and the local Blue Cross and Blue Shield will occasionally fly patients to the mainland United States for treatments not offered locally, like bone marrow transplant. In 2010, HPH worked with Mr. Sturm’s group to evaluate what they could do to better serve patients. Reviews showed that although the individual clinical programs were very good, leaders needed to improve leveraging of programs across the system. Patients and some referring physicians were “very clueless” about the

services offered by HPH, Ms. Chun said: “They would see one hospital, and one site of service, and think that’s what we had, not understanding that the four hospitals can provide pretty much any service you need.” Executives also discovered there were some redundancies in programs; there was no overriding physician leadership; and each hospital was focused on its own needs without an overarching direction.

share in the state, so we’re not out there necessarily to battle for market share. We are out there to make sure that when our patients come to us, we provide them with quality, coordinated care,” she added. Organizations looking to establish virtual cancer centers first need a strategic plan outlining the intended geographic locations the center would serve, the scope of services to be provided, any need to increase alignment with oncologists,

financial barriers to care. The number and type of navigators should match the needs of the program. “Everyone in the program should know what services are offered throughout the organization, where to find those [services] and how to access them,” he said. A six- to eight-member leadership council of physicians and administrators with expertise from different tumor sites or specialties most often governs

A virtual approach to coordinated care helps sidestep the financial burden of building a single comprehensive cancer center. Over the past two and a half years, HPH executives have worked to improve organizational structure, operations, technology and marketing. They named a medical director and an executive director of oncology, who work with the hospital chief operating officers (COOs) and report to HPH leadership. These leaders now work with the hospitals’ COOs, chief medical officers and oncology program managers to review program needs and share resources. All hospitals and clinics use the Epic electronic medical records (EMR) system, which allows for a seamless experience for patients and offers leaders easy access to volumes and outcomes data. They’re working to implement Epic in community physician offices; 150 joined them last year. They also are developing a comprehensive marketing tool to emphasize the scope and quality of services, Ms. Chun said. “We have the second largest market

and how to improve focus on patients, Mr. Sturm said. Successful cancer programs have eight key elements, he said, the first three of which are crucial to a virtual cancer center: physician leadership and expertise; coordinated clinical care through efforts like patient navigation or tumor boards; consistent protocols based on National Comprehensive Cancer Network or other guidelines; investment in diagnostic and treatment technologies; patient support services; making clinical research available to patients; use of quality improvement tools; and screening, outreach and prevention services. Patient navigation, technology and multidisciplinary care are the essential elements of clinical coordination in an oncology program, Mr. Sturm said. In virtual cancer programs, nurse navigators or trained lay personnel are critical to helping patients access clinical care and support services, and overcome logistical or

the centers. Each participating campus or location should be represented. Leaders need to provide strategic direction in research, technology, program development and quality. It is recommended that organizations have both an administrative and a physician leader, with time carved out for this purpose. EMRs also are key to keeping all providers up to date on patient care, and reducing the burden on patients of having to transport files from site to site. And, providers should work to offer multidisciplinary care, either through regular tumor conference meetings or teleconferences to review patient cases and devise treatment plans, or through multidisciplinary clinics where multiple specialists can see a patient in one visit. Finally, Mr. Sturm said, providers must develop and follow consistent clinical protocols so the same high-quality care is offered throughout the network. —Karen Blum

Keys To Making Your Virtual Cancer Center Work The Levine Cancer Institute Experience

evine Cancer Institute (LCI) at Carolinas HealthCare System was established in late 2010 as a one-of-a-kind model of integrated cancer care that connects the resources and cancer expertise of a network of affiliated hospitals and providers located across the Carolinas to improve access to highquality cancer care. This “cancer institute without walls” is connecting to cancer programs at Carolinas HealthCare to provide patients greater access to cancer specialists, treatment, clinical trials and support services, so they don’t have to travel for comprehensive medical care, and setting up a systematic way of treating patients and bringing research studies closer to people in the community. We are currently operating with 15 charter member centers across the Carolinas including numerous centers in the Charlotte region and in South Carolina, including Charleston and Anderson. We have established treatment guidelines and pathways that are being implemented across the system for cancer patients. Our virtual meetings occur with faculty throughout the system via video conferencing and webinars. Our clinical trials are approved through a central IRB and the research teams are coordinated in Charlotte. We believe that seamless communication and consistent care are the keys to delivering optimal patient experiences throughout a system. Community centers may find networks such as LCI attractive for several reasons. As opposed to large, broad-scale

networks, we still have an intimacy where communication occurs easily across the system, enhancing meeting participation and discussion of cases with specialists. Also, the access to cutting-edge clinical trials within the disease-specific sections allows trial par- Edward Kim, MD ticipation and options for patients to be treated close to home. The mission of improving patient care through multidisciplinary approaches, seeking opinions from experts, and emphasizing research opportunities can be attractive, but also difficult. It is always somewhat more challenging to find common ground and consistency of treatment with other experts as opposed to solo decision making. However, by allowing seamless communication with other system physicians, encouraging active participation through clinical pathway development, and access to clinical trials that can be run close to home, both care providers and patients will benefit from the development of networks among cancer centers. —Edward Kim, MD Dr. Kim serves as the chair of the Solid Tumor Oncology and Investigational Therapeutics Department at the Levine Cancer Institute.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

How I Manage ...

Transplant-Eligible Patients With Multiple Myeloma M

ultiple myeloma (MM) accounts for 1% of all cancers and 10% of hematologic neoplasms. In the last decade, survival of patients younger than 50 years with newly diagnosed MM has significantly improved, with the 10-year survival rate increasing from 24.5% to 41.3%. The favorable outcomes shown by multidrug inductions, consolidations and long-term maintenance approaches have challenged the role of autologous stem cell transplantation (ASCT). Progress in our ability to monitor disease during therapy has provided new insights and paved the way to improve existing risk stratification. In this article, some of the pressing questions that are important and practically relevant in the management of transplant-eligible patients with symptomatic MM are addressed.

What bone marrow studies do I perform before initiation of frontline therapy?

exact role of gene-expression profiling is under investigation.

I perform immunohistochemistry to evaluate the percentage of involvement with monoclonal plasma cells. Fluorescence in situ hybridization (FISH) studies can classify MM patients based on the following cytogenetic abnormalities: • high risk: t(14;16), t(14;20), del(17p); • intermediate risk: t(4;14); and • standard risk t(11;14) Cytogenetic findings of deletion 13 and hypoploidy confer intermediaterisk and hyperdiploidy confers standard-risk disease. These tests are recommended by the National Comprehensive Cancer Network (NCCN) guidelines for initial evaluation of bone marrow. The

Should complete (or stringent) remission be an important consideration in selection of initial therapy for MM? Complete response (CR) stringency has evolved, as has our ability to achieve deeper response with novel therapies. CR is defined as absence of monoclonal protein in blood or urine by immunofixation and normal bone marrow; stringent CR also requires a normal κ:λ-free lightchain ratio; and complete molecular response (CMR) now incorporates polymerase chain reaction (PCR) negativity for immunoglobulin gene rearrangement or multicolor flow immunofluorescence

Kenneth Anderson, MD Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute Boston, MA

negativity. Most recently, the value of positron emission tomography/computed tomography scanning is being used to define occult medullary or extramedullary residual disease. Because CMR can be achieved without transplantation using novel therapies, it is now a reasonable goal in most patients.

Which induction therapy is preferred in transplant-eligible MM patients? I select triple-drug therapy for all newly diagnosed patients who are eligible for transplantation. Lenalidomide (Revlimid, Celgene) plus bortezomib (Velcade, Millennium) and dexamethasone, or cyclophosphamide plus bortezomib and dexamethasone are both

We are now at a stage with MM that is similar to where chronic myelogenous leukemia was when imatinib was first able to achieve CMR; that is, now that we can achieve CMR in MM, clinical trials are needed to assess strategies to maintain CMR and define its clinical significance.

AT A GLANCE Proper risk assessment in multiple myeloma is important. Complete molecular response incorporates polymerase chain reaction negativity for immunoglobulin gene rearrangement or multicolor flow immunofluorescence negativity. Currently, triple-drug therapy for all newly diagnosed patients who are eligible for transplantation is preferred. Monitoring of minimal residual disease in MM is emerging as an important strategy. The role of early versus late autologous transplantation is being tested in the IFM/DFCI clinical trial.

reasonable triple-drug combinations. Recently, carfilzomib (Krypolis, Onyx) plus lenalidomide and dexamethasone has looked very promising, as combined they can achieve higher frequency, and deeper, CRs, including CMR.

Which MM patients should be spared up-front autologous stem cell transplantation? At present we do not know the answer to this question. The standard of practice, in my view, is a triple-drug regimen (lenalidomide-bortezomib-dexamethasone, thalidomide-bortezomib-dexamethasone, or cyclophosphamide-bortezomib-dexamethasone) as induction, due to the high overall response rate and extent of response, including CMR assessed by PCR and/or multicolor flow cytometry. After high-dose melphalan and autologous stem cell transplantation (ASCT) therapy, two to four cycles of consolidation therapy are given, often with the same triple-drug regimen used for induction. Consolidation can increase the extent and prolong the duration of response, and markedly enhance the frequency of CMR. This is followed by maintenance therapy with lenalidomide in standard-risk patients or by lenalidomide with bortezomib in high-risk patients. Among the former group of patients with standard-risk MM, lenalidomide doubles progression-free survival (PFS) and prolongs overall survival (OS); among the group with high-risk disease, lenalidomide alone does not confer a similar benefit and so combination maintenance is under evaluation. Integration of novel therapies into the transplant paradigm as induction, consolidation and maintenance has markedly improved outcome. Several randomized trials are now under way to evaluate the value of transplant in the era of novel therapies, and will ultimately define which patients should be spared up-front ASCT (Figure).

Which group of MM patients should receive consolidation therapy? I feel that all transplant patients should receive consolidation therapy. Now that we can measure minimal residual disease with PCR and multicolor flow cytometry, it is possible to demonstrate that consolidation therapy increases the rate of CMR. In terms

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

of its clinical significance, early studies suggest prolonged duration of response in patients who achieve negative minimal residual disease status. We are now at a stage with MM that is similar to where chronic myelogenous leukemia was when imatinib was first able to achieve CMR; that is, now that we can achieve CMR in MM, clinical trials are

needed to assess strategies to maintain CMR and define its clinical significance.

What are important considerations in the selection of maintenance therapy in patients with MM? Maintenance therapy is given to patients who have achieved any extent

Figure. IFM/DFCI 2009 trial in newly diagnosed multiple myeloma patients. An international trial by the French Francophone Myeloma Intergroup (IFM) and Dana-Farber Cancer Institute (DFCI) is evaluating lenalidomide plus bortezomib and dexamethasone induction with or without early high-dose melphalan and stem cell transplantation in myeloma.

Induction

of response to high-dose therapy and transplantation. There have been many attempts over the years to identify a maintenance therapy that can prolong PFS and OS following autologous transplant. The benefit of interferon was outweighed by its side-effect profile. Most recently, thalidomide has prolonged PFS and even OS post-transplant, often also increasing the extent of response achieved. However, progressive neuropathy can develop even with low-dose thalidomide as longterm maintenance therapy is administered. Lenalidomide has prolonged PFS and OS post-transplant in patients with standard-risk MM. There is a two- to three-fold risk for secondary malignancies with the use of lenalidomide maintenance; however, avoiding multiple DNA-damaging agents during induction may reduce this risk, and the benefit of lenalidomide maintenance far outweighs the risk for secondary cancers. In patients with high-risk MM, maintenance with lenalidomide alone does not confer benefit, and so bortezomib often is added. Oral proteasome inhibitors such as MLN9708 (ixazomib,

Takeda) and monoclonal antibodies such as elotuzumab (HuLuc63, BristolMyers Squibb) are among the promising novel agents now under evaluation as maintenance therapy.

References 1. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521-2526, PMID: 17901246. 2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9, PMID: 1897195. 3. van Lammeren-Venema D, Regelink JC, Riphagen II, et al. 18F-fluoro-deoxyglucose positron emission tomography in assessment of myeloma-related bone disease: a systematic review. Cancer. 2012;118:19711981, PMID: 21887677. 4. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686, PMID: 20385792. 5. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stemcell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791, PMID: 22571202.

Collection

Series Editor Consolidation

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

Coming soon Maintenance

How I Manage: Young Adults with AML by Elihu Estey, MD

Lenalidomide Indication Expanded To Include MCL T

he FDA has expanded its approval of lenalidomide (Revlimid, Celgene) to include mantle cell lymphoma (MCL), according to the agency and Celgene. Lenalidomide is now approved for the treatment of patients with MCL whose disease has recurred or progressed following two previous therapies, one of which included bortezomib. Lenalidomide is the first oral therapy in this type of lymphoma, according to a press release from Celgene. The drug is already approved for previously treated multiple myeloma and for transfusiondependent anemia due to deletion 5q myelodysplastic syndromes. The expanded indication is based on the results of MCL-001, a Phase II,

multicenter, open-label, single-arm trial that included 134 patients with MCL who had received prior treatment with rituximab, cyclophosphamide, an anthracycline or mitoxantrone, and bortezomib alone or in combination. Patients were required to have refractory or recurring disease. Celgene reported that in this trial, the overall response rate (the primary end point) for lenalidomide was 26% (34 of 133; 95% confidence interval [CI], 18.4%-33.9%). The complete response rate was 7% (nine of 133; 95% CI, 3.1%-12.5%). The median duration of response was 16.6 months (95% CI, 7.7-26.7). An analog of thalidomide, lenalidomide carries a black box warning for embryo-fetal toxicity as well

as hematologic toxicity and venous thromboembolism. Distribution is restricted to a program called REVLIMID REMS (Risk Evaluation and Mitigation Strategy). Allergic reactions and tumor lysis syndromes, including fatalities, have been reported with lenalidomide. Serious tumor flare reactions, hepatic failure and higher incidences of second primary malignancy also have been reported. The most common grade 3/4 adverse events reported in 5% or more of patients receiving lenalidomide were neutropenia, thrombocytopenia, anemia, pneumonia, fatigue, leukopenia, febrile neutropenia, diarrhea and dyspnea. —George Ochoa

Mantle cell lymphoma stain.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

MDS: Progress Is Slow, but Options on the Horizon Experts discuss difficulty of treating myelodysplastic syndromes New York—Over the past decade and a half, progress in the treatment of myelodysplastic syndromes (MDS) has been halting. David Steensma, MD, an expert in MDS at Dana-Farber Cancer Institute in Boston, likens work in the field to a quote from Albert Einstein, a man who experienced tremendous successes but also knew a thing or two about failure. “‘Success is stumbling from failure to failure with no loss of enthusiasm,’ which is certainly something we have done in the MDS field for the last 15-plus years,” Dr. Steensma said, speaking at the 17th Annual International Congress on Hematologic Malignancies. “We finally have drugs that have some effect, but they do eventually lose that effect,” he said, referring specifically to patients with MDS for whom the hypomethylating agents (HMA) azacitadine or decitabine have stopped working. In the AZA-001 randomized study, published in 2009, patients who received azacitidine (AZA; Vidaza, Celgene) lived a median of nine months longer compared with those who received conventional care, i.e. supportive care or cytotoxic chemotherapy ((Lancet Oncol 2009;10:223-232, PMID: 19230772). Additionally, multiple studies have shown that either AZA or decitabine (DAC; Dacogen, Eisai) can delay the progression to acute myeloid leukemia (AML), but only by about four to six months. Most series show a relatively low complete response rate (CRR) of 10% to 20% with these drugs, and a duration of usually not more than 12 to 18 months when CRR is achieved, although hematologic improvements can improve quality of life (e.g., reduce dependence on blood transfusions). As an example, Dr. Steensma described a 71-year-old woman with trilineage dysplasia, 11% blasts and a normal karyotype. Considered to have refractory anemia with excess blasts-2 (RAEB-2), she soon became transfusion-dependent and began treatment with AZA. Six cycles of treatment with AZA, however, had no effect, and the patient continued to be transfusion-dependent. Had AZA worked, it would likely have extended the patient’s life until it stopped working, which HMAs always do, unless the patient dies first of an unrelated cause. A large study of 435 patients investigating reasons for AZA failure found that 9% didn’t tolerate the drug, 55% never responded to the drug and about 36% experienced some response, mostly hematologic improvement, before the drug stopped working. Of the entire cohort, only 15%

Myelodysplastic syndrome cells.

‘What we really need are new options that fundamentally change the disease. We don’t understand the biology of MDS quite well enough to design these, but that’s coming along.’ —David Steensma, MD were alive two years later ((J Clin Oncol 2011;29:3322-3327, PMID: 21788559). After failure, the 37 (9%) patients who went on to allogeneic transplant survived an additional 19.5 months, but most patients received palliative/ supportive care or unknown subsequent therapy, and this group lived only another 4.1 or 3.6 months, respectively. “Patients thought to be candidates for subsequent chemotherapy [experienced survival] somewhere in-between those two groups,” Dr. Steensma said. At risk for illustrating Einstein’s famous quote associating insanity with the repetition of a procedure, process or approach to a problem and the expectation for different results, “you could d keep going with the AZA or DAC even though the patient is not responding, and you might reason that at least they’re not getting worse,” Dr. Steensma said. “But generally this is not a great strategy. And neither is switching to the other agent, since DAC is almost never effective if AZA didn’t work, and vice versa.” Other options include treating with a chemotherapeutic agent, such as lowdose cytarabine, “which we do sometimes, but we all know that has a very poor response rate,” Dr. Steensma said. For patients in this setting who have excessive blasts, his choice often is clofarabine, an expensive therapy approved not for MDS or AML, but approved for acute lymphoblastic leukemia. “Some patients—in the 20% range—will

respond to that if the HMA has failed them.” Survival with this approach in this setting has not yet been studied and is unknown, Dr. Steensma said. Stem cell transplant is an option for those patients who don’t respond to HMA or whose MDS progresses and are young and healthy enough to consider it, said Eric J. Feldman, MD, the director of hematologic malignancies at Weill Cornell Medical College in New York City. “The alternative—progressive bone marrow failure—means you’ll be in the hospital getting transfusions all the time; you’re going to get infections and it’s not going to be a great life for whatever time you have. A lot of people will take the upfront risks of a transplant, which I think is appropriate.” For patients over the age of 75, who are usually not good candidates for transplant, palliative/supportive care may be the only default. “We might enroll them in clinical trials to see if we can improve things, and that’s certainly appropriate, but so far we haven’t really shown any drug that can improve survival over supportive care at this point. So we just try to keep people’s quality of life as good as possible for as long as possible,” Dr. Feldman said. At present, the drug farthest along in the setting of MDS patients who have failed AZA or DAC is rigosertib (Onconova Therapeutics), a multikinase inhibitor that inhibits the phosphatidyl-inositol-3-kinase (PI3) kinase

pathway. “It also has some effects, probably indirect, on polo-like kinase during the cell cycle, and it reduces cyclin D1 levels,” Dr. Steensma said. “This drug got rolled out into a Phase III trial in MDS patients whose HMAs had failed based on limited Phase I/II data, before there was really a sense of exactly what it did, but the trial is really cooking along, which shows what a major unmet need this is.” Rigosertib is being randomized in a 2:1 ratio against supportive care or lowdose cytarabine in 270 HMA-refractory patients with 5% to 30% blasts and at least one cytopenia. The end point of this study, called ONTIME (ON 01910.NA Trial in Myelodysplastic Syndrome), is overall survival. “The current administration schedule of this drug is really inconvenient. It’s given as a 72-hour continuous infusion every two weeks,” Dr. Steensma said. “However, there is an oral formulation in development. So if this does show effectiveness and prolonged survival as a second-line therapy for MDS, then the oral agent could be used in other studies.” The ONTIME study met its enrollment goal of 270 patients in May, “and hopefully we will have some data within the next year,” Dr. Steensma said. “In this group of patients, with a median survival of only four to six months, you get your answer fairly quickly.” There are “a lot of new ideas, so we’re going to be testing a number of new things,” Dr. Feldman said. “There are a number of new drugs in clinical development, but they’re really early and nothing looks overwhelmingly great.” At present, Dr. Steensma is not optimistic that rigosertib will do much to change the natural history of the disease once AZA or DAC stop working. “It may be quite helpful for some patients, but because it is not targeted to a known common abnormality in MDS, I don’t think rigosertib is going to be a big step forward. At best, I think it will delay progression and improve survival by a few months. But that’s just a guess, and I would be happy to be wrong on this,” he said. “What we really need are new options that fundamentally change the disease. We don’t understand the biology of MDS quite well enough to design these, but that’s coming along.” —Monica Smith Dr. Steensma reported that his is one of 87 centers participating in the ONTIME trial mentioned in the article, but that he received no funding or protected time for this. Dr. Feldman had no disclosures.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

In hematologic malignancies ...

Genomic Revolution Under Way and Moving Fast New York—For those who are tired of hearing that genomic sequencing will soon transform cancer therapy, the wait may be over. The first trickle has begun, and it will likely become a flood of radical change in the treatment of malignancy, particularly hematologic malignancies. This prediction is based on two factors: the speed at which sequencing is now being performed, and confidence that identifying and hitting molecular targets with new drugs represents a critical revolution in medicine. In hematologic malignancies particularly, designing therapy for molecular subsets of specific cancer types is under way, according to Randy D. Gascoyne, MD, from the BC Cancer Agency Centre for Lymphoid Cancer in Vancouver, British Columbia, Canada. Speaking at the 17th International Congress on Hematologic Malignancies, Dr. Gascoyne described an example from work at his own center in diffuse large B-cell lymphoma (DLBCL): Just two years after a published description of a DLBCL mutation, targeted inhibitors are reaching clinical development.

The identification of small subsets of B-cell lymphomas with different pathogenetic mutations is consistent with the development of B cells, which modify their DNA in germinal centers to develop effective antibodies in response to a vast array of antigens. The differences in the risk for malignant transformation from these somatic hypermutations and recombinations make it important to “dissect cancer into molecular and clinically significant subtypes based on cell of origin expression,” Dr. Gascoyne explained. The gain-of-function somatic DLBCL mutation identified in an effort led by the University of British Columbia is known as EZH2Y641 and promotes proliferation through its ability to increase trimethylation ((Blood d 2011;117:2451-2459, PMID: 21190999). In the original publication, it was shown that knockdown of EZH2Y641 in GCB cell lines resulted in cell cycle arrest. The potential of an EZH2 inhibitor was immediately obvious and investigators moved quickly. “In the last four months, three published studies have described inhibitors of EZH2,” Dr. Gascoyne said. “The

‘I think we will be able to sequence all of the major lymphoma types at least before the end of next year.’ —Randy Gascoyne, MD

If, as expected, any of these inhibitors prove viable, “we are going to be able to pick off those cases with this mutation and deliver a very targeted and selective intervention,” Dr. Gascoyne said. He insisted this is no longer a futuristic vision, but just one example in a wave of advances that is expected to accelerate in a relatively short period and eventually dominate hematologic cancer therapy. Using a baseball analogy, Dr. Gascoyne indicated that most molecular targets identified through genomic sequencing will likely be “base hits.” Although there have been home runs, such as the BRAF V600E mutation, which was found in essentially 100% of hairy cell leukemias, and triples, such as the MYD88 mutation, which has been found in about 90% of Waldenstrom’s macroglobulinemia cases, many targets will be found in limited subsets of patients. The DLBCL mutation identified at Dr. Gascoyne’s center was found in just 22% of germinal center B-cell (GBC) DLBCL.

mutation was discovered in 2010, and we are now poised to bring targeted agents forward for this particular molecular target.” Other examples are plentiful. In a study that used RNA sequencing analyses to compare DLBCL and Burkitt’s lymphoma (BL), a mutation in the transcription factor TCF3 emerged as a key pathogenetic event in 38% of sporadic BL cases (Nature ( 2012;490:116-120, PMID: 22885699). While data from this study, with which Dr. Gascoyne was also affiliated, may be applied to identify new therapeutic targets, this and other unique mutations may change how cancers are classified. For example, in intermediate and largely unclassifiable B-cell lymphomas, “it is entirely possible that we can bring some resolution to these ‘gray zone’ cases by having an understanding of the distinct recurrent mutations,” Dr. Gascoyne said. The rapidly growing list of targeted therapies confirms that interrupting specific molecular processes can improve outcomes in cancer, but the

The idea of designing a therapy for a molecular subset of a specific cancer type is no longer a futuristic vision. genomic analyses that uncover a specific molecular mechanism within a cancer type offer an opportunity to create therapies with a far greater specificity of action. The impact is difficult to over-emphasize, according to Dr. Gascoyne, who suggested the parallel might be the discovery of the microscope. “Suffice it to say that the introduction of this technology will revolutionize medicine,” Dr. Gascoyne said. Although this kind of observation has been made for years, Dr. Gascoyne explained that it no longer involves speculation. The major change has been the speed of genomic analysis. He noted that it took 15 years to complete the Human Genome Project at a cost measured in billions of dollars. Due to improvements in technology over the past several years, current machines can now sequence a complete genome in less than a day at a cost of under $1,000. “I think we will be able to sequence all of the major lymphoma types at least before the end of next year,” said Dr. Gascoyne, who noted an intense competition among centers to generate clinically useful data. Genomic studies will reveal more about the origins of hematologic malignancies even as they identify important prognostic markers and new targets of therapy. Assays to evaluate molecular events also have the potential to determine whether therapy is effective. “Are patients going to want to be sequenced? I can tell you that I would want to be sequenced, particularly now that we can do it so well,” Dr. Gascoyne said. Based on the development of targeted therapies to use against specific mutations, “I think the genomic insights are beginning to penetrate practice in terms of DLBCL,” Dr. Gascoyne said. He indicated that one of the immediate limitations will be the development of assays to readily and efficiently identify mutations against which targeted therapies can be applied. However, he expects all of these steps to proceed rapidly from this point. “The status of mutations in hematologic malignancies is already starting to inform treatment decisions,” Dr. Gascoyne said. Based on the speed of current advances, Dr. Gascoyne said it “will

Lymphoma stain.

revolutionize medicine” even in the near term, suggesting that information on molecular subtypes of given cancers will grow exponentially in the coming decade. Laura Pasqualucci, MD, an associate professor of clinical pathology and cell biology at the Institute for Cancer Genetics at Columbia University in New York City, offered a similar but more cautious perspective. She agreed that the momentum in the understanding of the genetic basis of DLBCL, as well as other hematologic malignancies, has been accelerating rapidly, at least partly as a result of improvement in sequencing technologies. However, she cautioned that the complexity of the next steps should not be underestimated. “DLBCL is a heterogeneous disease and is likely due to the disruption of multiple different pathways and genetic abnormalities, as opposed to a single aberration. Thus, one of the challenges we will be facing now, in the ‘postgenomic’ era, is understanding which ones are the alterations—or the combinations of alterations—that drive the success or failure of existing treatments,” Dr. Pasqualucci said. Even after these aberrations are identified, Dr. Pasqualucci noted there are other potential obstacles, such as identifying and characterizing mechanisms underlying the development of secondary resistance. However, even if all this “takes some time to sort out,” she remains impressed with the progress at which “improved knowledge is being translated into the clinical arena.” —Ted Bosworth Dr. Gascoyne has served as an advisor or consultant for Roche Canada, Abbott Laboratories and Genentech. Dr. Pasqualucci reported no relevant conflicts of interest.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Experts Disagree on Role of Transplant in Myeloma New drugs provide powerful options, but little consensus on standard treatments New York—There is a profound disagreement over whether early stem cell transplant (SCT) should still be characterized as a standard early intervention for multiple myeloma (MM), even in relatively young patients. Newer drugs are yielding response rates comparable to transplant, and this development has fundamentally altered traditional approaches to this malignancy. At the 17th International Congress on Hematologic Malignancies, experts debated how these treatments have affected the role of transplant. “The treatment of multiple myeloma is no longer a 100-yard dash; it is a marathon,” said James R. Berenson, MD, the medical and scientific director of the Institute for Myeloma and Bone Cancer Research in West Hollywood, Calif. According to Dr. Berenson, better-tolerated, newer drug therapies now produce response rates that rival those produced with SCT, while preserving future options when the cancer progresses. “Patients need to be able to avail themselves of the opportunity to seek the newer therapies. Reducing that ability with too much prior treatment at too high of a dose is detrimental to their long-term outcomes, which not only includes their overall survival but their quality of life,” Dr. Berenson said. The opposite view, presented by Nikhil C. Munshi, MD, the associate director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute (DFCI) in Boston, is drawn from the results of six major trials that have associated up-front SCT with longer progression-free survival (PFS) and overall survival rates than comparator strategies in relatively young patients with MM. Although toxicity is greater with SCT, the survival advantage is observed even in MM of an advanced stage or with adverse cytogenetics. Although it might be reasonable to initiate treatment with newer therapies, such as bortezomib (Velcade, Millennium) and lenalidomide (Revlimid, Celgene), and then employ SCT as second-line therapy, Dr. Munshi is not convinced that the data supports this. “The question was: Can we delay transplant? And my question is, why?” Dr. Munshi said. Although he acknowledged that there is no well-established survival advantage with employing SCT early rather than late, there is “emerging data” that outcomes overall are better. Generally, SCT can be expected to be attractive early in the development of the disease when patients are healthier, and Dr. Munshi noted that delaying SCT in some cases may be detrimental, especially to those with extensive bone

disease, renal dysfunction and aggressive disease, or those near the age for which SCT becomes relatively contraindicated. The argument for SCT is that it has provided deeper responses than standard-dose therapy, including higher proportions of complete (CR) and molecular responses. In MM, like most other hematologic malignancies, deeper responses track with better outcomes. Although Dr. Munshi acknowledged that the advantage of SCT so far has been predominantly demonstrated against therapies with less activity than those now in widespread use, he said randomized trials using newer agents are needed to overturn the standard. In response, Dr. Berenson, while acknowledging the absence of head-to-head comparisons of SCT and combinations of newer agents, maintained that these newer regimens appear to consistently show greater antimyeloma activity than that of SCT. “What about the high CR rates?” Dr. Berenson said. “Well, guess what? The highest CR rates are no longer being achieved among transplant patients but were seen from the results of the trial involving carfilzomib, lenalidomide and dexamethasone. Moreover, I expect we will do even better as we figure out how to best use these newer agents together.” In regard to carfilzomib (Krypolis, Onyx) in combination with lenalidomide and low-dose dexamethasone (the “CRd regimen”), he specifically cited a recent Phase I/II trial in which 78% of the 36 patients who completed eight or more front-line treatment cycles achieved a near CR or better ((Blood 2012;120:18011809, PMID: 22665938). The 24-month PFS in this group was 92%. Both numbers are the highest yet reported to date in any clinical trial involving treatment of newly diagnosed MM patients.

However, Dr. Munshi does not discount the potential of combining SCT with newer therapies. He cited two studies that demonstrated further improvement in response by SCT following induction therapies with novel agent combinations that provide high responses. This suggests SCT could further add to the high responses now observed with novel combinations. The debate about the role of early SCT could be at least partially resolved with data generated from an ongoing trial known as Intergroupe Francophone du Myelome (IFM)/DFCI 2009 that Dr. Munshi has been closely involved in developing. In the trial, which has completed enrollment, patients between the ages of 18 and 65 with MM and no prior therapy were randomized to receive lenalidomide, bortezomib and dexamethasone (RVD) with or without SCT (see page 19). The primary outcome is PFS. Relative toxicity will be evaluated as a secondary end point even though quality-of-life comparisons are not a part of the formal design. The trial has the potential to establish whether SCT adds benefit when combined with newer agents, but Dr. Berenson is already impressed with the response rates with newer agents without SCT. He is convinced that SCT diminishes the options available to patients who are unable to tolerate treatments necessary to overcome their disease as it progresses over time. In addition to newer agents, patients now have access to combinations of these agents in multiple effective maintenance treatments such as lenalidomide and steroids, better supportive-care approaches and other viable strategies that prolong survival when first-line therapies become ineffective. “After failing their initial treatment,

There is fierce debate over whether or not new drugs for multiple myeloma have replaced stem cell transplant.

patients are no longer going over a cliff like they were in the 1990s when treatment options were so limited,” Dr. Berenson said. “We do not know what is ahead of us, but we do know that survival is now very long, so to compromise the patient’s ability to receive the many effective treatment options now available—and what I hope may be curative therapy in the future—because of the toxicity from high-dose therapy, is also important to consider.” As a result of these specific concerns, Dr. Berenson reported that he is no longer recommending SCT for any of his patients even as a second-line strategy. Although conventional wisdom supports the perspective of Dr. Munshi, whose approach is based on trials uniformly accepted as establishing the standards of clinical practice for MM, Dr. Berenson does not appear to be alone in his position. During a panel discussion that followed the debate, Ola Landgren, MD, PhD, the chief of the MM section at the National Cancer Institute (NCI) in Bethesda, Md., also suggested that the data generated by newer agents has changed practice at the NCI. “In our clinical trials, we no longer transplant up front,” Dr. Landgren said. Based on the kinds of deep responses achieved with chemotherapy alone, he indicated that the toxicity of SCT no longer appears warranted at least as an initial treatment approach. Although Dr. Munshi does not disagree that the activity of the newer agents is very promising, he countered that SCT would be an added consolidation component of this long-term strategy, further improving outcomes. The IFM/DFCI trial has the potential to determine whether chemotherapy alone is as good or better for longterm outcome as SCT plus chemotherapy, but equivocal results could be problematic for resolving this debate if further studies with CRd or other emerging agents suggest that these offer superior activity to those being employed in the IFM/DFCI study. Importantly, the goals in the current era differ from those when MM survival was measured in months. As survival rates increase, the most aggressive regimen may no longer be the best initial option if other options can preserve a good quality of life over a longer period. —Ted Bosworth Dr. Berenson has received research support or served as a speaker, consultant or advisory board member for Celgene, Medtronics, Millennium, Novartis and Onyx. Dr. Munshi has been a consultant for Celgene, Millennium, Novartis and Onyx. Dr. Landgren has no relevant conflicts of interest.

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Science in Oncology

Novel Inhibitors: Targeting the PI3K/AKT Pathway Liverpool, England—Developing inhibitors that target the phosphatidylinositol 3-kinase (PI3K)/AKT pathway is a critical avenue of oncology drug development, but knowing which aberrations to target along this pathway remains difficult, especially because of the possibility that multiple abnormalities may drive a single solid tumor. “Recent research has raised the issue of intratumor heterogeneity, which may lead to an underestimation of the tumor genomics landscape from single tumor biopsy specimens and present major challenges to drug and biomarker development,” said Timothy Yap, MBBS, a clinical research fellow at the Royal Marsden Hospital and The Institute of Cancer Research (ICR) in Sutton, England. “When dealing with solid tumors, there are likely to be multiple drivers of cancer. The challenges arise in determining the critical genetic aberrations responsible for driving cancer in each individual patient.” At the 2012 National Cancer Research Institute (NCRI) conference, Dr. Yap presented recent research efforts to target the PI3K/AKT pathway, which oversees cell growth and survival and is deregulated in many human cancers. The work included preclinical

and clinical development of novel AKT inhibitors with different mechanisms of action, and a pharmacodynamic biomarker assay to help assess how well such novel compounds work in individual patients (abstract PP02).

achieved in multiple human xenograft models and inhibit tumor growth. The investigators also identified two distinct mechanisms of action driving AT13148 and CCT128930; AT13148 primarily modulated genes involved in the apoptosis of tumor cells, where-

biomarker assay using human hair follicles and studied its utility in a Phase I study of the AKT inhibitor MK-2206 ((J Clin Oncol 2011;29:4688-4695, PMID: 22025163). “The aim of this assay is to determine if MK-2206 does indeed inhibit the phos-

‘Recent research has raised the issue of intratumor heterogeneity, which may lead to an underestimation of the tumor genomics landscape from single tumor biopsy specimens and present major challenges to drug and biomarker development.’

—Timothy Yap, MBBS

Specifically, Dr. Yap and his colleagues at the ICR assessed the preclinical pharmacology and antitumor activity of three novel AKT inhibitors—AT7867, CCT128930 and AT13148—developed in collaboration with Astex Pharmaceuticals in Dublin, Calif. In preclinical studies, all three compounds exhibited in vitro activity in multiple human tumor cell lines, including breast and prostate cancers ((Mol Cancer Ther 2010;9:11001110, PMID: 20423992; Mol Cancer Ther 2010;10;360-371, PMID: 21191045; Clin Cancer Res 2012;18:3912-3923, PMID: 22781553). Using in vivo mouse models, Dr. Yap found that active concentrations of the compounds could be

as CCT128930 predominantly modified genes that regulated the cell cycle (Clin Cancer Res 2012;18:3912-3923, PMID: 22781553). Because of its mechanism of action and potent anticancer activity, the researchers selected AT13148 for a firstin-human Phase I trial. Knowing which genetic aberrations drive cancer in individual tumors as well as having a method of screening tumors for predictive biomarkers are important for identifying patients who are more likely to benefit from a drug. Currently, however, “there are no robust, analytically validated and clinically qualified predictive biomarkers of response for PI3K/AKT pathway inhibitors,” Dr. Yap said. To assess the pharmacodynamic activity of AKT inhibitors, Dr. Yap and his colleagues developed an exploratory

phorylation of AKT,” Dr. Yap said. “Measuring such effects can help provide supporting evidence of proof of mechanism for a particular drug.” The trial examined the tolerability of MK-2206 in 33 patients with advanced solid tumors at a range of doses (30, 60, 75 or 90 mg) given on alternate days. Overall, the Phase I study of MK-2206 established the maximum tolerated dose of MK-2206 at 60 mg every other day, and demonstrated that MK-2206 safely induced significant AKT pathway blockade in tumor and hair follicles, with evidence of clinical activity. Dr. Yap was awarded the ACP McElwain Prize at the NCRI conference for his work developing AKT inhibitors. —Victoria Stern

by the

numbers: Accountable Care Organizations This month, nearly one-third of the health systems involved in Medicare’s Pioneer program to create accountable care organizations announced they will be leaving the program after the first year. A few numbers related to the ACO program’s development:

32 | $87.6 million | 0.3 |

Number of organizations selected to be involved in the Pioneer program Gross savings by the 32 programs Amount spending grew in the Pioneer program

Source: “Nine Pioneer ACOs jump ship after first year.” Kaiser Health News. July 16, 2013.

9| $4 million | 0.8 |

Number leaving after first year of the three-year program Amount two programs ended up owing Medicare Amount spending grew in the conventional Medicare program

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Nab-Pac Boosts Metastatic Pancreatic Cancer Survival Nab-paclitaxel plus gemcitabine new first-line standard of care San Francisco—Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane, Celgene), when given before gemcitabine therapy, extended the lives of treatment-naive patients with metastatic pancreatic cancer by nearly two months in the largest Phase III clinical trial in advanced pancreatic cancer completed to date. Median survival increased from 6.7 months for patients who received gemcitabine alone to 8.5 months for patients who received nab-paclitaxel ( =0.000015)—one of more significant (P improvements in overall survival ever reported for this challenging disease. Only a 2011 study of FOLFIRINOX reported longer survival times, a median 11.1 months for people with advanced pancreatic cancer who received the combination therapy (N ( Engl J Med 2011;364:1817-1825, PMID: 21561347). However, FOLFIRINOX—a regimen of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin—is associated with greater toxicities and side effects than standard gemcitabine and is not suitable for many patients. Nab-paclitaxel now joins FOLFIRINOX and gemcitabine as the standards for treating advanced pancreatic cancer, according to the study’s authors. “Nab-paclitaxel with gemcitabine is a new standard for the treatment of patients with metastatic pancreatic cancer and could become the backbone for new regimens,” lead investigator Daniel Von Hoff, MD, the physician-in-chief

and director of Translational Research at the Translational Genomics Research Institute in Phoenix, said. Dr. Von Hoff presented the results at the American Society of Clinical Oncology’s 2013 Gastrointestinal Cancers Symposium (abstract 148). Celgene, which manufactures nabpaclitaxel, funded the trial. The company will submit the data to the FDA as part of an approval application for pancreatic cancer. Nab-paclitaxel is already

One-year survival rose from 22% to 35% in patients who received the combination therapy ((P=0.0002). Two-year survival remains woefully low but more than doubled to 9% from 4% ((P=0.02) with the new therapy. The study was performed at 151 community and academic centers and is “highly representative of typical patients seen in everyday practice situations,” said Dr. Von Hoff. More broadly, the study raises ques-

The study raises questions for the pancreatic cancer community about what the relative roles will be for FOLFIRINOX and nab-paclitaxel in the future and how to sequence the two regimens. marketed for use in metastatic breast cancer and non-small cell lung cancer. MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) randomly assigned 861 patients with previously untreated metastatic adenocarcinoma of the pancreas to receive 125 mg/m2 of nab-paclitaxel followed by 1,000 mg/m2 of gemcitabine on days 1, 8 and 15 every four weeks or to 1,000 mg/m2 of gemcitabine weekly for seven weeks, and then on days 1, 8 and 15 every four weeks. Patients who received the nab-paclitaxel/gemcitabine combination experienced a 59% increase in one-year median survival rates over those who received gemcitabine alone.

tions for the pancreatic cancer community about what the relative roles will be for FOLFIRINOX and nab-paclitaxel in the future and how to sequence the two regimens, said Philip Agop Philip, MD, PhD, the director of gastrointestinal oncology at Karmanos Cancer Institute and a professor of oncology at Wayne State University in Detroit. “Obviously, a head-to-head comparison would answer these questions but I’m not sure that a study like that would happen. Whatever happens, we will have to wait several years before we get an answer,” he said. Dr. Philip outlined some key differences between FOLFIRINOX and

nab-paclitaxel. FOLFIRINOX may have an edge in terms of efficacy, according to the two studies, but that may reflect differences in patient populations. The FOLFIRINOX trial was limited to patients in France, whereas MPACT was worldwide. Patients experienced more fatigue and diarrhea with FOLFIRINOX but more neuropathy with nab-paclitaxel. However, the neuropathy may be more rapidly reversible with the newer therapy. In the MPACT study, 17% of patients on nab-paclitaxel experienced peripheral neuropathy compared with less than 1% in the gemcitabine arm. The median time to onset of grade III neuropathy was 140 days from the start of improvement. Patients improved by at least one grade within 21 days and 44% of patients resumed treatment. There were no grade IV neuropathies. Nab-paclitaxel was generally well tolerated; 81% of the nab-paclitaxel and 75% of the gemcitabine doses were given according to the study protocol. Median treatment duration was 3.9 months versus 2.7 months in the gemcitabine arm. —Christina Frangou

The study was funded by Celgene. Dr. Von Hoff reported receiving honoraria and research funding from Celgene and has worked in a consultant or advisory role for Celgene. Dr. Philip reported no conflicts of interest.

Gastrointestinal Cancers Symposium

Second-Line Chemo for Esophagogastric Cancer Validated San Francisco—For the first time, a Phase III study has demonstrated that second-line treatment with docetaxel results in longer overall survival without deterioration in quality of life compared with active symptom control in patients with advanced esophagogastric cancer (EGC), whose disease progressed after first-line chemotherapy. Investigators say the study provides “definitive support” for provision of second-line chemotherapy to patients with this cancer. The study was presented at the 2012 Gastrointestinal Cancers Symposium (abstract LBA4). Second-line chemotherapy is widely used in this very sick patient population but has never been validated in robust trials, largely because of the difficulty

‘Docetaxel should be a standard second-line treatment for esophagogastric cancer, and we think it’s going to be the future standard against which future treatments should be compared.’ —Hugo Ford, MD

of accruing patients. “This is the first trial to show secondline chemotherapy extends survival, without causing deterioration in quality of life,” said Hugo Ford, MD, the lead investigator and the director of cancer services at Addenbrooke’s Hospital in Cambridge, England. “We conclude that docetaxel should be a standard second-line treatment for EGC, and we think it’s going to be the future standard against which future treatments should be compared.” In this trial from the United Kingdom, 168 patients with locally advanced or metastatic esophagogastric adenocarcinoma whose disease progressed within six months of initial chemotherapy were randomly assigned to receive

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Gastrointestinal Cancers Symposium

Oncotype Colon Assay Alters Physicians’ Choices Oncotype appears beneficial in retrospective studies; prospective data needed

he Oncotype DX Colon Cancer Assay (Genomic Health) alters treatment recommendations and may reduce medical costs and improve patient well-being, according to posters presented recently at the 2013 Gastrointestinal Cancers Symposium in San Francisco. “This test is a useful tool for medical oncologists for risk assessment for their stage II patients beyond [how] the clinicopathologic factors alone can help us,” said Saima Sharif, MD, MS, the assistant director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project and an assistant professor of medicine at Temple University School of Medicine in Philadelphia. Dr. Sharif was not involved in the studies presented at the symposium. One of the studies (abstract 453) involved 141 stage II, T3 mismatch repair (MMR)–proficient colon cancer patients from 17 centers in the Mayo Clinic Cancer Research Consortium. The prospective study analyzed treatment decisions for the patients and found that the use of the Oncotype DX Colon Cancer Assay changed treatment decisions 45% of the time, with treatment intensity decreasing for 33% of patients and increasing for 11%. Recommendations for chemotherapy fell from 52% pre-assay to 30% post-assay. A second study (abstract 391) used the same data in a cost and qualityof-life analysis. Given the decrease in actual adjuvant chemotherapy recommendations (a 22% decline from 52% pre-assay to 30% post-assay), average total direct medical costs were calculated to decrease $4,203. The net effect on

average patient well-being was a gain of 0.083 quality-adjusted life-years. In a third study (abstract 349), 30 community-based and 20 university-based oncologists were surveyed to assess the agreement among physicians of their recurrence risk assessments of patients with stage II colon cancer. Each physician made an assessment in 10 cases using only clinicopathologic factors and in 10 separate cases using clinicopathologic factors plus Oncotype DX Colon Cancer recurrence score and MMR tests. Addition of the Oncotype DX Colon Cancer assay significantly increased oncologists’ agreement in their recurrence risk assessments in

either docetaxel 75 mg/m2 every three weeks for up to six cycles or active symptom control, which included any treatment considered appropriate for management including radiotherapy, steroids and supportive medications. Median overall survival among patients who received docetaxel was 5.2 months, about 40% longer than the 3.6-month survival among those who received active symptom control (P ( =0.01). The survival benefit was observed across the different tumor sites and stages of cancer. Patient age or gender had no effect. Johanna C. Bendell, MD, the director of the GI Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tenn., said the study

demonstrates that patients benefit from chemotherapy in the second-line setting but certain subsets of patients are most likely to benefit. In this study, the COUGAR-02 trial, patients who had a longer progression-free interval following their initial therapy and those who had a higher performance status were more likely to respond to second-line treatment with docetaxel. These are the patients who are most likely to feel better and live longer with chemotherapy, she said. “You have to keep these themes in mind when you think about treating this sick population,” Dr. Bendell said. The analyses of quality of life showed no significant differences between the two arms in either function or global health

both university and community settings. “I have used [the Oncotype DX Colon Cancer Assay] for selected cases, particularly those with pT3N0 pathologic stage or when there are conflicting traditional clinicopathologic features that, in some cases, are not supported by a consistently high level of evidence,” said Robin Katie Kelley, MD, an assistant professor of medicine at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, the lead author of the study. She noted that the assay could be helpful “in cases with average-risk, stage II colon cancer without distinct

Oncotype DX Colon Cancer Assay Cost: $3,640 Availability: Launched in January 2010. In June 2012, availability extended to stage III patients. What It Can Do: It is the first multigene expression test developed for the assessment of risk for recurrence in patients with stages II and III disease. What It Cannot Do: It is intended only for use with stage II or III colon cancer patients following surgery. Currently, it does not predict benefit from chemotherapy. Required Sample: The test is performed using formalin-fixed, paraffin-embedded colon tumor tissue obtained by surgical resection or biopsy. Source: Genomic Health

scores. Despite this, patients receiving docetaxel scored significantly better in assessments of symptom control, particularly for pain ((P=0.0008). Neal Meropol, MD, the chief of hematology and oncology at Case Western Reserve University in Cleveland, said the study results demonstrate that “there is not a detriment to patients due to the side effects of this treatment.” The study findings revealed the ill health of the study group. Only 23% of the docetaxel patients and 36% of the active-control patients completed the 18 weeks of therapy. The most common reasons for halting the treatment plan were, in the docetaxel and control arms, respectively: death (15% and 38%), progression of disease (40% and 2%) and

high- or low-risk features.” Dr. Kelley added, “[The test] has been analytically validated for its accuracy, and … has clinical validity from two large randomized data sets.” Dr. Sharif said the Oncotype DX Colon Cancer test “is a reliable assay based on retrospective data available for clinical use. It is yet to be evaluated prospectively in a randomized clinical trial to make treatment decisions and to look at outcomes of disease recurrence and death in patients. It is a useful tool for risk assessment of patients with stage II colon cancer but does not predict benefit from chemotherapy. … Based on each patient’s risk for recurrence, chemotherapy can be offered with the ‘hope’ but no definitive evidence that it will improve outcome of disease recurrence or death from cancer.” Asked how the Oncotype DX Colon Cancer Assay compares with the Oncotype DX Breast Cancer Assay, Dr. Kelley commented, “It is very familiar to the general oncologist in the community who also treats breast cancer.” Dr. Sharif responded, “Oncotype DX for breast has been around longer. It tells us which patients will benefit from chemotherapy while the one for colon does not.” —George Ochoa Dr. Kelley reported receiving research funding from Genomic Health for research on clinical utility of the Oncotype DX Colon Cancer Assay. Dr. Sharif reported involvement with clinical trials from which samples of tumor tissue were used to develop the assay but was not directly involved with its development.

toxicities (31% in the docetaxel group). Patients receiving docetaxel were more likely to experience neutropenia and febrile neutropenia, at 18% and 7% respectively, than control patients. There were no other significant differences in toxicity between the two groups. Besides docetaxel, patients may receive irinotecan and paclitaxel as second-line treatment. —Christina Frangou The study was funded by Cancer Research UK and docetaxel was supplied free of charge by Sanofi-Aventis. Dr. Ford disclosed receiving research funding from Sanofi. Dr. Meropol reported acting as a consultant for Precision Therapeutics. Dr. Bendell reported no relevant disclosures.

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CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

AACR Highlights: Breast, GI and Lung Cancers Washington—Researchers from around the world gave more than 6,000 presentations regarding prevention and treatment of cancer at this year’s American Association of Cancer Research (AACR) meeting. Following are a few highlights.

Older Women Who Skip Mammograms at Higher Risk for Breast Cancer Death Older women with a long period of time between their last mammogram and breast cancer diagnosis may be at increased risk for breast cancer mortality, according to new research (abstract 157). Women aged 75 years or older at diagnosis who had never had a mammogram or who had not had a mammogram in the previous five years were three times more likely to die of breast cancer compared with women who had mammograms within the previous year, according to a multisite review of 9,929 participants in the Women’s Health Initiative diagnosed with breast cancer during a 12-year follow-up. An interval of at least five years between a woman’s last mammogram and breast cancer diagnosis was associated with advanced-stage disease in 23% of women compared with 20% of women with an interval of six to 12 months ((P<0.05). Women with a longer versus shorter interval also were more likely to have estrogen receptor–negative disease (22% vs. 16%; P=0.03). Similar associations were not seen among women aged 50 to 74. “Our findings suggest that regular mammography should be continued for older women every one or two years,” said lead study author Michael Simon, MD, MPH, the leader of the breast multidisciplinary team at the Karmanos Cancer Institute in Detroit. Susan Harvey, MD, the director of breast imaging at Johns Hopkins Hospital in Baltimore, told Clinical Oncology News that none of the guidelines for mammography include an age at which screening should end, although women aged 75 to 85 are at quite high risk for breast cancer. “It’s not logical to stop screening at an age where women can be treated and cured,” she said. The Johns Hopkins breast imaging team recommends annual mammograms for women until the age of 90. After that age, clinical breast exams are recommended.

Black Women Have Higher Breast Cancer Mortality Black women with breast cancer have worse rates of survival compared with members of other racial and ethnic groups, and more often are diagnosed with less treatable types of breast cancer, according to a study by California

researchers (abstract 131). Candyce Kroenke, MPH, ScD, a research scientist at Kaiser Permanente’s Division of Research in Oakland, Calif., and her colleagues studied the link between race and breast cancer survival in a cohort of 1,688 breast cancer survivors from northern California participating in the Life After Cancer Epidemiology and Pathways studies, including 1,213 white women, 132 blacks, 142 Latinas and 154 Asian/Pacific Islanders. Survivors had been treated for luminal A, luminal B, basal-like or HER2-enriched breast cancer. Researchers reviewed mailed questionnaires and medical records, and tested samples of the patients’ tumors to determine molecular subtypes of cancer. After six years of follow-up, 499 women had died, 268 of them from breast cancer. Black women were nearly twice as likely to have died of breast cancer as white women and were less likely than whites to have been diagnosed with the more treatable luminal A or luminal B breast cancer subtypes. After adjusting for cancer subtype and other factors, black women had a significantly higher rate of recurrence and a 71% elevated risk for breast cancer death, Dr. Kroenke said. Latina women had a 45% reduced risk for recurrence compared with whites. Black women were 2.3 times more likely than whites to die of the luminal A subtype of breast cancer; 2.6 times more likely to die of the luminal B subtype; 1.3 times more likely to die of the basal-like subtype and 2.4 times more likely to die of the HER2-enriched subtype. More research is necessary to replicate these findings and tease out why this disparity persists, Dr. Kroenke said. Giuseppe Giaccone, MD, PhD, who moderated a press conference releasing the findings, said blacks also have worse mortality in other types of cancer, including prostate and lung cancer, but it is not yet clear why. “There may be some social aspects adding to survival but studying genetics is essential” to find out more, said Dr. Giaccone, the associate director for

clinical research at the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. The work was funded by the National Cancer Institute.

GIST: Blood Sample Screening Uncovers More Cancer Mutations Than Tumor Biopsies Screening the blood of patients with advanced gastrointestinal stromal tumors (GIST) may be more effective in identifying tumor mutations than tumor biopsies, according to an international study directed by Boston researchers (abstract LB-295). In an exploratory analysis of patients participating in the Phase III GRID (GIST-Regorafenib in Progressive Disease) trial, George Demetri, MD, the director of the Ludwig Center for Cancer Stem Cell Research and Medicine and the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston, and his colleagues assessed GIST genotypes. They isolated DNA from tumor tissue and analyzed it for mutations in the KIT T and PDGFRA genes, the most common drivers of GIST. They also took blood samples in patients following failed therapy with both imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer), the first two FDA-approved therapies for GIST, and analyzed the blood for mutations using BEAMing digital polymerase chain reaction (PCR) technology. The highly sensitive blood test combines digital PCR and flow cytometry technology. Researchers detected mutations in the KIT T gene in 83 of 138 (60%) blood samples and 64 of 99 (65%) tumor tissue samples. When focusing on secondary KIT T mutations that drive resistance to drug therapy, however, they found mutations in 48% of blood samples but only 12% of tumor samples. Nearly half of blood samples in which secondary KIT T mutations were found also harbored multiple secondary mutations. Most resistance mutations were localized in the “activation loop domain” of the gene, which “none of the drugs previously approved by the FDA hit very well,” Dr. Demetri said, and could be a target for future drug development.

Because tumors are heterogeneous, he said, biopsies, which sample only a portion of a tumor, may not provide a complete picture in identifying mutations. “Tumor cells are constantly dying and leaking DNA into the bloodstream,” he said, “so a sophisticated technology to detect these mutant DNA strands may give us a more comprehensive picture of all the mutations in any individual patient.” As GIST tumors develop evolving mutations causing drug resistance, these blood analyses, termed liquid biopsies, have potential to better match patients with the most effective therapies, Dr. Demetri said. BEAMing technology has promise to become a standard part of care in the next five to 10 years for multiple types of tumors and genes, he said. Dr. Giaccone, the study discussion moderator, said the technology might be applied more and more in patients who develop resistance. However, “we have to be aware that heterogeneity in tumors is a reality, so what is caught in the blood may not tell us everything,” he said, adding that some patients may still need extra tests or biopsies. The study was supported by Bayer Oncology. Dr. Demetri is a scientific consultant to several pharmaceutical companies, including Bayer.

Benign Disease Found After Lung Surgery Varies by State Nearly one in 10 older Americans undergoing surgery for suspected lung cancer received a benign diagnosis following surgery, Tennessee researchers have found, and rates of false-positives varied widely by state. Using the Medicare Provider Analysis and Review (MedPAR) Hospital National Limited Data Set from 2009, Stephen Deppen, a doctoral candidate in epidemiology and a database analyst at Vanderbilt University in Nashville, Tenn., and his colleagues evaluated medical data from 25,632 patients nationwide who had lung surgery for known or suspected lung cancers. They found 2,312 patients (9%) had a benign disease diagnosis following surgery. Benign diagnosis was more

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

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

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

3. True or False. In

QUESTIONS

newly diagnosed AML, four of five Phase III, randomized trials have shown a potential benefit from the addition of gemtuzumab ozogamicin (GO; Mylotarg, Wyeth) to induction therapy.

1. True or False. In

chronic lymphocytic leukemia (CLL), evidence of altered precursor messenger RNA (mRNA) splicing due to SF3B1 mutations is associated with more aggressive disease and shorter survival, which can be used as a prognostic marker to improve prediction of disease progression.

4. True

or False. The majority of patients with relapsed/refractoPrimum non nocere. ry diffuse large B-cell lymphoma (DLBCL) do (First, do no harm.) True or False. In not benefit from currelapsed FLT3-mutated acute myeloid rently available salvage strategies. leukemia (AML), a Phase II trial of azacytidine (Vidaza, Pharmion) and True or False. The prospective sorafenib (Nexavar, Bayer/Onyx) was not feasible mainly due to excessive non–myeloablative allogeneic stem cell transplantation in multiple myeloma toxicity.

(NMAM) 2000 trial by the European Group for Blood and Marrow Transplantation (EBMT) showed an improvement in overall survival (OS) with tandem autologous and reduced-intensity conditioning allogeneic transplantation compared with autologous transplant alone. 90

True or False. Banked third-party virus-specific T (VST) cells have a potential to safely and rapidly treat severe or intractable Epstein-Barr virus (EBV), adenovirus (AdV) and cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation.

Y-ibritumomab tiuxetan consolidation in patients who achieved complete remission (CR) or unconfirmed CR compared with the control group.

8. True or False. In normal cytoge-

netic AML, high expression of miR-155 portends favorable prognosis.

7. True or False. Long-term data 9. True from the First-Line Indolent Trial of yttrium-90 (90Y)–ibritumomab tiuxetan in advanced-stage follicular lymphoma showed an estimated 16% higher rate of progression-free survival (PFS) with

or False. Daratumumab (HuMax-CD38, Genmab/Janssen) targets CD138 protein in multiple myeloma (MM). for answers see CONUNDRUMS, S page 30

Denosumab Approved for Giant Cell Tumor of Bone O

n June 13, the FDA approved a new indication for denosumab (Xgeva, Amgen): treatment of adults and skeletally mature adolescents with giant cell tumor of bone (GCTB), a rare and usually noncancerous disease. Administered by subcutaneous injection, denosumab is indicated only in cases where GCTB is unresectable or where surgical resection is likely to result in severe morbidity, such as losing a limb or joint, according to an FDA press release. Denosumab is the first FDA-approved treatment for GCTB, an Amgen press release stated. A receptor activator of nuclear factor-κB ligand inhibitor, denosumab is already indicated for preventing skeletal-related events when cancer has spread to the bones. “Today’s approval of Xgeva provides a needed treatment option for patients with

GCTB who are not surgical candidates or who would otherwise have to undergo extensive, life-altering surgery,” Richard Pazdur, MD, the director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

The FDA approved denosumab, which has orphan product designation, following a priority review. According to the Amgen and FDA press releases, the safety and effectiveness of denosumab for GCTB were established in two openlabel trials enrolling patients with GCTB

prevalent among women (9.8%) than men (8.5%) after surgery. In-hospital mortality was 2.3% for all patients and 2.1% for patients with benign disease. Researchers observed a wide variation in the prevalence of benign disease by state, from 1.3% in Vermont to 25% in Hawaii. The median benign disease rate for all states was 8.8%. The reason for variation was not determined from the study but could result from variations in practice or locally endemic lung diseases, Mr. Deppen said.

Imaging results from computed tomography (CT) scans for suspected lung cancers are not completely clear, he told Clinical Oncology News, but “currently it’s the best we can do with the technology we have.” Some investigators are studying the potential of biomarkers added to imaging to improve diagnosis of lung cancer. The study was prompted by results of the NLST (National Lung Screening Trial), which showed that low-dose CT screening led to a 20% reduction in lung

cancer mortality compared with chest x-ray. However, 96% of positive screening results were false-positives and 24% of follow-up lung resections were negative for lung cancer. The U.S. Preventive Services Task Force is reviewing evidence to recommend for or against screening for lung cancers. The report should be issued later this year, Mr. Deppen said. Richard Battafarano, MD, PhD, the chief of thoracic surgery at the University of Maryland Medical Center

Giant cell tumor of bone.

that was recurrent or unresectable, or in which surgery would lead to severe morbidity. Of the 187 patients evaluated, 47 (25%) had an objective response, with an estimated median time to response of three months. Of those patients, 51% (24) had an eight-month duration of response. In three patients, over an average follow-up period of 20 months, disease progression occurred after an objective response. Safety was evaluated in 304 patients who received at least one dose of denosumab for GCTB. The most common adverse events were arthralgia, headache, nausea, fatigue and pain in the back or extremity. The most common serious adverse events were osteonecrosis of the jaw and osteomyelitis. —George Ochoa

in Baltimore, who has written about benign lung disease following surgery, said the study prompts additional questions. Hawaii has low lung cancer rates, he said, so that may account for the high number of benign cases there. “The challenge is that our best screening test has a high false-positive rate,” he said. “The NLST answers some questions but if we use screenings, we have to come up with a way to deal with the false-positives.” —Karen Blum

CURRENT PRACTICE

CONUNDRUMS continued from page 29

ANSWERS

True. SF3B1 is a critical component of the splicing machinery, which catalyzes the removal of introns from precursor mRNA. Dedicated efforts are needed to investigate the causative link between SF3B1 mutation and CLL pathogenesis. Mutated SF3B1 might be a good therapeutic target for the treatment of CLL if the underlying mechanism of the functional effect of SF3B1 in CLL can be clarified. Wan Y, Wu CJ. SF3B1 mutations in chronic lymphocytic leukemia. Blood. 2013;121:4627-4634, PMID: 23568491.

2. False. The combination of aza-

cytidine and sorafenib was effective for patients with relapsed AML and FLT3ITD in the Phase II setting. Patients received 5-azacytidine 75 mg/m2 intravenously daily for seven days and sorafenib 400 mg orally twice daily continuously; cycles were repeated approximately every month. The response rate was 46%, including 27% complete response with incomplete count recovery (CRi), 16% CR and 3% partial response (PR). The median time to achieve CR/CRi was two cycles (range, one to four), and the median duration of CR/CRi was 2.3 months (range, one to 14.3 months) in 37 evaluable patients. According to the investigators, future studies should evaluate this combination and other combinations of demethylating agents with FLT3 kinase inhibitors both in the relapse and frontline settings. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT3 internal tandem duplication mutation. Blood. 2013;121:4655-4662, PMID: 23613521.

3. True. In contrast to the SWOG 0106

study, four Phase III, randomized trials have shown a potential benefit from the addition of GO to induction therapy and

CLINICAL ONCOLOGY NEWS • AUGUST 2013 • CLINICALONCOLOGY.COM

consolidation therapy (with the exception of the Medical Research Council [MRC] AML16 trial). The positive trials that included the addition of GO include the following: 1) the MRC AML15 study, 2) the Groupe Ouest Est d’Etude des Leucémies Aiguës et Autres Maladies du Sang AML 2006 IR study, 3) the Acute Leukemia French Association 0701 trial for older adults, and 4) the MRC AML16 trial for older adults. Why the SWOG 0106 trial failed to find a similar benefit is not entirely clear. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121:4854-4860, PMID: 23591789.

4. True. According to a review pub-

lished in Hematology, the ASH Education Program, by Christian Gisselbrecht, MD, of the Institut d’Hématologie, Hôpital Saint-Louis in Paris, more than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed. The improvement in outcomes in this heterogeneous disease requires the firm commitment of treating physicians to encourage patients’ participation in well-designed clinical trials. Gisselbrecht C. Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Hematology. 2012;2012:410-416, PMID: 23233612.

5. True. At 96 months, the EBMT-

NMAM2000 study has demonstrated PFS and OS of 22% and 49% compared with 12% ((P=0.027) and 36% ((P=0.030) with tandem autologous/reduced intensity conditioning allogeneic transplant (auto/RICallo) and autologous transplant, respectively. This benefit was observed at the expense of 10% higher non-relapse mortality in the auto/RICallo arm at 36 months (13% vs. 3%; P=0.0004). There were 357 MM patients up to age 69 enrolled in this study. Patients with an HLA-identical sibling were allocated to auto/RICallo (n=108) and those without a sibling donor to autologous transplant

alone (n=249). Importantly, in this study 145 patients without a matched sibling donor received no further treatment following autologous transplant. These positive data favoring auto/RICallo must be interpreted in the context of the evolving treatment paradigm of MM with highly effective and less toxic novel agents during induction, consolidation and maintenance phases of therapy. Gahrton G, Iacobelli S, Björkstrand B, et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMTNMAM2000 study. Blood. 2013;121:5055-5063, PMID: 23482933.

(Programa para el Estudio de la Terapéutica en Hemopatía Maligna) cooperative group study—which compares the benefits of administering 90Y-ibritumomab or rituximab maintenance after rituximabcontaining first-line induction regimens in patients with previously untreated follicular lymphoma—will provide more insight (Clinicaltrials.gov: NCT00662948). Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular nonHodgkin lymphoma: updated results after a median follow-up of 7.3 years from the international, randomized, phase III first-line indolent trial. J Clin Oncol. 2013;31:1977-1983, PMID: 23547079.

6. True. In this multi-institution- 8. False. In normal cytogenetic AML, al study led by Ann Leen, PhD, of Baylor College of Medicine and Texas Children’s Hospital in Houston, a bank of 32 virus-specific lines from individuals with common HLA polymorphisms who were immune to EBV, AdV and CMV was rapidly (<24 hours) safely infused in 50 patients with severe and intractable viral infection. The cumulative rates of CR or PR at 6 weeks post-infusion were 74% (95% confidence interval [CI], 58.5%-89.5%) for the entire group, 66.7% (95% CI, 36.9%-96.5%) for EBV (n=9), 77.8% for AdV (n=18) and 73.9% (95% CI, 51.2%-96.6%) for CMV (n=23). Most of these responses (89%) were durable. Leen AM, Bollard CM, Mendizabal AM, et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood. 2013;121:5113-5123, PMID: 23610374.

7. True. The PFS advantage persisted 90

in patients who received Y-ibritumomab while in CR/CRu after induction, with an estimated eight-year PFS of 48% (i.e., 16% higher than in the control group) and also in patients with a PR after induction with an estimated eight-year PFS of 33% (i.e., 23% higher than in the control group). The actuarial eight-year incidence of treatment-induced myelodysplastic syndromes or AML was 4.2% in the 90Y-ibritumomab group. The ongoing Spanish PETHEMA

miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. High miR-155 expressers had an approximately 50% reduction in the odds of achieving CR and a 60% increase in the risk for death compared with low miR-155 expressers. Prospective validation of these findings is needed. Ongoing clinical development of compounds capable of downregulating microRNA expression in vivo offers hope for designing novel therapies for patients whose outcome is adversely affected by high miR-155 expression levels. Marcucci G, Maharry KS, Metzeler KH, et al. Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia: miR-155 upregulation independently identifies high-risk patients. J Clin Oncol. 2013;31:2086-2093, PMID: 23650424.

9. False. Daratumumab is an emerg-

ing and promising new agent in the treatment of MM. It is a first-in-class human therapeutic CD38-specific antibody with a broad mechanism of action. Daratumumab mediates MM cell death primarily via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. Plesner T, Lokhorst HM, Gimsing P, et al. Daratumumab, CD38 mAB, for the treatment of relapsed/refractory multiple myeloma patients: preliminary efficacy data from a multicenter phase I/II study. J Clin Oncol. 2012 (suppl; abstr 8019).

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature more in-depth coverage of practice-changing studies from the 2013 ASCO Annual Meeting And coverage of the Association of Community Cancer Centers’ (ACCC) national meeting of important financial and economic issues affecting community practices

—————————— Columns —————————— The September issue will also feature How I Manage: Young Adults with Acute Myeloid Leukemia by Elihu Estey, MD And expert commentaries on clinically meaningful research studies by the Levine Cancer Institute

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Harold J. Burstein September 11, 2013 This issue; focusing on breast cancer; includes topics such as clinical implications for breast cancer subsets defined by molecular diagnostics; management of CNS metastases in breast cancer; endocrine therr apy for advanced breast cancer; targeting the pi3k pathway in breast cancer; treating the older breast cancer patient; and novel radiotherapy approaches pp for earlyy breast cancer.

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Mahmoud H. Abdel Kader August 31, 2013 Photodynamic Therapy: From Theory to Application brings attention to this exceptional treatment strategy, which until now has not achieved the recognition and breadth of applications it deserves. The authors, all experts and pioneers in their field, discuss the history and basic principles of PDT, as well as the fundamentals of the theory, methods and instrumentation of clinical diagnosis and treatment of cancer.

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Christopher G. Willett August 11, 2013 This issue, devoted to practical radiation oncology covers topics such as radiotherapy after mastectomy, contemporary radiotherapy in head and neck cancer, image-guided brachytherapy: an update for gynecologic surr geons, radiation therapy in the current management of anal and rectal cancer, novel approaches to treatment of hepatocellular carcinoma and hepatic metastases etastases using us g thermal t e a ablation ab at o and a d thermosensitive t e ose s t e liposomes. poso es CO0813

To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MM112”

Individualizing Therapy in Metastatic Breast Cancer Release Date: October 22, 2012

Chair

Learning Objectives

Linda T. Vahdat, MD

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

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

Faculty

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

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

Expiration Date: October 22, 2013 in integrating this potentially practice-changing data. For these reasons, oncologists require education on clinically relevant recent studies, against a backdrop of evidence- and consensus-based treatment recommendations.

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

Course Format

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

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

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

Intended Audiences Oncologists

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

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

Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement

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

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