April 2014

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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • April 2014 • Vol. 9, No. 4

IMAGES in ONCOLOGY

SABCS 2013

INSIDE SOLID TUMORS NeoALLTo data supports pCR as end point in trials .........................

By the Numbers: Aromatase inhibitor adherence ...............................

6

6

HEMATOLOGIC DISEASE Transplant center volume influences outcomes ................................

Anti–IL-6 antibody effective for Castleman’s disease ........

7

Better Neoadjuvant Regimens With Carboplatin Trials show benefit for triple-negative breast cancer San Antonio—Results from three recent clinical trials demonstrate that clinicians can improve pathologic responses in women with triple-negative breast cancer by including carboplatin in a neoadjuvant regimen.

I-SPY 2 and the Cancer and Leukemia Group B (CALGB) trial 40603 were presented at the 2013 San Antonio Breast Cancer Symposium (SABCS). GeparSixto was presented at see TRIPLE-NEGATIVE, E page 8

Lymphoma lymphoid cell, close-up.

Image courtesy of Science Photo Library

14

Fixing the Health Care Payment System

CURRENT PRACTICE Maurie Markman, MD: Adherence: An underappreciated aspect of cancer care ........

9

Clinicians look for ways to ease effects of saline shortage ..................

14

Alternative medicine queries should be made routinely (but nonjudgmentally) .............

15

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

20

By the Numbers: ICD-10 ....................................

21

How I Manage…

Staying ahead of coming changes Boston—For years, oncologists have been raising the alarm that incentives in the buy-and-bill health care system are perverse. At a town hall discussion during the recent Association of Community Cancer Centers’ National Oncology Conference, several stakeholders weighed in on various potential fixes: clinical pathways, bundling and accountable care organizations (ACOs).

“There is currently no incentive to reduce hospitalizations and reduce ER [emergency room] visits, where there are so many wasted dollars, and see STAYING AHEAD, D page 18

Preventing Relapse After Autologous Transplant for Lymphoma A

utologous hematopoietic stem cell transplantation (auto-HCT) is an important therapeutic strategy for patients with chemosensitive lymphomas with the goal of improving disease-free survival by consolidating responses in highly selected patients. The majority of patients are recommended for this procedure after relapse. However, a small minority of patients with lymphomas undergo auto-HCT as part of front-line therapy. Despite the clear efficacy of auto-HCT in the majority of patients with lymphoma, disease relapse remains a major concern.

Michael R. Bishop, MD Over the past 40 years, there has been very little improvement in outcomes of patients with lymphoma who relapse after HCT.1 Today, these results are even more disappointing because a significant proportion of patients has see HOW I MANAGE, E page 16

RE VIE WS & COMMENTAR IES

Expert Insights From City of Hope Efficacy confirmed: Vismodegib for advanced, metastatic basal cell carcinoma ......... 10 Jae Y. Jung, MD, PhD

Nintedanib improves PFS in second-line docetaxel NSCLC therapy ...................... 12 Karen L. Reckamp, MD

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months

Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

1

8.3 months (95% CI: 6.3, 10.8)

Patients who achieved a PR

1

0

2

4

6

8

10

12

Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: 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 (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. 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 vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. 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. 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. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 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 Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥ 15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia.

Please see accompanying brief summary of Full Prescribing Information on following pages.

Learn more at TREANDAHCP.com.

Reference: 1. Data on file. Teva Pharmaceuticals.

©2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40313 December 2013.

Brief Summary of Prescribing Information for Indolent B-cell NonHodgkin’s Lymphoma That Has Progressed 1 INDICATIONS AND USAGE TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHL Recommended Dosage: g The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.

Dose Delays, y , Dose Modifications and Reinitiation of Therapy py for NHL: TREANDA administration should be delayed in the event of a 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 (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

2.3 Reconstitution/Preparation for Intravenous Administration Ãi«Ì V> ÞÊÀiV ÃÌ ÌÕÌiÊi>V Ê/, ÊÛ > Ê>ÃÊv ÜÃ\ÊUÊÓxÊ }Ê/,

vial: Add 5 mL of only Sterile Water for Injection, USP°Ê UÊ £ääÊ }Ê 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.

2.4 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.

3 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.

4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). 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 frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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 (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reac-

tions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing 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 vigorous hydration 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 [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. 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. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 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.

5.7 Extravasation Injury TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain.

Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal toxicity 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.

6 ADVERSE REACTIONS 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 (5.1); Infections (5.2); Infusion Reactions and Anaphylaxis (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasion Injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. 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.

6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (* 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (* 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain Infections and infestations Herpes zoster Upper respiratory tract infection Urinary tract infection

176 (100)

94 (53)

13 (7)

0

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

18 (10) 18 (10) 17 (10)

5 (3) 0 4 (2)

Number (%) of patients* All Grades Grade 3/4 0 15 (9) 9 (5) 14 (8) 11 (6) 11 (6) 2 (1) 11 (6) 0 11 (6)

System organ class Preferred term Sinusitis Pneumonia Febrile neutropenia Oral candidiasis Nasopharyngitis Investigations Weight decreased Metabolism and nutrition disorders Anorexia Dehydration Decreased appetite Hypokalemia Musculoskeletal and connective tissue disorders Back pain Arthralgia Pain in extremity Bone pain Nervous system disorders Headache Dizziness Dysgeusia Psychiatric disorders Insomnia Anxiety Depression Respiratory, thoracic and mediastinal disorders Cough Dyspnea Pharyngolaryngeal pain Wheezing Nasal congestion Skin and subcutaneous tissue disorders Rash Pruritus Dry skin Night sweats Hyperhidrosis Vascular disorders Hypotension

31 (18)

3 (2)

40 (23) 24 (14) 22 (13) 15 (9)

3 (2) 8 (5) 1 (<1) 9 (5)

25 (14) 11 (6) 8 (5) 8 (5)

5 (3) 0 2 (1) 0

36 (21) 25 (14) 13 (7)

0 0 0

23 (13) 14 (8) 10 (6)

0 1 (<1) 0

38 (22) 28 (16) 14 (8) 8 (5) 8 (5)

1 (<1) 3 (2) 1 (<1) 0 0

28 (16) 11 (6) 9 (5) 9 (5) 8 (5)

1 (<1) 0 0 0 0

10 (6)

2 (1)

*Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Hematology variable

Percent of patients All Grades

Grades 3/4

Lymphocytes Decreased

99

94

Leukocytes Decreased

94

56

Hemoglobin Decreased

88

11

Neutrophils Decreased

86

60

Platelets Decreased

86

25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in * 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval 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; pneumocystis jiroveci pneumonia and pneumonitis. 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 (5.5)] 10 OVERDOSAGE The intravenous LD50 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. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

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COMMENT: Innovation ‘If [Thomas] Edison were an American cancer investigator working in the early 21st century, delays in the supply chain would be the least of his perspiration-inducing problems. His shirt might be soaked with sweat, but his productivity would likely be meager and his name unknown at the patent office. Today, the inspirational idealism of newly minted medical faculty members with a driving ambition to “cure cancer”— oncology’s Edisons—is being smothered under a mountain of red tape, their good intentions crushed by the logistical reality of what it actually takes to open and execute a clinical study...

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...Given the extent of the clinical trial bureaucracy, it sometimes seems a wonder that successful trials occur at all. Imagine if, every time Edison or one of his competitors such as George Westinghouse had an idea, they had to wait nine months and let an application to experiment proceed through numerous committees, each with arbitrary ideas about how the experiments should be run, to get approval to try the idea. We would have no recorded music and no electric fans, and instead of seeing films, we would sit at home and read by gaslight.’

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics

—David P. Steensma, MD, and Hagop M. Kantarjian, MD, in the Journal of Clinical Oncology

Dan Radebaugh, Director of Production and Technical Operations Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 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. TREANDA is an antineoplastic product. Follow special handling and disposal procedures1.

16.2 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 single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial.

16.3 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.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd or its affiliates. All rights reserved.

8/2013 (Label Code: 00016287.06) TRE-40157 This brief summary is based on TRE-008 TREANDA full Prescribing Information.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • APRIL 2014 • 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 Johns Hopkins Kimmel Cancer Center Baltimore, MD

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

Oncology Nursing

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

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

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

Mayo Clinic Rochester, MN

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

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

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

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

Steven Vogl, MD

T

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.

Medical Oncologist New York, NY

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

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Albert Einstein College of Medicine, New York, NY

Infection Control

Mercy Medical Center St. Louis, MO

Edward S. Kim, MD

Richard J. Gralla, MD

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

John W. Finnie, MD

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

Matt Brow

Community Oncology

Genitourinary y Cancer Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

Ephraim Casper, MD

Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

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

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

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

University of Alabama Birmingham, AL

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

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

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

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

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

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.

5

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

SABCS 2013

NeoALLTo Data Supports pCR as End Point in Trials Surrogate end point may speed clinical trials, improve patient access to drugs San Antonio—Updated results from the NeoALLTo trial demonstrate that in breast cancer patients, a complete pathologic response (pCR) from treatment with neoadjuvant trastuzumab and lapatinib correlates with improved event-free survival and overall survival (OS). The results, presented at the San Antonio Breast Cancer Symposium (SABCS; abstract S1-01), support the use of pCR as an end point for breast cancer clinical trials.

The NeoALTTo study enrolled 450 patients with invasive, operable, HER2positive breast cancer, and randomized them to six weeks of treatment with lapatinib (Tykerb, GlaxoSmithKline), trastuzumab (Herceptin, Genentech) or lapatinib plus trastuzumab. Paclitaxel was added to all three arms at week 6 for an additional 12 weeks of neoadjuvant therapy. Following surgery and the administration of three cycles of anthracyclinebased chemotherapy, patients in the lapatinib arm received that drug for 34 weeks; women in the trastuzumab arm received their drug for 34 weeks; and patients in the triple combination arm

received both lapatinib and trastuzumab for 34 weeks.

Previously, researchers reported that patients were more likely to achieve a pCR if they received lapatinib plus trastuzumab (51%) than if they received monotherapy with either lapatinib (25%) or trastuzumab (30%). A pCR was defined at that point as no invasive disease in the breast.

invasive disease in the breast and the axilla, had a 62% lower risk for disease progression, cancer recurrence or death ( =0.0003), and a 65% lower risk for (P death from any cause ((P=0.005).

“The divergence of the curves is much more pronounced in the hormone receptor–negative, HER2-positive subgroup,” said Martine Piccart-Gebhart, MD, PhD, the director of the Medicine Department

‘[This] is encouraging because you know that adjuvant trials in breast cancer take forever, are very time- and money-consuming, and require thousands of patients.’

—Martine Piccart-Gebhart, MD, PhD In an updated analysis from the trial, there were trends for 22% better eventfree survival and 38% better OS rates with the combination therapy compared with trastuzumab, although they were not significant. Women who achieved a pCR before surgery, this time using the FDA’s recommended definition of no

at Jules Bordet Institute in Brussels, Belgium, who presented the results. She said the data was encouraging for the dual combination, but “do not indicate that we should change the standard of care yet.”

The study, she added, provides strong support for the concept of using pCR as an intermediate end point in neoadjuvant

trials in breast cancer. “[This] is encouraging because you know that adjuvant trials in breast cancer take forever, are very time- and money-consuming, and require thousands of patients,” Dr. Piccart-Gebhart said.

Jennifer Litton, MD, an associate professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, said the study was important because it provided further evidence that pCR was “a strong surrogate end point,” one that can be used “to develop new drugs and get them to patients quicker, with a smaller number of patients involved and less cost.”

In September, pertuzumab (Perjeta, Genentech) became the first breast cancer drug to be granted accelerated approval by the FDA for neoadjuvant treatment based on pCR. —Kate O’Rourke Dr. Piccart-Gebhart disclosed consulting fees from Roche. Dr. Litton has received grants and research support from Novartis.

by the

numbers

Aromatase Inhibitor Adherence Generic aromatase inhibitors (AIs) were introduced in 2010. At the recent San Antonio Breast Cancer Symposium, researchers evaluated how their introduction affected treatment adherence and copayments (abstract S3-02). Investigators analyzed data from 13,522 patients, 7,532 who did not switch between hormonal medications and 5,999 who switched at some time. Discontinuation was higher for both tamoxifen and brandname AIs compared with generic AIs. As copayments increase from <$10 for a 30-day supply to a $10-$20 copay and then to a >$20 copayment, the likelihood of discontinuation increases significantly. The message: Make medications more affordable and patients are more likely to stay on them.

Data courtesy of Dawn Hershman, MD

Adjusted Kaplan-Meier curve for continuation of hormonal therapy by drug type.

1.00

0.75

<$10 $10-$20 >$20

0.50

0.25

P<0.001

Proportion of Patients Who Continued Therapy

Adjusted Kaplan-Meier curve for continuation of hormonal therapy by prescription co-payment.

Proportion of Patients Who Continued Therapy

6

1.00

AI-Generic Tamoxifen AI-Brand

0.75

0.50

0.25

P<0.001 0.00

0.00 0

200

400

600

Time (Days)

Adjusted for drug type, age, surgery type, physician specialty, comorbidity, race, education, income, geographic region, Medicare status and prescription deductible type.

800

0

200

400

600

800

Time (Days)

Adjusted for age, surgery type, physician specialty, comorbidity, race, education, income, geographic region, Medicare status, prescription deductible type, adjusted 30-day average prescription copayment.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

7

Transplant Center Volume Influences Outcomes Early readmission has no effect in separate retrospective analysis New Orleans—For patients undergoing stem cell transplant for hematologic malignancies, the volume of cases at a transplant center appears to influence outcomes, according to data presented at the 2013 annual meeting of the American Society of Hematology (ASH). A separate study presented at ASH suggested that hospital readmission within 30 days of a transplant does not affect long-term outcomes, even if it increases costs.

In the study of transplant volume, outcomes were evaluated from 85 centers submitting data on adult allogeneic transplants to the Center for International Blood & Marrow Transplant Research.

When stratified by total volume of allogeneic transplants performed in the year 2010, the unadjusted one-year survival rates were 56% for centers where less than 20 transplants were performed, 58% for 21 to 40 transplants, 63% for 41 to 80 transplants, 62% for 81 to 150 transplants and 66% for more than 150 transplants (Figure).

Several distinctions between low- and high-volume centers may account for differences in outcome, according to lead author Navneet S. Majhail, MD, the director of Cleveland Clinic’s Blood and Marrow Transplant Program, who said the study “highlights substantial variation

in transplant provider and center characteristics.” The data supports further research to investigate modifiable factors that may influence outcome.

In another study, the goal was to evaluate the effect of early readmission on outcome. In this retrospective analysis of 91 consecutive patients with hematologic malignancies undergoing transplant, 38% had a readmission within 30 days

of discharge from the initial transplant admission. In multivariate analysis, only a documented infection predicted readmission, but there was no significant difference in overall survival or nonrelapse mortality in those with or without readmission within 30 days when compared after one year of follow-up.

According to the study’s lead author, Abraham S. Kanate, MD, an assistant

professor at West Virginia University in Morgantown, the data suggests that 30-day readmission is not a predictor of a poor outcome, but he did note that the median costs of care were nearly doubled in those who undergo readmission within 30 days.

—Ted Bosworth Drs. Majhail and Kanate reported no relevant conflicts of interest.

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8

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

Table 1. Selected Grade ≥3 Toxicities in CALGB 40603

TRIPLE-NEGATIVE

Chemo, %

Chemo + Bev, %

Chemo + Carbo, %

Chemo + Carbo + Bev, %

Neutropenia

22

27

56

67

Thrombocytopenia

4

3

20

26

Fatigue

10

12

10

20

continued from page 1

the 2013 annual meeting of the American Society of Clinical Oncology.

Roughly 15% to 20% of invasive breast cancers are triple-negative, meaning the breast cancer cells lack estrogen and progesterone receptors, and do not have an excess of the HER2 protein on their surfaces. Patients with metastatic (stage IV) triple-negative breast cancer have poor prognosis, with a median overall survival between one and two years. In early-stage triple-negative breast cancer, the recurrence rates remain higher than in estrogen receptor–positive cancers of the same clinical stage, even with aggressive adjuvant chemotherapy. However, patients who achieve a pathologic complete response (pCR) with neoadjuvant chemotherapy have a good prognosis and are much less likely to recur than patients who have residual cancer after neoadjuvant treatment.

CALGB 40603 involved 443 patients who had operable clinical stage II to III triple-negative breast cancer (abstract S5-01). Investigators used a 2 × 2 factorial design, with patients receiving paclitaxel (80 mg/m2 weekly for 12 weeks) followed by doxorubicin and cyclophosphamide (60 and 600 mg/m2 every two weeks for four weeks), with or without carboplatin (area under the curve of 6 every three weeks for four weeks) during paclitaxel, and with or without bevacizumab (Avastin, Genentech; 10 mg/kg every two weeks for nine weeks). Surgery was performed four to eight weeks after completion of chemotherapy. Sixty percent of patients were between the ages of 40 and 59 years; 68% had stage II disease; 66% had T2 disease; and the majority of patients were N0 (45%) or N1 (44%).

At SABCS, William Sikov, MD, an associate professor of medicine at Brown University in Providence, R.I., reported that patients receiving carboplatin had higher pCR rates in the breast than those who did not receive carboplatin (60% vs. 46%; odds ratio [OR], 1.76; P=0.00128). Patients receiving bevacizumab also had higher pCR rates in the breast than those who did not receive the anti-angiogenic agent (59% vs. 48%; OR, 1.58; P=0.0089).

Patients who received carboplatin also had higher pCR rates in the breast and axilla combined (54% vs. 41%; OR, 1.71; P=0.0029). There was no statistically significant difference in pCR in the breast and axilla based on receipt of bevacizumab. The investigators found no synergistic interaction between bevacizumab and carboplatin. Patients receiving carboplatin had higher rates of neutropenia, thrombocytopenia and fatigue (Table 1).

Patients receiving bevacizumab had clinically relevant increases in grade

3 hypertension, febrile neutropenia, non-neutropenic infections, bleeding, thromboembolic and surgical complications. “[Given the toxicities], it is difficult to recommend the routine inclusion of bevacizumab in neoadjuvant therapy for triple-negative breast cancer,” said Dr. Sikov. “On the other hand, the results suggest that oncologists could consider the addition of carboplatin to standard neoadjuvant chemotherapy for these patients when response in the breast and axilla are among the goals of treatment.”

Dr. Sikov said the study results were consistent with data reported from the GeparSixto trial, but CALGB 40603 used a better-tolerated and more standard chemotherapy regimen. GeparSixto used a combination of weekly paclitaxel, liposomal doxorubicin, and bevacizumab with or without carboplatin. GeparSixto patients receiving carboplatin had improved pCR rates (59% vs. 38%; P<0.05), but 38% of patients in the carboplatin arms were unable to complete the planned treatment (Table 2).

At SABCS, Hope Rugo, MD, a professor of medicine at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, presented the first results from one experimental arm of I-SPY 2 (abstract S5-02). I-SPY 2 is a neoadjuvant multicenter study that uses a novel adaptive trial design to screen a series of novel agents in combination with standard chemotherapy compared with treatment with chemotherapy alone. These novel agents are simultaneously assessed in multiple, a priori defined disease subsets, and randomization is adapted over

Bev, bevacizumab; Carbo, carboplatin; Chemo, chemotherapy

time within each treatment arm based on response by subtype. To be eligible for enrollment in I-SPY 2, patients must have tumors at least 2.5 cm that are triple-negative, HER2-positive, or hormone receptor–positive and high-risk by the genomic MammaPrint (Agendia) test.

In the results presented by Dr. Rugo, 72 patients, of whom 39 had triple-negative breast cancer, were randomized to receive veliparib (AbbVie) plus carboplatin concurrent with weekly paclitaxel followed by additional chemotherapy with an anthracycline and cyclophosphamide (AC). Sixty-two patients, 21 of whom had triple-negative breast cancer, were randomized to the standard weekly paclitaxel followed by AC neoadjuvant regimen.

The estimated pCR rate was 52% in patients with triple-negative breast cancer who were treated with carboplatin and veliparib and 26% in those who received standard neoadjuvant therapy, corresponding to a 99% likelihood that the combination is superior to control.

Importantly, pCR rates did not increase significantly in hormone receptor–positive and HER2-negative patients (n=33) who received veliparib plus carboplatin (estimated 19% vs. 14%). Patients receiving the veliparib combination had higher rates of grade 3/4 hematologic toxicities including febrile neutropenia (14% vs. 4.5%), neutropenia (37.5% vs.

11.4%), thrombocytopenia (15.3% vs. 0)

and anemia (30.6% vs. 0).

“Toxicity is increased as expected, but was managed well by dose reduction and delay,” said Dr. Rugo. She said the results predict a 90% probability that the addition of veliparib and carboplatin to standard neoadjuvant chemotherapy would be successful in a Phase III trial in patients with triple-negative breast cancer. Such a study will begin recruiting patients this year.

“Three randomized neoadjuvant studies have now established that inclusion of carboplatin increases pCR in triplenegative breast cancer,” Lajos Pusztai, MD, DPhil, director of the Breast Medical Oncology Section at Yale Cancer Center in New Haven, Conn., said at SABCS. “This provides a valuable new treatment option for patients with high-risk, triplenegative breast cancer. The impact on survival may be modest but will be real, I believe. Patient-level benefits other than survival also exist that can be derived from more effective neoadjuvant chemotherapies and should also be considered when selecting a neoadjuvant chemotherapy regimen.”

—Kate O’Rourke Dr. Pusztai disclosed a consultancy/advisor role for Medimmune, Merck, Novartis and Sanofi as well as research funding from Foundation Medicine, Genentech and Merck. Drs. Sikov and Rugo had no relevant disclosures.

‘[Given the toxicities], it is difficult to recommend the routine inclusion of bevacizumab in neoadjuvant therapy for triple-negative breast cancer. On the other hand, the results suggest that oncologists could consider the addition of carboplatin to standard neoadjuvant chemotherapy for these patients when response in the breast and axilla are among the goals of treatment.’

—William Sikov, MD

Table 2. Three Studies Showing Benefit of Carboplatin in Neoadjuvant Therapy in Triple-Negative Breast Cancer pCR Rate in Patients Receiving Chemotherapy, %

pCR Rate in Patients Receiving Chemotherapy Plus Carboplatin, %

P Value

CALGB 40603 (N=443)

41

54

0.003

GeparSixto (N=315)

38

59

<0.05

I-SPY 2 estimated pCR rates (95% probability interval)

26 (11%-40%)

52 (35%-69%)

99% probability that the combination is superior to control

pCR, pathologic complete response

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

Adherence: An Underappreciated Aspect of Care EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

A

recent commentary in a major general medical journal discussing the “epidemic” of obesity and the effect of specific diets on reducing body weight noted that after extensive research and multiple randomized trials, “the only consistent finding among the trials is that adherence—the degree to which participants continued in the program or met program goals for diet and physical activity—was most strongly associated with weight loss and improvements in disease-related outcomes.”1 Should we be surprised? Pick your diet. If the individual in question has been adherent to the dietary (and other) requirements, it is certainly far more likely to be successful in accomplishing its stated goals. Conversely, the lack of adherence by the individual to the specific diet should surely result in an inferior outcome.

Turning to cancer, we should acknowledge that the importance of drug adherence has been underappreciated—or at least inadequately discussed—in the oncology literature.

This issue also is not a novel concept in cancer medicine. In fact, in the early days of the antineoplastic chemotherapy

era, one of the major justifications for switching from the commonly (and successfully) employed multiday oral cyclophosphamide-based strategy for the management of breast cancer to a program in which the alkylating agent was given systemically was a concern for nonadherence to the oral treatment program.2 Even though it was generally well tolerated, oral cyclophosphamide commonly caused mild nausea, which negatively affected patients’ quality of life.

However, one can easily imagine that the psychological impact of this effect would be substantially magnified in a

relevant in settings where effective therapy is characterized by prolonged oral delivery, often over many years. For patients who feel essentially completely normal (as the cancer may be “in remission”), even minor side effects (e.g., fatigue, low-grade nausea) may lead to the decision to skip doses, reduce the planned dose or stop treatment entirely. Of course, the increasing cost of the required “pills” is another potential factor that might decrease adherence to oral antineoplastic drug therapy.3 How often is observed “tumor progression” the result of inadequate (or no) drug

How often is observed ‘tumor progression’ the result of inadequate (or no) drug concentrations?

Further, how frequently will insufficient drug levels biologically facilitate the subsequent emergence of clinically relevant resistant clones? patient who was completely asymptomatic, as would be the case if the drug was given in the adjuvant setting. Thus, a patient’s thinking might go: “What would be the big deal if [the doses in] the last three or four days of each cyclophosphamide cycle were not taken?” As a result, naturally, the patient may actually have felt much better. And, of course, there would likely be “no reason to tell the oncologist or even members of the family what has happened as they would likely not approve.”

With the increasing trend in oncology toward oral antineoplastic agents, the issue of nonadherence once again rears its ugly head. The concern is particularly

losing that clinical state than individuals with a higher adherence rate (n=64; 28.8% vs. 1.5% at two years). In addition, the adherent population had a greater likelihood of remaining on the agent at this same time point (90.6% vs. 64.5%). Further, the investigators identified adherence as the single most important factor defining failure to maintain a complete response.

We should conclude that adherence demands additional discussion and research within the oncology community. One would hope this becomes an important component of future investigative strategies in cancer care.

References 1. Pagoto SL, Appelhans BM. A call for an end to the diet debates. JAMA. 2013;310:687688, PMID: 23989081.

2. Cooper RG, Holland JF, Glidewell O. Adjuvant chemotherapy of breast cancer. Cancer.

1979;44:793-798, PMID: 476594.

concentrations? Further, how frequently will insufficient drug levels biologically facilitate the subsequent emergence of clinically relevant resistant clones?

Evidence of the effect of nonadherence among patients with chronic myelogenous leukemia not taking oral imatinib emphasizes the potential major negative impact of such activity.4 In a group of 87 patients who had achieved a complete cytogenetic response and who were in long-term follow-up, evaluation of adherence to imatinib that used a microelectrode monitoring system revealed that patients (n=23) who were “<85% adherent” had a dramatically greater risk for

3. Kelley RK, Venook AP. Nonadherence to imatinib during an economic downturn.

N Engl J Med. 2010;363:596-598, PMID: 20818898.

4. Ibrahim AR, Eliasson L, Apperley JF, et al.

Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on longterm therapy. Blood. 2011;117:3733-3736, PMID: 21346253.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

by the

numbers

Number of Active Drug Shortages From January 2007 Through June 2013 300

288

On Feb. 10, the Government Accountability Office published a new study of drug shortages in the United States. The bottom line: “Although reports of new drug shortages declined in 2012, the total number of shortages active during a given year— including both new shortages reported and ongoing shortages that began in a prior year— has increased since 2007,” the report said.

Most of the shortages affect generic sterile injectable drugs.

Source: GAO analysis of University of Utah Drug Information Service

Number of active shortages

Drug Shortages 250

New shortages, by year reported

200

Ongoing shortages, which began in prior years

255

201

261

205 195

157

150

137

127

114

100 73

74 56

50

0

40

2007

2008

2009

2010

Year

2011

2012

2013 (Through June 30)

9

10

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

Expert Insights From City of Hope Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care.

This month we continue with commentaries from City of Hope. We hope you find this Reviews & Commentaries section, both here and with additional commentaries at ClinicalOncology.com, to be a valuable tool.

Efficacy Confirmed: Vismodegib for Advanced, Metastatic BCC From the Journal of the American Academy of Dermatology

E

fficacy and safety results from an open-label study of patients with locally advanced or metastatic basal cell carcinoma (BCC) treated with vismodegib (Erivedge, Genentech) have corroborated efficacy and safety data and justified the FDA’s fast-track approval of the drug.

BCC, the most common human malignancy, can usually be cured; however, in cases of metastatic (mBCC) or locally advanced BCC (laBCC), no effective treatment exists. To that end, when an earlier Phase II clinical trial of vismodegib showed promise, the drug received priority FDA approval and the study was ended.

EXPERT INSIGHT Jae Y. Jung, MD, PhD Assistant Professor, Dermatology, City of Hope, Duarte, California

B

CC is the most commonly diagnosed human cancer, with nearly 2 million new cases annually. Surgical excision is curative in most cases, but 2% of these tumors progress locally, becoming inoperable or metastatic.

Although death due to BCC is rare, the economic effects of this cancer are among the highest (only the costs of lung, colorectal, breast and prostate cancers are higher).

Until the development of vismodegib,

In the present study, duration was 5.5 months researchers, led by Anne (range, 0.4-19.6) and mean Lynn Chang, MD, of follow-up for safety was 6.5 months (range, Stanford University School of Med1.4-20.6).

Nearly all patients icine, offer additional information experienced a treatand confirm priment-related adverse event (AE; n=116; or results in an arti97.5%). No significle published in the Journal of the American cant differences in AEs were reported between Academy of Dermatolopatients with laBCC and gy (2014;70:60-69, PMID: Basal cell carcinoma mBCC. Most commonly 24189279). reported AEs were of grades 1 Patients enrolled in this multicenter study were diagnosed or 2, and included muscle spasm (n=84; with mBCC (n=58) or laBCC (n=62). 70.6%), dysgeusia (n=84; 70.6%) and All study participants received 150 mg alopecia (n=69; 58.0%). These results oral vismodegib once daily in 28-day reflect earlier findings. treatment cycles. Median treatment Eight patients (8.4%) achieved

there was no effective systemic treatment for laBCC or mBCC. This study

by Chang et al confirms the safety and efficacy of this important drug. Results of the 119 evaluable patients in the present study were very similar to the initial trial of 33 patients,1 and showed response rates of 31% and 46% for mBCC and laBCC (inoperable), respectively. Eight patients (8%) achieved a complete response and only three patients (all with mBCC) showed progressive disease. This study also confirmed the incidence of common AEs, including muscle spasm, dysgeusia and alopecia. Treatment-related AEs led to discontinuation of drug administration in only two patients during the study.

An illustrative case presented in the article demonstrated partial and complete responses of tumors in a patient previously treated with vismodegib,

complete response to treatment (laBCC, 6; mBCC, 2); 30 patients achieved partial response (laBCC, 20; mBCC, 10); and 47 patients experienced stable disease (laBCC, 27; mBCC, 20) during the course of treatment. No patient with laBCC experienced disease progression, whereas three patients with mBCC exhibited progressive disease during the study.

The nine patients with laBCC who had received previous systemic chemotherapy had a significantly different objective response rate (ORR) than other study participants (0% and 55%, respectively; P=0.002). Stable disease was the best overall response achieved by this group, demonstrating the need for further studies to determine which patients will best benefit from vismodegib treatment.

Interestingly, different tumors on the same patient had variable responses, suggesting that compensatory mutations leading to resistance can be lost as well as gained. suggesting that retreatment can be beneficial for certain patients. Interestingly, different tumors on the same patient had variable responses, suggesting that compensatory mutations leading to resistance can be lost as well as gained.

Mutations within the Hedgehog pathway are responsible for the vast majority of BCCs, with 90% involving loss of Patched and 10% involving activation of Smoothened. Vismodegib is a novel, first-in-class inhibitor of Hedgehog pathway that has shown incredible efficacy for a highly prevalent and

costly cancer. Larger studies to assess predictors of response and long-term outcomes are currently being conducted. Additionally, new drugs targeting the Hedgehog pathway are also in development.

Reference 1. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179, PMID: 22670903.

Dr. Jung reported no relevant financial disclosures.

In the research of advanced cancers

What if inhibiting the PD-1 checkpoint pathway played an important role in restoring immune response to tumor cells?

In a normal state, the immune system recognizes tumors and can mount an active antitumor response1,2 Antigen-presenting cell

Step 1: Tumor releases antigen3

Active T cells

Step 2: Antigen-presenting cells activate T cells that proliferate and migrate to the tumor.

T cells then release apoptosisinducing proteins, which attack the tumor cells3,4

Tumor

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity, by converting active T cells to inactive T cells5-8

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 ligands on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway.

This inhibits activated T cells and suppresses T-cell attack 6-9

PD-1 receptor

Inactive T cells

Bristol-Myers Squibb is researching ways to block the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands to restore T-cell activation, which may play a role in helping the body fight cancer.8,10 PD-1=programmed death 1; PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2.

References: 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 2. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 3. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 4. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway.

Nat Rev Immunol. 2002;2(10):735-747. 5. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 6. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7): 3635-3643. 7. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 8. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation.

Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.pd1pathway.com.

Š2014 Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB00018-01-01 01/14 Printed in USA.

12

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ APRIL 2014 â&#x20AC;˘ CLINICALONCOLOGY.COM

Nintedanib Improves PFS in Second-Line Docetaxel NSCLC Therapy From Lancet Oncology

P

rogression-free survival (PFS) improved in patients with nonsmall cell lung cancer (NSCLC) when treated with a second-line regimen of docetaxel plus nintedanib (Boehringer Ingelheim).

Although a majority of patients with NSCLC respond to first-line platinum-containing therapy, nearly all suffer from disease progression, so there is significant interest in an effective second-line combination treatment. The authors of this Phase III, double-blind, randomized, controlled, international study,

whose principal author was Martin Reck, MD, of Lung Clinic Grosshansdorf, Germany, reported their results (Lancet ( Oncol 2014;15:143155, PMID: 24411639) after following 1,314 patients from 211 centers in 27 countries with confirmed stage IIIB/ IV recurrent NSCLC. Patients were assigned to IV docetaxel 75 mg/m2 on day 1 plus nintedanib 200 mg twice daily on days 2 to 21 every three weeks (n=655), or the same dosage and schedule of docetaxel plus placebo (n=659), until either disease progression or development of unacceptable adverse events (AEs). Median PFS in the nintedanib

EXPERT INSIGHT Karen L. Reckamp, MD Associate Professor of Medicine Co-Director, Lung Cancer and Thoracic Oncology Program City of Hope and Beckman Research Institute Duarte, California

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ngiogenesis plays an essential role in lung cancer development and progression, and many therapies have attempted to target blood vessel formation and maintenance to inhibit cancer growth. Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, was the first antiangiogenic drug approved for use in lung cancer as first-line therapy in combination with chemotherapy.1 This led to numerous trials evaluating both VEGF and VEGF receptor (VEGFR) antibodies as well as small molecule tyrosine kinase inhibitors in combination with chemotherapy, and also as a single-agent treatment, with limited efficacy. Despite this, the relevance of VEGF and targeting angiogenesis in NSCLC remains, and new paradigms for studying these agents and determining the appropriate patients to treat must be developed.

The results presented by Reck and colleagues in Lancet Oncologyy represent a new dawn of excitement for angiogenesis inhibitors in NSCLC. Patients were randomized to receive docetaxel and nintedanib or docetaxel plus

Non-small cell lung cancer.

placebo, and an improvement in PFS in the nintedanib group was seen. However, similar OS (10.1 vs. 9.1 months) and tumor response rates (4.4% vs. 3.3%) were demonstrated in the nintedanib and placebo arms, respectively. Toxicities between arms were not significantly different, but more patients died of AEs, especially infection-related events, in the docetaxel plus nintedanib group.

The authors performed numerous subgroup analyses and found that patients with adenocarcinoma who progressed on first-line treatment within nine months were most likely to benefit from the combination, which highlights

arm was 3.4 months (95% confidence interval [CI], 2.9-3.9) versus 2.7 months (95% CI, 2.6-2.8; hazard ratio [HR], 0.79; 95% CI, 0.68-0.92; P=0.0019). Similar PFS results were reported for all cohorts of patients with adenocarcinoma histology.

In patients with adenocarcinoma whose disease had progressed within nine months of the start of first-line treatment, median overall survival (OS) was significantly more improved in the docetaxel plus nintedanib group (n=206; 12.6 months; 95% CI, 10.615.1) than in the docetaxel plus placebo group (n=199; median, 10.9 months [95% CI, 8.5-12.6] vs. 7.9 months

[95% CI, 6.7-9.1; HR, 0.75; P=0.0073], respectively). These results were mirrored for all patients with adenocarcinoma histology: median OS was 12.6 months (95% CI, 10.6-15.1) in the nintedanib arm (n=322) and 10.3 months in the placebo arm (n=336; HR, 0.83; 95% CI 0.70-0.99; P=0.0359). Grade 3 or worse AEs were more common in the nintedanib group than the placebo group and were consistent with previous reports.

This study, named LUME-Lung 1, was the first to show a survival benefit surpassing one year for a second-line treatment for patients with adenocarcinoma NSCLC.

This study reminds us that we must understand the target and downstream effects when using tyrosine kinase inhibitors. the fact that there is no clear indication of who might derive an advantage from targeting angiogenesis in lung cancer.

Another intriguing finding in both this study and the Phase III trial by Hanna et al that evaluated pemetrexed and nintedanib2 is the low occurrence of antiangiogenic class-effect AEs, including hypertension, bleeding, perforation and thromboembolism. This is a potential advantage of the agent, but brings into question the true target of nintedanib and the effects on NSCLC. Furthermore, the Phase III trial of pemetrexed and nintedanib was discontinued early due to futility, although the analysis of those enrolled demonstrated an improvement in PFSâ&#x20AC;&#x201D;which stimulates additional questions regarding the application of nintedanib for the treatment of lung cancer.

This study reminds us that we must understand the target and downstream effects when using tyrosine kinase inhibitors. The benefit in targeting angiogenesis in lung cancer is complex, and without an optimal tool for patient selection, it is essential to obtain tissue that may be used to identify future biomarkers. Following the publication of this trial, we have learned that ramucirumab, an anti-VEGFR-2 human

immunoglobulin G1 monoclonal antibody, provided a survival advantage when combined with docetaxel over docetaxel alone as second-line therapy for NSCLC.3 We await the presentation of the full results of the trial, but the significance of angiogenesis in lung cancer remains strong and we must use this opportunity to take a fresh look at the implications for patient treatment.

References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550, PMID: 17167137.

2. Hanna NH, Kaiser R, Sullivan RN, et al.

LUME-Lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol.

2013;31(suppl; abstr 8034).

3. Lilly announces ramucirumab phase III lung cancer trial meets primary endpoint of overall survival. https://investor.lilly. com/releasedetail.cfm?ReleaseID=826569.

Accessed March 12, 2014.

Dr. Reckamp discloses that she has received compensation for consulting services from Boehringer Ingelheim.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

Review of Thyroid Cancer Trends Concludes Overdiagnosis From JAMA Otolaryngology— Head & Neck Surgery

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ver the past several decades, thyroid cancer has been overdiagnosed and thus overtreated, according to an analysis of cancer incidence.

The problem is particularly acute in women.

In 2006, Louise Davies, MD, and H. Gilbert Welch, MD, MPH, found increasing incidence of thyroid cancer in the United States from 1973 to 2002. In their latest research, the authors have extended their assessments of thyroid cancer trends to 2009 ((JAMA Otolaryngol Head Neck

Surgg 2014 Feb 20 [Epub ahead of print], PMID: 24557566).

Using population data, cancer incidence and treatment information from the Surveillance, Epidemiology and End Results (SEER) program, the authors found that the frequency of thyroid cancer has tripled since 1975, from 4.9 to 14.3 per 100,000 individuals (absolute increase, 9.4 per 100,000; relative rate [RR], 2.9; 95% confidence interval [CI], 2.7-3.1). Most of this increase is attributable to the detection of papillary thyroid cancer, from 3.4 to 12.5 per 100,000 (absolute increase, 9.1 per 100,000; RR, 3.7; 95% CI, 3.4-4.0).

After detecting these small, sometimes

John H. Yim, MD Associate Professor of Surgery, Division of Surgical Oncology, City of Hope, Duarte, California

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Examples they cited include “opportunistic screening,” such as a physical exam of the thyroid gland in patients with no symptoms; “diagnostic cascade,” by which multiple tests are performed to rule out vague metabolic complaints; and “serendipitous detection,” a suspect finding on imaging done for a completely unrelated reason.

Drs. Davies and Welch suggest that relabeling these incidentally identified neoplasms as something other than cancer may reduce overly aggressive treatment, and recommend clinical trials to compare current treatment with active surveillance without intervention.

The greatest danger in interpreting the SEER and the National Center for Vital Statistics data is that they do not provide any insight into the mechanism of what we are seeing, yet multiple attempts at providing such insight are made anyway.

EXPERT INSIGHT

rs. Davies and Welch conclude that thyroid cancer is being “overdiagnosed.” I think overdiagnosis is an inappropriate term. All of the patients are presumed to have been accurately diagnosed with thyroid cancer, primarily papillary thyroid cancer. The question is whether the thyroid cancer identified, particularly when small, will progress to become symptomatic or deadly. Clearly, some of these thyroid cancers will not only become symptomatic but deadly, resulting in a consistent 0.5 deaths out of every 100,000 individuals annually. This is higher than death rates for testicular, anal, bone and joint, Hodgkin lymphoma and small intestinal cancers according to seer.cancer.gov, and presumably basal cell and squamous cell cancers of the skin. A significantly larger number of patients with thyroid cancer will not die but will not be cured either, and others will progress to local metastasis and even distant metastasis, which may take years. None of these patients can be analyzed in the SEER data.

The greatest danger in interpreting

microscopic, thyroid nodules, the most common therapy is surgery and radioisotope treatment; a total thyroidectomy is performed in 85% of people diagnosed with thyroid cancer.

The authors also found the increase in cancer diagnosis was almost four times greater in women than men during this time period, from 6.5 to 21.4 (14.9 per 100,000 women) compared with 3.1 to 6.9 (3.8 per 100,000 men).

Because mortality from thyroid cancer has remained stable during the long study period (1975-2009), the authors maintained that thyroid cancer is overdiagnosed and likely the result of increased exposure to medical care.

the SEER and the National Center for Vital Statistics data is that they do not provide any insight into the mechanism of what we are seeing, yet multiple attempts at providing such insight are made anyway. For example, one assumption pointing to overdiagnosis is made simply because there is a large increase in incidence of thyroid cancer while mortality remains stable. The implication made is that most of the new cancers identified are not killing patients. Notwithstanding the inability to identify which new cancers identified are killing the patients and which ones aren’t, this assumption simply has not been tested at all in this study.

An example of a similar pattern is seen in the SEER data for another cancer, melanoma. The incidence of melanoma has increased from 12.8 new cases per 100,000 patients in 1985 to 23.6 new cases per 100,000 in 2010, almost doubling over 25 years. Yet the mortality rate has remained completely stable at 2.6 to 2.7 deaths per 100,000 individuals over that same span (seer. cancer.gov). Are we overdiagnosing

melanoma? Obviously the risk for death from a diagnosed melanoma is higher than thyroid cancer, but to discount the very plausible explanation that improved treatment of thyroid cancer has kept mortality stable simply cannot be made from interpreting this data in this way.

Nevertheless, less aggressive measures need to be taken when small thyroid cancers, the bulk of the new cancers, are identified. A thyroid lobectomy, removing only half of the thyroid, will never result in permanent hypoparathyroidism due to the presence of working parathyroids on the other side, and will frequently (i.e., about 80% in patients who have fully functioning thyroids) not require thyroid supplementation or monitoring. The rate of vocal cord paralysis should be less than 1%, and no radioiodine would be given in these cases. The American Thyroid Association already recommends that thyroid cancers less than 1 cm be treated with a thyroid lobectomy.

This should have decreased the total thyroidectomy rate to around 60%, although spread to lymph nodes may

have increased the indications for performing total thyroidectomy, also difficult to analyze from SEER data. If the cutoff were 2 cm, then only one-third of patients would receive total thyroidectomy and radioiodine.

The problem is we cannot follow these patients as easily for recurrence, both local and distant; but given the low mortality rate, perhaps finding a recurrence later would not affect symptoms or mortality. It is a consensus that a randomized clinical trial comparing lobectomy with total thyroidectomy cannot be performed due to the long survival time. Perhaps a randomized clinical trial can be performed comparing observation to surgery with or without radioiodine; but if comparing lobectomy with total thyroidectomy cannot be performed, then the only conclusion that could be reached by observation would be that it decreases survival over perhaps 10 to 20 years. And who would want to be in that observation arm, even 10 to 20 years later?

Dr. Yim reported no relevant financial disclosures.

More REVIEWS and COMMENTARIES from City of Hope Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

ASH 2013

Anti–IL-6 Antibody Effective for Castleman’s Disease Responses similar in pretreated patients and those taking steroids New Orleans—In a multinational, placebo-controlled trial, siltuximab (Janssen), a monoclonal antibody directed against interleukin-6 (IL-6), produced significant clinical improvements in multicentric Castleman’s disease (MCD).

The result is consistent with previous evidence that dysregulated IL-6 production drives MCD, which is a rare lymphoproliferative disorder characterized by lymph node hyperplasia and a variety of symptoms, including fever, weight loss and anemia. The evidence of efficacy with siltuximab comes from the first randomized trial ever conducted in MCD. The responses to siltuximab were characterized as “exciting” by the lead investigator, Raymond Wong, MD, a specialist in hematology at Prince of Wales Hospital in Hong Kong, China, because “there are no approved therapies for Castleman’s disease currently available.” Thirty-eight centers in 19 countries, including the United States, participated in the Phase II trial, which was presented at the 2013 annual meeting of the American Society of Hematology (ASH).

The study enrolled 79 patients who were randomized in a two-to-one ratio to siltuximab or placebo. Patients were required to be symptomatic, but those taking steroids or who had received a previous systemic therapy were included. Patients were excluded if they were positive for human herpesvirus-8 or HIV. The dose of siltuximab was 11 mg/kg, which, like placebo, was administered in a one-hour infusion once every three weeks. A tumor response of at least 18 weeks’ duration, reviewed centrally, was the major criterion for efficacy along with improvement in prospectively defined

symptoms, which were evaluated by the treating investigator.

Both efficacy criteria (tumor response and symptom improvement) were fulfilled in 34% of the 53 patients randomized to siltuximab versus none of the 26 patients randomized to placebo ( =0.0012). The median time to treat(P ment failure was 134 days in those receiving placebo and had not been reached in the siltuximab group ((P=0.0084), even though the median time on treatment was more than two times longer in the siltuximab group (354 vs. 152 days). A durable complete symptom response was achieved in 25% of patients receiving siltuximab versus none of those receiving placebo ((P=0.0037).

in the treatment arms was low and comparable. Of grade 3 or higher AEs that occurred in more than 5% of the study group, fatigue was reported by 9% of siltuximab patients, night sweats by 8%, and infections or infestations by 8%. In the placebo group, 12% of patients had anemia, 12% had dyspnea or another respiratory complaint, and 12% had infections or infestations. The most common of the less severe AEs associated with siltuximab included pruritus in 42%, upper respiratory tract infections in 36%, rash in 34% and peripheral edema in 32%. In the placebo group, the most common AEs were fatigue in 30% and dyspnea in 35%.

Of all participants in the study, about

‘The marked differences between siltuximab and control arms clearly establish a new therapy for Castleman’s disease, a rare illness that currently has no approved treatments.’

—Razelle Kurzrock, MD Laboratory analyses that associated siltuximab with large reductions from baseline in serum levels of C-reactive protein levels and fibrinogen, as well as improvement in erythrocyte sedimentation rate, also provided support for the monoclonal antibody’s efficacy in MCD. All of these values remained relatively unchanged from baseline in patients treated with placebo. The proportion of patients who achieved hemoglobin levels of 15 g/mL or greater was 61% in the siltuximab group versus 0% in those receiving placebo ((P=0.0002).

Although there was one anaphylactic reaction in the siltuximab group and none for placebo, the frequency of grade 3 or higher adverse events (AEs)

60% had received a prior therapy, and approximately 30% were receiving corticosteroids at the time of randomization. When stratified by these characteristics, patients’ responses to siltuximab were similar.

Siltuximab, a chimeric monoclonal antibody that binds to IL-6 to prevent it from reaching cell surface receptors, has been evaluated in early-phase studies against several malignancies, including metastatic renal cell cancer and prostate cancer. It remains an investigational agent, but an application for licensing for use in MCD has been submitted to the FDA. “The efficacy of siltuximab was clearly demonstrated in this study,” said Dr.

Castleman’s disease— plasma-cell variant.

Wong, indicating that it has the potential to become a standard therapy for a disease that has no established treatments.

Razelle Kurzrock, MD, the senior deputy center director of Clinical Science at the University of California, San Diego Moores Cancer Center in La Jolla, agreed that siltuximab appears to be a significant advance. Dr. Kurzrock was a coauthor of an initial study of siltuximab in 18 patients with Castleman’s disease that also showed activity (J ( Clin Oncol 2010:28:3701-3708, PMID: 20625121).

“The marked differences between siltuximab and control arms clearly establish a new therapy for Castleman’s disease, a rare illness that currently has no approved treatments,” Dr. Kurzrock said.

“The results seen in this seminal study are similar to those that we observed in earlier trials of this agent, which showed high rates of response with excellent tolerance in this group of patients.”

—Ted Bosworth Dr. Wong reported financial relationships with Alexion, Amgen, Baxter, Bayer, BiogenIdec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, MSD, Novartis, Pfizer and Roche. Dr. Kurzrock reported a financial relationship with Janssen.

Clinicians Look for Ways To Ease Effects of Saline Shortage A

shortage of IV sodium chloride solution has struck hospitals across the United States, forcing some clinicians to adopt conservative saline measures or to turn to alternative products.

To ascertain the effect of the shortage, the American Society of Health-System Pharmacists (ASHP) surveyed U.S. pharmacy directors in February. Of the pharmacists who responded, 76% reported that the shortage has affected their institutions. Among the pharmacists affected by the shortage, slightly more than half said conservation efforts have been sufficient to preserve supplies. Pharmacists who indicated their supply of saline was inadequate to fulfill patient needs, on the other hand, represented 29% of respondents.

“While the survey does not point to patients being harmed as a result of the shortage, such a severe shortage of this widely used intravenous solution is extremely concerning,” said Paul W. Abramowitz, PharmD, ScD (Hon.), the chief executive officer of ASHP, in a Feb. 11 statement.

‘We’re beginning to see that it’s more difficult to obtain some of the alternative fluids.’

—William L. Greene, PharmD

The ASHP survey revealed that the shortage has had a wider influence among certain areas of care than others. An impact on surgery and perioperative care was reported by 64% of pharmacists, whereas 10% of respondents cited an impact on pediatric care.

At St. Jude Children’s Research Hospital, in Memphis, Tenn., clinicians are “weathering the storm,” said William L. Greene, PharmD, St. Jude’s chief pharmaceutical officer. “Conservation efforts have focused on minimizing waste, especially at the bedside, where allowing longer hang times [up to 48 hours] of simple solutions reduces the need for replacement,” Dr. Greene said. Although changing IV bags at 24 hours is a common infection control

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

Alternative Medicine Queries Should Be Routine (But nonjudgmental) Chicago—If a survey of patients with lung cancer at a tertiary medical center is any indication, about 50% of cancer patients are taking complementary or alternative medicines either for concomitant medical conditions or for the goal of self-treating their cancer and its symptoms. The data provides a strong rationale for routinely inquiring about these agents.

“If patients are not asked, very few will volunteer the information. At least some patients are reluctant to admit to use of alternative medicines because they think their physicians will not approve,” said lead author Joshua Bauml, MD, of the University of Pennsylvania in Philadelphia. Presenting the results of a survey at last year’s annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Bauml said one of the main reasons for collecting the information was to consider potential interactions with conventional medicines that might inhibit a therapy’s efficacy or lead to adverse events.

In this survey, 296 individuals with lung cancer (77.5% response rate) were asked whether they took alternative or complementary medicines and which ones. Information on patient demographics and cancer stage also were collected. The mean age of those surveyed was 63.1 but ranged from 28 to 84 years. About 55% were women. Most patients were white, 12% were black and about 3% were Asian. About 33% had at least a fouryear college degree. Only 21% were never-smokers.

Of those surveyed, 50.9% reported using at least one form of complementary medicine. Vitamins (other than a multivitamin), taken by approximately 30%, were the most common, whereas some form of herb, taken by nearly 20%, was the second most common.

Some form of special diet was reported

by about 15%. Except for homeopathies, taken by less than 3%, all the other alternative treatment techniques involved some form of physical or largely external treatment, such as energy healing, acupuncture, massage or yoga.

There were no significant differences between sex, race, type or stage of lung cancer or whether patients were currently taking a conventional therapy. However, patients younger than age 65 were more likely (P ( =0.02) than older patients to be taking a complementary therapy, as were those with a college degree ((P<0.001) and those who had never smoked ((P=0.007). It is notable that those taking complementary medicine reported a perception of greater control over why they developed cancer.

One goal of inquiring about complementary medicines is to identify those with the potential to impair the efficacy of conventional treatments with a proven benefit, said Dr. Bauml. He noted that several herbs and vitamins have the potential to compete with the hepatic metabolism of chemotherapies.

However, a search of the National Cancer Institute’s (NCI) Office of Complementary and Alternative Medicine (OCCAM) website, and of published articles, such as one

earlier this year ((J Cancer Res Clin Oncol 2013;139:357-365, PMID: 23099993), produces very little evidence of major interactions. More frequently, the word “potential” is used when characterizing most interactions so far identified. Still, it is helpful to be aware of other steps patients are taking. Dr. Bauml suggested a nonjudgmental approach. He noted that cynicism should be tempered by the fact that in most cases there is an absence of evidence for benefit from complementary medicines, rather than evidence of no benefit or harm.

“For those who gain a perception of control over their lung cancer with complementary medicine, this alone may provide some psychological benefit,” Dr. Bauml said.

Asked to comment on the issue, Patricia Parker, PhD, and Lorenzo Cohen, PhD, of the University of Texas MD Anderson Cancer Center in Houston, agreed. Dr. Parker, an associate professor in the Department of Behavioral Science, and Dr. Cohen, the director of the Integrative Medicine Program at MD Anderson, have both written about the topic.

“It is now clear that it is critically important to ask patients about all of their medications including both conventional medicines as well as natural products,

such as herbs and supplements, in order to avoid possible negative drug–drug or drug–herb interactions,” Drs. Parker and Cohen said in a joint statement to Clinical Oncology News.

“For example, selective serotonin reuptake inhibitors and St. John’s wort may be useful to treat depressive symptoms. However, these medicines may also speed up metabolism along the cytochrome P450 metabolic pathway, which may make them contraindicated in breast cancer survivors taking tamoxifen. Additionally, high doses of fish oil may be an anticoagulant and contraindicated before surgery, and high doses of green tea, especially as a supplement or extract, can interfere with certain targeted therapies (e.g., bortezomib, verapamil, irinotecan),” they said.

Contending that natural products and integrative medicine approaches may be supportive and beneficial alongside conventional medications, Drs. Parker and Cohen agreed with Dr. Bauml that discussions of these approaches “are essential.”

—Ted Bosworth Drs. Bauml and Parker reported that they have no relevant financial disclosures.

Dr. Cohen has served as a consultant for Anhui Jinchan Biochemistry Sharers Co.

Web-based resources on integrative and complementary medicines for health care professionals NCI Office of Complementary and Alternative Medicine: http://cam.cancer.gov MD Anderson: www.mdanderson.org/integrativemed Memorial Sloan-Kettering Cancer Center: www.mskcc.org/cancer-care/ integrative-medicine/about-herbs-botanicals-other-products Natural Medicines Comprehensive Database: http://naturaldatabase.therapeuticresearch.com

method due to the perceived increase in risk for contamination over time, a 2009 study found no relationship between length of infusate use and bacterial colonization ((J Clin Nurs 2009;18:3022-3028, PMID: 19821874).

Lactated Ringer’s solution, dextrose and other fluids may provide health care systems with alternatives to saline, which 64% of the ASHP survey population report using. But these are not always good substitutions for sodium chloride solution, Dr. Greene noted; certain medications compatible with saline are incompatible with dextrose, for example, including the antifungal agent caspofungin, as well as the antibiotics daptomycin and meropenem.

The lack of saline has also started to put pressure on the supply of substitute options. “We’re beginning to see that it’s more difficult to obtain some of the

alternative fluids,” Dr. Greene said, “but it’s not elevated to the point where anyone would call it a shortage.”

The FDA, meanwhile, is pursuing the importation of sodium chloride, and other forms of saline may be available. Compounded saline or 0.45% sodium chloride solution, for example, could be used as alternatives to 0.9% saline, said Bona E. Benjamin, BS Pharm, the director of Medication-Use Quality Improvement at ASHP. For health care systems that choose to use compounded sodium chloride, purchasers should “make sure [saline] is compounded by an ethical, licensed pharmacy that observes sterile standards,” she said.

There are few details regarding why saline is in short supply. “Apparently, one manufacturer had some production problems, and that shifted demand to other providers,” Dr. Greene said. “This strain

on supplies was accentuated when another manufacturer had a scheduled shutdown … for maintenance purposes. Production levels simply have not returned to levels which meet demand.”

—Ben Guarino

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

HOW I MANAGE continued from page 1

Michael R. Bishop, MD Professor of Medicine Director, Hematopoietic Cellular Therapy Program University of Chicago Chicago, IL

received multiple lines of chemoimmunotherapy and newer FDA-approved targeted agents, creating a unique subgroup of patients with even higherrisk disease.

Because options are extremely limited once disease has recurred after autoHCT, research efforts have focused on preventing recurrence by carefully maneuvering preparative regimens and via employment of maintenance therapies and strategies to strengthen immune surveillance after HCT.

What is the role of maintenance therapy in mantle cell lymphoma after auto-HCT? For newly diagnosed mantle cell lymphoma (MCL) patients who are deemed transplant-eligible, the use of highdose therapy and auto-HCT is generally accepted as an important component of initial therapy in patients who achieve at least a partial remission with induction therapy. The use of high-dose therapy and auto-HCT in this setting has resulted in improved progression-free survival (PFS) and possibly improved overall survival (OS). These benefits have been observed across the clinical spectrum of patients with MCL, although greater benefit has been observed in patients with low- or intermediate-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) scores than in those patients with high-risk scores. Reported relapse rates after transplant for MCL in first remission vary between 20% and 50% with median follow-up times of three to five years.

The use of maintenance rituximab (RM; Rituxan, Genentech) after conventional therapy, specifically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) in patients with MCL deemed ineligible for transplant has resulted in improved PFS and OS compared with maintenance therapy with interferon-α. In light of these results, as well as others, there has been considerable interest in incorporating rituximab into both conditioning regimens and in the post-transplant setting as maintenance.

Based on the hypothesis that a successful therapeutic approach including

auto-HCT for newly diagnosed MCL should yield a two-year PFS of at least 50%, the Cancer and Leukemia Group B designed a regimen, 59909, in which patients received two or three cycles of rituximab combined with methotrexate and augmented CHOP.2 This was followed by intensification with high doses of cytarabine and etoposide combined with rituximab. Patients then received high-dose chemotherapy (carmustine, etoposide and cyclophosphamide) and auto-HCT. An additional two doses of RM were given at six and seven weeks after HCT. Seventy-eight patients were enrolled into this trial; there were two nonrelapse mortalities, neither occurring during auto-HCT. At a median follow-up of 4.7 years, the two-year PFS was 76% and the five-year PFS was 56%.

The five-year OS was 64%. The authors concluded that the incorporation of

rituximab with auto-HCT might have been responsible for the encouraging outcomes demonstrated in this study.

In a very novel therapeutic approach to the use of post-transplantation rituximab, the second Nordic MCL-2 protocol prospectively analyzed the efficacy of preemptive treatment with rituximab for molecular relapse after autoHCT for MCL.3 All patients with MCL enrolled into this study who underwent auto-HCT and had polymerase chain reaction (PCR) detectable molecular markers (n=78) were followed with serial PCR assessments of minimal residual disease (MRD) in consecutive bone marrow and peripheral blood samples after HCT. In those cases of molecular relapse with increasing MRD levels, patients were offered preemptive treatment with rituximab at 375 mg/m2 weekly for four weeks. Seventy-four of these patients were in complete remission (CR) after auto-HCT. Of those 74 CR patients, 36 experienced a molecular relapse up to six years (mean, 18.5 months) after HCT. Ten of these patients did not receive preemptive treatment mainly due to simultaneous molecular and clinical relapse, whereas 26 patients underwent preemptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse–free survival after preemptive treatment were 1.5 and 3.7 years, respectively. At the time of this report, 38 patients with MCL remained in molecular remission

AT A GLANCE • In lymphomas, options are extremely limited once disease has recurred after auto-HCT; because of this, research efforts have focused on prevention by carefully maneuvering preparative regimens and via employment of maintenance therapies and strategies to strengthen immune surveillance after HCT. • In addition to rituximab, there also has been considerable interest in the use of other agents that have activity against MCL, such as proteasome inhibitors (e.g., bortezomib), immunomodulatory agents (e.g., lenalidomide) and novel targeted agents (e.g., ibrutinib) for maintenance therapy in the post-HCT setting.

• After auto-HCT, there might be a role for maintenance therapy with brentuximab vedotin in patients with HL; the results of the AETHERA trial are eagerly awaited.

• The use of rituximab, as well as other novel agents, requires further prospective study as maintenance therapy after auto-HCT.

for a median of 3.3 years, and 33 were still in clinical CR. These data strongly suggest that there is a role for the postHCT use of rituximab to prevent clinical relapse. However, the timing, dose and duration of therapy have yet to be determined.

In addition to rituximab, there also has been considerable interest in the use of other agents that have activity against MCL, such as proteasome inhibitors (e.g., bortezomib [Velcade, Millennium]), immunomodulatory agents (e.g., lenalidomide [Revlimid, Celgene]) and novel targeted agents (e.g., ibrutinib [Imbruvica, Pharmacyclics]) for maintenance therapy in the post-HCT setting. These agents are highly attractive not only for their individual efficacy, but also for their potential synergistic activity, particularly lenalidomide plus rituximab.

In the setting of relapsed Hodgkin lymphoma, should maintenance therapy after autologous transplant be considered?

Relapsed Hodgkin lymphoma (HL) was one of the first indications for high-dose therapy and auto-HCT, and it still remains a primary indication of chemosensitive relapses and primary refractory disease. In marked contrast to the B-cell (and even T-cell) nonHodgkin lymphomas, the maintenance options for HL post-HCT are relatively limited. The majority of attention has been focused on the conjugated anti-CD30 monoclonal antibody, brentuximab vedotin (Adcetris, Seattle Genetics), which is specifically indicated for the treatment of relapsed HL after auto-HCT. In light of its efficacy in this setting, there have been anecdotal reports and the initiation of prospective trials evaluating brentuximab vedotin as maintenance therapy after auto-HCT for HL. A Phase III study (the AETHERA trial; ClinicalTrials. gov: NCT01100502) of brentuximab vedotin is currently being conducted in patients at high risk for residual HL after auto-HCT. This is a randomized double-blind, placebo-controlled, multicenter trial evaluating the efficacy and safety of brentuximab vedotin and best supportive care compared with placebo and best supportive care in the treatment of residual HL after auto-HCT. Enrollment in this study is complete, and results will be available shortly.

• The CORAL study did not show benefit for rituximab maintenance after auto-HCT.

In the setting of chemosensitive, relapsed indolent lymphomas, do data exist for maintenance therapy after auto-HCT?

• Romidepsin and vorinostat are being evaluated after auto-HCT in peripheral T-cell lymphomas.

This is an area where we have a significant scientific rationale relative to the use of RM after conventional

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chemoimmunotherapy for follicular lymphoma (FL), a relatively large amount of prospective data in the post-HCT setting, and maybe most controversially, as the role of auto-HCT keeps evolving as newer and more efficacious treatment options keep becoming available for FL. Probably one of the most important and informative trials on post-HCT maintenance therapy for FL was performed by the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (EBMT).4 They performed a prospective, randomized trial to assess the efficacy and safety of rituximab as in vivo purging before HCT and as maintenance treatment immediately after high-dose chemotherapy and autoHCT in patients with relapsed, chemosensitive FL. Patients were randomly assigned to receive rituximab once per week for four weeks or observation before HCT and to RM once every two months for four infusions or observation (NM) post-HCT. In all, 280 patients were enrolled into the trial, and the median follow-up was 8.3 years. Relative to the in vivo purging, the 10-year PFS was 48% for those patients who received rituximab before HCT and 42% for the patients who did not; this did not reach statistical significance ((P=0.18). In contrast, RM had a significant effect on PFS (10-year PFS: RM, 54% vs. NM, 37%; HR, 0.66; P=0.012). However, neither rituximab purging nor RM improved OS. The difficulty in using these results is that not all of the patients in this trial received rituximab before enrollment into the study. Because chemoimmunotherapy is now the standard of care as both front-line and subsequent lines of therapy in FL, it is difficult, if not impossible, to extrapolate whether the beneficial effects seen in the EBMT trial would be applicable to current patients with FL who are being considered as potential candidates for auto-HCT. The use of rituximab, as well as other novel agents, needs further prospective study as maintenance therapy after auto-HCT.

Do patients with relapsed diffuse large B-cell lymphoma benefit from maintenance therapy after auto-HCT? Relapsed diffuse large B-cell lymphoma (DLBCL) remains the most frequent indication for auto-HCT among all the lymphomas. However, as has

been emphasized with other lymphomas, relapse remains the primary cause of treatment failure. A relatively large number of trials have looked at the role of maintenance therapy after auto-HCT for DLBCL. Several Phase II trials have demonstrated improved PFS with the use of RM therapy after auto-HCT for DLBCL, but these trials failed to demonstrate a clear survival advantage and suffered a similar disadvantage to studies in FL, in that many patients had not received prior rituximab. As such, interpretation of data from these trials is difficult.

The international CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study partially addressed this issue, as it included patients with relapsed DLBCL who had received or were naive to prior rituximab.5 Patients were randomly assigned to two different salvage regimens: R-ICE (rituximab, ifosfamide, carboplatin and etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin). Patients whose disease was found to be responsive to their respective salvage proceeded to high-dose therapy and auto-HCT. Patients were then randomly assigned to either RM every two months for one year or observation.

The study included 477 patients with relapsed DLBCL; approximately 60% of patients had received prior rituximab, and all had received a CHOPlike regimen. There was no statistical difference in the responses to R-ICE and R-DHAP (overall response rates, 63% vs. 64%, respectively). After autoHCT, 122 patients received RM, and 120 patients were observed only. At a median follow-up time of 44 months, the four-year event-free survival (EFS) rates after transplant were 52% and 53% for the rituximab and observation groups, respectively (P ( =0.7). RM was associated with a 15% attributable risk for serious adverse events after day 100 post-HCT, with more deaths (six vs. three) than in the observation arm. An interesting observation was that prior treatment with rituximab was associated with poorer EFS (47% vs. 59%).

The authors recommended against RM after auto-HCT for relapsed DLBCL. There also has been interest in the use of radioimmunoconjugates in the peri- and post-transplant settings for DLBCL. This interest has been

dampened by the results of the North American Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0401 trial, which randomized relapsed DLBCL patients to receive BEAM (carmustine, etoposide, cytarabine and melphalan) with either iodine-131 tositumomab or rituximab pretransplant and found no difference in two-year PFS and OS.6 Although given in the immediate pretransplant setting, the lack of efficacy has given pause to the use of radioimmunoconjugates in the post-transplant setting.

Taken together, there is little evidence at this time for the use of maintenance therapy, specifically rituximab, after auto-HCT for DLBCL.

What are the interesting ongoing clinical trials addressing this issue?

As previously mentioned, we are awaiting the results of the AETHERA trial in HL. There are a number of ongoing studies evaluating the efficacy of lenalidomide, alone and in combination with other agents such as rituximab, in B-cell malignancies. Another agent under investigation for postHCT maintenance is bortezomib, particularly for MCL. Romidepsin (Istodax, Celgene) and vorinostat (Zolinza, Merck) are being evaluated postHCT in peripheral T-cell lymphomas.

Probably one of the most interesting developments is the remarkable clinical results that have been observed with chimeric antigen receptor (CAR) T-cell therapy in patients with refractory CD20-positive malignances.7 As a considerable percentage of lymphoma patients being considered for autoHCT have histologies that express CD20, the use of CAR T-cell therapy in the post-transplant setting is considered a logical step for this exciting therapy, and clinical transplant trials using this technology are currently under development.

References 1. Wayne AS, Giralt S, Kröger N, et al. Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: introduction. Biol Blood Marrow Transplant. 2013;19:1534-1536, PMID: 24035783.

stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27:61016108, PMID: 19917845.

3. Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:43654370, PMID: 19652064.

4. Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013;31:16241630, PMID: 23547078.

5. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30:44624469, PMID: 23091101.

6. Vose JM, Carter S, Burns LJ, et al. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013; 31:1662-1668, PMID: 23478060.

7. Barrett DM, Singh N, Porter DL, et al.

Chimeric antigen receptor therapy for cancer. Annu Rev Med. 2014;65:333-347, PMID: 24274181.

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

Coming Soon How I Manage Hematopoietic cell transplantation for myeloproliferative neoplasms

by Joachim Deeg, MD Fred Hutchinson Cancer Research Center

2. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous

Clinical Oncology News TWEETS!

Follow us @ClinOncNews And send your Twitter handle to managing editor Gabriel Miller at gmiller@mcmahonmed.com so we can follow you.

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STAYING AHEAD continued from page 1

improve palliative care and end-of-life issues,” said Stanley Marks, MD, the chairman of the University of Pittsburgh Medical Center (UPMC) Cancer Center. “Everything today is driven by billing more chemotherapy, more surgery and more imaging. We need to get away from the quantity drivers and move toward quality.”

Pathways to Care Across the country, some physicians are being paid to follow evidence-based pathways. UPMC’s model of care currently incorporates evidence-based pathways for choosing drug and radiation treatments, and soon the model will add palliative care pathways. “We have efforts under way to better integrate palliative care and lower our hospitalization rate,” Dr. Marks said. “The hospital is one of the highest components of cancer care.” Oncologists at UPMC have become comfortable with focusing on quality instead of drug cost margins.

Some observers think that savings found in the health care system can be used to fix the system itself. “There is just

payments. Kim Thiboldeaux, the president and CEO of Cancer Support Community in Washington, D.C., argued that bundles allowed for the integration of psychosocial interventions.

Dr. Marks said bundles that include drugs do not work because the drug landscape is changing too quickly, with first- and second-line therapy options changing frequently. He added that bundles that include evaluation and management (E&M) codes also do not work because they do not incentivize a doctor to do the extra work on a Friday to keep a patient out of the ER on a weekend. “If you bundle E&M codes, you disincentivize the physician to keep patients out of the hospital,” Dr. Marks said. According to Dr. Marks, radiation therapy was one area where bundling made sense. It involves a procedure with a finite start and end to treatment.

Dr. Kolodziej said adjustments need to be made to the current bundle structure.

“You [should] have a ‘modify’ for the bundle that rewards you for performing better than your in-market competition.

Your bundle would be plastic. It depends

‘There has been a lot of discussion in health care and oncology care about putting the patient at the center—patient-centric care—and I just don’t see it happening.’

—Kim Thiboldeaux so much waste,” Dr. Marks said, pointing to hospitalizations, chemotherapy in the last 14 days of life and the unnecessary use of high-cost drugs. “There are agents out there that are [costing] $10,000 per month that add very little, and often with no survival benefit. We have to rethink using those types of drugs.”

Michael Kolodziej, MD, the medical director for medical oncology strategies at Aetna, pointed out that a study by the Institute of Medicine has estimated that 30% of all clinical care spending could be avoided without worsening patient outcomes. When practices are rewarded for good behavior, Dr. Kolodziej said, they are more likely to have advanced care plans for their patients and take extra steps to reduce hospitalizations. In their hearts, physicians know they should ask a cancer patient with a fever of 99.8 ºF on a Friday afternoon to come to their office to avoid the risk for a weekend hospitalization, but they may not do it unless it is incentivized. “I think there is going to be a redistribution of wealth for high-performance providers,” Dr. Kolodziej noted.

Bundling Payments Participants in the town hall discussion had mixed reviews for bundled

on your performance, on your radiology evidence, laboratory evidence and ER hospitalizations,” Dr. Kolodziej said.

“Your bundle will, maybe, change from quarter to quarter or year to year. You will be incentivized to perform because your bundle will be better.”

According to Byran Litton, MBA, the senior director of U.S. oncology payer and strategy in Eli Lilly & Company’s oncology business unit, pathways and bundles don’t address a major concern: incorporating personalized medicine into the innovation process within the current intellectual property system and having that innovation recognized and appropriately rewarded. “On average, the industry is spending $5 billion for every new product that comes out. Only one drug in 20 that goes into human testing makes it.” These figures come from a 2012 study conducted

by Forbes.

“It’s very positive for all stakeholders in health care that we are now moving into an era of competitiveness,” Mr. Litton said. “In many tumors and stages of disease, there now may be two or three treatment options available for a patient.

Competition is the best form of price containment.”

Chance of five-year stage I breast cancer survival United Kingdom:

78% United States:

97%

In Dr. Kolodziej’s opinion, pharmaceutical companies need to operate in the same way that physicians who operate in a pay-for-performance environment do. “If you don’t perform, you don’t get paid. I think the pharmaceutical industry has to get comfortable with that,” he said. Clinicians need to stop using expensive drugs that provide minimal benefits, he added.

Accountable Care According to Ms. Thiboldeaux, some good solutions are getting a lot of lip service but no follow-through. “There has been a lot of discussion in health care and oncology care about putting the patient at the center—patient-centric care—and I just don’t see it happening,” Ms. Thiboldeaux said. ACOs are often cited as a model that “puts patients first” in the pursuit of lower costs.

“We know that screening patients for distress and providing basic low-cost, high-impact psychosocial interventions help to reduce costs and help patients with adherence to their therapies, yet we are not incorporating and paying for those kinds of interventions in cancer care in America,” Ms. Thiboldeaux noted. Most studies, she said, still look only at mortality rates and not at other patient outcomes and quality of life.

Dr. Kolodziej said the first thing he would do to tackle the flawed health care system is standardize medical records, so that performance can be accurately measured. Only in this way can ACOs be realized.

“I would require that all health information, all financial transactions in the health care system, everything that is in the claims database, everything in [the Centers for Medicare & Medicaid Services] and everything in individual [plans] be on the same electronic platform, be communicated real-time and

‘Everything today is driven by billing more chemotherapy, more surgery and more imaging.’

—Stanley Marks, MD be transparent to all the stakeholders,” Dr. Kolodziej said. This will help stakeholders to understand and define value, and ensure that money is spent up front as efficiently as possible, he said.

“Right now, let’s face it, there is really no accountability,” Dr. Kolodziej said.

“If we can get everybody to understand that they are playing by a certain rule book, that can be great for the patient because then they can behave like true health care consumers.”

Fear as Motivator The one thing that all of the town hall participants agreed about was that stakeholders in the oncology field need to act quickly. Mr. Litton thought fear of government intervention would be a big motivator.

“If a woman in the [United Kingdom] has stage I breast cancer, she has a 78% chance of five-year survival. If a woman has stage I breast cancer in the U.S., she has a 97% chance of five-year survival. We have to do something that allows us to continue to deliver the best care. If we move into a situation where we see governmental mandates that are arbitrarily set, we are going to see a reduction in the ability to innovate and a reduction in the ability to care,” Mr. Litton said. “Awareness should precipitate us to move faster.”

—Kate O’Rourke

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key efficacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Montefiore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify effective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics.

4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour

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METHOD OF PARTICIPATION There are no fees for participating and receiving CME/CE credit for this activity. During the period October 1, 2013 through September 30, 2014, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; and 3) complete the post-activity assessment.

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Prepared by

Syed A. Abutalib, MD

Clinical Conundrums NEJM, JCO, Blood and highlights of oral abstracts from ASH 2013—Part IV

5.

QUESTIONS

1. True or False. The

frequency of preeclampsia is not increased in pregnancies following recovery from thrombotic thrombocytopenic purpura (TTP).

2. Chronic

lymphocytic leukemia (CLL) can transform into all of the following diseases except: a. Diffuse large B cell lymphoma (DLBCL)

Primum non nocere.

(First, do no harm.)

b. Hodgkin lymphoma (HL) c. Acute lymphocytic leukemia

3. True or False. Two separate stud-

ies published in Blood d demonstrated that calreticulin (CALR)-mutated essential thrombocythemia (ET) is a distinct entity with reduced rates of thrombosis compared with ET in patients with JAK2 and MPL mutations.

4. True or False. The CORDE-

LIA trial demonstrated that the oral chelator deferasirox (Exjade, Novartis) is superior for removal of cardiac iron compared with deferoxamine in patients with heavily transfused β-thalassemia major.

ANSWERS

1. False.

The frequency of preeclampsia may be increased in pregnancies following recovery from TTP. The investigators suggested that women who become pregnant after recovery from TTP require careful monitoring by maternal-fetal medicine specialists. It is important to note that most pregnancies, which were drawn from an Oklahoma registry of patients, resulted in normal children.

Jiang Y, McIntosh JJ, Reese JA, et al. Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood.

2014;123:1674-1680, PMID: 24398329.

2. C. Transformation to DLBCL—

also known as Richter’s syndrome (RS)— occurs in approximately 2% to 10% of patients with CLL during the course of their disease, with a transformation rate of 0.5% to 1% per year. Hodgkin transformation of CLL is even less common but, like RS, has important treatment and prognostic implications.

Parikh SA, Kay NE, Shanafelt TD. How we

True or False.

Youn K. Shim, MD, and colleagues from the Division of Toxicology and Human Health Sciences, Agency for Toxic Substances and Disease Registry, Atlanta, reported the surprising observation that 7.1% of healthy blood donors older than age 45 years have detectable monoclonal B-cell lymphocytosis (MBL).

9.

True or False. In patients with CML, the DASISION study showed that BCR-ABL1 no greater than 10% at 10 months is associated with superior progression-free survival (PFS) and overall survival (OS) at three years, regardless of initial therapy.

True or False. In a study pub6. True or False. An 10. lished in The New England Journal of

open-label multicenter Phase II trial of lenalidomide (Revlimid, Celgene) monotherapy in refractory mycosis fungoides and Sézary syndrome reported substantial activity with acceptable toxicity.

7.

True or False. On behalf of the Center for International Blood and Marrow Transplant Research, Marclo Fernandez-Viña, MD, of Stanford University in Stanford, Calif., and colleagues reported that patients with unrelated donors with an allele mismatch at C*0303/C*0304 have outcomes that are similar to recipients of 8/8 matched unrelated donors.

8. True

or False. Immunohistochemical analysis of pretreatment marrow in patients with chronic myeloid

treat Richter syndrome. Blood. 2014;123:1647-1657, PMID: 24421328.

3. True. Mutations in the CALR

gene were recently discovered in patients with ET lacking the JAK2 V617F and MPL W515 mutations.

Two independent studies showed that patients with ET and CALR mutations exhibit lower leukocyte and hemoglobin values, higher platelet counts and lower thrombosis risk than patients who have JAK2 and MPL mutations.

There was no significant difference in myelofibrotic transformation between the two subtypes of ET. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2013 Dec 23.

[Epub ahead of print], PMID: 24366362.

Rotunno G , Mannarelli C, Guglielmelli P, et al.

Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood. 2013 Dec 26. [Epub ahead of print], PMID: 24371211.

4.

leukemia (CML) revealed that the presence of greater than 4% marrow-infiltrating CD8+ (but not CD4+) T cells predicted donor lymphocyte infusion (DLI) response, even in the setting of high leukemia burden.

False. In this randomized controlled trial published in Blood, the oral

Medicine (NEJM ( M), analysis of registry data from nonfederal emergency departments and acute care hospitals in California showed that the risk for a thrombotic event continues to be significantly elevated beyond the 12-week postpartum period.

ASH 2013 Oral Abstracts: Highlights—Part IV

11. True or False. DLBCL: Recent

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

12. True or False. Myelodysplastic

syndrome (MDS): Intermittent dosing of oral rigosertib (Onconova) is well tolerated and active in producing transfusion independence in patients at lower risk for MDS.

13. True

or False. Lymphomas: Body mass index (BMI) was significantly associated with clinical outcomes among patients with DLBCL and Hodgkin and follicular lymphomas in three prospective Phase III clinical trials.

14. True or False. DLBCL: Accord-

ing to outcomes from the CORAL trial, patients with relapsed DLBCL who fail second-line salvage therapy with R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin) or R-ICE (rituximab, ifosfamide, carboplatin and etoposide) should be recommended hospice.

15.

studies of ibrutinib (Imbruvica, Pharmacyclics) in combination with R-CHOP (rituximab [Rituxan, Genentech], cyclophosphamide, doxorubicin, vincristine and prednisone) in patients with de novo DLBCL reported an overall response rate (ORR) of 100%.

True or False. Multiple myeloma: A Phase II study of carfilzomib (Kyprolis, Onyx), cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma demonstrated one-year PFS and OS of 86% and 87%, respectively, after nine induction cycles.

chelator deferasirox met its primary end point of demonstrating noninferiority compared with deferoxamine for myocardial iron removal.

included fatigue (22%), infection (9%) and leukopenia (3%).

Pennell DJ, Porter JB, Piga A, et al. A 1-year randomized controlled trial of deferasirox versus deferoxamine for myocardial iron removal in betathalassemia major (CORDELIA). Blood. 2014 Jan 2. [Epub ahead of print], PMID: 24385534.

Querfeld C, Rosen ST, Guitart J, et al. Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sezary syndrome. Blood. 2014;123:11591166, PMID: 24335103.

7. True. The C*0303/C*0304 mis-

5. True. The risk for transmission

and engraftment of these premalignant cells is low; however, it does raise the question of screening for MBL in donated blood. Investigators recommend, at the very least, retrospective study of the outcomes following transfusion of MBLcontaining units.

matched and the 8/8 matched groups had identical outcomes (hazard ratio [HR], 0.96-1.05). The investigators concluded that the previous finding that HLA-C allele mismatches are not associated with adverse outcomes is explained by the predominance (69%) of the mismatch C*0303/C*0304 in this group, making it better tolerated.

Shim YK, Rachel JM, Ghia P, et al. Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. Blood.

2014;123:1319-1326, PMID: 24345750.

Fernandez-Viña MA, Wang T, Lee SJ, et al.

Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood.

2014;123:1270-1278. PMID: 24408320.

6. True. This study demonstrat- 8. True. Increasing evidence across

ed an ORR of 28%. Median OS was 43 months, median PFS was eight months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events

malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. Investigators of this study analyzed marrow-infiltrating immune populations in 29 patients (22

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CLINICAL ONCOLOGY NEWS • APRIL 2014 • CLINICALONCOLOGY.COM

responders, seven nonresponders) with relapsed CML who received CD4+ DLI in the pre–tyrosine kinase inhibitor era.

This data demonstrates that response to DLI is associated with quantity of preexisting marrow CD8+ T cells and local reversal of T-cell exhaustion. Furthermore, these interesting studies implicate T-cell exhaustion as a therapeutic target of DLI and support the potential use of novel anti-PD1/PDL1 agents in lieu of DLI. Bachireddy P, Hainz U, Rooney M, et al. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood. 2014;123:1412-1421, PMID: 24357730.

9.

False. In this study, BCR-ABL1 of no more than 10% at three months was associated with superior PFS and OS at three years with either dasatinib (Sprycel, Bristol-Myers Squibb) or imatinib (Gleevec, Novartis). Importantly, dasatinib resulted in faster and deeper responses compared with imatinib.

Jabbour E, Kantarjian HM, Saglio G, et al.

Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION).

Blood. 2014;123:494-500, PMID: 24311723.

10. False.

The risk for primary thrombotic events was markedly higher within six weeks after delivery than in the same period one year later.

There was also a modest but significant increase in risk during the period of seven to 12 weeks after delivery compared with the same period one year later. The risk for thrombotic events was not significantly increased beyond the first 12 weeks after delivery.

48 patients (12%); 17 (35%) experienced grade 2 urinary toxicity. Continuous dosing was stopped due to high urinary toxicity in nine patients, resulting in 39 patients receiving intermittent dosing.

Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014 Feb 13 [Epub ahead of print], PMID: 24524551.

13. False. Body mass index (BMI)

11. True. Based on the promising

early results, a randomized Phase III trial of R-CHOP with or without ibrutinib is ongoing in de novo DLBCL. Younes A, Flinn I, Berdeja J, et al. Combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): updated results from a phase 1b study in treatment-naïve patients with CD20-positive B-cell non-Hodgkin’s lymphoma (NHL). ASH Annual Meeting Abstracts. Blood. 2013;122:852.

12. True. Overall the drug was well tolerated, except for reversible grade 3 urinary toxicity (dysuria, hematuria, cystitis and urinary urgency) in six of

Raza A, Tycko B, Lee S, et al. Oral rigosertib (ON 01910.Na) treatment produces an encouraging rate of transfusion independence in lower risk myelodysplastic syndromes (MDS) patients; a genomic methylation profile is associated with responses. ASH Annual Meeting Abstracts. Blood. 2013;122:2745.

was not significantly associated with clinical outcomes. These findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies. In this study, the association between BMI at study entry and failure-free survival and OS was evaluated in three Phase III Eastern Cooperative Oncology Group–led trials, among patients with DLBCL (E4494), follicular lymphoma (FL; E1496) and HL (E2496).

Bartlett NL, Sharman JP, Oki Y, et al. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: Interim results in patients with DLBCL and other B-cell lymphomas. ASH Annual Meeting Abstracts. Blood. 2013;122:848.

14.

False. Although the outcome of DLBCL patients failing secondline R-DHAP or R-ICE is poor overall, response to third-line therapy occurs, and 44% of patients may be further transplanted. Long-term disease control can be observed, especially in patients achieving complete response after third-line therapy. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy.

Van Den Neste E, Gisselbrecht C, Schmitz N, et al. Diffuse large B-cell lymphoma (DLBCL) patients failing second-line R-DHAP or R-ICE chemotherapy included in the Coral study. ASH Annual Meeting Abstracts. Blood. 2013;122:764.

15. True. The CCd regimen is highly

active, showing rapid and deep responses and reaching, after nine cycles, a 64% rate of at least near-complete response and a 24% rate of stringent complete response, which improves approximately an additional 10% to 15% during maintenance.

Bringhen S, Cerrato C, Petrucci MT, et al. A Phase II study with carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts. Blood. 2013;122:685.

by the

numbers

Updated cost estimates to implement ICD-10 Large practice Medium practice

ICD-10 On Feb. 12, the American Medical Association (AMA) released an updated study of the cost to physician practices of implementing the ICD-10 code set. The 2014 study found that in some cases, the estimated costs were nearly three times what had been predicted in a 2008 landmark study done

by Nachimson Advisors, an IT consulting firm, the AMA said in a press release.

Incidentally, the day before, the Journal of Oncology Practice released a study by investigators at the University of Illinois suggesting that hematologist/ oncologists would actually lose money on certain procedures in the transition from ICD-9 to ICD-10.

Small practice

$56,639 56,639 $226,105 226,10

$213,364 213,364 $824,735 824,73

$2,017,151 ,017,15 $8,018,364 ,018,3

“Prior work stated hematology/oncology would be the least affected medical specialty. However, information loss affecting 5% of billing costs could evaporate the operating margin of a practice,” the authors, led by Neeta Venepalli, MD, wrote.

Information loss in the transfer from ICD-9 to ICD-10 at an academic cancer center

8.0% |

of Medicaid claims affected

2.9% |

of Medicaid reimbursements affected

5.3% |

of overall billing charges affected

The Centers for Medicare & Medicaid Services has estimated that claims denial rates could increase 100% to 200% in the early stages of coding with ICD-10.

Sources: “Identifying Clinically Disruptive International Classification of Diseases 10th Revision Clinical Modification Conversions to Mitigate Financial Costs Using an Online Tool.” J Oncol Pract. 2014 February 11.

[Epub ahead of print] “ICD-10 Cost Estimates Increased for Most Physicians.” American Medical Association. February 12, 2014.

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