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CANCER CENTER PROFILE
University of Michigan Comprehensive Cancer Center Evolving Role of the Oncology Pharmacist
Pharmacists Can Enhance Compliance With Oral Medications Dana-Farber Programs Show How It’s Done By Caroline Helwick
harmacists are vitally important in enhancing patients’ adherence to oral chemotherapy medications, and there are approaches that pharmacies can take to improve compliance, Sylvia Bartel, RPh, told attendees of the NCCN Pharmacy Program held during the
17th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida. “While oncologists prescribe oral chemotherapy for an increasing number of indications, we know little about safeguards, common practices for using these Continued on page 25
THE PATIENT’S VOICE Shawna Kraft, PharmD, BCOP, with pharmacy student Julia Carpenter (left) at the University of Michigan Hospital.
What Is in YOUR Lunch Box? By MMA
Photo by Gregory Fox/University of Michigan College of Pharmacy.
n 1986, the University of Michigan Comprehensive Cancer Center (UMCCC) was established as a center of excellence at the University of Michigan Medical Center. UMCCC is designated as a Comprehensive Cancer Center by the National Cancer Institute and is 1 of 21 cancer centers participating in the National Comprehensive Cancer Network. As an academic institution, there are more than 350 faculty members from 36 departments representing 9 schools at the University of Michigan. These faculty members are directly involved in cancer research and patient care. UMCCC conducts basic science and clinical/translational research programs, all with the goal of providing
Continued on page 24
remember picking out my lunch box. I had already decided it needed to have some sort of mechanism to keep its contents chilled for up to a few hours. It had to shield its contents from the sun to avoid spoilage. It had to be soft enough so that glass would not crack when hitting the sides and large enough to carry several small boxes tossed in with the occasional small bottle. I found just what I needed at a major national chain store in the United States known for its cheap
prices and relatively cheap quality: a red rectangle-shaped lunch box made out of pliable plastic with a gray vinyl lining, a zipper that sealed the 3 sides of the opening at the top, and a matching gray racing stripe all around, replete with 2 pockets for gel ice packs (included). I chose a model large enough to fit about 6 sandwiches stacked on top of each other and perhaps 2 small cartons of milk in the space left over. I stored my lunch box on top of my Continued on page 26
Lower Radiation Dose Effective for Thyroid Cancer
INSIDE News Briefs
By Alice Goodman
Olaparib Maintenance Therapy Potentially Useful for Aggressive Ovarian Cancer . . . . . . . . . . . . . . . . . . . 4
Human Papilloma Virus–Positive Oropharyngeal Cancers Respond to Radiation Alone . . . . . . 9
ower radioiodine doses given with recombinant human thyrotropin (thyrotropin alfa) was as effective as high-dose radioiodine, and the lowdose treatment was associated with fewer side effects. Use of thyrotropin alfa along with low-dose radiation allows patients to avoid fatigue, lethargy, and weight gain associated with thy-
roid hormone withdrawal. These results suggest that thyroid cancer treatment can be transformed into a safer, shorter session, according to researchers. The radioiodine dose used in the HiLo trial was one-third of the currently used level, setting a new standard of care, they said. “We are delighted that this
Mastectomy Risk Twice as High With Brachytherapy . . . . . . . . . . . . . 10
Continued on page 8 ©2012 Green Hill Healthcare Communications, LLC
Age and Comorbidity Affect Treatment Access for Lung Cancer . . . . . . . . . . . . . . . . . . . . 13 CoNfereNCe News: AsCo 2012 ANNuAl MeetiNg . . . . . . .
Abstracts of Interest CoMpliMeNtAry Ce
Considerations in Lymphoma—Ask the Experts: Mantle Cell Lymphoma
IV R FO AND D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU AD
If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies
If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1
If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen
VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.
CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.
WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended
ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.
Olaparib Maintenance Therapy Potentially Useful for Aggressive Ovarian Cancer By Alice Goodman
laparib maintenance therapy extended progression-free survival (PFS) in women with an aggressive form of platinum-sensitive
ovarian cancer with a previous response to platinum-based chemotherapy. Women receiving olaparib lived a mean of 4 months longer and also had a longer
Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.
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time to disease progression than those who had no maintenance therapy. These were the conclusions of a phase 2 study published in the New England Journal of
ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.
VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA
Medicine on April 12, 2012. “Maintenance treatment with olaparib was associated with significant improvement in PFS in patients with platinumsensitive, relapsed, high-grade serous ovarian cancer. At this interim analysis, this did not translate into an overall survival benefit,” wrote the authors. They noted that 21% of patients in the maintenance arm were still on olaparib, indicating prolonged disease control in some patients. They also emphasized a need to identify biomarkers that could be used to select patients most likely to respond to treatment with a poly ADP ribose polymerase (PARP) inhibitor, such as olaparib, so that this therapy could be targeted to the appropriate population. About 80% of patients with newly diagnosed ovarian cancer will respond to platinum-based chemotherapy, but most will relapse with only short-lived responses to subsequent lines of therapy. Maintenance therapy after response to first-line platinum-based therapy is an ongoing area of investigation to determine if response can be prolonged.
Maintenance therapy after response to first-line platinum-based therapy is an ongoing area of investigation to determine if response can be prolonged.
In the phase 2 trial, 265 patients were randomized to double-blind treatment with olaparib 400 mg BID or placebo. Median PFS was 8.4 months in the olaparib group versus 4.8 months with placebo, representing a 65% reduced risk of progression that was statistically significant (P <.001). The benefit of maintenance therapy was observed across all subgroups studied. Time to progression was also significantly longer in the group receiving olaparib: median 8.3 months versus 3.7 months for placebo, again a highly significant 65% reduction in risk of progression (P <.001). The interim analysis reported in the New England Journal of Medicine found no significant difference between groups in overall survival: median 29.7 months for olaparib and 29.9 months for placebo. The most commonly reported adverse events for olaparib versus placebo were nausea, 68% versus 35%; fatigue, 49% versus 38%; vomiting, 32% versus 14%; and anemia, 17% versus 5%, respectively. Most adverse events were grade 1 or 2. ●
THE AFINITOR® (everolimus) TABLETS $25 CO-PAY CARD FROM NOVARTIS PHARMACEUTICALS CORPORATION Designed to help make treatment more affordable for your eligible AFINITOR patients
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* Not valid for prescriptions for which payment may be made in whole or in part under federal or state health care programs, including, but not limited to, Medicare, Medicaid, or for residents in Massachusetts. Additional limitations may apply. This program is available for a limited time.
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From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko email@example.com Publisher John W. Hennessy firstname.lastname@example.org Director, Client Services Joe Chanley email@example.com Editorial Director Kristin Siyahian firstname.lastname@example.org
Patrick Medina, PharmD, BCOP Editor-in-Chief
n this issue of The Oncology Pharmacist (TOP), we start our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology, held earlier this month in Chicago, by presenting a summary of abstracts of interest to TOP readers. These studies are important as they help us keep current about the status of some of the latest research. You’ll see more in-depth coverage of the news from ASCO in upcoming TOP issues. We continue to hear from MMA, a patient undergoing treatment for cancer. In the April issue, she gave us her definition of “a good pharmacist.” This month, she tells us
Managing Editor Kristen Olafson email@example.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto firstname.lastname@example.org Executive Administrator Jackie Luma Circulation Department email@example.com
Although an uncommon cancer, sarcoma, which can arise in various connective tissues and therefore has many subtypes, is a frightening disease for both the young and old. For example, some types of bone cancer occur primarily in children, while others affect mostly adults. As we recognize Sarcoma Awareness Week this month, let’s delve into some statistics surrounding this multifaceted cancer.
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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: firstname.lastname@example.org. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.
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about her experiences with chemotherapy drugs when she was initially diagnosed with cancer while living and working in Mexico. It’s an interesting perspective on how chemotherapy treatment is handled and the role the patient plays in this process. Be sure to check out the cancer center profile interview with Shawna Kraft, PharmD, BCOP, from the University of Michigan Comprehensive Cancer Center. Shawna has some great tips to help pharmacists handle the all the news from the world of oncology—something we hope TOP does for readers of the journal and visitors to the Web site (www.TheOncologyPharmacist.com). ●
Editorial Contact: Telephone: 732-656-7935 Fax: 732-656-7938
Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief
Primary bone cancer is rare and accounts for less than 0.2% of all cancers. In 2012, an estimated 2890 people will be diagnosed with new cases of primary bone cancer. Approximately 1410 deaths will occur in 2012 from this disease. Different types of bone cancer are more likely to occur in certain populations: • Ewing sarcoma family of tumors (ESFTs) appears most often in children and adolescents under 19 years of age – These tumors are more prevalent in boys than in girls – In North America each year, about 225 children and teens are diagnosed with Ewing tumors
– Most of the patients are white, either nonHispanic or Hispanic; this disease is very rare among African Americans; it also seldom occurs in other racial groups • Osteosarcoma generally occurs between ages 10 and 19 years; however, people over age 40 who have other conditions, such as Paget disease, are at increased risk of developing this cancer – About 800 new cases of osteosarcoma are diagnosed each year in the United States, with 400 of these developing in children and teens – About 10% of all osteosarcomas occur in people older than age 60 years
• The risk for chondro sarcoma increases with advancing age – Patients aged 40 and older make up 70% of chondrosarcoma cases – The average age at diagnosis is 51 years; most cases are diagnosed at an early stage and are low grade For all cases of bone cancer combined (in both adults and children), the 5-year relative survival is about 70%. Furthermore, with modern surgical techniques, 9 out of 10 people who have bone cancer in an arm or leg may not need amputation. Sources www.cancer.gov/cancertopics/types/bone; http://www.cancer.org/Cancer/BoneCance r/DetailedGuide/bone-cancer-what-iscancer; http://www.cancer.net/patient/ Cancer+Types/Sarcoma?sectionTitle=Aft er%20Treatment.
Editorial Board EDITOR-IN-CHIEF
Patrick Medina, PharmD, BCOP
Anjana Elefante, PharmD, BSc, BSc Pharm, RPh
Dwight Kloth, PharmD, FCCP, BCOP
Oklahoma University College of Pharmacy Tulsa, OK
Roswell Park Cancer Institute Buffalo, NY
Fox Chase Cancer Center Philadelphia, PA
Beth Faiman, PhD(c), MSN, APRN-BC, AOCN
Jim Koeller, MS
Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL
University of Texas at Austin San Antonio, TX
Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA
John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
Christopher Fausel, PharmD
Christopher J. Lowe, PharmD
Indiana University Simon Cancer Center Indianapolis, IN
Indiana University Hospital Indianapolis, IN
David Baribeault, RPh, BCOP
Rebecca S. Finley, PharmD, MS
Emily Mackler, PharmD, BCOP
Burt Zweigenhaft, BS
Boston Medical Center Boston, MA
Jefferson School of Pharmacy Philadelphia, PA
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
BioPharma Partners LLC New York, NY
Betty M. Chan, PharmD, BCOP
David C. Gammon, BSPh
USC/Norris Cancer Hospital Los Angeles, CA
OncologyPharmacist.net Warwick, RI
Laura Boehnke Michaud, PharmD, BCOP, FASHP
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE
Marlo Blazer, PharmD, BCOP
The University of Texas MD Anderson Cancer Center Houston, TX
James Cancer Hospital & Solove Research Institute Columbus, OH
Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN
Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP
Lew Iacovelli, BS, PharmD, BCOP, CPP
LeAnn Best Norris, PharmD, BCPS, BCOP
Maine Center for Cancer Medicine Scarborough, ME
Moses H. Cone Health System Greensboro, NC
South Carolina College of Pharmacy Columbia, SC
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
JUnE 2012 I VOL 5, nO 4
News Briefs Lower Radiation Dose Effective for Thyroid Cancer Continued from cover study of thyroid cancer care will change international approaches to treating the disease more safely, by reducing the chance of another cancer developing later in life and other side effects. Patients will have a better quality of life, they will be treated more quickly, which will keep the disruption to their lives at
a minimum, as well as saving NHS [National Health Service] money,” stated lead author Ujjal Mallick, MD, Freeman Hospital in Newcastle, United Kingdom. Study results were published in the May 2 issue of the New England Journal of Medicine. HiLo was a ran-
domized, noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Of 438 randomized patients with stage T1-3 nonmetastatic thyroid cancer, 421 were evaluable. Successful thyroid
YOUR QUESTIONS ANSWERED
ablation was achieved in 85% of the low-dose radioiodine group versus 88.9% in the high-dose radioiodine group and 87.1% in the group undergoing thyroid hormone withdrawal. These percentages were within the 95% confidence intervals for noninferiority. Results were similar for lowdose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%).
These results suggest that thyroid cancer treatment can be
a safer, shorter Editor in Chief
Editor in Chief
Sagar Lonial, MD
Stephanie A. Gregory, MD
Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine
Topics include: • Newly Diagnosed Patients • Maintenance Settings • Transplant-Eligible and -Ineligible Patients • Retreatment Settings • Bone Health
The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University
Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma
These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.
These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.
ALL NEW CONTENT FOR 2012 Accreditation These activities will be accredited for physicians, nurses, and pharmacists. For complete accreditation information, please refer to each activity. This activity is jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC.
JUnE 2012 I VOL 5, nO 4
About 3 times as many patients randomized to high-rose radioiodine were hospitalized for at least 3 days versus those in the low-dose group: 36.3% versus 13%, respectively. More adverse events were observed with high-dose radioiodine as well: 33% versus 21% in the low-dose group (P = .007); adverse events were 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal. Current treatment is surgical removal of the thyroid gland followed by radioactive iodine taken in a capsule to destroy any remaining thyroid tissue that could presumably harbor cancer cells. This high-dose treatment requires at least 2 days of isolation in the hospital for the radiation to dissipate. High-dose radioiodine is associated with late-occurring side effects that affect quality of life. The low-dose treatment can be done on an outpatient basis and has fewer side effects. The rationale for the study was that newer surgical techniques are more successful in ablating thyroid tissue and therefore lower radioiodine doses could be adequate. The trial also showed that patients can continue taking thyroid hormone tablets if they are given thyroid-stimulating hormone (ie, thyrotropin alfa) before they take low-dose radioactive iodine. ●
Human Papilloma Virus–Positive Oropharyngeal Cancers Respond to Radiation Alone
ccording to a presentation at the recent European Society for Radiotherapy and Oncology (ESTRO) meeting in Barcelona, Spain, oropharyngeal cancers in patients who are positive for the human papilloma virus (HPV) and who never smoked or were light smokers may be treated effectively with radiotherapy alone, potentially sparing these selected patients from additional chemotherapy and its toxicity. In a retrospective analysis of 181 patients on the Danish Head and Neck Cancer Group database treated between 1992 and 2005 for advanced oropharyngeal cancer, HPV-positive patients had significantly improved local control, disease-specific survival, and overall survival at 5 years compared with HPV-negative patients. Analysis of smoking history showed that HPV-positive patients with a smoking history of less than 10 packyears (1 pack-year equals 20 cigarettes per day for 1 year) had improved outcomes compared with HPV-negative patients and those with a smoking history of more than 10 pack-years. “This study is part of an ongoing debate about how to treat patients according to known prognostic factors, in this case, tumor HPV status and smoking history,” stated Pernille Lassen, a radiation oncology resident at Aarhus University Hospital, Aarhus, Denmark. “These findings confirm the highly significant independent influence of HPV status on tumor control and survival in advanced oropharyngeal cancer that is treated with radiotherapy alone, without chemotherapy. Our results suggest that use of radiotherapy alone may be a safe treatment strategy in patients who are light or nonsmokers, while sparing them the side effects associated with chemotherapy. However, it is still too early to select patients for a specific treatment based on these factors; we still need more data,” she stated, according to a press release from ESTRO. All patients in the study received accelerated radiotherapy consisting of 6 fractions over 5 days along with nimorazole, a radiation sensitizer. No chemotherapy was used. Of the 181 patients, 103 (57%) were HPV positive. Tumor control was achieved in 81% of HPV-positive patients versus 48% of patients who were HPV negative. Five-year disease-specific survival was 90% versus 56%, respectively, and 5-year overall survival was 77% versus 38%, respectively. When smoking history was accounted for, favorable outcomes were
observed in HPV-positive light smokers or nonsmokers. For HPV-positive light smokers or nonsmokers versus HPV-positive heavy smokers, 5-year outcomes were as follows: tumor con-
trol at primary site, 91% versus 77%; disease-specific survival, 96% versus 81%; and overall survival, 90% versus 63%, respectively. Seventy-six of the 78 HPV-negative
patients were heavy smokers, and their outcome was significantly worse than HPV-positive patients, with a 5-year disease-specific survival of 50% to 52%. ● —AG
Announcing: J-code for YERVOY™ (ipilimumab) J9228 Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1
Replaces J9999, J3490, J3590, and C9284.
50-mg/10 mL (5 mg/mL), single-use vial of YERVOY
200-mg/40 mL (5 mg/mL), single-use vial of YERVOY
The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements. www.destinationaccess.com 1-800-861-0048 (phone) Monday through Friday, 8:00 1-888-776-2370 (fax)
Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on the following pages. REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011. 2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/ HCPCSReleaseCodeSets/Downloads/12anweb.zip. Accessed November 1, 2011.
JUnE 2012 I VOL 5, nO 4
Mastectomy Risk Twice as High With Brachytherapy
rachytherapy after lumpectomy is associated with greater morbidity and need for mastectomy compared with whole-breast radiation, according to a large retrospective study
of Medicare claims for older women with early invasive breast cancer (JAMA. 2012;307:1827-1837). Five years after treatment, the rate of mastectomy was twice as high in women
treated with brachytherapy versus whole-breast radiation. Both short- and long-term complications were significantly greater in women treated with brachytherapy in this review. The rate
of 5-year overall survival was the same in both groups (ie, brachytherapy and whole-breast radiation): 87%. Brachytherapy is becoming increasingly more common in the United States. An estimated 10% of women with invasive breast cancer are now receiving brachytherapy as an alternative to whole-breast irradiation following lumpectomy. The appeal of
Important Safety Information (cont) Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: t Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day t Failure to complete full treatment course within 16 weeks from administration of first dose t Severe or life-threatening adverse reactions, including any of the following – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients t Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis t Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immunemediated enterocolitis following inadequate response to corticosteroids t Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms t Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid
tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients t Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Immune-mediated Hepatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% t 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2) t Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution t Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids t Withhold YERVOY in patients with Grade 2 hepatotoxicity Immune-mediated Dermatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis t There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis t Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated t Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms
Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.
JUnE 2012 I VOL 5, nO 4
News Briefs brachytherapy versus whole-breast radiation is its delivery of radiation to a smaller field as well as its shorter course of treatment. Whole-breast radiation typically in volves daily treatments for 7 weeks. The lead author was Grace L. Smith, MD, University of Texas MD Anderson Cancer Center in Houston. The study included 92,735 women aged 67 years or
Five years after treatment, the rate of mastectomy was twice as high in women treated with brachytherapy versus whole-breast radiation. older with invasive breast cancer diagnosed between 2003 and 2007 and followed through 2008. Following lumpec-
tomy, 85,783 women (92.5%) were treated with whole-breast radiation and 6952 (7.5%) underwent brachytherapy.
A year later, brachytherapy led to infection of the skin or soft tissue in 16.20% of patients versus 10.33% of those treated with whole-breast radiation; furthermore, the rate of noninfectious complications was significantly greater in the brachytherapy group: 16.25% versus 9.0%. At 5 years, the rates of other compliContinued on page 12
Important Safety Information (cont) t Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: t In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported t Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported t Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes t Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: t In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients – All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism – 6 of the 9 patients were hospitalized for severe endocrinopathies t Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome t Median time to onset of moderate to severe immunemediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY t Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism – Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated
– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland t Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia t Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis t Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions t Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy Pregnancy & Nursing: t YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus t Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus t It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY Common Adverse Reactions: t The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)
Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.
© 2012 Bristol-Myers Squibb 731US11AB18314 YERVOY is a trademark of Bristol-Myers Squibb.
731US11AB18314 TRIM 7.25" x 9.75"
Printed in USA
JUnE 2012 I VOL 5, nO 4
News Briefs Mastectomy Risk Twice as High With Brachytherapy Continued from page 11 cations were also higher in the brachytherapy group compared with the whole-breast radiation group: breast pain, 14.55% versus 11.92%; fat necrosis, 8.26% versus 4.05%; and rib fracture, 4.53% versus 3.62%, respectively. Limitations of the study include its retrospective nature, being based on
Medicare claims data, and not taking into consideration improvements in technology since 2007 in delivering brachytherapy. Only a randomized controlled trial can definitively compare the 2 radiation techniques. An ongoing phase 3 randomized controlled trial sponsored by the National Surgical
Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG) is currently comparing the safety and efficacy of brachytherapy versus whole-breast radiation, but results will not be available for several years. â&#x20AC;&#x153;These results represent, to our knowl-
YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3â&#x20AC;&#x201C;5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.
edge, the first comprehensive, population-based study to directly compare the clinical outcomes associated with use of breast brachytherapy versus standard whole-breast radiation in older patients. Additional study is required to confirm the validity and generalizability of these findings,â&#x20AC;? wrote the authors. â&#x2014;? â&#x20AC;&#x201D;AG
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab). Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-BarrĂŠ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrĂŠ syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrĂŠ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3â&#x20AC;&#x201C;4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]
Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]
Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â&#x20AC;&#x201C;5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.
The following adverse reactions are discussed in greater detail in other sections of the labeling.
t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].
t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].
t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].
t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].
t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].
t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].
JUnE 2012 I VOL 5, nO 4
Age and Comorbidity Affect Treatment Access for Lung Cancer
ounger patients were more likely than older patients to get guideline-recommended treatment for nonâ&#x20AC;&#x201C;small cell lung cancer (NSCLC); conversely, the older the
patient, the less likely treatment was provided, according to a large study of veterans that was reported in the May 1 issue of the Journal of Clinical Oncology. Advancing age was the strongest nega-
tive predictor of receiving guideline-recommended treatment, regardless of cancer stage and comorbidity. â&#x20AC;&#x153;Individualized decisions that go beyond age and include comorbidity are
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.
The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â&#x20AC;&#x201C;5 events. Table 1:
Percentage (%) of YERVOY 3 mg/kg n=131
Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a
DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy
There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.
YERVOY 3 mg/kg+gp100 n=380
In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;4 weeks due to multi-organ infiltration and damage by lymphocytes.
Rates of treatment
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.
decreased more with
Nursing Mothers 31 29
Incidences presented in this table are based on reports of adverse events regardless of causality.
Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.
Pregnancy Category C
Selected Adverse Reactions in Study 1
System Organ Class/ Preferred Term
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.
Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients
Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c
YERVOY 3 mg/kg n=131
YERVOY 3 mg/kg+gp100 n=380
15 7 1 2 1 4 4 0
12 7 2 3 <1 1 1 1
0 0 1 1 0
<1 <1 0 0 <1
It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use
Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:
Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA
Including fatal outcome. Including intestinal perforation. c Underlying etiology not established. Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.
TRIM 7.25" x 9.75"
advancing age than with for all stages.
Safety and effectiveness of YERVOY have not been established in pediatric patients.
Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.
needed to better target NSCLC treatments to older patients who may reasonably benefit,â&#x20AC;? wrote lead author Sunny Wang, MD, San Francisco Veterans Affairs Medical Center, California. â&#x20AC;&#x153;It is clear that we fixate on age in deciding whether to pursue cancer treatments, including lung cancer treatments. Instead, we should be looking at our patientsâ&#x20AC;&#x2122; overall state of health,â&#x20AC;? she stated in a news release from the University of California San Francisco (UCSF). Previous studies show that older patients in good health can benefit from treatment for NSCLC, while those with comorbidities may not be able to tolerate chemotherapy and radiation. Also, significant comorbidity can lower life expectancy, raising doubt as to the wisdom of subjecting such sick patients to toxic treatments. The study included 20,501 patients aged 65 years and older treated at the San Francisco VA Medical Center and UCSF from 2003 to 2008. Patients were stratified by age (65 to 74 years; 75 to 84 years; and 85 years or older), Charlson comorbidity index score (0, 1 to 3, and 4 or above), and cancer stage (I to II, IIIA to IIIB, and IIIB with malignant effusion to IV).
Issued: March 2011
Guideline-recommended treatment was given to 51% of patients with local, 35% with regional, and 27% with metastatic disease. Rates of treatment decreased more with advancing age than with worsening comorbidity for all stages. Older patients with no comorbidity (who could presumably benefit from treatment) had lower rates of treatment than younger patients with severe comorbidity. For example, the rate of surgery was significantly different in favor of younger patients: 50% of patients aged 75 to 84 years with local disease had surgery compared with 57% of those aged 65 to 74 years with severe comorbidity (P <.001). â&#x20AC;&#x153;The message from our study is donâ&#x20AC;&#x2122;t base cancer treatment strictly on age. Donâ&#x20AC;&#x2122;t write off an otherwise healthy 75year-old, and donâ&#x20AC;&#x2122;t automatically decide to treat a really ill 65-year-old without carefully assessing the risks and benefits for that patient,â&#x20AC;? Wang said in the UCSF news release. She and her colleagues are currently conducting a follow-up study to compare survival in patients included in the study. â&#x2014;? â&#x20AC;&#x201D;AG
JUnE 2012 I VOL 5, nO 4
Conference News: ASCO 2012 Annual Meeting
Abstracts of Interest From the 2012 American Society of Clinical Oncology Annual Meeting By Caroline Helwick
Antipsychotic Controls Breakthrough Nausea and Vomiting Patients with chemotherapy-induced nausea and vomiting (CINV) that persists in spite of recommended prophylaxis may be helped by the antipsychotic medication olanzapine. In a double-blind randomized trial of patients with breakthrough CINV after highly emetogenic chemotherapy, 71% of patients given olanzapine 10 mg orally for 3 days had no further vomiting, compared with 32% who received metoclopramide 10 mg orally 3 times a day for 3 days, and 67% versus 24% had no further nausea. Navari RM, et al. Abstract 9064.
Glucocorticoid, Ginseng Reduce Cancer-Related Fatigue The use of dexamethasone for up to 15 days reduced cancer-related fatigue more effectively than placebo among patients with advanced cancer. The study randomly assigned 132 patients with documented fatigue to 4 mg dexamethasone twice a day or placebo for 14 days. On day 15, the dexamethasone group demonstrated significant improvements on measurements of fatigue, symptom distress, physical symptoms, and quality of life, while the placebo group did not improve over baseline. In a separate randomized study of 364 patients with fatigue, 8 weeks of ginseng (2000 mg ground Wisconsin ginseng root) also significantly improved fatigue scores, especially among patients currently on treatment. Yennurajalingam S, et al. Abstract 9002; Barton DL, et al. Abstract 9001.
Primary Care Providers Largely Unaware of Chemotherapy’s Late Effects A survey of primary care providers (PCPs) showed an alarming level of ignorance about the late effects of common chemotherapy regimens for common cancers. The 2009 Survey of Physician Attitudes Regarding the Care of Cancer Survivors involved 1072 PCPs and 1130 oncologists. Physicians were asked to select which of 5 late effects of 4 widely used breast and colorectal cancer drugs (doxorubicin, paclitaxel, oxaliplatin, and cyclophosphamide) they observed most often in their practices, or had seen reported. Among the PCPs, only 15% to 55% identified the common side
June 2012 I VOL 5, nO 4
effects with the drugs. While oncologists were much better—with 62% to 97% answering correctly—there was still some room for improvement, the authors suggested. Nakhlyudov L, et al. Abstract 6008.
T-DM1 Prolongs Remission in Metastatic Breast Cancer Trastuzumab emtansine (T-DM1), the antibody-drug conjugate linking trastuzumab to a cytotoxic agent, significantly prolonged disease-free survival in previously treated metastatic breast cancer in the international phase 3 EMILIA trial. Compared with a standard regimen, T-DM1 reduced the risk of disease progression by 35%, improving progression-free survival (PFS) from 6.4 to 9.6 months (P <.0001). Overall survival (OS) was numerically improved though the difference is not yet statistically significant. T-DM1 was also substantially better tolerated. Blackwell K, et al. LBA1.
Intermittent AndrogenDeprivation Therapy Should Not Replace Continuous Treatment in Prostate Cancer Continuous androgen-deprivation therapy should remain the standard of care for the treatment of men with hormone-sensitive metastatic prostate cancer, according to the results of the phase 3 international SWOG 9346 trial. The 17-year study treated 3040 newly diagnosed patients with gose relin and bicalutamide for 7 months. Those who achieved PSA ≤4 ng/mL were randomly assigned to continuous treatment or intermittent treatment upon signs of progression. The intermittent approach was “not shown to be non-inferior to” continuous treatment. Median OS was 5.8 years with continuous therapy and 5.1 years with intermittent therapy, and 7-year survival was 42% and 38%, respectively. Hussain M, et al. Abstract 4.
previously treated with chemotherapy, but these data suggest it would be effective earlier in the disease. The phase 3 AFFIRM trial of a similar drug, enzalutamide, in 1199 CRPC patients with prior docetaxel treatment, found a 4.8-month OS improvement, and a 5.4-month improvement in PFS (P <.0001). Ryan CJ, et al. LBA4518; de Bono JS et al. Abstract 4519.
months with standard therapy, a 42% reduction in risk (P = .0004). More strikingly, in patients with 2 common mutations, afatinib doubled the time in remission, from 6.9 months to 13.6 months (P <.0001). Afatinib blocks the EGFR pathway more thoroughly and permanently than current EGFRtargeted treatments, and also blocks the broader ErbB family of receptors. Yang J C-H, et al. LBA7500.
PD-1 Targeted Immune Therapy Active in Solid Tumors
Regorafenib Fills Unmet Needs in GI Tumors
In a phase 1 trial, the investigational drug BMS-936558 caused tumor shrinkage in about one-quarter of 296 patients with advanced melanoma (28% response rate), renal cancer (27%), and non–small cell lung cancer (18%). The antibody drug targets a key pathway in T cells called PD-1, which inhibits the body’s immune response to cancer. By blocking this pathway, BMS936558 may reactivate the immune system to attack the tumor. A subanalysis of the data hinted at a potential biomarker, a protein called PD-L1. One-third of patients expressing PD-L1 responded to this novel therapy. Topalian SL, et al. Abstract CRA2509.
In both colorectal cancer and gastrointestinal stromal tumors (GIST) refractory to current therapies, the oral multikinase inhibitor regorafenib improved outcomes in phase 3 trials. In the CORRECT trial of 770 advanced colorectal cancer patients, OS was improved by 29% with regorafenib, versus placebo, from 5.0 to 6.4 months (P = .0052). In the study of 199 patients with GIST, regorafenib improved PFS from 0.9 months with placebo to 4.8 months, a 73% reduction in risk (P <.0001). Side effects were in line with other tyrosine kinase inhibitors. Van Cutsem E, et al. Abstract 3502; Demetri GD, et al. LBA10008.
Crizotinib Effective in Pediatric Cancers
In Breast Cancer, Older Drug Wins Out
Crizotinib, already proven effective in non–small cell lung cancer patients with ALK gene abnormalities, shows promise for the treatment of anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors and aggressive forms of neuroblastoma in children, according to a study of 70 children whose cancer was refractory to standard therapies. The greatest activity, an 88% response rate, was for ALCL, though complete responses were observed in all 3 tumor types. Responders have remained on therapy for up to 2 years without progression. Mosse YP, et al. Abstract 9500.
In a phase 3 randomized trial of 799 patients, 2 newer and significantly more expensive drugs—nab-paclitaxel and ixabepilone—were not superior to standard weekly treatment with paclitaxel as first-line treatment for advanced breast cancer (most patients also received bevacizumab). Median PFS was 10.6 months for the paclitaxel arm, 9.2 months for nab-paclitaxel, and 7.6 months for ixabepilone. Weekly ixabepilone was significantly less effective than paclitaxel, and nab-paclitaxel was not superior to it. Grade 3 or 4 hematologic and nonhematologic toxicities were also lowest with paclitaxel, including peripheral neuropathy (16% vs 25% with either experimental arm). The authors suggested that nab-paclitaxel be reserved for patients with sensitivity reactions to paclitaxel and those for whom corticosteroids are not advised. Rugo H, et al. CRA1002.
Androgen Blockers Score Big in Prostate Cancer
Afatinib Delays Progression in Lung Cancer
For the treatment of metastatic castration-resistant prostate cancer (CRPC), 2 drugs targeting the androgen receptor returned impressive results. In men who had not been treated yet with chemotherapy, abiraterone significantly improved radiographic PFS in the phase 3 COU-AA-302 trial. Median PFS was 8.3 months with placebo, but has not been reached in the abiraterone group. The drug is currently approved for patients
In the phase 3 LUX-Lung 3 trial of 345 patients with advanced non–small cell lung cancer of adenoma histology harboring the epidermal growth factor receptor (EGFR) mutation, singleagent treatment with the oral EGFR inhibitor afatinib delayed disease progression by more than 4 months over a relatively new first-line regimen, pemetrexed and cisplatin. Median PFS was 11.1 months with afatinib versus 6.9
For Metastatic Kidney Cancer, Patients Prefer Pazopanib In a study with a novel aim and design, patients with metastatic renal cell carcinoma were treated with 2 approved agents, then asked which treatment they
Conference News: ASCO 2012 Annual Meeting preferred. Almost 50% more patients preferred pazopanib over sunitinib, citing less fatigue and better quality of life with this agent (the study did not evaluate efficacy). The PISCES study enrolled 169 patients assigned to one agent for 10 weeks, and to the other for 10 weeks after a 2-week washout period. At 22 weeks, 70% preferred pazopanib, 22% preferred sunitinib, and 8% had no preference (P <.001). Physicians also preferred pazopanib (61%) over sunitinib (22%) while 17% had no preference. Escudier BJ, et al. Abstract CRA4502.
Renal Impairment After Chemotherapy Underappreciated In lung, colorectal, and breast cancer patients, renal impairment after chemotherapy initiation may be underestimated, according to a study from Henry Ford Hospital in Detroit, Michigan. In an evaluation of almost 5000 patients, acute kidney injury was observed in 23% of lung cancer patients, 20% of colorectal cancer patients, and 8% of breast cancer patients, while chronic kidney disease was diagnosed in 48%, 56%, and 64%, respectively. The proportions were even higher among patients with preexisting kidney disease. Chu L, et al. Abstract 1590.
Amatuximab Active in Mesothelioma Amatuximab, an investigational monoclonal antibody to mesothelin, may enhance the effect of pemetrexed and cisplatin in patients with unresectable mesothelioma, without unacceptable toxicity. In a phase 2 study of 77 patients, partial responses were observed in 39% and stable disease in another 51%. Median PFS was 6.1 months, 6-month PFS rate was 52.2%, and median OS was 14.8 months. After completing 4 cycles, almost two-thirds of the patients continued maintenance therapy with single-agent amatuximab, with 6% remaining on therapy at the time of analysis. Hassan R, et al. Abstract 7030.
Melanoma Treatment Options Further Expand Patients with advanced melanoma who harbor the BRAF mutation may soon have treatment options beyond vemurafenib. In two phase 3 studies (METRIC and BREAK-3), the investigational BRAF inhibitor dabrafenib and the first-in-class MEK inhibitor trametinib, as single agents, essentially doubled the median PFS, compared with chemotherapy treatment (P <.0001 for both). But when the 2 were combined in an open-label phase 1/2 dose-finding study, the results were even better. Median PFS reached 7.4 months, and
rose to 10.8 months among patients who were optimally dosed. Importantly, the combination was associated with less skin toxicity (14%) than is observed with vemurafenib alone. Hauschild A, et al. LBA8500; Robert C, et al. LBA8509; Weber JS, et al. Abstract 8510
Glitazones Implicated in Bladder Cancer Type 2 diabetic patients taking glitazone drugs were significantly more likely to develop bladder cancer than those taking sulfonylurea agents, British researchers found. The relative increase was 72% for patients who had been on the drugs for at
least 5 years (P = .033). The study included 18,459 patients taking glitazones and 41,396 taking sulfonylurea drugs. The rising risk with duration of treatment applied both to pioglitazone and to rosiglitazone. Previous studies have raised concerns about this risk, the authors noted. Mamtani R, et al. Abstract 1503. â&#x2014;?
The Next Generation in Oncologic Care
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JUnE 2012 I VOL 5, nO 4
CONTINUING EDUCATION JUNE 2012 • VOLUME 4 • NUMBER 1
ASK THE EXPERTS: Mantle Cell Lymphoma LETTER PUBLISHING STAFF President & CEO Brian F. Tyburski
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According to recent estimates from the American Cancer Society, approximately 70,130 individuals will be diagnosed with non-Hodgkin lymphoma (NHL) in 2012 and about 18,940 deaths will be attributed to the disease. There has been significant progress in the treatment of these hematologic malignancies, including the development and approval of new, highly effective therapies. However, more progress is needed and numerous questions remain unanswered regarding the application and interpretation of recent clinical advances. The goal of our 4th annual “Considerations in Lymphoma” newsletter series is to provide clinicians with the latest evidence-based strategies for managing NHL in the era of novel agents. To address the needs of key members of the interdisciplinary team, frequently asked questions have been posed to physicians, midlevel providers, and pharmacists from leading cancer centers specializing in the treatment of lymphoma. In this first issue, experts from Fox Chase Cancer Center discuss the effective management of mantle cell lymphoma. It is our hope that the insight, knowledge, and experience offered by these professionals will facilitate the optimal care of your patients with NHL.
Sincerely, Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL
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Educational Objectives Upon completion of this activity, the participant will be able to: • Analyze results of recent clinical trials investigating the incorporation of newer agents into mantle cell lymphoma (MCL) treatment • Discuss the safety and efficacy of adding radioimmunotherapy to chemotherapy regimens for patients with MCL • Summarize common toxicities associated with treatments for MCL, and identify current approaches to reduce or ameliorate these effects Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12030.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or email@example.com. Physician Credit Designation The Medical Learning Institute, Inc. (MLI) designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical
Barbara Rogers, CRNP, MN, AOCN, ANP-BC, is on the advisory board for Celgene and Teva, and on the speaker’s bureau for Allos, Millennium: The Takeda Oncology Company, Spectrum Pharmaceuticals, and Teva. *Dwight Kloth, PharmD, FCCP, BCOP, is a member of the Director of Pharmacy Advisory Boards for Amgen, Celgene, Eisai, Hospira, and Prostrakan. *Content will include non–FDA-approved uses.
Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 04689999-12-014-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Ryan Sims, CRNA, MS, MLI Reviewer, has nothing to disclose. Shelley Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Stephanie A. Gregory, MD, is on the advisory board for Genentech/Roche, and Spectrum Pharmaceuticals, and on the data safety monitoring board for Genentech/Roche. Mitchell R. Smith, MD, PhD, is on the advisory board for Teva, and on the speaker’s bureau for Allos, Genentech, Millennium: The Takeda Oncology Company, and Spectrum Pharmaceuticals.
The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: June 11, 2012 Valid for CME/CE credit through: June 11, 2013
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Current and Emerging Treatment Strategies in Mantle Cell Lymphoma Mitchell R. Smith, MD, PhD Director, Lymphoma Service Fox Chase Cancer Center, Philadelphia, PA
ple, a minority of patients (about 5%-10%) have indolent disease.2-4 Therefore, it is important to factor in cell proliferation and other disease characteristics, in addition to age and performance status, to ensure that patients are not “overtreated.” MCL is essentially an incurable disease, and we do not want to subject individuals to severe drug-related toxicities that may shorten survival.
Introduction Mantle cell lymphoma (MCL) is an uncommon, clinically heterogeneous subtype of B-cell lymphoma. Although survival rates for patients
Which regimens can be used when an intensive approach to frontline treatment is necessary?
have improved over the past decade, the disease remains incurable. An individualized approach to treatment is essential, taking into account age, performance status, and whether a patient needs more or less aggressive therapy. In this article, Mitchell R. Smith, MD, PhD, answers questions related to the treatment of newly diagnosed and relapsed/refractory MCL and provides insights on recent developments that may lead to improved clinical outcomes.
Which factors need to be considered when choosing frontline therapy for patients with MCL?
Age, performance status, pace of disease, and goals of therapy are all important factors to consider when deciding on an approach to initial treatment. Older patients and individuals with compromised health status cannot tolerate some of the more intensive regimens used to treat MCL, such as those containing high-dose chemotherapy. Younger, more fit individuals can often endure these regimens1; however, this approach may not always be required. For exam-
To date, the best published outcomes data have been observed with a regimen of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HyperCVAD) alternating with rituximab plus high-dose methotrexate and cytarabine (R-MA).5,6 Investigators from MD Anderson Cancer Center recently published 10-year follow-up data on the safety and efficacy of this regimen, which they studied in an MCL population with no upper age limit. Survival was good, but toxicity was significant, especially in older patients.5,6 The Gruppo Italiano Studio Linfomi (GISL) reported that R-HyperCVAD/ R-MA was effective in patients 70 years, but only 22 of 60 patients could actually complete the 8 planned cycles.7 The Southwest Oncology Group (SWOG) also conducted a study that reached more or less the same conclusion: R-HyperCVAD/R-MA was difficult to complete, but the regimen provided reasonable results for those who could tolerate it.8 At our institution, we often use R-HyperCVAD/R-MA in patients who are 60 years of age or younger, and we ensure that patients near the cutoff age have good performance status before we decide to use this regimen.
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results suggest applicability in select older patients. These regimens appear to be feasible therapeutic options, but longer follow-up is necessary. An emerging trend is to combine ASCT with shorter courses of R-HyperCVAD/R-MA. The upcoming US Intergroup S1106 trial will treat patients 65 years old with 2 rather than 4 cycles of R-HyperCVAD/R-MA, followed by consolidation therapy and ASCT.13 This strategy will allow patients to receive intensive cytoreduction before transplantation. In my opinion, ASCT is easier for patients to endure than the 4 additional rounds of RHyperCVAD/R-MA used in the traditional protocol. S1106 also has a comparative arm of less-intensive induction with bendamustine plus rituximab (BR), followed by ASCT. Hopefully, results from this trial will offer insight on how intensive cytoreduction really needs to be prior to transplantation.
Figure. Response rates with VcR-CVAD plus rituximab maintenancea in MCL: interim results (n=76).18
80 60 40
21% 20 0
a Given to patients achieving stable disease, partial response, or complete response to VcR-CVAD. MCL indicates mantle cell lymphoma; VcR-CVAD, bortezomib, rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone.
Table. R-CHOP (4 cycles) Followed by RIT Consolidation With 90 Y-Ibritumomab Tiuxetan in MCL: Efficacy Results at 5-Year Follow-up (n=57)19 Endpoint PFS ➢ PFS in patients 65 years ➢ PFS in patients >65 years Overall response rate ➢ CR/CRu ➢ PR Number of patients in whom response improved after RIT Estimated median OS ➢ 5-year OS in patients 65 years ➢ 5-year OS in patients >65 years
Result 31 months 32 months 25 monthsa 82% 56% 26% 23/44 76 months
No significant difference between age groups. Significant difference between age groups (P=.023). CR/CRu indicates complete response/complete response unspecified; MCL, mantle cell lymphoma; OS, overall survival; PFS, progression-free survival; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RIT, radioimmunotherapy. b
For patients aged 60 to 70 years who are diagnosed with aggressive disease, we often use rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP),9 followed by consolidation with myeloablative chemotherapy and autologous stem cell transplantation (ASCT). A randomized trial by the European MCL Network (MCL net) showed that, in MCL patients treated with CHOP or R-CHOP, myeloablative radiochemotherapy plus ASCT prolonged progression-free survival (PFS) compared with interferon maintenance.10 The MCL net also studied a variation in treatment: alternating courses of R-CHOP plus rituximab, dexamethasone, cytarabine, and cisplatin (RDHAP), followed by high-dose cytarabine-based myeloablation and ASCT.11 This regimen had acceptable toxicity compared with a regimen of R-CHOP followed by cyclophosphamide-based myeloablation and ASCT. Similarly, the Nordic Lymphoma Group reported favorable outcomes with dose-intensified R-CHOP alternating with R-A, followed by ASCT.12 Although neither of these trials included patients older than 65 years, the favorable toxicity
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R-CHOP remains a common choice for patients who cannot tolerate aggressive treatment. Responses to this regimen are good, but not durable, in MCL.14 As a result, researchers are searching for alternative therapies. In a phase 3 trial by the German Study Group Indolent Lymphomas (StiL), Rummel and colleagues showed that BR was more effective (with better tolerability) than R-CHOP in a population of lymphoma patients that included individuals with MCL.15 This study has been the genesis of many ongoing trials of regimens based on BR. For example, the US Intergroup E1411 trial, which is set to open in the next few months, will evaluate a regimen of BR with or without bortezomib as frontline therapy.16 Kahl and colleagues studied a modified R-HyperCVAD regimen, which omitted the alternating cycle of R-MA but included rituximab maintenance.17 The results were intriguing, so the approach was extended to the ECOG E1405 trial, which also added bortezomib.18 This study of VcR-CVAD plus rituximab maintenance is now accrued and closed; interim results showed a high complete response rate (Figure), but we need longer followup to see whether this translates into better PFS and overall survival (OS).
76 months 66 monthsb
Which regimens can be used when a less-intensive approach to frontline treatment is necessary?
Hopefully, results from this trial will offer insight on how intensive cytoreduction really needs to be prior to transplantation. Our group conducted a separate ECOG trial (E1499), which evaluated RCHOP for 4 cycles (instead of the traditional 6 cycles), followed by a dose of radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan.19 This is a brief regimen, applicable to the vast majority of MCL patients, which results in relatively good outcomes (Table). We are using R-CHOP followed by RIT more frequently, keeping in mind that we do not have the breadth of data on this regimen for MCL that we do for follicular lymphoma via the phase 3 First-Line Indolent Trial.20 It appears that BR, modified R-HyperCVAD (with or without bortezomib) followed by rituximab maintenance, and R-CHOP followed by RIT are all reasonable choices for patients who require less-intensive regimens. Two of these options include consolidation of response, which I think is an important consideration in MCL. In the studies of modified R-HyperCVAD, rituximab maintenance appeared to be helpful.17,18 We have learned more from an MCL net trial conducted in elderly patients, which compared R-CHOP versus rituximab, fludarabine, and cyclophosphamide (R-FC), after which patients were ran-
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domized a second time to rituximab maintenance versus interferon.21 Patients receiving R-CHOP followed by rituximab maintenance had an excellent outcome, much better than we usually see in MCL—4-year OS was 87%, although this was limited to R-CHOP responders. Results were not as good with R-CHOP followed by interferon maintenance or R-FC followed by either type of maintenance. Moreover, R-FC followed by rituximab maintenance produced the highest infection rate (50%) of any induction/maintenance combination in the trial. One of the lessons of this study is that R-FC is probably not a good regimen for initial treatment of elderly patients with MCL. Another lesson is that, when R-CHOP or a similar regimen is used for initial therapy, rituximab maintenance is clearly beneficial. Ongoing trials continue to refine the role of maintenance therapy in MCL. For instance, the E1411 trial discussed earlier will also compare rituximab maintenance with lenalidomide-rituximab maintenance.16 What investigational agents and regimens are showing promise in the treatment of MCL?
We are excited about drugs that target the B cell receptor signaling pathway, including the Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765). Wang and colleagues recently presented data showing a high response rate with single-agent ibrutinib in the relapsed/refractory setting for MCL.22 The phosphatidylinositol 3-kinase (PI3K) inhibitor GS-1101 (formerly known as CAL-101) is also demonstrating good activity.23 Both ibrutinib and GS1101 are well-tolerated oral agents.22,23 BCL2 pathway inhibitors, such as obatoclax, navitoclax, and oblimersen, may also have a role in MCL.24 The mammalian target of rapamycin (mTOR) inhibitors, notably temsirolimus and everolimus, have clinical activity in MCL.25,26 Investigators are beginning to assess whether dual PI3K/mTOR inhibition may be effective in the treatment of the disease.27 Combining mTOR inhibition with something that targets B-cell receptor signaling allows us to hit 2 pathways. In principle, the cell will be less likely to have, or to develop, resistance to such a combination. There is also growing interest in the use of histone deacetylase inhibitors in combination with other agents for the treatment of MCL.28 A number of studies are combining investigational agents with chemotherapy or approved novel agents. One example is a trial of obatoclax plus bortezomib for the treatment of relapsed and refractory MCL.29 Trials like these reflect a useful strategy: combining a B-cell signaling agent and a pro-apoptotic agent, which may signal cells not to divide and at the same time to undergo cell death. Bortezomib is the only targeted agent approved by the US Food and Drug Administration for the treatment of relapsed MCL. Two groups recently evaluated bortezomib plus BR in trials of previously treated patients with lymphoma, including MCL.30,31 The results were interesting, and the combination was tolerable. While it may be advantageous to add these drugs together to treat patients with relapsed/refractory disease, it is not clear whether we should give bendamustine and bortezomib together or sequentially in this setting. Rituximab plus lenalidomide also has a role in the treatment of relapsed/refractory MCL. Given the clinical activity and tolerability of this combination,32 it is also being explored as maintenance therapy. Clearly, we have entered a very productive period of research in the treatment of the disease. Novel targeted agents and new combination regimens have the potential to prolong survival and improve clinical outcomes for patients diagnosed with MCL. ◆ References 1. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114:1469-1476. 2. Ondrejka SL, Lai R, Smith SD, Hsi ED. Indolent mantle cell leukemia: a clinicopathological
variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121-1127. 3. Vizcarra E, Martínez-Climent JA, Benet I, et al. Identification of two subgroups of mantle cell leukemia with distinct and biological features. Hematol J. 2001;2:234-241. 4. Fernàndez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408-1418. 5. Romaguera JE, Fayad L, Rodriquez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus Hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013-7023. 6. Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010;150:200-208. 7. Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012;156:346-353. 8. Epner EM, Unger J, Miller T, et al. A multi center trial of hyperCVAD+Rituxan in patients with newly diagnosed mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2007;110: Abstract 387. 9. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-1992. 10. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progressionfree survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677-2684. 11. Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) is superior to 6 courses CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL younger trial of the European Mantle Cell Lymphoma Network (MCL net). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 110. 12. Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112: 2687-2693. 13. Bernstein S; Southwest Oncology Group (SWOG). Phase II randomized study of induction therapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, dexamethasone, methotrexate, cytarabine, and leucovorin calcium versus rituximab and bendamustine hydrochloride followed by consolidation therapy and autologous stem cell transplantation in older patients with previously untreated mantle cell lymphoma (S1106). http://cancer.gov/clinical trials/search/view?cdrid=707601&version=healthprofessional. Accessed May 7, 2012. 14. Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 2002;20:1288-1294. 15. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as firstline treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 16. Smith MR; Eastern Cooperative Oncology Group (ECOG). Rituximab, bendamustine hydrochloride, and bortezomib followed by rituximab and lenalidomide in treating older patients with previously untreated mantle cell lymphoma (E1411). http://www.clinicaltrials.gov/ ct2/show/NCT01415752?term=E1411&rank=1. Accessed May 7, 2012. 17. Kahl BS, Longo WL, Eickoff JC, et al. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Ann Oncol. 2006;17:1418-1423. 18. Kahl BS, Li H, Smith MR, et al. The VcR-CVAD regimen produces a high complete response rate in untreated mantle cell lymphoma (MCL): first analysis of E1405—a phase II study of VcRCVAD with maintenance rituximab for MCL. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 1661. 19. Smith MR, Li H, Gordon L, et al. Phase II study of R-CHOP followed by 90Y-ibritumomab tiuxetan in untreated mantle cell lymphoma (MCL): 5 year follow-up of Eastern Cooperative Oncology Group E1499. Ann Oncol (ICML Annual Meeting Abstracts). 2011;22(suppl 4):Abstract 017. 20. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90–ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26:5156-5164. 21. Kluin-Nelemans JC, Hoster E, Walewski J, et al. R-CHOP versus R-FC followed by maintenance with rituximab versus interferon-alfa: outcome of the first randomized trial for elderly patients with mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 439. 22. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 442. 23. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 1777. 24. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nature Review Cancer. 2007;7:750-762. 25. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:3822-3829. 26. Renner C, Zinzani PL, Gressin R, et al. A multi-center phase II study (SAKK 36/06) of single agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 2803. 27. Meadows SA, Kashishian A, Johnson D, et al. CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K ), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mam-
Continued on page 23 www.TheOncologyPharmacist.com
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Improving Patient Outcomes in Mantle Cell Lymphoma Barbara Rogers, CRNP, MN, AOCN, ANP-BC Adult Hematology-Oncology Nurse Practitioner Fox Chase Cancer Center Philadelphia, PA
Introduction The treatment of mantle cell lymphoma (MCL) continues to evolve with the development of newer, more effective therapies. However, treatment-related adverse events remain a significant source of concern, as they may negatively impact clinical outcomes and quality of life. In this article, Barbara Rogers, CRNP, MN, AOCN, ANP-BC, answers questions concerning specific toxicities that may occur during treatment, including infection, myelosuppression, and hypersensitivity reactions. She also discusses the importance of individualizing management strategies to provide optimal patient care.
What steps are necessary to minimize infection in patients with MCL who undergo stem cell transplantation?
The National Comprehensive Cancer Network (NCCN) suggests highdose therapy with autologous stem cell transplant (ASCT) as consolidation for patients receiving first-line therapy for MCL and high-dose therapy with allogeneic SCT (allo-SCT) for consolidation in the second-line setting.1 Both of these approaches are myelosuppressive, with allo-SCT being associated with a much higher infection risk than ASCT.1 This risk may be lessened to some degree if a patient is treated with a nonmyeloablative allo-SCT. This type of transplant administers chemo radiotherapy with the intent of allowing for donor cell engraftment, with less of an emphasis on dose intensity. Based on emerging safety and efficacy data,2,3 nonmyeloablative alloSCTs may become the preferred transplant modality for patients with relapsed/refractory MCL when suitable donors are available. Regardless of the type of transplant a patient receives, nurses should carefully monitor patients for signs and symptoms of infection during all phases of the process. Patients must receive prophylaxis for bacterial, viral, and fungal infections, in accordance with guidelines published by the Centers for Disease Control and Prevention, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation.4 Patient education about infection precautions should include the importance of good hygiene (especially frequent hand washing), food safety, and strategies for avoiding or minimizing exposure to potentially infectious people and pets.4 Following transplant, patients must also be reimmunized with childhood vaccinations, because antibody titers to vaccine-preventable diseases decrease 1 to 4 years post-transplant. Guidelines suggest a schedule of reimmunization that begins 1 year after allo-SCT or ASCT.4 At our institution, we try to follow these recommendations as closely as possible. There are times, however, when we may need to alter the schedule due to specific medical situations, such as patients who are extremely immunocompromised after transplant.
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How do you minimize and manage infusion reactions associated with the use of rituximab?
Similar to other monoclonal antibodies, rituximab is associated with infusion reactions that are caused primarily by cytokine release, rather than true allergic reactions.5 The incidence of mild-to-moderate reactions is approximately 77% with the first infusion of rituximab and tends to decrease with subsequent infusions.5,6 Certain factors may increase the risk of a reaction, including having a hematologic malignancy such as MCL (Table 1).6 Patient education is the first step in the effective management of rituximab-related infusion reactions. We always inform patients of potential signs and symptoms that may occur during their first infusion. Common symptoms are fever, chills, and rigors; less frequent (and more severe) reactions include angioedema, bronchospasm, and dyspnea.5 All patients receiving rituximab must be premedicated with acetaminophen and diphenhydramine prior to each infusion. If we anticipate that a patient is at very high risk for a reaction,6 we will also administer a steroid such as dexamethasone. Risk factors for more significant infusion reactions are very high white blood cell (WBC) counts or untreated bulky disease.6 In patients with high counts, we may divide the dose of rituximab over 2 days. For example, we may administer 100 mg of the calculated dose on day 1 and the remainder of the dose on the following day. Alternatively, we may omit rituximab in the first cycle of treatment to allow for a decline of the WBC count, and add it during the second cycle instead. We start the rituximab infusion slowly and monitor vital signs every 30 minutes. If a reaction occurs, we stop the infusion, perhaps give more steroid
Table 1. Risk Factors for Hypersensitivity Reactions6 Asthma diagnosis Atopic patients (ie, patients who tend to react to specific allergens, such as hay fever, skin irritations, and asthma) Circulating lymphocyte counts 25,000 mm3 (lymphoma or leukemia) Concomitant -adrenergic blocker therapy Concurrent autoimmune disease Female gender Higher than standard drug doses Iodine or seafood allergies Newly diagnosed, untreated patients Older age Patients with hematologic malignancies such as mantle cell lymphoma and chronic or small lymphocytic leukemia Personal history of drug allergy or previous immediate reaction to a medication Preexisting cardiac or pulmonary dysfunction Previous exposure to the drug Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs. 2010;14:E10-E21. Reproduced with permission of the Clinical Journal of Oncology Nursing.
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or diphenhydramine, and wait for recovery. A histamine-2 receptor antagonist may also be added as a precautionary measure. We then resume rituximab at a slower rate. When a patient has a severe, anaphylactic-like reaction, the infusion is usually discontinued and reinitiated on an alternate day. In rare situations, we may need to halt rituximab therapy permanently. What strategies can be used to manage hematologic toxicities associated with treatments for MCL?
Our approach to the management of neutropenia, anemia, and thrombocytopenia is dependent on the severity of the myelosuppression itself, as well as patient-specific factors. We always use pegfilgrastim when administering chemotherapy regimens that pose a high risk of neutropenia, such as rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HyperCVAD). For older patients, who are at higher risk of neutropenic fever, we give neutrophil growth factors starting with the first cycle of treatment, in accordance with guidelines from the American Society of Clinical Oncology.7 However, younger, fit patients and those who are being treated with less aggressive chemotherapy combinations usually do not receive growth-factor support unless we see a need for it during treatment. If a patient develops anemia, transfusion may be necessary. However, according to current NCCN recommendations, the decision to transfuse should not be based solely on red blood cell count, but rather on patient-specific criteria.8 For example, patients with cardiac comorbidities are often transfused at a higher hemoglobin level than otherwise healthy individuals. We also use the erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa to treat anemia in some cases. Although these agents can be beneficial, as they help patients avoid transfusion, they are associated with serious risk, including increased mortality and tumor progression, thromboembolism, hypertension, and seizures.8 As a result, ESAs are contraindicated if the intention of treatment is to cure. Treatment with standard chemotherapy can cause a decline in platelet count. If a patient experiences severe thrombocytopenia (platelet count <10,000 platelets/mm3 without bleeding or 10,000 platelets/mm3 with bleeding),9 we initiate a platelet transfusion. Dose reductions of certain agents may be helpful for reducing a patient’s risk of experiencing severe thrombocytopenia in future cycles of therapy. In clinical practice, we have also learned that some drugs may be better tolerated if they are administered at a dose lower than what is listed in the package insert. For example, the approved dose of bendamustine for the management of non-Hodgkin lymphoma is 120 mg/m2.10 However, in a phase 3 trial of patients with mantle cell, indolent, and follicular lymphomas, Rummel and colleagues administered bendamustine at a dose of 90 mg/m2, in combination with rituximab (BR). This regimen was shown to be effective and well tolerated, with a reasonably good safety profile. As shown in Table 2, significant differences in grade 3/4 hematologic toxicities were observed between BR and a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).11 It is important to remember, however, that there are clinical scenarios in which dose-reducing bendamustine may not be the best course of action, and the full dose will be needed to obtain adequate response. The rate of recovery from hematologic toxicities varies, depending on the type of therapy the patient is receiving, as well as what he or she received in the past. With chemotherapy, the nadir occurs approximately 7 to 10 days after treatment. R-HyperCVAD/R-MA is associated with profound (grade 4) neutropenia and thrombocytopenia in spite of growth-factor support,12 and
Table 2. Grade 3/4 Myelosuppression in the Phase 3 StiL Trial of R-CHOP versus BR11 Toxicity
Use of G-CSF
BR indicates bendamustine plus rituximab; G-CSF, granulocyte colony-stimulating factors; R-CHOP; rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
patients treated with this type of aggressive regimen are at greater risk of developing neutropenic fever. Hematologic toxicities seen with regimens such as BR and R-CHOP tend to be less severe, but still require careful monitoring and management strategies.11,13 With radioimmunotherapy, the rate of myelosuppression is usually delayed; blood cell and platelet counts typically do not decline until approximately 1 month after treatment. For example, following 90Y-ibritumomab tiuxetan therapy, nadir counts occur at about 7 to 9 weeks post treatment and last approximately 1 to 4 weeks before recovery begins.14 As a result, patients do not receive additional antilymphoma therapies for approximately 3 to 4 months following treatment. Conclusion
Although advances in the treatment of MCL have led to improved outcomes, individuals who receive treatment with novel agents, with or without transplant, can potentially experience significant toxicities that can lead to greater morbidity and mortality. Nurses must be aware of evidence-based preventative and supportive care strategies for these toxicities so that patients can be promptly treated and continue with their therapy. ◆ References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™): Non-Hodgkin Lymphoma. Version 2.2012. http://www.nccn.org. Accessed May 14, 2012. 2. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21:4407-4412. 3. Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.D. Anderson Cancer Center riskadapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113:4144-4152. 4. Centers for Disease Control and Prevention; Infectious Diseases Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49:1-125. 5. Lenz H-J. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12:601-609. 6. Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs. 2010;14:E10-E21. 7. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2006;24:3187-3205. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™): Cancer- and Chemotherapy-Induced Anemia. Version 2.2012. http:// www.nccn.org. Accessed May 15, 2012. 9. Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007:172-1788. Review. 10. Treanda [package insert]. Frazer, PA: Cephalon, Inc; 2008. 11. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 12. Romaguera JE, Fayad L, Rodriquez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23: 7013-7023. 13. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-1992. 14. Witzig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:1263-1270.
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Pharmacologic Considerations in the Treatment of Mantle Cell Lymphoma Dwight Kloth, PharmD, FCCP, BCOP Director of Pharmacy, Fox Chase Cancer Center Philadelphia, PA
Introduction Historically, the treatment of mantle cell lymphoma (MCL) has relied on conventional chemotherapeutic agents, which, unfortunately, are not curative. Patients eventually relapse following initial treatment, and overall survival rates have remained quite variable,
of therapy to prolong survival while minimizing side effects? It is important to have an open dialogue with patients in order to review their treatment history, establish priorities, and ascertain which therapies offer the best chance of meeting therapeutic goals. For instance, if a patient expresses a desire to continue working at a job that requires great mental acuity, it may be prudent to avoid lenalidomide-based treatment, as this drug can cause significant drowsiness.2 Similarly, a patient’s ability to perform certain work-related tasks may be impaired by bortezomib-induced peripheral neuropathy.1 Consequently, it is imperative to consider the toxicity profile of any agent as part of the decision algorithm.
with most patients succumbing to the disease. In recent years, a number of newer therapies have been developed for MCL, leading to more durable responses in both the frontline and relapsed/refractory
What special requirements are necessary to administer radioimmunotherapy (RIT) to patients with MCL?
settings. With an ever-increasing array of choices, treatment decisions have become more complex, requiring careful consideration of numerous patient- and drug-related factors. In this article, Dwight Kloth, PharmD, FCCP, BCOP, answers questions related to the use of novel agents for MCL and provides his clinical perspectives on future directions in the treatment of the disease.
What are some of the pharmacologic issues that must be considered when using novel drugs in the relapsed/refractory setting for MCL?
We are fortunate to have several novel therapies available to treat patients with relapsed/refractory MCL. If we try 1 agent and it is not well tolerated or does not appear to be effective, we can usually offer the patient an alternative treatment. When choosing among the different agents, we must consider several factors. For example, the novel agents we are using with the greatest frequency in MCL—bendamustine, bortezomib, lenalidomide, and rituximab—have varied routes of administration. Bendamustine and rituximab can only be given by intravenous (IV) infusion, which lasts 60 minutes or longer. Bortezomib has traditionally been used as an IV drug but is increasingly being administered subcutaneously (SC). This new approach is based on a study in multiple myeloma patients that showed reduced neurotoxicity and similar therapeutic benefit with SC dosing.1 Lenalidomide is taken orally, which increases convenience but also raises issues concerning the teratogenic risk associated with this drug.2 Patients must be advised that the risk management program for lenalidomide is not trivial. Prior to prescribing a high-cost oral agent, it is important to ascertain whether a patient has a prescription drug benefit plan, and what the tier level for the out-of-pocket copay will be, as reimbursement issues can have a significant impact on patients and their families. Individuals may have coverage for an IV drug administered by a healthcare provider (eg, Medicare Part B or a commercial insurer’s major medical plan), but not for an oral self-administered agent, and this may affect choice of therapy. Other considerations include the patients’ ability to travel to the clinic for IV infusions and how well they are able to comply with and adhere to an oral drug regimen. Goals of therapy are another factor to consider when selecting treatments. Are we trying to prepare the patient for stem cell transplantation? Is the aim
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Clinical data regarding the use of RIT in MCL are somewhat limited. However, 90Y-ibritumomab tiuxetan consolidation therapy after a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone improved the quality of response in 57 previously untreated patients with stage III/IV MCL.3 The mechanism of action of RIT—radiation combined with a monoclonal antibody carrier—provides an interesting and effective way to target treatment right to the malignancy. The antibody binds to receptor sites on the tumor cell, and the radiation hits the cell where it is targeted. Radiation also hits neighboring tumor cells that may be inaccessible to the antibody due to penetration barriers—a phenomenon called radioactive crossfire.4 However, logistics can be a challenge with RIT. The half-life of the radiolabeled combination product makes this therapy extremely time sensitive,5 so everything has to be carefully staged and choreographed. The antibody must be radiolabeled by a nuclear-certified pharmacy in close geographic proximity to the treatment site; this needs to be done immediately before the scheduled time of treatment to ensure that radiation does not decay excessively. In addition, patients must have the necessary bone marrow reserves and hematologic status to undergo RIT (Table).4-7 Careful follow-up is needed postRIT, to prepare for the nadir of blood counts several weeks later.8 These issues almost always make it impractical for a small oncology practice to provide RIT to their patients. The therapy is usually coordinated and given by a nuclear medicine department and its affiliated pharmacy. These clinicians have the expertise to give RIT efficiently and safely, and to maintain continuity of care as patients return home and back to their oncology team.
Table. Bone Marrow Reserves and Hematologic Criteria for the Administration of Radioimmunotherapy4-7 • Bone marrow: - <25% bone marrow involvement with lymphoma, assessed via biopsy - No other evidence of bone marrow impairment • Blood counts: - Platelet count 100,000 cells/mm3 - Neutrophil count 1500 cells/mm3
CONSIDERATIONS IN LYMPHOMA
Figure. The central role of Btk in the B-cell fate.
apoptosis of non-Hodgkin lymphoma cell lines.11 The PI3-K pathway may have special relevance to MCL. It is part of a larger pathway—PI3-K/ Akt/mTOR (mammalian target of rapamycin)—involved in the transduction of signals from cell receptors to proteins that mediate cell cycling. These proteins include cyclin D1, which is overexpressed in MCL.12,13 Promising results with GS-1101 have been reported in a phase 1 study that included 16 heavily pretreated patients with relapsed/refractory MCL.11 ORR was 62%, with higher rates of response in the relapsed versus the refractory populations (73% and 40%, respectively). Median duration of response in MCL was 3 months (range, 1-8 months).11 Recent data show that GS-1101 is active in combination with the mTOR inhibitor everolimus, another agent that affects protein kinase pathways and interrupts translation of cyclin D1.12,13 Several investigative teams are now developing protocols with kinase inhibitors in combination with other drugs. These novel agents are an exciting development, because they are targeted to the B cell and to specific molecular pathways of MCL.9,12-14 The hope is that this kind of targeting will move us closer to our goal of prolonging survival in this difficult-to-treat population of patients. ◆
References Courtesy of Sabine Ponader, PhD.
Can you discuss the mechanism of action and clinical activity of the investigational agents ibrutinib (PCI-32765) and GS-1101 (formerly known as CAL-101)?
Ibrutinib (PCI-32765) is an inhibitor of Bruton’s tyrosine kinase (Btk), which is a key component of the B-cell receptor signaling pathway.9 This agent selectively and permanently inhibits Btk, which blocks B-cell activation and downstream signaling of the B-cell receptor (Figure). MCL cells are known to express Btk.9 Preliminary results of an ongoing phase 2 study of ibrutinib in MCL were recently reported.10 A total of 48 patients were enrolled, in cohorts of bortezomib-naive and bortezomib-exposed, with 24 patients evaluable for response. The objective response rate (ORR) for both cohorts was 67% (16/24); ORR was 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. Treatment was well-tolerated; the most frequent grade 1/2 toxicities included fatigue, diarrhea, and nausea. Grade >3 toxicities considered potentially related to ibrutinib were observed in 11% of patients.10 The expression of phosphatidylinositol 3-kinase (PI3-K) P110 in cells of hematopoietic origin influences B-cell proliferation and survival.11 GS-1101 is a selective inhibitor of PI3-K signaling and has been shown in vitro to induce
1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 2. Revlimid [package insert]. Summit, NJ: Celgene Corporation. October 2011. 3. Smith MR, Li H, Gordon L, et al. Phase II study of R-CHOP immunochemotherapy followed by 90Y-ibritumomab tiuxetan in untreated mantle cell lymphoma: 5-year Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. In press. 4. Rao AV, Akabani G, Rizzieri DA. Radioimmunotherapy for non-Hodgkin’s lymphoma. Clin Med Res. 2005;3:157-165. 5. Wagner HN Jr, Wiseman GA, Marcus CS, et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with 90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med. 2002;43:267-272. 6. Zevalin [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. November 2011. 7. Bexxar [package insert]. Research Triangle Park, NC: GlaxoSmithKline. February 2012. 8. Wiztig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:1263-1270. 9. Ponader S, Balasubramanian S, Pham LV, et al. Activity of Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in mantle cell lymphoma (MCL) identifies Btk as a novel therapeutic target. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 3688 and Poster. 10. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 442. 11. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 1777. 12. Meadows SA, Kashishian A, Johnson D, et al. CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K ), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mammalian target of rapamycin (mTOR), in mantle cell lymphoma (MCL). Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 3730. 13. O’Connor OA. Mantle cell lymphoma: identifying novel molecular targets in growth and survival pathways. ASH Education Book. 2007;2007:270-276. 14. Smith MR. Mantle cell lymphoma: advances in biology and therapy. Curr Opin Hematol. 2008;15:415-421.
Current and Emerging Treatment Strategies in Mantle Cell Lymphoma Continued from page 19 malian target of rapamycin (mTOR), in mantle cell lymphoma (MCL). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3730. 28. Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol. 2011;80:69-86. 29. Viallet J; Gemin X. Safety and efficacy of obatoclax mesylate (GX15-070MS) in combination with bortezomib for the treatment of relapsed or refractory mantle cell lymphoma (MCL). http://clinicaltrials.gov/ct2/show/NCT00407303. Accessed May 7, 2012. 30. Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rit-
uximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807-2812. 31. Fowler N, Kahl BS, Matous JV, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II vertical study. J Clin Oncol. 2011;29: 3389-3395. 32. Wang M, Fayad L, Wagner-Bartak N, et al. Oral lenalidomide plus 4 doses of rituximab induced prolonged remissions in relapsed/refractory mantle cell lymphoma: a completed phase I/II clinical trial. Ann Oncol. 2011;22(suppl 4):iv119. Abstract 109.
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Cancer Center Profile University of Michigan Comprehensive Cancer Center Continued from cover better care for patients. In addition, research at UMCCC is focused on cancer prevention and control and includes biomedical prevention and sociobehavioral research programs. UMCCC also offers a variety of support services for patients and their families and caregivers. Similar to research and patient care at UMCCC, the support services programs take a multidisciplinary approach—including social workers, art therapists, psychologists, nutritionists, and others who specialize in the needs of those facing a cancer diagnosis. Shawna Kraft, PharmD, BCOP, is a hematology/oncology clinical pharmacist at UMCCC and a clinical assistant professor at the University of Michigan College of Pharmacy. She answered our questions about the role of an oncology pharmacist.
What approach does your institution take to treating people with cancer? Shawna Kraft (SK): The University of Michigan Comprehensive Cancer Center really focuses on the “comprehensive” part of the care by ensuring multidisciplinary care for our patients. This is done by including many key providers, such as physicians, nurse practitioners/physician assistants, nurses, pharmacists, social workers, psychology/oncology, spiritual care, physical med-
focus on symptom management and supportive care, outpatient pharmacist opportunities in cancer centers have really expanded. Outpatient cancer centers are beginning to rely heavily on pharmacists to provide education, drug interaction screening, and side effect management for their ambulatory patients—akin to the traditional role for inpatient pharmacists.
The University of Michigan Comprehensive Cancer Center is located in Ann Arbor. Photo from the University of Michigan Comprehensive Cancer Center.
icine and rehabilitation specialists, dietitians, and many, many more.
How does that translate to better outcomes for your patients? SK: I believe that by treating the whole patient, meaning all of the different aspects of the patient beyond just his or her cancer treatment, we can improve our patient’s quality of life even if we can’t cure the disease. What are you excited about right now in the field of oncology?
SK: Oral anticancer agents! There are more and more oral anticancer medications rapidly becoming available; thus, patients are able to be at home more. This is also providing ample opportunities for pharmacists, given the multiple access issues, possible drug interactions, and ensuring adherence.
How has the role of the oncology pharmacist changed over the past 5 years? SK: I think with the explosion of oral anticancer agents and the increased
Reader Poll Results
Do patients talk with you about antiemetic control?
In the April issue, we published an article about a presentation at the 17th Annual Conference of the National Comprehensive Cancer Network that addressed what’s new in antiemetic control. We asked our online reading
community if antiemetic control was an issue they discussed with patients. • 79% have talked with their patients about this issue. • 21% have not discussed antiemetic control with patients.
Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 25 for details.
What inspired you to become an oncology pharmacist? SK: My hematology/oncology preceptor as a fourth year pharmacy student inspired me by her interactions as an inpatient clinical pharmacist. I was amazed by the impact she had with the patients and the medical team in everything from educating a newly diagnosed patient on his/her chemotherapy regimen to assisting the oncologist in managing the side effects. The imprint she made in every patient’s life was incredible. I truly believe the patients were better cared for because she was involved in their care. I really wanted to work closely with patients and providers and saw oncology pharmacy as a perfect fit in order to do so. Any advice for pharmacists just entering the field? SK: 2 things: 1. Try to come up with a strategy to stay on top of the ever-growing oncology literature. Subscribe to table of contents, set up a journal watch with colleagues, attend conferences, follow ASCO, NCI, etc on twitter, or do whatever works for you. Create a plan to try to stay current. It’s very difficult to do! 2. Take time for yourself. We are in a very difficult field that can easily become overwhelming and de pressing. Be sure to take time every now and then to regroup and rejuvenate so you don’t become burned out. If you weren’t a pharmacist, what would you be doing? SK: I would say a high school teacher or a chef/baker. I really enjoy teaching but I also love to cook and bake! ●
Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.
Contact firstname.lastname@example.org for more information. 24
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Best Practices Pharmacists Can Enhance Compliance With Oral Medications Continued from cover medications, and how to ensure adherence,” said Bartel, of the Dana-Farber Cancer Institute (DFCI) in Boston. “Pharmacists are in the best position to dispense medications. Without them, you are bypassing a key component of safety with oral medications.” By her definition, patients are adherent when they take at least 85% of their prescribed medication. Patients are nonadherent by failing to fill or refill their prescription, sharing medication, taking too little or too much, and substituting other products. While oral chemotherapy has quality-of-life advantages, it offers less opportunity for interaction with providers and clinical staff, especially if infusion is not part of the regimen, and providers are often unaware when patients are not compliant with treatment, she said. Nonadherence contributes to variability of therapeutic effect, which may lead to unnecessary changes in dose and regimen. It is associated with increased physician visits, higher hospitalization rates, longer hospital stays, worsening of disease, increased mortality, and higher healthcare costs. “We know that one-third to twothirds of medication-related hospital admissions are related to poor adherence,” she noted. “Suboptimal adherence may be the greatest barrier to the effective use of new oral agents.” Barriers to Adherence There are many reasons for nonadherence. The usual barriers, as reported in the literature and in Bartel’s own experience, include psychological problems, cognitive impairment, misper-
ceptions (eg, “If I feel good I don’t have to take my medicine today”), complexity of dosing schema, presence of comorbidities, older age, lack of social support, low literacy, inadequate follow-up, and cost of the drug. Measuring adherence is generally by indirect means: patient query or questionnaires, clinical response, pill counts (which can be manipulated), refill data, and patient diaries. Electronic medication monitors are used in clinical trials but are generally not available in usual practice. “We assume patients are taking their medications, but we really don’t know,” Bartel said.
Programs to Increase Adherence “Pharmacists play a key role in adherence. Establish honest and open communication with your patients so they will tell you the issues they are struggling with,” Bartel told attendees. At the very least pharmacists should review with patients and their families the medication timing, potential side effects and their management, and what to do with missed doses. They can help incorporate the drug schedule into the patient’s routine and improve the dosing schedule if needed. They can instruct patients on the use of schedule reminders such as calendars, pill organizers, alarms, and cell phone apps.
“Pharmacists play a key role in adherence. Establish honest and open communication with your patients so they will tell you the issues they are struggling with.” —Sylvia Bartel, RPh
In a survey from DFCI, 30 oral chemotherapy patients were assessed for their understanding of their regimens. Eleven patients had limited understanding about the management of side effects; 7 had limited knowledge of what to do if a dose is missed; 5 reported missing at least 1 dose in the past month due to side effects and forgetfulness; and 8 reported having no strategy to support adherence, such as an information sheet from their provider or pharmacy.
“An interactive dialogue is important,” she continued. “Ask if the patient understands the purpose of the medication, dose and schedule, side effects to look for, and strategies for missed doses. Provide written material and involve the patient’s partner.” Since such comprehensive counseling is hard to accomplish “at the pickup window,” she advocates structured programs. At DFCI, several such programs are in place. One is expressly for patients (and their caregivers) receiving autologous
bone marrow or stem cell transplants. Pharmacists review in detail their prescriptions (including a look at the actual pills or tablets) and provide written materials, managing about 15 patients each. An assessment of the program revealed that providers perceive their patients to be well informed, and the patients express a good understanding of their posttransplant medication needs. “Having this program has been helpful in this population of patients, and we are now extending this to the outpatient clinic,” she said. DFCI also has a similar program through its specialty pharmacy. Pharmacists review the medications when patients pick up their prescriptions. At the conclusion of the first cycle of treatment, the pharmacist calls the patient to discuss any issues, and calls whenever patients fail to pick up their next prescription. With this approach to patient consultation and follow-up, adherence to treatment has improved from about 50% to 97%, she reported. Bartel acknowledged that counseling for oral medications adds to the labor burden within pharmacy. It takes the pharmacist about 1 hour for the initial counseling of transplant patients and about a half hour within the specialty pharmacy program. Not all patients warrant this degree of intensive counseling. It would be ideal to have a screening instrument to help identify patients at risk for nonadherence, which can often be predicted by type of drug and complexity of treatment schedule. Efforts are under way at DFCI to create such a tool. ●
Reader Poll Do you think the increased use of oral chemotherapy medications has increased the incidence of patient nonadherence? r Yes
Go to www.TheOncologyPharmacist.com to cast your vote and add your comments. Please tell us what you think and how you address the issue of nonadherence. www.TheOncologyPharmacist.com
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The Patient’s Voice What Is in YOUR Lunch Box? Continued from cover refrigerator. That way, when needed, I could easily find it. I religiously froze the gel packs to ensure they were ready every time I needed them. The funny thing is, my lunch box never carried a morsel of food or a drop of drink. Rather, every 3 weeks, it carried my chemotherapy drugs. In May 2008, a fainting spell and case of severe anemia led to a cancer diagnosis. At the time, I worked in a border town in Northern Mexico. I had access
to the medical facilities and programs at a local university. At no cost to me, these facilities and programs covered everything from my diagnosis to the entire chemotherapy regimen that followed. The only wrinkle was that I had to go to the university’s pharmacy every 3 weeks, collect my multitude of chemotherapy drugs, pack them carefully into my lunch box, cautiously walk to my car and place my lunch box on the
front seat next to me, transport myself and the drugs to the nearby local hospital, leave my lunch box filled with potent drugs with the nurse who happened to be attending the nurse’s station at the time of my arrival, accommodate myself in my hospital room, and wait for the drugs to be administered. I never quite got comfortable with this lunch box system of transporting drugs, though I did get used to the routine of
Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE
www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.
STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.
EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients
Release Date: May 8, 2012 Expiration Date: May 7, 2013
FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA
E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC
Kathy D. Miller, MD Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.
ACCREDITATION Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.
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bringing the doctor’s drug orders for my next session of chemotherapy to the university’s pharmacy each time I finished a session and, a few weeks later, packing up the drugs right before the following session. Sometimes, I would get more drugs than could be stored in my lunch box (either because more had been ordered or because the quantities available— packages of 10 vials instead of 5—were larger than usual). On those occasions, I would place the surplus medications in an extra bag I had brought along, making sure to place those that had to be kept cool in my lunch box. Other times, the necessary drugs did not come in as planned. On those occasions, I would place all the available drugs in the lunch box, carefully putting paper towels from the university pharmacy’s restroom in between bottles. No matter what the situation, my time at the pharmacy window would always end with the zipping up of my lunch box and the kind words “Que se mejore” (“Get better”) from the pharmacist. I do not know if every patient in Mexico needs to carry his or her own chemotherapy drugs to the hospital. I do know that I was one of the lucky ones who had access to the drugs and treatment, and at no cost to me. Clearly, I know the cost got picked up somewhere along the system (taxes? university fees? a public–private bargain among the university, the hospital, and the city or state? a private–private deal between the pharmaceutical companies and the hospital?). Regardless, it was a shared cost. Right now, if I were still in Mexico, somehow I and others would be directly, maybe through a fee, or indirectly, maybe through taxes, paying for the treatment of an unknown individual if he or she belonged to the same system as I did. My sincere hope is that the person has a positive outcome, regardless of who he or she is. I also know that 4 years later, back in the US and receiving treatment at one of the best cancer centers in the world, I do not look back with nostalgia at the days when I carried potent chemotherapy drugs—or at least those available on that particular day—in my red lunch box made out of pliable plastic. I really do not have time to think about it much; now I have to worry about how I can possibly pay for all these drugs and treatments not covered by insurance, not whether they will break or not in my lunch box. From a patient’s point of view, I often wonder what matters more: my health or the money I have to spend on it? ● MMA is undergoing treatment for cancer. She wishes to use her initials.
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Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®. Our Specialists can help you navigate the process.
To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources
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