VOL 4, NO 1
For Payers, Purchasers, & Oncology P&T Committees CONFERENCE NEWS: ASHP
CANCER CENTER PROFILE
Interdisciplinary Care Taken to the Next Level
Pharmacist Review of Palonosetron Use Has Potential to Capture Inappropriate Use and Save Money
By Dawn Lagrosa
By Wayne Kuznar
Waukesha Memorial Hospital’s Regional Cancer Center
ANAHEIM—Pharmacist assessment of palonosetron use for the prevention of emesis associated with chemotherapy has the potential to capture inappropriate use and result in cost savings, said John P. Jezak, PharmD. Palonosetron, like the other 5-hydroxytryptamine-3 (5-HT3) antagonists, is indicated for the prevention of emesis with highly and moderately emetic chemotherapy regimens, and although it has not Left to right: Kelli K. Pettit, MD, breast surgeon; James C. Jones, MD, radiation oncologist; Peter Johnson, MD, medical oncologist; Jennifer T. Bergin, MD, breast imaging radiologist; Christine Wynveen, MD, breast pathologist; and Michelle Willman, RN, BSN, OCN, CBCN, breast care coordinator.
hat started as tumor board conferences a decade ago has grown into a true multidisciplinary team approach to comprehensive breast care. ProHealth Care’s Center for Breast Care at Waukesha Memorial Hospital’s Regional Cancer Center in Waukesha, Wisconsin, is an interdisciplinary breast cancer clinic where patients can see multiple specialists in one visit. With the opening of the clinic, the various specialists involved in patient care can talk to each other about a patient in real time, not replacing tumor board conferences, but taking patient care to the next level.
Continued on page 21
CONFERENCE NEWS: SABCS
Denosumab Beats Zoledronic Acid in Delaying Breast Cancer Skeletal Events By Daniel M. Keller
SAN ANTONIO—Denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in 2046 women with advanced breast cancer and bone metastases, according to new trial results. Denosumab, a monoclonal antibody acting via a novel
mechanism, targets the receptor activator of nuclear factor kappa-B (RANK) ligand, important for the survival of osteoclasts, and thereby inhibits bone resorption. In this phase 3 trial, participants were randomized to receive every 4 weeks
been proven to be superior to other 5-HT3 antagonists for preventing acute emesis, palonosetron has been shown superior for the prevention of delayed emesis, probably owing to its long half-life (approximately 40 hours), notes Jezak, a pharmacy practice resident at DartmouthHitchcock Medical Center, Lebanon, New Hampshire. 5-HT3 antagonists are recommended by the National Comprehensive Cancer Continued on page 6
One-year Findings in Metastatic Melanoma Confirm Rose Bengal Benefit By Walter Alexander
SYDNEY—One-year results in metastatic melanoma for PV-10 (Rose Bengal, Provectus Pharmaceuticals) confirm positive interim findings found earlier with the first 40 patients. The updated analysis of the full 80-patient cohort was presented by Sanjiv Agarwala, MD, at the 4th Interdisciplinary Melanoma & Skin Cancer Centres Meeting, held at the 2010 International Melanoma Research Congress. Interim findings had been presented
at the annual meeting of the American Society of Clinical Oncology in June. All patients had stage III/IV melanoma. PV-10 is a proprietary, injectable formulation of Rose Bengal, a small-molecule agent that has been in use for nearly 30 years by ophthalmologists as a diagnostic agent for assessing damage to the eye. It has also been used intravenously to diagnose liver ailments. Rose Bengal was initially developed in Continued on page 12
INSIDE COMPLIMENTARY CE
Maintainence therapy for non–smallcell lung cancer
San Antonio Breast Cancer Symposium
Continued on page 14
American Society of Health-System Pharmacists Fostering a Dialogue to Improve Patient Care & Outcomes
Submit your cases online today at
American Society of Hematology
www.myelomacases.com ©2011 Green Hill Healthcare Communications, LLC
MULTIDISCIPLINARY TUMOR BOARD CASE STUDY . . . . . . . . . .
Metastatic gastrointestinal stromal tumor T.O.P. PHARMACIST AWARD
We present the finalists
Editorial Board EDITOR-INCHIEF Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK
Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Jim Koeller, MS University of Texas at Austin San Antonio, TX
Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA
Christopher J. Lowe, PharmD
John M. Valgus, PharmD, BCOP
Indiana University Simon Cancer Center Indianapolis, IN
Indiana University Hospital Indianapolis, IN
University of North Carolina Hospitals and Clinics Chapel Hill, NC
David Baribeault, RPh, BCOP
Rebecca S. Finley, PharmD, MS
Emily Mackler, PharmD, BCOP
Boston Medical Center Boston, MA
Jefferson School of Pharmacy Philadelphia, PA
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
Gary C. Yee, PharmD, FCCP, BCOP
Betty M. Chan, PharmD, BCOP
David C. Gammon, BSPh
Laura Boehnke Michaud, PharmD, BCOP, FASHP
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
USC/Norris Cancer Hospital Los Angeles, CA
Christopher Fausel, PharmD
OncologyPharmacist.net Warwick, RI
University of Nebraska College of Pharmacy Omaha, NE
Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY
The University of Texas M. D. Anderson Cancer Center Houston, TX
Marlo Blazer, RPh, PharmD Steven L. Dâ€™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
James Cancer Hospital & Solove Research Institute Columbus, OH
Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN
Anjana Elefante, PharmD, BSc, BSc Pharm, RPh
Dwight Kloth, PharmD, FCCP, BCOP
Steve Stricker, PharmD, MS, BCOP
Roswell Park Cancer Institute Buffalo, NY
Fox Chase Cancer Center Philadelphia, PA
Samford University McWhorter School of Pharmacy Birmingham, AL
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
FEBRUARY 2011 I VOL 4, NO 1
From the Editor For Payers, Purchasers, & Oncology P&T Committees
Publisher Philip Pawelko email@example.com Editorial Director Christin Melton firstname.lastname@example.org Associate Editor Dawn Lagrosa email@example.com Quality Control Director Barbara Marino Directors, Client Services John W. Hennessy firstname.lastname@example.org Joe Chanley email@example.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto firstname.lastname@example.org Executive Administrator Andrea Boylston Circulation Department email@example.com
Cost of Care Projected to Rise Over Next 10 Years
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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 ©2011 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.
FEBRUARY 2011 I VOL 4, NO 1
American Society of Hematology Annual Meeting & Exposition shows us the need to remain vigilant. We may wish to help our patients or our institutions by switching branded drugs with less costly generic versions; however, before doing so we should check their efficacy and safety profiles. With all our roles, it may be difficult to choose just one T.O.P. Pharmacist. This issue, however, will introduce our four finalists. By recognizing those among us who make outstanding contributions to oncology pharmacy, we not only acknowledge their accomplishments but also realize our own potential—all oncology pharmacists have something to offer, be it to their patients, their community, or the profession at large. As you read this issue of The Oncology Pharmacist, each study reported on, each case presented, each treatment discussed (and of course each pharmacist profiled) highlights the achievements of those in our chosen profession. As always, I hope this issue provides you with information that helps you in your practice, in your career, and in meeting the ever-changing challenges of today’s healthcare environment. We look forward to your feedback. ●
Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938
ncology pharmacists perform many roles, from inpatient and outpatient care to applying evidence-based medicine to safe handling to verifying order sets to research. Of all the varied roles, some of us enjoy working in patient care, either directly or through tumor board participation; others enjoy delving into research or educating fellow pharmacists. Patrick Medina, With this issue, we touch on many PharmD, BCOP of our multiple roles. Our coverage of Editor-in-Chief the American Society of HealthSystem Pharmacists’ midyear meeting highlights our role in ensuring that our care can continue in tough economic times by implementing simple measures for cost-effectiveness as well as by assuring patient safety. Two studies presented at the San Antonio Breast Cancer Symposium remind us to look further than just the latest and greatest new agents and turn a scientific eye toward traditional remedies. And a study presented at the
With the population expanding and aging, the costs of cancer care could reach at least $158 billion (in 2010 dollars) by 2020, according to a National Institutes of Health (NIH) analysis. This 27% increase over 2010 costs may rise even higher if newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, potentially reaching as high as $207 billion (J Natl Cancer Inst. Epub January 12, 2011). Researchers at the National Cancer Institute calculated cancer prevalence from incidence and survival models estimated from Surveillance, Epidemiology and End Results data. Data from Medicare beneficiaries without cancer were used as controls. Early detection and survivorship care are projected to add cost to the overall financial burden of cancer. Researchers analyzed cost for continuing care, which they defined as the period between the first 12 months postdiagnosis and the last 12 months before death. Prostate cancer and breast cancer care during this period represented the largest increases. Their projections—13.8 million and 18.1 million cancer survivors in 2010 and 2020, respectively—correlate with the cost of care rising from $124.57 billion in 2010 to $157.77 billion in 2020. The authors noted that their “findings have implications for policymakers in planning and allocation of resources.”
Too Many Screening Options May Lead to Confusion, Decreased Adherence Oncology nurses may be more effective in screening education with a less-is-more approach
New empirical evidence linking confusion about the multiple screening options for colorectal cancer with a reduced likelihood of adherence to screening guidelines should help oncology nurses tailor information when involved in patient education and outreach activities. The cross-sectional study found that patients confused about their options were 1.8 times more likely to be nonadherent with screening recommendations (Cancer
Epidemiol Biomarkers Prev. 2010;19:2821-2825). For their study, researchers at Virginia Commonwealth University Massey Cancer Center surveyed 6100 patients aged 50 to 75 years who had visited a physician within the previous 2 years. Of the responses, 1707 patients reported being presented with more than one screening option. Using weighted frequencies and multivariate logistic regression, they found that nonadherent patients reported greater confusion (P <.01). Among patients presented with two or more options, confusion was 1.6 times more likely than among those presented with one option (95% CI, 1.08-2.26). In turn, those who reported being more confused were less likely to be adherent than unconfused patients (95% CI, 1.14-2.75).
Nanoparticle-encapsulated Prodrug Delivery May Reduce Side Effects Reduced, but equally effective amount of chemotherapy delivered in the form of a prodrug encapsulated in a nanoparticle targeted to tumor cells
With just one third of the standard dose of cisplatin, researchers successfully shrank tumors in mice, without sacrificing efficacy. They were able to do this by encapsulating the prodrug form of the agent in a nanoparticle, which they then targeted to prostate tumor cells. Because less drug is used, the hope is that potentially severe side effects will be reduced, for cisplatin, those include kidney and nerve damage. In addition, the nanoparticle delivery system, which included a coating of molecules that bind to prostate-specific membrane antigen, increased the amount of cisplatin that reached the tumor. By encasing a derivative of cisplatin in a hydrophobic nanoparticle, researchers found that the drug circulated in the bloodstream for 24 hours, which is five times longer than conventional cisplatin. They also noted less accumulation in the kidneys. The researchers, from Massachusetts Institute of Technology and Brigham and Women’s Hospital, published their findings online January 11, 2011, in the Proceedings of the National Academy of Sciences of the United States of America. This research updates their previous efforts, which showed that the technology worked in vitro. The team now plans to move to human trials. ●
A pioneer in cancer innovation — exploring new directions
At Genentech BioOncology, we’re leading the ﬁght against cancer with innovative science and are working to transform cancer treatment. A family of ﬁrsts — Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States. A robust pipeline — Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.
© 2010 Genentech USA, Inc. All rights reserved. BIO0000015901 Printed in USA.
Conference News 45TH MIDYEAR CLINICAL MEETING OF THE AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS
Pharmacist Review of Palonosetron... Continued from cover Network (NCCN) for use with chemotherapy that has high or moderate risk for emesis, but “the NCCN guidelines don’t really differentiate if there’s a preferential antiemetic drug for a specific clinical situation,” he said. Palonosetron has an average wholesale price (AWP) that is 50 times greater than ondansetron, so curbing inappropriate use could result in substantial savings, he said. He conducted a retrospective evaluation of 129 patients (involving 269 encounters) who received palonosetron at the Dartmouth-Hitchcock infusion center over a 2-month period in 2010. Each patient’s chemotherapy regimen was evaluated on the level of acute and delayed emesis potential. The regimens considered as a risk for delayed-onset emesis, as established by the NCCN, are those containing carboplatin, cisplatin, cyclo-
phosphamide, and doxorubicin. “We decided that any patient that had delayed-onset risk of emesis, based on the four regimens listed in the NCCN criteria, was automatically deemed appropriate for palonosetron use,” said
either low or minimal emetic risk, experiencing no prior 5-HT3 failure, and having no risk for delayed-onset emesis were deemed inappropriate for palonosetron use. Potential interchange of palonosetron with another 5-HT3
Pharmacist intervention identified 47 cases of inappropriate palonosetron use and 17 cases for a potential 5-HT3 interchange.
Jezak. “The other qualifier we used is failure of another 5-HT3, such as ondansetron. It would also be appropriate to use palonosetron in this type of patient.” Therefore, patients receiving chemotherapy regimens considered to possess
antagonist would be appropriate for patients receiving chemotherapy regimens considered to possess either high or moderate emetic risk, experiencing no prior 5-HT3 failure, and having no risk for delayed-onset emesis. Pharmacist intervention identified
47 cases of inappropriate palonosetron use and 17 cases for a potential 5-HT3 interchange. Preventing inappropriate use had the potential to result in a cost savings of $8792 during the 2-month study period, assuming that the actual drug acquisition cost was 65.93% below AWP. “Ours is an outpatient facility, so we’re actually billing for this medication; we’re getting reimbursed,” said Jezak. “Each institution would have to consider the full financial impact—what is their reimbursement rate and what is their true cost for the medication?” He said that the ease of the intervention—a simple phone call—argues for its use. “Our pharmacists are already entering the orders for these medications, so it’s just the matter of picking up the phone and suggesting the use of a medication based on the emetic risk and the patient’s history,” he said. ●
Timing of Empiric Antibiotic Administration Affects Outcomes in Febrile Neutropenia By Wayne Kuznar
ANAHEIM—Antibiotics are being delayed in patients with febrile neutropenia, found George Varughese, PharmD. After a patient is diagnosed with neutropenia, guidelines from the Infectious Diseases Society of America recommend prompt initiation of an antibiotic. “Ideally, prompt is considered to be administration in less than 1 hour,” said Varughese, a pharmacy resident at the University Hospital-Health Alliance of
Greater Cincinnati at the University of Cincinnati at the time the study was conducted. His retrospective chart review of 67 patients with a diagnosis of febrile neutropenia, covering 74 documented episodes, found that the guideline is not being followed. “We wanted to see if it’s given within 1 hour or so in a hospital setting,” he said. “A secondary objective was to measure the impact of the timing of
Recent FDA Approvals Gardasil for Prevention of Anal Cancer The FDA has approved a new indication for Gardasil—the prevention of anal cancer and associated precancerous lesions caused by the human papillomavirus (HPV) types 6, 11, 16, and 18 in patients 9 to 26 years of age. The vaccine is already approved for the prevention of cervical, vulvar, and vaginal cancer in the female cohort of this population, as well as the prevention of genital warts in men and women. Approval was based on a randomized, controlled trial of men who have sex with men, a population with high incidence of anal cancer. Gardasil was 78% effective in the prevention of anal cancer related to
FEBRUARY 2011 I VOL 4, NO 1
HPV 16 and 18. Because the disease is the same in both sexes, approval was granted for prevention in men and women. Lung Optimizing Treatment Tool for Radiosurgery The FDA has issued 510(k) clearance to market a new component of the CyberKinfer VSI System (Accuray). This Lung Optimizing Treatment tool increases flexibility in delivering radiosurgery treatments to patients with lung cancer. This noninvasive treatment option offers the accuracy and steep dose falloff required to safely treat lung tumors, even for those close to critical structures. The tool also does not require fiducial implantation.
“We wanted to see if it’s given within 1 hour or so in a hospital setting. A secondary objective was to measure the impact of the timing of antibiotic administration on the patient’s clinical status.” —George Varughese, PharmD
antibiotic administration on the patient’s clinical status [the incidence of septic shock, sepsis, and death] as well as the length of hospital stay after the diagnosis of neutropenic fever.” The mean time to the first dose of an antibiotic after the diagnosis was 4.97 hours, and the median time was 3.67 hours. The length of hospital stay after empiric antibiotic administration correlated weakly with the timing of antibiotic administration. Length of hospital stay was a median of 4 days in those patients treated with an empiric antibiotic in 4 hours or less, compared with a median of 7 days in patients who received an antibiotic more than 4 hours after diagnosis (P = .0003). Antibiotic therapy was changed in 61 (82.4%) patients. Three (4%) patients died, and nine (12.2%) experienced sepsis. The incidence of negative composite clinical outcomes (sepsis, septic shock, length of intensive care unit stay, or death) was 31.1%, and negative composite outcomes
occurred significantly more often (P = .0103) in the group that waited longer than 4 hours to receive an antibiotic. “Diagnostic uncertainty of febrile neutropenia may cause delay in the administration of the antibiotic,” said Varughese. Another possible contributor to the delay is that emergency room physicians may have difficulty determining if the patient had a fever of 100.4°F for more than 1 hour, “which requires relying on the patient’s statement,” he said. There were also times when emergency room physicians miscalculated the absolute neutrophil count (ANC) and “therefore the true time of febrile neutropenia was misinterpreted,” he continued. “We need to educate emergency room physicians and all the nurses in the emergency room about measuring the patient’s fever and doing the ANC calculation and then getting the patient an antibiotic as soon as possible, hopefully within an hour.” ● Conference News continued on page 8
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Conference News 45TH MIDYEAR CLINICAL MEETING OF THE AMERICAN SOCIETY OF HEALTH-SYSTEM PHARMACISTS
For Overweight Patients, Dosing Chemotherapy Based on Total Body Weight Does Not Lead to More Toxicities By Wayne Kuznar
ANAHEIM—Overweight as well as obese chemotherapy recipients who are dosed according to total body weight do not experience more adverse drug events or cycle delays than normal weight recipients. The finding, which comes from a 10-year retrospective analysis of patients with gastrointestinal (GI) cancers, should allay concerns about overdosing and the potential for increased toxicities when calculating the chemotherapy dose using total body weight, said lead investigator Tiffany Dea, PharmD. Dea and colleagues sought to determine how chemotherapy is dosed in practice in normal weight, overweight, and obese patients as well as that dose’s impact on adverse drug events. They assessed 42 patients with GI cancers identified through a tumor registry who were treated at the San Francisco Veterans Affairs Medical Center. The chemotherapy drugs used in treatment were bevacizumab, capecitabine,
cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, leucovorin, mitomycin, and oxaliplatin. Of the 42 patients included, 13 were normal weight (body mass index [BMI], 18.5-24.9 kg/m2), 22 were overweight (BMI, 25-29.9 kg/m2), and seven were obese (BMI, >30 kg/m2).
“We didn’t find that overweight or obese patients had more side effects than normal weight patients.” —Tiffany Dea, PharmD
“Most of our oncology fellows are dosing on total body weight for overweight patients,” said Dea, an oncology pharmacist. “There is some literature out there that says that you shouldn’t cap the body surface area, but there’s no rationale for that. A lot of oncolo-
gists still prefer to dose based on adjusted or capped body surface area.” All 13 of the normal weight patients were dosed using total body weight. Of the 29 overweight or obese patients, 21 were dosed using total body weight— one using adjusted body weight, five using capped body surface area, and two using both total body weight and capped body surface area. “We didn’t find that overweight or obese patients had more side effects than normal weight patients,” said Dea. Grade 1 or 2 toxicities were experienced by 100% of the normal weight patients and 79.3% (16) of the overweight/obese patients. Of the overweight or obese patients experiencing toxicities, 76% were dosed according to total body weight compared with 100% dosed using adjusted body weight and 60% dosed using capped body surface area. “In looking at the cancer stage, more normal weight patients were in stage IV disease; in the overweight/obese category, there were more in stage III disease,” she said. “Whether or not that
may have been a factor in the rate of side effects isn’t known.” Some 54% of normal weight patients had stage IV disease, 50% of overweight patients had stage III disease, and 43% of obese patients had stage II disease. Thirty-one percent of normal weight patients had decreases in their dosage between cycle 1 and 2 compared with 14% of overweight/obese patients. Second cycle delays were also more frequent in the normal weight patients versus the overweight/obese patients (31% vs 28%, respectively). ●
Did You Know? In some states, chemotherapy drug parity legislation requires plans to charge the same cost-sharing amounts for oral and IV formulations. —Health Leaders InterStudy
Hospital Implements New Oral Chemotherapy Handling Process in Effort to Increase Safety ANAHEIM—A new process for handling oral chemotherapy medications that delineates prescriber privileges may help to avert errors or drug–drug interactions, said Brian L’Heureux, PharmD. On August 1, 2010, at Suburban Hospital in Bethesda, Maryland, a new procedure for processing oncology orders was implemented, said L’Heureux, an oncology pharmacy resident. Under the new system, oncologyspecific medications have to be ordered by prescribers with delineated privileges using a specific chemotherapy order form. In explaining the need for the new process, he said that most outpatient oral chemotherapy medications were continued by admitting physicians who were unfamiliar with them. “Therefore, they were prescribing medications for which they didn’t necessarily know all of the ins and outs, and this was particularly true of oral chemotherapy,” he said. More important, oral chemotherapy medications were being improperly handled by nurses on patient care units who were not chemotherapy certified. The new process did allow for some exceptions for ordering medications
FEBRUARY 2011 I VOL 4, NO 1
that can also be used outside of oncology, such as methotrexate and hydroxyurea, for nonchemotherapy indications. L’Heureux and colleagues conducted a medical use evaluation for the immediate 2 months following implementation of the new process for handling oral chemotherapy medications. Daily
write chemotherapy orders, the person transcribing the order to the chemotherapy order form, any major drug–drug interactions that required intervention, and whether certified chemo therapy nurses administered the medication. “A big part was whether chemotherapy nurses were actually administering
“Previously, on admission, if the prescribing doctor didn’t write that it’s chemotherapy, and the drug is continued, the nurses would not necessarily know that the [continued] drug is a chemotherapy medication.” —Brian L’Heureux, PharmD reports were generated through the pharmacy computer system, searching for formulary and nonformulary oral chemotherapy. Concurrent chart reviews were performed on all patients receiving oral chemotherapy. The data collected included drug name, drug class, indication, the name of the prescriber and whether the prescriber had delineated privileges to
the medication. Previously, on admission, if the prescribing doctor didn’t write that it’s chemotherapy, and the drug is continued, the nurses would not necessarily know that the [continued] drug is a chemotherapy medication,” he said. “When it was entered into our computer system, it came across as patients on medication, so there weren’t a lot of flags telling the nurses.”
Twenty-six oral chemotherapy orders were reviewed over the 2-month period. Seventy percent of the orders were written by physicians with delineated privileges and 23 orders were written on the appropriate form, of which 17 were transcribed by the pharmacist. The prescribing physicians were hospitalists 46% of the time, hematologists/oncologists 23% of the time, and intensivists 8% of the time. “With this information, we progressed to better delineated privileges to finalize who was allowed to prescribe which drugs,” said L’Heureux. Eight drug–drug interactions were identified during chart review; of these, one was intervened upon at the time of the chemotherapy order. “In the Pyxus automated dispensing machines that we use, there are alerts for an oncology nurse to come down and give the medication, but we found that many times, nurses weren’t alerted to come down and administer it,” he said. During the 2 months of the oral chemotherapy review, only 70% of chemotherapy orders were administered by chemotherapy-certified nurses. —WK ●
Conference News The following articles are based on presentations at the 52nd American Society of Hematology Annual Meeting & Exposition held December 4-7, 2010, in Orlando, Florida
Favorable Findings for Continuous Lenalidomide Maintenance in New Multiple Myeloma By Walter Alexander
ORLANDO—In newly diagnosed multiple myeloma, the greatest benefits of continuous lenalidomide maintenance after melphalan, prednisone, and lenalidomide induction (MPR-R) are conferred to patients aged between 65 and 75 years. The finding emerged from results of the MM-015 study presented by Antonio Palumbo, MD, University of Torino, Italy. Palumbo’s analysis of the phase 3 study also showed continuous lenalidomide therapy to be superior to regimens of limited duration. The MM-015 study evaluated the efficacy and safety of continuous lenalidomide maintenance after MPR-R induction versus fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in 459 transplant-ineligible patients aged ≥65 years. Patients were randomized to MPRR, MPR, or MP, receiving melphalan 0.18 mg/kg (days 1-4) and prednisone 2 mg/kg (days 1-4), with or without lenalidomide 10 mg/day (days 1-21) for nine 28-day cycles. Following nine cycles of MPR, patients received maintenance lenalidomide 10 mg/day (days 1-21) or placebo until progression; MP patients received placebo until progression. Nearly 50% of patients were high risk (International Staging System [ISS] stage III). Typical multiple myeloma trials, Palumbo commented, include 25% to 30% high-risk patients. Median patient age was 71 years. Response improved over time, such that the rates of more than a very good partial response continued to increase through nine treatment cycles, reaching nearly 30% compared with about 10% for MP. Time to response, Palumbo noted, was much shorter for the three-drug combination. Risk of progression was reduced 60% for MPR-R at a median follow-up of 25 months. Median progression-free survival (PFS) was 31 months for MPR-R, 14 months for MPR, and 13 months for MP (P <.0000001 for MPR-R vs MP; hazard ratio, 0.398). “This is a PFS you might see in many studies with autologous transplant,” Palumbo commented. Although median PFS among patients aged 65 to 75 years was not yet reached (risk reduced by 69%), median PFS among patients aged >75 years was not reduced.
Adverse events led to discontinuations in 19% of patients in the older group, despite a lower dose intensity of
approximately 50%. “This tells us that it is very important in the future to define a schema for patients older than 75,
because in frail patients we are ending up with too high a discontinuation rate.” Continued on page 10
ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN)
EGFR-Expressing Metastatic Colorectal Cancer (mCRC)
in Combination With RT in Locoregionally Advanced Disease
after Irinotecan and Oxaliplatin Failure as a Single Agent
ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck
Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations
ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.
Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.
FEBRUARY 2011 I VOL 4, NO 1
Conference News 52ND AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING & EXPOSITION
Favorable Findings for Continuous Lenalidomide... Continued from page 9 Neutropenia and thrombocytopenia were higher in the lenalidomide-containing regimens. Among patients receiving lenalidomide-containing regimens, solid tumors were reported in <4%, acute myelogenous leukemia (AML) in 3%, and myelodysplastic
syndrome in <3%. Palumbo noted that risk of secondary tumors and AML in patients receiving autologous transplants or alkylating agents in previous reports among larger sequences of patients has been as high as 8%. Overall survival was similar between
groups (1 year, 92%-93%; 2 years 75%82%). Overall survival hazard ratios favored MPR-R over MP in all subgroups (aged ≤75 years, lower ISS stage, good renal function, low beta-2 microglobulin ≤5.5 mg/L) except for patients aged >75 years.
“MPR-R is highly active, with the greatest benefit in patients [aged] 65 to 75 years,” Palumbo concluded at his presentation. He added, “Continuous lenalidomide therapy achieved an unprecedented median PFS of 31 months.” ●
ERBITUX Signiﬁcantly Increased SCCHN in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)
Median overall survival 49.0 months
RT alone (n=213)
HR: 0.74; 95% CI: 0.57-0.97; P=0.03
3-year overall survival rate 55%
19.7 month improvement
RT=radiation therapy; HR=hazard ratio; CI=conﬁdence interval. A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2
■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1
ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
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Neurocognitive Problems Linked to Use of Dexamethasone in Survivors of Acute Lymphoblastic Leukemia By Debra Wood
ORLANDO—Adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with dexamethasone may have greater risk for neurocognitive
impairment and poor emotional regulation than patients treated with prednisone, and they exhibited symptoms of physical stress.
A pilot study conducted by Kevin R. Krull, PhD, at St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues found an
association between the use of dexamethasone during the pediatric patients’ chemotherapy regimen and neuContinued on page 34
Overall Survival in Both: EGFR-Expressing mCRC after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)
4.57 months BSC alone (n=285)
HR: 0.77; 95% CI: 0.64-0.92; P =0.0046
BSC=best supportive care. CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1
■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1
ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.
Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).
FEBRUARY 2011 I VOL 4, NO 1
Hematologic Cancers One-year Findings in Metastatic Melanoma... Continued from cover the 1870s as a coal tar–derived wool dye. Agarwala, who is section chief of hematology/oncology at St. Luke’s Hospital and Health Network in Bethlehem, Pennsylvania, stated that investigators treated up to 10 target lesions ≥0.2 cm in diameter and observed up to two untreated “bystander” lesions. Retreatment of
new or partially responsive lesions was allowed. Objective responses (ORs; complete response [CR] + partial response [PR]) were reported in 49% of patients (CR, 24%; PR, 25%), with 72% achieving locoregional control (stable disease [SD] or better) in their injected lesions.
Among those with ORs, progressionfree survival (PFS) was 11.7 months. Progressive disease, defined as ≥20% increase in tumor volume, was reported in 23%. Among the 55 patients with cutaneous or nodal disease, OR and locoregional control were 55% and
78%, respectively. OR and locoregional control rates were considerably lower, at 37% and 55%, in the 25 patients with visceral metastases. Among patients having an evaluable bystander lesion at baseline, an OR was achieved in 37%, with 55% achieving locoregional disease control. Bystander
Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy
Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed
Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects
ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events
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Hematologic Cancers response in these untreated lesions was closely correlated with successful ablation of injected lesions, with 67% of patients achieving an OR of their bystander lesions if they achieved an OR in their injected lesions. The rate was only 5% in patients who did not achieve an OR in their injected lesions (P <.001). The respective locoregional control rates (CR + PR + SD) were 72% and 35% (P = .049).
Agarwala noted that two stage I patients with lung metastases experienced complete regression following PV-10 ablation of their cutaneous lesions. He commented, “The bystander effect, which appears to result from an immunologic response stimulated by PV-10 chemoablation, is especially intriguing. The immunologic processes whereby PV-10 produces systemic response are the topic of a phase 2B
study.” Agarwala also pointed out that responses were higher in patients with unresectable stage III disease (CR + PR, 53%; CR + PR + SD, 77%) than in those with stage IV M1c (27% and 55%, respectively). Mean PFS in these two groups was 8.8 months and 6.2 months, respectively. Adverse events were generally mild to moderate, locoregional, and transient. Agarwala concluded, “PV-10 is well
tolerated, eliciting a robust response in a majority of patients.” The safety and efficacy profiles compare favorably with those of existing and emerging therapies. He said further that PV-10 treatment is suitable for repeat treatment to maximize OR, ablate new lesions or to enhance long-term outcomes. Finally, he noted that with PV-10, it is quickly clear which patients are nonresponders, allowing rapid transition to alternate therapy. ●
Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary
Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)
Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).
©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB08613
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Conference News 33RD ANNUAL SAN ANTONIO BREAST CANCER SYMPOSIUM
Denosumab Beats Zoledronic Acid... Continued from cover either denosumab 120 mg subcutaneously (SC) plus intravenous (IV) placebo or ZA 4 mg (adjusted for renal function) IV plus placebo SC. All patients received supplemental calcium and vitamin D. Lead investigator Alison Stopeck, MD, associate professor of medicine and director of the Clinical Breast
Cancer Program at the Arizona Cancer Center of the University of Arizona in Tucson, reported that denosumab treatment resulted in a median 5-month longer time to a first on-study SRE compared with ZA during 33 months of observation (32.4 vs 27.4 months, respectively; hazard ratio [HR], 0.82;
P = .0096). The median time to a first on-study SRE or hypercalcemia was 7 months longer with denosumab (32.4 vs 25.1 months; HR, 0.82; P = .0076). An SRE was defined as a fracture, radiation or surgery to bone, or spinal cord compression. A multiple event analysis indicated a 22% delay in the time to
ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.
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first and subsequent SREs with denosumab versus ZA (P = .0008). Stopeck said average life expectancy with metastatic breast cancer is about 2.5 years “So if you can prolong the time without a skeletal-related event by 5 months, you are substantially benefiting the patient.” Overall survival
Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:
Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fever1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 16 0 5 0 Chills1 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 38 1 24 1 Aspartate Transaminase, high3 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2
Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.
Conference News and disease progression were similar for the two groups. Almost all patients (>96%) in each group experienced adverse effects (AEs). Serious AEs affected about half of the patients in each group. More AEs related to renal toxicity (9.4% vs 5.4% with denosumab) and more acute-phase reactions (28.2% vs 10.7% with denosumab) occurred with ZA. The incidence of osteonecrosis of the jaw was low and not
significantly different between the arms (1.8% with ZA, 2.5% with denosumab; P = .286). More hypocalcemia, mostly grade 1 or 2, occurred with denosumab (6.1% vs 3.7% with ZA). Stopeck noted that SC administration makes denosumab more convenient than the IV dosing of ZA and that renal monitoring and dose adjustments are not required. She speculated that these study results will change practice
Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:
Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 Infusion Reactions3 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1
Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 2 3
The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.
for women with breast cancer and bone metastases. In the AZURE trial, also presented at the symposium, ZA did not prolong overall or disease-free survival in women with stage II/III breast cancer. William Gradishar, MD, professor of medicine and director of breast medical oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, who was not associ-
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA
Copyright © 2004–2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved. 1236886A7
Rev September 2010
ated with either study, said preclinical data suggest RANK ligand may have an effect in tumor cells. “There’s reason to think that interrupting that pathway is going to have some effect,” he said, “but we just don’t have clinical data to support it at this point.” A phase 3 trial (D-CARE; NCT01077154) is currently recruiting patients to study the effect of adjuvant denosumab on disease recurrence in bone or elsewhere in the body for women with earlystage breast cancer who are at high risk of disease recurrence. ●
Women Often Shun Mammography Guidelines By Jill Stein
SAN ANTONIO—Researchers are reporting “woefully inadequate” mammography rates in American women, even in those with healthcare coverage. Milayna Subar, MD, National Practice Leader, Medco Oncology Therapeutic Resource Center in Franklin Lakes, New Jersey, and colleagues analyzed medical claims data obtained for more than 1.5 million women between 2006 and 2009. All of the women had health insurance through their employer or Medicare. The results showed that only 50% of women 40 to 85 years of age had a mammogram in any given year and only 60% had two or more mammograms over 4 years.
Inconsistent guidelines for breast cancer screening using mammography may be a factor.
The average yearly mammography rates were 47% for women aged 40 to 49 years, 54% for women aged 50 to 64 years, and 45% for women 65 years of age and older. Subar, who is a Medco vice president, noted that her study did not examine reasons for the low screening rates but suggested that inconsistent guidelines for breast cancer screening using mammography may be a factor. Multiple organizations have issued guidelines for mammography, she said. Such organizations include the AmContinued on page 34
FEBRUARY 2011 I VOL 4, NO 1
Multidisciplinary Tumor Board Case
Treatment of Metastatic Gastrointestinal Stromal Tumor: A Multidisciplinary Approach By Lindsay C. Overton, MD1,2; Joseph Bubalo, PharmD, BCPS, BCOP2; Anne C. Kratz, RN, BSN, OCN2; Michael C. Heinrich, MD, FACP1,2 1
Division of Hematology and Medical Oncology, Portland VA Medical Center; 2Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon
Case Presentation Chief complaint: Abdominal pain and weight loss for 3 months. History of present illness: A 53-year-old white man with a history of hyperlipidemia treated with atorvastatin originally presented in 2007 to the emergency department with worsening constipation, abdominal pain, and a 20-lb weight loss. Given concerns about diverticular disease or colon cancer, computed tomography (CT) imaging was done that showed a 6-cm small bowel mass with evidence of partial small bowel obstruction. No other masses were visible on CT imaging. The patient underwent surgical resection. Pathology revealed a gastrointestinal stromal tumor (GIST) with spindle cell morphology, dimensions of 6 cm x 4 cm x 3 cm with 12 mitotic figures per 50 high power fields. Given the primary site, tumor size, and mitotic rate, the patient was believed to have an 85% risk of recurrent disease. At the time of his diagnosis, there were no published data regarding adjuvant therapy, and the patient was monitored clinically for recurrence. Three years after resection, the patient presented to his primary care provider with abdominal bloating and fatigue. Laboratory tests revealed worsening iron deficiency anemia. Repeat CT scan showed multiple peritoneal implants; the largest measured 2 cm x 2 cm. A CT-guided biopsy was performed, with pathology consistent with GIST. At that time, mutational testing was performed on the patient’s original surgical tumor specimen, which showed a KIT exon 9 mutation. He was started on standard-dose imatinib (400 mg/day), and
Physicians’ perspective Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the abdominal cavity. GIST usually arises from the muscular wall of the stomach, but can arise in the small or large intestine (including the rectum). In the United States, there are an estimated 4000 to 6000 new cases diagnosed annually.1 Before 2000, there was no active medical treatment for metastatic GIST.2 As will be discussed, the introduction of small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of GIST. Currently, there are two US Food and Drug Administration (FDA)- approved treatments for advanced GIST: imatinib for first-line treatment, and sunitinib for treatment of patients who are intolerant of imatinib or whose disease has progressed on imatinib therapy. A number of other TKIs have been tested in the third-line or later clinical setting in phase 2 clinical trials. Overall, the prognosis for patients with metastatic GIST has markedly improved over the past decade, with median survival increasing from an estimated 1 to 1.5 years to the current 4 to 5 years.3-5 A landmark study by Hirota and colleagues in 1998 reported that most
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then after 1 month of treatment, his imatinib dose was increased to 400 mg twice daily. Given the interaction between imatinib and atorvastatin, the patient was changed to pravastatin. In addition, the patient was advised to discontinue use of St. John’s wort. The patient was also treated for iron deficiency anemia. Six months later, repeat CT imaging showed decreased size of all peritoneal masses, the largest now 1.0 cm x 0.8 cm. Medical history: Hyperlipidemia; mild depression treated with St. John’s wort. Surgical history: Tonsillectomy, 1965; small bowel resection, 2007. Family history: Mother: 75 years old with diabetes and hypertension. Father: deceased at age 45 in motor vehicle accident. Paternal uncle: colon cancer at 72. No other family history of cancer. Social history: Patient is divorced with two grown children. He works as a foreman at a construction site. He quit smoking 30 years ago, with a 10 pack-year history. He drinks 1 to 2 drinks per week and occasionally smokes marijuana. Medications: Pravastatin, 40 mg by mouth daily; aspirin, 81 mg by mouth daily; daily multivitamin. Allergies: Penicillin causes hives. Physical examination: General: Overweight man who appears older than stated
age, well groomed in no acute distress. Vital signs: Temperature: 98.1°F; heart rate: 93 bpm; blood pressure: 134/86 mm Hg; oxygen saturation: 98% on room air; height: 70 inches; weight: 100 kg. Head, ears, eyes, nose, throat: Pupils equal, round, reactive to light; conjunctiva pale, no sclera icterus; mucous membranes moist. Neck: Soft, supple; no appreciated jugular venous distension; no cervical, supraclavicular or infraclavicular lymphadenopathy. Respiratory: Clear to auscultation bilaterally; no wheezing, rhonchi, or rales. Cardiovascular: Regular rate and rhythm; no murmur, rubs, or gallops noted. Abdomen: Well-healed midline laparotomy scar noted; normoactive bowel sounds; distended abdomen; no fluid wave appreciated; no tenderness to palpation noted. Extremities: Trace bilateral edema to ankles. Laboratory values: White blood cell: 3.2 K/cu mm; hemoglobin: 10.3 g/dL; hematocrit: 30.1%; platelet count: 200 K/cu mm; segmented neutrophils: 63%; lymphocytes: 30%; eosinophils: 2%; basophils: 1%; monocytes: 4%; sodium: 144 mmol/L; potassium: 4.1 mmol/L; chloride: 104 mmol/L; carbon dioxide: 26 mmol/L; blood urea nitrogen: 20 mg/dL; creatinine: 1.1 mg/dL; glucose: 95 mg/dL; ferritin: 21 ng/mL
Lindsay C. Overton, MD
Michael C. Heinrich, MD, FACP
GISTs (~80%) harbored a gain of function mutation in the KIT receptor tyrosine kinase (Figure).6 Approximately 8% of GISTs have an activating mutation of the homologous platelet-derived growth factor receptor-alpha (PDGFRα) tyrosine kinase.7 Ten to fifteen percent of adult GISTs lack mutations of KIT or PDGFRα and are referred to as wildtype GIST.1 Shortly thereafter, in vitro data demonstrated the potency of the small-molecule kinase inhibitor imatinib (formerly STI-571) against mutant and wild-type KIT kinases.8 These studies led to the hypothesis that imatinib might be active against advanced GIST. In 2000,
imatinib was used on a compassionate basis to treat one patient with metastatic GIST.9 Notably, this patient had a remarkable clinical and imaging response to treatment, leading to further testing in phase 2 studies.10,11 In the pivotal phase 2 study (B2222) leading to FDA approval of imatinib for treatment of GIST, 147 patients were treated in a multicenter study, with 82% of patients having partial response or stable disease.10 Similarly, the European Organisation for Research and Treatment of Cancer (EORTC) phase 1/2 study reported an overall response rate of 68.1%.12
During the phase 2 studies, various imatinib dosing regimens were used, varying from 400 mg daily to 1000 mg daily. Based on these studies, 800 mg total daily dose was established as the maximally tolerated dose. Parallel phase 3 trials were performed to determine the optimal imatinib dose for treatment of metastatic GIST. Both the EORTC/ Italian/Australasian and the Southwest Oncology Group (SWOG)/National Cancer Institute (NCI) Canada studies compared 400 mg/day with 800 mg/day as the target imatinib dose. The results of these studies have been published separately.5,13 Notably, these two studies were intentionally designed to be evaluated in a meta-analysis (known as MetaGIST), involving a total of 1640 patients. The MetaGIST study found a small but significant progression-free survival (PFS) advantage for patients treated in the high-dose arm (hazard ratio [HR], 0.89; P = .04). No difference was observed between the two arms for overall survival (OS; HR, 1.00; P = .97) or objective response.3 Translational studies using tumor samples from these clinical studies have identified tumor genotype as a strong predictor of clinical benefit for patients with metastatic GIST treated
Multidisciplinary Tumor Board Case Study
with imatinib. Specifically, patients whose tumor harbors a KIT exon 11 mutation (~70% of GIST) have the highest rates of objective response, PFS, and OS compared with patients whose tumors have no kinase mutations (wild-type GIST, approximately 10%-15% of GIST) or GIST with somatic KIT exon 9 mutations (~10% of patients).14 In the SWOG/NCI Canada study, PFS for these three groups was 24.7 months for KIT exon 11–mutant tumors compared with 16.7 months for wild-type GIST and 12.8 months for patients with KIT exon 9–mutant tumors. In terms of the effect on OS, KIT exon 11–mutant GIST patients had a median OS of 60 months compared with 38.4 months for wild-type GIST patients and 49 months for KIT exon 9– mutant GIST patients.15 The effect of tumor genotype and imatinib dose on clinical outcomes also was analyzed in the MetaGIST study. Within patients in KIT exon 9–mutant GIST, PFS was significantly longer for patients treated in the high-dose arm (P = .017). For patients whose tumor had a different genotype, no difference was observed between treatment arms. In terms of OS, there was a trend toward a survival advantage for patients with KIT exon 9– mutant GIST treated with high-dose therapy (P = .15).3 Overall, imatinib has revolutionized the treatment of GIST, as it has for treatment of chronic myeloid leukemia (CML). For most patients, imatinib 400 mg once daily is the optimal dose (Figure). However, in patients with KIT exon 9–mutant tumors, data support a target dose of 400 mg twice daily. These dosing recommendations have recently been incorporated into the National Comprehensive Cancer Network clinical practice guidelines for GIST.16 Based on these guidelines, our patient was started on imatinib 400 mg once daily to assess drug tolerance and then underwent dose escalation to 400 mg twice daily after his first month of therapy. At the time when this patient underwent surgical resection of his primary tumor, there were no data regarding adjuvant therapy with imatinib. Consequently, this patient was monitored for recurrence. However, risk analysis of his tumor (based on size, origin, and mitotic rate) indicated that he had a greater than 85% chance of recurrence.17 It was not until 2009 that data regarding the adjuvant use of imatinib were published by DeMatteo and colleagues.18 This study showed that adjuvant therapy with imatinib prolonged PFS after 1 year of therapy. Currently, patients with intermediate- or high-risk resect-
ed primary GIST should be considered for treatment with at least 1 year of adjuvant imatinib.16 Notable findings in this patient were iron deficiency and anemia. Iron deficiency is a common finding in GIST patients and usually a consequence of bleeding from the primary tumor. The patient’s anemia is likely due to his iron deficiency, although an element of anemia of chronic disease and/or imatinib-induced myelosuppression also could exist. It is important to recognize and treat iron deficiency in GIST patients, as anemia is a common side effect of imatinib treatment. Patients with metastatic GIST and uncorrected iron deficiency anemia may experience severe anemia and fatigue during imatinib treatment. It is important to recognize that oral iron replacement may not be effective in patients with previous total/subtotal gastrectomy or patients treated with proton pump inhibitors, because an acidic environment is required for iron absorption. Nurse’s perspective The initial visit to an oncologist can be a stressful experience. Hearing about one’s cancer diagnosis, assimilating prognosis, treatment plans, and follow-up
Patients should have easy written access to the clinic phone number to report all side effects and receive reliable phone triage of their symptoms and reported side effects of therapy. —Anne C. Kratz, RN, BSN, OCN
care can be emotionally overwhelming. Timing of the first appointment is critical to the start of treatment but the patient may still be in shock. This shock can be lessened by the oncology nurse specialist. The oncology nurse should assess the patient and care partner’s learning style and educational needs in order to offer appropriate information related to the disease process and treat-
Imatinib 400 mg/day Imatinib 800 mg/day
Exon 9 (10%) Exon 11 (70%) Exon 13 (2%) Exon 17 (1%) Representation of the KIT protein with the location and approximate frequencies of KIT mutations in GIST. Dosing recommendations based on the site of KIT mutation are shown (green boxes, 400 mg once daily; red boxes, 400 mg given twice daily).1,2 Dosing recommendations for other tumor genotypes as are as follows: (1) patients with wild-type GIST (no mutation of KIT or PDGFRα) genes should be treated with 400 mg/day of imatinib; (2) patients with mutations of exon 12 or 14 of PDGFRα should be treated with 400 mg/day; (3) patients with mutations of exon 18 of PDGFRα should be considered for treatment with 400 mg twice daily, but expert consultation is advised for this uncommon GIST subtype. References 1. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28:1247-1253. 2. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8(suppl 2):S1-S41. Figure. Dosing recommendations for KIT-mutant GIST based on tumor genotype.
ment plan. If the treatment plan contains oral targeted cancer treatment such as imatinib, the nurse hopes to instill trust and empower the patient to be an active partner in the treatment of their disease. Patients should have easy written access to the clinic phone number to report all side effects and receive reliable phone triage of their symptoms and reported side effects of therapy. The patient’s imatinib prescription will be written by the physician. An important role of the oncology nurse is to help guide the patient through the maze of insurance authorizations, copays, mail-order pharmacies, and patient-assistance programs. Again, this partnership with the patient instills trust and opens the patient to active participation in his or her care. Medication adherence strategies are very important with imatinib and other oral agents, because the patient is responsible for his or her own therapy. Skipped doses, patient drug holidays, or simple forgetfulness can all result in suboptimal clinical outcomes, such as loss of tumor response and/or decreased duration of response. Although not as well studied in GIST, patient noncompliance during imatinib treatment of CML has been shown to be a common problem. For example, Wu and colleagues estimated average imatinib medication compliance to be only 79% during a 6-year study of 592 patients. Imatinib noncompliance in CML patients is associated with higher overall healthcare costs and less favorable treatment results.19
Health literacy screening at the onset of therapy and ongoing follow-up is necessary to remove any barriers the patient may have to achieving good medication adherence. Nurses can provide practical tools such as calendars, electronic reminders, and enlisting phone calls from family and friends to ensure adherence to the treatment regimen. By enlisting patients as partners, the oncology nurse, in partnership with the oncology pharmacist, hopes to empower them to learn, question, and report side effects. Each patient should have a planned drug supply (these are expensive medications), guidance for managing side effects, a list of which side effects require prompt follow-up, phone numbers to call, and a plan to integrate this medication into everyday life to improve patient quality of life and to maintain lifestyle expectations. A patient taking imatinib may experience myriad side effects or none at all.20 Drug side effects can make a patient feel unsure and vulnerable with continuing the treatment plan. Upfront education about side effects and a partnership between the physician/patient/nurse/ pharmacist to manage these effects empowers the patient to report and comply with side-effect management strategies. Common side effects in which the GIST patient receiving imatinib should be counseled on and given management strategies for include gastric irritation with nausea and vomiting and, although rare, gastrointestinal Continued on page 18
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Multidisciplinary Tumor Board Case Study Treatment of Metastatic Gastrointestinal Stromal Tumor... Continued from page 17 Table
Clinically Significant Inducing or Inhibiting Medications and Probable or Known Natural Productsa
Carbamazepine Dexamethasone Fosphenytoin Nevirapine Oxcarbazepine Phenobarbitol Phenytoin Primidone Rifabutin Rifampin
Amprenavir Atazanavir Clarithromycin Erythromycin Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Posaconazole Ritonavir Saquinavir Telithromycin Voriconazole
CYP3A4 inducing supplements Gingko Grape seed extract Guggul Quercetin St. John’s wort
CYP3A4 inhibiting supplements American elder Berberine Bishop’s weed Bitter orange Cat’s claw Devil’s claw Dehydroepiandrosterone Echinacea Eucalyptus oil Feverfew Garlic
German chamomile Goldenseal Goldthread Grapefruit juice Kava kava Pomegranate Red clover Schisandra Star fruit Valerian Wild cherry
Common CYP3A4 substrates Alprazolam Amiodarone Atorvastatin Buspirone Citalopram Cyclosporine Felodipine Lovastatin Simvastatin Sirolimus Tacrolimus Triazolam CYP2C9 Warfarin
This is not a comprehensive listing. Readers are advised to carefully consult additional references when checking for potential drug–drug interactions between imatinib and other medicinal or natural products.
Sources: References 22 and 23.
hemorrhage, edema, electrolyte imbalances (especially potassium and magnesium), rashes, alopecia, hepatotoxicity, and liver function test abnormalities. Gastrointestinal side effects can be managed by dosing with food or judicious use of antiemetics, electrolytes with oral supplementation, and edema with salt and fluid management strategies. Rashes often respond to topical corticosteroid or moisturizing creams but should be followed closely as severe bullous reactions (including erythema multiforme and Stevens-Johnson syndrome) have occurred with imatinib. The oncology care team should encourage patients to report side effects and the effectiveness of supportive care interventions to ensure continued adherence to imatinib therapy.20 Imatinib can also cause bone marrow suppression or have adverse effects on liver enzymes. Patients should expect frequent lab draws to monitor blood counts and liver tests. The nurse should be a partner in explaining the blood test results and the meaning of the values to help patients understand this complex assessment tool. As will be discussed, patients should understand that oral targeted therapies may interact with other medications they are taking. Patients should be encouraged to disclose all their prescribed and complementary medications. As partners in therapy, patients should know that becoming pregnant or fathering a child while taking imatinib is not advised. Open discussion of sexuality is always encouraged. The management of patients being treated for GIST is complicated and
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requires a multidisciplinary approach. The role of the nurse is pivotal in patient education, side-effect management, and ongoing patient support. Pharmacist’s perspective The oncology pharmacist should interact with the patient on a variety of levels to increase medication understanding, safety, and success with imatinib therapy. Notably, careful review of drug–drug interactions between imatinib and other agents is a common and important area of focus for oncology phar-macists. In vivo, imatinib is a strong, competitive inhibitor of CYP3A4 and CYP2C9 and a relatively weak inhibitor of CYP2D6. Imatinib is metabolized primarily by CYP3A4, with minor contributions from CYP1A2, CYP2D6, CYP2C9, and CYP2C19.21 Thus, imatinib is not only affected by CYP3A4 inducers and inhibitors, but it also inhibits the metabolism of other drugs metabolized by CYP3A4. Although many agents are metabolized via the CYP enzyme systems, these interactions are critically important when the affected medication has a narrow therapeutic margin, is metabolically affected to a large degree, or is a critical element of patient care (Table). In this case, our patient was taking St. John’s wort, a dietary supplement sometimes used for managing mild depression and a known potent inducer of multiple enzyme systems. In a drug interaction study in 12 healthy volunteers, those taking St. John’s wort had a 43% reduction in the imatinib area under the curve (AUC) from base-
line.24 This magnitude of change could significantly diminish the clinical response in our patient. Other potent inducers (Table) have been shown to affect imatinib to a similar or greater degree and should be avoided when possible. If the inducing agents cannot be avoided, then the dose of imatinib may need to be adjusted upward, but there are no clear guidelines for this situation.
Each medication or supplement that a patient is receiving should be reviewed…to look for common CYP substrates.
Significant CYP3A4 inhibitors (Table) need to be addressed in a similar fashion. For example, ketoconazole has been shown to raise the AUC of imatinib by 40% after a single dose and could greatly increase side effects in patients in whom the interacting agent was not discontinued or replaced with another agent.25 In this case, the St. John’s wort was discontinued because its clinical benefits were uncertain. The patient also was cautioned to have any additional dietary supplements being contemplated for use reviewed by the team, because there are multiple agents known to modify CYP activity. With respect to imatinib’s effects on other agents, atorvastatin is a CYP3A4
substrate and imatinib increases the blood levels of a similarly metabolized statin, simvastatin, by 2- to 3.5-fold. This degree of increased drug exposure can significantly increase the risk for side effects, such as myalgias, hepatotoxicity, and rhabdomyolysis.26 In the current case, we substituted pravastatin for atorvastatin. This agent is expected to provide similar antilipid benefits, but is only a minor CYP substrate. It is important for the GIST patient care team, especially the oncology pharmacist, to review each medication or nutritional supplement in the patient’s medication list for potential drug–drug interactions and/or overlapping side effects. Many other medications can be similarly affected, because CYP3A4 is among the most common pathways used for medication metabolism. Medications with narrow therapeutic margins, where small changes in blood level can cause profound physiologic effects, are the most concerning when reviewing for drug interactions. For example, although imatinib inhibition of CYP2C9 is not as significant as its effects on CYP3A4, CYP2C9 is the primary enzyme that metabolizes warfarin. Imatinib treatment can inhibit CYP2C9 sufficiently to decrease warfarin metabolism and cause patients to become excessively anticoagulated and at increased risk for bleeding events. Each medication or supplement that a patient is receiving should be reviewed in a similar manner to look for common CYP substrates (Table) and to assess the risk of interaction or overlapping side effects. Patients should be advised to contact the oncology care team whenever any change in medication profile is considered (including both adding and subtracting medications). Conclusions The introduction of TKIs has revolutionized the treatment of metastatic GIST. However, obtaining optimal treatment results requires a multidisciplinary approach by physicians, oncology nurses, and oncology pharmacists. In particular, patient education to ensure medical compliance, and successfully manage side effects and concomitant medications are critical elements for successful treatment of patients with GIST. Although this review has emphasized first-line treatment of metastatic GIST with imatinib, similar multidisciplinary coordination of care is required when using sunitinib for second-line treatment of metastatic GIST. ● Disclosures Funding was provided in part by a Merit Review Grant from the Veterans Affairs Administration (MCH) as well as Continued on page 20
ALOXI provides powerful CINV prevention that can’t be ignored. ®
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Eisai offers: s Contracting opportunities
Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.
Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on ﬁle. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.
STARTS STRONG. LASTS LONG.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083C 08/10
Multidisciplinary Tumor Board Case Study Treatment of Metastatic Gastrointestinal Stromal Tumor... Continued from page 18 from the GIST Cancer Research Fund (MCH) and the Life Raft Group (MCH). All potential conflicts of interest have been reviewed and managed by Conflict of Interest Committees at the Portland VA Medical Center and the Oregon Health and Science University. ●
References 1. Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3:557-586. 2. DeMatteo RP, Heinrich MC, el-Rifai W, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466-477. 3. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J
Clin Oncol. 2010;28:1247-1253. 4. Blanke CD, Demetri GD, von Mehren M, et al. Longterm results from a randomized phase II trial of standardversus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620-625. 5. Verweij J, Casali PG, Zalcberg J, et al. Progressionfree survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364:1127-1134. 6. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-
function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. 7. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710. 8. Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925-932. 9. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056. 10. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347: 472-480. 11. Van Oosterom AT, Judson I, Verweij J, et al. STI571, an active drug in metastatic gastrointestinal stromal tumors (GIST) an EORTC phase I study. Proc Am Soc Clin Oncol. 2001;20(1A):Abstract 2. 12. Van Oosterom AT, Judson I, Verweij J, et al; for the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001; 358:1421-1423. 13. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008; 26:626-632. 14. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. 15. Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26:5360-5367. 16. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8(suppl 2):S1-S41. 17. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70-83. 18. DeMatteo RP, Ballman KV, Antonescu CR, et al; for the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 373:1097-1104. 19. Wu EQ, Johnson S, Beaulieu N, et al. Healthcare resource utilization and costs associated with non-adherence to imatinib treatment in chronic myeloid leukemia patients. Curr Med Res Opin. 2010;26:61-69. 20. Joensuu H, Trent JC, Reichardt P. Practical management of tyrosine kinase inhibitor-associated side effects in GIST. Cancer Treat Rev. May 28, 2010. Epub ahead of print. 21. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44:879-894. 22. Lacy CF, Armstrong LL, Goldman MP. Drug Information Handbook. Hudson, OH: Lexi-Comp, Inc; 2010. 23. Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://naturaldatabase.thera peuticresearch.com/nd/products.aspx?AspxAutoDetect CookieSupport=1. Accessed October 6, 2010. 24. Frye RF, Fitzgerald SM, Lagattuta TF, et al. Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther. 2004;76:323-329. 25. Dutreix C, Peng B, Mehring G, et al. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol. 2004;54:290-294. 26. O’Brien SG, Meinhardt P, Bond E, et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer. 2003;89:1855-1859.
Did You Know?
For 2010-2011, board-certified oncology pharmacists are expected to make between $68,150 and $121,027. —The PayScale Report
FEBRUARY 2011 I VOL 4, NO 1
Cancer Center Profile Waukesha Memorial Hospital’s Regional Cancer Center... Continued from cover “One of the things that are really hard for patients is the amount of information coming at them when they first are diagnosed with breast cancer, understanding what that all means. In addition, they hear about meeting a surgeon and the treatment the surgeon might offer, and that they might be meeting a radiation oncologist, and later even a medical oncologist. It is all these nebulous specialists they are hearing about out in their future,” explained Katherine M. Bayliss, MD, medical director of the Center for Breast Care. “Instead what we do is create this team of specialists that they can meet and sort of get their arms around upfront; they are real people. The patients can get an understanding upfront about the various roles the specialists play. They are also then connected with the other team members, such as the geneticist or others that offer supportive services.” Building the approach The Center for Breast Care instituted its comprehensive breast services in phases. At its beginning in 1995, the center served mainly as a screening/ diagnostic center, where patients received immediate results of their imaging. Also available since that time are two nurse care coordinators who “help navigate the patients in our health system, providing education and support from the time of abnormal mammogram and breast cancer diagnosis to follow-up care, including surgical visits and periodic phone checks. We link them with our community resources,” explained Michelle Willman, RN, BSN, OCN, CBCN, one of the nurse care coordinators. In September 2009, an onsite breast surgeon was installed and the interdisciplinary clinic begun. To round out the staff, a group of surgeons is available to see patients, as are medical and radiation oncologists, specially trained radiologists and technologists dedicated to breast imaging, and pathologists specializing in breast cancer diagnosis. Support services are also offered, including a dietitian, a genetic counselor, a supportive care coordinator, a social worker, and a financial counselor. Intercommunicating The weekly conferences allow all the specialists to discuss as a group what is in the best interest of each patient. These discussions provide an avenue for all disciplines to interact and learn. Bayliss, a pathologist, gave this example: “Over time as you share these discussions and treatment plans, there is greater understanding of what each other’s roles are, what each other’s issues might be, what
information I might have that might matter to physicians taking care of that specific patient or vice versa. The lines of communication become much better and our understanding of what each person does and what the nuances are of the pieces that they need to know becomes more evident. From a pathology standpoint, I think that I have done a better job of presenting information for my colleagues who treat the patient because I have a better understanding of what they are up against. Conversely, I think that my clinical colleagues have come to better understand things that aren’t so black and white for us, things that can be challenging for us, how they
ologist is needed, for example, when a patient comes from another healthcare system, then the radiologist is involved prior to the patient’s day of appointment, talking to the patient and the other care providers, explained Bergin. “It is extremely rewarding, just being able to talk with the physicians and talk with the genetic counselors. Having that interaction is really rewarding and important, and having everybody in one place fosters that communication,” said Kelli K. Pettit, MD, a surgical oncologist. This face-to-face real-time interaction with colleagues during a patient visit not only provides the specialists an opportunity to understand what infor-
“Over time as you share these discussions and treatment plans, there is greater understanding of what each other’s roles are, what each other’s issues might be, what information I might have that might matter to physicians taking care of that specific patient or vice versa.” —Katherine M. Bayliss, MD can help us interpret a patient’s pathology specimen by providing us the right information.” This holds true for the radiologists as well. “It gets us more involved. As breast imagers, we like to be more involved in patient care, and the weekly tumor conferences give us a way of making recommendations and lending expertise to their care,” said Jennifer T. Bergin, MD, a radiologist, who is the director of breast imaging. Now that everyone can interact daily in the clinic, discussion has been turned up a notch. “Typically, we will discuss a patient in that week’s conference, for which we have gathered as much information that is available, then come up with a plan. Then, we may meet that patient later in the week, or even that same day. There may or may not be additional information available at that time, for example, the hormone receptor profile may have returned in the interim or radiographic data,” explained Peter Johnson, MD, a medical oncologist. “We will then incorporate that new information into the plan and see the patient at the clinic visit.” It also offers each physician a chance to “know exactly what the surgeon was thinking or why something happened,” James C. Jones, MD, a radiation oncologist, told The Oncology Pharmacist. In addition, all team members “can express a concern, explaining why they would rather do this than that.” And this interaction can involve specialists beyond just medical, surgical, and radiation oncologists. If a radi-
mation the patients receive from the other physicians but also gives patients information about their treatment, according to Pettit. Improving patient care All this communication leads to enhanced patient outcomes. Over time the ongoing interaction between pathologists and surgeons has improved the ability to accurately assess margins, ensuring that the orientation of the specimen is optimized, and confidence that the tumor was completely excised, according to Bayliss. Moreover, patient waiting times are kept short. Willman gave these examples: “If a patient needs a biopsy, the time from abnormal mammogram to biopsy may be as soon as same day to within 1 to 2 weeks per patient preference. The time to get to the surgeon appointment is 1 to 2 days. Many of our patients are having surgery within 1 to 2 weeks of their diag-
nosis. Once we have all the pathology, oncologist consults occur quickly.” In addition, the Center for Breast Care offers a more holistic approach to patient care. To complement traditional oncology treatments, the center incorporates supportive oncology including dietary nutrition support, emotional support, and Reiki and relaxation therapy. For Pettit who finished her fellowship training in June of 2009, “I probably offer my patients more of those healing therapies and talk to them more about the supportive aspects of our care as opposed to focusing just on the medicine aspect. Obviously, we talk about the surgery, we talk about chemotherapy. But I’ve also realized that most patients at some point during their treatment are looking for something else, something to make them feel empowered. I think that some of those other therapies, the nutrition, the Reiki therapy, the counseling, provide this for the patients.” The team believes that the multidisciplinary aspect affords optimal care in general and that the clinic provides the best vehicle for that approach. “Having the multidisciplinary clinic after not having one for 16 years,” said Jones, “has been more beneficial than I might have imagined it would have been for communication and providing the best care for the cancer patients.” Johnson seconds that opinion: “We have had excellent feedback from patients about how they have come away from their visits quite gratified and reassured that they at that point have received a comprehensive assessment of their situation and a plan for dealing with it.” The Center for Breast Care has not only received positive feedback from patients, it has received recognition from peers. ProHealth Care’s Regional Cancer Center, of which the breast center is a part, has been awarded a contract from the National Cancer Institute Community Cancer Centers Program, making it one of 30 such community cancer centers in the nation. ●
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FEBRUARY 2011 I VOL 4, NO 1
CONTINUING EDUCATION PROGRAM P10065 • RELEASE DATE: OCTOBER 15, 2010 • EXPIRATION DATE: OCTOBER 15, 2011 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST TEST AT WWW.THEONCOLOGYPHARMACIST.COM
Maintenance Therapy for Non–small-cell Lung Cancer: A Value-based Approach to Improve Patient Care and Outcomes, Part I of II TARGET AUDIENCE
This activity was developed for oncology pharmacists and other healthcare professionals practicing in oncology. LEARNING OBJECTIVES
Upon completion of this activity, participants will be able to: • Evaluate the benefits and risks of maintenance therapy compared with re-treating upon disease progression in order to rationalize maintenance in patients with stage IIIB or IV non–small-cell lung cancer (NSCLC) who have responded to or are stable after induction therapy • Identify molecular and histologic characteristics of NSCLC tumors that impact choice of therapeutic agent for specific patient populations and formulate strategies for value-based care • Develop optimal side effect management strategies for patients receiving maintenance therapy for NSCLC in order to provide optimal care while considering the associated costs.
ung cancer is the most common type of cancer in the United States.1,2 An estimated 221,520 people (115,750 men and 105,770 women) will be diagnosed with cancer of the lung and bronchus in 2010, and only 15.8% of patients with lung cancer survive 5 years or more after diagnosis.3 Lung cancer accounts for more cancer deaths in the United States than any other type of cancer.4 Advances in surgical techniques and combined therapies have helped increase the 1-year relative survival for patients with lung cancer to 42% in 2002-2005, from 35% two decades earlier in 1975-1979.2 Although the 5-year survival rate is greater than 50% for early-stage disease, unfortunately only 15% of lung cancers are detected when the disease is still localized.2 According to the National Cancer Institute, lung cancer costs the American public an estimated $10.3 billion a year and is the third costliest cancer after breast cancer and colorectal cancer.5 Furthermore, lung cancer tops the list in terms of lost productivity, accounting for $36.1 billion in lost lifetime earnings—lost productivity costs three times greater than those associated with breast cancer or colorectal cancer.5 The financial burden of cancer may continue to expand with
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the aging of the US population, improved survival, and the increasing cost of cancer treatments.5 The median age at diagnosis of lung cancer is 71 years.3 As the baby boom generation (people born between 1946 and 1964) reaches age 65 and older over the next two decades,6 the number of Americans in this age-group is expected to increase by 36% from 2010 to 2020.7 Because lung cancer is widespread and carries a dire prognosis, urgency prevails in the search for better therapies and improved outcomes for patients. Efforts are particularly robust in non–small-cell lung cancer (NSCLC), which accounts for 85% of all cases.4 For patients with advanced NSCLC, maintenance therapy may help control the disease and extend a patient’s life.8 Administered after induction chemotherapy and generally in lower doses than initial chemotherapy, maintenance therapy often involves standard chemotherapy (an agent used in the initial treatment plan therapy or another drug), or it may include a combination of therapies, including vaccines, hormones, or other drugs.8 Decisions about maintenance therapy include consideration of the associated benefits, risks, and costs, as well as patient-specific factors and preferences. Two chemotherapy agents have recently received US Food and Drug Administration (FDA) approval for the maintenance therapy of patients with advanced NSCLC. PHARMACISTS DESIGNATION
Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-10-059-H01-P. INSTRUCTIONS FOR CREDIT
1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE Activity Evaluation 7. Print your Statement of Completion This activity is provided free of charge to participants. Upon completion of the evaluation and scoring 70% or better on the posttest, you will
Recent advances have also yielded a number of novel agents that target specific molecular pathways in tumor cells, and research on these discoveries is ongoing. The molecular/genetic profiling of NSCLC can now be used to characterize tumors by their expression of specific markers. These molecular profiles hold promise for their potential in predicting a response, or resistance, to specific standard or novel therapies and in identifying a benefit from a new or standard agent, based on clinical trial evidence.9 Maintenance therapy brings a new treatment approach for advanced NSCLC Maintenance therapy, a relatively new paradigm in the treatment of NSCLC, constitutes a shift from the past paradigm of treating recurrent disease.10 However, maintenance therapy has been used for years in the treatment of patients with acute lymphocytic leukemia and acute myeloid leukemia to lower the risk of disease recurrence, and it is also being studied in a number of other cancers.8 Histologic information about the lung carcinoma is particularly useful for tailoring maintenance therapy toward improving outcomes for patients with NSCLC.11 Molecularly targeted agents, including those that inhibit epidermal growth factor receptor (EGFR) and vascular endothelial growth factor, also represent a crucial 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. FACULTY DISCLOSURES
inroad into personalized therapy for patients with lung cancer.9 Maintenance therapy has been shown to prolong progression-free survival (PFS) and overall survival (OS) in the appropriate patients, based on randomized, controlled studies of two agents—pemetrexed and erlotinib.12-14
Pemetrexed In July 2009, pemetrexed was the first drug to be FDA-approved for maintenance therapy of advanced or metastatic lung cancer.15 Pemetrexed, a folate analog metabolic inhibitor, received this new indication specifically for patients with nonsquamous NSCLC that has not progressed after four cycles of platinum-based first-line chemotherapy.16 Pemetrexed is also indicated for initial treatment in combination with cisplatin, as well as after prior chemotherapy as a single agent in patients with locally advanced or metastatic nonsquamous NSCLC.16 Based on a randomized, double-blind, phase 3 international study (N = 663), patients with stage IIIB or IV NSCLC (without progress after four cycles of platinum-based chemotherapy) who were treated with pemetrexed showed a significant improvement in PFS: 4.3 months (95% confidence interval [CI], 4.1-4.7) compared with 2.6 months (95% CI, 1.7-2.8) in the placebo group (hazard ratio [HR], 0.50; 95% CI, 0.420.61; P <.001).13 The pemetrexed group or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months. DISCLAIMER
Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions.
The information provided in this 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. Trade names used in this supplement are for the learner’s reference only. No promotion of or bias toward any product should be inferred.
Beth Eaby-Sandy, CRNP, is on the speaker’s bureau for Genentech, Eli Lilly and Company, and Merck.
Loretta Fala participated in the development of this article. She has no financial relationships to disclose. 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
This activity is jointly sponsored by Medical Learning Institute, Inc. (a nonprofit medical accreditation company), and Center of Excellence Media, LLC. COMMERCIAL SUPPORT ACKNOWLEDGMENT
This activity is supported by an educational grant from Eli Lilly and Company.
To Receive Credit, Complete the Posttest at www.TheOncologyPharmacist.com also showed a significantly greater OS: 13.4 months (95% CI, 11.9-15.9) versus 10.6 months (95% CI, 8.7-12.0) in the placebo group (HR, 0.79; 95% CI, 0.650.95; P = .012). No pemetrexed-associated mortalities occurred.13 Grade 3 or higher adverse events were more frequent in the pemetrexed group than in the placebo group, and included fatigue (5% vs 1%) and neutropenia (3% vs 0).13 The most common any-grade adverse reactions compared with placebo were nausea (19% vs 6%) and anorexia (19% vs 5%).16
Erlotinib In April 2010, the FDA approved an expanded indication for erlotinib, a tyrosine kinase inhibitor (TKI), as a maintenance treatment for patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinumbased first-line chemotherapy.17,18 Erlotinib is also indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.18 Results from a randomized, doubleblind, international phase 3 study (N = 889) showed a significant median PFS of 12.3 weeks for patients in the erlotinib group versus 11.5 weeks for the placebo group (HR, 0.71; 95% CI, 0.62-0.82; P <.001).14 In patients with EGFR-positive immunohistochemistry treated with erlotinib, compared with EGFR-positive patients receiving placebo, PFS was also significantly longer in the erlotinib group (12.3 weeks) versus the placebo group (11.1 weeks; HR, 0.69; 95% CI, 0.58-0.82; P <.001).14 The study also showed an improvement in OS of 1 month with erlotinib versus placebo as maintenance therapy (HR, 0.81; 95% CI, 0.70-0.95; P = .009).18 Serious adverse events were reported in 11% of the patients in the erlotinib group compared with 8% in the placebo group; the most common serious adverse events were pneumonia (2% with erlotinib vs <1% with placebo).14 The most common grade 3 or higher adverse events included rash (9% in the erlotinib group vs 0 in the placebo group) and diarrhea (2% in the erlotinib group vs 0 in the placebo group).14 The most common any-grade adverse reactions compared with placebo were rash (49.2% vs 5.8%) and diarrhea (20.3% vs 4.5%).18 Maintenance therapy: benefits, risks, and costs Maintenance therapy is associated with several potential benefits, including preventing the recurrence of cancer, slowing disease growth, and prolonging life.8 However, these benefits must be weighed against potential risks, which include increased side effects, more frequent doctor visits, and drug resistance.8 Maintenance therapy may also be asso-
ciated with higher treatment costs.8 In addition, the data on the survival benefits associated with maintenance therapy are limited,8 as are data on the quality of life associated with maintenance therapy8,19—in particular, the cumulative toxicity of prolonged chemotherapy.19 Other study limitations include the variability in measurable end points such as the definition of progression (in PFS) and frequency of response assessment; additionally, the use of multiple agents in the poststudy setting may confound the impact of maintenance treatment.19 Although patients receiving maintenance therapy may not have the opportunity of a reprieve from chemotherapy during the “wait-and-see” period, this period is often accompanied by anxiety about disease progression or recurrence.19 The rising cost of cancer care persists as a major healthcare challenge. The American Society of Clinical Oncology (ASCO) encourages members to discuss the cost of care directly with patients.10 Although maintenance chemotherapy for advanced NSCLC is associated with increased costs, it may decrease costs related to palliative radiotherapy and hospital admissions resulting from deteriorating performance status.12 Furthermore, the concept of extended survival—in terms of additional months, or even weeks of life—may represent an immeasurable benefit for patients and their loved ones. The importance of histology and molecular biomarkers Lung cancer is classified as either non–small-cell or small-cell, based on its biology, therapy, and prognosis.4 The 5year survival rate for NSCLC is 17%, compared with a lower survival rate of 6% for small-cell lung cancer.2 NSCLC is categorized into two types: nonsquamous carcinoma (adenocarcinoma, large-cell carcinoma, and others) and squamous cell carcinoma.4 Squamous cell lung carcinoma accounts for 25% of lung cancers in the United States, whereas large-cell carcinoma (nonsquamous) accounts for 10% to 20% of all lung cancers.20 Identifying the histologic subtype of NSCLC is an essential step in selecting the appropriate therapy, and it may also be particularly useful when augmented by molecular testing.21 For example, the detection of the bronchoalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment strategy, particularly if it carries specific mutations in the EGFR tyrosine kinase domain, suggesting it will respond to treatment with an EGFR TKI.21 Several of the key predictive molecular biomarkers in the treatment of NSCLC include4: • Presence of the EGFR exon 19 deletion or exon 21 L858R mutation is associated with a treatment benefit from EGFR TKI therapy
Table NCCN Guideline Recommendations (March 2010) for NSCLC Maintenance Therapy Continuation Maintenance Therapya
Switch Maintenance Therapyb
Continue with biologic agents (given initially in combination with conventional chemotherapy) until disease progression or unacceptable toxicity (per clinical trial design that led to approval): • Bevacizumab may be continued beyond four to six cycles of platinumdoublet chemotherapy given with bevacizumab (Category 1) • Cetuximab may be continued beyond four to six cycles of therapy with cisplatin, vinorelbine, and cetuximab (Category 1) • Pemetrexed may be continued after four to six cycles of therapy with cisplatin and pemetrexed for patients with nonsquamous cell carcinoma (Category 2B)
Initiation of pemetrexed or erlotinib after first-line chemotherapy (four to six cycles) in patients without disease progression, based on two recent studies demonstrating a benefit in progression-free survival and overall survival: • Pemetrexed may be initiated after four to six cycles of first-line platinum-doublet chemotherapy in patients with nonsquamous cell carcinoma (Category 2B) • Erlotinib may be initiated after four to six cycles of first-line platinumdoublet chemotherapy (Category 2B) • Docetaxel may be initiated after four to six cycles of first-line platinumdoublet chemotherapy (Category 3)
• No randomized trial data are available to support continuing maintenance of conventional cytotoxic agents beyond four to six therapy cycles • Pemetrexed is not recommended for patients with squamous cell carcinoma • Close follow-up without therapy is a reasonable alternative to switch maintenance a Continuation maintenance = use of at least one of the agents administered as first-line therapy. b Switch maintenance = initiation of an agent that was not included as part of the first-line treatment regimen. NCCN indicates National Comprehensive Cancer Network; NSCLC, non–small-cell lung cancer. Data adapted from reference 4. Refer to that source for definitions of evidence categories.
• High levels of ERCC1 expression are associated with a poor response to platinum-based chemotherapy • The presence of KRAS mutations is associated with a lack of benefit from platinum/vinorelbine chemotherapy or from EGFR TKI therapy • High levels of RRM1 expression are associated with a poor response to gemcitabine-based chemotherapy. Patients with EGFR mutations E19 deletion and L858R mutation have shown a significantly better response to erlotinib or gefitinib (both EGFR TKI agents), with initial retrospective studies suggesting that an estimated 90% of patients with a tumor response to these agents had mutations, whereas patients without a response did not have these mutations.4 According to the National Comprehensive Cancer Network (NCCN) practice guidelines for NSCLC, pathologic evaluation should be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the benefit of, or resistance to, EGFR TKI therapy.4 Preoperative assessment may include bronchial brushings or washings, fine-needle aspiration biopsy, core needle biopsy, endobronchial biopsy, transbronchial biopsy, as well as sampling of mediastinal lymph nodes to stage the disease and help determine therapeutic options. Intraoperative (lobectomy or pneumonectomy) evaluation may include determining the sur-
gical resection margin status, diagnosing any incidental nodules found during the surgery, or checking the status of regional lymph nodes.4 Postoperative pathology provides information necessary for classifying the tumor type, stage, and prognostic factors. According to NCCN guidelines, the surgical pathology report should use the histologic classifications established by the World Health Organization for lung carcinomas.4 Adequate tissue sampling may provide the key to identifying the treatment most appropriate for a specific patient and improving the likelihood of identifying an effective treatment as early as possible.21 Refinements in histology and the evolving role of molecular testing will undoubtedly play a role in predicting responses to particular treatments for NSCLC.21 Clinical practice guidelines for maintenance therapy The NCCN practice guidelines for NSCLC, which were updated in March 2010, added a new section with recommendations on maintenance therapy (Table). Although ASCO released a clinical practice guideline update on chemotherapy for stage IV NSCLC, the guideline went to press in 2009 without the opportunity of a comprehensive data review on recent data supporting the indication/use of pemetrexed for maintenance therapy in patients with advanced NSCLC.22 In Continued on page 24
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CONTINUING EDUCATION Continued from page 23
Maintenance Therapy for Non–small-cell Lung Cancer... this 2009 update, ASCO included an announcement that an update would be forthcoming on consideration of relevant data on the use of pemetrexed in maintenance therapy. Results of two studies evaluating erlotinib as maintenance therapy were also anticipated by the ASCO review committee at the time of the 2009 guideline publication.22 In June 2010, the National Institute for Health and Clinical Excellence, based in London, issued guidance to the National Health Service, United Kingdom, recommending pemetrexed for the maintenance treatment of NSCLC.23 The guidance states that pemetrexed is recommended as an option for maintenance therapy in people with locally advanced or metastatic NSCLC other than predominantly squamous cell histology if the cancer has not progressed immediately after platinumbased chemotherapy in combination with gemcitabine, paclitaxel, or docetaxel.23,24 It also states that people who have received pemetrexed in combination with cisplatin as first-line therapy cannot receive pemetrexed maintenance treatment.23,24
Maintenance therapy considerations Treatment considerations include the stage of the cancer and invasion status, the type of cancer, the patient’s performance status, patient-specific preferences, the costs of treatment, as well as other patient- and agent-specific factors. Evidence-based clinical practice guidelines can be a valuable decision-support resource for clinicians.
Selecting the appropriate patient population is a guiding factor in selecting the appropriate maintenance therapy. Selecting the appropriate patient population, as characterized by histologic (nonsquamous) or molecular (EGFR mutation) profile, is a guiding factor in selecting the appropriate maintenance therapy.19 Furthermore, the use of a wellcharacterized tumor profile as a tool for
Recent FDA Approvals Denosumab for Prevention of Skeletal-related Events The FDA has approved denosumab (XGEVA, Amgen) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. This receptor activator of factor kappa-B ligand inhibitor is the first in its class to be approved for this indication. Denosumab is not approved for patients with multiple myeloma or other cancers of the blood. After 6-month priority review, approval was based on three phase 3 head-to-head trials comparing denosumab (120-mg subcutaneous injection every 4 weeks) with zoledronic acid (15-minute intravenous infusion every 4 weeks). The trials totaled 5723 patients. One trial focused on patients with breast cancer; another on patients with prostate cancer; a third on patients with a variety of cancers. In prostate cancer, median time to an SRE was 21 months with denosumab compared with 17 months with zoledronic acid. In breast cancer, median time to an SRE was 26 months with zoledronic acid and has not yet been reached with denosumab. In other solid tumors, time to development of an SRE was similar for both groups.
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Transmucosal Tablets for Breakthrough Cancer Pain The FDA has approved a fentanyl immediate-release transmucosal tablet (Abstral, ProStraken) for breakthrough cancer pain in adults, making it the only fast-acting lingual tablet on the US market. The tablet is indicated for those patients who already use opioid pain medication and can safely use high doses of an additional opioid medication. This schedule II opioid is available only through a risk evaluation and mitigation strategies (REMS) program. The manufacturer’s REMS program will allow patients to fill prescriptions at retail pharmacies and for access to be available in the hospital setting. Approval of the transmucosal form of the drug (fentanyl buccal tablets and patches are already approved) was based on data from safety studies. Based on data from 311 opioid-tolerant patients with breakthrough pain, common adverse reactions included nausea, constipation, drowsiness, and headache. Serious adverse reactions have been previously reported in patients on other immediate-release transmucosal fentanyl products; however, deaths have been attributed to improper patient selection and/or improper dosing.
selecting the appropriate patients for maintenance therapy may improve the therapeutic index, and thereby improve the survival benefit in these patients.19 In addition, identifying predictive biomarkers for specific agents used in maintenance therapy may help to improve the benefits and reduce risks. Pemetrexed is a maintenance therapy option for patients with nonsquamous histology.4 Moreover, a molecular-based strategy may be important for selecting the appropriate subgroup of patients best suited for maintenance therapy with erlotinib.19 The risks and benefits of maintenance therapy must be considered and weighed, along with the safety, efficacy, and tolerability of the agents used in this setting. Similarly, the risks associated with delaying additional therapy must also be considered: a delay strategy may be associated with a faster disease progression and shorter survival time than immediate additional therapy.25,26 Extending chemotherapy, particularly with a third-generation regimen, has been shown to improve PFS substantially, and OS modestly.26 Conclusion Maintenance therapy represents a new treatment paradigm for patients with advanced NSCLC, given its potential for improved survival. Ideally, the agent selected for maintenance therapy should be well-tolerated by the patient, have minimal side effects/cumulative toxicities, and demonstrate improved patient outcomes.19 The histology of the carcinoma is an important tool in tailoring maintenance therapy for a specific patient. In addition, molecular profiling can help characterize tumors and predict response or resistance after standard or novel therapies.27 Molecular tests will continue to play an important role in redefining patients with NSCLC into specific subgroups that may respond to different optimal treatment pathways.22 The risks and benefits of maintenance therapy must be considered and addressed with the patient. Similarly, the risks and benefits of a delayed/wait-andsee treatment approach must likewise be weighed carefully. The future holds promise, based on recent advances that foster targeted, personalized treatment approaches with the potential to improve response and survival for patients with advanced NSCLC. ● References 1. National Cancer Institute, National Institutes of Health. Common cancer types. www.cancer.gov/cancer topics/typescommoncancers. Accessed September 21, 2010. 2. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010. 3. National Cancer Institute, National Institutes of Health. Surveillance, Epidemiology, and End Results. SEER Stat Fact Sheets: Lung and Bronchus. http://seer. cancer.gov/statfacts/html/lungb.html. Accessed September 20, 2010.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn.org/ professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010. 5. Wang BH. The financial burden of cancer—NCI benchmarks. April 23, 2010. http://benchmarks.can cer.gov/2010/04/the-financial-burden-of-cancer/. Accessed September 20, 2010. 6. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. Washington, DC: US Census Bureau; May 2010. 7. US Department of Health and Human Services, Administration on Aging. A Profile of Older Americans: 2007. www.agingcarefl.org/aging/AOA-2007 profile.pdf. Accessed August 27, 2010. 8. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/Can cer.Net+Feature+Articles/Treatments%2C+Tests%2C+a nd+Procedures/Explaining+Maintenance+Therapy. Accessed September 20, 2010. 9. Herbst RS, Lippman SM. Molecular signatures of lung cancer—toward personalized therapy [editorial]. N Engl J Med. 2007;356:76-78. 10. Peck P. Maintenance pemetrexed extends NSCLC survival by three months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010. 11. Lilly receives fourth FDA approval for ALIMTA— first chemotherapy approved as maintenance therapy for nonsquamous non-small cell lung cancer. Medical News Today. July 8, 2009. www.medicalnewstoday.com/arti cles/156659.php. Accessed September 22, 2010. 12. Eaton KD. Maintenance chemotherapy in nonsmall cell lung cancer. J Natl Compr Canc Netw. 2010;8: 815-821. 13. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009. 14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010. 15. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm1705 15.htm. Accessed September 22, 2010. 16. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010. 17. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/ viewarticle/720446. Accessed September 22, 2010. 18. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010. 19. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504. 20. Cleveland Clinic. Lung cancer overview. Reviewed October 23, 2008. http://my.clevelandclinic.org/dis orders/Lung_Cancer/hic_Lung_Cancer.aspx. Accessed September 23, 2010. 21. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010. 22. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27:6251-6266. 23. NICE recommends pemetrexed for the maintenance treatment of non-small-cell lung cancer [press release]. Medical News Today. June 23, 2010. www.medicalnew stoday.com/articles/192709.php. Accessed September 22, 2010. 24. National Institute for Health and Clinical Excellence (NICE). Final appraisal determination—pemetrexed for the maintenance treatment of non-small cell lung cancer. March 2010. www.nice.org.uk/nicemedia/ live/12091/48303/48303.pdf. Accessed September 22, 2010. 25. Belani CP, Liao J. Maintenance therapy for nonsmall cell lung cancer [comment]. Lancet. 2010;375: 281-282; Stinchcombe T, West H. Comment in: Lancet. 2009;374:1398-1400. 26. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009. 27. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer. N Engl J Med. 2008;359:1367-1380.
Conference News 33RD ANNUAL SAN ANTONIO BREAST CANCER SYMPOSIUM
Preoperative Treatment with Anti-HER2 Agents Yields Benefits in Key Studies By Caroline Helwick
SAN ANTONIO—For women with human epidermal growth factor receptor type 2 (HER2)-overexpressing breast cancer, preoperative treatment with agents that block HER2 leads to high rates of pathological complete response (pCR), according to the results of three studies. The studies used various combinations of trastuzumab, lapatinib, and pertuzumab (a novel monoclonal antibody) in the neoadjuvant setting. Neil Spector, MD, director of translational research in oncology at the Duke Cancer Institute in North Carolina, moderated a press conference where the results were announced, at which he commented, “This is a very exciting area. We have gone from HER2-overexpressing disease being the most lethal type of breast cancer to a subtype that we are talking about curing.” Two of the studies evaluated the tyrosine kinase inhibitor lapatinib, but this agent proved second-best to trastuzumab. In the phase 3 Neo ALTTO trial, 455 women were randomized to lapatinib, trastuzumab, or lapatinib plus trastuzumab, all with paclitaxel. Patients received 6 weeks of the biologic, with weekly paclitaxel added to the regimen for 12 more weeks, yielding a total of 18 weeks of neoadjuvant treatment. The pCR rate by National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines (absence of invasive cancer cells in the breast at surgery or only noninvasive in situ cancer in the breast) was 51.3% with lapatinib plus trastuzumab versus 24.7% for lapatinib, and 29.5% for trastuzumab (P = .0001). In the breast plus lymph nodes, pCR rates were 47% with lapatinib plus trastuzumab, 20% with lapatinib, and 28% with trastuzumab, reported Jose Baselga, MD, of Massachusetts General Hospital Cancer Center, Boston. In the phase 3 GeparQuinto study, 620 patients were randomized to epirubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles plus trastuzumab or lapatinib initiated with chemotherapy. The trastuzumab arm achieved a significantly higher pCR rate than the lapatinib arm according to the NSABP definition—50.4% and 35.2%, respectively (P <.05)—and also by the investigators’ more stringent definition of no microscopic evidence of residual tumor cells in the breast or nodes: 31.3% versus 21.7%, respectively (P <.05), reported Michael Untch, MD, of the Multidisciplinary Breast Cancer Center at the Helios Clinic, Berlin.
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Pertuzumab/trastuzumab led to high responses In the phase 2, four-arm NeoSphere trial of 417 women, triple therapy with pertuzumab, trastuzumab, and docetaxel produced 50% more pCRs than were
achieved with trastuzumab and docetaxel, reported Luca Gianni, MD, of the Fondazione IRCCS Istituto Nazionale Tumori in Milan, Italy. “In addition, this combination without chemotherapy was capable of erad-
icating the tumor in a remarkable number of cases (17%), therefore avoiding the toxicities seen with chemotherapy,” Gianni noted. The pCR rate (by NSABP definition) was 45.8% with trastuzumab/per-
March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel
First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team PROGRAM OVERVIEW
PRIMARY CONFERENCE LOCATION
This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.
WHO SHOULD ATTEND All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Medical Directors • Surgical Oncologists • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)
CONTINUING EDUCATION INFORMATION Goal The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care. Objectives • Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients Co-Chairs
Gary Owens, MD
Burt Zweigenhaft, BS
President, Gary Owens Associates
President, CEO, OncoMed
Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Phone: 215-627-1200 http://www.loewshotels.com/en/Philadelphia-Hotel
ACCREDITATION INFORMATION PHYSICIAN ACCREDITATION Science Care designates this activity for a maximum of 6.0 AMA PRA Category 1 Credit(s)™. Science Care is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 6.0 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 7.50 contact hours (0.750 CEUs) of continuing education credit. The Universal Activity Number for General Sessions is: 0468-9999-11-072-L01-P. The Universal Activity Number for the lunch symposium is: 0468-9999-11-071-L01-P.
CONFERENCE REGISTRATION Register Online at
www.regonline.com/avbcc-2011 $250 Includes 1-year association membership $355 Includes 3-year association membership
CONTACT/SUPPORT If you have any questions please contact: Association for Value-Based Cancer Care™ 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831 Phone: 732-992-1040 email@example.com
REGISTER ONLINE AT
Conference News tuzumab/docetaxel, compared with 24.0% with pertuzumab/docetaxel (P = .003), 29.0% with trastuzumab/docetaxel, and 16.8% with trastuzumab/ pertuzumab (P = .0198). This effective three-drug regimen was quite well tolerated, although â€œstrikingly low toxicityâ€? was seen when the docetaxel was omitted in the trastuzumab/pertuzumab arm. Grade 3/4 toxicity was seen in less than 4% of these patients, compared with approximately 50% of patients in the chemotherapy
arms, Gianni said. Unexpectedly in Neo ALLTO and GeparQuinto, pCR rates were higher in the estrogen receptor (ER)-negative patients than in the ER-positive ones. Although both hormone subgroups benefited from the HER2 blockade, pCR rates climbed to more than 60% in the ER-negative subgroup. All regimens were well tolerated in general; however, those containing lapatinib had much higher rates of diarrhea, the investigators noted. In Neo
Tuesday, March 29 1:30 â€“ 3:30 pm PAYER PRE-CONFERENCE (Off-site) Ritz-Carlton Philadelphia 10 Avenue of the Arts, Philadelphia, PA 19102 Payer Trends in Oncology - Panel Discussion MODERATOR Burt Zweigenhaft, BS PANEL Scott Breidbart, MD â€” CMO, Empire BCBS Nick J. Calla, RPh â€” VP, Trade Relations, Walgreens Specialty Pharmacy Maria Lopes, MD â€” CMO, AMC Health Mona Chitre, PharmD â€” Director, Clinical Strategy, Policy, and Services, Excellus
GENERAL PRE-CONFERENCE SESSIONS Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Value-Based Insurance Design in Oncology CHAIR A. Mark Fendrick, MD â€“ Co-Director, University of Michigan Center for Value-Based Insurance Design Cancer Care from a Large Insurerâ€™s Perspective Donald Liss, MD â€“ Senior Medical Director, Independence Blue Cross of Philadelphia The Role of Diagnostics from a PBMâ€™s Standpoint Jane F. Barlow, MD, MPH, MBA â€“ VP, Clinical Innovation, MEDCO Health Solutions Panel Discussion
Wednesday, March 30
Corporate-Sponsored Breakfast Symposium Havalenâ„˘ (eribulin mesylate) Injection: A New FDA-approved Treatment Funded by Eisai Inc.
ALLTO, grade 3 diarrhea was observed in more than 20% of patients on lapatinib compared with 2% of patients on the single agent trastuzumab. In Neo ALLTO and GeparQuinto, approximately 35% of patients in the lapatinib arms were unable to receive the full planned doses of this agent and, in GeparQuinto, there were 10% more treatment discontinuations with lapatinib than with trastuzumab (23% vs 13%), largely due to side effects, Untch said. â—?
Oncology Practicesâ€”Issues with Managed Care Craig Deligdish, MD â€“ Medical Director, Florida Comprehensive Care Network Yu-Ning Wong, MD â€“ Fox Chase Cancer Center Winston Wong, PharmD â€“ Associate VP, Pharmacy Management, CareFirst BCBS PAYER TRACK Medicare and Reimbursement Issues Kip Piper, MA, FACHE â€“ President, Health Results Group Jayson Slotnik, JD â€“ Counsel, Foley Hoag Oncology Drug Reimbursement and Administration Issues John Aforismo, BSc Pharm, RPh, FASCP â€“ President & CEO, RJ Health Systems Peyton Howell, MBA â€“ AmerisourceBergen Scott Breidbart, MD â€“ CMO, Empire BCBS Evolutions in Oncology Pharmacy Management MODERATOR Burt Zweigenhaft, BS ROUNDTABLE Alan Lotvin, MD â€“ President, ICORE Kristen M. Reimers, RPh â€“ Clinical Pharmacy Operations Manager, Excellus Jeff Ulanet â€“ VP, Oncology, MEDCO
LUNCH SYMPOSIUM Best Practices for Management of CINV: A Value-Based Approach Supported by an educational grant from Eisai Inc. Shawna Kraft, PharmD, BCOP â€“ Hematology/Oncology Clinical Pharmacist, University of Michigan Health System Beth Faiman, RN, MSN, CNP, AOCN â€“ Nurse Practioner, Cleveland Clinic Taussig Cancer Center
Cancer Care and the New Healthcare Legislation: What to Expect Next MODERATOR Jayson Slotnik, JD PANEL Scott Gottlieb, MD â€“ Resident Fellow, American Enterprise Institute Joseph Bailes, MD â€“ Texas Oncology
Strategies for Improving Oncology Pharmacy and Care Management Models MODERATOR Burt Zweigenhaft, BS PANEL Ira M. Klein, MD â€“ Medical Director, Aetna Oncology Strategy Dan McCrone, MD â€“ CMO, New Century Health Jeffery Scott, MD â€“ SVP/CMO, P4 Healthcare, Cardinal Health Winston Wong, PharmD
Stephen C. Malamud, MD â€“ Beth Israel Medical Center
NCCN Guidelines Acceptance and Compliance Al Benson, MD â€“ President, ACCC
The Impact of Personalized Oncology Therapies MODERATOR Gary Owens, MD PANEL Perry Dimas â€“ VP, Premier Source Diagnostics Richard Bender, MD â€“ CMO, Agendia Beth Davis â€“ Senior Director, Managed Care, Agendia Gene Morse, PharmD â€“ University of Buffalo
Afternoon Break in the Exhibit Hall
Morning Break in the Exhibit Hall
Clinical Fragmentation: Impact of Oral, Injected, and Infused Therapies MODERATOR Gary Owens, MD ROUNDTABLE Atheer Kaddis, RPh â€“ VP, Managed Markets, Diplomat Pharmacy Services Kirby Eng, RPh â€“ Director, Oncology Management Services, CVS Caremark Ellen Scharaga, BS â€“ SVP, Pharmacy Operations, OncoMed
Cocktails/Networking in the Exhibit Hall
BREAKOUT SESSIONS PROVIDER TRACK Community Oncology: Trends Ted Okon â€“ Executive Director, Community Oncology Alliance Patient Navigation/Patient Assistance Steven Patierno, PhD â€“ Executive Director, George Washington University Cancer Institute Dawn Holcombe, MBA, FACMPE, ACHE â€“ President, DGH Consulting Monica Knoll â€“ Executive Director/Founder, CANCER101
Obesity May Worsen Survival in Chemotherapytreated Breast Cancer Patients By Jill Stein
SAN ANTONIOâ€”Obese breast cancer patients receiving chemotherapy have a significantly shorter overall survival (OS) than nonobese women, researchers reported. Thomas Samuel, MD, a medical oncologist at Georgiaâ€™s Health Sciences University in Augusta, and colleagues examined the correlation between body mass index (BMI) and OS in 259 breast cancer patients receiving chemotherapy between 1997 and 2006. The investigators used data obtained from their institutionâ€™s tumor cancer registry. Overall, 67 women had a BMI â‰Ľ35, which the World Health Organization (WHO) categorizes as class II obesity, and 192 women had a BMI <35. Breast cancer is the most common noncutaneous malignancy and the second-leading cause of cancer-related mortality among US women, Samuelâ€™s team noted in their poster presentation. According to the American Cancer Society, there were 209,060 new cases of breast cancer in the United States in 2010 and 40,230 deaths from the disease. Although some studies have shown a correlation between obesity and increased breast cancer mortality, few studies have looked at the effect of BMI on prognosis in breast cancer patients receiving chemotherapy. The study found that women who were WHO class II obese or more and received chemotherapy for breast cancer were 1.83 times more likely to die than women who have lower BMI within about 10 years of starting chemotherapy. Whatâ€™s more, OS was shortened in obese breast cancer patients receiving chemotherapy, irrespective of their race or age at diagnosis. Race and age at diagnosis are known to influence survival. The authors cautioned that the studyâ€™s small sample size may be a possible limitation. Adjustments to chemotherapy dosing in patients with BMI â‰Ľ35 may also have altered survival outcomes. Finally, they noted that future research will look at the effect of obesity on the biological characteristics of the breast cancer in terms of tumor size, lymph node involvement, and metastatic â€œpotential.â€? Studies should also aim to examine the effect of the type and dosing of chemotherapy regimens used, estrogen receptor status, comorbidities, presence of insulin resistance with metabolic syndrome, and actual cause of death in this cohort of patients. â—?
FEBRUARY 2011 I VOL 4, NO 1
Conference News 33RD ANNUAL SAN ANTONIO BREAST CANCER SYMPOSIUM
Benefits with Tamoxifen plus Everolimus in Aromatase Inhibitor–pretreated Breast Cancer By Walter Alexander
SAN ANTONIO—In the phase 2 TAMRAD trial, tamoxifen (TAM) with everolimus (RAD) conferred the greatest clinical benefits over tamoxifen alone among patients with secondary hormone resistance after treatment with an aromatase inhibitor (AI). Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has shown promising activity in an in vitro model of hormone resistance, stated lead investigator Thomas Bachelot, MD, Centre Léon Bérard in Lyon, France, in a presentation. Everolimus has also been shown to significantly increase the neoadjuvant antitumor activity of letrozole. Although previous randomized trials of first-line hormone therapy plus mTOR inhibition in metastatic breast cancer (mBC) have been disappointing, Bachelot said, selection of mBC patients previously treated with an AI may enrich the study population with subjects whose tumors are driven by activation of the PI3K/AKT/mTOR pathway. Dysregulation of this pathway has been found in a variety of cancer cells, and constitutively active PI3K/AKT signaling has been identified as a major determinant for cell
growth and survival in an array of cancers. The TAMRAD trial’s goal was to estimate the clinical benefit rate (CBR) of the tamoxifen/everolimus combination in such a population after 6 months of treatment. After stratification according to primary or secondary hormone resistance (determined by early or late progression after previous AI treatment), TAMRAD patients were randomized 1:1 to receive either tamoxifen (20 mg/day) alone or tamoxifen/everolimus (everolimus 10 mg/day; tamoxifen 20 mg/day). Among 111 included patients, median age was 64 years (range, 41-86). Previous AI treatment had been given to 34 (31%) patients in the adjuvant setting, 67 (60%) patients in the metastatic setting, and 10 (9%) in both the adjuvant and metastatic setting. The population was poorly hormone sensitive in that all but 10 (9%) patients had progressed either during or within 6 months after adjuvant AI treatment. Furthermore, 57 (51%) patients and 28 (25%) patients had received previous chemotherapy in the adjuvant and/or metastatic setting, respectively. The primary end point was
CBR, defined as complete response plus partial response plus stable disease at 6 months. TAMRAD patients (tamoxifen, 57; tamoxifen/everolimus, 54) had a median duration of metastatic disease of ~13.8 months. Patients were divided evenly between those with primary and secondary hormone resistance. In an exploratory analysis after a median follow-up of ~22.5 months, the CBR was 42.1% for the tamoxifen group and 61.1% (P = .045) for the tamoxifen/ everolimus group. Similarly, time to progression (TTP) favored the combination group (tamoxifen 4.5 months vs tamoxifen/everolimus 8.6 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.35-0.81; exploratory log-rank P = .0028), as did overall survival (HR, 0.32; 95% CI, 0.15-0.68; exploratory log-rank P = .0019). Although adverse event–associated treatment discontinuations were not higher with the combination (7.0% tamoxifen vs 5.6% tamoxifen/everolimus), adverse events overall were higher with the combination, in particular, fatigue, stomatitis, rash, anorexia, and
diarrhea, requiring dose reductions in 28% of patients (none for tamoxifen). Secondary hormone resistance was defined as late relapse (≥6 months) or previous response and subsequent progression to metastatic AI treatment. CBR differences were accentuated in patients with secondary hormone resistance (44.8% for tamoxifen vs 77.8% for tamoxifen/everolimus). Looking at TTP as a function of intrinsic hormone resistance, Bachelot noted that among patients with primary resistance, TTP was 3.9 months for tamoxifen and 5.4 months for the combination (HR, 0.74). Among those with secondary hormone resistance, TTP was 5.0 months for tamoxifen and 17.4 months for tamoxifen/everolimus (HR, 0.38). TAMRAD results, Bachelot said, confirm the importance of the PI3K/ AKT/ mTOR pathway. “It seems to be very important when they [patients] respond to hormone therapy and then become resistant.” The phase 3 Breast Cancer Trials of Oral Everolimus (BOLERO-3) is under way, Bachelot noted. ●
Breast Cancer Patients May Benefit from Multivitamins with Minerals By Jill Stein
SAN ANTONIO—Breast cancer patients who take multivitamins with minerals are less likely to have disease recurrence than patients who do not take multivitamins with minerals, according to new data. The routine use of multivitamins with minerals also appears to be associated with a decreased risk of breast cancer– specific and overall death. Findings of the prospective Life After Cancer Epidemiology study were reported by Heather Greenlee, ND, PhD, who is a naturopathic physician and assistant professor of epidemiology and medical oncology at Columbia University Mailman School of Public Health in New York City. Her group analyzed questionnaires completed by 2239 women diagnosed with a first primary early-stage breast cancer between 1997 and 2000. “Many women diagnosed with breast cancer have questions about what lifestyle changes they can make to improve their prognosis as a breast cancer survivor, including whether taking vita-
FEBRUARY 2011 I VOL 4, NO 1
min supplements can reduce adverse side effects from treatment, decrease their risk of recurrence, and improve survival,” Greenlee pointed out.
Compared with healthy women, breast cancer patients appear to be more frequent users of multivitamins and vitamin/mineral supplements, she added. In fact, data from the 1999-2000 National Health and Nutrition Exam-
ination Survey showed that 57% to 62% of women with breast cancer use multivitamins compared with only 38% of healthy women. “To date, no studies have examined the association between multivitamin use either pre- and/or postdiagnosis and the risk of breast cancer recurrence and death,” she said. Of the study population, there were 363 breast cancer recurrences, 202 deaths from breast cancer, and 372 deaths overall, as of May 7, 2010. Forty-four percent of patients reportedly took multivitamins with minerals at least three times a week for at least 12 months during the 5 years before they had been diagnosed with breast cancer. After diagnosis, 60% of women reported using multivitamins with minerals. In the study, women who were categorized as having used multivitamins and minerals after their diagnosis had to have taken them at least three times a week for at least 1 year after their diagnosis. Women who reported that they had continually taken multivitamins with
minerals before their diagnosis and continuing afterward were 31% less likely to have a disease recurrence than women who said that they had never taken multivitamins with minerals. They were also 47% less likely to die of breast cancer and 27% less likely to die of any cause. Further analysis revealed that the protective associations occurred only in women who had undergone radiation and adjuvant hormone therapy. The use of multivitamins without minerals did not confer consistent benefits. “Considering that few studies to date have addressed how multivitamin use during treatment for breast cancer influences outcomes in breast cancer patients, our results warrant confirmation in observational or intervention studies of breast cancer survivors,” Greenlee said. She emphasized that the results do not prove that multivitamins with minerals reduce breast cancer relapses, deaths from breast cancer, and overall death. Women who routinely take multivitamins with minerals are more likely to have healthy lifestyles in general, she added. ●
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It was not easy, but we have selected four finalists from among the peers you nominated for the inaugural T.O.P. Pharmacist award. All the nominees were outstanding, but these four individuals stood out for their embrace of evidence-based practices, commitment to teamwork, and compassion. Now, it's your turn. After reading up on each finalist, go to www.TheOncologyPharmacist.com/award and tell us which one we should name the T.O.P. Pharmacist for 2011. We will announce the readers' choice in the April issue of The Oncology Pharmacist. George W. Carro, RPh, MS, BCOP Kellogg Cancer Center NorthShore University HealthSystem Evanston, Illinois In 1977, George Carro started as a staff pharmacist at NorthShore University HealthSystem in Evanston, Illinois. Today he serves as Northshore’s senior director of oncology pharmacy services. Carro has worked tirelessly to integrate oncology pharmacists into the multidisciplinary teams responsible for patient care at NorthShore, which has gone from a single oncology pharmacist to a comprehensive oncology pharmacy program with an outpatient pharmacy. Carro attributes much of his success to his physician colleagues. “We have been incredibly fortunate to have medical and surgical oncologists as mentors. Their support has helped define the role of the oncology pharmacist here,” said Carro. His colleagues believe much of the credit belongs to Carro. “George has made pharmacy an integral part of the system in the eyes of the physicians,” wrote a pharmacy employee, who predicted that “they would cease to run the clinic for the day if the pharmacy was not here...due to how important George has made our department to the physician.” At NorthShore, under Carro’s stewardship, the pharmacists run an anemia pro-
Lindsay Kaster, PharmD Boise VA Medical Center Boise, Idaho Lindsay Kaster has only been a pharmacist for a few years, but her determination to make a difference in the lives of patients with cancer has not escaped the attention of the colleagues, who nominated her. “Lindsay is the most enthusiastic and motivated young pharmacist I have worked with,” wrote one. “We are extremely fortunate to have someone as kindhearted and clinically minded as Lindsay to serve our veterans,” said another. Since arriving at the Boise VA Medical Center, where Lindsay is a clinical oncology pharmacist, she led efforts to bring the service in compliance with new oncology regulations from the Office of the Inspector General and the Joint Commission on Accreditation of Hospital Organizations. Working with the oncology team, she instituted processes to prevent errors, to review patients’ adverse drug reactions, and to educate providers on preventing their recurrence. She also developed charts for the pharmacy and nursing staff to make the delivery of chemotherapy safer and more efficient. “This dedication to continuous improvement of work processes and procedures has led to enhanced service delivery to our veterans,” her colleagues remarked. Another challenge that Kaster rose up to meet was finding ways to save the government facility and its patients money. She developed a dose-rounding program
gram and a tobacco cessation program, are active in symptom management, conduct research, educate patients and medical professionals, and have instituted initiatives to improve and monitor quality of care. Carro’s team also developed an electronic health record treatment plan that is used across all disease sites and regimens. Carro said his primary motivation is “to assure that every patient who comes through our cancer center is aware that a pharmacist is involved and available to help them through treatment.” He described each patient as special. “We learn as much from our patients as they do from us.” Carro noted that the pharmacist’s role in patient care is expanding, and it troubles him that the Centers for Medicare & Medicaid Services does not recognize pharmacists as healthcare providers. “It is crucial to achieve recognition of pharmacy cognitive services by healthcare third-party payers,” he said, pointing out that increased involvement by pharmacists in areas like symptom management correlates with better outcomes. He also called for involving oncology pharmacists more in molecular medicine and referring patients to clinical trials. In addition to a long list of professional accomplishments, including awards and affiliations with various oncology organizations, Carro’s employees say he is a great boss. Carro expressed equal fondness for his team. “I am most proud of the people who I have had the privilege to work with and continue to work with,” he said. “The oncology residents and all the pharmacists involved in our oncology program have fostered and improved the core values of patient care and teamwork in NorthShore’s Kellogg Cancer Center.” and a vial-rounding program to reduce drug waste, which are expected to save the center thousands of dollars, and forged relationships with organizations that assist and advocate for patients with cancer. “I believe that an oncology pharmacist is invaluable in the care of heme/onc patients, and this role will only continue to expand in the future,” Kaster said. She pointed to her institution as an example of how essential clinical oncologists are to the oncology treatment team. “Ninety-eight percent of supportive care decisions in our clinic are made by a team of a pharmacist, nurse practitioner, and primary nurse.” As someone just starting out, Kaster said there are innumerable things she wants to accomplish in what she hopes will be a long career. “I have hundreds of ideas for projects—from research ideas to prove how much a pharmacist can impact oncology patient care and books I would like to author, to safety and cost-saving strategies for my facility.” Kaster said she would love an opportunity to teach, motivating students and residents to choose oncology as a career choice and “eventually starting my own PGY2 residency program.” Kaster said no matter what projects or programs she initiates, she “will always strive to provide each of my patients with evidence-based, compassionate, and fully engaged care.” Her coworkers attest to this, noting that the busy Kaster finds time to maintain positive relationships with patients and staff members at the center. Kaster said every day reinforces that there is no better job than oncology pharmacist. “From simple smiles to bear hugs and tears of gratitude, patients remind you daily that giving your best care matters deeply to them.” T.O.P. Pharmacist award finalists continued on page 32
FEBRUARY 2011 I VOL 4, NO 1
YOUR QUESTIONS ANSWERED
Editor in Chief
Editor in Chief
Associate Professor of Hematology and Oncology Emory University School of Medicine
The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University
Stephanie A. Gregory, MD
Sagar Lonial, MD
Topics include: â€˘ Newly Diagnosed Patients â€˘ Maintenance Therapy â€˘ Transplant-Eligible Patients â€˘ Retreatment â€˘ Transplant-Ineligible Patients â€˘ Cytogenetics â€˘ Side-Effect Management â€˘ Bone Health
Topics include: â€˘ Hodgkinâ€™s Disease â€˘ Follicular Lymphoma â€˘ Mantle Cell Lymphoma â€˘ Waldenstromâ€™s Macroglobulinemia â€˘ Diffuse Large B-Cell Lymphoma â€˘ T-Cell Lymphoma
This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.
This activity is supported by educational grant from Cephalon Oncology and Millennium Pharmaceuticals, Inc.
Target Audience These activities were developed for physicians, nurses, and pharmacists.
Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ„˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.
For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or firstname.lastname@example.org. COEKsize21111MM
Continued from page 30
Judith A. Smith, PharmD, BCOP, FCCP, FISOPP The University of Texas M. D. Anderson Cancer Center Houston, Texas A fourth-generation pharmacist, Judith Smith decided to specialize in oncology because of the pharmacologic challenges involved in finding a cure for cancer. Today, she is an associate professor and director of pharmacology research in the Department of Gynecologic Oncology at The M. D. Anderson Cancer Center. She is also a faculty member of the Graduate School of Biomedical Sciences and an assistant professor for the Department of Obstetrics/Gynecology and Reproductive Sciences at the University of Texas Health Science Center and an adjunct professor with the Department of Clinical Sciences at the University of Houston College of Pharmacy. Notwithstanding the lengthy series of titles, Smith said she is a “clinical pharmacy researcher at heart” and outlined an ambitious agenda. “I still want to answer how to overcome drug resistance, [identify the] safe and optimal administration of chemotherapy in patients with organ dysfunction as well as for pregnant patients with cancer...and to provide data on integration of nutritional and herbal supplements with traditional cytotoxic chemotherapy to improve patient outcomes.” In nominating Smith, associates lauded her vigorous efforts in “pushing for a much needed standardization in the assessment of renal function as it applies to drug dosing.” A great deal of controversy surrounds the discussion over the optimal formula for administering carboplatin and other oncology drugs with doses that must be adjusted for patients with compromised renal function, but this “has not distracted her from her ultimate goal of ensuring
Barbie Edwards Jacks, BSPS Clearview Cancer Institute Hampton Cove, Alabama Although Barbie Jacks has 25 years of experience in the pharmacy field, she only started specializing in oncology pharmacy 3 years ago, when she accepted a position managing the outpatient clinical pharmacy at Clearview Cancer Institute. “It is definitely the most challenging job I have ever had, but also the most rewarding,” Jacks said. “I am reminded each and every day why I love working at Clearview Cancer Institute with oncology patients.” Beyond dispensing oral chemotherapeutics and medications to help manage treatment-related adverse effects, patient care is a top priority for Jacks. She emphasized how essential it is for oncology pharmacists to help ensure that patients have access to their prescribed medications and counsel them on proper use of a drug. “If we educate and counsel the patient on their chemotherapy medication, intervene to manage side effects, and dose-adjust as needed, studies show that patients stay on their medication longer [and] this increases overall survival and time to progression.” Jacks’ genuine concern for her patients’ well-being is a chief reason her colleagues nominated her for the T.O.P. Pharmacist award. Even when the pharmacy is at its most hectic, colleagues said she always “takes time to make sure patients are supported emotionally, financially, and clinically.” At Clearview, Jacks took the lead in implementing programs to assist patients with copayments and other financial needs. In addition, “She has pushed for programs that give her pharmacy access to limited distribution medications,” wrote an associate, describing her as a “true patient advocate.” Jacks has also worked with physicians and nurses at Clearview to improve patient counseling, particularly for oral oncolytics. The oncology pharmacists developed medication education kits for each oral oncolytic, which they review with patients and caregivers. Although the facility has made great strides, Jacks hopes to do more, including taking measures to improve adher-
FEBRUARY 2011 I VOL 4, NO 1
Don't forge t!
This is you ra Vote now fo r
ward to giv e.
your choice .
om/award The winner will be anou n ced in the April issue.
safe administration of chemotherapy for her patients,” wrote a colleague. Working with pharmacists, physicians, and other medical professionals in industry and academia, Smith has spearheaded efforts to foster consensus on this critical oncology issue. Smith’s leadership on this issue is consistent with her description of the oncology pharmacist’s role on the healthcare team, which includes ensuring that patients receive chemotherapy at a safe, intended dose “by creating order set forms verification processes and providing drug resources for the medical team.” Another important role, said Smith, is “to provide chemotherapy education to the patient not only about the chemotherapy but also regarding supportive care.” Smith said pharmacists contribute to improved quality of life for patients and promote treatment adherence by managing nausea and vomiting, helping patients maintain good bowel function, and preventing complications from myelosuppression or electrolyte imbalances. They also help patients minimize pain. Smith recalled a defining moment early in her pharmacy training that steered her toward gynecologic oncology. Her first clinical pharmacy rotation required her to provide several pain interventions for a 26-year-old woman with stage IV ovarian cancer. The woman died during the night, and Smith said she choked up when she reported the news to her preceptor, Barry Goldspiel. “I remember Barry asking if I still want to do oncology pharmacy, and I replied, ‘Now more than ever. This shouldn’t happen.’ At that time, I vowed that some day, some how, I would make a difference.” Every year, said Smith, she participates in The M. D. Anderson Sprint for Life fundraiser in memory of this patient. She said various patient interactions throughout her career have reaffirmed her decision to become an oncology pharmacist several times over. “This is the best place for me to be,” Smith concluded. ence through better patient follow-up, developing an oncology pharmacist advisory panel, and using genetic testing to direct therapy and improve response. Some of Jacks’ motivation stems from her father’s cancer diagnosis and death 1.5 years later. “I remember all that our family went through during that difficult time, and how much it would have meant to each of us to have someone do what we try to do for our patients.” Jacks said this experience and the diversity of pharmacy positions she has held—in independent pharmacy, with the pharmaceutical industry, and at an indigent clinic—helped prepare her to become an oncology pharmacist. Jacks acknowledged that getting so close to patients only to lose them is difficult. “But we are better off for having known them…and I feel blessed for this opportunity!” she concluded.
For Payers, Purchasers, & Oncology P&T Committees
Honorable Mentions Michael S. Edwards, PharmD, MBA, BCOP Walter Reed Army Medical Center
Christopher A. Fausel, PharmD, BCPS, BCOP Indiana University Simon Cancer Center
John McCormick, BS, PharmD, BCNSP St. Jude Children’s Research Hospital
Challenging Cases in Multiple Myeloma A WEBINAR SERIES A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes
Register online today at www.myelomacases.com/webinar PROGRAM DESCRIPTION
LIVE WEBINAR DATES
This continuing medical education webinar series will serve as a forum for discussion of current questions and concerns regarding the treatment and management of patients through the multiple myeloma (MM) life cycle. By thoroughly engaging participants with interactive cases and physician point-counterpoint–style discussions, this activity will provide evidence-based treatment and management recommendations and address new treatment regimens and management strategies based on recent clinical trials and emerging data. In addition, barriers and/or limitations faced by community cancer centers and private-practice oncologists will be debated.
Monday, March 72011
Tuesday, March 152011
At the end of this activity participants will be able to: • Apply early management strategies that consider new diagnostic and staging criteria for SMM, MGUS, and MM and new imaging studies in order to improve prognosis for your patients. • Evaluate novel therapeutic regimens as induction therapy for your patients considering an SCT in order to provide the most rapid response and allow the largest amount of stem cell collection, while maintaining safety and tolerance. • Integrate novel agent–based regimens that provide optimal outcomes and a survival benefit into your management strategy for patients ineligible for SCT after appraising emerging data from clinical trials. • Identify patient- and disease-associated factors that impact choice of therapeutic agent and formulate management strategies using a risk-adapted approach to treatment of MM. • Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myeloma patients across the life cycle of the disease.
TARGET AUDIENCE This activity has been developed for hematologists and medical oncologists, as well as nurses, pharmacists, and other allied health professionals who are interested in meeting the challenges faced when treating patients with multiple myeloma in academic and community settings.
12:00 PM ET • 11:00 AM CT • 10:00 AM MT • 9:00 AM PT
Tuesday, March 82011 3:00 PM ET • 2:00 PM CT • 1:00 PM MT • 12:00 PM PT
9:00 PM ET • 8:00 PM CT • 7:00 PM MT • 6:00 PM PT
Friday, March 252011 1:00 PM ET • 12:00 PM CT • 11:00 AM MT • 10:00 AM PT
Thursday, March 312011 6:00 PM ET • 5:00 PM CT • 4:00 PM MT • 3:00 PM PT
FACULTY G. David Roodman, MD, PhD Professor of Medicine Vice Chair for Research Department of Medicine Director, Myeloma Program Director, Bone Biology Center University of Pittsburgh Medical Center Pittsburgh, PA
ACCREDITATION INFORMATION Physician Accreditation
The University of Cincinnati designates this activity for a maximum of 1 AMA PRA Category 1 Credit ™. The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation
Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.
Hakan Kaya, MD Oncologist/Hematologist, Cancer Care Northwest Director, Inland Northwest Myeloma/ Lymphoma & Transplant Program Clinical Asst. Professor of Medicine, University of Washington School of Medicine Spokane, WA
Registered Pharmacy Designation
Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-11-010-L01-P.
Fostering a Dialogue to Improve Patient Care & Outcomes
ACKNOWLEDGMENT This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.
This activity is jointly sponsored by the University of Cincinnati, Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC. COEKsize21411MMweb
For Multiple Myeloma Patients at High Risk for Infection, Chemotherapy without High-dose Dexamethasone Can Help By Dawn Lagrosa
voiding intermittent highdose dexamethasone (HD) when administering the vincristine/doxorubicin/dexamethasone (VAD) regimen can reduce the risk for bacterial infection in patients with multiple myeloma (MM), suggest the results of a Japanese study published in the January issue of the International Journal of Hematology. Although the VAD-HD combination is often used as primary therapy in MM patients who are candidates for high-dose therapy or present with renal
failure, the high doses of a glucocorticoid can suppress their immune system, placing them at high risk for bacterial infections. To test if the VAD regimen could be equally effective without the HD component (and thus reduce patients’ risk for infection), the researchers retrospectively evaluated MM patients receiving VAD with or without HD. In the VAD group (n = 37), patients were treated in two to four 21-day cycles on days 1 to 4. In the VAD-HD group (n = 40), patients underwent the same dosing schedule plus intravenous dexametha-
No statistically significant differences in overall response rates were found. sone on days 9 to 12 and 17 to 20 of each 28-day cycle. The researchers identified 48 infection episodes, including pneumonia, urinary tract infections, and staphylococcus infections, in 39 patients. Of these, 32 episodes in 26 patients were grade 3. Analyzing each patient, they found
VAD-HD to be associated with risk of all-grade and severe bacterial infection; ISS stage ≥2 independently correlated with severe bacterial infection. No statistically significant differences in overall response rates were found; 62.9% in the VAD group versus 50% in the VAD-HD group. ●
CONFERENCE NEWS: ASH
CONFERENCE NEWS: SABCS
Neurocognitive Problems Linked to Use of Dexamethasone...
Women Often Shun Mammography Guidelines
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rocognitive difficulties as adults. The researchers used data from the St. Jude Lifetime Cohort Study involving adult survivors of childhood cancers. Patients in the study are at least 10 years from diagnosis. The 39 participants completing the pilot had received chemotherapy, with no cranial radiation therapy. The team also excluded any patients with Down syndrome or neurologic injury.
“The body understands [there is stress] but the mind might have adjusted...We can teach individuals to control, recognize, and address that stress.” —Kevin R. Krull, PhD
Patients underwent neurocognitive evaluations, physical examinations, and laboratory testing after overnight fasting. The dexamethasone group demonstrated significantly lower performance on multiple measures of neurocognitive function, including mathematic problem solving, semantic verbal memory, and cognitive flexibility. “The dexamethasone group had a significantly higher degree of difficulty regulating emotion, but there was no
FEBRUARY 2011 I VOL 4, NO 1
increase in emotional distress,” Krull said. “They had difficulty expressing emotion but not more depression and anxiety.” Biological evaluations revealed that patients who had received dexamethasone displayed higher systolic blood pressure than those in the prednisone-exposed group, and their diastolic blood pressure trended higher. Survivors originally treated with dexamethasone also displayed significantly less suppression of cortisol following the dexamethasone-suppression test than people in the prednisone group, which Krull said suggested reactivity within the hypothalamic-pituitary-adrenal axis. “The body understands [there is stress] but the mind might have adjusted,” Krull said. “We can teach individuals to control, recognize, and address that stress.” Krull continues to enroll survivors in the study, with plans to bring in 210 more patients, and said that additional follow-up is needed before drawing any definitive conclusions. In the meantime, he suggested that providers not settle for patients’ response that they are fine, but should ask more in-depth questions to ensure that patients are not struggling unnecessarily. “They have adjusted after more than 30 years of survivorship,” said Krull, explaining that what they now refer to as ‘normal’ has become “a way of life that may be different from their siblings or peer group.” ●
erican College of Obstetricians and Gynecologists, the American Cancer Society, the National Cancer Institute, the National Comprehensive Cancer Network, and the Society of Breast Imaging/American College of Radiology. Patient concerns regarding cost, procedure-related discomfort, and fear are also likely to contribute to noncompliance, she said.
Patient concerns regarding cost, procedure-related discomfort, and fear are also likely to contribute to noncompliance.
In addition, access to breast cancer screening may interfere with compliance. Notably, the number of mammogram facilities decreased from 9400 to 8600 between 2000 and 2003. There is also an ongoing need for more specialists in breast imaging, which may be the result of a lack of adequate training programs and a fear of litigation, she said. Subar commented that the prevalence of mammography in her study was “considerably lower than expected” given the public outcry following a recommendation by the US Preven-
tive Services Task Force (USPSTF) last year that women undergo their first mammographic screening at age 50 rather than 40. In fact, around 75% of women surveyed after the USPSTF recommendation was issued maintained that they intended to undergo or continue mammographic testing during their forties. She also pointed out her study shows that the Healthy People 2010 goal of achieving 70% compliance with a mammogram within the past 2 years for women 40 years of age or older has still not been met. “In 2005, the last time data were available, 67% of women had had mammograms within the previous 2 years; however, this information was based on selfreports,” she noted. “We found that the current annual mammography rate is only 50%.” Finally, Subar said that the findings underscore the need for continued public education and access to mammography to reach targets for breast cancer screening. ●
Did You Know? Of the estimated 400 antineoplastic agents in the drug development pipeline, approximately 25% are oral oncolytics. —Drug Topics
THANK YOU FOR MAKING US
In a recent survey, oncology pharmacists said that they read The Oncology Pharmacist 1.5 times more* than its closest competitor in the pharmacy market. Source: ÂŠ Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)
ead R * 1 # e Th acy m r a h P y Oncolog blication u Tabloid P
The Oncology Pharmacist
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Manufactured in Italy under license from Sinclair Pharmaceuticals Ltd., Godalming, Surrey GU7 1XW UK. Distributed by ALIGN Pharmaceuticals, LLC, Berkeley Heights, NJ 07922 USA www.alignpharma.com 1. Primavera G., et al. A double-blind, vehicle-controlled clinical study to evaluate the efficacy of MAS065D (Xclair), a hyaluronic acid-based formulation, in the management of radiation-induced dermatitis. Cutaneous and Ocular Toxicology, 25: 1–7, 2006. © 2011 ALIGN Pharmaceuticals, LLC All rights reserved.