TON APRIL 2013 by The Oncology Nurse

April 2013

www.TheOncologyNurse.com

Vol 6, No 3

Side Effects Management

Cancer Center Profile

Center for Cancer Prevention and Treatment at St. Joseph Hospital Nurse Navigators and the Continuum of Care

New Developments in the Management of Hand-Foot Syndrome Associated With Oral Anti-VEGF Tyrosine Kinase Inhibitor–Targeted Anticancer Therapies By Joanna Schwartz, PharmD, BCOP, and Shannon Hogan, PharmD Albany College of Pharmacy and Health Sciences—Vermont Campus Colchester, Vermont

and-foot skin reaction (HFSR), also known as hand-foot syndrome or palmar-plantar erythrodysesthesia (PPE), is an adverse effect of several chemotherapeutic agents. The syndrome is characterized by redness, swelling, pain, and tingling in the palms

of the hands and the soles of the feet. Other symptoms may include sensitivity or intolerance to hot or warm objects or fluids, hyperkeratosis (callus), blistering, and dry skin. Callus-like thickened tender blisters with some surrounding Continued on page 31

The Patient’s Voice The team of oncology nurse navigators at the Center for Cancer Prevention and Treatment at St. Joseph Hospital (left to right): Stacey Ferrante, RN, Breast Program Navigator; Pam Matten, RN, Thoracic Oncology Program Navigator; Enza Esposito-Nguyen RN, MSN, ANP-BC, Urologic Oncology Program Navigator; R. David Sanders, PA-C, Liver, Bile Duct, and Pancreas Program Navigator; Heather Stern, RN, Head and Neck Program and NeuroOncology Program Navigator; and Denise Morales, Financial Navigator.

he Center for Cancer Prevention and Treatment at St. Joseph Hospital in Orange, California, is a stand-alone cancer center. It was one of the first to be designated as a National Cancer Institute (NCI) Community Cancer Center Program. The center offers all the services that a cancer patient will require within a single location. It provides clinical care supported by dedicated oncology-trained navigators (an advanced nurse practitioner, a physician assistant, and clinical nurse specialists), an infusion center, Continued on page 33

The Devil Is in the Details By MMA

f I had to grade my oncology nurses, I would give them, as a group, an A+. They have saved my life, cleaned my privates, kept me company, rejoiced with me when I was discharged, and consoled me with every wave or trickle of bad news I have faced during my care. Yet, the devil is in the details. There are some things they have not done, that I need them to do. I do not know enough about hospital administration and organization to know if these tasks fall to them, but the nurses are there in my room more

Conference News

Prostate and Kidney Cancer News From the 2013 Genitourinary Cancers Symposium

pproximately 2350 urologists, oncologists, surgeons, radiation oncologists, and other oncology healthcare professionals gathered in Orlando, Florida, to attend the 2013 Genitourinary Cancers Symposium. The symposium, sponsored by the American Society of Clinical Oncology, the American Society

for Radiation Oncology, and the Society of Urologic Oncology, allows attendees to learn about the latest strategies for preventing, detecting, and treating cancers arising in the genitourinary organs. Following are summaries of some of the noteworthy abstracts presented at the symposium.

often than anyone except my family— and I expect the nurses to do them. Help with my toenails. Admittedly, my toenails have always resembled dinosaur claws rather than human nails. Yet, since being told about a year ago I could not get a pedicure, they have deteriorated to thick, yellowish, nonmammalian entities. They hurt. I tell my nurse. “Get a file,” she tells me. Well, I cannot. I do not know enough about pedicure procedures, I do not have the energy to do anything, Continued on page 13

inside Ovarian Cancer . . . . . . . . . . . . . . . . .

Deviation From Clinical Guidelines Takes Toll on Ovarian Cancer Survival The Whole Patient. . . . . . . . . . . .

Issues of Self-Image, Disfigurement, and Sadness in People Living With Cancer Genetic Counseling. . . . . . . . . .

2013 NCCN Guidelines Mention Gene Panels

Conference News: NCCN. . . . . . .

Complimentary CE Considerations in Multiple Myeloma —Ask the Experts: Frontline and Retreatment Settings Complete the pretest, posttest, and evaluation online at www.mlicme.org/P13008A.html

See page 14

Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

NOVEMBER 15-17, 2013 CONFERENCE CO-CHAIRS Lillie D. Shockney, RN, BS, MAS AONN Program Director University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, Johns Hopkins Clinical Breast Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Department of Surgery and Oncology Associate Professor, JHU School of Medicine Departments of Surgery, Oncology, and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

www.AONNonline.org AONNKsize31413

Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Elizabeth Bilotti, RN, MSN, APRN, BC, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

PhD, RN, AOCN

Avid Education Partners, LLC Sharpsburg, MD

CS, FNP

Mayo Clinic Rochester, MN

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Shannon Hazen,

Melinda Oberleitner, RN,

Karla Wilson, RN,

MSN, CRNP

RN, BSN, OCN Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

MSN, FNP-C, CPON

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Jayshree Shah, NP

Pharmacy John F. Aforismo,

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

BSN, OCN

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Sandra E. Kurtin,

Lori Stover, RN,

Patient Advocate Peg Ford

Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance San Diego, CA

Ann McNeill,

Joseph D. Tariman,

Social Work Carolyn Messner,

AOCN, LNC

Fox Chase Cancer Center Philadelphia, PA

Wendy DiSalvo,

DNP, APRN, AOCN Genentech New London, NH

Denice Economou,

RN, MN, CNS, AOCN City of Hope National Medical Center Duarte, CA

Constance Engelking, RN,

MS, CNS, OCN

The CHE Consulting Group, Inc. Mt. Kisco, NY

Amy Ford, RN,

BSN, OCN Quintiles Dallas, TX

NP, MSN, ACNP-C

RN, MS, AOCN, ANP-C

MSN, RN, NP-C, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Kena C. Miller, RN, MSN, FNP

Roswell Park Cancer Institute Buffalo, NY

Patricia Molinelli, MS, RN, APN-C, AOCNS

Somerset Medical Center Somerville, NJ

MSN, NP, ANP-BC, AOCNP

BSN

PhD, APRN, BC

BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

Northwestern University Myeloma Program Chicago, IL

DSW, MSW, LCSW-R, BCD

Jacqueline Marie Toia, RN, MS, DNP

Genetic Counseling Cristi Radford,

Northwestern University Myeloma Program Chicago, IL

Pamela Hallquist Viale, RN, MS,

CS, ANP, AOCN Saratoga, CA

CancerCare New York, NY

MS, CGC

Sarasota, FL

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

Sharon S. Gentry, RN, MSN, AOCN

Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

www.TheOncologyNurse.com

Ellen A. Neylon, MSN, FNP-BC, CCRP, OCN

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

Connie Visovsky, RN, PhD, APRN

University of South Florida College of Nursing Tampa, FL

Isabell Castellano, RN

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Jeanne Westphal, RN

Meeker County Memorial Hospital Litchfield, MN

April 2013 I VOL 6, NO 3

From The Editor PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Director, Client Services Eric Iannaccone eric@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com

his issue of The Oncology Nurse-APN/PA (TON) is packed with news about what is happening in the world of oncology research and brings you information that helps you in your day-to-day practice. We highlight news from the 2013 Genitourinary Cancers Symposium and the Hematology/Oncology Pharmacy Association (HOPA) 9th Annual Beth Faiman, PhD(c), Conference. The HOPA news MSN, APRN-BC, AOCN includes coverage of a study showEditor-in-Chief ing that a gene analysis can identify a specific mutation that allows for personalization of 5-fluorouracil therapy to reduce a patient’s risk of toxicity.

Senior Copy Editor BJ Hansen

Be sure to read our coverage from the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN). The inaugural NCCN Guidelines on Survivorship were unveiled at the meeting and “are intended as a library of tools for a provider to use when assessing a cancer survivor.” Our coverage from NCCN ties in with The Whole Patient article that addresses the psychosocial impact of the perception of disfigurement as a result of treatment for cancer. The authors discuss some of the biopsychosocial issues that cancer survivors may confront and how oncology nurses are at the forefront in being able to help their patients process the “new normal.” Please let us know what you think of this issue of TON. Tell us what topics you want to see covered. We appreciate your feedback—positive and negative—about what you see in print and on the website. Visit www.TheOncologyNurse. com and email us at editorial@greenhillhc.com. l

Reader Poll

Copy Editor Rosemary Hansen Editorial Assistant Jennifer Brandt Production Manager Stephanie Laudien

President/CEO Brian Tyburski

Do you talk to patients about any perceptions of disfigurement they may have as a result of cancer and treatment? o Yes o No

Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Business Manager Blanche Marchitto Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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April 2013 I VOL 6, NO 3

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s the “Issues of Self-Image, Disfigurement, and Sadness in People Living With Cancer” article discusses, many patients and survivors may need to find a “new normal.” As the number of newly diagnosed cancer patients increas-

es and survival rates improve, psychosocial and emotional outcomes are being recognized as an important component of patient care. Do patients talk to you about these issues? How do you talk to patients about coping with these feelings?

Go to www.TheOncologyNurse.com to answer the question and add your comments.

The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2013 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse-APN/PA® 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 Nurse-APN/PA®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. 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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Nurse-APN/PA® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in The Oncology Nurse-APN/PA® 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.

www.TheOncologyNurse.com

Noteworthy Numbers

Testicular Cancer Testicular cancer, or testis cancer, is most often found in young men. With the use of surgery, radiation therapy, and/or chemotherapy, this type of cancer is highly treatable, and it is often curable. Although the specific cause of testicular cancer is unknown, there are several risk factors related to the disease. These include age, family history, race, and cryptorchidism (undescended testicles). To explore this disease further, let us examine the following statistics associated with testicular cancer.

In the United States, approximately 7920 new cases of testicular cancer will be diagnosed in 2013.1

Sources 1. http://www.cancer.org/cancer/testicularcancer/detailed guide/index. 2. http://www.cancer.net/cancer-types/testicular-cancer. 3. http://seer.cancer.gov/statfacts/html/testis.html.

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy

Although the risk of death from this disease is very small (about 1 in 5000), in 2013 approximately 370 men will die of testicular cancer.1

Phase 3 study with approximately 3,000 subjects at 500 study sites globally

From 2005 to 2009, the median age at death for testicular cancer was 41 years, according to SEER.3

KEY ELIGIBILITY CRITERIA*

PRIMARY ENDPOINT

• Stage IV NSCLC

• Overall survival

• Receiving 1st-line myelosuppressive

SECONDARY ENDPOINTS

chemotherapy

• Progression-free survival

• Hemoglobin (Hb) ≤ 11 g/dL

• Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

• ECOG score ≤ 1

S:9.75”

A man’s chance of developing testicular cancer in his lifetime is about 1 in 268.3 However, there are several risk factors associated with the disease that may increase that chance.

Darbepoetin alfa 500-mcg Q3W

2:1 Randomization (darbepoetin alfa:placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria and additional study details can be found in the protocol. ECOG = Eastern Cooperative Oncology Group; Q3W = once every 3 weeks.

Cory Docken/Getty Images

For more information, please email Study-20070782@amgen.com or call 1-866-965-0782. Products under investigational study have not been approved by the FDA for the use under investigation in this trial.

Heredity has a slight influence on risk, yet only about 3% of testicular cancer cases occur within families.1 www.TheOncologyNurse.com

Between 2002 and 2008, the overall 5-year relative survival rate for this disease was 95.2%, among 18 SEER geographic areas.3

S:7.25”

The disease is most often found in men between the ages of 20 and 45 years.2 In fact, 33 years was the median age at diagnosis for testicular cancer between 2005 and 2009.3

Non-Hispanic white men are more than 3 times more likely to develop testicular cancer than Asian American and Native American men and about 5 times more likely than black men. The risk for Hispanic men falls between that for Asians and non-Hispanic white men.1

After having cancer in 1 testicle, men are at an increased risk of developing cancer in the other testicle, and it is estimated that 2% of men with testicular cancer will develop cancer in the other testicle.2

AOCO3X0071_Recruitment782_AdAsize_r3.indd 1

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Ovarian Cancer

Deviation From Clinical Guidelines Takes Toll on Ovarian Cancer Survival By Charles Bankhead

ccording to a retrospective review of more than 13,000 cases, most women with ovarian cancer received substandard care that significantly reduced their survival odds. The analysis showed that 37% of the patients were treated in accordance with guidelines established by the National Comprehensive Cancer Network (NCCN). Treatment at high-volume centers (≥20 cases/ year) and by high-volume surgeons (≥10 cases/year) improved the chances that a woman would receive recommended therapy, but even then, the care fell short of NCCN standards half the time. Treatment that diverged from current guidelines increased the 5-year survival hazard by a third, as compared with patients who received recommended care, Robert Bristow, MD, reported at the Society of Gynecologic Oncology 44th Annual Meeting on Women’s Cancer in Los Angeles, California. “Adherence to NCCN guidelines for

ovarian cancer is associated with overall survival and may be a useful measure of quality cancer care,” said Bristow, director of gynecologic oncology at the University of California Irvine. “Highvolume providers are significantly more likely to provide NCCN guideline-ad-

our efforts to ensure that ovarian cancer patients receive the best care possible, and that means getting them to high-volume surgeons and centers.” A critical need exists for research to identify traits that distinguish the best-performing providers from the oth-

“Adherence to NCCN guidelines for ovarian cancer is associated with overall survival and may be a useful measure of quality cancer care.” Robert Bristow, MD

herent care, which is associated with improved survival.” Noting that fewer than 20% of patients received care from high-volume providers, Bristow said, “We have a lot of work to do. In particular, we have to increase

ers, and then to use that information to establish best practices and enforce guidelines to improve care, he added. The findings came from a retrospective review of the California Cancer Registry to identify women with newly

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diagnosed epithelial ovarian cancer from 1999 through 2006. All patients underwent a minimum surgical procedure of oophorectomy. The primary objectives were to identify structural healthcare characteristics that could predict adherence to NCCN guidelines and to validate guideline adherence as a quality process measure associated with improved survival. Investigators defined adherence as use of stage-appropriate surgical procedures and chemotherapy as adopted by the NCCN. The analysis included 13,321 patients. Overall, 37.2% of patients received guideline-adherent care. High-volume centers accounted for 18.8% of cases, and high-volume surgeons cared for 38% of the patients. However, the surgeon was not identified in 22% of the cases, meaning that treatment by a high-volume surgeon could be verified in only 16.4% of cases, said Bristow. Patients had a significantly better chance of receiving guideline-consistent care at high-volume centers (50.8%) compared with low-volume centers (34.1%, P <.001). High-volume surgeons treated patients in accordance with NCCN guidelines significantly more often (47.6%) than did low-volume surgeons (34.5%, P <.001). An adjusted analysis showed that low-volume centers and low-volume surgeons were significantly associated with deviation from NCCN guidelines (odds ratio 1.83 and 1.19, respectively). A multivariate analysis of survival showed that nonadherence to NCCN guidelines had a significant association with worse 5-year survival (hazard ratio [HR], 1.34). After adjustment for guideline adherence, low-volume hospitals and low-volume surgeons remained independent predictors of worse survival (HR, 1.08 and 1.18, respectively). While exhorting his gynecologic oncology colleagues to advocate aggressively for better ovarian cancer care, Bristow also encouraged patients to be their own advocates and insist on treatment by high-volume providers. “If a surgeon performs only 2 ovarian cancer surgeries a year, you don’t want to be 1 of those 2,” he said. l Reference

Bristow R, Chang J, Ziogas A, et al. NCCN treatment guidelines for ovarian cancer: a population-based validation study of structural and process quality measures. Presented at: 44th Annual Meeting on Women’s Cancer; March 9-12, 2013; Los Angeles, CA. Abstract 45. https://www.sgo.org/wp-content/uploads/2013/03/ SGO_Abstract_v3.pdf. Accessed March 22, 2013.

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Not having a choice can be hard to swallow

Introducing

THE ONLY LIQUID FORM OF TAMOXIFEN AVAILABLE

Offering patients a choice may help improve long-term adherence $10 CO-PAY * FOR MOST PRESCRIPTIONS PLEASE SEE THE COMPLETE BLACK BOX WARNING AND BRIEF SUMMARY ON THE FOLLOWING PAGES. IMPORTANT SAFETY INFORMATION Tamoxifen citrate is contraindicated in patients with known hypersensitivity and also in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.

WARNING In Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer Serious and life-threatening events were associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence In High Risk Women). Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer. www.Soltamox.com www.DaraBiosciences.com

Improving the Lives of Oncology Patients

*With free co-pay assistance; certain patients, including Medicaid, Medicare, or any other federal or state program may not be eligible. For full details please visit www.Soltamox.com.

SOLTAMOX - tamoxifen citrate solution Brief Summary: Consult package insert for full prescribing information FOR WOMEN WITH DUCTAL CARCINOMA IN SITU (DCIS) AND WOMEN AT HIGH RISK FOR BREAST CANCER Serious and life-threatening events associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence In High Risk Women in the full prescribing information). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for tamoxifen vs. 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women years of 0.17 for tamoxifen vs. 0.0 for placebo)*. For stroke, the incidence rate per 1,000 women years was 1.43 for tamoxifen vs. 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women years was 0.75 for tamoxifen versus 0.25 for placebo**. Some of the strokes, pulmonary emboli, and uterine malignancies were fatal. Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer. * Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS, Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma. ** See Table 3 under (see CLINICAL PHARMACOLOGY, Clinical Studies in the full prescribing information) INDICATIONS AND USAGE Metastatic Breast Cancer Tamoxifen citrate is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen citrate is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen citrate therapy. Adjuvant Treatment of Breast Cancer Tamoxifen citrate is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen citrate adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate is indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen citrate therapy is likely to be beneficial. Tamoxifen citrate reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen citrate therapy for breast cancer. Ductal Carcinoma in Situ (DCIS) In women with DCIS, following breast surgery and radiation, tamoxifen citrate is indicated to reduce the risk of invasive breast cancer see (BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support five years of adjuvant tamoxifen citrate therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women Tamoxifen citrate is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label). Tamoxifen citrate is indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5-year predicted risk of breast cancer3 1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5-year risk³ 1.67% are: Age 35 or older and any of the following ombination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or CIS Age 40 or older and any of the following combination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. Age 50 or older and any of the following combination of factors: At least 2 first degree relatives with a history of breast cancer; or History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: 5-year predicted risk of breast cancer³ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-833-3533. There are no data available regarding the effect of tamoxifen citrate on breast cancer incidence in women with inherited mutations (BRCAl, BRCA2). After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen citrate for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen citrate therapy. In the NSABP P-1 trial, tamoxifen citrate treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk. CONTRAINDICATIONS Tamoxifen citrate is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. WARNINGS Effects in Metastatic Breast Cancer Patients. As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma. An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (³ 2 years) of tamoxifen than nonusers. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27-4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78-13.16). Among women £ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer,

compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants £ 49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women³ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average=32 months) from the start of treatment. In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one patient randomized to placebo FIGO IA); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the one patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in five other NSABP clinical trials. Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial. NonMalignant Effects on the Uterus. An increased incidence of endometrial changes including hyperplasia and polyps has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen. There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen. There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events. Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-tamoxifen, 6-placebo, RR=3.01, 95% CI: 1.15-9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months (average = 27 months) from the start of treatment. In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was seen in the tamoxifen group (30tamoxifen, 19-placebo; RR=1.59, 95% CI: 0.86-2.98). The same increase in relative risk was seen in women £ 49 and in women³ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, deep vein thrombosis events occurred between 2 and 57 months (average=19 months) from the start of treatment. There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24-placebo; 34-tamoxifen; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the tamoxifen group were fatal. Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of treatment. Effects on the Liver: Liver Cancer. In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the tamoxifen treated group vs. 1 case in the observation group (See PRECAUTIONS,-Carcinogenesis). In other clinical trials evaluating tamoxifen, no cases of liver cancer have been reported to date. One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen. Effects on the Liver: Non-Malignant Effects. Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis

and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected. Other Cancers: A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be evaluated. Effects on the Eye: Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen. In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540-tamoxifen; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101-tamoxifen; 63-placebo; RR=1.62, 95% CI 1.18-2.22). Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201-tamoxifen; 129-placebo; RR=1.58, 95% CI 1.26-1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. Pregnancy Category D. Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clearcell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome. Reduction in Breast Cancer Incidence in High Risk Women -Pregnancy Category D For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative b-HCG immediately prior to the initiation of therapy is sufficient (See PRECAUTIONS Information for Patients -Reduction in Breast Cancer Incidence in High Risk Women). PRECAUTIONS General Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to tamoxifen therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving tamoxifen; this can sometimes be severe. In the NSABP P-1 trial, 6 women on tamoxifen and 2 on placebo experienced grade 3-4 drops in platelet count (£ 50,000/mm3). Information for Patients Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen citrate is dispensed. The complete text of the Medication Guide is reprinted at the end of the Full Prescribing Information. Reduction in Invasive Breast Cancer and DCIS in Women with DCIS Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxsifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen decreased the incidence of invasive breast cancer, but has not been shown to affect survival. Reduction in Breast Cancer Incidence in High Risk Women Women who are at high risk for breast cancer can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman’s personal health history and on how she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are considering tamoxifen therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence. Women should understand that tamoxifen reduces the incidence of breast cancer, but may not eliminate risk. Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%. Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal

women taking tamoxifen and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. in women with menstrual irregularity, a negative b-HCG immediately prior to the initiation of therapy is sufficient (See WARNINGS-Pregnancy Category D). Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1. Monitoring During Tamoxifen Therapy Women taking or having previously taken tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take tamoxifen. Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation. Laboratory Tests Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained. Drug Interactions When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient’s prothrombin time is recommended. In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (See CONTRAINDICATIONS). There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen. Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect. One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen. Drug/Laboratory Testing Interactions During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism. Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given tamoxifen. In the postmarketing experience with tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias (See ADVERSE REACTIONS Postmarketing Experience section). Carcinogenesis A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/ kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/ day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m2 basis). Mutagenesis No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro-and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells. Impairment of Fertility Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on a mg/ m2 basis). There were no teratogenic changes in either rats or rabbits. Pregnancy Category D Nursing Mothers Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known. There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis. It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Pediatric Use The use of SOLTAMOX™ in pediatric patients has not been evaluated. Geriatric Use In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger

patients. In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients. ADVERSE REACTIONS Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients. Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo. In one single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal female volunteers, throat irritation was reported by 3 of 60 evaluable subjects (5.0%) in the SOLTAMOX™ treatment groups while none of the subjects in the tamoxifen reference group reported this event. All events were mild and occurred within an hour after dosing. All events were resolved within 24 hours. Metastatic Breast Cancer Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen and generally subside rapidly. In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen is hot flashes. Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/ or partial hair loss, and vaginal dryness. Premenopausal Women The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. Table 1. Summary of Incidence of Adverse Reactions Reported at Frequency of ≥2% From Clinical Trials Tamoxiden Ovarian Ablation All Effects All Effects % of Women % of Women Adverse Reactionsa n = 104 n = 100 Flush 33 46 Amenorrhea 16 69 Altered Menses 13 5 Oligomenorrhea 9 1 Bone Pain 6 6 Menstrual Disorder 6 4 Nausea 5 4 Cough/Coughing 4 1 Edema 4 1 Fatigue 4 1 Musculoskeletal Pain 3 0 Pain 3 4 Ovarian Cyst(s) 3 2 Depression 2 2 Abdominal Cramps 1 2 Anorexia 1 2 a = Some women had more than 1 adverse reaction. Male Breast Cancer Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported. Adjuvant Breast Cancer In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died. In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical significance. NSABP B-14 Study Table 2. Comparison of Tamoxifen to Placebo Administered for 2 Years to Women Following Mastectomy % of Women Adverse Reactions Tamoxifen (n = 1422) Placebo (n = 1437) Hot Flashes 64 48 Fluid Retention 32 30 Vaginal Discharge 30 15 Nausea 26 24 Irregular Menses 25 19 Weight Loss (>5%) 23 18 Skin Changes 19 15 Increased SGOT 5 3 Increased Bilirubin 2 1 Increased Creatinine 2 1 2 1 Thrombocytopeniaa Thrombotic Events Deep Vein Thrombosis 0.8 0.2 Pulmonary Embolism 0.5 0.2 Superficial Phlebitis 0.4 0.0 a = Defined as a platelet count of <100,000/mm3. SGOT = Serum glultamic oxalo-acetic transaminase. In other adjuvant studies, Toronto and tamoxifen Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group. Ductal Carcinoma in Situ (DCIS) The type and frequency of adverse events in the NSABP

B-24 trial were consistent with those observed in the other adjuvant trials conducted with tamoxifen. Reduction in Breast Cancer Incidence in High Risk Women In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group). The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on tamoxifen than placebo are shown. NSABP P-1 Trial: All Adverse Events Table 3. Adverse Events Observed in NSABP P-1 by Treatment Arm: Adverse Events More Common on Tamoxifen Than Placebo % of Women Treatment Arm/ Tamoxifen Placebo Adverse Event (n = 1422) (n = 1437) N = 6469a Self-Reported N = 6441a Symptoms Hot Flashes 80 68 Vaginal Discharges 55 35 Vaginal Bleeding 23 22 N = 6535b Laboratory N = 6520b Abnormalities Platelets Decreased 0.7 0.3 Adverse Effects N = 6492c N = 6484a Other Toxicities Mood 11.6 10.8 Infection/Sepsis 6.0 5.1 Constipation 4.4 3.2 Alopecia 5.2 4.4 Skin 5.6 4.7 Allergy 2.5 2.1 a = Number with quality of life questionnaires. b = Number with treatment follow-up forms. c = Number with adverse drug reaction forms. In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively, withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%). In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen and placebo therapy, respectively, withdrew for non-medical reasons. On the NSABP

P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms. Postmarketing Experience Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen (see PRECAUTIONS, Drug/Laboratory Testing Interactions section). OVERDOSAGE Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3-5 days of beginning tamoxifen and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day. In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose. No specific treatment for overdosage is known; treatment must be symptomatic. DOSAGE AND ADMINISTRATION For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). A 20 mg dose of SOLTAMOX™ is administered as 10 mL (equivalent to 2 teaspoons) of the oral solution. In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit. In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen citrate therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS) The recommended dose is tamoxifen citrate 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women The recommended dose is tamoxifen citrate 20 mg daily for 5 years. There are no data to support the use of tamoxifen citrate other than for 5 years. RX only Dated: 9/14/2006 Manufactured by: Rosemont Pharmaceuticals Ltd, Yorkdale Industrial Park, Braithwaite Street Leeds, LS11 9XE, UK. Distributed by: Cytogen Corporation Princeton, NJ 08540, USA.

Conference News: ASCO GU Continued from cover

Adjuvant Radiotherapy Reduces Risk of PSA Failure, Compared With Wait-and-See Approach, in Locally Advanced Prostate Cancer

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were low, compared with previous trials conducted by SWOG and EORTC in this setting. Formal discussant Anthony D’Amico, MD, of the Dana-Farber Cancer Center, Harvard Medical School, Boston, Massachusetts, said that until results of 2 ongoing trials evaluating adjuvant radiotherapy versus delayed radiotherapy are available, the decision to initiate adjuvant radiotherapy should be based on the number of risk factors, including Gleason score, surgical margins, extension into the seminal vesicles, and nodal status. Thomas Wiegel, MD

No significant benefit was observed for adjuvant radiotherapy regarding metastasis-free survival or overall survival, although the trial was not powered to show this benefit.

The relative risk of biochemical failure was reduced for patients with positive surgical margins, higher PSA level, stage T3a/b, and higher Gleason scores. Wiegel said that late toxicity rates

Reference

Wiegel T, Bottke D, Bartkowiak D, et al. Phase III results of adjuvant radiotherapy (RT) versus waitand-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95): ten years follow-up. Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 4.

Eighteen Months of Hormone Therapy Leads to Survival Similar to 36 Months in Combination With Radiation

Photo by © ASCO/Todd Buchanan 2013.

Extended follow-up of the German ARO 96-02 trial adds to the evidence that adjuvant radiotherapy reduces the risk of biochemical failure following radical prostatectomy in locally advanced prostate cancer (stage T3) versus a wait-and-see (WS) approach. Adjuvant radiotherapy reduced the risk of biochemical failure (rising prostate-specific antigen [PSA] level) by 49% at 10 years in this trial. “Our long-term follow-up shows that it is incorrect to say that adjuvant radiation for patients with positive surgical margins stage is overtreatment. It is clear that adjuvant radiotherapy reduces biochemical evidence of disease after 10 years. It is quite important that we had a low rate of side effects, with only 1 case of grade 3 late toxicity,” stated presenting author Thomas Wiegel, MD, from the University of Ulm, Germany. The study randomized 385 men with stage T3 prostate cancer following radical prostatectomy in a 1:1 ratio of adjuvant radiotherapy versus a WS approach. A unique feature of this study—compared with other phase 3 trials in this setting—was that patients randomized to adjuvant radiotherapy received treatment following surgery before they were found to have an undetectable PSA level (<.05 ng/mL). The median number of positive nodes was 8; median follow-up was 112 months. After exclusions for a variety of reasons, an intent-to-treat analysis was based on 114 patients in the adjuvant radiotherapy arm and 159 in the WS arm. All patients had stage T3 disease; 27% had T3c (extension of cancer to the seminal vesicles). The majority of patients had Gleason scores ranging from 7 to 9. The rate of 10-year freedom from biochemical failure was 56% in the adjuvant radiotherapy arm versus 35% in the WS arm, a significant absolute difference of 21% favoring adjuvant treatment (P = .00002).

Abdenour Nabid, MD

Patients with high-risk prostate cancer treated with radiation and hormones as their primary therapy had similar survival with 18 months of hormone therapy, compared with 36 months, according to results of a randomized phase 3 study. “Hormone ablation therapy makes most men’s lives miserable,” stated presenting author Abdenour Nabid, MD, of the Centre Hospitalier Universitaire de Sherbrooke in Sherbrooke, Canada. Specifically, he said that the “castration syndrome” of lack of libido, erectile dysfunction, and hot flashes compromises quality of life. Other symptoms include fatigue, weight gain, and mood irritability, and a small number of men have cardiovascular effects. “Shorter-term hormone therapy could have a big impact on the lives of men with prostate cancer, reducing the quantity and intensity of its unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years,” he told listeners. The optimal duration of androgen ablation therapy in

high-risk prostate cancer is controversial. An EORTC study conducted in 2009 found that 6 months of androgen ablation in this setting was inferior to 36 months. The present study was designed to show that 18 months was superior to 36 months. The study randomized 630 patients with node-negative, high-risk prostate cancer to radiotherapy to the pelvic area and prostate bed plus 18 months of androgen ablation therapy versus 36 months of androgen ablation therapy (bicalutamide 1 month plus goserelin every 3 months). Demographic and disease characteristics of the study population were well balanced between the 2 arms. The median age was 71 years, the median PSA was 16 ng/mL, and the median Gleason score was 8. Most patients had stage T2-T3 disease. “These were truly high-risk patients,” Nabid noted. At a median follow-up of 77 months, mortality was similar in the 2 arms: 22.9% in the shorter-duration hormone-therapy arm versus 23.8% in the longer-duration arm. Among 147 deaths reported, 116 were not due to prostate cancer but to other causes. At 5 years, overall survival rates were 92.1% versus 86.8% for the 2 arms, respectively, and 10-year survival rates were 63.6% versus 63.2%, respectively. Diseasespecific survival rates at 5 years were 97.6% versus 96.4%, respectively, and 10-year disease-specific survival rates were 87.2% in both arms. “Importantly, the number of men dead due to prostate cancer was identical at 10 years,” he stated. Bruce Roth, MD, of Washington University in St. Louis, Missouri, was encouraged by these findings. He said that he wanted to examine the full peer-review publication of the study, but he was hopeful that the study would be practice-changing. Reference

Nabid A, Carrier N, Martin A-G, et al. High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: results of a phase III randomized study. Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 3.

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Conference News: ASCO GU African Americans and Elderly Are at Increased Risk of High-Risk Prostate Cancer Elderly men and African American men whose prostate cancer was detected by PSA are at increased risk of developing high-risk prostate cancer, according to a large, population-based, retrospective study. The findings imply that PSA testing may be warranted in elderly and African American men to find high-risk cancers so that they can be treated early, but more research is needed to demonstrate that early detection and treatment for high-risk prostate cancer can improve outcomes. These findings are interesting in light of the US Preventive Services Task Force (USPSTF) recommendation to curtail routine PSA testing.

The findings imply that PSA testing may be warranted in elderly and African American men to find high-risk cancers so that they can be treated early, but more research is needed.

“If we stop PSA screening altogether [as recommended by the USPSTF], there is no other method to detect this form of prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients. The findings of this study will help physicians and certain patients make more informed decisions on whether or not they want to proceed with PSA testing, although more research (and longer follow-up) is needed to determine the effects of early detection and intervention on outcome in these highrisk patients,” stated lead author Hong Zhang, MD, PhD, of the University of Rochester, New York. The study found that about 40% of cases of high-risk, PSA-detected prostate cancer occur in men over the age of 75 years, and elderly men are 9.4 times more likely than men under the age of 50 years to be at high risk. African American men of any age are more likely than white men to have high-risk disease. The study identified 70,345 men from the SEER registry data diagnosed with early-stage (T1c), node-negative, prostate cancer between 2004 and 2008. The investigators determined the probability of developing low-, intermediate-, and high-risk prostate

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cancer based on PSA criteria and 35.9% intermediate-risk, and 16.5% Gleason stage. Low risk was defined as high-risk. PSA <10 mg/L and Gleason score of 6 Men over the age of 75 years accounted or lower; intermediate risk was defined for 11.8% of the entire study population as PSA 10-20 mg/L and/or Gleason but comprised 24.3% of intermediatescore of 7; and high-risk disease was and 26.1% of high-risk disease. African defined as PSA of >20 mg/L and/or American men had a 50% higher chance Gleason score of 8 or higher; 47.6% of developing intermediate-stage prostate were found to have low-risk disease, COEAsizeCE_fish_71112_House Ad 7/11/12 11:47 AMcancer, Page 1 compared with white men, and an

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84% increased likelihood of developing high-risk prostate cancer than white men (P <.01 for both comparisons). Reference

Zhang H, Travis LB, Messing EM, et al. PSAdetected prostate cancer in the United States: a population-based study of 70,345 men with AJCC stage T1cN0M0 disease. Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 50.

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Surveillance Is as Safe as Surgery for Management of Small Kidney Masses in Elderly

William C. Huang, MD

In elderly patients in whom small asymptomatic kidney masses are found on imaging, surveillance is as safe and effective as surgery, especially in patients who are not good surgical candidates and/or who have comorbidities. In a retrospective analysis of more than 8300 elderly patients with small kidney masses, surveillance and surgery led to comparable kidney cancer– specific mortality, but surgery was associated with a higher risk of cardiovascular complications and all-cause mortality. “Our analysis indicates that physicians can comfortably tell an elderly patient, especially a patient that is not healthy enough to tolerate anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney sur-

gery is unlikely to extend their lives. However, since it is difficult to identify which tumors will become lethal, elderly patients who are completely healthy and have an extended life expectancy may opt for surgery,” stated lead author William C. Huang, MD, of the New York University Medical Center, New York City. The study used SEER registry data linked to Medicare claims for patients aged 66 years or older to identify 8317 patients diagnosed with small renal masses (ie, under 1.5 inches in diameter); 5706 (69%) underwent surgery and 2611 (31%) underwent surveillance. At a median follow-up of 4.8 years, 2078 deaths were reported (25% of the population); 277 deaths (3%) were due

to kidney cancer. The rate of kidney cancer–specific death was identical with both surveillance and surgery. In an analysis adjusted for patient and disease characteristics, patients who were managed with surveillance had a significantly lower risk of death from any cause as well as a lower risk of a cardiovascular event. The authors concluded that surveillance with modern imaging techniques is a safe option for management of small renal masses in elderly patients. Reference

Huang WC, Pinheiro LC, Russo P, et al. Surveillance for the management of small renal masses: utilization and outcomes in a population-based cohort. Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 343.

Detection of Prostate Cancer Increases With 10 to 12 Biopsy Specimens Urologists across the United States have largely adopted the evidence“Segregation of prostate biopsy cores into 10-12 based practice of obtaining 10 to 12 unique vials per biopsy has been adopted by core biopsies of the prostate for the diagnosis of prostate cancer, and this urologists across sites of service, and it appears practice has led to an increase in the to be the de facto national standard of care.” rates of detection of prostate cancer, according to the results of one of Carl A. Olsson, MD the largest studies ever done in this setting. “Segregation of prostate biopsy across sites of service, and it appears A. Olsson, MD, of Integrated Medical cores into 10-12 unique vials per biop- to be the de facto national standard Professionals, LLC, New York City. AONN_Filler7x5_31413_AONN_Filler 31413 3/14/13 10:58stated AM Page 1 sy has been adopted by urologists of care,” presenting author Carl The massive study included more

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than 4.2 million specimens collected from about 440,000 biopsies. Data were collected from an annual mean of 1756.7 urologists in 765.6 practices in the United States. Biopsy rates and core-sampling patterns were assessed in patients whose biopsies were submitted to either a national reference library (NRL) or a laboratory integrated into a urology group practice (UPL). The investigators analyzed the association between the rates of positive biopsies and the number of specimens per biopsy according to needle biopsy and anatomic pathology sampling. The analysis excluded saturation biopsies. For each year studied, the positive biopsy rate and the number of specimens per biopsy were recorded for both NRL and UPL, separately and combined. In 2005, the positive biopsy rate was 38.2%, and the number of specimens per biopsy was 7.9; by 2011, the positive biopsy rate was 42.6%, and the number of specimens per biopsy was 10.7. “The transition point was in 2008, suggesting that urologists were responding to published literature and guidelines recommending increased prostate sampling. Physicians utilizing UPL adopted these changes earlier than those using the NRL,” Olsson indicated in the poster. The steepest increase in the number of specimens obtained occurred between 2005 and 2008, which was during the development of core-sampling regimens. The number of specimens obtained did not differ significantly across practice settings. l Reference

Olsson CA, Kapoor DA, Mendrinos SE, et al. Utilization and cancer detection by U.S. prostate biopsies (2005-2011). Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 107.

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The Patient’s Voice

The Devil Is in the Details Continued from cover and I am in constant pain. Why can’t Make sure I have some way to wash to even clean my hands. So, I trans- ogy nurses who have given me so much my nurse simply call someone to help my hands. Oftentimes, I use the fer back to my bed, aware that if I and cared for me through the course me? Why do they always give me some bedside commode. I do my business, eat or sleep or anything else I run the of this illness. However, all job perforunhelpful suggestion and then never get up, and look around for a way risk of contaminating myself with mance can be improved. Nurses may mention it again? Perhaps I have not to wash my hands. No one is in the excrement bacteria. All a nurse has not even be aware that, from a patient’s been proactive enough. Perhaps I need room, I am too weak to walk to the to do is make sure I have wipe cloths, point of view, sometimes the devil is in to bring this up with the doctor. Yet, bathroom, and apart from the toilet hand sanitizer, or some other way to the details. l justified or not, I blame the nurses for paper tucked on my chemo pole (if keep myself clean. not helping me. My suggestion? Look at ASTUTE_DCIS someone has remembered it It was hard to write this article. It MMA is undergoing treatment for cancer. Ad_50712_Layout 1 5/11/12 5:07 PM to Pageput 1 the feet of your patients and ask them if there), there is no sign of anything seems sacrilegious to criticize the oncol- She wishes to use her initials. they need help with their toenails! Find a solution! Please! Clean out the apparatus from my bathroom. Every time I want to take a shower at the hospital, I find myself confronted with chemo poles, bedside commodes, and other assorted paraphernalia stuffed in the bathroom, usually in the shower stall. Has no one noticed that maybe, just maybe, a patient cannot take a shower with all that junk dumped in the shower stall? Do you take a shower at your own house surrounded by heavy metal that you cannot move easily? Please make sure it is out of there before I need to take my shower. To me, when you do not, it Release Date: May 8, 2012 Expiration Date: May 7, 2013 suggests that no one really cares. TARGET AUDIENCE Place my chemo pole so I can easily This initiative will target medical oncologists, hematologists, breast surgeons, radiation access the restroom. In my case, bathroom FACULTY oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician functions dominate my hospital stays. I assistants, oncology pharmacists, managed care professionals, and others with clinical Chair: am given medicine to either make me research and management interest in treatment of ductal carcinoma in situ (DCIS) and Lawrence J. Solin, MD, FACR, urinate or make me have endless bowel early-stage breast cancer. FASTRO movements. I find it embarrassing and Chairman Department of Radiation Oncology humiliating. Worse yet, many times I STATEMENT OF NEED Albert Einstein Medical Center do not make it to the restroom in time, Ability to detect DCIS has dramatically improved in recent decades, and the current inciPhiladelphia, PA instead having accidents on the floor. dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased 1,2 While sometimes this problem is solved use of mammography screening. However, attempts to identify subsets of DCIS women E. Shelley Hwang, MD, MPH when I am told to use the bedside comwho may be spared radiotherapy and perhaps treated with surgery alone have heretofore Professor and Chief, Breast Surgery been unsuccessful. This inability to predict which patients will develop recurrent DCIS or mode, it is still often the case that I just Duke University Medical Center invasive disease has complicated DCIS management. Many clinicians and other healthdo not arrive. Why? I would estimate Durham, NC care professionals dealing with patients diagnosed with DCIS are unaware or incompletethat 90% of the time it is because of 2 ly knowledgeable about the most recent results from a clinical trial examining the ability Kathy D. Miller, MD factors: one, I cannot get the chemo pole of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and Associate Professor to wheel over the bump that leads to the the implications these findings may have for management of their patients with DCIS. Department of Medicine bathroom, or, two, I cannot disconnect 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. IU School of Medicine 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, the cord from the wall and wrap it up in treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178. Indianapolis, IN time to grab the chemo pole, navigate the door opening to the bathroom, get EDUCATIONAL OBJECTIVES This activity is supported over that hump, and get to the toilet. I After completion of this activity, participants will be better able to: by an educational grant from consider that a nurse could easily accomGenomic Health, Inc. • Identify approaches currently available or in development to predict recurrence risk modate the equipment in a way that in DCIS patients would reduce these incidents. • Explain how the 12-gene expression assay for DCIS was developed and how it Clean up after my vomiting/diarrhea compares with the 21-gene assay for early invasive breast cancer episodes. Do you know what it is like to • Describe the design and findings of the ECOG 5194 validation study be vomiting, for hours on end, some• Apply the 12-gene assay for DCIS into clinical decision-making times intermittently, sometimes in • Explain relevant information about the 12-gene DCIS assay and DCIS score to retching fits? Do you know how humilpatients iating it is to not be able to control your bowel movements, and instead to dirty yourself time and time again? Do ACCREDITATION you know that most of the people who Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical are caregivers for us are not trained in Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity the medical field? Do you know that, for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their as far as I know, it is not my caregiver’s participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) job to do yours. Do not expect my careCommission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does giver to clean up my mess! You need to not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. do it! You are trained in the art of care. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Please use that training. Come quickly! Certification. Case Managers number 790005057. Help me! Please clean up! I need you to do it!

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CONTINUING EDUCATION 6th Annual

APRIL 2013 • VOLUME 6 • NUMBER 1

CONSIDERATIONS in

Multiple Myeloma

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LETTER

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EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma (MM), including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this first issue, experts from the John Theurer Cancer Center at Hackensack University Medical Center answer questions related to the management of patients with newly diagnosed and relapsed/refractory myeloma in the era of novel agents. Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

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FACULTY David Siegel, MD, PhD Chief, Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-007-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of novel

agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens

Board for Celgene Corporation and on the Research Advisory Board for Eli Lilly. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708, oprozomib, BT062, CC-223, and BHQ880.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose. Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose. Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices. David Siegel, MD, PhD, is on the Speaker’s Bureau and Advisory Boards for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDA-approved or investigational use for the following products/devices: MLN9708, oprozomib, daratumumab, and Arry-520. Elizabeth Bilotti, MSN, BSN, APN-C, is on the Advisory Board and Speaker’s Bureau for and is a Consultant to Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. She does not intend to discuss any non– FDA-approved or investigational use for any products/devices. Greg Eskinazi, RPh, MAS, BCOP, is on the Pharmacist Advisory

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008A. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: April 11, 2013 Valid for CME/CPE/CE credit through: April 11, 2014 SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Recent Advances in the Management of Multiple Myeloma David Siegel, MD, PhD

Chief, Myeloma Division, John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The positive impact of novel therapies on newly diagnosed and relapsed/refractory multiple myeloma (MM) has been observed in both transplant-eligible and -ineligible patients. The development of next-generation agents, as well as new dosing schedules and modes of administration, have also contributed to greater efficacy and tolerability for many patients. In this article, David Siegel, MD, PhD, discusses some of the latest advances in myeloma treatment and offers insights on therapy selection and future directions in the management of the disease.

Given the wide array of choices available, is there a standard of care for the frontline treatment of transplant-eligible patients with MM? In myeloma, the main goal of induction therapy is disease cytoreduction. This is important for improving performance status in newly diagnosed patients, which makes them more viable candidates for autologous stem cell transplantation (ASCT). It is critical during induction to reduce the tumor burden and increase the amount of healthy bone marrow to optimize stem

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cell mobilization. As shown in Table 1a, there are numerous options for treating newly diagnosed transplant-eligible patients.1 Among these choices, I think the most commonly used regimens, at least in larger cancer centers, are lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD), which have both demonstrated good efficacy and ease of use. In a phase 1/2 study in newly diagnosed patients, treatment with RVD resulted in a partial response (PR) or better rate of 100%, with a 74% very good partial response (VGPR) or better rate in the phase 2 population.2 In a phase 2 study, CyBorD also demonstrated significant activity in newly diagnosed MM, including an overall response (OR) rate of 88% and a VGPR or better rate of 61% after 4 cycles of therapy.3 In the phase 2 EVOLUTION study, CyBorD and RVD were shown to have similar activity4; complete response (CR) was achieved in 22% and 47% of patients treated with 2 different schedules of CyBorD and 24% of patients treated with RVD. The fact that we are now able to offer patients subcutaneous (SQ) bortezomib has decreased the incidence and severity of peripheral neuropathy (PN) with these and other bortezomib-containing regimens. The 2012 approval of SQ bortezomib by the US Food and Drug Administration (FDA) was based on data from a few different studies, including the MMY-3021 trial, which compared the safety and efficacy of SQ versus intravenous (IV) administration in the relapsed myeloma setting.5 Rates of CR and VGPR after 4 cycles, OR after 8 cycles, time to response, duration of response, time to progression, progression-free survival (PFS), and 1-year overall survival (OS) were similar between treatment arms. However, the SQ route demonstrated improved tolerability compared with the IV route, especially in terms of PN.

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CONTINUING EDUCATION

Table 1a. NCCN Recommendations: Initial Therapy for Transplant-eligible Patients1 Preferred Regimens

Category

Other Regimens

Category

Dexamethasone

PAD

DVD

VTD

CRd

CyBorD

RVD

Which regimens are being used for newly diagnosed patients who are not eligible for transplant?

CRd indicates carfilzomib/lenalidomide/dexamethasone; CyBorD, cyclophosphamide/bortezomib/dexamethasone; DVD, liposomal doxorubicin/vincristine/dexamethasone; NCCN, National Comprehensive Cancer Network; PAD, bortezomib/doxorubicin/dexamethasone; Rd, lenalidomide plus low-dose dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; TD, thalidomide plus dexamethasone; VD, bortezomib plus dexamethasone; VTD, bortezomib/thalidomide/dexamethasone.

Table 1b. NCCN Recommendations: Initial Therapy for Transplant-ineligible Patients1 Preferred Regimens

Category

Other Regimens

Category

Dexamethasone

DVD

VMP

MPR

MPT

VAD

DVD indicates liposomal doxorubicin/vincristine/dexamethasone; MP, melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPT; melphalan/prednisone/thalidomide; NCCN, National Comprehensive Cancer Network; Rd, lenalidomide plus low-dose dexamethasone; TD, thalidomide plus dexamethasone; VAD; vincristine/doxorubicin/dexamethasone; VD, bortezomib plus dexamethasone; VMP; bortezomib/melphalan/prednisone.

There are clinical scenarios in which a 2-drug regimen may be a better option than a 3-drug regimen. For example, in patients who present with significant preexisting PN caused by diabetes or the myeloma itself, clinicians may choose to use lenalidomide plus low-dose dexamethasone (Rd), which has been shown to be active in newly diagnosed MM.6 Conversely, in patients who have significant renal dysfunction, bortezomib plus dexamethasone (VD), which has also demonstrated good clinical activity in the frontline setting,7 may be the preferred option, as physicians may be concerned about adequately dose-adjusting lenalidomide. There is a fear of using lenalidomide in the setting of renal insufficiency, which is based on the false perception that it is going to impact renal function. Physicians do, however, need to carefully follow dose-adjustment recommendations when using lenalidomide in renally impaired patients, because myelosuppression will be impacted by renal function.8 Another 3-drug regimen that is showing impressive results is carfilzomib/ lenalidomide/dexamethasone (CRd), which is the most recent addition to the National Comprehensive Cancer Network (NCCN) recommendations for frontline treatment of transplant-eligible patients.1 This combination was recently evaluated in a multicenter phase 1/2 trial, in which newly diagnosed patients (N=53) received carfilzomib at 20, 27, or 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for 8 cycles. The 20- and 27-mg/m2 doses were infused over 5 to 10 minutes, whereas the 36-mg/m2 dose was infused over 30 minutes. Patients also received lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly for cycles 1 to 4, and 20 mg weekly for cycles 5 to 8.9 Transplant-eligible patients who achieved â&#x2030;ĽPR could proceed to stem cell collection after 4 cycles. All patients received 4 more cycles of CRd, with transplant-eligible patients having the option to proceed with ASCT. Patients who continued therapy beyond 8 cycles received maintenance CRd in 28-day cycles at the doses tolerated at the end of 8 cycles. Results showed that patients experienced a rapid and good initial response to CRd, and their responses improved as the trial continued. Of the 49 pa-

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tients who completed 4 treatment cycles, 67% achieved at least near-complete response (nCR), with 45% in stringent complete response (sCR), defined as no detectable tumor cells or myeloma protein in the blood or bone marrow. Of the 36 patients who completed 8 or more treatment cycles, 78% achieved nCR with 61% achieving sCR. The investigators also reported PFS rates of 97% at 12 months and 92% at 24 months. This regimen was well tolerated, and PN rates were low. However, I think it is important to remember that this was a relatively small study, and more follow-up with larger cohorts of patients is warranted.

Again, we are fortunate to have numerous combinations to treat this population of patients (Table 1b).1 RVD, although not listed as an NCCN recommendation in the nontransplant setting, is now being widely used, at least here in the United States, where there is less pressure to use melphalan plus prednisone (MP). To date, there are no clinical trial data that clearly show an advantage with MP compared with dexamethasone or other corticosteroids. If you look at results from the large UPFRONT trial by Niesvizky and colleagues, which compared VD versus bortezomib/thalidomide/dexamethasone (VTD) versus bortezomib/melphalan/prednisone (VMP) as initial therapy in nontransplant patients, you will see that there was no advantage in terms of response or tolerability with VD versus VMP.10 Furthermore, after 22 months of follow-up, median PFS rates were 13.8 months for VD, 14.7 months for VTD, and 17.3 months for VMP; these are not statistically different. One-year OS rates were also similar (87.4%, VD; 86.1%, VTD; 88.9%, VMP). At our center, we routinely recommend ASCT for patients up to 75 years of age, and in some cases, offer transplant to those between 75 and 80 years. It is important to consider which factors make an individual â&#x20AC;&#x153;transplant-eligible,â&#x20AC;? not just at the time when initial therapeutic decisions are being made, but later in the course of treatment as well. If you have a patient whose disease is refractory to RVD, it may become necessary to consider them for transplant in the secondary setting. Hence, we want to avoid MP whenever possible even in these patients, so we do not compromise stem-cell reserve. Beyond that, even if a patient is never transplanted, given the improved efficacy seen with novel therapies, he or she may live many years, even decades, after diagnosis. Therefore, it is important to consider the bone marrow injury and risk of secondary malignancies associated with alkylating agents11 and the impact this may have on survival and quality of life. Which investigational agents are showing the most promise in MM treatment? I think that MLN9708, which is a next-generation oral proteasome inhibitor, has the potential to be a game-changing drug. This agent is being combined with lenalidomide and dexamethasone in a phase 1/2 trial of newly diagnosed patients.12 After establishing the maximum tolerated dose (MTD) of the drug, 65 patients were evaluated in the study. In the 20 patients who were to undergo ASCT, stem cells were successfully collected. Overall, 52 patients were evaluable for response after a median of 6 cycles of treatment; of these patients, 58% achieved at least a VGPR, 32% achieved a PR, and 23% had a CR. Twenty-one patients (32%) reported neuropathy, which was grade 1 in 20% of patients, grade 2 in 9%, and grade 3 in 3%. Mild rash, fatigue, nausea, vomiting, and diarrhea were reported in 40% of patients. These were well managed with dose reductions and supportive care. Two grade 4 adverse events (AEs) were observed, including end-stage renal disease in 1 patient (resulting from disease progression) and deep vein thromboembolism in 1 patient. In light of the promising results seen with MLN9708, this drug has entered a phase 3 trial, and 2 other trials are planned in newly diagnosed patients and in those with relapsed and refractory disease. Another second-generation oral proteasome inhibitor that is showing good activity is oprozomib. In a phase 1b study, this agent was administered on days 1 to 5 of a 14-day cycle with a standard 3 + 3 dose-escalation scheme.13 Treatment was initiated at 120 mg/day, with 4 to 6 hours between doses. To date, 13 patients with hematologic malignancies (MM and chron-

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 2. Common Grade 3/4 Adverse Events in ≥15% of Patients in the Phase 2 MM-002 Trial19 POM + LoDex (%)

POM Alone (%)

Neutropenia

Anemia

Thrombocytopenia

Pneumonia

Toxicity

LoDex indicates low-dose dexamethasone; POM, pomalidomide.

ic lymphocytic leukemia [CLL]) have been treated. Treatment duration up to 38 weeks has been observed thus far, and MTD has not been reached up to a 210-mg/day dose. Ten patients were evaluable for antitumor activity (9 with MM, 1 with CLL), and PRs were seen in 2 patients with MM and 1 patient with CLL. Researchers also are excited about daratumumab, a humanized anti-CD38 monoclonal antibody with broad-spectrum killing activity, which is showing promise as a single agent in relapsed/refractory MM,14 and Arry-520, a novel kinesin spindle protein inhibitor, which is showing activity alone and in combination with dexamethasone in patients refractory to bortezomib and lenalidomide.15 Can you comment on recent advances in the relapsed/refractory setting? We now have 2 new agents available for the treatment of relapsed/refractory MM: carfilzomib and pomalidomide. Carfilzomib, a next-generation IV proteasome inhibitor, is currently FDA approved for patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory drug (IMiD), and who have demonstrated disease progression on or within 60 days of therapy completion.16 This agent represents an important advance in treatment, given its proven efficacy and good safety profile. In the phase 2 PX-171-003-A1 trial, heavily pretreated patients (N=266) received single-agent IV carfilzomib, given over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, for up to 12 cycles. The dose for cycle 1 was 20 mg/m2, which was escalated to 27 mg/m2 for all cycles thereafter provided that patients tolerated the initial dose level of 20 mg/m2.17 Of the evaluable patients, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. The OR rate was 23.7%, median duration of response was 7.8 months, and median OS was 15.6 months. Reported AEs included fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). The rate of treatment-related PN was only 12.4%, and this was almost exclusively grade 1 and 2. Pomalidomide, a next-generation oral immunomodulator, is also approved for patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.18 This approval was based on data from the multicenter phase 2 MM-002 trial of patients with relapsed/ refractory MM who had previously received lenalidomide and bortezomib and were refractory to their last therapy. The treatment arms were pomalidomide plus low-dose dexamethasone (POM/LoDex) or pomalidomide alone (POM).19 Of the 221 patients evaluated for response, 29.2% achieved a PR or better with POM/LoDex versus 7.4% with POM. The most common grade 3/4 AEs in both arms are shown in Table 2. At a median follow-up of 14.2 months, median PFS was 4.6 months in the POM/LoDex arm and 2.6 months in the POM arm.20 Pomalidomide is also being evaluated in combination with carfilzomib and dexamethasone in a heavily pretreated, lenalidomide-refractory population with prior bortezomib exposure.21 Preliminary results show that this regimen is well tolerated and, among the 30 evaluable patients, the OR rate was 50%, including a VGPR rate of 13% and a PR rate of 37%. A phase 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone in relapsed/refractory MM is also under way.22 This regimen shows good activity,

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with 73% of 15 evaluable patients responding to treatment (VGPR, 27% and PR, 46%). The most common AEs were fatigue (60%), edema (40%), and low platelet counts (40%). I think that myeloma treatment will continue to evolve with the use of these agents, as well as monoclonal antibodies and other kinds of immunomodulatory manipulators, like the anti-PD1 antibodies that are making an impact on solid tumors. We are definitely going to see immunomanipulation as a breakthrough area in MM in the relatively short-term future. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed March 25, 2013. 2. Richardson P, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116: 679-686. 3. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib, and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 4. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382. 5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncol. 2011;12:431-440. 6. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomized controlled trial. Lancet Oncol. 2010;11:29-37. 7. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. 8. Niesvizky R, Naib T, Christos PJ, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing frontline lenalidomide and dexamethasone therapy. Br J Haematol. 2007;138:640-643. 9. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 10. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 478. 11. Alkeran [package insert]. Rockville, MD: ApoPharma USA, Inc.; November 2011. 12. Kumar SK, Berdeja JG, Niesvizky R, et al. Phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332. 13. Savona MR, Berdeja JG, Lee SJ, et al. A phase 1b dose-escalation study of split-dose oprozomib (ONX 0912) in patients with hematologic malignancies. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 203. 14. Lokhorst H, Gimsing P, Nahi H, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma - preliminary efficacy and pharmacokinetics data from a dose-escalation phase I/II study. Program and abstracts of the 17th Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, the Netherlands. Abstract 1143. 15. Shah JJ, Zonder JA, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 449. 16. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 17. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825. 18. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013. 19. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634. 20. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Blood (ASH Annual Meeting Abstracts). 2012;120: Abstract 450. 21. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74. 22. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose for the combination of pomalidomide, bortezomib, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 727.

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Nursing Considerations in the Frontline and Relapsed/Refractory Settings Elizabeth Bilotti, MSN, BSN, APN-C

Nurse Practitioner, Multiple Myeloma Division John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction Patients with multiple myeloma (MM) present with numerous disease- and treatment-related symptoms that require supportive care. Monitoring for these complications and intervening with appropriate nursing strategies is critical for maintaining the delicate balance of therapeutic efficacy and tolerability. This requires a thorough knowledge of the toxicity profiles of agents currently used to treat the disease, as well as the latest guidelines for dose adjustments and other interventions. In this article, Elizabeth Bilotti, MSN, BSN, APN-C, discusses approaches used at her center for managing common adverse events (AEs) in both the newly diagnosed and relapsed/ refractory settings.

How do you manage common toxicities related to the use of lenalidomide/bortezomib/dexamethasone (RVD)? Every time a patient comes into the clinic, we conduct an assessment for AEs related to the drugs used in the RVD regimen. Importantly, we compare how patients are currently feeling with how they were feeling at their last appointment and prior to starting treatment. We inform patients of the common toxicities that may develop and encourage them to contact the office immediately if they are unsure how to manage them or feel that they cannot wait until the next follow-up visit. Toxicities related to dexamethasone used in RVD can be variable and extensive. Some of the subjective symptoms that patients report include insomnia, which may occur for a few days after treatment, as well as a “let-down effect,” which is characterized by an increase in energy for 1 or 2 days, followed by a “drained” feeling.1 We advise patients to be aware of their energy levels throughout the day, and if possible, look for patterns, so that they can modify their schedules around tasks they need to accomplish and when they have the ability to do them. Treatment with dexamethasone can also increase a patient’s blood glucose levels, which may remain elevated for 24 to 48 hours after each dose.1,2 If a patient is receiving dexamethasone twice weekly as part of a standard RVD regimen, it is not unusual for glucose levels to be compromised 4 or more days each week. When treating a diabetic patient with MM, we notify his or her endocrinologist or primary care physician, so that necessary adjustments in medications can be made. In patients who are not diabetic, we still carefully monitor blood glucose levels throughout each treatment cycle. In addition, we watch for other signs and symptoms of elevated glucose levels, such as increased thirst or urination. It is also important to evaluate for myopathies or muscle weakness, especially in the quadriceps, hamstrings, gluteal, and upper arm muscles, as these areas can be affected by the long-term use of dexamethasone, especially in elderly patients who are at greater risk for muscle wasting.1 We encourage individuals to exercise these muscles to reduce the risk of injuries due to falls. The RVD regimen combines dexamethasone with the immunomodulatory drug (IMiD) lenalidomide, which increases the risk of venous thromboembolism (VTE).3 Therefore, it is important for patients to be educated on the potential signs and symptoms of this complication, which usually includes pain in the calf muscles (while walking or at rest), and in some cases, unilateral

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swelling or warmth.3 We tell our patients that anything out of the ordinary should be reported immediately so that we can determine whether further evaluation is necessary. In patients receiving IMiDs in combination with steroids, it is critical to provide effective VTE prophylaxis.3-7 There are several risk factors, both patient and treatment related, that must be considered when evaluating for this risk in MM. Guidelines on risk assessment and prophylaxis of VTE have been established (Table),4-7 and we follow these recommendations, using aspirin or anticoagulation with low-molecular-weight heparin or warfarin, based on the number of risk factors and the regimen being administered. One of the common AEs related to the use of lenalidomide is myelosuppression.8,9 When patients become anemic during therapy, they may feel fatigue throughout the day, or it may be evident only when they exert themselves. For example, individuals may report that they need to stop and catch their breath after climbing a flight of stairs, which they never had to do before. Interestingly, aside from these types of symptoms, patients often do not know that their blood counts are low until we make a formal assessment. We also urge patients to immediately report any unusual bleeding or signs of infection, including a fever higher than 101°F (or higher than 100.5°F that occurs twice during a 24-hour period), which can signal infection or febrile neutropenia.8 Other possible signs of infection may include cough and increased frequency of (or burning during) urination. When necessary, the dose or schedule of lenalidomide may need to be adjusted until blood counts return to normal. Growth factor support may also need to be initiated. Gastrointestinal (GI) toxicities that patients experience while on lenalidomide include constipation, diarrhea, and bloating.9 It is important to gauge how a patient’s condition has changed since he or she started treatment so that proper interventions, including laxatives, antidiarrheals, adequate fluid intake, or changes in the diet, can be initiated. Immediately addressing these toxicities helps to prevent further complications, such as weight loss, dehydration, bowel obstruction, and electrolyte disturbances. Patients can also develop a low-grade rash from lenalidomide.9 This is more common during the first and second cycles of treatment and usually manifests as itching and redness of the scalp, which can be treated with an over-thecounter antihistamine. If patients report a whole-body rash, we ask that they come into the clinic to be assessed. In some cases, newly diagnosed patients are receiving prophylactic antibiotics, which may also lead to rash. Therefore, it is important to determine which medication is causing the problem so that the appropriate intervention can be chosen.

In patients receiving immunomodulatory drugs in combination with steroids, it is critical to provide effective VTE prophylaxis. A well-known and challenging AE related to bortezomib use is peripheral neuropathy (PN).10 However, our ability to administer this drug subcutaneously (SQ) has helped to reduce the risk and severity of this toxicity, although some patients still experience it to some degree. Our center has completely switched over to SQ bortezomib, based on results of the phase 3 noninferiority trial by Moreau and colleagues.11 Our approach to monitoring and managing PN has not changed with this new route of administration. Assessing for neuropathy includes posing questions to the patient each time they come in, to determine whether there has been a change in sensation, pain, or function since baseline. When necessary, we withhold or dose-reduce as recommended until we see improvement in symptoms. Fortunately, bortezomib-based PN is often reversible when managed promptly.12

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table. Risk Assessment for VTE Prophylaxis in Patients Treated with Immunomodulatory Drugs4-7 Individual Risk Factors

Treatment-Related Risk Factors

Obesity (BMI ≥30 kg/m )

High-dose dexamethasone (≥480 mg/month or 120 mg/week)

Previous VTE

Doxorubicin

Central venous catheter or pacemaker

Combination chemotherapy

Chronic renal disease (CrCl <40 mL/min) Diabetes Medications (erythropoietin, estrogen) Immobility General surgery Trauma (major or lower extremity) Blood-clotting disorders Number of Risk Factors

Prophylaxis

0-1

Aspirin 81-325 mg daily

LMWH (enoxaparin 40 mg SQ daily, or equivalent) Warfarin (INR 2-3)

BMI indicates body mass index; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SQ, subcutaneously; VTE, venous thromboembolism.

Bortezomib use can increase the risk of herpes zoster reactivation.13 Therefore, for patients being treated with RVD, we always include antiviral prophylaxis with acyclovir or another agent in its class. Similar to lenalidomide, bortezomib can also cause GI toxicities,10 which are managed with the interventions discussed earlier. What are some of the important nursing considerations related to the use of carfilzomib and pomalidomide in the relapsed/ refractory setting? When considering the use of carfilzomib for relapsed/refractory MM, the oncology team needs to ascertain whether the patient will be able to travel back and forth to the center for the necessary infusions. Fortunately, there is assistance available through nonprofit groups that help with transportation and lodging expenses for those who live far from the clinic. It is important for patients and their families to be made aware of these resources, to ensure that they have access to necessary treatment. Some of the organizations that provide useful information are Cancer Support Community (www.cancer supportcommunity.org), Chronic Disease Fund (www.cdfund.org), International Myeloma Foundation (www.myeloma.org), and Multiple Myeloma Research Foundation (www.themmrf.org). When treating patients in the relapsed/refractory setting, myelosuppression is often a concern because patients have received multiple lines of therapy. Baseline blood counts may be problematic in all cell lines as these patients may be older, are heavily pretreated, and many have been transplanted. Although carfilzomib and bortezomib are both proteasome inhibitors, their effects on complete blood cell counts are different. Bortezomib causes transient cyclical thrombocytopenia; platelet counts predictably nadir following the last dose of each cycle (day 11), then typically recover prior to the next cycle.10,14 The platelet reduction with carfilzomib is also transient and cyclical, but the nadir occurs on day 8 of treatment.15 This is important to remember, as the most significant drop in platelet count occurs after 2 doses of this drug. In some instances, a patient with relapsed disease will have bone marrow that is packed with myeloma cells. However, we may see improvement in blood counts if we can get the disease under control. For this reason, we try to forge

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ahead with carfilzomib treatment despite low counts, knowing that we can give blood products and growth factor support to help patients get through to their next cycle of therapy. Carfilzomib may cause infusion-related reactions, including myalgias, arthralgias, shaking, chills, fever, and shortness of breath.15 These typically occur 6 to 8 hours after initial exposure to the drug or after the dose is escalated for the first time, which is typically on day 1 of cycle 2. When reactions do occur, they are usually transient and dissipate within 24 hours. It is important to recognize, however, that symptoms can develop at any time, not just during the first few cycles. To lower the incidence of these infusion reactions, patients must be premedicated with dexamethasone 4 mg prior to all doses during cycle 1, prior to all doses during the first cycle of dose escalation to 27 mg/m2, and thereafter if infusion reaction symptoms occur during subsequent cycles.15 One of the advantages of pomalidomide is that it is an orally administered agent.16 This can be an attractive option for patients with relapsed or refractory MM, who have already spent a lot of time in the clinic. One of the disadvantages with an oral agent, however, is patient adherence to therapy. Once individuals leave the clinic, there is no guarantee that they are taking all of their doses as prescribed. It is important for the nursing staff to maintain regular contact with patients on pomalidomide or other oral medications, to assess how they are doing. The recommendation with pomalidomide is to perform weekly blood counts for the first 8 weeks of treatment, as one of the most common toxicities is neutropenia.16 We like to see patients very frequently during the first 2 cycles of therapy. After that, it really depends on how well they are tolerating the drug. The resources listed earlier in this article can be used to help patients who are concerned about the high out-of-pocket costs or copayments associated with pomalidomide. In some cases, patients may be eligible to receive treatment at a reduced cost or for free if they have no insurance or are underinsured. It is primarily the responsibility of the nurse, nurse navigator, or social worker to make sure that patients are aware of these and other services. ♦ References

1. Faiman B, Bilotti E, Mangan PA, Rogers K; IMF Nurse Leadership Board. Steroidassociated side effects in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):53-63. 2. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15: 469-474. 3. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):21-28. 4. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 5. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71. 6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. 7. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin prophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:983-993. 8. Miceli T, Colson K, Gavino M, Lelleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 9. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012. 10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012. 11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120. 13. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 14. Lonial S, Walter EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106:3777-3784. 15. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 16. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013.

April 2013 I VOL 6, NO 3

CONTINUING EDUCATION

Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Greg Eskinazi, RPh, MAS, BCOP

Oncology Research Pharmacist John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The development and approval of more effective drugs have led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements and to identify the needs of each patient to promote individualized care. In this article, Greg Eskinazi, RPh, MAS, BCOP, discusses new directions in the treatment of myeloma and answers questions related to the evaluation of new agents in clinical trials.

What are some of the promising investigational agents being evaluated in clinical trials at your center? We have a very robust clinical research department at the John Theurer Cancer Center, with just under 200 studies available to our patients. Approximately 70% of these studies have a pharmacy component and many of them include the treatment of MM. We were deeply entrenched in the studies leading to the recent US Food and Drug Administration (FDA) approvals of carfilzomib and pomalidomide, which are indicated for the treatment of relapsed and/or refractory MM.1,2 The approvals have afforded us the opportunity to continue the evaluation of these agents in other settings, including frontline and maintenance, and as early therapy for the management of smoldering myeloma. Our center currently has 6 open trials of carfilzomib that are accruing patients. We are also evaluating several investigational agents that have shown evidence of antimyeloma activity. MLN9708 is a selective inhibitor of chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM, respectively.3 In an upcoming phase 3 trial, patients with relapsed and/ or refractory MM will be randomized to receive lenalidomide (25 mg) on days 1 through 21, dexamethasone (40 mg) on days 1, 8, 15, and 22 every 28 days, and MLN9708 (4 mg orally) on days 1, 8, and 15; or the same dose and schedule of lenalidomide and dexamethasone plus placebo.4 The primary end point of this trial is progression-free survival (PFS), and secondary end points include overall survival (OS), rate of complete and very good partial response, duration of response, time to progression, safety profile, pain response, change in global health status, OS and PFS in the high-risk population, and pharmacokinetic data. The immunoconjugate BT062 is comprised of the anti-CD138 chimeric monoclonal antibody nBT062 and the cytotoxic agent maytansinoid DM4.5 The proposed mechanism of action of BT062 is mediated by binding to CD138-positive myeloma cells. Once the immunoconjugate is internalized into the target cell, DM4 is released from the targeting molecule, thereby restoring the original toxicity of the drug. Thus, BT062 is considered a tumor-activated prodrug because the conjugation of DM4 to nBT062 keeps the cytotoxic drug inactive until it is released within the CD138-expressing target cell. A phase 1/2a study is under way to determine dose-limiting toxicities (DLTs) and/or the maximum tolerated dose (MTD)/recommended phase 2 dose of BT062 in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory MM.6 The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase family. It

April 2013 I VOL 6, NO 3

functions as a sensor of mitogen, energy, and nutrient levels and is a central controller of cell growth.7 In a phase 1/2 study, investigators are assessing the safety and tolerability of the mTOR kinase inhibitor CC-223 when administered orally and will try to define the MTD and the nontolerated dose. They will also be determining the preliminary pharmacokinetics of CC-223 following both single and multiple oral dosing.8 What are some of the challenges related to the evaluation of novel agents in clinical trials? Depending on a patient’s condition at the time of diagnosis, the need for immediate disease control must be addressed. Patients with symptomatic disease requiring treatment may present with 1 or more of the following: hypercalcemia, renal insufficiency, anemia, and/or bone lesions (Table).9 Advances in screening procedures (ie, serum protein electrophoresis, urine protein electrophoresis, and serum free light chain assays) and diagnosis and prognostic indicators based on the Durie-Salmon staging system10 and the International Staging System11 enable us to more accurately assess patients to determine the best course of treatment. Being able to offer our patients a wide variety of approved treatments or the opportunity to take part in clinical trials allows us greater leeway in terms of options. There are, however, challenges related to treating patients in clinical trials, as outlined below. • Screening and enrollment of patients into clinical trials is a very labor intensive process. Patients must meet extremely detailed inclusion and exclusion criteria. Many times, due to advanced age and concomitant disease states, patients will not be eligible for participation. • Laboratory reports, scans, and test results must be ordered as mandated by the sponsors of the trial. In some cases, these are performed more frequently than some insurance companies deem necessary, and valuable time is spent trying to obtain permissions. • Adverse events (AEs) and admissions to the emergency department or other outside facility must be documented and reported to the appropriate agencies. Oftentimes, these admissions may be disease related and not based on the clinical treatment. Strict, detailed instructions are typically included in the protocols, including dose interruptions and/or reductions and procedures for infusion-related reactions.

Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop. • Many agents are still in the development phase and not yet commercially available. Careful attention to AEs related to these medications is imperative. Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop. • Risk Evaluation and Mitigation Strategies (REMS), often based on the FDA-regulated “Black Box warnings,” involve specialized educational aspects that patients must be aware of prior to consenting to treatment. For most agents, the REMS address fertility/pregnancy concerns, which fortunately do not affect most of our patient population but still create issues related to drug procurement. • The newest oral agents in development require strict adherence to be effective. Compliance is a concern because directions are very specific regarding the way that these drugs must be taken. To improve adherence, we encourage patients to keep diaries to help them remember when to take their medications.

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CONSIDERATIONS IN MULTIPLE MYELOMA • Transportation issues need to be addressed because many patients must be available for day-long pharmacokinetic sampling and frequent office visits. From a pharmacy perspective, we must stay informed of the differences that exist between approved and investigational agents, as well as the doses and schedules that are used outside of standard treatment regimens. Pharmacies may have multiple studies using the same investigational product at different dosages, routes of administration, and treatment schedules. Accountability concerns are addressed by separating drugs by study or by investigational versus commercial supply. Single- and double-blind studies may require the pharmacist to handle the final step in the randomization process to determine the patient’s actual treatment. The educational needs of the pharmacy and nursing staff must also be met. Study-specific educational documents derived from the protocol and investigator’s brochure are prepared for every study with specific instructions for the staff. How does the multidisciplinary team approach at your center contribute to better patient outcomes? The John Theurer Cancer Center is comprised of 14 specialized divisions, featuring teams of experts for specific types of cancer. This allows each patient to be evaluated and treated by a specialist in the field. The myeloma division is staffed by oncologists, advanced practice nurses, a research team, and support personnel that focus solely on this disease. The patient will stay with this unit throughout their treatment and will have access to the most comprehensive therapies available, including clinical trials when appropriate. If transplant is an option, appropriate strategies will be followed while patients are prepared for this procedure, at which time they will be transferred to our transplant division.

We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant. Our Blood and Marrow Transplant program has performed more than 3000 transplants since its inception. We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant. The class is taught by advanced practice nurses, staff nurses, nutritionists, pharmacists, and psychosocial workers, who are all dedicated to the education of transplant patients and their families. Toxicities must be closely monitored and handled expediently. An evidence-based guidelines tool for symptom management has been developed to promote standardized and appropriate management of several of the commonly observed AEs related to therapy. These guidelines were recently published in an issue of the Clinical Journal of Oncology Nursing.12 Our center has an onsite chemotherapy pharmacy that is open 7 days a week. It is staffed by 13 pharmacists, 4 pharmacy assistants, and 1 research pharmacist (myself). All outpatient treatments are prepared in our facility. A specialty retail pharmacy is located in the lobby to handle patients’ pre-

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Table. Diagnostic Criteria for Multiple Myeloma9 Clonal bone marrow plasma cells >10% Presence of serum and/or urinary monoclonal protein (except in cases of true nonsecretory myeloma) Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically CRAB): • Calcium elevation: serum calcium ≥11.5 mg/dL or • Renal insufficiency: serum creatinine >2 mg/dL • Anemia: hemoglobin >2 g/dL below lower limit of normal or value <10 g/dL • Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

scription needs. As a specialty pharmacy, we can provide access to many medications that are not available in most standard pharmacies. We offer consultations with our board-certified nutritional staff, and our center boasts a test kitchen in which weekly demonstrations are held to teach patients better nutritional habits. We also have an on-site meditation room and a resource library that addresses patient needs and provides literature search requests from the staff. ♦ References

1. US Food and Drug Administration announcements. FDA approves Kyprolis® (carfilzomib) for some patients with multiple myeloma. July 20, 2012. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm312920.htm. 2. US Food and Drug Administration announcements. FDA approves Pomalyst® (pomalidomide) for advanced myeloma. February 8, 2013. http://www.fda.gov/Drugs/Information OnDrugs/ApprovedDrugs/ucm339286.htm. 3. Ocio EM, Mateos MV, San-Miguel JF. Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs. 2012;21:1075-1087. 4. ClinicalTrials.gov. A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients with Relapsed and/or Refractory Multiple Myeloma. http://clinicaltrials.gov/ct2/show/NCT01564537. 5. Ikeda H, Hideshima T, Fulciniti M, et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028-4037. 6. ClinicalTrials.gov. A Phase I/IIa Multi-dose Escalation Study of BT062 in Combination With Lenalidomide and Dexamethasone in Subjects with Relapsed or Relapsed/refractory Multiple Myeloma. http://www.clinicaltrials.gov/ct2/show/NCT01638936. 7. Keen H, Ricketts S-A, Bales J, et al. The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG. Mol Cancer Ther. 2009;8(suppl 1):Abstract A225. 8. ClinicalTrials.gov. A Phase 1/2, Multi-center Open Label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTOR Kinase Inhibitor CC-223 Administered Orally to Subjects with Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Multiple Myeloma. http://clinicaltrials.gov/show/ NCT01177397. 9. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757. 10. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842-854. 11. Griepp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420. 12. Weber MS, Eskinazi G. The development of evidence-based supportive therapy guidelines for symptom management. Clin J Oncol Nurs. 2012;16:343-345.

April 2013 I VOL 6, NO 3

The Whole Patient

Issues of Self-Image, Disfigurement, and Sadness in People Living With Cancer Carolyn Messner, DSW, LCSW-R, Director of Education and Training, CancerCare; Tatiana Vera, Prep for Prep—Prep 9, Sophomore, Barnard College; Christin Washington, Prep for Prep 9, Loomis Chaffee ’13; Imani Doyle, Prep for Prep, Poly Prep Country Day School ’13; Sarah Quinlan, BA, Education Technical Coordinator, CancerCare; Alicia Wong, BBA, Consultant, CancerCare; Dawn Zador, Senior Education Program Manager, CancerCare

Carolyn Messner, DSW, LCSW-R

Tatiana Vera

“I spent five years of my life being treated for cancer, but since then I’ve spent fifteen years being treated for nothing other than looking different than anyone else. It was the pain from that, from feeling ugly that I always viewed as the great tragedy of my life. The fact that I had cancer seemed minor in comparison.”1 —Lucy Grealy, 2003, Autobiography of a Face

his article will address the psychosocial impact of the perception of disfigurement as a result of treatment for cancer. Our intent is to provide the context, guidelines, and recommended interventions for oncology nurses to consider when treating patients whose surgeries leave disfiguring scars. By providing this guidance, we hope to help nurses both ameliorate their patients’ suffering and help them achieve their “new normal.” Issues related to self-image, disfigurement, and sadness continue to gain importance as the number of newly diagnosed cancer patients increases and survival rates improve.2,3 Oncology health professionals may not always realize that, in spite of a favorable prognosis, many patients experience significant levels of anxiety, sadness, and depression long after their diagnosis.4 What might be considered a routine treatment or workup by the oncology healthcare team may be a traumatic and frightening experience for the patient. It is essential that treatment plans include a comprehensive assessment of patients’ biopsychosocial distress and a well-thought-out protocol for intervention and care.5 Anxiety, Depression, and Self-Esteem Anxiety during and after cancer treatment is normal. For some it is a constructive part of their coping process. However, anxiety may continue long after treatment ends and become a major disruptor in a survivor’s life, lead-

April 2013 I VOL 6, NO 3

Christin Washington

Imani Doyle

ing to depression and loss of self-esteem.6 Survivors often struggle with feelings of being “damaged goods,” flawed, or defective for years after treatment. Some may try to hide their personal feelings about their cancer experience from their family, spouses, partners, and close friends. Rediscovering a whole and worthy sense of self is difficult and takes time.7 Many surgeries leave visible scars for patients. Consider the short-term and long-term impact of the following: mastectomy, colostomy, hysterectomy, prostatectomy, head and neck surgery, and amputation. In addition, patients experience hair loss or excessive hair growth, weight changes, hot flashes or hot flushes, incontinence, impotence, loss of libido, fatigue, neuropathy, and chemobrain due to treatment side effects. These contribute to a changed or altered sense of self and body image.

Sarah Quinlan, BA

Alicia Wong, BBA

of anxiety, fear, sadness, insomnia, and depression after a diagnosis.4 Many cancer centers now routinely screen for sadness, distress, anxiety, and depression.8 Although some adjuvant therapies may enhance control of the primary tumor, thereby increasing quality of life and survival, the patient’s experience with these therapies may vary due to increased time in the hospital, doctor visits, side effects, loss of wages, decreased energy or time for social activities, recuperation time, and added stress on family and friends. Monitoring a patient’s self-esteem and sense of well-being, as well as screening for distress while preserving physiologic functioning, provides the best possible quality of life for patients. Disfigurement We live in a society that is consumed by

Patients interpret their feelings of well-being through the filter of their own expectations, perceptions, experience, and religious, cultural, and/or community beliefs. Quality of Life Quality of life refers to the psychosocial, emotional, and physical outcomes of cancer treatments. It is constantly susceptible to variation—highs and lows. Patients interpret their feelings of well-being through the filter of their own expectations, perceptions, experience, and religious, cultural, and/or community beliefs. It is not possible to make assessments about a patient’s quality of life without speaking with the person directly, as it is the patient’s own perception and life experience that informs his/her quality of life. Clinicians may not always realize that, in spite of a favorable prognosis, many patients experience high levels

the ideal image of beauty. Attractive individuals have been known to receive preferential treatment in healthcare, academia, and when seeking employment or career progression. There are few positive role models of disfigured people in the media. Social norms change when a person looks, smells, or sounds different. Patients may feel highly visible—people stare. Strangers feel they have permission to comment and ask questions about their appearance. A person with a disfigurement may feel uncertain of what to expect from others or what to say in response. Many feel they are on display all the time and have to main-

Dawn Zador

tain a constant vigilance, which results in increased self-consciousness. Some will feel alone and isolated. Others may restrict their social activities or believe they cannot have intimate relationships.9 They often express feelings of anger, unfairness, embarrassment, and a need to be fixed. Sometimes there is a lack of communication with family and friends. Patients also endure social pressure associated with their changed or disfigured appearance. These physical changes can affect psychosocial functioning, leading to low self-esteem, depression, somatization, withdrawal, and social distress. A visible disfigurement impacts not only the thoughts, feelings, and behaviors of the patient or survivor, but also how they are perceived and treated by others.10 Other Factors to Consider “What changed…was other people’s perceptions of me. …Everyone…regarded me as someone who had been altered irrevocably. …I had become special, no longer like them. Their genuine concern for what had happened to me and their complete separateness from it expressed exactly what I had felt all my life about anyone I had ever known who had experienced tragedy.”11 —Alice Stewart Trillin, 1981, “Of Dragons and Garden Peas—A Cancer Patient Talks to Doctors,” New England Journal of Medicine

Alice Trillin poignantly describes how the diagnosis of cancer exquisitely changed others’ and her self-perception. How patients feel they are perceived, as well as social factors (both positive and negative) that they experience throughout life, may affect their body image, and a negative body image and low self-esteem have a major impact on feelings of depression and quality of life. Communication is important for many in resuming intimacy after cancer. Patients and survivors often benefit Continued on page 24

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much? John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future? Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015? Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery. • Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered. • Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively. • Examine the current trends in personalized care and companion diagnostics. • Analyze the patient issues around cost, quality, and access to care.

TARGET AUDIENCE

SPONSORS

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

SATURDAY, MAY 4, 2013

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

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The Whole Patient

Issues of Self-Image, Disfigurement, and Sadness... Continued from page 22 from seeking professional counseling to delivering their care, helps patients feel cope. Oncology nurses play a key role in less stigmatized and more accepted. The helping patients, initially by helping them expertise and compassion of a skilled view disfiguring surgery in the security oncology nurse speaks volumes to patients and comfort of a cancer center, coupled dealing with disfiguring surgery, and their with compassionate and practical instruc- caring acceptance of the patient creates a tion to patients and caregivers on wound spark of hope for those in despair of being and ostomy care.12 The oncology nurseâ&#x20AC;&#x2122;s abandoned by others. willingness to care for these patients, The location of the disfigurement or Bendamustine Asize_030413_TON0210 3/13/13 4:34 PM Page 2 to talk with them and touch them in scar plays a role in the patientâ&#x20AC;&#x2122;s risk for

psychosocial distress: visible scars on the face, hands, arms, and legs as opposed to scars on the body, which are more easily camouflaged. However, hidden disfigurements and scars may be as distressing as visible ones, as patients may be concerned about concealment and inadvertent exposure of their disfigurement. Body image may be associated with the type and location of cancer, treatment

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Faculty Perspectives

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Body Image Information MD Anderson Cancer Center Body Image Therapy Service http://www2.mdanderson.org/ cancerwise/2011/05/qa-body-imagetherapy-service.html

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side effects, cancer recurrence, frequency of hospital and doctor visits, and the treatment course.10 Ethnicity, race, socioeconomic status, age, and gender may all play a crucial role in how one recovers from a cancer-causing disfigurement. Every culture is different in how it perceives disfigurements. Also, individual characteristics such as optimism, extroversion, athleticism, and a repertoire of coping skills may facilitate better adjustment and coping throughout treatment and posttreatment survivorship. Stage in the life cycle is critically important to keep in mind in assessing the impact of cancer and disfigurement. Much attention has been paid recently to adolescents and

General Cancer Information American Cancer Society www.cancer.org American Psychosocial Oncology Society www.apos-society.org American Society of Clinical Oncology www.cancer.net CancerCare www.cancercare.org Cancer Support Community www.cancersupportcommunity.org Caregiver Action Network www.caregiveractionnetwork.org

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April 2013 I VOL 6, NO 3

National Coalition for Cancer Survivorship www.canceradvocacy.org

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The Whole Patient young adults with cancer and how best to assist them, including “peer support and technology-based interventions.”13 Appearance concerns have been associated with decreased quality of life, anxiety, and depressive symptoms. These symptoms require assessment and intervention by the healthcare team, which can be individual, group, or community-based supportive interventions. Professionally led support groups in the community help cancer survivors with self-esteem and disfigurement issues bond with others to feel more connected with a cohesive network. Individual, group, and community-level interventions such as counseling and awareness programs in cancer centers are important psychosocial interventions. Adjustment is an ongoing process, unique to each person, and close surveillance, distress screening, and follow-up visits are important, since the needs of patients and survivors change over time. With the aid of educational workshops, booklets, and fact sheets, patients can learn creative problem-solving techniques to help them cope with their cancer trajectory and its particular challenges.14 The Role of the Healthcare Team Diminished contact with the healthcare team posttreatment is perceived as a loss to patients who believe that the care provided contained or cured their cancer. This perceived abandonment by the healthcare team may cause patients to feel more vulnerable and anxious. It also severs what seems like the last tie to a group that understands the patient/survivor’s feelings. Survivors may become impatient, frustrated, and isolated, and feel alone when they are unable to find people who can relate to their story. The healthcare team may be able to provide assurance that these feelings are normal; they can also refer the patient to an oncology nurse or social worker to address the distress that is being expressed or to a community-based or national nonprofit organization for psychosocial support.7 Many patients benefit from participation in 1-hour teleconference workshops, webcasts, and podcasts that do not require travel time or costs. These virtual programs, coupled with telephone and online supportive interventions, provide a community of support for patients and survivors.15 Many cancer survivors become lost in transition and receive inadequate and poorly coordinated follow-up care.16 The reasons for this failure are many and include the tendency of the oncology team to underestimate the distress felt by patients and therefore not provide them with appropriate or adequate resources.8 To ensure the most efficient way to deliver psychosocial services, the following guidelines

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Care for Nurses Oncology nurses must also be diligent in their own self-care, as their work involves both risks and rewards. Team meetings, in-service training, ongoing professional skill-building seminars and courses, career progression, vacation time, health-promoting behaviors, time with loved ones and friends, hobbies, and joyous moments all enable oncology nurses to stay the course over the long haul with these patients, to witness their struggles, and to evoke an empathic stance in working with this population.

are recommended: identify psychosocial needs; refer patients to needed services; support patients and families in managing cancer and survivorship; coordinate their care; and schedule follow-up psychosocial care to support their ongoing functioning.5,16 It is critically important that the healthcare team take note of the psychological and social aspects of their patients,5,17 as these are key life components that impact daily quality of life. As additional resources and support are made available to survivors, their emotional and psychological well-being may be enhanced to facilitate finding their “new normal.”

Survivors may become impatient, frustrated, and isolated, and feel alone when they are unable to find people who can relate to their story.

For example, MD Anderson Cancer Center recently launched The Body Image Therapy Service, which provides support and counseling to patients experiencing distress about changes to their body image. This service is available to patients being seen in the Center for Reconstructive Surgery and Head and Neck Center. The Body Image Therapy Service program offers a multidisciplinary coordinated service for patients to discuss their body image concerns and how these are impacting their daily life. Michelle Cororve Fingeret, PhD, a clinical psychologist and body image specialist in the program, works with patients individually to teach coping strategies “to promote body image acceptance, focus on ways to increase self-confidence in social situations, discuss treatment decisions they need to make that will affect their bodies, set realistic

expectations for body and appearancerelated changes and communicate more effectively with others about appearance and body changes.”10 How Nurses Make a Difference When a person is diagnosed with cancer, the oncology healthcare team will be involved in the medical and psychosocial management of the cancer patient. The team includes oncology medical specialists, oncology nurses, oncology social workers, reconstructive and plastic surgeons, rehabilitation specialists, pain and palliative care teams, speech and swallowing clinicians, dermatologists, and dietitians.

Using a biopsychosocial approach, oncology nurses help patients address their medical questions, pain, and sadness. Patients and their caregivers can talk with oncology nurses about their concerns and worries and receive practical guidance in their management of cancer treatments, surgeries, side effects, and pain. These practical and informative conversations with oncology nurses provide physical support while being a beacon of hope, not only for patients but for their caregivers as well. Nurses can help patients normalize the appearance-related changes that can occur during and after cancer treatment. By providing an objective view of how an affected area appears, including offering a mirror to patients during the initial dressing change and discussing how the patient is feeling, nurses can help patients open up to different possibilities in their way of thinking about how to cope with their disfigurement, both practically, psychologically, and spiritually.12 There are many steps the oncology nurse can take to help patients achieve a positive body image, including discussing with patients what they can Continued on page 26

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We’re interested in articles about the everyday issues that affect nurses—everything from chemotherapy safe handling to supportive care for patients to challenging cases.

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The Whole Patient

Issues of Self-Image, Disfigurement, and Sadness... Continued from page 25 do—their strengths—and what they are not able to do; helping patients access reconstructive and rehabilitative teams to help them cope with the challenges imposed by surgery or treatment; discussing the special attributes they value in themselves; and referring patients to support groups and individual counseling and guidance.10,15

These practical and informative conversations with oncology nurses provide physical support while being a beacon of hope, not only for patients but for their caregivers as well.

Posttraumatic Growth After Cancer Posttraumatic stress is defined by feel- ly experiencing struggles with their ings of anxiety and fear following a trauma. Nevertheless, some patients frightening or life-threatening expe- and survivors are able to “create rience, such as receiving a cancer meaning through their experiences diagnosis and undergoing treatment. with cancer.”19 Posttraumatic growth is by no means However, for some, this experience promotes the potential for transforma- universal. Research suggests there are tive change. Posttraumatic growth is certain factors that make patients “positive psychological change experi- more likely to experience transformaenced as the result of struggle with high- tive growth. These include participaly challenging life circumstances.”18 The tion in professionally facilitated support lessons learned through the process of groups, ability to confront trauma and coping with a challenging situation may focus on new experiences, and access translate into personal growth that to a support network that encourages may be expressed in a number of ways: personal growth and individual coping • Improved interpersonal relation- strategies that help patients adapt to ships new challenges.20 Although patients may have visi• New life experiences and career ble and invisible scars from their canchoices cer treatment, there are many clinical • A greater appreciation for life • A sense of personal strength and interventions to help patients and their loved ones cope. Body image therapy endurance can be extremely beneficial in restruc• Spiritual development It should be noted that experienc- turing distorted thoughts and/or beliefs ing transformative growth does not about a patient’s appearance. Behavioral necessarily mean that the patient/ strategies may promote positive selfsurvivor has overcome the stressor. In care activities and decrease avoidance/ WCMC_2013Conf_horizontalV382012_Layout 1 8/20/12 9:44 AM social Page skills 1 In addition, may be fact, most people who report person- distress. al growth also report simultaneous- taught using role-play so that patients

learn how to deal with their disfigurement in social encounters. Body image therapy also educates the patient about the particular disfigurement and its treatment options, thus allowing patients to know about treatment choices and learn decision-making skills.10 Conclusion: Lessons Learned “Illness is the night-shade of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.”21 —Susan Sontag, 1978, Illness as Metaphor

The oncology nurse is strategically positioned to make a major difference in patient care and contribute to the lives of both patients and caregivers. Because they are at the patients’ bedside right after surgery as well as there to care for them during the course of treatment and survivorship, oncology nurses gradually, day-by-day, intro-

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April 2013 I VOL 6, NO 3

duce patients to other members of the healthcare team. The oncology nurse is well versed in the unfairness of life, cancer, and its random quality. The compassion and expertise of oncology nurses can help relieve the stigma, despair, suffering, and aloneness that patients feel, and the empathy, acceptance, and skilled care they provide to patients living with disfigurement, as well as the debilitating side effects of treatment, are a lifeline of hope for those whose world has been forever changed. l References

1. Grealy L. Autobiography of a Face. New York, NY: Harper Perennial; 2003. 2. Alfano C, Rowland J. Recovery issues in cancer survivorship: a new challenge for supportive care. Cancer J. 2006;12(5):432-443. 3. Spiegel D. Mind matters in cancer survival. JAMA. 2011;305(5):502-503. 4. Korfage IJ, Essink-Bot ML, Janssens AC, et al. Anxiety and depression after prostate cancer diagnosis and treatment: 5-year follow-up. Br J Cancer. 2006;94(8):1093-1098. 5. Institute of Medicine (US) Committee on Psychosocial Services to Cancer Patients/Families in Community Setting; Adler NE, Page AEK, eds. Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. Washington, DC: National Academies Press (US); 2008. http://www.nap.edu/openbook.php?record_id= 11993&page=1. Accessed March 21, 2013. 6. Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer. 2008;112(11 suppl):2577-2592. 7. Auchincloss SS. After treatment: psychosocial issues in gynecologic cancer survivorship. Cancer. 1995;76(10 suppl):2117-2124. 8. Mitchell AJ, Vahabzadeh A, Magruder K. Screening for distress and depression in cancer settings: 10 lessons from 40 years of primary-care research. Psychooncology. 2011;20(6):572-584. 9. Hordern AJ, Street AF. Constructions of sexuality and intimacy after cancer: patient and health professional perspectives. Soc Sci Med. 2007;64(8):17041718. 10. Fingeret MC. Coping with body image changes. News From SPOHNC. 2011;20(6):1-3. 11. Trillin AS. Of dragons and garden peas: a cancer patient talks to doctors. N Engl J Med. 1981; 304(12):699-701. 12. Freysteinson WM, Deutsch AS, Lewis C, et al. The experience of viewing oneself in the mirror after a mastectomy. Oncol Nurs Forum. 2012;39(4):361-369. 13. Zebrack B, Isaacson S. Psychosocial care of adolescent and young adult patients with cancer and survivors. J Clin Oncol. 2012;30(11):1221-1226. 14. Bucher J, Zabora J. Building problem-solving skills through COPE education of family caregivers. In: Holland JC, Breitbart WS, Jacobsen PB, et al, eds. Psycho-Oncology. 2nd ed. New York, NY: Oxford University Press; 2010:469-472. 15. Messner C. Resources for cancer patients. In: Carr B, Steel J, eds. Psychological Aspects of Cancer. New York, NY: Springer; 2013:chap 42. 16. Jacobsen PB. Clinical practice guidelines for the psychosocial care of cancer survivors. Cancer. 2009;115(18 suppl):4419-4429. 17. Miller HH. Collaborative care plans for post treatment cancer survivors. Oncology Nurse Advisor. October 2010:45-46. media.oncologynurseadvisor. com/documents/16/ona_cancercare1010_c_3849.pdf. Accessed March 17, 2013. 18. Tedeschi RG, Calhoun LG. Posttraumatic growth: conceptual foundations and empirical evidence. Psychological Inquiry. 2004;15(1):1-18. 19. Park CL. Positive psychology perspectives across the cancer continuum: meaning, spirituality, and growth. In: Carr BI, Steel J, eds. Psychological Aspects of Cancer. New York, NY: Springer; 2013:chap 7. 20. Kissane DW. Survival following psychotherapy interventions. In: Holland JC, Breitbart WS, Jacobsen PB, et al, eds. Psycho-Oncology. 2nd ed. New York, NY: Oxford University Press; 2010:479-482. 21. Sontag S. Illness as Metaphor. New York, NY: Farrar, Straus & Giroux; 1978.

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Genetic Counseling

2013 NCCN Guidelines Mention Gene Panels By Cristi Radford, MS, CGC Sarasota, Florida

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cancers were updated.1 Among the updates is a section on “gene panels.” Gene panels allow multiple genes to be analyzed simultaneously for mutations,

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at a cost that is often comparable to testing for a single inherited condition. In the case of cancer risk assessment, gene panels contain genes associated with an increased risk of developing cancer. For example, the panel may be targeted for a particular disease type, such as one containing a multitude of genes that are all associated with a high risk of colon cancer, or it may be targeted for several disease types, such as breast cancer, colon cancer, and ovarian cancer. Further, each laboratory selects which genes are included on their panels; thus, it cannot be assumed that a “colon panel” or a “breast panel” at various laboratories will include the same genes. Genes included on breast/ovarian panels include ATM, BARD1, BRIP, CDH1, CHEK1, CHEK2, MLH1, MSH2, MSH6, MUTYH, MRE11A, NPN, PALB2, PMS2, PTEN, RAD50, RAD51B, RAD51C, RAD51D, STK11, and TP53.1

Gene panels allow multiple genes to be analyzed simultaneously for mutations, at a cost that is often comparable to testing for a single inherited condition.

One premise behind cancer panels is reflected in the statement “individually rare, collectively common.” This concept is best illustrated by a study conducted by Walsh and colleagues,2 in which 360 women with primary ovarian, peritoneal, or fallopian tube carcinoma were screened for mutations in 21 genes. Participants were not selected on the basis of age or family history. Approximately 1 in 4 women (82/360, 24%) were found to carry a germline, loss-of-function mutation. Mutations in BRCA1/2 accounted for 18% of the mutations, while mutations in 10 other genes accounted for the remaining 6%. Thus, although the non-BRCA mutations could be considered individually rare, ranging from 0.03% to 1.4%, the chance of carrying a mutation became more common when they were analyzed collectively. Additionally, gene panels are also providing more insight into the pheno-

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Genetic Counseling types of hereditary cancer syndromes. Gene panels allow a clinician to cast a wider net and analyze genes that may have been low on their differentials list or not on it at all. This was also demonstrated in the study by Walsh and colleagues, where of the 3 individuals found to have a mutation in TP53, which is associated with Li-Fraumeni syndrome, none actually met the testing criteria for Li-Fraumeni syndrome. Additionally, whereas only 2 individuals were found to have germline mutations associated with Lynch syndrome and both mutations were in MSH6, neither of these individuals had a family history of Lynch syndrome. Furthermore, if genetic testing had relied on an age less than 60 years, 30 individuals (>35%) with germline mutations would have been missed. To further understand the applications of gene panels, consider Marie’s family history. Marie reports being recently diagnosed with invasive lobular breast cancer at age 34. She has one brother, aged 38, who has a daughter, aged 12. Her mother, aged 67, has a large family with no reported cancers. Her father, aged 68, has no siblings. His father (Marie’s paternal grandfather) died at age 85 from complications of a stroke. His mother (Marie’s paternal grandmother) died from cancer at age 44; the type of cancer is unknown, but the family believes it was “stomach or abdominal.” Additionally, Marie has a history of a thyroid nodule and reports a history of skin biopsies that “weren’t melanoma.” Based on reported information, your differentials may include BRCA1/2, TP53, and CDH1.1 Additionally, depending on the skin findings and/or your degree of suspicion, you may also be interested in testing for PTEN and moderate penetrance breast cancer genes. Prior to the development of next-generation sequencing technologies, testing all of these genes would most likely have been cost and time prohibitive. However, with the advent of gene panels, a clinician now has the option of testing for BRCA1/2 mutations and then proceeding with a gene panel for other breast cancer genes. Currently, due to restrictive patents, BRCA1/2 is not clinically available on a gene panel. As a result of the new technology, researchers and clinicians are beginning to see a shift in how inherited cancer is investigated and diagnosed. Gene panels provide the following benefits: (1) simultaneously testing multiple genes can be more time- and cost-effective; (2) when clinical criteria are uncertain or multiple differentials are present, gene panels can aid in clinical diagnosis; and (3) as many high-risk patients are negative for BRCA1/2 mutations, gene panels provide an expanded method of screening for less common mutations.

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However, as with any new technology, there are also limitations, including a higher chance of obtaining a variant of uncertain significance (VUS) result or finding a mutation in a gene with undefined cancer risks and/or medical management guidelines. Listed below are a number of issues a provider should consider when developing a genetic testing strategy:

Laboratory and Gene Analysis Considerations • Does the panel of interest contain all of the genes in your differential diagnosis? • What is the turnaround time (TAT) for the test? n If you were to order an analysis of each gene individually rather than as part of a panel,

would the TAT be longer or shorter? • What is the out-of-pocket cost for the patient? n If you were to order an analysis of each gene individually rather than as part of a panel, would the expense be more or less? Continued on page 30

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Genetic Counseling

2013 NCCN Guidelines Mention Gene Panels Continued from page 29 â&#x20AC;˘ Can you find out the cost to your patient before the test is performed? Does the laboratory stand by its quote? â&#x20AC;˘ What findings are reported (for example, polymorphisms, muta-

tions, and/or variants of uncertain significance)? Are all findings confirmed and how? â&#x20AC;˘ How often is the result â&#x20AC;&#x153;VUSâ&#x20AC;? reported? What is the laboratoryâ&#x20AC;&#x2122;s experience interpreting VUS

results? How often do they reclassify VUS results? What is the notification process? Are their internal studies available to your patient to help reclassify a VUS? Does the laboratory provide you with

GBC2013Asize20813_Layout 1 2/8/13 11:12 AM Page 1

ANNUAL CONFERENCE

"! ! !

! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

* 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges â&#x20AC;˘ Closing Remarks

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

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April 2013 I VOL 6, NO 3

Take-Home Messages â&#x20AC;˘ Gene panels allow a clinician to cast a wider net. This can be useful when syndromes have overlapping phenotypes, family history is uncertain, or there are multiple genes in your differential diagnosis. â&#x20AC;˘ Although gene panels appear promising, limitations include a higher chance of receiving a VUS result and the possibility of finding a mutation in a gene with cancer risks that arenâ&#x20AC;&#x2122;t well defined. l References

PMPMERSONALIZED EDICINE IN ONCOLOGY O

Counseling Considerations â&#x20AC;˘ As multiple genes are analyzed at the same time, what is your pre- and posttest genetic counseling strategy? â&#x20AC;˘ How would the test result impact your patientâ&#x20AC;&#x2122;s medical management? â&#x20AC;˘ How crucial is TAT in medical management decision making for the patient? â&#x20AC;˘ Do you know of available research studies/cancer registries to help further delineate the risks associated with various genes? â&#x20AC;˘ The level of risk conveyed with a particular gene may not be well defined and therefore guidelines on risk management may not be available. How would you counsel an individual who receives a positive, negative, or VUS result? How would you counsel his or her family members? â&#x20AC;˘ Does the mutation track with the cancers in the family?

The level of risk conveyed with a particular gene may not be well defined and therefore guidelines on risk management may not be available.

7:00 am - 8:00 am

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

resources to help you determine the functional significance of the VUS? â&#x20AC;˘ What regions of the genes are analyzed? Is rearrangement analysis performed?

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2013. http://www.nccn.org/professionals/physician_ gls/recently_updated.asp. Accessed March 12, 2013. 2. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037.

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Side Effects Management

New Developments in the Management... Continued from cover erythema are most typically localized to areas of pressure or friction, such as the heel and forefoot. The National Cancer Institute has classified the clinical manifestations by grades, ranging from 1 to 3. Grade 1 is characterized by minimal skin changes and dermatitis without pain; grade 2 presents with some skin changes and pain; and grade 3 is characterized by pain, severe skin changes such as blistering and/or desquamation, and an inability to undertake adequate self-care activities of daily living (ADL).1 Along with agents that are known to cause HFSR, such as liposomal doxorubicin and capecitabine, newer molecularly targeted oral anti–vascular endothelial growth factor receptor (VEGFr) tyrosine kinase inhibitor (TKI)-targeted therapies used in several cancers also have been found to cause HFSR. The syndrome begins within the first 2 to 4 weeks of therapy with TKIs, presenting with tender blisters, redness, and swelling, which can progress to thickened and painful lesions that may interfere with ADL such as walking or bathing.2-4 Although oral VEGFr-TKI agents are convenient to administer and generally well tolerated, with the most common adverse effects being diarrhea, rash, fatigue, and hypertension, the rates of HFSR can be significant. The incidence of HFSR syndrome with sorafenib, sunitinib, pazopanib, axitinib, vandetanib, cabozantinib, and regorafenib, and approved indications for their use, are shown in Table 1.3-7 The management of HFSR syndrome caused by these agents has only recently been studied. The mechanism of action in HFSR is yet unknown, although some researchers propose that it is distinct from other agents, such as decreased repair mechanisms by endothelial cells to the vasculature after trauma to high-pressure areas such as the palms and soles. Moreover, because most of these agents are multitargeted and affect several receptor TKIs, the HFSR mechanism may be related to other repair functions, such as platelet-derived growth factor receptor. Of note, the intravenous monoclonal antibody inhibitor of VEGF, bevacizumab, does not cause HFSR. HFSR with VEGFr TKIs does not predict drug efficacy, as has been shown with the acne-like skin rash caused by epidermal growth factor receptor inhibitors.2-4 Interest in the prevention and treatment of HFSR syndrome is on the rise, as these therapies have become standards of care for advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer. Prompt recognition and treatment will mini-

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Joanna Schwartz, PharmD, BCOP

Shannon Hogan, PharmD

mize the impact on patients’ quality of life and may prevent unnecessary treatment interruptions or dose reductions.

who were receiving their first cycle of capecitabine 2000 or 2500 mg/m2 daily for 14 days. Patients received either a urea/lactic acid–based topical keratolytic agent or a placebo cream, applied twice daily for 21 days after the start of capecitabine therapy. The study found no signif-

Trials of HFSR Prevention and Treatment Several recent trials have been published on the topic of HFSR, but with

Although oral VEGFr-TKI agents are convenient to administer and generally well tolerated, with the most common adverse effects being diarrhea, rash, fatigue, and hypertension, the rates of HFSR can be significant.

a number of limitations, notably that the majority of current studies explored HFSR caused by capecitabine; VEGFr TKIs were not included in several of these trials. A study by Zhang and colleagues suggested the use of celecoxib to prevent HFSR in patients receiving capecitabine for colorectal cancer.8 The study concluded that celecoxib was beneficial for preventing HFSR in these patients; however, among other limitations, the recent warnings surrounding celecoxib’s cardiac adverse-event profile limits the generalizability of these results.9 Kang and colleagues assessed the benefit of pyridoxine for the prevention of capecitabine-induced HFSR.10 The patients in this study, who were chemotherapy naive and being treated with a capecitabine-containing regimen, were randomized to receive 200 mg of pyridoxine or placebo daily. Pyridoxine was not found to be an effective prophylactic therapy for HFSR caused by capecitabine. Wolf and colleagues evaluated a urea/ lactic acid–based topical keratolytic agent in capecitabine-induced HFSR.11 This randomized, double-blind, phase 3 trial was conducted with 137 patients

icant difference in the percentage of patients with moderate or severe HFSR between the 2 arms (P = .768); therefore, this cream with lactic acid should not be recommended.

While the previously mentioned studies have investigated prophylactic treatments for capecitabine-induced HFSR, few so far have investigated treatment and prevention in the oral anti–VEGF-TKI population, perhaps owing to the more recent approval dates of these therapies. One such study was conducted using a Chinese herbal extract that is not available from community pharmacies in the United States and did not have statistically significant results; thus, this study was not included in the present review.12 A randomized, prospective, openlabel trial in Japan plans to enroll 100 patients receiving sorafenib 400 mg twice daily to determine the usefulness of high-slip skin care pads (Remois pads) in controlling pain and preventing skin damage in patients with HFSR. The study is comparing a high-slip skin care pad, changed every 2 to 3 days, with 10% urea cream, used 2 to 3 times a day. Progress will be monitored every 2 to 4 weeks, and the primary end point is the incidence of grade 2 or 3 HFSR during therapy. As of the 2011 abstract publication, 19 patients had been enrolled in the study. No results are currently available.13 The only other study on the subject of HFSR caused by VEGFr TKIs was presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). The large randomized study by Zhenggang and colleagues introduces a promising new treatment using a topical lowcost, over-the-counter (OTC) cream, Continued on page 32

Table 1 Rates of HFSR Oral AntiVEGFr TKI

FDA-Approved Indications

All Grades Grades 3-4 HFSR (%) Severe HFSR (%)

Sorafenib

Renal cell carcinoma, hepatocellular carcinoma

Sunitinib

Renal cell carcinoma, GIST, PNET

Pazopanib

Renal cell carcinoma, advanced soft-tissue sarcoma

Axitinib

Renal cell carcinoma

Vandetanib

Advanced medullary thyroid cancer

Cabozantinib

Advanced medullary thyroid cancer

Regorafenib

Metastatic colon cancer, GIST

Abbreviations: FDA, US Food and Drug Administration; HFSR, hand-foot skin reaction; GIST, gastrointestinal stromal tumor; PNET, pancreatic neuroendocrine tumor; TKI, tyrosine kinase inhibitor; VEGFr, vascular endothelial growth factor receptor.

April 2013 I VOL 6, NO 3

Side Effects Management

New Developments in the Management... Continued from page 31 with a low risk of either systemic adverse effects or possible interactions with any chemotherapy agent.14 The prospective phase 3 study compared the prophylactic effect of urea-based cream, specifically Eucerin Intensive Repair

Extra-Enriched Foot Crème (10% urea; Beiersdorf AG), and best supportive care. The study followed up patients taking sorafenib 800 mg daily for advanced hepatocellular carcinoma; 868 patients with similar baseline characteristics were

Figure Currently Recommended Treatments Therapy Initiation -No HFSR (grade 0)

Maintain consistent communication with practitioner to diagnose HFSR early Proactive self-care: full-body skin exam, wear thick cotton gloves/ socks; avoid hot water, constrictive footwear, and unnecessary friction If symptoms develop within the first month, continue to the next step

Grade 1 -Numbness, tingling, dysesthesia, paresthesia, painless swelling, erythema, discomfort of hands or feet, no interference in ADL

Grade 2 -Painful erythema, swelling of hands/feet, interference in ADL

Grade 3 -Moist desquamation, ulceration, blistering, severe pain of hands/feet, patient unable to perform ADL

Continue current dose of TKI; watch for changes in severity Continue with self-care as above, use moisturizing creams and 20%-40% urea creams for relief If symptoms worsen after 2-week evaluation, continue to the next step

Reduce the dose of the TKI by 50% for 1-4 weeks Treat as grade 1 with the subsequent additions: clobetasol 0.05% ointment, 2% lidocaine, and codeine and pregabalin as necessary for pain

Discontinue treatment for 1 week until toxicity improves to grade 0 or 1 Continue treating toxicity as before in grades 1 and 2

Abbreviations: ADL, activities of daily living; HFSR, hand-foot skin reaction; TKI, tyrosine kinase inhibitor.

Table 2 Urea-Containing Creams and Lotions Brand

Ingredients

Eucerin (Beiersdorf AG, Hamburg, Germany) Intensive Repair – Very Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Professional Repair – Extremely Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Smoothing Repair – Dry Skin Lotion*

Urea 5%

Eucerin (Beiersdorf AG, Hamburg, Germany) Urea 5%/Lactic Acid 2.5% Intensive Repair – Extra-Enriched Hand Crème* Eucerin (Beiersdorf AG, Hamburg, Germany) Intensive Repair – Extra-Enriched Foot Crème*

Urea/Lactic Acid

Udderly Smooth (Redex Industries, Salem, Ohio) Extra Care with 10% Urea for Dry Skin

Urea 10%

Lespain Spray (DTR Dermal Therapy Research Inc., London, Ontario)

Urea 10%/Lidocaine 4%

Carmol 40 Cream (Groupe Parima Inc., Montreal, Quebec)

Urea 40%

Nutraplus Lotion (Galderma Laboratories LP, Fort Worth, Texas)

Urea 10%

* Generic may be available, ask your pharmacist to help select the correct product.

enrolled. Patients in arm A received urea-based cream twice a day starting on day 1 and continuing for up to 12 weeks, while those in arm B received best supportive care based on the practitioner’s preference, excluding urea-based creams. A significantly lower incidence of HFSRs of all grades was observed in arm A compared with arm B (P <.0001). Furthermore, there was a trend toward a lower incidence of grade ≥2 HFSR in arm A compared with arm B, but it did not reach statistical significance (P = .1638). The findings of this study indicate that urea-based creams may be effective in preventing HFSR caused by sorafenib and could be applicable to other related oral VEGF TKIs. One limitation is that the study results have not yet been published in a peer-reviewed journal.

April 2013 I VOL 6, NO 3

The findings...indicate urea-based creams may be effective in preventing HFSR caused by sorafenib.

Treatment Guidelines While the study by Zhenggang and colleagues shows great promise for managing the adverse effects of VEGFinhibiting TKIs, randomized controlled trials in this area are lacking, and currently there are no ASCO or National Comprehensive Cancer Network guidelines on this topic. However, because these medications are self-administered, patients still need effective education on HFSR management. Mario Lacouture and Eugene Balagula, who research and write extensively on this topic, have published several excellent reviews of the data and evidence as well as consensus panel–based recommendations in journals and in the 2012 edition of The MASCC Textbook of Cancer Supportive Care and Survivorship (chapter 35, Dermatologic Toxicities).15 The Figure details the treatments recommended in the review by Lacouture and colleagues.16 The currently available OTC urea-containing creams and lotions are listed in Table 2. Because HFSR associated with antiVEGF TKIs is widely considered to be one of the most clinically significant toxicities of these agents, additional research into the prevention and treatment of HFSR is paramount. l References

1. National Cancer Institute. Common Terminology Criteria for Adverse Events, version 4.03. http://ctep. cancer.gov/protocolDevelopment/electronic_applica

tions/ctc.htm. Published June 14, 2010. Accessed March 17, 2013. 2. Rosen AC, Wu S, Damse A, et al. Risk of rash in cancer patients treated with vandetanib: systemic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(4):11251133. 3. Chu D, Lacouture M, Fillos T, et al. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008;47(2):176-186. 4. Chu D, Lacouture M, Weiner E, et al. Risk of handfoot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer. 2009;7(1):11-19. 5. Balagula Y, Wu S, Su X, et al. The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs. 2012;30(4):1773-1781. 6. Caprelsa [package insert]. Wilmington, DE: AstraZeneca; 2012. 7. Michaelson MD, Rini BI, Escudier BJ, et al. Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell carcinoma: updated results among cytokine-treated patients. J Clin Oncol. 2012;30(suppl):Abstract 4546. 8. Zhang RX, Wu XJ, Wan DS, et al. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol. 2012;23(5):1348-1353. 9. US Food and Drug Administration. Postmarket drug safety information for patients and providers. http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/default.htm. Updated March 8, 2012. Accessed March 17, 2013. 10. Kang YK, Lee SS, Yoon DH, et al. Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol. 2010;28(24):3824-3829. 11. Wolf SL, Qin R, Menon SP, et al. Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol. 2010;28(35):5182-5187. 12. Jia L, Lou Y, Tian A, et al. Randomized, multicenter, phase II trial of compound Chinese herbal extract LC09 versus placebo for external treatment of hand-foot syndrome induced by anticancer therapy. J Clin Oncol. 2011;29(suppl):Abstract 9049. 13. Shinohara N, Nonomura N, Kimura G, et al. A randomized multicenter phase II trial on efficacy of highslip skin care pad for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma. J Clin Oncol. 2011;29(suppl):Abstract TPS233. 14. Zhenggang R, Kangshun Z, Kang H, et al. A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. J Clin Oncol. 2012;30(suppl):Abstract 4008. 15. Balagula E, Lacouture ME. Dermatologic toxicities. In: Olver IN, ed. The MASCC Textbook of Cancer Supportive Care and Survivorship. New York, NY: Springer; 2011:361-380. 16. Lacouture ME, Wu S, Robert C, et al. Evolving stratAVBCC_2013Conf_vertical_62512_Layout 1 7/9/12 12:5 egies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13(9):1001-1011.

Influencing the Patient-Impact Factor

THIRD ANNUAL CONFERENCE May 2-5, 2013 Westin Diplomat Hollywood, Florida REGISTER TODAY AT www.AVBCConline.org

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Cancer Center Profile

Center for Cancer Prevention and Treatment... Continued from cover leading-edge imaging technology, multidisciplinary site-specific clinics and cancer conferences, cancer genetics consultation, education, pharmacy, clinical laboratory, clinical cancer research, comfortable amenities, and an appearance center to assist with prostheses and cosmesis. The center has 9 navigators, 1 for each cancer program, including an Asian-Pacific Islander lay navigator and a financial navigator. The Oncology Nurse-APN/PA spoke with Enza Esposito-Nguyen, RN, MSN, ANP-BC, nurse navigator for the Urologic Oncology Program, about the benefits and challenges of her job at the Center for Cancer Prevention and Treatment.

What exactly is your role as nurse navigator in the Urologic Oncology Program? Enza Esposito-Nguyen (EE-N): I am responsible for the care of a cancer patient throughout the trajectory of the continuum of care. I arrange appointments, diagnostic tests, and treatments and make sure nothing falls through the cracks. The goal is to provide a seamless transition throughout the journey of a patient with urologic cancer (prostate, bladder, testis, kidney cancer).

The center has 9 navigators, 1 for each cancer program, including an AsianPacific Islander lay navigator and a financial navigator. How do your efforts translate to better outcomes for patients? EE-N: I can give you a specific example. This week I was involved in planning care for a 50-year-old underserved man with stage IV bladder cancer. His cancer had progressed because he did not seek treatment for a year after his diagnosis. I suggested that we present his case at our Urologic Oncology cancer conference, so that he could get the necessary scans and biopsies and have his history reviewed by our team of experts. I also liaised with our financial navigator, who was able to assist with insurance coverage. This exemplifies how I can assist in guiding a patient through the system to ensure that he or she gets the very best care. It’s a complete multidisciplinary approach.

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What are you excited about in the field of oncology right now? EE-N: I find it inspiring that we now have data showing that state-of-the-art cancer care can extend the life expectancies of patients with breast, lung, prostate, and renal cell carcinoma, due to several major advances in treatment. Thanks to

Treatment for the past 6 months, and I have over 15 years of experience as an oncology nurse. I love that every day is different, and that I can use all of my clinical skills plus my 15 years of experience in this job. We are looking for more ways of integrating my NP [nurse practitioner] skills into my role as nurse navigator.

My colleagues and I agree that 5 years is the minimum number of years of experience as an oncology nurse that one should have before becoming a nurse navigator. Enza Esposito-Nguyen, RN, MSN, ANP-BC

What inspired you to become a nurse navigator in oncology? EE-N: It was an opportunity to incorporate my skill set as a nurse practitioner and my experience in oncology in one What do you enjoy about your work? role. I am now an educator, supporter, EE-N: I have been a nurse navigator at clinician, and patient advocate, and I the Center for Cancer Prevention and use skills every in my WCMC_2013Conf_horizontalV491212_Layout 1 these 9/13/12 4:32 PMday Page 2 practice. new technology to manage early prostate cancer with active surveillance, we are able to save patients from the morbidity of unnecessary treatments.

What advice would you give to someone entering the field? EE-N: Find a specialty that you love and where you can thrive. Then try to learn as much as you can about that specialty and gain experience. Also, further your career through education, and get your master of science in nursing. My colleagues and I agree that 5 years is the minimum number of years of experience as an oncology nurse that one should have before becoming a nurse navigator. You need at least that many years of experience to develop a full skill set. What would you do if you weren’t a nurse navigator? EE-N: I can’t picture myself doing anything else as a career. I have been an oncology nurse for 16 years. I have worked in medical, surgical, and radiation oncology, in infusion centers, and in the inpatient and outpatient setting. I have also worked inside the US and outside the US. I feel that I am in the most suitable job I could have. l

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2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

April 2013 I VOL 6, NO 3

Prostate Cancer

Is Fatherhood a Risk Factor for Prostate Cancer? By Rosemary Frei, MSc

ocioeconomic status and other nonphysiologic factors may be largely responsible for the apparent association between having fathered a child and an increased risk for prostate cancer, Swedish researchers have concluded. They analyzed data from the National Prostate Cancer Register of Sweden and found that, although childless men had a significantly lower risk of prostate cancer than fathers, this association was attenuated when they took into account marital status and educational level. The unadjusted odds ratio (OR) of developing cancer among childless men compared with fathers was 0.71 for

cancers diagnosed by prostate-specific antigen (PSA) testing, and after adjustment it was 0.86. The ORs for cancers detected as a result of symptoms were 0.86 and 0.90, respectively. “Our data indicate that the association between fatherhood status and prostate cancer is due to a large extent to socioeconomic factors influencing healthcare-seeking behavior, including testing of PSA levels, and that the remaining association may be due to confounding factors,” concluded lead investigator Pär Stattin, MD, PhD, Department of Urology, Umeå University, Sweden, and colleagues in a new study (Wirén SM, et

al. Int J Cancer. 2013 Jan 25 [Epub ahead of print]). The investigators analyzed data from 117,328 men with prostate cancer and 562,644 without prostate cancer. They found an OR of 0.83 for prostate cancer among childless men compared with fathers in a univariate analysis. When the researchers then focused only on low-risk, localized tumors, they found the OR was even lower (0.74), whereas for metastatic cancer it was higher (0.93). After adjusting for marital status and educational level in a multivariate analysis, the team found that the overall OR for prostate cancer increased to 0.91 for childless men

Multiple Myeloma

Infection Poses Lethal Risk Early in Patients With Multiple Myeloma By Charles Bankhead

any patients with multiple myeloma succumb to infection before they have a chance to benefit from cancer therapy, according to a new study from Sweden. More than 20% of patients died of infection within a year of myeloma diagnosis. Patients had heightened susceptibility to bacterial and viral pathogens, reported Cecilie Blimark, MD, a consultant hematologist at Sahlgrenska University Hospital, Gothenburg, Sweden, at the 54th Annual Meeting of the American Society of Hematology. “We found the risk of specific infections, such as pneumonia and septicemia, to be more than 10 times higher in patients [with myeloma] than in controls during the first year after diagnosis of multiple myeloma,” said Blimark. Infection risk doubled from the 1986-1993 period to the 2000-2004 period, raising questions about the possible contributions of modern myeloma therapy to the risk of infection. “The increasing risk we observed in later years calls for more studies concerning new strategies regarding infectious complications and their prevention,” said Blimark. This first study of its kind was a large, population-based investigation of the magnitude of infection risk in patients with myeloma. Infection has long been recognized as a major cause of morbidity and mortality in this patient population, but the extent of the risk had not been previously characterized.

The data came from the Swedish national cancer registry and included 9610 patients who had newly diagnosed multiple myeloma between 1988 and 2004. For each patient, investigators identified 4 individuals without myeloma who were matched for age, sex, and county of residence. The follow-up continued through 2007. The results showed that 22% of the patients with myeloma died of infection during the first year after diagnosis. In addition, the patients had an infection hazard almost 12 times greater than that of the control group, including hazard ratios (HRs) of 11.0 for bacterial infections and 18.0 for viral infections. Throughout the entire study, patients with myeloma had an infection HR of 7.1 versus the control group. Overall HR was 7.0 for bacterial infections and 9.0 for viral infections. The greatest differentials in HRs included those for meningitis (HR, 16.6), septicemia (HR, 15.6), and herpes zoster (HR, 14.8); other significant differences (P <.05) involved bacterial pneumonia (HR, 7.7), viral influenza (HR, 6.1), endocarditis (HR, 5.3), osteomyelitis (HR, 3.5), cellulitis (HR, 3.0), and pyelonephritis (HR, 2.9). l Reference

Blimark C, Mellqvist U-H, Landgren O, et al. Multiple myeloma and infections: a population-based study based on 9,610 multiple myeloma patients. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 945.

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Clinical Approaches to Targeted Technologies™

April 2013 I VOL 6, NO 3

versus for fathers. The respective adjusted ORs for low-risk cancer and for metastatic disease were 0.87 and 0.92. Married men had an unadjusted OR of 1.31 for prostate cancer, whereas divorced men had an unadjusted OR of 1.19. Overall, men with more education had an unadjusted OR of 1.16 compared with men with less education. There was a stronger association for low-risk tumors but a slightly weaker association for metastatic prostate cancer. In addition, an unadjusted analysis indicated men without children had an OR of 0.71 for cancer diagnosed by PSA testing and of 0.86 for cancer detected from symptoms. These associations were attenuated in the adjusted analysis.

The investigators analyzed data from 117,328 men with prostate cancer and 562,644 without prostate cancer. The team also found, overall, that the lowest OR for developing prostate cancer was in childless men with a low educational level. In a separate analysis, they found the association between fatherhood status and the risk of prostate cancer was stronger for low-risk tumors among men with a low educational level than among those with a high educational level. “These associations are likely due to a higher uptake of PSA testing among married men and men with high educational levels,” the researchers concluded. That is, the results reflect propensity to obtain a diagnosis. The extent to which the small remaining reduction in risk for cancer among childless men after adjustment for marital status and education is a result of residual confounding factors “cannot be elucidated by use of our data.” l

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Conference News: NCCN Distress Screening Should Be Integrated Into Routine Cancer Care By Audrey Andrews

ignificant distress frequently accompanies the diagnosis and treatment of cancer but is often overlooked and is rarely screened for, according to Jimmie C. Holland, MD, of Memorial Sloan-Kettering Cancer Center, New York. Holland discussed recommendations from the Distress Management Panel of the National Comprehensive Cancer Network (NCCN) at the group’s 18th Annual Conference, held in Hollywood, Florida.1 “Along with all the advances in the science of care, we surely have lagged way behind with the issue of distress in cancer,” said Holland, who is the Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering and chair of the Distress Management Panel of the NCCN. Approximately one-third of cancer patients report significant distress, she noted. In recent years, however, psycho-oncology, the term applied to the psychosocial concerns of cancer patients, has become a multidisciplinary subspecialty within oncology. It pertains to the emotional responses of patients at all stages of disease, as well as those of their families and their healthcare providers. A diagnosis of cancer was once a carefully guarded secret, and therefore little to no attention was paid to the corresponding emotions, Holland noted. This changed in the 1970s, when some cancers became curable and negative attitudinal barriers were replaced with a growing optimism. “Around 1975, patients began to be told their diagnosis and treatment options. Their psychological responses could finally be explored,” she said. Although the area of psycho-oncology was born at this time, it remained a subjective concept based largely on the physician’s observation; patient’s selfreports were not trusted. Eventually, as a means of measuring subjective symptoms, validated tools and scales were developed to assess health-related quality of life, pain, fatigue, anxiety, depression, and delirium. In clinical trials, these tools began to produce data showing that effective interventions could affect symptoms.

Guidelines From the NCCN In 1997, the NCCN settled on the term “distress” as a way to describe the continuum ranging from normal fears, worries, and sadness to severe distress, including depression, anxiety, family crises, and spiritual needs. The development of the NCCN Clinical Practice Guidelines in Oncology for Distress Management2 reflects the growing importance of this area of oncology, Holland said. These NCCN guidelines recommend

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that distress be recognized, monitored, documented, and treated promptly during the initial patient visit and as clinically appropriate. Screening should identify the level and nature of the distress, and symptoms of distress should be managed according to these guidelines, she said. The guidelines encompass screening tools for measuring distress, including a 0–10 screening scale and a problem

mild distress or a score of <4 on the screening tool should be provided with relevant resources, while those with clinical evidence of moderate-to-severe distress should be assessed by their primary oncology team, including an oncologist, a nurse, and a social worker, the guidelines state. The healthcare provider should seek to identify highrisk patients, as indicated by periods of vulnerability and risk factors for

list that queries patients on a variety of issues. Patients can complete this form while in the waiting room, and those with scores indicating moderate or severe distress can be evaluated further during the office visit by a nurse or a physician. “This approach has been validated in 15 different countries in different languages. It is a brief broad brushstroke that is a good start,” Holland noted. Patients with clinical evidence of

distress. These risk factors include practical problems (such as transportation, child care, insurance), family problems, spiritual/religious concerns, social problems, and physical problems. Unrelieved physical symptoms can be treated according to disease-specific or supportive care guidelines. Where indicated, referrals can be made to mental health services, social work and counseling services, or pastoral services.

Beyond the NCCN: Support for Psycho-oncology The integration of psycho-oncology into cancer care has been endorsed by numerous other organizations, including the Institute of Medicine, which in 2007 issued the landmark white paper Cancer Care for the Whole Patient that included a model for the delivery of psychosocial services. The American College of Surgeons Commission on Cancer is developing a new standard of accreditation for 1500 cancer centers, requiring that the psychosocial domain be a component of routine care by 2015. In addition, the American Psychosocial Oncology Society, the Association of Oncology Social Work, and the Oncology Nursing Society are developing guidelines for helping cancer centers implement new requirements for psychosocial care. Furthermore, the International Psychooncology Society (IPOS) established an international quality standard to integrate the psychosocial domain into routine care, and that standard has now been endorsed by 57 organizations. IPOS has proposed that distress should be monitored routinely as the “sixth vital sign,” after pain. In closing, Holland commented, “We have developed a science of care, which was essential to get ourselves a place at the table with the oncologist and to become a subspecialty.” Along with science, she suggested that empathy—the humanistic dimension— remains critical. l References

1. Holland JC. Distress screening and the integration of psychosocial care into routine oncologic care. Presented at: 18th Annual Conference of the National Comprehensive Cancer Network; March 13-17, 2013; Hollywood, FL. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Distress Management. Version 2.2013.

Reader Survey

Do patients talk to you about how best to adhere to their medication regimen when at home?

n the February issue we published the article “Adherence to Therapy at Home: The Personal Touch.” This article, written by MMA, a woman undergoing treatment for cancer, addressed the idea that patients feel overwhelmed when they return home with “a bagful” of medications that they must incorporate into their daily life.

We asked our online reading community to let us know if this is a topic they address with their patients. The answer was a resounding yes. All respondents said they do talk to patients about adhering to their medication regimen at home. Respondents indicated that they provide information about how and when to take the medication for the best results.

Want to participate in the new poll? See page 4 for details.

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April 2013 I VOL 6, NO 3

Conference News: NCCN NCCN Issues Guidelines for Survivorship Care By Audrey Andrews

hereas survivorship should be viewed as another stage in the cancer journey—the same as diagnosis and treatment—concerns related to surviving cancer have been largely neglected. This is beginning to change, as evidenced by new guidelines revealed by the National Comprehensive Cancer Network (NCCN) at the group’s 18th Annual Conference held in Hollywood, Florida.1,2 Although the number of cancer survivors has increased exponentially over the past 30 years, survivorship care is still an overlooked phase of the cancer care continuum, according to Jennifer A. Ligibel, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts, who serves on the NCCN Guidelines survivorship panel. Many survivors and their families remain “lost in transition,” she said. To address the issues faced by survivors and their families and to offer practical recommendations for use in the clinic, these guidelines were developed. “They are intended as a library of tools for a provider to use when assessing a cancer survivor,” said Crystal S. Denlinger, MD, of Fox Chase Cancer Center, Philadelphia, Pennsylvania, who serves as chair of the NCCN Guidelines survivorship panel. The guidelines should help to standardize

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what is now a system of heterogeneous survivorship care across the country. Survivorship Issues Have Been Ignored Cancer survivors have a variety of needs. However, there are common components of care that all should receive, centering on prevention, surveillance, intervention, and coordination of care, Ligibel noted. In particular, survivorship care should address

The inaugural NCCN Guidelines on Survivorship focus on the impact of a cancer diagnosis on the adult survivor, with subtopics related to anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders.

the potential for long-term side effects of treatment, the importance of follow-up visits, maintenance of a healthy lifestyle, prevention of new and recurrent cancer, and access to psychological services, according to the landmark 2005 Institute of Medicine report, 12:47 PM Pa From Cancer Patient to Cancer Survivor: Lost in Transition. Until recently, clear guidelines for caring for these patients, including skills training for oncology providers, have been lacking, she said. The inaugural NCCN Guidelines on Survivorship, unveiled at the meeting, focus on the impact of a cancer diagnosis on the adult survivor, with subtopics related to anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders. At the conference, Ligibel and Denlinger addressed exercise, cognitive function, immunization, and sexual function. The survivorship guidelines are not intended to replace the existing disease-specific guideline recommendations for cancer surveillance, but to accompany them.

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April 2013 I VOL 6, NO 3

cancer recurrences were reduced by 50%, and mortality was lower as well, for women who exercised more than 3 hours/week, versus more sedentary women (Holmes MD, et al. JAMA. 2005;293:2479-2486). Similar associations have been shown for colon cancer (Meyerhardt JA, et al. J Clin Oncol. 2006;24:3535-3541) and prostate cancer. In a recent study of the latter, men with clinically localized prostate cancer who walked briskly for at least 3 hours/

Exercise Is Always Beneficial The benefit of exercise has been shown for patients with breast, colorectal, or prostate cancer. In breast cancer, Ballard-Barbash and colleagues concluded from a systematic literature review that women who exercise have lower breast cancer–specific and overall mortality than less active individuals (Ballard-Barbash R, et al. J Natl Cancer Inst. 2012;104:815-840). In the prospective Nurses’ Health Study, breast

week had a 57% lower risk of disease progression than did men who walked more slowly for less time (Richman EL, et al. Cancer Res. 2011;71:3889-3895). The NCCN survivorship guidelines, therefore, strongly encourage physical activity, tailored to the individual’s abilities and preferences (with special considerations for specific populations, such as persons with ostomies or peripheral neuropathy). In general, the recommendation is for 75-150 minutes/week of moderate-intensity activity coupled with strength training and stretching. Cognitive Dysfunction Is Increasingly Recognized “We struggled with this topic a bit as a panel, because cognitive function has been so ill-defined,” Ligibel acknowledged. Cognitive dysfunction manifests as problems with memory, executive function, learning, and processing speed. Patients most at risk include those with primary central nervous system tumors or brain metastases, but cognitive dysfunction in breast cancer and lymphoma patients has been commonly reported. The NCCN panel presented general principles related to this complication while acknowledging a lack of evidence-based guidance. Clinicians should screen for reversible contributing factors and should approach the evaluation with a focused history first. Imaging or neuropsychologic evaluation is suggested in the presence of focal neurologic deficits, known metastatic disease, or a primary brain tumor. Practical interventional strategies are centered on patient/family education and counseling.

Immunizations Are Important Because of a higher than normal risk for infections and inadequate immunization, the guidelines recommend that adults with cancer routinely receive appropriate vaccinations based on their age and medical condition. Vaccines considered safe for cancer patients, transplant recipients, and close contacts include those for influenza, pneumonia, meningitis, and hepatitis. Live attenuated vaccines, such as those for measles, mumps, and rubella, are contraindicated or should be used with caution, Denlinger said. She recommended vaccinating patients at least 3 weeks prior to starting cancer treatment to obtain the full benefit of immunity. Sexual Dysfunction Is Underappreciated Sexual dysfunction has been reported by up to 90% of prostate cancer survivors, 75% of rectal cancer survivors, and 50% of breast and gynecologic cancer survivors, although this multifactorial problem is rarely discussed with healthcare providers. In addition to erectile dysfunction for men and dyspareunia and vaginal atrophy for women, other problems common to both genders are loss of libido, infertility, negative body image, and partner distress, said Denlinger. “Complex factors” are at play, she added. The NCCN guidelines provide validated tools for assessment—a brief sexual symptom checklist for women and a sexual health inventory for men—along with suggestions for additional evaluation and treatment. “We tried hard to minimize the interventions to things an oncology provider could do versus things that need to be referred,” she said. Moving the Guidelines Into the Clinic Both Ligibel and Denlinger acknowledged that incorporating these guidelines into daily clinical practice may be initially challenging, but the baseline tools provided in the guidelines should help. They recommended evaluating survivors for survivorship issues at regular intervals using standardized questionnaires to assess symptoms, new-onset and late effects of treatment, receipt of preventive health services, and personal health behaviors. Such is meant to be “a quick, down, and dirty screening assessment” that will trigger a larger discussion of the patient’s big concerns, Denlinger said. l References

1. Denlinger CS, Ligibel JA. New NCCN guidelines for survivorship. Presented at: 18th Annual Conference of the National Comprehensive Cancer Network; March 13-17, 2013; Hollywood, FL. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Survivorship. Version 1.2013.

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Conference News: NCCN Enhancing Communication in the Advanced-Disease Setting By Audrey Andrews

onversations with terminally ill patients about treatment options for end-of-life care often occur when the patient is in pain, heavily medicated, and quite ill—on average, just 1 month before the patient dies. Just as often, such discussions may be altogether absent, or they may occur in a manner that is more uncomfortable than it has to be, for patients and providers alike. Two palliative care specialists would like to improve on these scenarios. At the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN), Lillie D. Shockney, RN, BS, MAS, and Anthony Back, MD, shared their approach to communicating with patients who have advanced-stage cancer. These conversations require honesty balanced with sensitivity and respect for the patient’s own goals, and they should occur within a time frame that allows patients and families time to prepare, they said. “It is very unfortunate to be looking at a jaundiced 85-year-old with metastatic cancer for whom there has been no conversation at all about end of life,” said Shockney, associate professor of surgery, gynecology, oncology, and obstetrics at Johns Hopkins, Baltimore, Maryland. According to Shockney, who is a breast cancer survivor herself, research has shown that patients want to know the truth, that a patient’s future course can be predicted with some accuracy, and that an honest conversation does not “rob patients of their hope,” trigger depression, or hasten death. In the discussion about continuing or stopping further treatment, the patient’s own goals must be clarified. Is it the patient’s wish to see a grandchild born in the coming months? Is it the patient’s wish to maintain quality of life without aggressive toxic treatment? “To engage in such a discussion, there are some things you can ask,” she said (Figure). “Take time to ask the patients what gave them their greatest joy before their diagnosis of advanced cancer,

Figure. Questions for the End-of-Life Discussion • How much do you want to know about your cancer? • Tell me what you currently know about your cancer. •W hom do you want to include in discussions about your cancer and its treatment options? •D o you want to have information written down by me regarding your cancer? • Tell me what is important to you. • Tell me what you are hoping for. • Tell me your understanding of your clinical situation. and discuss whether these joys might be restored,” she suggested. As an example, she described how her own brother-in-law wished to see his grandson born, but time was running out. Shockney arranged to have him taken by ambulance to the imaging center to be present for an ultrasound. He saw the baby moving, and he framed the ultrasound picture. “That’s my grandson,” he tells visitors.

Communication at Seattle Cancer Care Alliance. The patient says, “Don’t talk to me about anything negative,” and “I can do more.” The oncologist says, “I don’t think he’s ready for the conversation” and “I don’t have time for it.” The primary nurse worries, “He’s running out of time to take that trip,” and he or she questions, “I’m not sure if it’s OK for me to raise this issue.” These different dots remain uncon-

End-of-life care discussions may be altogether absent, or they may occur in a manner that is more uncomfortable than it has to be, for patients and providers alike.

A Typical Scenario Communicating with patients about end-of-life care must bring together the multiple points of view of the various parties, and this is challenging, said Back, who is professor of medicine and adjunct associate professor in the Department of Bioethics and Humanities at the University of Washington School of Medicine, and director of the Program on Cancer

nected. The oncologist laments that the patient did not respond to third-line chemotherapy. The nurse acknowledges the “disconnect” between the patient’s experience and expectations, but resigns himself or herself to the possibility that “this may be the best we can do,” Back said. “The best care engages patients—at the level of their story, their values, their families in ways that amplify their resilience,” he emphasized.

Paradigm Shift Is Needed Back said a “paradigm shift” is needed for communicating with patients in the advanced-disease state. This shift would include a better understanding by patients that treatment will no longer be curative, greater access to early integrated palliative care, evidence-based skills training in end-of-life communications, and a system infrastructure that captures data, displays progress, and prompts clinicians about end-of-life care planning, he suggested. The new paradigm would reflect a shift in thinking from “the patient is resistant” to “I can use a toolbox of skills to cultivate trust,” and from an attitude of “I don’t have time” to “I’ll do my share as part of the team,” he added. The Patient Encounter The speakers emphasized that the oncology staff should prepare for these difficult conversations. This preparation includes knowing what a conversational encounter should accomplish, and limiting the conversation to just a few key points. They suggested “double framing” of the pros and cons of the treatment options to minimize bias. An example is this: “With this option, 30 out of 100 patients would have their cancer shrink for a few months, but another way of saying this is that 70 out of 100 would have their cancer grow or just stay the same,” Back pointed out. The conversation should be paced, with the easier decisions made first, he said. And it should reinforce the positive things that patients and families are already doing. Finally, make a recommendation that brings together the elements of the conversation, he suggested. Instead of saying, “This is what we have to do,” tell the patient, “This is how I think we can move forward in a way that honors the kind of life you’ve lived.” l Reference

Back A, Shockney LD. Communicating with patients on treatment options for advanced disease. Presented at: 18th Annual Conference of the National Comprehensive Cancer Network; March 13-17, 2013; Hollywood, FL.

Take action: get YOUR cancer center profiled! We are looking to interview oncology nurses from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for information. www.TheOncologyNurse.com

April 2013 I VOL 6, NO 3

Side Effects Management

Preventing Methotrexate Toxicity: Know How to Use Leucovorin, Glucarpidase By Wayne Kuznar

xtremely high levels of methotrexate can lead to precipitation of the drug in the renal tubules, delayed drug clearance, and the potential for acute renal failure. Preventing high-dose methotrexate toxicity requires effective methotrexate monitoring and knowledge of the appropriate protocols for leucovorin rescue and the role of glucarpidase, said Katherine Mandock, PharmD, BCPS, at the Hematology/Oncology Pharmacy Association 9th Annual Conference. Methotrexate toxicity is a function of both the concentration of the drug and duration of exposure. Acute consequences of high concentrations (>5-10 µM) of methotrexate include severe renal and hepatic dysfunction. Sustained, elevated plasma levels of methotrexate (>0.1 µM) can lead to life-threatening myelosuppression and mucositis.

The first step to managing high-dose methotrexate administration (>1000 mg/m2 requiring leucovorin rescue) is to check for potential drug interactions, said Mandock, clinical oncology pharmacist at Smilow Cancer Hospital at YaleNew Haven, Connecticut. Weak organic acids (ie, nonsteroidal anti-inflammatory drugs) compete with methotrexate for tubular secretion, resulting in decreased renal clearance of methotrexate. Highdose vitamin C will acidify the urine and cause crystallization of methotrexate in the kidney, interfering with clearance. Proton pump inhibitors have been shown to cause methotrexate accumulation in the kidney. Because methotrexate accumulates in third-space fluid, “in patients who have third-space fluid such as ascites or pleural effusion, you should think twice, if at

all, about using high-dose methotrexate,” Mandock said. Poor hydration or dehydration, a urine pH <6.5, decreased creatinine clearance, and third spacing are all risk factors for methotrexate toxicity. “When plasma concentrations of methotrexate are >10 to 100 µM, high doses of leucovorin are unlikely to completely reverse the toxicity of methotrexate, leading to ineffective leucovorin rescue,” she said. To prevent high-dose methotrexate toxicity, the urine should be alkalinized via administration of sodium bicarbonate. “We keep the urine pH >7.5 because methotrexate and its metabolites are less soluble at lower urine pH’s,” Mandock reported. To be effective, leucovorin rescue must be started within 24 to 48 hours of methotrexate initiation, or within 24 hours of

Personalized Medicine

Gene Analysis Allows for Personalization of 5-FU to Reduce Risk of Toxicity

bout 3% to 5% of the general population is believed to have a mutation in the gene that encodes a major 5-fluorouracil (5-FU) metabolizing enzyme. This mutation can extend the half-life of 5-FU, leading to increased plasma concentrations and potential toxicities, said Colleen Rock, PharmD, PhD, at the Hematology/Oncology Pharmacy Association 9th Annual Conference, held in Los Angeles, California. Comprehensive analysis of the gene—DPYD—can be used to personalize a patient’s 5-FU/capecitabine therapy, she said. The rate-limiting enzyme in the metabolism of 5-FU (and its oral prodrug capecitabine) is dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene. “A mutation in the gene can lead to drug accumulation; approximately 80% of 5-FU is rapidly metabolized by DPYD in the liver,” said Rock, clinical research associate at Myriad Genetic Laboratories, Inc, Salt Lake City, Utah. “If there’s a mutation that affects the protein function, it’s not going to be metabolized. There’s going to be accumulation, and this can lead to toxicity.” Analyzing the DPYD gene “can allow us to decide whether to potentially reduce the dose of 5-FU in a patient or even switch to a different drug,” she said. The data she presented were from an analysis of full gene sequencing test results from 3083 patients. DPYD analysis was performed by polymerase chain reaction and DNA sequencing. Genetic variants were tested using multiple variant classification techniques, including comparison with a consensus wild-type DPYD sequence. “Because of the large number of patients included in this analysis, we have good information regarding prevalence, and found that the prevalence for the common DPYD mutations in the testing population is 7.3%,” said Rock. The 3 common

April 2013 I VOL 6, NO 3

high-risk mutations were IVS14+1G>A (52.0%), D949V (40.5%), and 1560S (7.5%). Full sequence analysis of the gene allowed for detection of a unique variant—E412E—that has been linked with a deleterious mutation in DPYD in some cases (N=12). “When we take the E412E variant into account, along with the common mutations, the potential exists for an almost 11% prevalence of gene mutation,” she reported. “These patients who have this mutation are at risk for toxicity. Only full gene sequencing allows for identification of both common and novel mutations that may be associated with 5-FU toxicity.” In a subset of 24 patients who were tested for DPYD mutations in response to an elevated 5-FU plasma level, gene variants were identified in 7 of the 24. In this population, the E412E variant occurred with similar frequency as that of the common high-risk mutations. DPYD mutations were found with greater frequency in patients who suffered a greater number of 5-FU toxicities prior to DPYD gene testing. While the majority of patients were tested after experiencing at least one 5-FU toxicity, among those without pretest toxicities, the prevalence of DPYD mutations was 4.7%, which increased to 31.6% in patients with 4 toxicities. Among the 5-FU toxicities, the prevalence of mutations (18.5%) was greatest for hematopoietic events, followed by hand-foot syndrome and stomatitis (12.6% each). Most providers choose to submit a sample for testing after a 5-FU toxicity has occurred, noted Rock. “I think that the preference would be to prevent toxicities and therefore test ahead of time, including for the E412E mutation,” she said. The prevalence of mutations also varied by ancestry, with mutations most common among European and Latin American patients. l —WK

completion. It should be continued until the methotrexate level falls below 0.1 µM. The amount needed to reverse toxicity is proportional to the methotrexate concentration. Essentials of Glucarpidase Rescue Glucarpidase is a methotrexate antidote that was approved by the US Food and Drug Administration on January 17, 2012. It metabolizes circulating methotrexate to 2,4-diamino-N10-methylpteroic acid (DAMPA). “In patients who have impaired renal function secondary to high levels of methotrexate, we’re now providing a nonrenal route of elimination for methotrexate in the form of DAMPA,” said Mandock. It is indicated for the treatment of methotrexate concentrations >1 µmol/L (or plasma concentrations >2 standard deviations of the mean methotrexate concentration curve at least 12 hours following methotrexate administration) in patients with delayed methotrexate due to impaired renal function. Plasma concentrations of methotrexate decrease by 99% on average within 15 minutes of glucarpidase administration. About 40% of patients given glucarpidase will experience a slight rebound in methotrexate concentrations, “but for most of these patients, the levels are decreased by >90% for a duration of 8 days,” she reported. Glucarpidase will not reverse toxicities present prior to its administration, is most effective when given within 96 hours of methotrexate administration, and is not a substitute for leucovorin because glucarpidase does not gain entry into cells, Mandock cautioned. The schedule of leucovorin should be adjusted so that it is not administered 2 hours prior to or for 2 hours following glucarpidase. Other standard-of-care treatments (hydration, alkalization of urine) should be continued. Serum levels interpretation should consider whether the laboratory uses high-performance liquid chromatography or immunoassays. Since glucarpidase converts circulating plasma methotrexate into DAMPA, and DAMPA interferes with the immunoassay measurement, use of immunoassays can result in methotrexate concentrations that are falsely elevated. “The half-life of DAMPA is 9 hours, so for 48 hours after the administration of glucarpidase, immunoassays are not reliable measures of methotrexate plasma concentrations,” she said. “It’s also important that we base the leucovorin dose on pre-glucarpidase methotrexate levels for 48 hours post-glucarpidase” because leucovorin is a substrate for glucarpidase. l Reference

Mandock K. Monitoring methotrexate, leucovorin dose escalation, and the role of glucarpidase. Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 20-23, 2013; Los Angeles, CA.

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Gibbs Cancer C OFILE en Regional Health ter, Spartanburg care System By Alice Goodm an

• Cancer Center Profiles

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• Latest Research Findings by Disease State • Supportive Care Management Considerations

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THE PATIENT ’S VOICE

Adherence to T The Personal Toherapy at Home: uch By MM A

Sharon Bartelt, RN, MSN, OCN ; Lucy Gansaue BSN, OCN; Krist r, RN, MSN, OCN en Beeker, RN, ; Carol Lynn Cole BSN, OCN, CBN Cancer Center (left to right), onco , RN, in South Carolina. logy nurses at the Gibbs

he Gibbs Cancer Center, part of the Regional Healthc Spartanburg (So are System, is uth Carolina) 1 of 21 National (NCI)-designated Cancer Institut community can 2007 that 85% e cer centers. Rec of all cancer pat ognizing in ients receive the nity, NCI set ben ir car chmarks for elev setting. The Gib ating cancer car e in the commubs e in the commu nity nity cancer cen Cancer Center and other NC I-designated com ters have to me et standards on mu disparities, enh anc reducing healthc follow-up, collect ing community outreach for are cancer screening ion of high-quali and of cancer care, ty research, and exp biospecimens, improving qua vivorship, and lity anding informa palliative care. tion technology, App surdiagnosed and roximately 170 0 cancer patient treated at the Gib s are bs Cancer Cen them underinsur ter ed or uninsured , with low levels each year, many of of literacy.

CONFEREN CE NEWS

Continued on page

Highlights From the San Antonio Breast Cancer S ym posium By Alice Goodm an

he 2012 Annual Meeting of the CTRC-AACR San Antonio Bre ast Can cer Sym pos ium (SABCS) offered a to attendees from wealth of news around the wor The symposium ld. , held December 4-8, 2012, presented the latest informa -

tion about the experimental bio logy, etiology, preven tion, diagnosis, and therapy of bre ast malignant breast cancer and predisease. Follow ing are some of the highlights from the conference. Continued on page

spent 8 long mon ths my own, undergo in a city far from ing intense chemotherapy and then cell transplant. Eve an autologous stem ntually, after a long than-I-would-hav e-liked stay in the erpital and another hosfew weeks living close to the hospital in case sent back home with of emergency, I was a bagful of medicin and instructions es on how/when/with what to take them. Much discussion exists around the issue of how to get pati ents to adhere to their treatment regimen at home. I must admit

I worried about this arrived back in my , too. When I first city, I felt a com plete disconnect from the turmoil and commotion associated with being a can patient at a major cer cancer treatment center. I did not want to be anymore. I wanted that cancer patient to go back to my precancer—progress life in my career, ene to shuttle my chil rgy dren to and from their activities, enough resources to actu save some money, ally and the freedom to eat at my favorite rest aurants. Though many Continued on page

GENETIC CO UNSELING

Inherited Colon Cancer: Peutz-Jeghers Syndrome,

Syndrome, and Cowden

By Cristi Radford , MS, CGC

Juvenile Polyposi s Syndrome

olorectal cancer (CR third most common C) is the type of non– skin cancer in both men and women. As wit h other cancers , majority are spo radic, 15% are fam the ilial, and 5% to 10% are 25% of CRC case hereditary. Thus, in s a familial clus tering is present, and further risk asse ssment and possibly gen etic testing are indicat ed. The 2 most well-described form s of

THE WHOLE PAT IENT . . . . .

.......

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Benefit for Neoadju vant Chemotherapy Seen in Very You ng Patients With Trip le-Negative and Luminal-Like Bre ast Cancer Survival Benefit for ER-Negative Local Breast Cancer Rec urrence

Continued on page

INSIDE

Approaches to Sexual Dysfunc tion in Breast Cancer Survivors BREAST CAN CER . . . . .

inherited CRC are familial adenom atou polyposis (FAP) and Lynch syndro s also known as hereditary nonpoly me, posis syndrome. FAP is cha to 1000s of colo racterized by 100s nic polyps, whe Lynch syndrome reas has a more div phenotype and is erse associated with at least 10 extracolonic cancers. Both hav e been discussed in prev ious articles.

CONFERENCE

NEWS: ASH. . ..

. . . 17 Abstracts of Inte rest From the 54th Annual Meeting of Society of Hematolthe American ogy

THROUGH THE EYES OF AN ADVOCATE . . ..... ............

The Pace of Med icine

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IN THIS ISSUE

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

ancer is an illness associated with substantial cancer.1 More than half are living well beyond 5 years physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. 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