Oncology Nurse Advisor March/April 2014

ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014

March/April 2014

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FREE CONTINUING EDUCATION INSIDE! Understanding current and emerging therapies for HNC, PAGE 19

FEATURE

Is CAM helpful or harmful with cancer therapies?

FEATURE

Genomic testing in HER2+ breast cancer: Supporting evidence still insufficient

FEATURE

Yoga practice and breast cancer survivorship

ISSUES IN CANCER SURVIVORSHIP

Encouraging colorectal cancer awareness and survivorship

VOLUME 5, NUMBER 2

ASK A PHARMACIST

Vincristine-related peripheral neuropathy

RADIATION THERAPY

Recall phenomenon: A delayed effect of post irradiation drug therapy Tamoxifen-related rash on the foot of a 69-year-old woman undergoing breast cancer treatment

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PUBLISHING STAFF Editor Joyce Pagán editor.ona@haymarketmedia.com

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Contributing writer Bette Weinstein Kaplan Editorial coordinator Candy Iemma Group art director, Haymarket Medical Jennifer Dvoretz Production editor Kim Daigneau Production director Kathleen Millea Grinder Production manager Krassi Varbanov krassi.varbanov@haymarketmedia.com Circulation manager Paul Silver Assistant circulation manager Priti Shah Audience development director John Crewe

Account manager Henry Amato, (646) 638-6096 henry.amato@haymarketmedia.com Senior director of operations Audra Schlesinger Senior vice president, Haymarket Oncology Tammy Chernin, RPh

Ann J. Brady, MSN, RN-BC Huntington Cancer Center Pasadena, California

Jia Conway, DNP, FNP-BC, AOCNP, NP-C Cancer Care Associates of York York, Pennsylvania

Michele M. Farrington, BSN, RN, CPHON University of Iowa Hospitals and Clinics Iowa City, Iowa

Donald R. Fleming, MD Cancer Care Center, Davis Memorial Hospital Elkins, West Virginia

CEO, Haymarket Media Inc Lee Maniscalco

Arati Jairam-Thodla, MSN, CNP

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EDITORIAL BOARD

Northwestern Memorial Prentice Women’s Hospital Chicago, Illinois

Karen MacDonald, RN, BSN, CPON William Beaumont Hospital Royal Oak, Michigan

Marlene McGuire, RN, MA, ANP-C The Cancer Institute of New Jersey New Brunswick, New Jersey

Maribel Pereiras, PharmD, BCPS, BCOP Hackensack University Medical Center Hackensack, New Jersey

NC NN

Leah A. Scaramuzzo, MSN, RN-BC, AOCN Billings Clinic, Inpatient Cancer Care

National Coalition of Oncology Nurse Navigators Billings, Montana

Oncology Nurse Advisor (ISSN 2154-350X), March/April 2014, Volume 5, Number 2. P ­ ublished 6 times annually by Haymarket Media Inc, 114 West 26th Street, 4th Floor, New York, NY 10001. Oncology Nurse Advisor is available on a paid subscription basis at the following annual rates: USA $75, Canada $85, all other Foreign $110; Single copy price: USA $20; Foreign $30. To order, visit our Web site at www.

OncologyNurseAdvisor.com or call (800) 558-1703. For advertising sales, call (646) 638-6000 (M-F, 9am-5pm, ET). Postmaster: Send changes of address to Oncology Nurse Advisor, P.O. Box 316, Congers, NY 10920. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

Lisa A. Thompson, PharmD, BCOP Kaiser Permanente Colorado

Rosemarie A. Tucci, RN, MSN, AOCN Outside Front

Lankenau Hospital Wynnewood, Pennsylvania

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 5

CONTENTS 10

March/April 2014

10

IN THE NEWS • Oophorectomy reduces cancer risks • ASCO report highlights cancer care trends • Navigator Notes: Distress screening and support • Humidification during radiation reduces mucositis, hospital stay

13

ONCOLOGY NURSE ADVISOR FORUM • Creating effective navigation tools for patients • Some port maintenance is outside the scope of nursing practice • Delivery order in IV/IP chemotherapy administration • How to manage myoclonus in patients taking high-dose opioids

19

CONTINUING EDUCATION Understanding current and emerging therapies for HNC

19

Donald R. Fleming, MD

32

29

FEATURES Supplement use with cancer treatment: Helpful or harmful?

Bryant Furlow

32

Guideline update leaves out novel breast cancer tests Kathy Boltz, PhD

41

Yoga has a positive impact on breast cancer survivorship Bette Weinstein Kaplan

45

FIND US ON

43

STAT CONSULT Gemcitabine (Gemzar)

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6 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com



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JOIN OUR COMMUNITY Submit a question to an oncology nurse advisor Have a question? Our panel of oncology clinicians is available to answer your questions. Submit questions to editor.ona@HaymarketMedia.com.

45

COMMUNICATION CHALLENGES Unattended grief Ann J. Brady, MSN, RN-BC

47

RADIATION & YOUR PATIENT Diagnosis of radiation recall hampered by delayed occurrence Bryant Furlow

50

ONA asks… Answer our poll question and compare your opinions with those of your colleagues on key nursing issues at OncologyNurseAdvisor.com Subscribe to ONA newsletters

ISSUES IN CANCER SURVIVORSHIP A 40-foot colon and 10 years of Colondars celebrate cancer awareness and survivorship Bette Weinstein Kaplan

52

Answer the ONA poll question

ASK A PHARMACIST Managing peripheral neuropathy related to vincristine Lisa A. Thompson, PharmD, BCOP

Stay current with daily news reports and special series from key oncology conferences on our Web site, sign up for our e-newsletters at OncologyNurseAdvisor.com/subscribe.

Earn CE credits Each issue offers one new CE activity co-provided by the Nurse Practitioner Healthcare Foundation. Activities are active for 2 years.

Socialize electronically

ON THE

WEB

THE TOTAL PATIENT CBT/CBTH mitigates fatigue in patients with breast cancer undergoing radiotherapy Bette Weinstein Kaplan

Keep up with the oncology field through our social media. We’re on Twitter and Facebook. Now, we’re on Pinterest, too.

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DAILY ONCOLOGY NEWS EBCC: Routine mammograms for most women 70+ not beneficial PADT does not lower mortality for localized prostate cancer Oropharyngeal cancer symptoms vary by HPV status

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 7

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IN THE NEWS WOMEN WHO carry a BRCA gene mutation and opt for a preventive oophorectomy had an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer. Also, they had a 77% reduction in all-cause mortality.

The best age for women to undergo the surgery and its impact on mortality has not been well studied. This study is the first to observe these effects over a nearly 6-year follow-up period ( J Clin Oncol. 2104; doi:10.1200/ JCO.2013.53.2820).

The study identif ied 5,783 women from an international registry who had a BRCA1 or BRCA2 mutation. The women completed a baseline questionnaire and one or more follow-up questionnaires. Their average age at cohort entry was 46 years. The women were followed until either a diagnosis of ovarian, fallopian tube, or peritoneal cancer; death; or date of most recent follow-up.

Among the 5,787 women, 2,274 did not have oophorectomy, 2,123 had already had the surgery when they began the study, and 1,390 underwent oophorectomy during the study follow-up period. After an average follow-up period of 5.6 years (with some women followed for as long as 16 years), 186 women developed either ovarian, fallopian tube, or peritoneal cancer.

Of the 511 women who died during this study, 333 died of breast cancer; 68 of ovarian, fallopian tube, or peritoneal cancer; and the remainder died of other causes. Prophylactic oophorectomy reduced the risk of death by any cause by 77% (largely by lowering the risks of ovarian, fallopian tube, peritoneal, and breast cancers). Corresponding author Steven Narod, MD, a senior scientist at Women’s College Research Institute in Toronto, Ontario, Canada, noted that the 77% decrease in risk is even greater than the benefit of chemotherapy, and was equally strong for both BRCA1 and BRCA2 mutation carriers.

The authors explained that, although the 77% reduction in mortality risk after oophorectomy largely came from the reduced incidence of ovarian,

Unilateral oophorectomy with chromosome 17 (top right, location of the BRCA1 gene) and chromosome 13 (top left, location of the BRCA2 gene)

“These data are so striking that we believe prophylactic oophorectomy by age 35 [years] should become a universal standard for women with BRCA1 mutations.”

10 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

tubal, and peritoneal cancers, an important component also came from reducing incidence and mortality from breast cancer. A total of 46 invasive cancers were identified in 1,390 women at the time of prophylactic oophorectomy. These cancers had a prevalence of 4.2% in BRCA1 mutation carriers and 0.6% in BRCA2 mutation carriers.

The results differed between mutations in BRCA1 and in BRCA2. Narod explained, “To me, waiting to have oophorectomy until after 35 [years] is too much of a chance to take.

These data are so striking that we believe prophylactic oophorectomy by age 35 [years] should become a universal standard for women with BRCA1 mutations.

Women with BRCA2 mutations, on the other hand, can safely delay surgery until their 40s, since their ovarian cancer risk is not as strong.”

Although oophorectomy is a safe procedure, it can carry some complications, including premature menopause. The study also stated that previous studies had found that women who had an early oophorectomy reported an increase in symptoms of menopause such as hot f lashes and palpitations, loss of libido, and a modest decrease in quality of life.

“After an oophorectomy, the long-term effects on a woman’s cardiovascular health and her bone health are less well known, and further research is needed,” said first author Amy P.M. Finch, MD, also of the Women’s College. ■

© K. SOMERVILLE / CUSTOM MEDICAL STOCK PHOTO

Oophorectomy reduces cancer risks

ASCO report highlights cancer care trends THE STATE OF Cancer in America: 2014, a landmark report from the American Society of Clinical Oncology (ASCO), is the first-ever comprehensive assessment of the US cancer care system.

A significant concern highlighted in the report is a predicted shortage of oncologists. The 2013 ASCO census revealed that oncology practices had increased their number of allied health personnel, including certified oncology nurses, nurse practitioners, and licensed practical nurses, as well as physician assistants and medical assistants to address the need for more clinicians.

Furthermore, the trend is predicted to continue. According to the ASCO report, oncology practices are planning to hire more certified oncology nurses and nurse practitioners in the year ahead to meet the needs of increasing patient volume.

The State of Cancer in America: 2014 offers recommendations designed to help oncology clinicians ensure continued availability of oncology services, sustain oncology practices’ ability to meet patient needs in every community, and enhance quality and consistency of care. A downloadable PDF of the complete report is available at www.asco. org/stateofcancercare. ■

NC NN

National Coalition of Oncology Nurse Navigators

Navigator Notes: Distress screening and support Oncology Nurse Navigators (ONNs) provide individualized assistance to patients, families, and caregivers to help overcome health care system barriers and to facilitate timely access to quality medical and psychosocial care from prediagnosis through all phases of the cancer experience. These challenges may change throughout the patient’s cancer treatment and may never be eliminated. Patients with a cancer diagnosis may experience a range of and varying levels of anxiety or distress, but only small percentages of them receive help.

ONNs have the ability to address this anxiety and distress from the moment the nurse engages with the patient. The distress experienced by the patient can be an unpleasant emotional, psychological, social, or spiritual experience that interferes with the patient’s ability to cope with cancer treatment. At any time, a patient may experience strong emotions such as fear, anger, sadness, depression, anxiety, panic, and/or isolation. The lack of psychosocial support can interfere with a person’s ability to relate to family, friends, coworkers, and others throughout the normal routines of daily living. Social distress can be overwhelming. This social distress may be just as overwhelming as when the patient first heard the words “You have cancer.”

Cancer patients are often removed from the flow of life, spending their time getting treatment rather than being at work or with family. Cancer can be a very isolating experience. Patients and their caregivers need to be encouraged to reach out to family and friends or to join a support group to help establish these relationships. Because friends may not always know when or how to offer help, it is important that patients understand the

benefits of talking with a mental health professional about their concerns and worries. The navigator may be the first care team member to recognize that a patient could benefit from meeting with a licensed clinical social worker or psychologist.

Based on the bond that patients build with the ONN, the nurse navigator relationship may make it easier for the patient to open up and express his or her concerns.

The ONN can assist their patients by • Listen closely to the patient’s concerns • Show interest in the patient’s ­experience with cancer • Ask who will provide support ­during cancer treatment; will it be family, friends, or someone else?

• Ask how the patient is adjusting to the cancer and treatment plan • Encourage the patient to continue using coping strategies that are successful • Suggest additional coping strategies to address the patient’s concerns In addition, ONNs can use a distress thermometer. Based on a scale of 0 to 10, the tool is easy to use. Originally designed to be used by physicians to assess patient distress levels, it is available at www.nccn. org. The tool comes with a checklist to help evaluate and recognize distress in patients with cancer.

Because a diagnosis of cancer never interrupts a patient’s life when it is convenient or economically acceptable, the psychosocial well-being of your patient may never be addressed or will be addressed late in the patient’s treatment. ONNs can provide a comprehensive understanding of the patient to other members of the multidisciplinary team and take the lead role in assessing the patients’ needs for possible referral to a mental health specialist. ■ Outside Front

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 11

IN THE NEWS

FDA Update The US FDA expanded the approved use of ibrutinib (Imbruvica) to include patients with chronic lymphocytic leukemia (CLL) who have received at least one previous therapy. Ibrutinib works by blocking the enzyme that allows cancer cells to grow and divide. In November 2013, the FDA granted ibrutinib accelerated approval to treat patients with mantle cell lymphoma, a rare and aggressive blood cancer, if those patients received at least one prior therapy. The most common side effects observed with ibrutinib include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, fever, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness.

The US FDA recently launched a national public education campaign to prevent youth tobacco use and reduce the number of kids between the ages of 12 and 17 years who may potentially become regular smokers. “The Real Cost” campaign is the FDA’s first of several planned tobacco education campaigns.

Subsequent campaigns will target additional discrete audiences, including multicultural youth, rural youth, and lesbian, gay, bisexual, and transgender (LGBT) youth. ■

Humidification during radiation reduces mucositis, hospital stay PATIENTS WHO RECEIVED daily humidification of the mouth and throat region beginning from day one of radiation therapy treatment spent nearly 50% fewer days in the hospital to manage their side effects, according to a study conducted by the Trans Tasman Radiation Oncology Group that evaluated 210 patients with head and neck cancer in New Zealand and Australia from June 2007 through June 2011.

Patients in this phase 3 trial were randomized to institutional standard of care (control arm) or humidification using the Fisher & Paykel Healthcare MR880 humidifier. The humidified air was delivered through the nose via a plastic mask-type apparatus that can be worn while sleeping or while sitting during the day.

Patients began humidification on day 1 of radiation therapy and continued until the ulceration in their mouth and throat had

The return of eating patterns to close to normal was significantly higher at 3 months after radiotherapy in the group using humidifiers.

ONA ASKS …

YES

resolved. On average, humidification patients spent almost half as many days in the hospital to manage side effects (2.3 days vs 4.1 days for control patients). The return of eating patterns to close to normal was also significantly higher at 3 months after radiotherapy in the group using humidifiers.

Only 42% of the humidification group met the defined benchmark of humidification adherence and were able to contribute to the per protocol analysis; the mean average use of humidification for these patients was 3.6 hours per day.

The researchers explained that despite the adherence issues these results are encouraging, particularly because humidification was favored across clinician-reported outcomes, patient-reported outcomes, and independent data such as hospitalizations. The next step is to work at increasing the proportion of patients who use the humidifier effectively. ■

NO

Do you discuss practices such as yoga, cognitive behavioral therapies, or hypnosis with patients?

Go online to answer our poll question. We’ll publish the results and a new question in the next issue. … AND YOU ANSWERED In the last issue we asked if your patients talk to you about dietary supplements they may be taking while undergoing cancer treatment.

70% Yes, often 30% Yes, but rarely

12 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

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ONCOLOGY NURSE ADVISOR FORUM QUESTIONS & ANSWERS

Our Consultants

CREATING EFFECTIVE NAVIGATION TOOLS FOR PATIENTS Would a patient navigation tool be Web-based resources, printed materials, or both? Which member of the treatment team is the ideal person to introduce the resource to the patient and when? — Robert Mark Baldridge

Ann J. Brady, RN, BSN, symptom management care coordinator at the Cancer Center, Huntington Hospital, Pasadena, California.

Jia R. Conway, DNP, FNP-BC, NP-C, oncology nurse practitioner at Cancer Care Associates of York in York, Pennsylvania.

Abimbola Farinde, PharmD, MS, BCPP, CGP, LCDC, PM/ PRC, FASCP, FACA, FNAP, Rsci, ARSPharmS, clinical pharmacist specialist, Clear Lake Regional Medical Center, Webster, Texas Donald R. Fleming, MD, hematologist/oncologist, Cancer Care Center, Davis Memorial Hospital, Elkins, West Virginia.

Kerstin L. Lappen, RN, MS, ACNS, ACHPN, clinical nurse specialist, palliative care consult service, Abbott Northwestern Hospital, Allina Health System, Minneapolis, Minnesota.

K. Lynne Quinn, RN, MSN, CRNP, AOCNP, director of oncology, Bryn Mawr Hospital and Bryn Mawr Health Center, Bryn Mawr, Pennsylvania.

Ideally, a patient navigation tool is easy for the patient to use, and the patient can easily understand the information provided. Many patients are savvy Internet users and have at least one device with which to access the Internet; therefore, web-based resources are helpful. Other advantages include the resource is more likely to be upto-date each time the patient refers to it; the resource is usually available 24 hours a day, 7 days a week; and a greater selection of resources may be available. In addition, some web-based tools are designed specifically for navigators for monitoring patient status and where patients are along the continuum of care. This method usually also allows for creating end-of-treatment documentation that can be shared with the patient and their primary care physicians. This tool then allows all who might be caring for the patient (now survivor) to correctly order needed follow up studies, etc, to do lifetime monitoring.

Printed materials, however, have a few advantages as well. They can be handed to the patient and easily reviewed in person. Patients can show their nurses which information is confusing to them and ask questions, and nurses can be more confident the patient is referring to reliable information. Disadvantages include the increased administrative work to maintain the supply of materials, as well as keeping the supply up-to-date.

The ideal time to introduce a patient navigation tool is at the first patient-education session with the patient’s nurse. Then, at each subsequent visit, the navigation tool can be reviewed, updated, and adjusted to the patient’s information needs. As with many aspects of cancer care, an approach tailored to the patient’s needs is the most effective one. For many patients, a combination of both Web-based resources and printed materials would provide the information they need in a format that enables them to navigate their cancer journey. —The Editors

SOME PORT MAINTENANCE IS OUTSIDE THE SCOPE OF NURSING PRACTICE Is it within a nurse’s scope of practice to flip a port over with a physician’s order? I am getting mixed responses from colleagues, and cannot find any literature that either supports or refutes nurses performing this task. —Jennifer Edwards, RN, BSN, OCN

Lisa A. Thompson, PharmD, BCOP, clinical pharmacy ­specialist in oncology, Kaiser Permanente, Colorado

Rosemarie A. Tucci, RN, MSN, AOCN, manager for oncology research & data services, Lankenau Hospital, Wynnewood, Pennsylvania

This is a controversial question, as nursing practice can differ from state to state. That being said however, Oncology Nursing Society’s standards for caring for vascular

DO YOU HAVE A QUESTION FOR OUR CONSULTANTS? Send it to editor.ona@haymarketmedia.com.

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 13

Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

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

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

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

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40315 January 2014.

727-37345

DIGITAL

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

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

Learn more at TREANDAHCP.com.

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Job Number: 20391 Revision No: 0 Date: 01/08/14

Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

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

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

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

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40315 January 2014.

727-37345

DIGITAL

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

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

Learn more at TREANDAHCP.com.

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Job Number: 20391 Revision No: 0 Date: 01/08/14

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 1 INDICATIONS AND USAGE TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.

Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

2.3 Reconstitution/Preparation for Intravenous Administration Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution.

After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light.

Administration of TREANDA must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1)]

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5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports.

Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials.

Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged.

Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment.

Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal toxicity TREANDA can cause fetal harm when administered to a pregnant woman.

Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infections (5.2); Infusion Reactions and Anaphylaxis (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6). The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial.The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve.

All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse

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Job Number: 20391 Revision No: 0 Date: 01/08/14

reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA (N=153) System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes Simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

Chlorambucil (N=143)

All Grades

Grade 3/4

All Grades

Grade 3/4

121 (79)

52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

0

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

0

5 (3)

0

11 (7)

3 (2)

2 (1)

0

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150

Chlorambucil N=141

Laboratory Abnormality

All Grades n (%)

Grade 3/4 n (%)

All Grades n (%)

Grade 3/4 n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

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In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known.

Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is an antineoplastic product. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial.

16.3 Storage TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

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

All rights reserved.

(Label Code: 00016287.06) 8/2013 TRE-40156 This brief summary is based on TRE-008 TREANDA full Prescribing Information.

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Job Number: 20391 Revision No: 0 Date: 01/08/14

ONCOLOGY NURSE ADVISOR FORUM Management of myoclonus in patients receiving opioids include reduce the drug doses; use muscle relaxants, benzodiazepines, or GABA antagonists; or rotate opioid therapies, utilizing equigesic dosing to control pain. ports does not leave flipping a port as a nursing responsibility. As one can flip the port in the wrong direction, allowing for further kinking and/or breakage of the internal catheter, this should be a procedure done by a physician—preferably under fluoroscopy or after viewing the diagnostic radiographs. Patient safety should always come first. —Rosemarie A. Tucci, RN, MSN, AOCN

DELIVERY ORDER IN IV/IP CHEMOTHERAPY ADMINISTRATION Oncology nurses are taught to always administer platinums before taxanes for IV chemotherapy regimens. Does this still hold true when the taxane is ordered IV, and the platinum is ordered IP? Also, when IV mannitol is ordered, can that be run concurrent with the IP platinum? —Cathy Ollom RN, BSN, OCN When cisplatin is administered before paclitaxel, the beneficial effects of paclitaxel may be decreased. Administering cisplatin before paclitaxel may also change how the patient’s body processes paclitaxel, which can increase its toxic effects. This rule is primarily applicable to IV administration of both drugs. But IP administration changes the dynamics as IP drug delivery is delayed and sustained, so order of administration does not make much difference. Concurrent use of paclitaxel and mannitol is compatible. —Donald R. Fleming, MD

ONCOLO

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Our Con sultants Ann J. Brady, RN, BSN, symptom management coordinator at the Cancercare Center, Hunting ton Hospita Pasadena, l, California.

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HOW TO MANAGE MYOCLONUS IN PATIENTS TAKING HIGH-DOSE OPIOIDS My patient is on high-dose opioids and is experiencing myoclonus. How should this be managed? —Jeri L. Ashley, MSN, RN, AOCNS, CHPN Myoclonus appears to be related to dosing levels of opioids; however, there are also factors related to the specific patient that can contribute. For instance, is the patient experiencing liver or renal insufficiencies? If that is the case, since opioids are excreted through the liver and kidneys, other pain control methods may need to be investigated. Another factor might be one of hydration; make sure the patient is well-hydrated.

Management of myoclonus in patients receiving opioids include reduce the doses of the drugs being administered; use muscle relaxants, benzodiazepines, or GABA antagonists to manage myoclonus symptoms; or rotate opioid therapies, utilizing equigesic dosing to control pain.

Consultation with a palliative care team, if available, would be an excellent resource for managing the symptoms these patients experience. Palliative care clinicians are well-versed in the equigesic doses of pain medications and rotating regimens, as well as the use of the other medications mentioned. —Rosemarie Tucci RN, MSN, AOCN

Let us answer your questions!

Readers are invited to submit clinical questions and requests for advice to our expert Advisor Forum at editor.ona@haymarketmedia.com.

Use “Advisor Forum” in the subject line.

Readers’ drug-related questions are answered by our oncology pharmacist. Submit questions to editor.ona@haymarketmedia.com, with “Ask A Pharmacist” in the subject line.

Please include your full name and degrees, name of institution or practice, and city and state with your question.

18 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

CONTINUING EDUCATION Disclosure of Conflicts of Interest The Nurse Practitioner Healthcare ­Foundation (NPHF) assesses conflict of interest with its instructors, planners, reviewers, and other ­individuals who are in a position to control the content of CE activities. All relevant conflicts of interest that are identified are thoroughly vetted by NPHF for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations.

NPHF is committed to providing its learners with high quality CE activities and related ­materials that promote improvements or quality in health care.

The faculty: Donald R. Fleming, MD, reported no financial relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CE activity.

The planners, reviewers, and staff: Fiona J. Shannon, MHS, FNP; Joyce Pagan; Kristen Childress, DNP, ARNP; Connie Morrison-Hoogstede, MN, ANP, AOCNP; and Genean M. Page, RN, OCN, reported no financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CE activity.

Disclaimer The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of or imply ­endorsement by Nurse Practitioner Healthcare Foundation, American Nurses Credentialing Center, or Haymarket Media Inc. As this article contains only a review, participants have an implied responsibility to use this newly acquired information while also consulting other appropriate sources of information in order to gain full understanding of the topic.

EDUCATIONAL OBJECTIVES After participating in this activity, clinicians should be better able to • Explain the impact of HPV infection on the incidence of head and neck cancer • Explain the staging system used for head and neck cancer • Describe the multimodal approach to managing head and neck cancer

Understanding current and emerging therapies for HNC Donald R. Fleming, MD STATEMENT OF NEED/PROGRAM OVERVIEW Cancers that develop in and around the oral mucosa are collectively referred to as head and neck cancers (HNCs). Although the major risk factors (tobacco use and excessive alcohol use) and most prevalent population (persons older than 60 years) are well-known, a new patient demographic is emerging. A recently identified association between HNCs, particularly oropharyngeal cancer, and human papillomavirus (HPV) infection is reflected in increased incidence of oropharyngeal cancer in younger patients with no other risk factors. In addition, HPV status has an impact on response to treatment. This activity can help oncology nurses refresh their knowledge of the risks and treatments for HNCs, and keep pace with emerging trends in patient populations and new treatment approaches.

CE INFORMATION

Title: Understanding current and emerging therapies for HNC Release date: December 31, 2013 Expiration date: December 31, 2015 Estimated time to complete this activity: 30 minutes

Free continuing nursing education credit of 0.5 is available, of which 0.25 is pharmacology. After reading the article, go to mycme.com to register, take the posttest, and receive a certificate. A score of 80% is required to pass.

Please note that the posttest is available only on myCME.com.

The article may also be viewed at OncologyNurseAdvisor.com and on the Nurse Practitioner Healthcare Foundation Web site: www. ­nphealthcarefoundation.org. For more information, contact Fiona Shannon at fiona@­nphealthcarefoundation.org.

This continuing nursing education activity is provided by the Nurse Practitioner Healthcare Foundation (NPHF).

NPHF is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Target audience: This activity has been designed to meet the educational needs of registered nurses and nurse practitioners involved in the management of patients with cancer.

Media: Journal article and Web site (myCME.com;

OncologyNurseAdvisor.com; nphealthcarefoundation.org)

Co-provided by the Nurse Practitioner Healthcare Foundation and Haymarket Media Inc.

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 19

CONTINUING EDUCATION

EDUCATIONAL OBJECTIVES After participating in this activity, clinicians should be better able to • Explain the impact of HPV infection on the incidence of head and neck cancer • Explain the staging system used for head and neck cancer • Describe the multimodal approach to managing head and neck cancer

Understanding current and emerging therapies for HNC Head and neck cancer treatments have high morbidity rates. Newer options reduce morbidities and offer patients better quality of life after treatment.

DONALD R. FLEMING, MD

© MEDICIMAGE / SCIENCE SOURCE

Dissection of the connective tissue surrounding the isthmus during a thyroidectomy

T

he typical signs and symptoms that can arouse suspicion of cancers in the head, neck, and throat can lead to a delayed diagnosis, as they are manifestations of less morbid conditions. In addition, new associations have been discovered between potential causative factors and head and neck cancers (HNCs).

Advances in radiation modalities, the advent of biologics, and evolving patient demographics challenge oncology clinicians to keep pace with a rapidly changing clinical environment.

The most definitive and significant risk factors for HNCs are tobacco use, excessive alcohol use, and poor oral hygiene. Further, recent research revealed that human papillomavirus (HPV) infection is also associated with these cancers, especially in younger patients.1-5 Approximately 25,000 new cases of throat cancer are diagnosed in the United States each year.2 The typical signs and symptoms that arouse suspicion of cancer in these areas are persistent cough, unexplained voice changes, persistent earaches, and an often-painless

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enlargement in the neck region.6-8 This article provides a review of the anatomy, pathophysiology, and treatment options for head and neck cancers, with a focus on throat cancer. In addition, it will review recent findings on the association between head and neck cancers and exposure to HPV. ANATOMY AND PHYSIOLOGY Cancers within the head, neck, and throat, collectively referred to as HNCs, are pathologically similar. In medical parlance, throat cancer is a subset of HNCs that manifests along the 5-inch, muscular, tubelike structure (pharynx) that sits behind the nose and extends down to the anatomic voice box (larynx). Histologically, HNCs are squamous cell types. Consequently, cancers in the head, neck, and throat are treated similarly regardless of the precise tumor location.6-8 Cancers of the throat are referred to in subtypes: nasopharyngeal cancer (behind the nose), pharyngeal cancer (the back of the mouth), and hypopharyngeal cancer (the lower throat above the esophagus and trachea).6,7 The remaining throat cancers manifest in the glottis, the opening inside the larynx between the true vocal cords. Glottic cancers are further classified as supraglottis and subglottis. The supraglottis is the upper portion of the larynx that extends upward from the glottis to the epiglottis, a flap that protects the trachea when swallowing. The subglottis is the area below the vocal cords and extends to the trachea.2,9,10 THE HPV CONTROVERSY More than 100 types of human papillomavirus have been identified, but only a little more than a dozen types are associated with cancer, as opposed to being the cause of benign lesions, often referred to as genital warts. Types 16 and 18 are the most common cancer-causing HPV types. Whereas HPV16 and HPV18 cause cervical, anal, and penile cancers, only HPV16 has a confirmed association with oropharyngeal cancer.11,12 The choice of diagnostics for HPV has been debated.

Various molecular testing techniques exist but a consensus on the optimal method is not established, as there are no reliable antibodies to the virus. Designation of p16 positivity by molecular testing is generally used in clinical settings and is believed to regulate the adverse prognosis RB gene, which is often unregulated in malignancies, to effect resistance. Reports show that up regulation of p16 expression via HPV downregulates/inactivates RB expression/activity.11,12 HPV-associated head and neck cancers usually involve the oropharyngeal region, including the tongue and the back of the throat.13-16 Oropharyngeal cancer is historically prevalent in people age 60 years and older with a history of alcohol and tobacco product exposure. Currently, prevalence of

oropharyngeal cancer trends toward an association with HPV infection in younger persons.14 Although only 40% to 50% of nonsmokers with oropharyngeal cancer are HPV16-positive, more than 90% of those cancers are HPV16-associated.16 Despite manifesting as larger tumors, the response to both radiation and chemotherapy is much better in patients with HPV-associated cancers than those with non-HPV-associated cancers.13-16 IDIOSYNCRACIES IN STAGING HNC The American Joint Committee on Cancer (AJCC) delineates solid tumors in stages based on location of the primary tumor, nodal status, and metastasis. However, staging head and neck cancers is unique.2,17

Chemotherapy, often administered in conjunction with radiotherapy, was initially pioneered to avoid the need for morbid laryngectomy surgery.

Tumor (T) The greatest variation in staging is relative to the T status.17 Stages T1, T2, and T3 are based on the size of the tumor in some cases (lip and oral cavity, oropharynx, and hypopharynx), but most are staged according to the structure(s) into which the tumor extends (eg, T1 nasopharynx tumors are confined to the nasopharynx; T2 tumors extend to the oropharynx and nasal cavity).

Nodal status (N) Staging nodal status is generally the same among the various subtypes, with nasopharyngeal cancer a lone exception.17 Most notably, N2 status of HNCs is defined differently for tumors of the nasopharynx than for tumors on the other head and neck sites (Table 1). In addition, N3 status includes two subcategories based on whether nodal metastasis greater than 6 cm extends to the supraclavicular fossa.17 Metastasis (M) Head and neck cancer is also somewhat unique in that stage IV disease may not be metastatic per se, but rather is locally advanced, unresectable disease. In almost all other malignancies, stage IV indicates distant metastasis.

Positron emission tomography (PET) is useful for staging HNCs at the start of treatment. PET is also useful for monitoring whether the cancer has remained in remission.

Regardless of disease stage or treatment, diligent followup for evidence of recurrence is necessary for all patients regardless of disease stage or treatments used. Recent data demonstrated that a 12-week posttreatment CT/PET scan is very predictive of sustained disease-free survival.18-20 Continues on page 22

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CONTINUING EDUCATION | Head and neck cancer TABLE 1. Nodal (N) staging for head and neck cancers N stage

All sites except nasopharynx

Nasopharynx

Nx

Regional lymph nodes cannot be assessed

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

No regional lymph node metastasis

N1

• Metastasis in a single ipsilateral lymph node • Tumor ≤3 cm

• Unilateral metastasis in lymph node(s) ≤6 cm • Above the supraclavicular fossaa

N2

• Metastasis in a single ipsilateral lymph node, 3-6 cm OR • Metastasis in multiple ipsilateral lymph nodes, none >6 cm OR • Metastasis in bilateral or contralateral lymph nodes, none >6 cm

• Bilateral metastasis in lymph node(s), ≤6 cm • Above the supraclavicular fossa

N2a

Metastasis in a single ipsilateral lymph node 3-6 cm

N2b

Metastasis in multiple ipsilateral lymph nodes, 3-6 cm

N2c

Metastasis in bilateral or contralateral lymph nodes, none >6 cm

N3

Metastasis in a lymph node >6 cm in greatest dimension

• Metastasis in a lymph node(s), ≤6 cm • Extends to supraclavicular fossa

N3a

>6 cm

N3b

Extends to the supraclavicular fossa

a

Nonthyroid/salivary gland cancers

TREATMENT REGIMENS As with most solid tumors, surgical excision is the treatment of choice. In some cases, however, adequate surgical margins are difficult to achieve without significantly impairing the swallowing mechanism; radiation therapy is preferred in these cases. Advances in robotic surgery have improved morbidity associated with surgical resection, especially for oropharyngeal tumors. As a result, definitive surgery is an additional option for early-stage cancers in this anatomic location, whereas combined chemotherapy/radiation (chemoradiation) were used in the past.21 Early stage disease Stage I or II HNC typically is fairly localized to where it originated; either resection or radiation alone provides effective treatment. Intervention is based on existing comorbidities, and at times, patient preference. A multimodality approach may be necessary if the lymph nodes or surrounding organs are involved (stage III or IVa disease

or possibly metastatic stage IVb). However, most patients with stage IV disease and some patients with stage III disease are treated for palliative purposes only because relapse is likely and prognosis is poor. The goal is to minimize the side effects of progressive cancer.6,7,22 Complete resection of the tumor often results in extreme disabilities (eg, permanent tracheotomy, loss of functional swallowing); therefore, organ preservation is a strong secondary goal.23,24 Chemotherapy, often administered in conjunction with radiotherapy, was initially pioneered to avoid the need for morbid laryngectomy surgery, after which the patient’s inability to talk normally is permanent. However, this regimen still produces many side effects including extreme irritation or burning of the tissue treated and difficulties with swallowing for a long time afterward, possibly indefinitely.23,24 Advanced disease Chemotherapy for HNC consists primarily of regimens of cisplatin and fluorouracil (5-FU).

More recent regimens incorporate alternative platinum-based drugs, such as carboplatin, and the taxanes (eg, docetaxel [Docefrez, Taxotere, generics] and paclitaxel [Abraxane, Taxol]).25-27 Locally advanced disease (stage III or greater) requires aggressive therapy (ie, chemoradiation).

The effectiveness of preemptive or induction chemotherapy followed by chemoradiation, surgery, or both for locally advanced disease is controversial. The primary indications for induction chemotherapy are breathing or swallowing is compromised, comorbidities necessitate delaying other modes of therapy, and presence of T4 laryngeal lesions. In these patients, immediate improvement is desired to avoid clinical decline. HNC is immensely chemosensitive; therefore, induction chemotherapy is effective. In randomized trials, the TPF regimen (docetaxel, cisplatin, 5-FU) demonstrated optimal outcomes in this setting.28 However, despite early evidence that radiation treatment ports may be reduced to a less morbid size, improved outcomes have not been demonstrated.

Radiation, with or without chemotherapy, is often needed after initial surgery to prevent disease recurrence. Although extracapsular invasion and positive margins mandate the additional therapy, no consensus of opinion is established on whether multiple sites of lymph node involvement and lymph vascular/perineural invasion are reasons for additional postoperative therapy.25,26 The initial effects of radiation are an acute inflammatory, painful response followed by permanent scarring of normal tissue, rendering the tissues dysfunctional. At the very least, xerostomia can result; in more severe cases, lifelong problems with dysphasia and odynophagia can result. Some patients may need to use a percutaneous endoscopic gastrostomy (PEG) tube for nutritional support permanently.

22 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

Advances in intensity modulated radiation therapy (IMRT) have changed how radiotherapy is used to treat locally advanced HNC. The computer-directed precision of IMRT reduces the radiation exposure to normal tissue surrounding the tumor. IMRT-based radiation therapy is more appropriate for early-stage and nasopharyngeal primary tumors, rather than large invasive primary tumors or bilateral lymph node involvement.29,30 Nasopharyngeal cancer Nasopharyngeal cancer deviates from the staging parameters used for other head and neck cancers.31,32 Likewise, nasopharyngeal carcinoma is also an unusual exception in treatment approach. Induction chemotherapy with a platinum-based doublet regimen is a common initial therapy, followed by chemoradiation. Surgery plays little if any role in treating nasopharyngeal carcinoma outside of diagnostics. Weekly, low-dose, platinum-based therapies, as opposed to bolus dosing, are used only in highlevel studies conducted in this setting.32 HPV-associated HNC Higher doses of chemotherapy may not be necessary for HPV-associated head and neck cancers, as these tumors tend to have a high sensitivity to older treatment modalities. Thereby, side effects can be avoided yet cure is still achieved. Researchers postulate that HPV infection downregulates the RB gene expression, as well as the p53 mutation effect on cancer cells; in return, the cancer cells are more susceptible to apoptosis when insulted with radiation and chemotherapy. HPV status may become an intricate part of treatment decisions based on this theory as nearly all clinical trials involving oropharyngeal cancers are being stratified based on HPV status to allow attenuation of therapy.11,12 A very recent discovery has led to the potential development of a medication that can block the ability of HPV to convert normal squamous cells to squamous carcinoma cells.33 The results are very preliminary, but appear to indicate the protein E6 can interact with the p53 gene to prevent its conversion from a tumor suppressor gene to a powerful tumor promoter. If these results translate to clinical applications, even previously infected people may be able to minimize their risk of developing cancer.33 Another area of molecular testing that impacts patients with HNC involves gene mutations. Mutant-allele tumor heterogeneity (MATH) is a measure of the degree of genetic mutations and directly correlates with the prognosis for patients with HNC.34 As the MATH score increases, the prognosis worsens. As one may expect, HPV-negative patients have a significantly higher MATH score than HPVpositive patients. This is a dynamic property of the tumor, as the more chemotherapy a patient receives the higher the MATH score can become.34

EMERGING OPTIONS In recent years, targeted and biologic therapies have entered into the mix of therapeutic options. These agents target epidermal growth factor receptors (EGFRs), which are expressed by 90% of head and neck squamous cell carcinomas (HNSCCs). When activated, EGFRs promote cancer growth and metastasis.35,36 Cetuximab (Erbitux) is currently the only EGFR inhibitor FDA approved for HNC. It is approved for initial therapy of locally advanced head and neck cancer, in conjunction with radiation.37-39 The agent effectively inhibits the growth of head and neck cancer cells as monotherapy; however, its effect is more profound when combined with radiation. The agent also seems to enhance the activity of chemotherapy drugs such as cisplatin and, therefore, is also approved for use in conjunction with cisplatin for advanced/ metastatic head and neck cancer.37-39 Panitumumab (Vectibix), an EGFR monoclonal antibody FDA approved for the treatment of colorectal cancer, is fully humanized and has no murine proteins; because of this, it seems to be less likely to cause the hypersensitivity reactions seen in some patients taking cetuximab. Early evidence in a recent study indicates panitumumab, which is not currently FDA-approved for HNC, was effective in patients with head and neck cancers.40 The randomized Spectrum trial showed that adding panitumumab

As in the emerging options for other solid tumors, biologics are likely to play an increasingly significant role in the treatment of HNCs. to conventional chemotherapy for advanced HNC improved outcomes; however, HPV-positive patients did not seem to benefit from EGFR inhibition.40 No trial to date supports combining an EGFR inhibitor with chemotherapy and radiation for locally advanced disease. The standard of care remains chemotherapy or radiation with an EGFR inhibitor but not both, as toxicity is increased but not efficacy.41,42 Integrating alternative forms of anti-EGFR therapies such as oral tyrosine kinase inhibitors (TKIs) has had limited success when erlotinib (Tarceva) was used. Afatinib (Gilotrif), a combination EGFR-inhibitor and HER-receptor inhibitor, may prove more efficacious, but the data are not complete.13,14 Nevertheless, as in the emerging options for other solid tumors, biologics are likely to play an increasingly significant role in the treatment of HNCs. Continues on page 24

www.OncologyNurseAdvisor.com â&#x20AC;˘ MARCH/APRIL 2014 â&#x20AC;˘ ONCOLOGY NURSE ADVISOR 23

CONTINUING EDUCATION | Head and neck cancer Dental issues should be evaluated and corrected prior to therapy, especially if the prescribed regimen is chemoradiation.

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin.

2010;60(5):277-300.

3. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-475.

4. Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer

SUPPORTIVE CARE

In addition to the psychological, social, and spiritual care needs of all patients with cancer, patients with HNCs may be challenged by side effects unique to the location of their tumor.

Supportive care that minimizes or relieves the side effects of the cancer and its treatment is essential for a desired outcome.

For example, impaired eating and swallowing are frequent side effects of HNC treatment. A percutaneous endoscopic gastrostomy tube is often placed prior to initiating therapy in anticipation of the risk for moderate-to-severe oral mucositis associated with radiation therapy. Patients undergoing concurrent chemotherapy and radiation are at higher risk for oral mucositis, and PEG tube placement ensures adequate nutrition can be maintained without interrupting treatment. Although preemptive PEG tube insertion is supported, nonprospective data indicate the practice delays recovery of functional swallowing. A central infusion access device is more universally utilized in patients undergoing chemotherapy.43 Dental hygiene is another essential supportive care need.

Patients with head and neck cancer should undergo a pretreatment dental consultation, preferably by a dentist or orthodontic surgeon subspecializing in head and neck cancers. Any dental issues should be evaluated and corrected prior to therapy, especially if the prescribed regimen is chemoradiation.44

Inst. 2007;99(23):1801-1810.

5. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010. http://www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/document/acspc026238.pdf. Accessed March 26, 2014.

6. DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

7. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer.

Lancet. 2008;371(9625):1695-1709.

8. Piccirillo JF, Lacy PD, Basu A, Spitznagel EL. Development of a new head and neck cancer-specific comorbidity index. Arch Otolaryngol Head Neck Surg. 2002;128(10):1172-1179.

9. Rodu B, Cole P. Oral cavity and pharynx-throat cancer in the United States, 1973-2003. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.

2007;104(5):653-658.

10. Kakodkar KA, Schroeder JW Jr, Holinger LD. Laryngeal development and anatomy. Adv Otorhinolaryngol. 2012;73:1-11.

11. Kimple RJ, Harari PM, Torres AD, et al. Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin Cancer Res. 2013;19(4):855-864.

12. Wittekindt C, Wagner S, Mayer CS, Klussmann JP. Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2012;11:Doc09.

13. Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous

CONCLUSION Head and neck cancers represent a significant form of cancer. Treatment is often associated with extreme morbidity, and mortality rates in patients with HNCs are high. New interventions, however, including biologic therapy to treat and immunologic therapy that prevent these cancers, may significantly improve patient outcomes in the near future.

As with all cancers, prevention by avoiding risk factors is the best defense against head and neck cancers. ■

cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. Head Neck. 2009;31(11):1393-1422.

14. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.

15. Schlecht NF, Burk RD, Adrien L, et al. Gene expression profiles in HPVinfected head and neck cancer. J Pathol. 2007;213(3):283-293.

16. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human

Donald Fleming is an oncologist/hematologist at the Cancer Care Center, Davis Memorial Hospital, Elkins, West Virginia, and a member of the Oncology Nurse Advisor editorial board..

papillomavirus-associated cancers? Cancer. 2007;110(7):1429-1435.

17. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual.

7th ed. New York, NY: Springer; 2009.

18. Yao M, Smith RB, Hoffman HT, et al. Clinical significance of postradio-

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www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 25

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

» Safety was evaluated in 3 Phase III clinical trials1

Indication

Important Safety Information (continued)

» GRANIX (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction

» Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur

TM

in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40137 January 2014.

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

» Safety was evaluated in 3 Phase III clinical trials1

Indication

Important Safety Information (continued)

» GRANIX (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction

» Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur

TM

in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40137 January 2014.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

FEATURE | CAM and cancer treatment

Supplement use with cancer treatment: Helpful or harmful?

Helping patients understand that CAM products and dietary supplements may impede their cancer treatment is an essential part of patient education.

© THINKSTOCK

Caption here like this one here like so.

BRYANT FURLOW

H

oping to improve their symptoms and outcomes, many patients with cancer consume antioxidants, herbs, and other dietary supplements while undergoing radiotherapy and chemotherapy—usually without telling the clinicians who are caring for them.

Oncology team members should seek open discussions with patients about these alternative treatments, including the unknowns and potential risks associated with their use during cancer treatment.

Although herbal and other dietary supplements are little regulated, these substances can have important, and in some cases potentially dangerous, metabolic and drug interactions.1-4 Reports of promising preclinical findings indicating that mixtures of soy isoflavones may mitigate radiotherapy toxicities in the lung are likely to spark increased patient interest in complementary and alternative medicines (CAMs) such as dietary supplements and herbal remedies in general. But not all supplements are as promising, and some may even diminish the therapeutic benefits of conventional cancer treatments.

USE OF CAM PRODUCTS IS COMMON Recent studies indicate that more than a third— possibly more than half—of adult patients with cancer consume complementary medicine supplements while undergoing radiotherapy and chemotherapy, including herbal teas, vitamins and antioxidants, and herbal supplements such as traditional Chinese plant medicines.5,6 Usage www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 29

FEATURE | CAM and cancer treatment is even higher among specific patient populations such as women with breast cancer; usage is prevalent even in children, as up to 84% of pediatric cancer patients are given complementary medicines.7 These substances can be expensive, with older adult patients spending as much as $300 a month on CAM products.6,8 Surveys also reveal that many patients who consume these products do so every day, in the expectation that the products will increase the efficacy of chemotherapy or radiotherapy and extend survival time.5,6 Such optimism about outcomes is out of step with a scant research evidence base, and appears to involve the assumption by patients and advocates that supplements are, at worst, ineffective.

Even more significant, most patients surveyed do not discuss their use of these substances with clinicians.5,6 One recent survey of patients undergoing radiotherapy found that 44% used CAM products while undergoing treatment, but only 12% discussed this with their radiation oncology clinicians.9 Female patients and those with full-time jobs are less likely to discuss the issue with clinicians than are other patients.9

Most cancer patients who report using supplements want specialized consultations to discuss CAM use during cancer treatment.

MORE HARMFUL THAN HARMLESS This is a potentially important gap in clinical communication, treatment planning, and patient education. Some of these substances can affect drug metabolism and, potentially, the efficacy of conventional anticancer treatments. For example, one study revealed that 29% of patients undergoing radiotherapy consume supplementary antioxidants, which can diminish the free-radical tumor-killing effects of irradiation.6,10 Clinical data suggests that antioxidants such as β-carotene and α-tocopherol—a form of the antioxidant vitamin E— can reduce radiotherapy-associated toxicity, but at the lifethreatening cost of reduced tumor control.10 Antioxidant supplements are associated with increased disease recurrence and cancer-specific mortality, as well as reduced overall survival, among smokers undergoing radiotherapy; however, these effects are not associated with nonsmokers undergoing radiotherapy.10 The available scientific literature regarding the effects of dietary supplements during cancer treatment is contradictory

and overwhelmingly preclinical.11 (A prohibition on federally funded medical marijuana research has prevented robust development of an evidence base on marijuana use among cancer patients.12) Clearance and circulating concentrations of medications that are metabolized by P450 enzymes (eg, CYP3A4) might be modulated by herbs that inhibit P450 activity, such as goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts.13 Their use has potentially important but poorly understood implications for chemotherapy and radiochemotherapy. Furthermore, the constituent and active ingredients of popular herbal supplements, such as black cohosh, grape seed and green tea extracts, and gingseng, vary between commercial brands, resulting in inconsistent and variable dosing and making it difficult to extrapolate research outcomes to patients’ dosing and outcomes.14 For example, green tea extract appears to interact significantly with P450 CYP3A4-metabolized drugs, but to varying degrees depending on the brand of extracts involved.14 Preclinical research also suggests that vitamin C (ascorbic acid) may reduce the bioavailability of bortezomib (Velcade) and that black cohosh increases tamoxifen toxicity, while immunomodulating supplements (eg, echinacea) might diminish the effects of cancer immunotherapies.15 COMMUNICATION IS KEY Communication between oncology team members and their patients about supplement use during conventional therapy is important. Patients’ understanding of the risks and benefits of supplements are often rooted in nonscientific or quasiscientific online literature, books, and supplement manufacturers’ brochures, and word-of-mouth communication with other patients and well-intentioned family members, coworkers, and friends.5 Patients can only make informed decisions about the risks and potential benefits of supplement use during cancer therapy if they are aware of the unknowns and the evidence for interactions between supplements and cancer therapies.

Although most patients with cancer do not discuss their use of CAM products with their cancer care teams, most of those who report using supplements say they want specialized consultations to discuss CAM use during cancer treatment.5 However, clinicians are not always prepared to discuss these issues with their patients; for example, physicians have reported being uncomfortable discussing the issue.9 No randomized, controlled clinical trials have addressed how best to discuss these issues with patients, but researchers have developed some guidelines using the weaker evidence.16 They recommend discussing patients’ use of alternative

30 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

The uncertainties and concerns about dietary supplements should be openly, but respectfully, communicated to patients.

sources of information and the need for counseling [published online ahead of print September 30, 2013]. Eur J Cancer Care (Engl). 2013. doi:10.1111/ecc.12132 6. Gillett J, Ientile C, Hiscock J, et al. Complementary and alternative medicine use in radiotherapy: what are patients using? J Altern Complement Med. 2012;18(11):1014-1020.

7. Kelly KM. Complementary and alternative medical therapies for children

medicines, with respect to their cultural beliefs. Oncology nurses should ask questions about their use of CAM products, and provide balanced, evidence-based advice. The discussion should be documented, and any reports of using alternative medicines or supplements should be noted. Some researchers have recommended monitoring for potential adverse effects associated with alternative treatments during conventional treatment.16 The uncertainties and concerns about dietary supplements—both their efficacy and their possible negative interactions with conventional cancer therapies—should be openly and clearly, but respectfully and supportively, communicated to patients. ■

with cancer. Eur J Cancer. 2004;40(14):2041-2046.

8. Palatty PL, Haniadka R, Valder B, et al. Ginger in the prevention of nausea and vomiting: a review. Crit Rev Food Sci Nutr. 2013;53(7):659-669. doi:10.

1080/10408398.2011.553751.

9. Ge J, Fishman J, Vapiwala N, et al. Patient-physician communication about complementary and alternative medicine in a radiation oncology setting. Int J Radiat Oncol Biol Phys. 2013;85(1):e1-e6. doi:10.1016/j.ijrobp.

2012.08.018.

10. Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?

J Natl Cancer Inst. 2008;100(11):773-783.

11. Haniadka R, Popouri S, Palatty PL, et al. Medicinal plants as antiemetics in the treatment of cancer: a review. Integr Cancer Ther. 2012;11(1):18-28. doi:10.1177/1534735411413266.

Bryant Furlow is a medical journalist based in Albuquerque, New Mexico.

12. Furlow B. States and US government spar over medical marijuana.

Lancet Oncol. 2012;13(5):450. doi:10.1016/S1470-2045(12)70152-3.

13. Etheridge AS, Black SR, Patel PR, et al. An in vitro evaluation of cyto-

REFERENCES

chrome P450 inhibition and P-glycoprotein interaction with goldenseal,

1. Gorman GS, Coward L, Darby A, Rasberry B. Effects of herbal supple-

Gingko biloba, grape seed, milk thistle, and ginseng extracts and their

ments on the bioactivation of chemotherapeutic agents. J Pharm Pharmacol. 2013;65(7):1014-1025. doi:10.1111/jphp.12055.

constituents. Planta Med. 2007;73(8):731-741.

14. Wanwimolruk S, Wong K, Wanwimolruk P. Variable inhibitory effect of

2. Schönthal AH. Adverse effects of concentrated green tea extracts. Mol

different brands of commercial herbal supplements on herbal cyto-

Nutr Food Res. 2011;55(6):874-885. doi:10.1002/mnfr.201000644.

3. Yokotani K, Chiba T, Sato Y, et al. Effect of three herbal extracts on cyto-

chrome P-450 CYP3A4. Drug Metabol Drug Interact. 2009;24(1):17-35.

15. Furlow B. Understanding the interaction between food and treatment.

chrome P450 and possibility of interaction with drugs [in Japanese].

Oncol Nurse Advis. 2010;1(4):29-34. http://www.oncologynurseadvisor.

Shokuhin Eiseigaku Zasshi. 2013;54(1):56-64.

com/understanding-the-interaction-between-food-and-treatment/

4. Hermann R, von Richter O. Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Med. 2012;78(13):1458-

article/177852/. Accessed March 26, 2014.

16. Schofield P, Diggens J, Charleson C, et al. Effectively discussing comple-

1477. doi:10.1055/s-0032-1315117.

mentary and alternative medicine in a conventional oncology setting:

5. Pihlak R, Liivand R, Trelin O, et al. Complementary medicine use among cancer patients receiving radiotherapy and chemotherapy: methods,

communication recommendations for clinicians. Patient Educ Couns.

2010;79(2):143-151.

FROM THE ONA FACT SHEETS LIBRARY

ON THE

WEB

Breast Cancer Risk in American Women

Colorectal Cancer: The Importance of Screening and Early Detection

Finding Emotional Support for LongTerm Illness

Share these and other Fact Sheets with your colleagues and patients.

For these and more fact sheets on oncology topics go to www.OncologyNurseAdvisor.com/fact-sheets

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 31

FEATURE | Genomic testing in HER2+ breast cancer

Guidelines update leaves out novel breast cancer tests ONA talked to an expert in genomic testing about why the updated ASCO/ CAP guidelines should support the use of mRNA and DNA microarray assays.

© LAWRENCE BERKELEY NATIONAL LABORATORY/ SCIENCE SOURCE

Illustration of a technique for reading DNA microarrays, which allow thousands of genes to be tested at once.

KATHY BOLTZ, PhD

R

ecent guidelines state that all patients with invasive breast cancer should have their human epidermal growth factor receptor 2 (HER2) status determined.1 The guidelines support the use of immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH), but not genomic testing through mRNA or DNA microarrays. The guidelines were jointly issued by the American Society for Clinical Oncology (ASCO) and the College of American Pathologists (CAP), and they are an update of guidelines issued in 2007.2 The recent guidelines define a tumor as HER2-positive (HER2+) when IHC determines protein overexpression or when FISH determines gene amplif ication. In cases where the results are equivocal, an alternative assay (IHC or FISH) should be performed.

Furthermore, the test should be repeated if its results seem discordant with other histopathologic findings. These tests are recommended in the new guidelines because they are evidence-based.

However, the guidelines do not support the use of mRNA or DNA microarray assays. The Update Committee stated that, in their opinion, “there is insufficient evidence to support the use of mRNA or DNA microarray assays to determine HER2 status in unselected patients.”1 Oncology Nurse Advisor (ONA) spoke with Massimo Cristofanilli, MD, about his concerns about genomic testing being left out of the new guidelines. Cristofanilli is director of

32 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

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FEATURE | Genomic testing in HER2+ breast cancer [Cristofanilli’s] study found that the molecular subtyping led to a more accurate molecular classification than classification by IHC/FISH. the Breast Care Center at the Kimmel Cancer Center and Thomas Jefferson University and Hospitals in Philadelphia, Pennsylvania. He considers the new guidelines a missed opportunity to incorporate genomic testing as part of the standard of care, and he argues that tumor heterogeneity will never be completely captured by single-gene testing.

His research demonstrates that more accurate subtyping results in better treatment.

Cristofanilli recently presented research on the use of tumor subtyping through the combined use of genomic testing with MammaPrint and BluePrint (both from Agendia; Irvine, California) to identify disease subgroups.3 The retrospective study of 374 patients had a median follow-up of 9.7 years, and it used the genomic tests to determine molecular subtypes of the patients’ tumors. The molecular subtypes for breast cancer are luminal A, luminal B, HER2, and basal. The patients had been classified by IHC/FISH into three categories: hormone receptor-positive/HER2–, HER2+, or triple-negative. The study examined how subtypes and prognostic stratification varied with genomic testing versus IHC/FISH. The researchers found that the molecular subtyping led to a more accurate molecular classification than classification by IHC/FISH. Also, molecular subtyping allowed for clinically significant prognostic stratification. Based on their data, the authors advocate considering the use of MammaPrint and BluePrint to select adjuvant therapy in patients with primary breast cancer.

ONA: What is the message from your recent research? How does the additional information from molecular subtyping affect a patient’s treatment plan?

Cristofanilli: The message is that IHC-defined subtypes are not accurate. They do not necessarily reflect biology.

We found that up to 25% of IHC-defined subtypes did not correspond to molecular subtypes.

This finding had a number of implications. For example, a patient who was defined as estrogen receptor-positive, but who in reality had a basal-like subtype, would likely not receive a lot of benefit from 5 to 10 years of endocrine therapy.

Accurate selection of subtypes can help in the selection of treatment and in the subsequent outcomes. Molecular subtypes determine sensitivity to chemotherapy and pathological response.

ONA: Why did the ASCO/CAP Update Committee conclude that evidence was insufficient to support using mRNA or DNA microarray assays in HER2 testing?

Cristofanilli: A number of reasons exist for that decision.

First, there is a lack of strong prospective study data. Right now, we are anxiously awaiting results from the TAILORx trial, which is testing Oncotype DX (Genomic Health Inc; Redwood City, California) in patients with early breast cancer. (Oncotype DX examines tumor tissue at the molecular level to make predictions about the likelihood of chemotherapy benefit and of recurrence.)

Even though there is not a large volume of data indicating clinical efficacy in a large prospective trial, genetic profiling has been shown to be able to identify a patient who has a need for chemotherapy or who has a subtype for which chemotherapy is not indicated.

Another obstacle is cost. Any new test has a cost, and because of this cost, even when it is FDA approved and has partial reimbursement by insurance, some physicians are reluctant to use it in practice.

ONA: What proportion of patients would be affected if molecular testing is not done?

Cristofanilli: The figures are around 20% to 25%. As clinicians, we need to inform patients. Sometimes patients are awaiting additional test results to understand their disease.

Many times patients are more eager to select treatment immediately, and we just provide recommendations to patients without the background or knowledge that testing provides. It is essential that patients want to know more.

Clinicians need to have an open discussion with patients.

Every health care provider, including nurses, needs to be educated and to provide, as much as possible, unbiased information to their patients. ■ Kathy Boltz is a medical writer based in Phoenix, Arizona.

REFERENCES 1. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013.

2. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):118-145.

3. Yao K, Turk M, Kaul K, et al. MammaPrint and BluePrint in early breast cancer: clinical implications of prognostic stratification and molecular subtyping. Poster presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, Texas. Poster P2-11-23.

40 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

FEATURE | Yoga improves survivorship issues

Yoga has a positive impact on breast cancer survivorship A clinical trial demonstrated that hatha yoga practice improved fatigue and lowered inflammatory markers IL-6, TNF-α, and IL-1β in women survivors.

At 3-month follow-up, Sue Cavanaugh (pictured) and other study participants experienced a 57% reduction in fatigue and a drop in inflammation of as much as 20%.

BETTE WEINSTEIN KAPLAN

A

focus on feeling good about yourself is always a good goal, and the more often a patient does things that are good for her, the better she feels. So it is with yoga for breast cancer survivors. A newly published study, the largest ever on the medical benefits of yoga, provides clinical evidence that practicing Hatha yoga can diminish inflammation and reduce fatigue in breast cancer survivors—and these results can be achieved in as short a time as 3 months. Furthermore, the investigators found that the more often the women practiced yoga, the more effective it was.1 Given that chronic inflammation contributes to such health-related issues as type 2 diabetes, arthritis, Alzheimer disease, coronary heart disease, and age-related decline, controlling or reversing it can have wide-ranging benefits.

Janice Kiecolt-Glaser, PhD, professor of psychiatry and psychology at The Ohio State University, in Columbus, is lead author of the study.1 Kiecolt-Glaser is also an investigator at Ohio State’s Comprehensive Cancer Center and the Institute for Behavioral Medicine Research, both also in Columbus.

© OSUCCC – JAMES

SELECTION CRITERIA AND STUDY METHODOLOGY

The study was a randomized, controlled clinical trial that lasted 5 years, and comprised 200 participants ranging in age from 27 years to 76 years. The investigators chose women whose breast cancer treatments were completed before www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 41

FEATURE | Yoga improves survivorship issues the study began. They also chose women whose cancer stage ranged between 0 and IIIa, and whose treatments were different, as well. Kiecolt-Glaser explained that the wide range in variables was deliberate so the study results could apply to a broad population of cancer survivors.

The investigators were concerned with how practicing yoga affects inflammation, cancer-related fatigue, depression, sleep quality, energy, and vitality among women who survived breast cancer. The effects were measured using scores from standard assessment tools for fatigue, depression, and overall health, and blood tests, all obtained at baseline, at the immediate conclusion of a 12-week treatment period, and 3 months after completing treatment.

The frequency of yoga practice was more strongly associated with improvements in fatigue and vitality than with depression.

Results were assessed via the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the Center for Epidemiologic Studies Depression scale (CES-D), and the vitality scale from the Medical Outcomes Study 36-item short form (SF-36). Blood tests evaluated lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β).

The women were divided into groups of four to 20 women.

Each group attended two 90-minute yoga sessions per week for 12 weeks. If a participant missed a session, the instructor called her to follow up. The women also practiced their yoga poses at home, and kept a log of their classes attended and home practice times for each week. None of the women had practiced yoga prior to participating in the study, and all groups were instructed in identical yoga poses.

A broad assessment of symptoms revealed an atypical presentation The patient’s symptoms suggested airway obstruction due to a hypopharyngeal tumor; however, imaging studies showed a mass in an unexpected location.

MArciA M. KendAll, dnP-c, APrn-Bc, AcHPn; Teri KAul, PHd, rn, APrn-Bc, APnP

Mr. N. was a 45-year-old man with a history of end-stage renal disease (ESRD) receiving dialysis three times per week and had been a patient in the palliative care clinic for the past 2 years. He had gone to the trauma and emergency center (TEC) 3 days earlier after having passed out and reported dizziness and shortness of breath (SOB). Laboratory tests from the TEC visit included hemoglobin, 7.7 g/dL, a decrease from test results obtained 2 weeks earlier (9.9 g/dL); creatinine, 4.4 mg/dL, which was within normal limits for this patient; and d-dimer, 500 ng FEU/mL, which was deemed to be inconclusive because the patient had a bruise on his right rib cage area. He was given two units of packed blood red cells (RBCs) and discharged home with instructions to perform Hemoccult testing and to return to the palliative care clinic for follow-up.

Per instructions from the TEC, Mr. N. was at the palliative care clinic for the follow-up. His girlfriend of many years was with him because she had witnessed the fall on the day he presented to the TEC, and she was concerned about the syncopic episode. A subjective history revealed that Mr. N.

RESULTS WERE IMPRESSIVE, AND IMMEDIATE Improvements were reported as soon as the treatment phase of the trial was completed. The yoga group reported that they were sleeping better. They were found to have an average of 41% less fatigue and their vitality score was 12% higher compared with the control group. At the 3-month followup, reported fatigue was 57% lower among the yoga group than the control group, and a 20% reduction in inflammatory markers was seen as well.

Depression, however, was not significantly different between the two groups at the end of treatment or at 3-month follow-up. Secondary analyses showed that the frequency of yoga practice was more strongly associated with improvements in fatigue and vitality than with depression.

The researchers concluded that fatigue and inflammation were substantially reduced in those survivors who engaged in yoga practice. Vitality was higher among the yoga practitioners immediately posttreatment, and both vitality and fatigue were improved at 3 months posttreatment. In addition, inflammatory markers IL-6, TNF-α, and IL-1β were lower in the yoga group.

Furthermore, the women who practiced more frequently saw greater benefit from the treatment. “This is the first physical activity trial with breast cancer survivors to show significant inflammatory changes,” the researchers said.

“If yoga dampens or limits fatigue and inflammation, then regular practice could have substantial health benefits.”1 ■ Bette Weinstein Kaplan is a medical writer based in Tenafly, New Jersey.

REFERENCE 1. Kiecolt-Glaser JK, Bennett JM, Andridge R, et al. Yoga’s impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial [published online ahead of print January 27, 2014]. J Clin Oncol. 2014.

Do you have a Case Study to share?

case study

CASE

The researchers also included a wait-list control group. At the conclusion of the 12-week treatment, the control group was offered the yoga program.

had sustained multiple falls during the past month. In describing three of the falls, Mr. N. reported experiencing a tunnellike sensation closing in on him and his windpipe “clamping off just before he went down.” His girlfriend reported noting that his lips were blue and he was gurgling. She dialed 9-1-l and opened his airway. Mr. N. became responsive after paramedics arrived and administered oxygen.

Mr. N.’s social history included a 32-year history of smoking 1.5 packs of cigarettes per day and past alcohol addiction with no current use. Other past drug use included methamphetamines and hallucinogens. Mr. N. also reported increasing shortness of

breath, wheezing, chest pain, insomnia, confusion, constipation, mild edema in the lower extremities, and difficulty walking.

Physical examination findings

included BP, 100/70 mm Hg; heart rate, 78 beats per minute and regular; oxygen saturation, 92% at rest and 90% with ambulation; and respiratory rate, 24 breaths per minute. Oral mucosa was dry, pink, and no masses were noted in the throat. No lymphadenopathy was noted. The patient was alert and oriented to person, place, and time, and mildly anxious with depressed affect.

His skin was pale, he was cachetic, and appeared ill. Bilateral lower extremity edema was 2+. Cardiovascular rate and

Case Study articles are valuable learning tools and a great way to share your clinical knowledge and experiences with your colleagues. And our template makes writing one so easy.

1. Go to our author guidelines at OncologyNurseAdvisor.com/author-guidelines 2. Scroll down to Case Study and “click here for a template to follow …”

3. Submit your Case Study to editor.ona@haymarketmedia.com.

FIGuRe 1. Anteroposterior and lateral radiographs of the patient’s neck

42 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com www.OncologyNurseAdvisor.com • JANUARY/FEBRUARY 2011 • oNcologY NURsE AdvisoR 27

ONA_YogaFeature0414.indd 42

3/31/14 4:39 PM

STAT CONSULT

© COURTESY OF ELI LILLY AND COMPANY

Gemcitabine (Gemzar) Drug type

• A nucleoside metabolic inhibitor Indications

• In combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy

• In combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure or prior anthracyclinecontaining adjuvant chemotherapy, unless anthracyclines were clinically contraindicated • In combination with cisplatin for the treatment of nonsmall cell lung cancer • As a single agent for the treatment of pancreatic cancer

——Teratogenic, embryotoxic, and fetotoxic in mice and rabbits • Lactation ——Not known whether gemcitabine is excreted in human milk Contraindications

Mechanism of action

• Contraindicated in patients with a known hypersensitivity to gemcitabine

• Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary

Cautions

Dosage and administration

• Ovarian cancer ——1,000 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle • Breast cancer ——1,250 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle • Non-small cell lung cancer ——1,000 mg/m2 over 30 minutes on days 1, 8, and 15 of each 28-day cycle; or ——1,250 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle • Pancreatic cancer ——1,000 mg/m 2 over 30 minutes once weekly for the first 7 weeks, then 1 week rest, then once weekly for 3 weeks of each 28-day cycle Pregnancy and lactation

• Pregnancy category D

• Schedule-dependent toxicity ——Increased toxicity with infusion time >60 minutes or dosing more than once weekly • Myelosuppression ——CBC with differential should be checked prior to each cycle and reduce or withhold dose for severe myelosuppression • Pulmonary toxicity and respiratory failure ——Discontinue immediately for unexplained new or worsening dyspnea • Hemolytic-uremic syndrome (HUS) ——Monitor renal function at baseline and during therapy ——Discontinue for HUS or severe renal impairment • Hepatic toxicity ——Monitor hepatic function at baseline and during therapy ——Discontinue for severe hepatotoxicity • Embryofetal toxicity ——Advise women of potential risk to the fetus • Exacerbation of radiation therapy toxicity ——Severe and life-threatening toxicity may occur when

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 43

STAT CONSULT administered during or within 7 days of radiation therapy • Capillary leak syndrome ——Discontinue gemcitabine • Posterior reversible encephalopathy syndrome (PRES) ——Discontinue gemcitabine Adverse effects

• Most common adverse reactions (≥20%) ——Anemia ——Dyspnea ——Elevated alkaline phosphatase and transaminases ——Fever ——Hematuria ——Nausea/vomiting ——Neutropenia ——Peripheral edema ——Proteinuria ——Rash ——Thrombocytopenia Interactions

• No formal clinical drug interaction trials have been conducted What to tell your patient

• Your doctor has prescribed this anticancer medicine that is used either in combination with another agent or on its own to help treat a variety of cancers (ovarian, breast, non-small cell lung, and pancreatic cancers).

• This medication is only given intravenously.

• Tell your nurse or doctor if ——You have had allergic reactions in the past.

——You have kidney or liver problems.

——You have any other medical conditions.

• Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

• Gemcitabine may harm the fetus.

——You should not plan to have children while receiving chemotherapy or for a while after treatments.

——Use a reliable method of birth control to prevent pregnancy.

• Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do no have serious side effects.

• Always inform your health care provider if you experience any unusual symptoms.

• This medication may cause low blood cell counts and

severe and life-threatening infections.

——Contact your physician or nurse immediately if you have signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath.

• This medication may cause serious side effects.

——Pulmonary toxicity, including respiratory failure and death ■■ Contact your health care provider for shortness of breath, wheezing, or cough ——Hemolytic-uremic syndrome and associated renal failure ■■ Contact your health care provider if you notice changes in the color or volume of urine output or if you have increased bruising or bleeding ——Hepatic toxicity, including liver failure and death ■■ Contact your health care provider if you notice any yellowing of the skin and eyes (jaundice) or for pain/ tenderness in the right upper abdomen ——Posterior reversible encephalopathy syndrome ■■ Contact your health care provider for drowsiness, seizures, vomiting, confusion, diminished speech and spontaneity, and visual abnormalities ——Severe allergic reactions ■■ May occur within a few minutes after your infusion starts, especially during the first and second infusions ■■ Your doctor should prescribe medicines before each infusion to help prevent severe allergic reactions.

■■ Tell your nurse or doctor right away if you have any of these symptoms of a severe allergic reaction during or soon after an infusion »» Breathing problems »» Chest or throat tightness »» Feeling dizzy or faint »» Rash or itching »» Skin redness »» Swelling of face ——Gastrointestinal symptoms ■■ Severe vomiting and diarrhea with this medication can lead to loss of too much body fluid (dehydration), or too much of your body salts (electrolytes) ■■ Tell your nurse or doctor if you have vomiting or diarrhea ——Kidney failure ■■ Kidney failure may occur because of severe infection, dehydration, and other reasons ■■ Tell your nurse or doctor if you develop »» Swelling of your face or body »» Decrease in the amount of urine ■ Prepared by Ashley Purohit, PharmD.

44 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

COMMUNICATION CHALLENGES

Unattended grief

© ISTOCK

Ann J. Brady, MSN, RN-BC

Many nurses follow an unspoken code of silence in regard to grief.

H

ow do you handle work-related grief?

Can you leave it at work, or do you take it home with you? What support is the most helpful to you when a patient dies?

CASE Tracy washed her hands at the sink behind the nurse’s station. I leaned against the wall next to her. “How are you doing?” I asked.

“Me?” She looked up with surprise. “Oh, I’m fine.”

“I wanted to check in. Seems like we’ve lost quite a few patients lately.”

“I’m OK.” She focused on scrubbing her hands.“Just have to keep going.”

I took a step back. The last thing I wanted was to make her feel like I was grilling her.

“Sure, but let me know if you want to talk.”

She shrugged. “Thanks for checking.”

I walked down the hall knowing that for the moment there was nothing else to do. I

was satisfied that I had at least made an effort to check in with her. In oncology, we share patients and are impacted by their disease process in different ways, yet how we choose to handle it is a personal choice.

There is a saying that bad things happen in threes. We had seen a trio of deaths on the unit; all three were relatively young patients, which made it especially difficult on everyone involved in their care. One patient in particular touched many of us.

Susanna was a young mother, that was part of it, but perhaps a bigger part was that she faced it full on, and with grace. I don’t know why it happens that we get attached to some patients more than others, but she was one of them. Her death hit us all hard.

A day after Susanna died, I stopped by the unit and spoke with Kate, a nurse who had taken care of Susanna more often than the others.

“Doing okay?” I asked.

She smiled but did not look up. “Yeah.”

“Been a tough couple of weeks.”

She looked up then, blinking back tears.“It’s just so sad. I thought I was okay but later, when I was getting meds for another patient, I started to cry.”

“It’s hard.”

“I didn’t want anyone to see me crying.”

As a new grad, Kate worried that showing her grief would make her look like a “bad” nurse to the more experienced staff, as if showing her grief made her weak when she was supposed to be strong. In the article, “A Time to Grieve,” the author says many nurses follow an unspoken code of silence in regard to grief, and just as Kate did, worry that showing grief will make them look weak to other nurses.1 We nurses are trained to

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 45

COMMUNICATION CHALLENGES assess our patient’s needs, everything from physical to psychological, but at times we may not look up long enough to assess our fellow nurses, or even ourselves.

“Let me know if you need to talk.”

She wiped a tear, “Okay.”

As I walked away I realized I was more comfortable with Tracy stoically washing her hands while we spoke than I was when Kate told me she had gone into the med room and cried. I followed the unspoken code of silence, too. It wasn’t that I judged Kate negatively because she cried, but it made me uncomfortable. It was easier if she nodded and said she was okay.

Becoming desensitized to death is easy; yet doing so is unhealthy for us and for those in our care.

DISCUSSION There are many books written about grief, there are grief support groups, there is talk of burnout and compassion fatigue, yet my struggle was anxiety that I might say or do the wrong thing. Dealing with expressions of grief can be complicated. My uncertainty about saying the right thing held me back.

What if Kate started to cry again? What if Tracy felt threatened or scrutinized by me?

There are certain things that are dangerous to leave unattended. A baby should not be left unattended in a bath. A campfire should not be left unattended in the forest.

Grief is another thing that should not be left unattended. Stoicism in the face of grief and hiding our grief from others are ways of failing to attend to grief. The trio of deaths, and especially Susanna dying, triggered an awareness that leaving grief unattended

JOIN THE CONVERSATION • Are you comfortable talking about your grief to other nurses?

• What do you do when another nurse (health care provider) expresses difficulty coping with loss and grief?

ON THE

WEB

Go to OncologyNurseAdvisor.com/challenges_grief to join the conversation in the Comments section on how you manage your grieving process after the loss of a patient.

was not healthy. Wenzel and colleagues describe a qualitative research project that helped identify the challenges of workrelated bereavement.2 One consistent report from the nurses in the study was that giving staff the opportunity to debrief and dialogue about their grief had a positive impact on managing work-related bereavement.

The loss of three patients in a short period of time made it clear that we needed to address feelings of grief and loss. After several discussions with the palliative care team, the physician member approached management about offering a grief workshop. In a surprisingly short period of time, we were able to organize a program that followed a workshop format with an emphasis on the shared experience of grief and loss. By validating grief, the workshop allowed those of us who participated to acknowledge the impact those patient losses made. It encouraged us to develop a team approach to dealing with the losses.

One communication challenge in oncology is how to address the toll grief takes on our practice. Frequently checking in with staff creates the environment that allows for expression of grief. Becoming desensitized to death is easy; yet doing so is unhealthy for us and for those in our care. I was anxious about my conversations with Tracy and with Kate, worried about saying the wrong thing.

But in both cases asking was as important as what I asked because it started a conversation. The workshop helped us continue the conversation. ■ Ann Brady is the symptom management care coordinator at the Cancer Center, Huntington Hospital, Pasadena, California.

REFERENCES 1. Achenbach S. A time to grieve. Johns Hopkins Nursing Magazine. 2010;8(1):44-46. http://magazine. nursing.jhu.edu/2011/11/a-time-to-grieve/.

Accessed March 5, 2014.

2. Wenzel J, Shaha M, Klimmick R, Krumm S. Working through grief and loss: oncology nurses’ perspectives on professional bereavement. Oncol Nurs Forum. 2011;38(4):E272-E282.

46 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

RADIATION & YOUR PATIENT

© DR. P. MARAZZI / SCIENCE SOURCE

R Taxomifen-related rash in a woman with breast cancer

Diagnosis of radiation recall hampered by delayed occurrence Bryant Furlow Long recognized as an uncommon but potentially serious side effect of systemic cytotoxic anticancer therapies administered after irradiation, radiation recall phenomenon is now associated with the administration of targeted therapies after radiotherapy, as well. The available literature is almost exclusively anecdotal, and the evidence base for this syndrome’s management is scant. Most commonly, treatment involves dose reduction or discontinuation, anti-inflammatory medication, and drug rechallenge. However, anecdotal reports suggest that in mild cases, close monitoring against worsening symptoms might allow continued administration of triggering drugs, including targeted biologics.

adiation recall is an acute, druginduced inflammatory reaction in previously irradiated—but usually, previously normal-appearing— tissues.1,2 Recall tends to be a localized reaction; however, it can spread.1 First described in 1959 after administration of the antibiotic actinomycin D, the majority of cases involve the skin; but in approximately one-third of cases, other tissues are involved including the oral mucosa, respiratory tract and digestive mucosa, genitourinary tract, muscle, lung tissue, and the brain.1-4 Radiation recall has been reported as late as 25 years after irradiation, and in rare cases, as late as 9 months after cessation of the triggering chemotherapy agent—suggesting that the syndrome involves long-lasting or permanent changes to a patient’s irradiated tissues.1,5 Radiation recall is most commonly reported after administration of systemic anticancer agents such as doxorubicin (Doxil, generics), docetaxel (Docefrez, Taxotere, generics), paclitaxel (Abraxane, Taxol, generics), gemcitabine (Gemzar, generics), and capecitabine (Xeloda, generic), but can occur with antibiotics and other drugs ( Table 1). Howard Burris III, MD, and Jane Hurtig, of the Sarah Cannon Research Institute in Nashville, Tennessee, advise clinicians to keep the potential for radiation recall in mind with the use of any drug after radiotherapy.1,8,9 In recent years, however, reports have also described radiation recall reactions to targeted anticancer therapies, such as kinase and angiogenesis inhibitors (eg, bevacizumab [Avastin], sunitinib [Sutent, generic], pazopanib [Votrient], sorafenib [Nexavar], vemurafenib [Zelboraf]).10-15 “Radiation recall is drug-specific for any given patient; it is not possible to predict which patients will react to

which drugs,” report Burris and Hurtig.1 Because radiation recall can be misdiagnosed as a nonradiotherapy-related adverse drug reaction or infection, or go undiagnosed, its incidence among cancer patients is not well understood.1 Some small studies have estimated frequencies of approximately 9% of patients who receive chemotherapy after radiotherapy.16 MECHANISM OF ACTION The mechanisms of radiation recall are not yet understood; hypothesized factors include stem cell depletion or acquisition of genetic mutations by stem cells within irradiated volumes, changes in irradiated vasculature, oxidative

Patients commonly have no history of acute reactions in the affected tissues. stress and local DNA damage, upregulation of drug-specific pathways, and drug hypersensitivity reactions.1,17 In the case of trastuzumab emtansine (T-DM1)-triggered symptomatic brain edema in patients with brain-metastatic breast cancer who previously underwent stereotactic radiosurgery, it has been hypothesized that radiation upregulates HER2/neu gene expression, possibly in normal glial cells, increasing subsequent sensitivity to trastuzumab.4 Radiation recall is sometimes described as a delayed variant of radiosensitization, but the mechanisms of recall and radiosensitization might well be different.1 Patients commonly have no history of acute radiation reactions in the affected tissues.1 Continues on page 48

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 47

RADIATION & YOUR PATIENT TABLE 1. Cancer treatments that can trigger radiation recall symptoms Nontargeted therapies

Targeted/biologic agents

• Bleomycin

• Bevacizumab (Avastin)1

• Capecitabine (Xeloda, generic)

• Erlotinib (Tarceva, generic)10

• Cisplatin, administered with epirubicin

• Gefitinib (Iressa)1

• Cyclophosphamide

• Ixabepilone (Ixempra kit)7,10

• Cytarabine (Cytosar-U, Depocyt, generics)

• Pazopanib (Votrient)10

• Dacarbazine (DTIC-DOME, generics)

• Sunitinib (Sutent, generic)10,13

• Dactinomycin (Cosmegen, generics)

• Sorafenib (Nexavar)10,14

• Docetaxel (Docefrez, Taxotere, generics)

• Trastuzumab (Herceptin)4,10

• Doxorubicin (Doxil, generics)

• Vemurafenib (Zelboraf )20

1

• Epirubicin (Ellence, generics), administered with docetaxel or cisplatin • Etoposide • Gemcitabine (Gemzar, generics) • Idarubicin (Idamycin PFS, generics) • Interferon α-2b (Intron A) • Letrozole (Femara, generics)6 • Lomustine (Ceenu) • Methotrexate (Otrexup, Trexall, generics) • Oxaliplatin (Eloxatin, generics) • Paclitaxel (Abraxane, Taxol, generics) • Pemetrexed (Alimta) • Tamoxifen (Soltamox, generics) • 5-Fluorouracil (5-FU)

As with radiation recall, radiosensitization is emerging as a pattern of dermatologic toxicity with targeted therapies such as epidermal growth factor receptor [EGFR] blockade.11,18 Clinically, radiation recall is distinguished from drug radiosensitization by its later appearance—weeks, months, or years after radiotherapy—but in most cases, relatively soon after systemic drug or targeted agent therapy.1 Although there is no clear specific window of risk, most cases occur immediately or within a few weeks of drug administration.1 Therefore, some researchers suspect that a longer interval between radiotherapy and initiation of chemotherapy (eg, more than 3 weeks1) might reduce the risk of radiation recall reactions.

MANAGING RADIATION RECALL SYMPTOMS

Management of recall reaction has not undergone randomized, controlled clinical study, but usually involves drug discontinuation or dose reduction, topical or systemic corticosteroids, or nonsteroidal anti-inflammatory therapy, and rechallenge after symptoms abate.1,2 Patients with radiation recall symptoms should be told to avoid sun exposure and advised to use sunscreen and to avoid tanning beds.1 Antihistamines might help relieve symptoms in some patients.1 Isolated case reports have attempted to identify candidate topical agents that might allow treatment without drug discontinuation, such as hyaluronic acid, which increases wound granulation.19

48 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

In mild cases, drug reduction or continued medication at target therapeutic doses with supportive care is viable.

Recall reactions associated with systemic agents very rarely resolve without drug discontinuation, but that might not be the case for targeted agents.1 More research is needed before clinical guidelines can be promulgated, but anecdotal reports suggest that in mild cases triggered by targeted agents such as vemurafenib or erlotinib (Tarceva, generic), monitoring and management of radiation recall symptoms with corticosteroids might allow continued use of the triggering agent without dose reduction.3,20 In the lung, these can appear as radiographic opacities and consolidation in lung tissues with preexisting radiation fibrosis that can be mistaken for new nonradiationassociated, drug-induced lung damage.3 Optimal time intervals for drug dose reduction or interruption are not well understood, and might reflect triggering agents’ pharmacokinetics. Typically, with systemic anticancer drugs, symptoms resolve within 2 weeks (or even within hours of discontinuation when intravenous drugs are involved).1 Except in severe cases, rechallenge is commonly attempted after drug interruption.1 “The risk versus benefit balance and availability of alternative equallyeffective agents must be considered,” note Burris and Hurtig.1 Rechallenge is not always successful.1,17 Because of the anecdotal nature of the available literature, success rates for rechallenge are not known. Some authors have suggested that corticosteroid premedication prior to rechallenge might reduce the risk of recall recurrence, but this claim has not undergone clinical study.1 “Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized

by using the lowest possible dose of radiation and prolonging the interval between completion of radiotherapy and initiation of chemotherapy,” Burris and Hurtig conclude.1 ■

6. Foster LM, Mahoney ME, Harmon MW, et al.

triggered radiation recall dermatitis with

apy in breast cancer [published online ahead

a disseminated exanthematous reaction.

of print January 3, 2014]. Clin Breast Cancer.

Radiat Oncol J. 2013;31(3):171-174.

2014;pii:S1526-8209(13):00316-9. doi:10.1016/ j.clbc.2013.12.011.

Bryant Furlow is a medical journalist based in Albuquerque, New Mexico.

7. Takiar V, Strom EA, Baumann DP, et al.

Locoregional interaction of ixabepilone (ixempra) after breast cancer radiation.

REFERENCES

Oncologist. 2013;18(3):265-270.

1. Burris HA 3rd, Hurtig J. Radiation recall

8. Haas RL, de Klerk G. An illustrated case of

with anticancer agents. Oncologist.

doxorubicin-induced radiation recall derma-

2010;15(11):1227-1237.

titis and a review of the literature. Neth J Med.

2. Caloglu M, Yurut-Caloglu V, Cosar-Alas R, et

2011;69(2):72-75.

al. An ambiguous phenomenon of radia-

9. Eckardt MA, Bean A, Selch MT, Federman N.

tion and drugs: recall reactions. Onkologie.

A child with gemcitabine-induced severe

2007;30(4):209-214.

radiation recall myositis resulting in a com-

3. Arakawa H, Johkoh T, Sakai F, et al.

Exacerbation of radiation fibrosis with erlotinib: another pattern of radia-

14. Oh D, Park HC, Lim HY, Yoo BC. Sorafenib-

Radiation recall reaction with letrozole ther-

15. Azad A, Maddison C, Stewart J. Radiation recall dermatitis induced by pazopanib. Onkologie. 2013;36(11):674-676. doi:10.1159/000355649.

16. Kodym E, Kalinska R, Ehringfeld C, et al.

Frequency of radiation recall dermatitis in adult cancer patients. Onkologie.

2005;28(1):18-21.

17. Barlési F, Tummino C, Tasei AM, Astoul P. Unsuccessful rechallenge with pemetrexed after a previous radiation recall dermatitis.

Lung Cancer. 2006;54(3):423-425.

18. Furlow B. New patterns of dermatologic

partment syndrome. J Pediatr Hematol Oncol.

toxicity with radiation and EGFR blockade.

2013;35(2):156-161.

Oncol Nurse Advis. 2012;3(4):2931. http://www.

10. Levy A, Hollebecque A, Bourgier C, et al.

oncologynurseadvisor.com/new-patterns-

tion recall phenomenon. Jpn J Radiol.

Targeted therapy-induced radiation recall.

of-dermatologic-toxicity-with-radiation-

2011;29(8):587-589.

Eur J Cancer. 2013;49(7):1662-1668.

and-egfr-blockade/article/246307/. Accessed

4. Carlson JA, Nooruddin Z, Rusthoven C, et al. Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in

11. Niyazi M, Maihoefer C, Krause M, et al.

Radiotherapy and “new” drugs-new side effects? Radiat Oncol. 2011;6:177.

March 13, 2014.

19. Bauer SM, Bauer C. The use of sodium hyaluronate for the treatment of radia-

clinically significant brain edema [published

12. Bourgier C, Massard C, Moldovan C, et al.

online ahead of print February 3, 2014]. Neuro

Total recall of radiotherapy with mTOR

2009;15(2):123-126. http://opp.sagepub.com/

Oncol. 2014. doi:10.1093/neuonc/not329.

inhibitors: a novel and potentially frequent

content/15/2/123.refs?patientinform-links=

5. Melnyk SM, More KF, Miles EF. Idiopathic

side-effect? Ann Oncol. 2011;22(2):485-486.

yes&legid=spopp;15/2/123 [subscription

radiation recall dermatitis developing nine

tion recall dermatitis. J Oncol Pharm Pract.

13. Yuasa T, Kitsukawa S, Sukegawa G, et al. Early

required]. Accessed March 13, 2014.

months after cessation of cisplatin therapy in

onset recall pneumonitis during targeted

20. Boussemart L, Boivin C, Claveau J, et al.

treatment of squamous cell carcinoma of the

therapy with sunitinib. BMC Cancer. 2013;13:3.

Vemurafenib and radiosensitization. JAMA

tonsil. Case Rep Oncol Med. 2012;2012:271801.

http://www.biomedcentral.com/1471-2407/

Dermatol. 2013;149(7):855-857. doi:10.1001/

doi:10.1155/2012/271801.

13/3. Accessed March 13, 2014.

jamadermatol.2013.4200.

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www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 49

© COURTESY OF THE COLON CLUB

ISSUES IN CANCER SURVIVORSHIP

Molly McMaster crawls through the Colossal Colon

D

o you have a 2014 Colondar hanging on your wall? You should. It sends a powerful message of hope. You may have read about the Colondar in a prior “Issues in Cancer Survivorship” story about Lynch Syndrome survivor David Dubin, who was Mr. January in 2012.1 This is the 10th year that the unique calendar is being distributed. Published by The Colon Club, each month of the Colondar features a revealing photograph of a survivor of colorectal cancer. No stereotypical older men appear in this calendar; for this year’s Colondar, the models are 12 young men and women who received their diagnoses of colorectal cancer before they were 50 years old.

THE COLON CLUB Two young women started the Colon Club in 2003: survivor Molly McMaster whose colon cancer diagnosis came on her 23rd birthday, and Hannah Vogler, whose cousin and McMaster’s friend, Amanda Sherwood Roberts, died of colon cancer when she was 27 years old.

McMaster and Vogler wanted to spread the word that anyone could have colon cancer. Their goal was to bring colon talk to the table; to spread the knowledge about colon cancer to as many people as possible, as early as possible, and to do it in interesting, unique, and outside-thebox ways. They proposed that colon cancer should be part of normal, everyday

A 40-foot colon and 10 years of Colondars celebrate cancer awareness and survivorship Bette Weinstein Kaplan conversation, with discussions including risk factors, symptoms, and the appropriate time to go for screening.

Crazy projects According to the Colon Club web site: “Our crazy projects are designed to get people of all ages to finally pay attention to colorec-

The message boards on Colon Talk share poignant questions and answers. tal cancer, to help prevent the disease and to SAVE LIVES!”2 The first crazy project Molly McMaster undertook was Rolling to Recovery, a 2,000-mile inline skate ride from New York to Colorado following her diagnosis and treatment. When she was chosen to take a turn at carrying the Olympic Torch in 2002, Katie Couric invited her to discuss colon cancer on the Today Show.

Couric’s husband died of colorectal cancer, and she is an important advocate of colorectal cancer awareness. She gave McMaster a challenge to come up with something crazy for March, Colorectal Cancer Awareness Month. The young women took up the gauntlet and built the “Colossal Colon,” which made its debut on the Today Show.

50 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com

The Colossal Colon At 40 feet long and 4 feet tall, this crazy project is a model of the human colon designed for children and adults to crawl through.

But this is not just any 40-foot long colon—this one accurately depicts cancerous and noncancerous polyps, the stages of colorectal cancer, and diseases such as Crohn disease, ulcerative colitis, diverticulosis, and hemorrhoids.

Artists created the colon using colonoscopy images, carving and painting each feature by hand. For those who would rather not take the invasive journey, Coco—yes, it has a nickname— has windows along its length. People can peek at a polyp, or see why those hemorrhoids are so bothersome. Coco travels, and enhances colorectal cancer awareness by visiting hospitals, malls, museums, and other locations throughout the United States and Canada.

COLON TALK FORUM The Colon Club web site (www.colon club.com) is a resource for education and support about colorectal cancer survival. The message boards on its Colon Talk support forum are full of poignant questions and answers.

Conversations pull no punches; one recent post was about cancer growing on a patient’s scar tissue, another asked “How do we die?” But other posts discuss exercise and fitness, modeling for the 2015 Colondar, and invitations

to special events or a night out. There is a lot of humanity here.

SPREADING AWARENESS AND HOPE

The Colon Club does amazing things.

It raises hope. It sponsors bike rides, ice hockey games, and soccer events.

It provides support and answers for patients, families, and caregivers. The website has a store stocked with the practical (personal cleanliness items), the whimsical (a semi-colon T-shirt), jewelry, and of course, the annual Colondar.

Colon Talk recently launched a partnership with Michael’s Mission, an organization devoted to improving the quality of life and treatment options for people with colorectal cancer. Both organizations will improve the quality of life for cancer patients with one interactive, web-based platform.

And then there is the new 2014 Colondar, sponsored by a number of businesses and nonprofit organizations that support the mission of colon cancer advocacy and awareness. The awardwinning Colondar’s special mission is to raise awareness of how prevalent

colon cancer is and to encourage screening among young adults. You can get yours at the Colon Club store. ■ Bette Weinstein Kaplan is a medical writer based in Tenafly, New Jersey.

REFERENCES 1. Kaplan BW. First a patient, now a patient advocate, Dave Dubin is more than a cancer survivor [Issues in Cancer Survivorship]. Oncol Nurse Advis. 2012;3(6):45-46.

2. Crazy projects. The Colon Club web site. http://www.colonclub.com/crazy-projects/.

Accessed March 12, 2014.

VIRTUAL SUMMIT: Best Practices Our Conference Hall is Still Open!

If you missed our virtual conference, want to review the two CE webcasts — Evidence-Based Skin Care Strategies for Managing Dermatologic Effects of Radiotherapy Presented by K. Lynne Quinn, RN, MSN, CRNP, AOCNP — The Long and Short of Pain Management: A Review Presented by Anna E. Hitron, PharmD, MS, BCOP or want to revisit the Exhibition hall, you can access the archived conference

OncologyNurseAdvisor.com/summit12014

www.OncologyNurseAdvisor.com • MARCH/APRIL 2014 • ONCOLOGY NURSE ADVISOR 51

© DAVID MACK / SCIENCE SOURCE

ASK A PHARMACIST

Conceptual illustration of a stimulated site of pain (ball of barbed wire)

Managing peripheral neuropathy related to ­vincristine Has any medicine or supplement been shown to help lessen severity of peripheral neuropathy related to vincristine? Glutamine or gabapentin has not been successful in our experience.

—Carrie L Lewis, RN, MSN, CPNP, CPON

Vincristine (Oncovin) is used in the treatment of a variety of cancers, including some leukemias and lymphomas. Rates of peripheral neuropathy with vincristine vary between regimens and patient populations, and have been reported in 35% to 45% of patients in some studies. Risk factors for development of peripheral

neuropathy include higher doses of vincristine, larger cumulative doses of vincristine, the presence of baseline neuropathy, and some drug-drug interactions. Patients experiencing peripheral neuropathy due to vincristine may experience pain, tingling, numbness, and reduced sensation in the hands and feet.

Management of peripheral neuropathy may depend on the severity of symptoms and the patient’s treatment course.

Patients with clinically significant neuropathy during vincristine therapy should be monitored closely and considered for a dose-reduction or vincristine discontinuation. Improvement or resolution of neuropathy may take up to 2 years, and some patients may experience a worsening of their neuropathy symptoms after vincristine is discontinued.

Unfortunately, some patients may have ongoing neuropathy even after this time.

Treatment options for vincristine and other chemotherapy-induced peripheral neuropathy include tricyclic antidepressants (eg, amitriptyline [Elavil]), anticonvulsants (eg, carbamazepine [Tegretol]), gabapentin (Neurontin), pregabalin (Lyrica), and serotoninnorepinephrine reuptake inhibitors (eg, duloxetine [Cymbalta]). Some supplements, such as glutamine and pyridoxine, have also been studied in the prevention of peripheral neuropathy.

Although multiple agents have been studied to treat chemotherapy-induced peripheral neuropathy, no agents have consistently shown a benefit in randomized phase 3 clinical trials. Opioids

or other analgesics may be required to control pain symptoms in patients whose pain is not managed.

Early detection of vincristine-induced peripheral neuropathy with appropriate adjustment of a patient’s vincristine therapy is critical to reduce the risk of long-term neuropathy symptoms after treatment. Patients with persistent symptoms should be referred to a neurologist for a thorough work-up and consideration of alternate therapies. Working with an occupational therapist may also be helpful to restore lost function due to neuropathy.

TIP FOR PATIENTS National Drug Take-Back Day: April 26, 2014

Spring 2014 DEA Drug Take Back Day events will be held on Saturday, April 26, from 10 AM to 2 PM. These events are a great way for patients to dispose of expired or unwanted medications, including controlled substances such as pain medications. Since beginning in 2010, these events have disposed of more than 1,733 tons of prescription medications. For more information, including collection sites in your area, please visit www.deadiversion.usdoj.gov/ drug_disposal/takeback/ after April 1st.

For information on how to advise patients regarding other ways to dispose of nonchemotherapy medications, please visit www.oncologynurseadvisor.com/ educating-patients-about-the-properdisposal-of-old-drugs/article/168850/. ■

Lisa A. Thompson, PharmD, BCOP Clinical Pharmacy Specialist in Oncology Kaiser Permanente, Colorado

52 ONCOLOGY NURSE ADVISOR • MARCH/APRIL 2014 • www.OncologyNurseAdvisor.com