MEDICAL MINUTES Regular exercise cuts young women’s risk of early breast cancer
ONCOLOGY NUTRITION Registered dietitians play varied roles in cancer care
CANCER CENTER PROFILE Multidisciplinary team at Cleveland Clinic Taussig Cancer Institute provides patient-centered care
JUNE 2008 • VOL. 1, NO.2
© Bridget Laudien
New ONS President Seeks to Elevate Voice of Oncology Nursing An interview with Brenda Nevidjon, MSN, RN, FAAN President, Oncology Nursing Society Brenda Nevidjon, MSN, RN, FAAN, spoke with The Oncology Nurse shortly after assuming her new duties as president of the Oncology Nursing Society (ONS). She spoke about
Nurses convene at the 33rd Annual Congress of the Oncology Nursing Society.
her own education and training, discussed the importance of participation in professional associations for new and experienced nurses, and outlined the goals she hopes to achieve during her term in office.
What made you decide to become a nurse? I have a fourth-grade essay that describes why I wanted to be a nurse, so my interest began early.
Prevention and Management of
College of Nursing Continuing Nursing Education
Good Hand Hygiene Reduces Hospital-acquired Infections
ith the diagnosis of cancer comes the reality of an unforgiving disease process that renders the body’s natural defenses impotent. While this causes great anguish in and of itself, it is often what comes next that proves to be more troublesome. The cancer treatment itself presents formidable challenges to patients—the chemotherapy-induced neutropenia, persistent nausea and vomiting, alopecia,
PHILADELPHIA—Rigorous attention to hand hygiene rather than a complicated antibiotic regimen is the optimal means of lowering the risk of hospitalacquired infections in oncology patients, researchers pointed out at the 33rd Annual Congress of the Oncology Nursing Society.
Continued on page 14
Continued on page 5
Complimentary CE Credit
Continued on page 7
Cetuximab-induced Hypersensitivity: Case Reports and Discussion of Management
PAID LEBANON JUNCTION, KY
© 2008 Green Hill HealthCare Communications, LLC
CLINICAL TRIALS UPDATE
Trials of new therapies for early breast cancer under way
Beth Faiman, RN, MSN, APRN, BC, AOCN Taussig Cancer Institute
Medical Minutes BY JOHN SCHIESZER
Aspirin May Do More than Help with a Headache John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at email@example.com.
An aspirin a day may help reduce a woman’s risk of developing the most common kind of breast cancer, according to researchers at the National Cancer Institute (NCI). Previous studies have shown that aspirin can help combat some cancers, notably those of the lung, bowel, and pancreas. Now, for the first time aspirin has been shown to lower the risk for hormone-sensitive breast cancer. In 75% of breast cancers, tumors are fueled by estrogen. As reported in the May 2008 issue of Breast Cancer Research, Gretchen Gierach, MD, of the NCI, Rockville, Maryland, and her colleagues studied 127,000 women and found that aspirin was linked to a small reduction in the risk of having estrogen receptor (ER)–positive breast cancer. The women, aged 51 to 72 years,
were enrolled in the National Institutes of Health AARP Diet and Health Study, which is examining the links between diet, behavior, and cancer. The general use of non-steroidal anti-inflammatory drugs (NSAIDs) had no influence on overall susceptibility to breast cancer. Daily doses of aspirin, however, resulted in a 16% reduction in risk for ER-positive cancer. The researchers believe these new findings support further evaluation of the relationship between aspirin and ER-positive cancer in prospective studies with well-defined measures of NSAID use. In addition, they believe more research should be done to evaluate individual NSAID types and their effect on ER status.
Girls and young women who exercise regularly between the ages of For the current analysis, the researchers examined data on a 12 and 35 years have a substantially lower risk of breast cancer before subset of women enrolled in the Nurses’ Health Study II, a menopause than those who are less active, researchers at Washington prospective study of registered nurses ages 24 to 42 years. These University School of Medicine, St. Louis, and Harvard University, 64,777 women had completed detailed annual questionnaires Boston report. about their levels of physical activity from age 12 and older. The study, which involved nearly 65,000 women, was the largest After 6 years of follow-up, 550 women had been diagnosed with and most detailed analysis to date of the effects of exercise on pre- breast cancer. menopausal breast cancer. It showed that those who were physicalThe researchers found the age-adjusted incidence rates for ly active had a 23% lower risk of breast cancer before menopause. invasive breast cancer dropped from 194 cases per 100,000 perIn particular, high levels of physical activity from ages 12 to 22 years son-years in the least active women to 136 cases in the most were the strongest contributors to the lower breast cancer risk. active. The levels of physical activity reported by the most “We don’t have a lot of prevention strategies for premenopausal active women were the equivalent of running 3.25 hours per breast cancer, but our findings clearly show that physical activity week or walking 13 hours per week. The benefit of exercise was during adolescence and young adulthood can pay off in the long run not linked to a particular sport or intensity but was related to by reducing a woman’s risk of early breast cancer,” said lead study total activity. (See also story on page 22.) investigator Graham Colditz, MD, who is associate director of prevention and control at the Siteman Cancer Center at Blood Test for Lung Cancer Showing Promise Washington University School of A simple blood test may be able to detect whether or not cancer was present,” Dr Medicine. “This is just one more reason to lung cancer in its earliest stages with Vachani explained. encourage girls and young women to exerunprecedented accuracy, according to new cise regularly.” To test the accuracy and validity of the research presented at the American method, the researchers recruited 44 Nearly one fourth of all breast cancers are Thoracic Society’s 2008 International patients with early- stage lung cancer and 52 diagnosed in women before menopause. Conference in Toronto, Canada. Numerous studies have shown that physical controls who were matched for age, smoking “CT [computed tomography] screening status, sex, and race. They used a number of activity reduces the risk of postmenopausal results in the detection of lung nodules in genetic arrays to determine the best targets breast cancer, but the few studies that have 20% to 60% of subjects,” said Anil Vachani, for detecting the presence of cancer and looked at the influence of exercise on breast MD, an assistant professor of medicine at the found that a 15-gene array had the highest cancer risk before menopause have proUniversity of Pennsylvania, Philadelphia. accuracy at 87%. duced conflicting results. “This high false-positive rate requires “These findings suggest that lung cancers patients to undergo extensive follow-up interact with circulating white blood cells investigations, such as serial CT scans or and change the types of genes that are active biopsies. This [blood] test may be able to in these cells. This finding can be potentially obviate the need for such things if it is devel- used to develop a noninvasive diagnostic test oped into a large-scale diagnostic tool.” for patients suspected of having lung cancer,” Because lung cancer is a very diverse dis- Dr Vachani said. “A diagnostic test that could ease, screening for it can be difficult. The more accurately determine the risk of cancer researchers hoped to identify a stable and in patients would be extremely valuable and consistent way of determining the presence have very important economic implications of lung cancer by testing for the gene expres- by reducing unnecessary surgery, biopsies, and sion of white blood cells. Rather than repeated imaging tests.” screening for factors released by the incipiThe researchers now plan to perform valient tumor into the bloodstream, the test Dr dation studies to further evaluate the utility Vachani and colleagues used looked at gene of this approach for diagnosing lung cancer expression in the subject’s own circulating in a larger population. If the results are white blood cells. “We found that the type of encouraging, they hope to conduct a gene present in these cells could tell us prospective clinical trial. June 2008
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Young Women May Cut Their Risk of Early Breast Cancer through Regular Exercise
Vol. 1, No. 2
9 Conference News: Scenes from the 33rd Annual Congress of Oncology Nursing Society
10 Cancer Center Profile Cleveland Clinic Taussig Cancer Institute
17 Continuing Education
1 Medical Minutes 16
Clinical Trials Update
Cetuximab-induced hypersensitivity: Case reports and discussion of management
20 Oncology Nutrition Role of the Registered Dietitian in Cancer Care
The Official Newspaper of Record for the Hem/Onc Nurse
EDITORIAL BOARD EDITOR-IN-CHIEF
Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH Isabell Castellano, RN Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ Deena Damsky Dell, RN, MSN, AOCN, BC Fox Chase Cancer Center Philadelphia, PA Wendy DiSalvo, BSN, MSN, FNP, AOCN Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center Lebanon, NH
Denice Economou, RN, MN, AOCN City of Hope National Medical Center Duarte, CA Amy Ford, RN, BSN, OCN Creative Cancer Concepts, Inc. Rockwall, TX
The Official Newspaper of Record for the Hem/Onc Nurse
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Marilyn L. Haas, PhD, RN, CNS, ANP-C Mountain Radiation Oncology Asheville, NC Cassandra J. Hammond, RN, MSN, CRNP Avid Education Partners, LLC Sharpsburg, MD Taline Khoukaz, NP, MSN, ACNP-C University of Southern California Norris Cancer Center & Hospital Los Angeles, CA Sandra E. Kurtin, RN, MS, AOCN, ANP-C Arizona Cancer Center Tucson, AZ Ann McNeill, MSN, RN, NP-C, OCN The Cancer Center at Hackensack University Medical Center Hackensack, NJ Kena C. Miller, RN, MSN, FNP Roswell Park Cancer Institute Buffalo, NY Dolores “Jeff” Nordquist, RN, MS, CS, FNP Mayo Clinic Rochester, MN Melinda Oberleitner, RN, DNS, APRN, CNS College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA Lisa Schulmeister, MN, RN, APRN-BC, OCN, FAAN New Orleans, LA
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Joseph D. Tariman, RN, MN, ARNP-BC, OCN University of Washington School of Nursing Seattle, WA Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN Saratoga, CA Connie Visovsky, RN, PhD, APRN University of Nebraska, College of Nursing Omaha, NE Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN Frank P. Whyte, RN, OCN Mount Carmel Hospital—St. Ann’s Westerville, OH Rita Wickham, OCN, PhD, RN Rush University College of Nursing Rush-Presbyterian-St. Luke’s Medical Center Chicago, IL Karla Wilson, RN, MSN, FNP-C, CPON City of Hope National Medical Center Duarte, CA OTHER SPECIALTIES Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ Barbara Savage, LISW Cleveland Clinic Taussig Cancer Institute Cleveland, OH Amanda Saldivar, MS, RD, LD Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Gelclair ® can bring a smile to the face of patients with oral mucositis
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GELCLAIR ® provides soothing, long-lasting pain relief1 at the first sign of oral mucositis. Contains no alcohol and no lidocaine, so patients won’t experience drying, stinging or numbing.
Prescribe 6 boxes of GELCLAIR® for a 30 day supply GELCLAIR® is available at your local pharmacy and at:
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For additional information, visit www.gelclair.com or call 1-877-GELCLAIR. Ingredients: Water, Maltodextrin, Propylene Glycol, Polyvinylpyrrolidone (PVP), Sodium Hyaluronate, Potassium Sorbate, Sodium Benzoate, Hydroxyethylcellulose, PEG-40 Hydrogenated Castor Oil, Disodium Edetate, Benzalkonium Chloride, Flavoring, Saccharin Sodium, Glycyrrhetinic Acid. Contents: 15 mL per single-use packet. Commercial boxes contain 15 single-use packets. (NDC 24477-010-15) Indications: GELCLAIR® has a mechanical action indicated for the management of pain and relief of pain by adhering to the mucosal surface of the mouth, soothing oral lesions of various etiologies, including oral mucositis/stomatitis (may be caused by chemotherapy or radiation therapy), irritation due to oral surgery, traumatic ulcers caused by braces or ill-fitting dentures, or disease. Also indicated for diffuse aphthous ulcers. Contraindications: The administration of GELCLAIR® is contraindicated in any patient with a known or suspected hypersensitivity to any of its ingredients. Side effects: At the time of producing this leaflet, no adverse effects have been reported in clinical trials with the use of GELCLAIR®. Postmarketing reports have included infrequent complaints of burning sensation in the mouth. Reference: 1. Innocenti M, Moscatelli G, Lopez S. Efficacy of Gelclair® in reducing pain in patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:455-457. GELCLAIR® is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland. Manufactured for Helsinn Healthcare SA, Lugano, Switzerland. Marketed and distributed by EKR Therapeutics, Inc., Cedar Knolls, NJ 07927.
© 2008 EKR Therapeutics, Inc. All rights reserved.
A Letter from the Editor
O BETH FAIMAN, RN, MSN, APRN, BC, AOCN
ncology nurses recently convened in Philadelphia for the 33rd Annual Congress of the Oncology Nursing Society (ONS). In an interview, Brenda Nevidjon, new president of ONS, discusses her own education and training and shares her thoughts on why involvement in professional organizations such as ONS is important for both new and experienced nurses. As she points out, oncology offers a wide variety of opportunities for nurses throughout their career. Nurses can not only work in any of the many subspecialties of oncology but also in diversified settings, such as inpatient, outpatient, home, and hospice care. To keep up with this complex and rapidly advancing field, continuing education (CE) is essential. This month, The Oncology Nurse is proud to introduce the first in a series of complimentary continuing education articles accredited by the University of Nebraska Medical Center College of Nursing Continuing Nursing Education. The articles in this series are based on outstanding articles in the peerreviewed literature with commentaries on their potential clinical implications by oncology nurses and pharmacists. The CE article this month addresses the issue of hypersensitivity reactions to cetuximab. Findings of a study recently reported in the
New England Journal of Medicine (NEJM) suggest a possible cause for these reactions: preexisting immunoglobulin E antibodies were highly predictive of cetuximab-induced anaphylaxis. The CE article in this issue summarizes the key points of the NEJM article and provides case reports and commentaries on the potential application of these important findings in clinical practice. Oral mucositis is another serious complication of cancer therapy that can have a major impact on the patient’s quality of life and ability to tolerate therapy. The article by Frank P. Whyte in this issue provides practical recommendations for prevention and management of this common, debilitating side effect. Also in this issue, is the first in a series of profiles of major cancer centers. This month features my own institution, the Cleveland’s Clinic Taussig Cancer Institute. The articles in this series are meant to convey the unique features of a particular institution and their approach to cancer care as well as to provide staff members’ insights into what it is like to work there. We welcome your thoughts on this issue and suggestions on what clinical and nonclinical topics you would like to see covered in future issues of The Oncology Nurse. Please send your comments to Karen@greenhillhc.com.
To the Editor am not an oncology nurse. However, I have the privilege of working in the Nursing Department at Fox Chase Cancer Center, as a project manager in the Department of Nursing Research. My job involves projects for the principal investigator, who also happens to be the director of nursing research. I understand that you are interested in thoughts regarding life without an oncology nurse. I had an immediate visceral response to
issues and symptoms seemed to be lacking. In my friend’s case, she had a particular visit to the hospital with severe neuropathic pain. The care she received for her pain fell short, as I personally witnessed her suffering. Ultimately, she had a stroke and had to spend time in a rehabilitation center recovering from the results of the stroke. I firmly believe that if she had been in a cancer center, where there is a greater awareness and understanding of the need to control cancer-related pain and how to control that pain, her and suffering may have I believe that care by trained oncolo- stroke been avoided. Of course, I realize that sometimes with gy nurses could have made a differeven the best of care, cancer pain can be difficult to conence in my friend’s case. trol. Nonetheless, I believe that care by trained oncology this query. One of the reasons that I am in the nurses could have made a difference in my friend’s field of healthcare, particularly in the area of case. This is one of the many reasons why oncolooncology, is that I had the experience of being a gy nurses are essential to the quality of care that a close caregiver of a dear friend. She was treated cancer patient receives. at a cancer center in a hospital in Philadelphia, Thank you for broaching this topic. but during her hospitalizations, the nurses caring for her were not necessarily oncology nurses. Of Sincerely, course, I cannot verify that, but the hospital is a Katie Stewart, MSPH general hospital, and, although she may have Project Manager - Nursing Research been placed in a room on an oncology floor, the Fox Chase Cancer Center primary focus of the hospital was not cancer care. As a result, the sensitivity to specific cancer Cheltenham, PA
Life without an oncology nurse Oncology nurses play many essential roles in the care and support of patients with cancer and their caregivers. Write to Karen@greenhillhc.com to share your thoughts on what a cancer patient’s life would be like without an oncology nurse. 4
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CONFERENCE NEWS Continued from cover
“According to the Centers for Disease Control (CDC), 90,000 of the roughly two million hospitalized patients who contract a hospital-acquired infection each year will die from their infection or related complications,” said Julie Overbey, RN, BSN, nursing education specialist at Banner Good Samaritan Medical Center in Phoenix, Arizona. “Nonetheless, hand hygiene, which is the simplest and most effective intervention for decreasing the risk of such infections, has been the most problematic in terms of compliance from healthcare providers, patients, and family members.”
The hand hygiene program has rules aimed to prevent the possible spread of organisms to patients The risks are especially pronounced in oncology patients because of their compromised immune system, she added. “Compliance with hand hygiene is thus particularly important in this population.” Ms Overbey and her colleagues recently launched a comprehensive hand hygiene program at their institution, which aims to boost awareness among staff as well as patients and their families. The program guidelines are patterned after the hand hygiene guidelines issued by the CDC and the World Health Organization. Compliance with the guidelines is recognized as a key component of the Joint Commission’s national patient safety program. Recommendations on hand hygiene for staff are as follows: • When hands are visibly dirty, contaminated, or soiled, wash with nonalcoholic or nonantimicrobial or antimicrobial soap and water. • If hands are not visibly soiled, use an alcohol-based handrub for routine hand decontamination. • Use alcohol-based handrubs only five times and then wash with soap and water. Using alcohol-based handrubs requires less time than standard hand-washing using soap and water, Ms Overbey said. They are also more accessible than sinks and better at decreasing bacteria counts on the hands. Overall, alcohol-based handrubs kill about 99% of germs in 30 seconds but
are not effective for Clostridium difficile because they are not effective against spores. Alcohol-based handrubs also cause less skin irritation and dryness than handwashing with soap and water. The hand hygiene program has also implemented rules aimed to prevent the possible spread of organisms to patients as well as the risk of nosocomial infections that result from organisms on artificial or natural fingernails. In short, artificial nails are banned for staff members working in patient care areas with direct patient contact and those who prepare
track the success of the program via hand hygiene audits by staff and interviews with patients and family members. “Early results show a resistance to education as everyone believes they do a good job of hand hygiene,” she said. However, the audits are revealing a much different story. “We are continuing with intensive followup education and increased audit surveillance to get the message across.” —Jill Stein Continued on page 6
POWER AND PERFORMANCE VIDAZA hits MDS with the strength of transfusion independence.1,2 • 44% of red blood cell (RBC) transfusion-dependent patients achieved RBC transfusion independence.1* • Median time to RBC transfusion independence was about 2.5 months.1 • In responding patients,† transfusion independence was durable, lasting a median of 330 days.2
Important Safety Information • VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors. • In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%), and malaise (10.9%). The most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%). • Because treatment with VIDAZA is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. • Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. • VIDAZA may cause fetal harm. While receiving treatment with VIDAZA, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with VIDAZA should not nurse.
VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome (MDS) subtypes2‡: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL. 9221 Study Design: A randomized, open-label, phase III study comparing the efﬁcacy and safety of VIDAZA plus supportive care vs supportive care alone. 191 patients (132 male, 59 female, age 31–92) with all 5 subtypes of MDS classiﬁed according to the French, American, British (FAB) classiﬁcation system were studied. VIDAZA was administered to patients subcutaneously at a dose of 75 mg/m2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based on response or adverse events. The primary study endpoint was response rate. Response Criteria: Complete response was deﬁned as <5% blasts in the bone marrow, absence of blasts in the peripheral circulation, and normal CBC (if abnormal at baseline) maintained for at least 4 weeks. Partial response was deﬁned as at least a 50% decrease in bone marrow blasts and improvement of bone marrow dyspoiesis (for RAEB, RAEB-T, and CMMoL only) plus, for all subtypes, at least a 50% restoration in the deﬁcit from normal of baseline white cells, hemoglobin, and platelets (if abnormal at baseline) and no blasts in the peripheral circulation maintained for at least 4 weeks. For CMMoL, if white cells were elevated at baseline, PR also required at least a 75% reduction in the excess count over the upper limit of normal, maintained for at least 4 weeks.
Please see the brief summary of prescribing information on the adjacent page.
*Of the 66 VIDAZA-treated patients who were RBC transfusion dependent at baseline, 29 (44%) achieved RBC transfusion independence.1 CR + PR = 16%. ‡ According to the FAB Classiﬁcation System.
VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved. 2007288 May 2007 Printed in the USA.
References: 1. Data on ﬁle. Pharmion Corporation. 2. VIDAZA full prescribing information.
products for patients. This applies to a range of personnel, including nurses, unit aides, respiratory therapists, physical and occupational therapists, physicians, technicians, case managers, social workers, chaplains, educators, beauty salon operators, phlebotomists, and environmental service personnel, among others. As part of the program, all patients receive a brochure that explains the importance of hand hygiene. Patients are also told that “it’s alright to ask your healthcare providers if they have cleaned their hands.” Ms Overbey and her colleagues plan to
6/19/07 1:54:43 PM
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
ONS: Acyclovir May Prevent Herpes Zoster in Multiple Myeloma Patients PHILADELPHIA—Early results suggest a role for acyclovir in the prevention of herpes zoster in multiple
Brief Summary of Prescribing Information VIDAZA (azacitidine for injection) only For subcutaneous and intravenous use only INDICATIONS AND USAGE VIDAZA is indicated for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. CONTRAINDICATIONS VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. VIDAZA is also contraindicated in patients with advanced malignant hepatic tumors. (See PRECAUTIONS). WARNINGS Pregnancy - Teratogenic Effects: Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3–12 mg/m (approximately 4%–16% the recommended human daily dose on a mg/m basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4–8 (postimplantation) at a dose of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis), although treatment in the preimplantation period (on gestation days 1–3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3–12 mg/m (approximately 8% the recommended human daily dose on a mg/m basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/ encephalocele), limb anomalies (micromelia, clubfoot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities). There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.) PRECAUTIONS General Treatment with VIDAZA is associated with neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the ﬁrst cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response as described in DOSAGE AND ADMINISTRATION. Safety and effectiveness of VIDAZA in patients with MDS and hepatic or renal impairment have not been studied as these patients were excluded from the clinical trials. Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors (See CONTRAINDICATIONS). Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, deﬁned as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held as described in DOSAGE AND ADMINISTRATION. Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (see DOSAGE AND ADMINISTRATION section). Information for Patients Patients should inform their physician about any underlying liver or renal disease. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Men should be advised to not father a child while receiving treatment with VIDAZA. Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. Drug Interactions No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted. (See CLINICAL PHARMACOLOGY.) ®
CONFERENCE NEWS 6
No patient treated with acyclovir developed
myeloma patients who are being treated with the proteasome inhibitor bortezomib. The data were reported at the 33rd Annual Congress of the Oncology Nursing Society. Dawn Marie DePaolo, RN, BSN, CCRP, Department of Clinical Research Services at Roswell Park Cancer Institute in Buffalo, New York, and colleagues, assessed the effect of oral acyclovir in 51 consecutive multiple myeloma patients who were being treated with bortezomib.
Continued from page 5
Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) administered IP 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m (approximately 20%–80% the recommended human daily dose on a mg/m basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m (approximately 9% the recommended human daily dose on a mg/m basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats three times per week for 11 or 16 weeks at doses of 15–30 mg/m (approximately 20%–40%, the recommended human daily dose on a mg/m basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. (See WARNINGS.) Pregnancy Teratogenic Effects: Pregnancy Category D. (See WARNINGS.) Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions, women treated with azacitidine should not nurse. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients in the 3 clinical studies described in CLINICAL STUDIES, above, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse events observed in patients 65 years and older compared to younger patients. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION section). ADVERSE REACTIONS Overview Adverse Reactions Described in Other Labeling Sections: neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma. Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also include petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia (5.0%), thrombocytopenia (3.6%), neutropenia (2.7%). Dose Held: leukopenia (4.5%), neutropenia (4.5%), febrile neutropenia (2.7%). Dose Reduced: leukopenia (4.5%), neutropenia (4.1%), thrombocytopenia (3.2%). Discussion of Adverse Reactions Information The data described below reﬂect exposure to VIDAZA in 268 patients, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately 1 year). VIDAZA was studied primarily in supportive-care-controlled and uncontrolled trials (n = 150 and n = 118, respectively). The population in the subcutaneous studies (n = 220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n = 48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m . The following table presents the most common adverse events, whether or not considered drug related by investigators, occurring in at least 5% of patients treated with VIDAZA in the supportive-care-controlled trial and the uncontrolled subcutaneous trial combined. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. 2
herpes zoster compared with 13% of historical controls. Bortezomib is effective in patients with refractory and relapsed multiple myeloma, Ms DePaolo pointed out. She and her colleagues found in an earlier study, however, that the agent may cause immunosuppression that may, in turn, lead to herpes zoster reactivation.
Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a Continued
Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a b
All VIDAZA (N=220) At least 1 TEAE 219 (99.5) Nausea 155 (70.5) Anemia 153 (69.5) Thrombocytopenia 144 (65.5) Vomiting 119 (54.1) Pyrexia 114 (51.8) Leukopenia 106 (48.2) Diarrhea 80 (36.4) Fatigue 79 (35.9) Injection site erythema 77 (35.0) Constipation 74 (33.6) Neutropenia 71 (32.3) Ecchymosis 67 (30.5) Cough 65 (29.5) Dyspnea 64 (29.1) Weakness 64 (29.1) Rigors 56 (25.5) Petechiae 52 (23.6) Injection site pain 50 (22.7) Arthralgia 49 (22.3) Headache 48 (21.8) Anorexia 45 (20.5) Pain in limb 44 (20.0) Pharyngitis 44 (20.0) Back pain 41 (18.6) Contusion 41 (18.6) Dizziness 41 (18.6) Edema peripheral 41 (18.6) Erythema 37 (16.8) Chest pain 36 (16.4) 36 (16.4) Epistaxis Febrile neutropenia 36 (16.4) Myalgia 35 (15.9) Weight decreased 35 (15.9) Abdominal pain 34 (15.5) Pallor 34 (15.5) Nasopharyngitis 32 (14.5) Pitting edema 32 (14.5) 32 (14.5) Skin lesion Dyspnea exertional 31 (14.1) Injection site bruising 31 (14.1) Rash 31 (14.1) Injection site reaction 30 (13.6) Anxiety 29 (13.2) Appetite decreased 28 (12.7) Fatigue aggravated 28 (12.7) 28 (12.7) Hypokalemia Upper respiratory tract 28 (12.7) infection Pruritus 27(12.3) Abdominal tenderness 26 (11.8) Depression 26 (11.8) Productive cough 25 (11.4) Insomnia 24 (10.9) Malaise 24 (10.9) Pain 24 (10.9) Pneumonia 24 (10.9) Abdominal pain upper 23 (10.5) Crackles lung 23 (10.5) Sweating increased 23 (10.5) Cardiac murmur 22 (10.0) 22 (10.0) Rhinorrhea Gingival bleeding 21 (9.5) Lymphadenopathy 21 (9.5) Herpes simplex 20 (9.1) Hematoma 19 (8.6) Night sweats 19 (8.6) Rales 19 (8.6) Tachycardia 19 (8.6) Wheezing 19 (8.6) Cellulitis 18 (8.2) Dysuria 18 (8.2) Breath sounds 17 (7.7) decreased Lethargy 17 (7.7) Oral mucosal 17 (7.7) petechiae Stomatitis 17 (7.7) Urinary tract infection 17 (7.7) Peripheral swelling 16 (7.3) Dyspepsia 15 (6.8) 15 (6.8) Hemorrhoids Hypotension 15 (6.8) Injection site pruritus 15 (6.8) Transfusion reaction 15 (6.8) Pleural effusion 14 (6.4) Abdominal distension 13 (5.9) Muscle cramps 13 (5.9) Post procedural 13 (5.9) hemorrhage
Observation (N=92) 89 (96.7) 16 (17.4) 59 (64.1) 42 (45.7) 5 (5.4) 28 (30.4) 27 (29.3) 13 (14.1) 23 (25.0) 0 6 (6.5) 10 (10.9) 14 (15.2) 14 (15.2) 11 (12.0) 19 (20.7) 10 (10.9) 8 (8.7) 0 3 (3.3) 10 (10.9) 6 (6.5) 5 (5.4) 7 (7.6) 7 (7.6) 9 (9.8) 5 (5.4) 10 (10.9) 4 (4.3) 5 (5.4) 9 (9.8) 4 (4.3) 2 (2.2) 10 (10.9) 12 (13.0) 7 (7.6) 3 (3.3) 9 (9.8) 8 (8.7) 15 (16.3) 0 9 (9.8) 0 3 (3.3) 8 (8.7) 4 (4.3) 12 (13.0) 4 (4.3) 11 (12.0) 1 (1.1) 7 (7.6) 4 (4.3) 4 (4.3 1 (1.1) 3 (3.3) 5 (5.4) 3 (3.3) 8 (8.7) 2 (2.2) 8 (8.7) 2 (2.2) 4 (4.3) 3 (3.3) 5 (5.4) 0 3 (3.3) 8 (8.7) 6 (6.5) 2 (2.2) 4 (4.3) 2 (2.2) 1 (1.1) 2 (2.2) 3 (3.3) 0 5 (5.4) 5 (5.4) 4 (4.3) 1 (1.1) 2 (2.2) 0 0 6 (6.5) 4 (4.3) 3 (3.3) 1 (1.1)
All VIDAZAc Observationd (N=220) (N=92) At least 1 TEAE 219 (99.5) 89 (96.7) Postnasal drip 13 (5.9) 3 (3.3) Rhonchi 13 (5.9) 2 (2.2) Syncope 13 (5.9) 5 (5.4) Urticaria 13 (5.9) 1 (1.1) Anemia aggravated 12 (5.5) 5 (5.4) Loose stools 12 (5.5) 0 Nasal congestion 12 (5.5) 1 (1.1) Atelectasis 11 (5.0) 2 (2.2) Chest wall pain 11 (5.0) 0 Dry skin 11 (5.0) 1 (1.1) Dysphagia 11 (5.0) 2 (2.2) Dyspnea exacerbated 11 (5.0) 3 (3.3) Hypoesthesia 11 (5.0) 1 (1.1) Injection site 11 (5.0) 0 granuloma Injection site 11 (5.0) 0 pigmentation changes Injection site swelling 11 (5.0) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Post procedural pain 11 (5.0) 2 (2.2) Sinusitis 11 (5.0) 3 (3.3) Skin nodule 11 (5.0) 1 (1.1) Tongue ulceration 11 (5.0) 2 (2.2) a Mean VIDAZA exposure = 11.4 months. Mean time in observation arm = 6.1 months. b Multiple reports of the same preferred terms for a patient are only counted once within each treatment group. c Includes events from all patients exposed to VIDAZA, including patients after crossing over from observation. d Includes events from observation period only; excludes any events after crossover to VIDAZA. For SC VIDAZA administration, nausea, vomiting, diarrhea, and constipation all tended to increase in incidence with increasing doses of VIDAZA. Nausea, vomiting, injection site erythema, constipation, rigors, petechiae, injection site pain, dizziness, injection site bruising, anxiety, hypokalemia, insomnia, epistaxis, and rales tended to be more pronounced during the ﬁrst 1-2 cycles of SC VIDAZA treatment compared with later cycles of treatment. There did not appear to be any adverse events that increased in frequency over the course of treatment. There did not appear to be any relevant differences in adverse events by gender. Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be speciﬁcally associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious treatment-related adverse events occurring at a rate of <5% (not described in Table 4) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow depression, splenomegaly. Cardiac disorders: atrial ﬁbrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inﬂammatory response syndrome. Hepatobiliary disorders: cholecystitis Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, blastomycosis, injection site infection, Klebsiella sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspeciﬁed: leukemia cutis. Nervous system disorders: convulsions, intracranial hemorrhage. Psychiatric disorders: confusion. Renal and urinary disorders: hematuria, loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung inﬁltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. Manufactured for: Pharmion Corporation Boulder, CO 80301 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Edition Date: 9 January 2007 Brief Summary of Prescribing Information VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved. VIDB010907A January 2007 Printed in USA.
Although the cause of herpes zoster reactivation is not known, prolonged lymphopenia may be a factor, she added. In the present study, 11 patients received single-agent bortezomib. Forty one patients received bortezomib in combination with other antimyeloma agents, including thalidomide, pegylated liposomal doxorubicin, dexamethasone, cyclophosphamide, and/or lenalidomide. All participants received oral acyclovir 400 mg twice daily for the duration of bortezomib therapy. The investigators found that no patient treated with acyclovir developed herpes zoster compared with 13% of historical controls. Ms DePaolo said that the study is the first to examine the efficacy of acyclovir for the prevention of bortezomibassociated herpes zoster in multiple myeloma patients. —JS Continued on page 7
Coming in the next issue CE article: Calculating the Dosage of Anticancer Drugs in Obese Patients
Reports from ASCO: Advances in Treatment of Colorectal Cancer, Melanoma, Breast Cancer, Kidney Cancer, Hematologic Malignancies
New Approaches to the Treatment of Pediatric Neuroblastoma Managing Opioid-induced Constipation in Patients with Advanced Cancer New IMF Guidelines on Management of Side Effects of Novel Therapies Cancer Center Profile: H. Lee Moffitt Cancer Center & Research Institute
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NEW ONS PRESIDENT Continued from cover
My mother had a great influence on my decision. She was not a nurse, but she was the caregiver in the family and took care of older members of the family as well as her children. I think what impressed me at a young age was the care-giving kinds of behaviors I observed in my mother. Where did you go to nursing school, and when did you become interested in oncology nursing? I got my bachelor’s degree at Duke University, and then my master’s in nursing at University of North Carolina, Chapel Hill. At that time, there wasn’t a specialty called oncology nursing. In my senior year of nursing school, I did an independent study of people with chronic illness in the end stage of their illness, and I worked
CONFERENCE NEWS Continued from page 6
ONS: Group Support/Pelvic Exercise Combination Prevents Post-prostatectomy Incontinence in Cancer Patients PHILADELPHIA—The use of psychosocial support plus pelvic floor muscle exercises (PFME) improves urinary incontinence and quality of life in post-prostatectomy prostate cancer patients more than PFME alone, according to preliminary data announced at the 33rd Annual Congress of the Oncology Nursing Society. Urinary incontinence occurs in up to 25% to 70% of patients who undergo radical prostatectomy, and nearly one third of patients remain incontinent a year later. Amy Zhang, PhD, MS, assistant professor at the Frances Payne School of Nursing at Case Western Reserve University in Cleveland, Ohio, and associates compared the two approaches in 29 men with stage I to III prostate cancer who had undergone a prostatectomy 6 months earlier and had complained of urinary incontinence during the past week. “While the use of PFME has been shown to improve symptoms in the first 6 months after surgery, data on its effects on urinary incontinence lasting longer than 6 months have been inconclusive,” Dr Zhang said. “Because support groups can significantly increase a patient’s motivation to fight cancer, we believed that practicing PFME within a group may provide more motivation and feedback June 2008
with a number of patients who were referred to me, some of whom had cancer. The focus of the study was not on the physical care of those individuals, but rather their psychosocial care. From this experience, I knew I wanted to specialize in working with people who have chronic/terminal illnesses.
Did you pursue these interests when you started to work? In my early experience as a registered nurse at Duke Hospital, we had many patients in the unit with chronic illnesses, such as renal failure and cancer, and I seemed to gravitate towards these patients. I was comfortable talking with and caring for them, and it just naturally evolved. While I was in graduate school, I moved from a staff nurse position into what was called a nurse clinician position, which predated the clinical nurse specialist and unit- based nurse educator positions we have today. During my 2 regarding PFME and thereby improve urinary incontinence more effectively than performing the exercises individually,” she added. Participants in the trial learned PFME through biofeedback and were then randomized to two study arms. Patients assigned to the support group had six 90-minute biweekly group meetings for 3 months, while patients assigned to the control group practiced PFME individually at home. Biofeedback training in PFME was provided by a licensed physical therapist. A sensor inserted into the patient’s rectum was connected to a computer, and the patient was instructed in PFME while viewing a computer monitor that taught him how to exercise his muscles. Support group patients were instructed to perform the exercises two to three times per day for 5 to 10 minutes at a time. At the support group meetings, a psychologist discussed the physiology of urinary incontinence and the rationale for PFME. Patients were encouraged to share their experience with PFME as well as lifestyle issues, their relationship with their spouse, and concerns about socialization, isolation, and stigma. At 3-month follow-up, 86% of support group patients versus 46% of controls reported that they practiced PFME from 4 to 7 days per week as recommended. In addition, only 50% of support group patients used incontinence pads at three months versus 84.6% of controls. Nearly twice as many support group patients reported that they were able to stop the urge to urinate and prevent leakage at 3 months (71.4% versus 38.5%). Trial participants were asked to rate the impact of urinary incontinence on multiple activities of daily living, which included self-care such
It’s important for people to be connected and to join their voice with the voice of their colleagues. years in that role, I became an expert resource to the staff on two patient populations, patients with diabetes and patients with cancer. I then went to Basel, Switzerland, and worked on an oncology unit there. In 1975, I had my first experience with bone marrow transplantation while working there. When I returned to the states, I went back to Duke. In the time that I was gone, Duke had begun building its comprehensive cancer center. When the cancer center opened, I became nurse manager of the inpatient cancer research unit. At what point did you become active in ONS? While I was in Switzerland, I saw a column in the American Journal of
as bathing and driving, their relationship with their spouse, meeting friends and other people, work performance, household chores such as cooking and gardening, going to places such as the theater and movies, and recreational activities. Support group patients scored significantly lower on the severity of problems in daily living secondary to urinary incontinence, especially in terms of their relationship with their spouse and social outings. Finally, Dr Zhang said that the evidence supports the provision of biofeedback-PFME training as standard care and the social support as part of this follow-up care. She emphasized that larger studies of the efficacy and mechanisms of the combined PFME and social support intervention are needed. The study was funded by the American Cancer Society. —JS Continued on page 8
Nursing announcing the formation of the Oncology Nursing Society. The secretary of the organization was Daryl Maas Mathers, who was a classmate of mine at Duke. I wrote to her, and when I came back to the states in 1977, I joined. What roles have you played in ONS over the years? While I was at Duke, my staff and I were active in ONS, submitting abstracts to and attending the annual Congress. We also formed a local interest group. My volunteerism at the national level began when I moved to Canada through a serendipitous event. The woman who was the chief nursing officer at the hospital in Vancouver, British Columbia, where I was working, was on medical leave and I was covering some of her responsibilities. She was a reviewer for the Oncology Nursing Forum, and they sent her a manuscript and asked her to review it by a certain date. I called Susan Baird , who was the editor at the time, and asked if she wanted me to review it instead. That led to my becoming first a reviewer for the Oncology Nursing Forum and then an associate editor. Later, I became the editor of ONS News, which predated ONS Connect, and served as editor of that for 10 years. Along the way, I also served on different kinds of tasks forces and eventually became president of the ONS Foundation board. I now have the privilege of serving as ONS president. Why is it important for both new and experienced nurses to become involved in ONS? I believe that nurses in general need to be active in professional organizations. We can’t complain if we’re not going to step forward and try and change things in the healthcare environment. One way to do that is through our professional organizations. Professional organizations represent their members in educating elected officials in Washington or with regulatory agencies about key issues for nursing. ONS has a specific health policy agenda with priorities for cancer care and the nursing profession. As ONS has grown and become more complex, it needs the experience and wisdom of longer term members. But, it also needs the engagement of newer members, who can bring fresh ideas and who are going to be the leaders in the next phase of our development. We need the synergy of experienced and new members. It’s important for us to always be looking at succession needs, that is, how to get people involved in the organization and prepare them to lead the organization. It’s important for people to be con-
© Bridget Laudien
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NEW ONS PRESIDENT Continued from page 7
nected and to join their voice with the voice of their colleagues. What advice would you give to a young nurse who’s considering a career in oncology nursing? Once nurses start working in oncology, they often stay with it for the rest of their professional lives. They may move in many different directions, however, because of the diversity of subspecialization in oncology and the different types of settings in which one can work—inpatient, outpatient, home care, hospice, and so on. Even someone working in an acute care inpatient hospital could work in a bone marrow transplant unit, a surgical unit, or a medical oncology unit. Oncology nursing is a specialty in which a nurse can continue to grow, develop skills and interests, and find opportunity in many different settings. It’s also one of the specialties in which nurses who welcome long-term relationships with patients and their families find a lot of reward. Nurses who are drawn into this specialty, regardless of the subspecialty, get deep personal and professional satisfaction from their relationship with patients and families. These intrapsychic rewards are the reasons people stay in the profession. Oncology nurses tend to be more satisfied than nurses in other specialties when we look at employment satisfaction scores. I think this is partly because of the appreciation they get from making a difference for patients and their families. They have the opportunity to work with patients and families over many interactions, not just for one episode. Nevertheless, they must experience a very high level of stress at times. How do they cope with it? Self-care of nurses is a topic frequently addressed in the literature and at meetings. One thing that helps in coping with stress is our support and care of each other, and the col-
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ONS: Program Aims to Cut Falls in Oncology Infusion Center PHILADELPHIA—A nursing team at the University of Michigan Health System in Ann Arbor has launched a fall reduction program for the institution’s five ambulatory infusion centers. “While there have been only 15 falls in the center over the past 3 years, which is small given that up to 800 patients 8
laboration and professional development that ONS provides. There has always been a very high level of professionalism among the oncology nurses. This sort of professional support is another good reason for get involved in ONS. What are some of the greatest challenges facing oncology nurses today? The challenges for oncology nurses are not unlike challenges facing nurses in general. The healthcare environment can be very stressful for many reasons. Partly that is because of the complexity of care and the stresses related to high acuity levels in this patient population whether in the hospital or at home. Part of the problem is related to staffing issues. The nursing shortage that is occurring today is nowhere near what is predicted for the coming decade. Although we are seeing increased enrollment in nursing programs, many of us working today are baby boomers, who are approaching retirement. There is a critical need for more nurses. We are seeing some very innovative ways of dealing with the shortage. For instance, after a nurse is licensed and hired, internship programs provide an opportunity to develop not only as a new nurse, but also to acquire specialty skills. Oncology units have used internship programs for years to help new nurses or even experienced nurses who are not specialized in oncology gain the knowledge and skills they need for giving high-quality patient care. What are your goals for your term as president of ONS? Over the next couple of years, we have several priorities. We’re in the process of finalizing our strategic plan for 2009 to 2012. The needs of our members come first and foremost. Cancer diagnosis and treatments are changing, and preparing nurses for the future cancer care environment is essential. We will continue to provide an excellent standard in our educational resources for members and the research support that we provide our nurse scientists. Also, much cancer
present to our center each week, a fall can have devastating sequelae for the patient and family members,” said Phyllis Patterson, MS, APRN, BC, AOCN, clinical nurse specialist at the University of Michigan Health System in Ann Arbor. Ms Patterson and her colleagues have developed a fall reduction standard of care action plan that is applied uniformly to all patients admitted to the cancer center’s infusion units. The decision to manage all patients uniformly was made after a review of 1,762 patients by nursing staff found no correlation between risk factors and
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care is given by nurses who do not identify themselves as oncology nurses. Reaching out to the non-onocology nurses and providing resources for them is a priority. How we engage in international acitivities is another key focus for us in the next couple of years. Healthcare, like so many other sectors, is increasingly global. We need to define how we work with colleagues in other countries to support the emergence of an oncology specialty. Determining how to share our resources appropriately in those countries will help support the care of cancer patients around the world. We must do this sensitively and effectively and balance international efforts with our commitment to our members. Lastly, elevating the voice of oncology nursing on issues critical to us is a strategic priority and one for which I have a personal passion. Ensuring that our voice is heard in the political and regulatory worlds is essential. This year, we sponsored legislation that Representative Steve Israel from New York introduced in the House (HR 5585), which calls for Medicare funding for patient and family education at the initiation of treatment. We are 37,000 members strong and we represent thousands, if not hundreds of thousands, of people living with cancer. In this year’s presidential campaign and with the subsequent new administration, we must advocate for our patients, their families, and our profession. Ensuring that our voice is heard in the political and regulatory worlds is essential and can be accomplished through our advocacy and in partnerships with other key organizations.
venous fluids, or diuretics during their infusion visit, Ms Patterson said. Patients are also assessed to make certain they are wearing nonskid footwear.
Interventions The fall reduction program includes a broad list of interventions. Below are a few of the interventions: • Personal items such as a pillow, water, or tissues are placed within the patient’s reach • Beds and stretchers are maintained in a low position, with wheels remaining locked, unless the staff is in immediate attendance at chairside or bedside • Patients are routinely provided with a device that allows them to call a nurse and taught how to use it • Patients are also taught how to avoid sudden changes in position and encouraged to make sure they are not lightheaded or dizzy when they change positions before proceeding with activity. Ms Patterson and her colleague, Jody Giannotti, MSN, RN, AOCN, have also developed a simple brochure focusing on safety measures that is given to infusion patients and family members at their initial visit to the infusion center. The brochure advises patients and their families to alert the infusion area staff on arrival if the patient has a history of falls or is at increased risk of a fall. The brochure includes tips for patients, such as: • Wear sensible, stable shoes or slip-resistant socks • Call for assistance when getting up from the infusion chair or bed • Do not use unsteady items, such —Karen Rosenberg as your infusion pole or pump, to lean on when standing up. The brochure includes tips for family members as well, such as: • Assist your loved one when walking around the infusion area, and remind them to call for assistance when you leave The average starting salary for • Help keep the infusion area safe 2008 nursing graduates will be by keeping the floor uncluttered. $52,129. Source: www.career Notify staff of any spills or other builder.com unsafe condition. The brochure also includes tips on how to maintain a safe home environment. For more information falls in the 16% of patients who had a please contact Jodi Giannotti at history of falls. In fact, 42% of those email@example.com who fell had no apparent risk factors for falls. The core components of the —JS program include a risk assessment tool specific to the oncology population, interventions, and patient and staff education.
Assessment Although all patients presenting to the ambulatory infusion centers are considered to be at high risk for falls, based on previous fall data, special attention is given to patients needing blood transfusions, intra-
© Bridget Laudien
Scenes from the ONS Congress MAY 15-18, 2008, PHILADELPHIA, PA
ONS 33rd Annual Congress Held in Philadelphia
he 33rd Annual Congress of the Oncology Nursing Society (ONS) opened with a colorful procession led by members of the famed Philadelphia Mummers band. Nurses from the
Philadelphia and other Pennsylvania chapters of ONS followed carrying umbrellas and banners (Figures 1, 3). After addresses by outgoing ONS president Georgia Dekker and Philadelphia chapter president Carol Grande (Figures 4, 5), awards were presented to nurses for outstanding research, patient care, and community service. Patrick “Lips” Houlahan, a former US Marine Corps fighter pilot presented the keynote address (Figure 10), in which he explained how the Flawless Execution model (ie, plan, brief, execute, debrief, win) used in military mission planning can be used to achieve goals in the healthcare and other settings. During the busy days that followed, oncology nurses from the US and around the world attended poster sessions and panel discussions (Figures 8, 11) visited commercial and ONS exhibits (2, 6, 9, 12), and enjoyed an editorial board dinner (Figure 7).
All photos © 2008 Bridget Laudien. All Rights Reserved. To contact Bridget, e-mail firstname.lastname@example.org
11 June 2008
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CANCER CENTER PROFILE
Taussig Cancer Institute Photo courtesy of Cleveland Clinic
patient-centric focus drives the design and function of the Taussig Cancer Institute at the Cleveland Clinic, from electronic medical record keeping, multidisciplinary models of patient care, and extensive support services. As Ohio’s largest cancer center, total visits to the Taussig Cancer Institute in 2006 numbered 181,798, and 35,576 treatments were delivered. It is rated by U.S. News & World Report as one of the top 15 cancer centers in the nation. “Our ‘patients first’ philosophy is a very useful focusing tool for everybody at all times…everything flows down from that,” said Derek Raghavan, MD, PhD, director of the Taussig Cancer Institute. “In the past 4 years, 50 new faculty members have been recruited, all of whom are engaged in active clinical practice. Everybody from top down sees patients. Everybody who is a leader and running programs is also seeing patients.” The Taussig Cancer Institute has set standards in the management of early prostate cancer, as well as kidney and bladder cancer. Cleveland Clinic researchers were involved in a seminal study published this year in the New England Journal of Medicine in which the outcomes, toxicities, and quality of life associated with the various prostate cancer treatments were measured.1 The Bone Marrow Transplant Research Team in the Department of Hematologic Oncology and Blood Disorders boasts a 30-day survival rate of 100% for autologous bone marrow transplantation. The
achievement is noteworthy given that 30-day survival rates of 20% for leukemia transplant patients were not uncommon at most institutions in the past.
CANCER CENTER PROFILE
Extensive research program In 2007, the Leukemia and Lymphoma Society and the Cleveland Clinic Taussig Cancer Institute announced a partnership, The Clinical Trial Center for Hematologic Malignancies, to make hematologic cancer clinical trials available to patients in the community. The Taussig Cancer Institute was chosen for this collaboration because of its unique structure of 45 oncologists at its main campus and another 20 staff throughout regional hospitals, allowing patients to participate in the center’s clinical trials while remaining with their own team of cancer specialists. “With the volume of patients—about 7,000 new cases of cancer per year—we have a mechanism for defining clinical trials that can be executed within other cities,” said Dr Raghavan. The partnership is expected to accelerate the process of developing cancer drugs since clinical trials will be conducted within a single clinical center. The electronic medical record system facilitates this new paradigm of clinical research by permitting clinicians at regional sites nearly instant access to patients’ records. Patients also have access to their own electronic record on request (sometimes after a review by his/her physician). “Top down, there’s very active patient involvement,” said Dr Raghavan. All cancer departments have extensive research programs. The breast cancer program received federal funding to join two multi-institutional trials in collaboration with Washington University, and the renal cancer program is collaborating with Ohio State University on federally funded clinical trials. The large volume of patients at the Taussig Cancer Institute enables groundbreaking work in diagnostics. For example, researchers at Taussig discovered that the level of circulating tumor cells in peripheral blood before treatment was able to predict survival in patients with metastatic breast cancer,2 with the potential to individualize treatment. The same diagnostic assay is being used to predict survival in prostate cancer. A novel blood test to predict thyroid cancer was tested by pathobiologists at the Cleveland Clinic and was found to distinguish accurately between benign and malignant cells. The test detects cancer cells in the bloodstream by amplifying thyroid-stimulating hormone receptor or thyroglobulin messenger ribonucleic acid by reverse transcription polymerase chain reaction. The Taussig Cancer Institute is also a major player in clinical trial groups, such as the Southwest Oncology Group and the Radiation Therapy Oncology Group. “We have a very active program of
Photo courtesy of Cleveland Clinic
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
Interview with Taussig Institute Nurse
Beth Faiman, RN, MSN, APRN, BC, AOCN As an advanced oncology-certified nurse in the multiple myeloma program at the Taussig Cancer Institute of the Cleveland Clinic, Beth Faiman is part of a team that manages 1,800 patients with plasma cell dyscrasias. “We see more patients with multiple myeloma than any center in the state of Ohio and most cancer centers around the country,” she said. She has worked in hematology since becoming a nursing unit assistant at the Cleveland Clinic in 1994, and now triages patients entering the practice, engages in nursing and community education on the diagnosis and management of multiple myeloma and associated disorders, and serves as chair of the Advanced Practice Nursing Council for the Cleveland Clinic. The multidisciplinary model of patient management at Taussig allows for comprehensive care of patients with multiple myeloma, she said. “We have the knowledge, experience, and resources to take care of the high volume. Because cancer tends to affect more than one organ system, which is especially true in multiple myeloma, strong relationships with other subspecialists, including palliative medicine, are necessary. These patients are often diagnosed with bony disease, they develop anemia, and the disease affects their kidneys.” Ms Faiman has been involved in a number of key discoveries made at the Taussig Cancer Institute’s multiple myeloma program, including the efficacy of thalidomide in previously untreated and relapsed/ refractory multiple myeloma, the value of aspirin in preventing thrombotic complications, and the role of plasmapharesis in multiple myeloma patients who develop renal insufficiency or acute renal failure. She has also participated in research measuring the effects of socioeconomic status and distance traveled on outcomes in patients treated in a specialized myeloma center. She is currently writing a research protocol for the treatment of peripheral neuropathy in patients with multiple myeloma. As editor-in-chief of The Oncology Nurse, Ms Faiman hopes to further educate nurses and nursing students about cutting edge research in cancer in an easily read format. “Being an editor-in-chief is a large undertaking but it’s exciting because hopefully we’ll be able to bring needed information to the nurses and find unique ways to disseminate it. We want to present research in a sensible manner that can be obtained in one location. Nurses don’t have the time to sift through journal after journal.”
Continued on page 23
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CRs Correlate with Clinical Benefit in APEX1 OVERALL SURVIVAL STRATIFIED BY QUALITY OF RESPONSE 1.0
Proportion of Patients
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Time (months) CR (n=27)
PR with ≥90% decrease (n=31)
PR with ≥50% and <90% decrease (n=77)
All other (n=180)
CLINICAL BENEFIT OF VELCADE® BY QUALITY OF RESPONSE* CR
(≥90% M-protein reduction)
(≥50% and <90% M-protein reduction)
Patients, n (%)
Treatment-free interval (months)
24.1 (9.7, 24.4)
6.9 (5.5, 11.1)
6.4 (4.4, 10.3)
Time to next treatment (months)
27.1 (15.2, 32.0)
13.6 (10.0, 17.3)
14.0 (12.6, 16.1)
Time to progression (months)
9.7 (7.8, 17.7)
10.8 (8.1, 14.4)
8.5 (7.0, 9.9)
Not yet reached
Not yet reached
Not yet reached
M CRs deliver greater clinical benefit than any other responses *In APEX, 315 VELCADE patients were evaluable for response. Responses were based on criteria established by the European Group for Blood and Marrow Transplantation (EBMT). Complete response (CR) required 100% disappearance of the original myeloma protein from blood and urine on at least 2 determinations 6 weeks apart by immunofixation, <5% plasma cells in the bone marrow, stable bone disease, and normal calcium. Partial response was stratified into 2 categories; M-protein reduction of either ≥ 90% or of ≥ 50% and <90% determined on at least 2 occasions, 6 weeks apart. Both categories required ≥ 90% reduction in urine myeloma protein upon at least two determinations six weeks apart, stable bone disease and normal calcium.
VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. References: 1. Data on file. Millennium Pharmaceuticals, Inc.
Please see Brief Summary of full Prescribing Information on adjacent page, also available at www.VELCADE.com.
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 ÂŠ2008 Millennium Pharmaceuticals, Inc. All rights reserved.
Printed in USA
ORAL MUCOSITIS Continued from cover
neuropathies, myalgias, and other related symptoms. Among these, perhaps none is as demoralizing as oral mucositis, a constellation of symptoms affecting the oral mucosa that is induced by chemotherapy and radiation therapy for cancer. Oral mucositis is different from oral lesions with other pathogenic origins, which are generally referred to as stomatitis.1 Inflammation and infection of the oral mucosa lead to a reduced ability to consume food and fluids at a time when nutrition and hydration are critical to the prospect of treatment success. Oral mucositis is also painful and often requires substantial daily doses of opiates. Treatment often requires inpatient admission to the hospital, usually through the emergency department, leading to a significant increase in overall treatment-related expenses. Once admitted, patients are at an increased risk for nosocomial infection, experience a serious disruption of their daily activities, and face the possibility that their treatment protocols will be delayed or even discontinued.
Epidemiology of oral mucositis Symptoms of oral mucositis may be mild or severe and can vary from vague discomfort to severe pain and an inability to tolerate food and fluids (Table 1). Approximately 400,000 FRANK P. WHYTE, new cases of treatmentRN, OCN induced damage to the oral cavity are reported annually in the United States.2 These include cases of mucositis (stomatitis); xerostomia (dry mouth syndrome); bacterial, viral, and fungal infections; dental caries; disruption of taste; and osteoradionecrosis.2 From 5% to 40% of patients who are treated with standard chemotherapy regimens will develop some form of mucositis.3 In patients receiving more aggressive regimens with agents such as fluorouracil, methotrexate, cyclophosphamide, or cisplatin, the incidence can be much higher and the symptoms much more debilitating.4 Among patients who receive high-dose
Table 1. Grades of Oral Mucositis: NCI Common Toxicity Criteria
Grade 1: Erythema (redness) Grade 2: Patchy ulcerations Grade 3: Confluent ulcerations Bleeding with minor trauma
Grade 4: Necrosis, significant spontaneous bleeding Life-threatening
Grade 5: Death related to toxicity Source: Common Terminology Criteria for Adverse Events v3.0. National Cancer Institute; 2006.
chemotherapy in advance of bone marrow transplantation, the incidence can be as high as 75% to 100%.3 Similarly, more than 80% of patients who receive high-dose radiation for head and neck cancers will be affected.3,4 The incidence of oral mucositis will be higher for patients receiving both chemotherapy and radiation.5 The degree and duration of symptoms are related to radiation source, cumulative dose, intensity, and the total volume of irradiated mucosa.6
Pathogenesis of oral mucositis Stephen Sonis, DMD, the preeminent authority on oral mucositis, has suggested a four-stage developmental process for this disorder. According to Sonis and colleagues, there is an initial or vascular stage of development, when exposed cells in the buccal mucosa release free radicals, modified proteins, and proinflammatory cytokines. The net effect of this process is that vascular permeability of mucosal cells is greatly increased, which leads to an increased uptake of cytotoxic drugs into these cells.7,8 This vascular phase then gives way to the epithelial phase, when cell division is retarded and epithelial turnover is reduced, resulting in subsequent epithelial breakdown. Erythema and epithelial atrophy can be expected 4 to 5 days after chemotherapy, and patients may suffer microtrauma of the tissue resulting from speech, swallowing, and chewing.7,8
Table 2. Treatments to Relieve the Symptoms of Oral Mucositis Topical agents Artificial saliva solution (Caphosol)16 “Magic” or “Miracle” mouthwash, includes lidocaine, benzocaine, kaolin, pectin, and chlorhexidine9 Bioadherent oral gel (Gelclair)14 Single agents: benzydamine; morphine9
Systemic agents Patient-controlled analgesia with morphine for stem cell transplant patients Transdermal fentanyl: further study needed9
Antibiotics/antiviral Delivered by appropriate route depending on type of infecting organism: fungal, bacterial, viral
Of particular note, 75% of the population has some degree of periodontal disease, which is a known risk factor. This, coupled with the fact that after chemotherapy many patients will develop acute bacterial super-
Erythema and epithelial atrophy can be expected 4 to 5 days after chemotherapy. Approximately 1 week after treatment, this degenerative process enters the ulcerative or bacteriologic phase, when there is a loss of epithelial cells, exudate formation, and the production of pseudomembranes and ulcers. It is at this time of complete cellular breakdown that cells become colonized by gramnegative organisms and yeast.7,8 The fourth and final phase is the healing phase, which can be expected to last for 12 to 16 days, depending on several factors, including epithelial proliferation rate, hematopoietic recovery, and a reestablishment of normal local microbial flora. Healing will occur as long as there is no persistent infection or mechanical irritation.7,8
Risk factors Several patient-related factors increase the risk of oral mucositis. Individuals at an increased risk for developing oral mucositis include young patients, given their rapid mitotic rate; patients with poor nutritional status and decreased neutrophil counts prior to beginning treatment; and those with preexisting xerostomia. The type of malignancy being treated also plays a role. The risk is particularly high in those with hematologic cancers because of the prolonged and intense myelosuppression associated with these malignancies. Increased epidermal growth factor receptors, poor oral hygiene, ill-fitting dental prostheses, and use of medications with anticholinergic effects, such as tricyclic antidepressants, all predispose patients to developing oral mucositis.6
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
infections, suggests that clinical vigilance for signs and symptoms of oral mucositis in patients undergoing medical or radiation therapy is well justified.5
Prevention and treatment None of the available treatments is completely successful at preventing oral mucositis.9 A thorough dental evaluation to detect problem areas should be conducted on every patient before beginning treatment.6 Patients should also be encouraged to use a soft toothbrush with fluoridated toothpaste, and toothbrushes should be replaced monthly. If financial hardship is an issue, advise patients to run their existing toothbrush through the dishwasher monthly instead.5 A balanced and nutritious diet is also essential for maintaining oral health.9 Although oral mucositis cannot be totally prevented, there are a number of interventions that nurses can undertake to reduce the risk and to treat it if it develops. Clinical studies evaluating the benefit of cryotherapy, which refers to the nearconstant use of ice chips during the at-risk period in the days immediately following the administration of chemotherapy, has shown some benefit. It is thought that the vasoconstriction caused by the cold temperature reduces uptake of cytotoxic materials at a time when mucosal cells would be otherwise at an increased risk, secondary to permeability changes as described in the Sonis paradigm.9-11
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Continued on page 16
CAPHOSOL – Proven Efficacy Against Oral Mucositis Confirmed in a randomized, placebo-controlled trial1 Days of Mucositis > Grade 1
Reduction in duration of mucositis • Caphosol 3.7 days vs control (fluoride rinse) 7.2 days
40% of CAPHOSOL-treated patients
had no mucositis (vs 19% control) *
Don’t Wait – Start cancer therapy...start CAPHOSOL
• 4 doses per day from the onset of the cancer treatment • Use for the duration of the treatment or as instructed by physician For a Cytogen Representative or Reimbursement Assistance, Please Call 800-833-3533. For more information visit www.Caphosol.com. Important Safety Information Avoid eating or drinking at least 15 minutes after use. Patients restricted to a low sodium diet should consult their physician before use. Federal law restricts this device to sale by or on the order of a physician or dentist. KEEP OUT OF REACH OF CHILDREN. * Mucositis ≤ Grade 1. Reference 1. Papas AS, Clark RE, Martuscelli G, O’Loughlin KT, Johansen E, Miller KB. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2003;31:705-712. Caphosol is used in conjunction with standard oral care.
Start Cancer Therapy...Start Caphosol
CAPHOSOL® is a registered trademark of Cytogen Corporation. © 2007 Cytogen Corporation
All rights reserved.
ORAL MUCOSITIS Continued from page 14
There have also been numerous studies evaluating the benefit of certain mouthwash preparations. Amifostine, which is associated with certain tolerability issues,9,12 palifermin,13 and Gelclair bioadherent oral gel,14 have all shown similar limited benefit, as have fluoride tray treatments, when given before chemotherapy administration. A study published in 2003 by Papas and associates showed significant decreases in the incidence, frequency, and severity of oral mucositis with the use of a supersaturat-
Oral Mucositis: Facts and Concerns • Chemotherapy damage to mucosal tissues is reversible. • Radiation damage to mucosal tissues is permanent. • Mucosal infection should be of primary concern. • Mucositis will have a great impact on quality of life. • Tooth enamel is not connected to the rest of the body except through saliva. • Humans need saliva to keep food from sticking to the side of the mouth. • Decreased saliva can lead to an inability to speak. • Saliva flow is decreased at night, often causing patients to awake. • Oral infection is a significant cause of death in immunocompromised patients. • The normal flora of the oral cavity is changed with neutropenia. • The mouth and tongue must be kept as clean as possible to prevent infection and improve function. • Irradiated patients may need to use a saliva substitute for the remainder of their lives. • The pseudomembranes of mucositis can become infected.
• The microenvironment of the oral mucosa can be stabilized with electrolyte solutions. • Prevention is the goal but may be difficult to achieve. • Targeted therapies increase the risk of mucositis. • Nurses must be aware of mucositis risk and educate patients about the importance of early intervention.
ed calcium phosphate oral rinse, commercially available as Caphosol.15,16 Caphosol was originally designed to restore the normal ionic and pH balance of the oral cavity. In their study, Papas and associates discovered that when the rinse was used in conjunction with four fluoride tray treatments, it reduced total days of mucositis, peak level of mucositis, and days requiring treatment with morphine for the discomfort associated with mucositis. Forty percent of patients treated with Caphosol had no mucositis compared with 19% of the controls treated with fluoride rinse alone. Compared with controls, those in the Caphosol group had 49% fewer days of mucositis and a 67% lower peak median level of mucositis. Caphosol was particularly beneficial in patients who were intensely myelosuppressed before hematopoietic stem cell transplantation and in those with xerostomia.16 In addition to recommending commercially available products, nurses can do much in their daily practices to assist their chemotherapy and radiation therapy patients with oral mucositis. • As much as possible, patients should be positioned sitting up at a 90-degree angle with their heads tilted slightly forward. • Frequent use of ice chips in the days immediately following treatment is recommended. • Patients should be encouraged to eat small, frequent meals. Food and drinks should be warm, not hot, to avoid scalding mucosal tissues. Patients should select soft foods and avoid crunchy foods. • If poor appetite is an issue or if oral mucositis has decreased a patient’s desire to eat, suggest baby food or highprotein milkshakes as an alternative. Commercially available products, such as Ensure or Boost, may also help to provide adequate caloric intake. • Alcohol and tobacco should also be avoided, as should spicy and acidic foods. • Patients should be instructed not to talk while they have food in their mouth. • Patients should rinse their mouth thoroughly before and after meals.3,6,9
Conclusions In recent decades, oral mucositis has been recognized as a significant disorder that can have a serious impact on cancer treatment. Severe discomfort can lead to reduced intake of food and fluids, depression, and potentially nonadherence during a critical period in initial and subsequent treatment cycles. Oral mucositis can also lead to long-term destruction of the teeth and bony structures of the oral cavity. New research has led to the development of products that are yielding positive results. Nurses should be aware of the potentially catastrophic results of severe mucositis and should promote within their practices interventions and products that can prevent or control this disorder.
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
References 1. Dose AM. The symptom experience of mucositis, stomatitis, and xerostomia. Semin Oncol Nurs. 1995;11:248-255. 2. Naidu MU, Ramana GV, Rani PU, et al. Chemotherapy-induced and/or radiation therapyinduced oral mucositis—complicating the treatment of cancer. Neoplasia. 2004;6:423-431. 3. Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol. 2006;4(2 suppl 1):9-13. 4. Silverman S Jr. Diagnosis and management of oral mucositis. J Support Oncol. 2007;5(2 suppl 1):13-21. 5. Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol. 1998; 25:538-551. 6. Berger AM, Kilroy TJ. Oral complications. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2001: 2714-2725. 7. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapyinduced stomatotoxicity. Oral Oncol. 1998;34:39-43. 8. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 suppl):1995-2025. 9. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100(9 suppl):2026-2046. 10. Rocke LK. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer. 1993;72:2234-2238. 11. Mahood DJ, Dose AM, Loprinzi CL, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol. 1991;9:449-452. 12. Köstler WJ, Hejna M, Wenzel C, et al. Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin. 2001;51:290-315. 13. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590-2598. 14. Gelclair (bioadherent oral gel) [package insert]. Cedar Knolls, NJ: EKR Therapeutics, Inc; 2006. 15. Caphosol [package insert]. Princeton, NJ: Cytogen Corporation; 2007. 16. Papas AS, Clark RE, Martuscelli G, et al. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transpl. 2003;31:705-712.
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Continuing Education 08CE059a • RELEASE DATE: June 25, 2008 • EXPIRATION DATE: June 25, 2009 EDITORIAL BOARD Emily Chan, MD, PhD Department of Cancer Biology Vanderbilt University School of Medicine Nashville, TN 37332-6307
Cetuximab-induced Hypersensitivity: Case Reports and Discussion of Management BY EMILY CHAN, MD, PhD,1 AND CHRISTINE H. CHUNG, MD2 1 Division of Hematology/Oncology, Department of Medicine and 2Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee HOW TO RECEIVE NURSING CREDIT To receive continuing education credit, learners must • Read the article in its entirety • Take the CE self-assessment test by accessing the website: http://app1.unmc.edu/ nursing/conweb/OE_UNMC_Online_home.cfm • Complete and submit the evaluation form online (enter program number 08CE059a). Nurses must answer at least 70% of the questions on the post-test correctly. If Internet access is not available, please fax a request for an evaluation form to 402-559-6379, attn: Anji Wittman, (please include return fax number) or e-mail email@example.com • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test.
PROGRAM GOAL To educate oncology nurses about the incidence, prevention, and treatment of severe hypersensitivity reactions to cetuximab.
DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center College of Nursing Continuing Nursing Education.
TARGET AUDIENCE Advanced practice nurses, registered nurses, and other interested healthcare professionals, especially those caring for cancer patients.
While the University of Nebraska Medical Center College of Nursing Continuing Nursing Education is an ANCC accredited organization, this does not imply endorsement by the UNMC or ANCC of any commercial products affiliated with this activity.
etuximab is a chimeric antibody against the epidermal growth factor receptor. According to the cetuximab package insert, the incidence of severe hypersensitivity reactions is 3%.1,2 Higher incidence rates have been reported, however, in the southeast region of the United States, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee, with reaction rates up to 22% in recent studies.3,4 Signs and symptoms of hypersensitivity reactions include fever, rash, flushing, bronchospasm, urticaria, edema/ angioedema, hypotension, and anaphylaxis (Table 1). Presented here are two cases that illustrate the characteristics and management of a severe hypersensitivity reaction.
Case 1 SS, a 52-year-old man, initially underwent resection of a stage III colon cancer. He received adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin. Approximately 4 years later, he developed recurrence with metastatic disease in the mediastinum and abdomen. He was treated with 5-FU, leucovorin, oxaliplatin, and bevacizumab, but had to discontinue treatment because of toxicity. Subsequently, he was treated with capecitabine, irinotecan, and bevacizumab, but again developed progressive disease. He then enrolled in a phase 2 clinical trial for metastatic colorectal cancer with the combination of cetuximab and celecoxib. He was premedicated with dexamethasone 20 mg intravenously (IV) and diphenhydramine 50 mg IV. Approximately FACULTY/PLANNER DISCLOSURES All planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, College of Nursing Continuing Nursing Education are expected to disclose to the audience any significant support or substantial relationship(s) with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporters of the activity. In addition, all faculty are expected to openly disclose any off-label, experimental, or investigational use of drugs or devices discussed in their presentation. The planners and faculty and have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to
LEARNING OBJECTIVES At the conclusion of this activity, participants should be better able to: • Explain the hypothesis about the link between immunoglobulin E antibodies and cetuximab-induced hypersensitivity reactions. • Recognize the signs/symptoms of a hypersensitivity reaction. • Describe an appropriate premedication regimen for a patient being treated with cetuximab. • Summarize appropriate management of cetuximab-induced hypersensitivity reactions.
COST This program is complimentary for all learners.
20 minutes into his initial cetuximab infusion, the patient experienced pruritus and facial flushing. He then developed chest tightness and felt as though he was wheezing although his lungs were clear on examination. Cetuximab was stopped when the symptoms developed. Supplemental oxygen was started, and the patient was given an additional 25 mg of IV diphenhydramine as well as methylprednisolone 125 mg IV, and albuterol nebulizer treatment. His symptoms improved, but because of his grade 3 hypersensitivity reaction, he was removed from the study and was not rechallenged with cetuximab.
Case 2 DB is a 54-year-old man with stage IV oropharyngeal squamous cell carcinoma. He was treated with induction chemotherapy followed by concurrent chemoradiation therapy using carboplatin and paclitaxel. Approximately 6 months after completing the primary treatment, he had disease recurrence with lung metastasis and was treated on a phase 2 clinical trial regimen containing docetaxel and bortezomib; however, his disease progressed after 6 weeks. He was given cetuximab as a palliative measure. His premedication regimen was diphenhydramine 50 mg IV and dexamethasone 12 mg IV. Within 5 minutes of starting the infusion, he became unarousable and apneic. Blood pressure was not measurable because of severe hypotension. The infusion was immediately stopped. He was given epinephrine 1:1000 intramuscularly and hydrocortisone 100 mg IV.
accepted standards of experimental design, data collection, and analysis. The following authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity. • Lisa Anzai, RN, MA • Catherine Bevil, RN, EdD • Cass Hammond, RN, MSN, CRNP • Lara J. Reiman • Karen Rosenberg • Audrea H. Szabatura, PharmD, BCOP
The following authors, reviewers, and/or planners have stated that they have the following financial relationship(s): Emily Chan, MD, PhD, states that she is on the advisory boards of Bristol-Myers Squibb and Amgen and receives honoraria for her services. She receives research funds from Amgen. Christine H. Chung, MD, states that she receives honoraria from Bristol-Myers Squibb and Amgen for her services at educational activities. Taline Khoukaz, NP, MSN, ACNP-C, states that she is on the speakers bureau of sanofi-aventis and BristolMyers Squibb/ImClone and a consultant to BristolMyers Squibb/ImClone.
Christine H. Chung, MD Division of Hematology/Oncology Department of Medicine Vanderbilt University School of Medicine Nashville, TN 37332-6307 Taline Khoukaz, NP, MSN, ACNP-C University of Southern California Norris Cancer Center and Hospital Los Angeles, California 90033 Audrea H. Szabatura, PharmD, BCOP Department of Pharmacy University of Massachusetts Memorial Medical Center Levine Cancer Center Worcester, MA 01605 PLANNING COMMITTEE Lisa Anzai, RN, MA Nurse Planner University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, Nebraska 68198-5330 Catherine Bevil, RN EdD Director, Continuing Nursing Education and Evaluation University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, Nebraska 68198-5330 Lara J. Reiman Managing Editor Green Hill HealthCare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill HealthCare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 REVIEWER Cass Hammond, RN, MSN, CRNP Avid Education Partners 18071 Crampton Lane Sharpsburg, MD 21782
CONTINUING NURSING EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is provided for 1.0 contact hours under ANCC criteria. Provided for 1.2 contact hours under Iowa Provider #78. Provider Approved by the California Board of Registered Nursing, Provider #13699 for 1.2 contact hours.
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Continuing Education 08CE059a • RELEASE DATE: June 25, 2008 • EXPIRATION DATE: June 25, 2009 Table 1. National Cancer Institute Common Toxicity Criteria for Allergic Reaction/hypersensitivity Grade 1 2 3
Description Transient flushing or rash; drug fever <38oC (<100.4oF) Rash; flushing; urticaria; dyspnea, drug fever ≥38oC (≥100.4oF) Symptomatic bronchospasm, with or without urticaria; parenteral medication(s) indicated; allergy-related edema/ angioedema; hypotension
ferase, an enzyme that adds oligosaccharide to cetuximab. Most of the other monoclonal antibodies in clinical use are produced in a Chinese hamster ovary cell line that does not express the enzyme. • Our study is the first to show that IgE antibodies can be made against a sugar molecule, while it is well known that IgE antibodies can be made against a protein epitope. • The results of this study also have potential implications for patients receiving other monoclonal antibodies or immunotherapies for other conditions, including inflammatory bowel disease, rheumatoid arthritis, and asthma.
What we do not know: • The exact reasons why individuals in certain areas of the United States to produce the IgE antibodies that react with cetuximab. For exam-
ple, are the specific IgE antibodies the result of differences in regional exposures to ticks or other parasites or to infectious organisms that express alpha-1,3-galactosyltransferase? • The implications of our findings in screening the patients before the use of cetuximab as well as other monoclonal antibodies for other diseases.
Clinical management of hypersensitivity reactions The majority of hypersensitivity reactions to cetuximab occur during the first infusion. Therefore, these patients should be watched closely during the first infusion and observed for an hour after the infusion. In addition, there should be a stocked crash cart readily available. Prompt recognition and immediate medical attention is key to management. Given the high rate of grade 3-4 hypersensitivity reaction seen at the authors’
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Reprinted with permission from Reference 2.
He was transferred to the emergency department and admitted to the intensive care unit for close monitoring. Because of his grade 4 hypersensitivity reaction, he was not rechallenged with cetuximab after his recovery.
Retrospective study findings We learned from a retrospective study4 that severe hypersensitivity reactions to cetuximab tend to occur within minutes of initial exposure to the drug, which suggests the presence of preexisting immunoglobulin (Ig) E antibodies against the drug, such as in the cases described above. We examined this hypothesis by analyzing serum samples from 538 individuals for IgE antibodies against cetuximab, including 76 samples from cetuximab-treated cancer patients. Of the 76 cetuximab-treated patients, 25 developed hypersensitivity reactions, and 17 of these individuals demonstrated a positive reaction for IgE antibodies to the drug. Of the 51 patients who did not have a hypersensitivity reaction, only one had these antibodies before the start of cetuximab therapy. Both patients described in the case studies tested positive for the IgE in the pretreatment sera. Using a new immunoassay, we also found that the IgE associated with cetuximab-induced hypersensitivity is specific for the oligosaccharide, galactose-alpha-1,3galactose, which is located on the Fab portion of the cetuximab heavy chain and attached to cetuximab during the manufacturing process by an enzyme, alpha-1,3galactosyltransferase, present in the cell line. Clinical implications Our recent study, along with information from published studies, case reports, and our own anecdotal observations, has significantly improved our understanding about the relationship between cetuximab and severe hypersensitivity reactions. What we now know: • Severe hypersensitivity reactions to cetuximab have a marked regional pattern in the United States, with more clustered cases in North Carolina, Arkansas, Missouri, Virginia, and Tennessee. • Galactose-alpha-1,3-galactose is attached to cetuximab because cetuximab is produced in the cell line SP2/0, which expresses alpha-1,3-galactosyltrans18
Cetuximab-induced Hypersensitivity: A nurse’s perspective BY TALINE KHOUKAZ, NP, MSN, ACNP-C University of Southern California, Norris Cancer Center and Hospital, Los Angeles
etuximab is a chimeric murine-human immunoglobulin G1 monoclonal antibody, which is indicated for the treatment of colorectal cancer and squamous cell carcinoma of the head and neck. Although the drug does not have significant side effects other than the development of an acne-like rash, 3% of cetuximab-treated patients can expect to develop a severe hypersensitivity reaction. Ninety percent of the reactions are associated with the first infusion of cetuximab, despite the use of prophylactic antihistamines. It has been observed that most severe hypersensitivity reactions have an unusual geographic distribution, primarily concentrated in the southeast region of the United States. Dr Chung and her colleagues recently reported their finding of an immunoglobulin E (IgE) antibody against cetuximab, which was present in pretreatment blood samples of 68% of patients who had a hypersensitivity reaction to the drug, but only 2% of those did not have a reaction.1 Using a newly developed assay, the researchers analyzed sera from patients with severe hypersensitivity reactions to cetuximab. They noted that hypersensitivity reactions were associated with IgE antibodies specific for sugar galactosealpha-1,3 galactose, which is present on the Fab portion of the cetuximab heavy chain. The researchers are trying to determine what causes a high proportion of the population in certain parts of the United States to produce these particular IgE antibodies that react with cetuximab. Another question remains: Are there any potential implications of these findings for nurses administering cetuximab or other monoclonal antibodies, and if so, what are they? A complete record of the patient’s prior history to allergies is imperative. The risk of an allergic or anaphylactic reaction is greater in those
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with multiple allergies. Furthermore, it is essential to be able to differentiate between an allergic reaction and a common side effect, such as nausea and vomiting. Before administering cetuximab, it is important to review the relevant protocols of the institution in case an infusion reaction occurs. The crash cart and supportive medications should be available and up to date, including sufficient amounts of epinephrine, diphenhydramine, bronchodilators, intravenous fluids, and oxygen. Because the majority of hypersensitivity reactions to cetuximab occur during the first infusion, these patients should be monitored closely. Vital signs should be checked before, during, after, and one hour after the infusion is administered. All patients should be premedicated with dexamethasone and diphenhydramine or any antihistamine before cetuximab infusion. At the first sign of an infusion reaction, the infusion should be stopped and supportive medication should be administered. For mild-to-moderate (grade 1 to 2) reactions, treatment can continue using a reduced rate (reducing the rate by half) once the symptoms have resolved. For severe (grade 3 to 4) reactions, patients should not be rechallenged, and cetuximab should be discontinued. There is no US Food and Drug Administration–approved test to screen for the presence of the IgE antibodies against cetuximab. Increased awareness of the potential adverse reactions, particularly when treating patients who live in known high-risk areas, can lead to management that is more effective and will minimize the frequency and severity of treatment-related adverse events. References 1. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-1117.
Continuing Education 08CE059a • RELEASE DATE: June 25, 2008 • EXPIRATION DATE: June 25, 2009 Table 2. Suggested Management of Anaphylaxis Drug Epinephrine*
Dosage For mild-to-moderate anaphylaxis 0.3 to 0.5 mg IM (1:1000), repeated every 15-20 minutes if no clinical improvement For mild-to-moderate anaphylaxis 0.1 mg IV (1:10000) infused slowly over 5 minutes. Infusion rate of 1-4 mcg/min may prevent the need for frequent epinephrine injections Close patient monitoring is necessary because fatal epinephrine overdose has been reported
Administer at high flow rates
Rapid infusion of 1-2 L if hypotension is present
(eg, normal saline)
Diphenhydramine 25-50 mg slowly via IV or IM
Cimetidine 300 mg IV Ranidtidine 50 mg IV Famotidine 20 mg IV
Inhaled betaAlbuterol nebulizer treatment adrenergic agents Corticosteroids
Methylprednisolone 30-125 mg IV Hydrocortisone 100 mg IV Dexamethasone 20 mg IV
*Patients taking β-blockers can develop a paradoxical reaction to epinephrine. Inhaled ipratropium or glucagon may be useful in treatment of bronchospasm in these patients. IM indicates intramuscular; IV, intravenous. Adapted with permission from Reference 5.
institution in Tennessee, premedication with oral dexamethasone 20 mg the night before and the morning of treatment in addition to diphenhydramine before treatment was incorporated into a clinical trial; we have seen, however, that the infusion reactions can still occur even with this premedication. The cetuximab infusion should be discontinued immediately after the recognition of a hypersensitivity reaction, and supportive medications should be given. Supportive medications include epinephrine, steroids, IV antihistamines, bronchodilators, H2 blockers, and oxygen (Table 2).5 In the case of a severe (grade 3 to 4) reaction, as in the cases reported above, patients should not be rechallenged.1 In the case of a mild-to-moderate (grade 1 to 2) reaction, patients can be rechallenged at a slower infusion rate (decreasing the rate by half) once the symptoms have completely abated.1 June 2008
At present, there is no US Food and Drug Administration–approved test for the existence of this antibody nor are there prospective data showing that screening for this antibody is useful. It may eventually be possible to prescreen patients using the ImmunoCAP assay that was used in our study4 before cetuximab treatment. The patients residing in high-risk areas would be the probable target population. If we can identify the patients at risk of severe reaction, we can use alternative therapies instead of cetuximab, minimize unnecessary use of premedications and monitoring, and select candidates appropriate for desensitization to cetuximab as a clinical trial. Further studies are ongoing to resolve these issues for safe administration of cetuximab. Acknowledgement: Supported by grant from the Vanderbilt University GI SPORE (P50-CA-95103); and by the Damon Runyon Clinical Investigator Award (CL-28-05) and National Institutes of Health R01-DE-017982 to Dr Chung.
To receive complimentary CE credit, log onto http://app.1.unmc.edu/nursing/con web/OE_UNMC_online_home.cfm References 1. Erbitux [package insert]. New York, NY: ImClone Systems, Inc, and Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0. http://ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed May 16, 2008. 3. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25:3644-3668. 4. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:11091117. 5. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 10.6: Anaphylaxis. Circulation. 2005;112:IV-143-IV-145.
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Cetuximab-induced Hypersensitivity: A pharmacist’s perspective BY AUDREA H. SZABATURA, PHARMD, BCOP Department of Pharmacy, University of Massachusetts Memorial Medical Center, Levine Cancer Center, Worcester
mmune-mediated hypersensitivity reactions complicate up to 10% of therapeutic drug courses.1 Cetuximab specifically has been noted to cause severe hypersensitivity reactions in 3% of patients.2 A recent article by Chung and colleagues reveals new information regarding underlying mechanisms of infusion reactions.3 The investigators’ findings suggest a potential way to tailor drug therapy according to individual needs, especially in cases where an alternative agent exists. With this information, patients at risk for hypersensitivity reactions may be screened in advance, potentially preventing life-threatening adverse reactions. Furthermore, the investigators’ results have implications for research and development of monoclonal antibodies in the future. If we can knock out the gene for alpha-1,3-galactosyltransferase in a strain of pigs, which is one of the major barriers to organ transplantation, perhaps this can be accomplished as we go forth in drug development.4 It is interesting that the investigators reveal that many patients (68%) in their study who experienced hypersensitivity reactions to cetuximab, already had immunoglobin E (IgE) antibodies against cetuximab before the initiation of therapy. These antibodies were specific for the sugar molecule galactose-alpha-1,3-galactose, which is found on the Fab portion of the cetuximab heavy chain. Furthermore, there have been correlations between the incidence of cetuximab-related infusion reactions and certain areas of the United States, such as North Carolina and Tennessee.5 Chung and colleagues note that natural exposure to galactose-alpha1,3-galactose seems to stimulate production of
IgE antibodies and suggest that tick bites are the most likely cause.2 It is interesting, however, that a report by the Centers for Disease Control and Prevention shows that the geographical area with the highest incidence of Lyme disease cases, and therefore exposure to ticks and potential production of IgE antibodies, is the northeast.6 This seems contrary to Chung’s results, in which only 0.6% of patients in the Boston area had IgE antibodies against cetuximab. Chung and colleagues provide new information concerning the mechanism of hypersensitivity reactions; however, many questions remain, especially regarding the production of IgE antibodies. Also yet to be determined is how the findings by Chung and colleagues might change policies or protocols regarding hypersensitivity reactions at large institutions, and, of even greater concern, in the oncologist office setting, where access to personnel or resources may be more limited. References 1. Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68:1781-1790. 2. Erbitux [package insert]. New York, NY: ImClone Systems, Inc, and Princeton, NJ: Bristol-Myers Squibb Company; 2007. 3. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-1117. 4. Liu QP, Yuan H, Bennett EP, et al. Identification of a GH110 subfamily of alpha-1,3-galactosidases: novel enzymes for removal of the alpha-3Gal xenotransplantation antigen. J Biol Chem. 2008;283:8545-8554. 5. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25:3644-3648. 6. Centers for Disease Control and Prevention Division of Vectorborne Infectious Diseases. Reported Lyme disease cases by state, 1993-2006. http://www.cdc.gov/ncidod/dvbid/Lyme/ ld_rptdLymeCasesbyState.htm. Accessed May 16, 2008.
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Role of the Registered Dietitian in Cancer Care BY AMANDA SALDIVAR, MS, RD, LD TAUSSIG CANCER INSTITUTE, CLEVELAND, OHIO
n March 2008, the American Dietetic Association offered its first certification examination in the specialty of oncology nutrition, allowing registered dietitians to verify their expertise as a provider of nutrition care to oncology patients. This has further strengthened several cancer organizations’ guidelines regarding the role nutrition plays in the prevention, treatment, and survivorship of oncology patients.1-3 The registered dietitian’s responsibilities include patient care and education as well as education for other members of the healthcare team.
Patient care Patient care includes the assessment of the patient, identifying nutrition-related problems, providing nutrition-related intervention, and monitoring the patient’s progress, both in acute and outpatient settings; this is the standard of care established by the American Dietetic Association that all dietitians follow.4 Most often, we help patients overcome side effects from treatment (radiation, chemotherapy, biological therapy, and surgery), which can improve their intake of the recommended amounts of calories and proteins. These are often increased in oncology patients to prevent cancerinduced weight loss. Registered dietitians also provide sound, scientifically based education to assist patients sort through the overwhelming information about nutrition and cancer that they see on the Internet or news, hear from friends and family, and read in magazines and books. A registered dietitian can play a valuable role in improving patients’ quality of life and the outcomes of oncology treatment. Often significant weight loss is what causes a patient to seek a diagnosis. Therefore, oncology patients are often malnour-
ished before even visiting a physician. Cancerinduced weight loss differentiates itself from typical weight loss because of several physiologic processes and tends to be more difficult to overcome than typical weight loss.5 Poor nutritional status has been recognized as a contributing factor to increased morbidity and mortality among patients with cancer.6-10 It is important to note that malnutrition not only involves body weight, but also the patient’s previous eating habits. A diet that is varied and includes all of the food groups can benefit the patient throughout treatment, helping to sustain adequate blood counts and prevent delays in the treatment schedule. Helping the patient to consume adequate calories, protein, and micronutrients often involves more than simply telling them to eat more food. It includes creative ideas to overcome the physical, psychologic, and socioeconomic barriers that many newly diagnosed cancer patients contend with.
The interdisciplinary team Nurses and other members of the interdisciplinary team play an integral role in supporting the registered dietitian by participating in the nutrition screening process. Simply asking patients whether they wish to meet with a dietitian may not always be the best approach, since many patients are unaware of how we can help them. Because nursing staff most often has first contact with patients, they may receive vital information on the patient’s nutritional status. This includes all factors that may interfere with normal dietary intake, such as pain, anorexia, gastrointestinal issues, swallowing difficulty, fatigue, depression, or lack of access to food. It is ideal to take a proactive approach in discussing nutrition with patients and their families rather
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than waiting for a problem to arise. Having a registered dietitian included in the continuum of care allows patients to have more available access and provides an opportunity to speak with a nutrition professional that they may not have initiated on their own.
Referral to a registered dietitian If there is not a registered dietitian at your facility, a referral to one may be necessary. It is important to note that there is a difference between a registered dietitian and someone who simply disseminates nutrition advice. A registered dietitian is a nutrition professional who has received a bachelor’s degree from a university that provides coursework approved by the Commission on Accreditation for Dietetics Education (CADE, the accrediting body of the American Dietetic Association); has completed a supervised 6- to 12-month program that has also been approved by CADE; passes a national certification examination administered by the Commission on Dietetic Registration; and once registered, continues to complete required continuing professional education (75 hours are required every 5 years) and follows a code of ethics.11 Registered dietitians may also be required to be licensed by the state in which they practice. This required licensing ensures that those who represent themselves as dietitians are providing safe and sound nutrition advice. These laws protect the public, especially oncology patients who often turn to complimentary medicine during treatment. If you do refer a patient to an outside nutrition professional, it is vital that you emphasize that he or she see a registered dietitian. As more dietitians are completing the certification examination in oncology, patients can begin looking for the credentials CSO. A registered dietitian can be found by logging onto the American Dietetic Association’s homepage at www.eatright.org. References 1. National Cancer Institute. Nutrition in cancer care: physician data query. http://www.cancer.gov/cancertopics/pdq/supportivecare/ nutrition/healthprofessional. Accessed May 6, 2008. 2. American Cancer Society. Nutrition for the person with cancer. http://www.cancer.org/docroot/MBC/MBC_6.aspsitearea=ETO. Accessed May 6, 2008. 3. American Institute of Cancer Research. Diet and cancer: what’s the link? http://www.aicr.org/site/PageServer?pagename=dc_diet. Accessed May 6, 2008. 4. Robien K, Levin R, Pritchett E, et al. American Dietetic Association: standards of practice and standards of professional performance for registered dietitians (generalist, specialty, and advanced) in oncology nutrition care. J Am Diet Assoc. 2006;106:946-951. 5. Cravo ML, Glória LM, Claro I. Metabolic responses to tumour disease and progression: tumour-host interaction. Clin Nutr. 2000; 19:459-465. 6. Trabal J, Leyes P, Forga MT, et al. Quality of life, dietary intake and nutritional status assessment in hospital admitted cancer patients. Nutr Hosp. 2006;21:505-510. 7. Ravasco P, Monteiro-Grillo I, Vidal PM, et al. Cancer: disease and nutrition are key determinants of patients’ quality of life. Support Care Cancer. 2004;12:246-252. 8. Ravasco P, Monteiro-Grillo I, Camilo ME. Does nutrition influence quality of life in cancer patients undergoing radiotherapy? Radiother Oncol. 2003;67:213-220. 9. Ravasco P, Monteiro Grillo I, Camilo M. Cancer wasting and quality of life react to early individualized nutritional counselling. Clin Nutr. 2007;26:7-15. 10. Marín Caro MM, Laviano A, Pichard C. Impact of nutrition on quality of life during cancer. Curr Opin Clin Nutr Metab Care. 2007;10:480-487. 11. American Dietetic Association. Registered dietitian information sheet. http://www.eatright.org/cps/rde/xchg/ada/hs.xsl/home_6658_ENU_ HTML.htm. Accessed May 6, 2008.
The Official Newspaper of Record for the Hem/Onc Nurse
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Presents The First Annual 2008 Curriculum for
CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.
SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University
# Earn Continuing Education Credits # Each newsletter will feature:
Clinical Topics: • Renal Dysfunction • Hard-to-Treat Patients • Treatment-Naive Patients • Health Economics
• Contributions from thought-leading physicians, pharmacists, and nurses • Continuing Education credits available to physicians, pharmacists, and nurses
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About Multidisciplinary Cancer Care Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community. Target Audience This educational publication is designed for physicians, nurses, and pharmacists who wish to enhance their knowledge concerning the management of patients with multiple myeloma and renal dysfunction.
Learning Objectives At the completion of this educational activity, you should be able to • Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM) • Recognize the special challenges in pharmacologic treatment of the many patients with MM who also have renal insufficiency, especially those requiring dialysis • Discuss the results of studies showing treatments that are active and safe in MM patients with renal impairment, including those with advanced renal failure requiring dialysis
Accreditation Physicians This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of CME Consultants and Center of Excellence Media. CME Consultants is accredited by the ACCME to provide continuing medical education for physicians. CME Consultants designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Supported by an educational grant from Millennium Pharmaceuticals, Inc.
Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.
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Career Builder: Best Ways to Impress Job Recruiters Nursing recruiters want to be impressed by potential recruits, and a mere list of skills will not do it. “I like to see people who are involved, who are advancing the practice,” advised Gayle Kerfoot, RN, a recruiter at City of Hope in Duarte, California. Presenting a mini session entitled “How to Impress Recuiters” at the Oncology Nursing Society (ONS) annual conference in Philadelphia in May, she said she wants to know what an applicant did that was special. As examples, she cited publishing articles, instituting programs, or serving on a committee, such as one to improve patient safety or to write protocols or other procedures. Professional involvement, such as with the ONS or other organizations, is also valuable. Ms Kerfoot suggested not just listing a job history and duties. “We’re all looking for the superstar,” she said. Highlight specific accomplishments that show leadership qualities, and then project those qualities and skills to the new position. She wants to hear how applicants envision themselves in the new job. Do they want to
publish, start or take on new projects, and, if so, what kind? “Program development is a big thing,” she emphasized. “Is she a good coach? Is he a leader?” She advised applicants to do their homework before applying. It is all right to call an institution and ask to speak to people in the specialty area for which an applicant wants a position. Similarly, good information can be obtained by calling and asking to speak to a recruiter. Know as much as you can about the job and the institution before going into the interview, and learn more while you are there. Ask questions about the job, institutional goals, and opportunities for training and for contributing to the employer. It is very appropriate and necessary to talk about one’s accomplishments in an interview. Excessive modesty is not a virtue in this setting. Think about how you want to present the complete package, the package being you: accomplishments, professional dress, good eye contact, and being on time. Impress the recruiter with what you can do for them. —Daniel M. Keller
Summer Squash—A Seasonal Delight One of the gastronomic delights of the peak of summer is the prevalence of summer squash varieties. Many people are familiar with the zucchini, or courgette, as it is known in some places, but there are hundreds of other varieties from this family. Try a Costa Romanesca, which is pale with a ribbed skin and is known for a delicate flavor that complements other flavors. Fragile Squash blossoms are also part of this family and are very popular in Mexican and other South American recipes. Pattypan squash are cylindrical and best when small. Although their flavor is not as defined as that of a zucchini, they are an excellent aesthetic component in dishes and pair well with other textures. Look for these more exotic varieties at gourmet markets or farmers’ markets. Thin-skinned, unlike their winter squash counterparts such as butternut squash, the flavors of summer squashes are delicate, and they contain a lot of water, which makes them a low-calorie meal ingredient.
Some serving/preparation suggestions for zucchini or summer squash: • Because of their fairly high water content, there can be a slight bitterness to the taste. To rid them of this, salt the sliced squash and leave it in a colander to drain for at least half an hour before preparation. • Select squash with shiny, smooth skin and solid flesh. Slight imperfections such as light bruising or scratching are fine and do not affect the taste. Do, however, avoid squash with a spongy texture. • To wash squash, use a vegetable brush to gently remove any dirt. Squash can be kept in the refrigerator for up to 3 days. • An idea for a light meal or a great side dish: sauté thin slices in olive oil and garlic until they soften a bit, but still have crunch (about 3-5 minutes). Garnish with parmesan cheese, salt, and pepper and serve alone or over pasta or rice. • Complementary flavors: parmesan cheese, garlic, feta cheese, goat cheese, basil, mint, tomatoes, onions, and corn. 22
• Because of its high moisture content, recipes can be found for zucchini as the “secret ingredient” in some sweet cakes, such as muffins and chocolate cake.
Recipe: Zucchini Pancakes Courtesy of Chad Goslee
1 lb small to medium zucchini (2-3 pieces) 1 egg 1/2 cup ricotta cheese 1/4 cup flour 1 tbsp fresh basil, chopped 1/2 tbsp fresh mint, chopped 1 clove of garlic, minced salt and pepper 2 tbsp extra virgin olive oil Grate zucchini on the large holes of a box grater and toss with 1/2 tsp salt. Place zucchini in a colander to drain for at least 30 minutes. After zucchini has drained, place in a clean kitchen towel or cheesecloth and squeeze out as much liquid as possible. Whisk egg and ricotta together until fairly smooth, and then whisk in flour. Add drained zucchini, herbs, garlic, salt, and pepper. Mix well. Heat 1-2 tbsp of oil in a skillet over medium-high heat. Drop zucchini mixture by spoonfuls into skillet, using a spatula to flatten them. Cook until browned on first side, then flip and brown on the second side. Top with a spoonful of cherry tomatoes (optional) and enjoy! —Amy
What’s Your Favorite Healthy Recipe? With a little creativity, healthy foods can be delicious as well as nutritious. Do you have a favorite healthy recipe that you would like to share with your colleagues and patients? Send your recipe and its source (family recipes are welcome) to firstname.lastname@example.org.
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Moderate Exercise Cuts Risk of Mild Cognitive Impairment CHICAGO—A new study provides yet another reason to exercise. In addition to its other benefits, the findings suggest that routine moderate exercise during middle age may help prevent the development of mild cognitive impairment (MCI), investigators reported at the 60th Annual Meeting of the American Academy of Neurology. Yonas Geda, MD, of the Mayo Clinic, Rochester, Minn, and colleagues reviewed physical exercise data obtained from 128 individuals 70 to 89 years of age who had MCI and 740 cognitively normal elderly persons who were enrolled in the ongoing Mayo Clinic Study of Aging. Participants in the trial underwent neurological, psychometric, and neuropsychiatric evaluations. A consensus panel of physicians, nurses, and psychologists determined the classification of normal cognitive aging, MCI, or dementia based on published criteria. Results showed that moderate physical exercise two to five times per week during the ages of 50 to 65 years was associated with a decreased risk of MCI; however, the individual’s exercise habits during the year prior to the survey were not associated with a reduced risk. The findings were not related to age, sex, education, apathy, or depression. Dr Geda said that he cannot yet explain the findings, but it may be that physical exercise protects against MCI via its well-known beneficial effects on cognition. Also, physical exercise may be a marker for a healthy lifestyle. The Minnesota researcher emphasized that the results may be weakened by the study’s potential for recall bias since the exercise data were dependent on the recall of the participants’ exercise habits between ages 50 through 65. He was quick to add, however, that “it is reassuring” that studies elsewhere that analyzed exercise data using objective measures, such as treadmill duration test and peak oxygen consumption, reported similar findings that physical exercise protects against incidence cognitive decline. At any rate, prospective cohort studies that measure incident MCI as an outcome are needed to corroborate the findings, he added. June 2008
TAUSSIG Continued from page 10
nursing research and we do a lot to educate our nurses,” said Dr Raghavan. The entire nursing team in the hematologic and medical oncology outpatient treatment facility is certified in the administration of chemotherapy.
Therapeutic discoveries The renal cancer program has been successful at refining therapies. Taussig Cancer Institute investigators have found that sorefanib is associated with a doubling of the average progression-free survival in patients with advanced renal cell carcinoma. Investigators in the renal cancer program led an international group that conducted studies on a tyrosine kinase inhibitor (sunitinib malate) for the treatment of kidney cancer, which received priority review and was approved in less than 6 months. The agent is indicated for the treatment of patients with renal cell cancer (and gastrointestinal stromal tumors who have disease progression despite treatment with imatinib mesylate or who are unable to tolerate imatinib). In patients with metastatic kidney cancer whose tumors progressed following cytokine-based therapy, sunitinib was associated with an overall response rate of 26% to 37%. Taussig researchers in hematologic oncology contributed to the discovery that AMG-531, a thrombopoiesis-stimulating protein, can stimulate platelet production in patients with immune thrombocytopenic purpura. Another clinical trial in which Taussig Cancer Institute researchers participated led to the approval of dasatinib for use in adults with chronic-phase, accelerated-phase, or myeloid or lymphoid blast–phase chronic myeloid leukemia. In lung cancer research, bevacizumab, which is approved for the treatment of advanced colon cancer, is being explored for early cancer.
Extensive support services Patients and families have access to a wide variety of support services to help them cope with cancer and its treatment. The Scott Hamilton CARES Initiative is one of the features that sets the Taussig Cancer Institute apart from others, Dr Raghavan believes. It was developed by the ice skater Scott Hamilton, who was treated there for testicular cancer and has since helped to raise more than $10 million in funds for CARES through various philanthropic functions.
Photo courtesy of Cleveland Clinic
CARES is focused on cancer education, research, and support. As part of CARES, a program called the 4th Angel Mentoring Program was developed in which former cancer patients are matched with new patients with the same type of cancer. The 4th Angel mentor is a cancer survivor trained in peer counseling and one-on-one outreach and support.
Patients undergoing chemotherapy participate in customized classes led by oncology nurses to lessen anxiety and prepare them for the treatment process.
Multidisciplinary approach Multidisciplinary management is a pillar of cancer management at the Taussig Cancer Institute. Patients are typically managed by a team of staff physicians, nurses, residents, and pharmacists to provide a level of expertise that may not be available at smaller institutions. “A patient with breast cancer will have the opportunity of involvement by a surgeon, radiation therapist oncologist, diagnostic radiologist, mammographer, and medical oncologist from the beginning,” said Dr Raghavan. “Someone with node-positive disease would see everybody.” He continued, “One of our models, because we’re so multidisciplinary, is that we have a lot of neoadjuvant studies. The idea is that we’ll give either chemotherapy, a novel agent, or a differentiating agent to a patient who is due to have a mastectomy or prostatectomy or bladder cancer removal, and it would be part of a standard of care. If a patient has a high-risk tumor, we might give chemotherapy and try to shrink the cancer, and at the same time we’ll look at the molecular biology— what has happened to that tumor after it has had that particular agent. This is obviously done only in the context of a clinical trial, with informed consent.” A recent study assessed a nano-engineered taxol derivative and the molecular correlates of its success and failure, he said. Other novel chemotherapy studies have been performed in patients with breast cancer. —Wayne Kuznar References 1. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261. 2. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791.
Pain Beliefs in Cancer Patients Probed A new study adds to the evidence indicating that patient-related factors may contribute significantly to cases of inadequate pain relief (Cancer Nurs. 2008;31:E1-E6). Of patients in the study, 41% said they strongly agreed with the statement, “People get addicted to pain medication very easily.” Furthermore, patients who strongly agreed with this statement reported significantly more pain than did patients who did not strongly agree. The investigators suggest that patients harboring such beliefs may be reluctant to either report pain or to accept medication to treat it, and that healthcare providers need to be vigilant for this. “As health professionals, part of our role is to ensure that patients have quality information about their treatment options and that any fears/issues they may have are discussed,” said lead investigator Mari Botti, RN, DipN, BA, PhD, professor, Faculty of Health, Medicine, Nursing, and Behavioural Sciences, Deakin University, Victoria, Australia. “Although we need to respect the decisions patients make, if patients were better informed about the sequelae associatJune 2008
ed with poor pain management, they would make different decisions.” Barbara Murphy, MD, who is director of the Pain and Symptom Management Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, agrees. “I think what’s coming to light now is that patient-related barriers are major contributors to uncontrolled pain,” said Dr Murphy. “[The implication is] we can’t concentrate just on writing the prescription, or just putting the patient’s pain intensity in our notes; we need to follow through, and try to understand why patients aren’t taking the prescribed treatment.” Dr Botti and her colleagues interviewed 126 cancer patients 48 hours after admission to an urban and a regional hospital in Australia. They found that 38% of the patients had a pain-related condition or comorbidity, such as chronic back pain or bone metastases. Furthermore, 54.8% of the patients had experienced pain in the previous 24 hours. Most—83.3%—had prescriptions for at least one type of analgesic, either paracetamol, with or without codeine, or an opioid. Symptom management drugs
were available to 8.7% of the patients. However, overall patients received only 40.4% of their available analgesics. Of the 69 patients who had experienced pain in the previous 24 hours, 79.7% said they had reported their pain to a clinician. Furthermore, 72.5% said they had never refused pain medication, and 79.7% said they would want a stronger medication if pain persisted. The main reason reported for not taking prescribed analgesics on a regular basis or not wanting stronger medication was the side effects of the medication, such as nausea, decreased mental alertness, and constipation. The patients’ answers to questions about their beliefs and attitudes towards pain indicated that many had misconceptions about pain and pain relief. The investigators found a correlation between patient belief in addictiveness of pain medications and having intense pain, but they did not probe whether patients with more intense pain had refused analgesics or had deliberately not accurately reported the level of their pain.
Nurse Practitioner Clinical Fellowship Cancer Pain Management & Palliative Care MSKCC, the leader in defining new standards of cancer care, is offering an excellent opportunity for a nurse practitioner: a oneyear clinical fellowship, sponsored by the Pain and Palliative Care Service. The selected candidate will train alongside physician pain and palliative care fellows in an active, multidisciplinary clinical environment, in both the inpatient and outpatient setting. The training will emphasize the management of pain and other symptoms as well as enhancing communication skills. Requirements include a Master's degree in nursing, NYS RN and NP license, prescriptive privileges (or eligible), and 2 years related clinical experience. This position offers a comprehensive benefits package including a housing stipend. For further information please contact: Nessa Coyle, NP, PhD, Pain and Palliative Care Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, phone: 646-888-2693. fax: 646-888-2735, or e-mail: email@example.com. EOE/AA.
—Rosemary Frei G REEN H ILL H EALTH C ARE C OMMUNICATIONS
CANCER CENTER PROFILE
Clinical Trials Update CLINICAL TRIALS UPDATE
New Trial Will Examine the Role of Tykerb in Early Breast Cancer A multicenter phase 3 trial has been initiated to assess lapatinib (Tykerb) as neoadjuvant therapy for women with early-stage, human epidermal growth factor 2 (HER2)-positive breast cancer. The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (Neo-ALTTO) trial will randomize patients to one of three treatments prior to surgery: lapatinib, trastuzumab (Herceptin), or a combination of both agents. The primary objective of this trial is to evaluate and compare the rate of pathological complete response asso-
ciated with each therapy. Researchers are aiming for a total enrollment of 450 patients at approximately 130 clinical trial centers worldwide.
Enrollment Under Way in Pivotal Phase 3 Trial of Bevacizumab and Trastuzumab for Early Breast Cancer A pivotal phase 3 trial is recruiting patients with early-stage breast cancer to evaluate the clinical benefit of treatment with two well-known monoclonal antibodies plus chemotherapy. The Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-positive Breast Cancer (BETH) trial will ran-
domize patients with early-stage, HER2-positive breast cancer to a regimen of chemotherapy plus trastuzumab (Herceptin), with or without bevacizumab (Avastin). Trastuzumab is a targeted agent that has already demonstrated a survival benefit in patients with all stages of HER2-positive breast cancer. Bevacizumab, an antiangiogenic agent, has shown promising efficacy when combined with chemotherapy for the treatment of metastatic breast cancer. BETH is the first phase 3 trial to evaluate the combination of these two monoclonal antibodies in early-stage breast cancer and is aiming to enroll as many as 3,500 patients.
Your subscription at NO CHARGE is just a signature away! Written by and for oncology nurses offering you the following: • Concise reviews of hot topics in the peer-reviewed literature by clinical specialists with key point ‘takeaways’ • Coverage of key research studies and on-the-scene reports from oncology medical meetings • Continuing education articles at no charge and post-tests, offering you a convenient way to obtain contact hours
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First Stage of Bavituximab Trial in Breast Cancer Has Completed Enrollment Enrollment is now complete in the first stage of a phase 2 open-label, multicenter trial in which patients with advanced breast cancer will receive combination therapy consisting of docetaxel (Taxotere) plus the novel agent bavituximab. This new monoclonal antibody works by binding to a basic component of the cell structure called a phospholipid that is exposed only on the surface of tumor blood vessel cells. The binding action of bavituximab alerts the body’s immune system to attack the tumor and its blood supply, resulting in the inhibition of tumor growth and development. The primary end point of this trial is to assess the overall response rate to docetaxel plus bavituximab. Secondary end points include time to disease progression, duration of response, overall survival, and safety. Currently, only 15 patients are enrolled in this trial; however, up to 31 additional patients may be recruited if the initial cohort responds well to treatment. Phase 3 Trial Will Evaluate CB7630 in Advanced Prostate Cancer Cougar Biotechnology, Inc. has begun recruiting patients with advanced prostate cancer for its phase 3 trial of CB7630 (abiraterone acetate), an investigational agent that has demonstrated encouraging clinical activity in phase 2 trials. The phase 3 COU-AA-301 trial is a double-blind, placebo-controlled study that will randomize patients with metastatic, hormone-refractory prostate cancer who have failed docetaxel-based therapy to prednisone plus CB7630 or prednisone plus placebo, with the primary objective of assessing overall survival. Target enrollment for this trial is 1,160 patients with approximately 150 clinical trial centers participating throughout North America. BiPar Sciences Expands Phase 2 Clinical Trials of BSI-201 in Ovarian Cancer A phase 2 trial has been initiated to assess BSI-201, a poly ADP-ribose polymerase (PARP) inhibitor, in patients with difficult-to-treat ovarian cancer. This is the third major clinical trial of BSI-201 that BiPar Sciences has launched in the past 6 months, expanding on its ongoing trials in breast and brain cancer. This latest trial is being conducted at MSKCC and will evaluate the efficacy of singleagent BSI-201 in patients with mutations in their BRCA1 or BRCA2 genes, a hereditary genetic defect linked to ovarian cancer. A fourth trial, which will evaluate BSI-201 in uterine cancer, is expected to begin enrollment in the near future. June 2008
Meetings JULY 2008 2008 Breast Cancer Symposium www.astro.org
19 – 23 SAN FRANCISCO, CA 7th International Conference on Head and Neck Cancer The American Head and Neck Society www.ahns.info
24 – 26 CANCUN, MEXICO 3rd Interamerican Breast Cancer Conference www.imedex.com/calendars/ oncology.asp
3– 8 VAIL, CO Methods in Clinical Cancer Research Joint ASCO/AACR Workshop www.aacr.org
27 – 31
GENEVA, SWITZERLAND International Union against Cancer (UICC) World Cancer Congress www.uicc-congress08.org
RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases for which Rituxan has not been approved. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal
17 – 20 SAN FRANCISCO, CA 19 – 20 MIAMI, FL 25th National Oncology Economics Conference www.accc-cancer.org
9th Annual Perspectives in Colorectal Cancer www.imedex.com
perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence *25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving RCHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. NonHodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Rituximab is a genetically engineered IgG molecule, and IgG crosses the human placenta. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Other than target B lymphocytes, rituximab is not known to bind to any normal human tissues in an ex vivo assay. However, it is not known if binding occurs to unique embryonic or fetal tissue receptors in vivo. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) frequently among elderly patients. Serious pulmonary adverse reactions were also Respiratory System 38 4 Any Adverse Events 99 57 more common among the elderly, including pneumonia and pneumonitis. Low86 10 Increased Cough 13 1 Body as a Whole Fever 53 1 Rhinitis 12 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Chills 33 3 Bronchospasm 8 1 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 numbers of patients aged 65 and over to determine whether they respond Headache 19 1 Metabolic and Nutritional Abdominal Pain 14 1 Disorders 38 3 differently from younger subjects. OVERDOSAGE There has been no experience Pain 12 1 Angioedema 11 1 with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Flushing 5 0 LDH Increase 7 0 Heme and Lymphatic System 67 48 Digestive System 37 2 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 studies have been performed to establish the carcinogenic or mutagenic potential Neutropenia 14 6 Vomiting 10 1 of Rituxan or to determine potential effects on fertility in males or females. Thrombocytopenia 12 2 Nervous System 32 1 Anemia 8 3 Dizziness 10 1 PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Skin and Appendages 44 2 Anxiety 5 1 Night Sweats 15 1 Musculoskeletal System 26 3 Medication Guide and provided an opportunity to read prior to each treatment Rash 15 1 Myalgia 10 1 session. Because caution should be exercised in administering Rituxan to patients Pruritus 14 1 Arthralgia 10 1 Urticaria 8 1 Cardiovascular System 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a b Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy. Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
5 – 7 WASHINGTON, DC
For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
When planning a treatment course for DLBCL
Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL
in 7-year OS in GELA* trial 1,2
• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5
BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5
Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
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©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 3 Printed in USA on Recycled Paper 8974801 April 2008