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VOL 3, NO 8
CANCER CENTER PROFILE
Geisinger Medical Center’s Cancer Institute Joins the NCCCP By Dawn Lagrosa
Multigene Signature Scores and Breast Cancer 2010 By Deena Damsky Dell, MSN, RN-BC, AOCN Clinical Nurse Specialist, Fox Chase Cancer Center, Philadelphia
he addition of new biomarkers for establishing a prognosis for patients with breast cancer has been recommended in the 2010 edition of the American Joint Committee of Cancer’s Cancer Staging Handbook.1 Human epidermal growth factor receptor type 2 (HER2) status and multigene signature “scores” have been added to estrogen receptor (ER) and progesterone receptor (PR) determinations.1 So, where are we regarding multigene signature scores? At this time, two tests are commercially
available in the United States: Oncotype DX (Genomic Health) and MammaPrint (Agendia). 21-gene recurrence score assay Available since 2004, Oncotype DX uses a process called reverse-transcriptase polymerase chain reaction (RT-PCR) to look at 21 genes: 16 are linked to breast cancer and five are reference genes used for normalizing the expression of the cancer-related genes. The chosen genes have Continued on page 12
Mammography technologist Jessica Davis, RT(R) (M), is part of a multidisciplinary breast cancer care team working to improve access to screening, treatment, and research.
Oncology Nursing Society’s 11th Annual Advanced Practice Nursing Conference/ Institutes of Learning Orlando, Florida, November 11-14, 2010. See who was there: page 8.
his past April, Geisinger Medical Center’s (GMC) Cancer Institute became one of 14 sites added to the National Cancer Institute Community Cancer Centers Program (NCCCP). Joining this national network of community cancer centers offers GMC the opportunity to expand its state-of-the-art cancer care and research in northeast Pennsylvania. GMC is a part of Geisinger Health System (Geisinger), which serves a mostly rural population and has cancer centers in Danville, WilkesBarre, State College, and Hazleton. Geisinger takes pride in its innovative approach to healthcare delivery to this population, which also includes many elderly patients. In addition, a significant portion is underserved because of socioeconomic status and transportation problems. Thanjavur Ravikumar, MD, FACS, director of the Center for Surgical Innovation, and co-chair of the oncology service line at
Continued on page 18
Kimberly Gessner, Holly Gentry, and Marlene Ferguson display copies of The Council of Dads, a book by keynote speaker Bruce Feiler.
Journal of Oncology
NAVIGATION & SURVIVORSHIP
Lung Cancer Stereotactic Radiation for Non–small-cell Lung Cancers
Continuing Education Maintenance erapy in Patients with Advanced Non–small-cell Lung Cancer
Submit your cases online today at
Fostering a Dialogue to Improve Patient Care & Outcomes
The Official Journal of the Academy of Oncology Nurse Navigators ® DECEMBER 2010
VOL 1, NO 7
City-wide Patient Navigation Network Coordinates Washington, DC, Cancer Care By Karen Rosenberg
Leadership Council Lillie Shockney, RN, BS, MAS Johns Hopkins Breast Center Johns Hopkins University School of Medicine Baltimore, Maryland Sharon Gentry, RN, MSN, AOCN, CBCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, North Carolina Nicole Messier, RN Vermont Cancer Center Burlington, Vermont Pamela Matten, RN, BSN, OCN St. Joseph Hospital Orange, California Elaine Sein, RN, BSN, OCN, CBCN Fox Chase Cancer Center Partners Rockledge, Pennsylvania Tricia Strusowski, MS, RN Helen F. Graham Cancer Center Christiana Care Health System Newark, Delaware
he George Washington Cancer Institute (GWCI) recently received a $2.4 million grant from the DC Cancer Consortium to establish and coordinate a City-wide Patient Navigation Network (CPNN) in Washington, DC. The CPNN will create a seamless, cohesive framework for coordination of cancer care throughout the city to ensure that all city residents get appropriate cancer screening and treatment regardless of their ability to pay. The network will also help patients identify support services throughout the cancer continuum, including posttreatment survivorship. Twenty-five separate institutions, including hospitals, cancer centers, and community organizations in the Washington, DC, area are members of
the network, and patient navigators are embedded at every site, said Steven Patierno, PhD, executive director of the GWCI.
and a secure Internet-based data collection process, which allows the navigators to upload their navigation logs and their patient interactions in real time.
“The CPNN will create a seamless, cohesive framework for coordination of cancer care throughout the city. ” —Steven Patierno, PhD
The program, he explained, provides training once a month to every navigator and every navigator’s supervisor. It also provides a central communications portal
Journal of Oncology Navigation & Survivorship™
He gave an example of how coordination of care works. “If a patient is seen at a community advocacy group that does Continued on page 2
Center Provides Platform for Discussion of Cancer Survivorship, Navigation, and Policy By Karen Rosenberg
Fast Neutron Radiotherapy
Breast Cancer Prolonging Chemotherapy in Metastatic Breast Cancer Improves Survival Page 44
©2010 Green Hill Healthcare Communications, LLC
Linda Fleisher, MPH, PhD(c) Fox Chase Cancer Center Cheltenham, Pennsylvania Susan M. Gardner, RN, CBEC, CBCN Valley Medical Center Renton, Washington Jay R. Swanson, RN, BSN, OCN Saint Elizabeth Cancer Institute Lincoln, Nebraska Carol Lewis, RN, BSN, OCN, CRNI Memorial Hermann The Woodlands, Texas
he Center for the Advancement of Cancer Survivorship, Navigation, and Policy (caSNP), a collaboration of the George Washington Cancer Institute (GWCI) and the university’s School of Public Health and Health Services Department of Health Policy, was established in 2009 with support from Pfizer and the Pfizer Foundation. The center’s goals are to advance patient navigation and cancer survivorship efforts both locally and nationally through training, research,
policy analysis, and education. caSNP grew out of the understanding that there is “overlap between patient navigation, survivorship, and policy and both of these intersect with local and national healthcare policy,” explained Steven Patierno, PhD, executive director of the GWCI. “We wanted to create a platform to talk about navigation and survivorship in the context of policy in a united program.” The center offers training programs at three levels:
• Navigation training is designed for navigators, including nurses, social workers, and lay persons. Trainees from institutions across the country learn about barriers that affect their patients, are trained to launch or improve programs, and gain tools for implementing institutional change. • Executive level training is designed for chief executive officers, chief financial officers, hospital adminis-
AONN Staff Sean T. Walsh Executive Director sean@AONNonline.org
GUIDE OUR PATH Start a Local, State, or Regional Affiliate, Join a Committee
www.AONNonline.org ©2010 Green Hill Healthcare Communications, LLC
Continued on page 2
between pages 34 and 35
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Announcing the first and only monoclonal antibody indicated for use in HER2+ metastatic gastric and gastroesophageal junction (GEJ) cancer Indication Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.
to drive outcomes in HER2+ metastatic gastric/GEJ cancer
Boxed WARNINGS Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death
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Herceptin plus chemotherapy* extended median overall survival (OS) in HER2+ metastatic gastric and GEJ cancer1 In the ToGA trial†: •
The final overall survival analysis demonstrated a 13.5-month median OS with Herceptin + chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) vs an 11.0-month median OS with chemotherapy alone1
The updated overall survival analysis demonstrated a 13.1-month median OS with Herceptin + chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) vs an 11.7-month median OS with chemotherapy alone1
Herceptin should be administered until disease progression or unacceptable toxicity in HER2+ metastatic gastric and GEJ cancer
Trastuzumab in gastric cancer.
Final Median Overall Survival Analysis1
Hazard Ratio = 0.73 95% CI: 0.60-0.91 P=0.0038
11.0 Updated Median Overall Survival Analysis1‡
13.1 Hazard Ratio = 0.80 95% CI: 0.67-0.97
Months Herceptin plus chemotherapy* (n=298) Chemotherapy alone* (n=296) *Chemotherapy was cisplatin and either capecitabine or 5-FU. ‡ The updated analysis was conducted one year after the final analysis. No P value was associated with the updated analysis in the Herceptin Prescribing Information because there was no preplanned statistical testing for OS after the final analysis.
Additional Important Safety Information Exacerbation of chemotherapy-induced neutropenia has also occurred Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy The most common adverse reactions associated with Herceptin were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia Please see brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages. Reference: 1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.
©2010 Genentech USA, Inc.
So. San Francisco, CA
All rights reserved.
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HERCEPTIN® (trastuzumab) Brief Summary For full Prescribing Information, see package insert. WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy Herceptin administration can result in sub clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration] Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions] Embryo-Fetal Toxicity Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. [see Warnings and Precautions, Use in Specific Populations] INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies] breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • with docetaxel and carboplatin • as a single agent following multi-modality anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Metastatic Gastric Cancer Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline. Withhold Herceptin for * 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and * 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration]. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of Herceptin • LVEF measurements every 3 months during and upon completion of Herceptin • Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration] • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as * 50%) on continuing medical management at the time of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of CHF Study Regimen Herceptin Control 1 & 2a ACbAPaclitaxel+ Herceptin 2% (32/1677) 0.4% (7/1600) 3 ChemoAHerceptin 2% (30/1678) 0.3% (5/1708) 4 ACbADocetaxel+ Herceptin 2% (20/1068) 0.3% (3/1050) 4 Docetaxel+Carbo+ Herceptin 0.4% (4/1056) 0.3% (3/1050) a b
Includes 1 patient with fatal cardiomyopathy. Anthracycline (doxorubicin) and cyclophosphamide
Table 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies
Study 5 (AC)b 5 (paclitaxel) 6
Incidence NYHA I−IV NYHA III−IV Herceptin Control Herceptin Control
Event Cardiac Dysfunction 28% 7% 19% 3% Cardiac Dysfunction 11% 1% 4% 1% Cardiac Dysfunctionc 7% N/A 5% N/A a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy. In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens: (AC-TH: 0.3% (3/1068) and TCH 0.2% (2/1056)) as compared to none in AC-T. Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions] In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications. Embryo-Fetal Toxicity Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide contraception counseling to women of childbearing potential. [see Use in Specific Populations, Patient Counseling Information]. Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials the per-patient incidences of NCI CTC Grade 3−4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not. [see Adverse Reactions] HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDAapproved tests for the specific tumor type (breast or gastric/ gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several FDA-approved commercial assays are available to aid in the selection of breast cancer and metastatic gastric cancer patients for Herceptin therapy. Users should refer to the package inserts of specific assay kits for information on the Intended Use, and the validation and performance of each assay. Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Herceptin benefit. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) and for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Tables 8 and 10. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Study 7 demonstrated that gene amplification and protein overexpression were not as well correlated as with breast cancer. Treatment outcomes for metastatic gastric cancer (Study 7), based on HER2 gene amplification (FISH) and HER2 protein overexpression (IHC) test results are provided in Table 12. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions] • Infusion reactions [see Warnings and
Precautions] • Embryo-fetal Toxicity [see Warnings and Precautions] • Pulmonary toxicity [see Warnings and Precautions] • Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. In the metastatic gastric cancer setting, the most common adverse reactions (* 10%) that were increased (* 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Herceptin-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to Herceptin across three randomized, openlabel studies, Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. Table 3 Adverse Reactions for Study 3, All Gradesa : Adverse Reaction
1 Year Herceptin Observation (n= 1678) (n=1708)
Cardiac Hypertension 64 (4%) Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) Palpitations 48 (3%) Cardiac Arrhythmiasb 40 (3%) Cardiac Failure Congestive 30 (2%) Cardiac Failure 9 (0.5%) Cardiac Disorder 5 (0.3%) Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders Cough 81 (5%) Influenza 70 (4%) Dyspnea 57 (3%) URI 46 (3%) Rhinitis 36 (2%) Pharyngolaryngeal Pain 32 (2%) Sinusitis 26 (2%) Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders Diarrhea 123 (7%) Nausea 108 (6%) Vomiting 58 (3.5%) Constipation 33 (2%) Dyspepsia 30 (2%) Upper Abdominal Pain 29 (2%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) Back Pain 91 (5%) Myalgia 63 (4%) Bone Pain 49 (3%) Muscle Spasm 46 (3%) Nervous System Disorders Headache 162 (10%) Paraesthesia 29 (2%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) Nail Disorders 43 (2%) Pruritis 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Aesthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (0.06%) Infections Nasopharyngitis 135 (8%) UTI 39 (3%) Immune System Disorders Hypersensitivity 10 (0.6%) Autoimmune Thyroiditis 4 (0.3%) a
35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%) 0 (0%) 0 (0%) 16 (1%) 19 (1%) 10 (0.6%) 17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (0.6%) 0 (0%) 10 (0.6%) 6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)
The incidence of Grade 3/4 adverse reactions was <1% in both arms for each listed term. Higher level grouping term. The data from Studies 1 and 2 were obtained from 3206 patients, of whom 1635 received Herceptin; the median treatment duration was 50 weeks. The median age was 49 years (range: 24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 4% Asian. In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events were Grade b
2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during chemotherapy and/ or Herceptin treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25−77 years). Eighty-nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for * 6 months and * 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28−86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for * 6 months and * 12 months were 31% and 16%, respectively. Table 4 Per-Patient Incidence of Adverse Reactions Occurring in * 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)
M ( d
Herceptin Single + Paclitaxel Herceptin ACb a Agent Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body as a Whole Pain 47% 61% 62% 57% 42% Asthenia 42% 62% 57% 54% 55% Fever 36% 49% 23% 56% 34% Chills 32% 41% 4% 35% 11% Headache 26% 36% 28% 44% 31% Abdominal pain 22% 34% 22% 23% 18% Back pain 22% 34% 30% 27% 15% Infection 20% 47% 27% 47% 31% Flu syndrome 10% 12% 5% 12% 6% Accidental injury 6% 13% 3% 9% 4% Allergic reaction 3% 8% 2% 4% 2% Cardiovascular Tachycardia 5% 12% 4% 10% 5% Congestive 7% 11% 1% 28% 7% heart failure Digestive Nausea 33% 51% 9% 76% 77% Diarrhea 25% 45% 29% 45% 26% Vomiting 23% 37% 28% 53% 49% Nausea and vomiting 8% 14% 11% 18% 9% Anorexia 14% 24% 16% 31% 26% Heme & Lymphatic Anemia 4% 14% 9% 36% 26% Leukopenia 3% 24% 17% 52% 34% Metabolic Peripheral edema 10% 22% 20% 20% 17% Edema 8% 10% 8% 11% 5% Musculoskeletal Bone pain 7% 24% 18% 7% 7% Arthralgia 6% 37% 21% 8% 9% Nervous Insomnia 14% 25% 13% 29% 15% Dizziness 13% 22% 24% 24% 18% Paresthesia 9% 48% 39% 17% 11% Depression 6% 12% 13% 20% 12% Peripheral neuritis 2% 23% 16% 2% 2% Neuropathy 1% 13% 5% 4% 4% Respiratory Cough increased 26% 41% 22% 43% 29% Dyspnea 22% 27% 26% 42% 25% Rhinitis 14% 22% 5% 22% 16% Pharyngitis 12% 22% 14% 30% 18% Sinusitis 9% 21% 7% 13% 6% Skin Rash 18% 38% 18% 27% 17% Herpes simplex 2% 12% 3% 7% 9% Acne 2% 11% 3% 3% < 1% Urogenital Urinary tract infection 5% 18% 14% 13% 7% a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
Tract Inf R
For Studie o
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Metastatic Gastric Cancer The data below are based on the exposure of 294 patients to Herceptin in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Herceptin plus chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1-14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks; median number of Herceptin infusions administered was eight.
Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (ACAT) or paclitaxel plus Herceptin (ACATH). Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (ACAT) or docetaxel plus Herceptin (ACATH); docetaxel and carboplatin plus Herceptin (TCH).
Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of *10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
Table 5 Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence * 5% between Arms) or Grade 3 /4 (Incidence >1% between Arms) and Higher Incidence in Herceptin Arm Herceptin +FC (N = 294) N (%) Body System/ Adverse Event Investigations Neutropenia Hypokalemia Anemia Thrombocytopenia Blood And Lymphatic System Disorders Febrile Neutropenia Gastrointestinal Disorders Diarrhea Stomatitis Dysphagia Body as a Whole Fatigue Fever Mucosal Inflammation Chills Metabolism And Nutrition Disorders Weight Decrease Infections And Infestations Upper Respiratory Tract Infections Nasopharyngitis Renal And Urinary Disorders Renal Failure and Impairment Nervous System Disorders Dysgeusia
3 n = 135
All Grades Grades 3/ 4
230 (78) 83 (28) 81 (28) 47 (16)
101 (34) 28 (10) 36 (12) 14 (5)
212 (73) 83 (29) 69 (24) 16 (6) 61 (21) 30 (10) 33 (11) 8 (3)
109 (37) 72 (24) 19 (6)
27 (9) 2 (1) 7 (2)
80 (28) 43 (15) 10 ( 3)
11 (4) 6 (2) 1 ()1)
Time 0 is the date of randomization.
102 (35) 54 (18)
12 (4) 3 (1)
82 (28) 36 (12)
7 (2) 0 (0)
Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of * 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
37 (13) 23 (8)
6 (2) 1 ()1)
18 (6) 0 (0)
2 (1) 0 (0)
56 (19) 37 (13)
0 (0) 0 (0)
29 (10) 17 (6)
0 (0) 0 (0)
LVEF *10% *16% <50% decrease decrease
7% 4 studies, a
Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of * 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event
Time 0 is the date of randomization.
LVEF <50% and Absolute Decrease from Baseline
Studies 1 & 2b ACATH 22.8% (366) (n=1606)
Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.
The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, metastatic gastric cancer, or postmarketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or * 15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). Table 6a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4
FC (N = 290) N (%)
Absolute LVEF Decrease <20% and *10% *20%
Study 3 Herceptin (n=1678)
Study 4c TCH (n=1056)
For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization.
The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I−IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. In Study 7, 5.0% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a * 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2-5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm the overall incidence of anemia was 28% compared 21% and of NCI CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4−5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2−5 neutropenia (7.1% vs. 4.5% [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm, the incidence of NCI CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2−5 infection/febrile neutropenia
(22% vs. 14% [Study 1]) and of selected Grade 3−5 infection/ febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3−4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2−5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3−5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2−5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2−5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multiorgan system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2−5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3−5 diarrhea (1.6% vs. 0% [Study 2]), and of Grade 1−4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3−4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1−4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In Study 7 (metastatic gastric cancer) on the Herceptin-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy only arm. In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzymelinked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. Post-Marketing Experience The following adverse reactions have been identified during post approval use of Herceptin. 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. • Infusion reaction [see Warnings and Precautions] • Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions] • Glomerulopathy [see Adverse Reactions] DRUG INTERACTIONS In Study 5, the mean serum trough concentration of trastuzumab was consistently elevated approximately 1.5-fold, when administered in combination with paclitaxel as compared to trough concentrations of trastuzumab when administered in combination with an anthracycline and cyclophosphamide. In other pharmacokinetic studies, where Herceptin was administered in combination with paclitaxel, docetaxel or doxorubicin, Herceptin did not alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed. In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin,
capecitabine and their metabolites were not altered when administered in combination with Herceptin. USE IN SPECIFIC POPULATIONS Pregnancy: Category D [see Warnings and Precautions, Nonclinical Toxicology] Herceptin can cause fetal harm when administered to a pregnant woman. In postmarketing reports use of Herceptin during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Herceptin either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred. Monitor women exposed to Herceptin during pregnancy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of IV hydration in management of oligohydramnios due to Herceptin exposure is not known. Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy. Encourage pregnant women with breast cancer who are using Herceptin to enroll in MotHER-the Herceptin Pregnancy Registry: phone 1-800-690-6720. [see Patient Counseling Information]. No teratogenic effects were observed in offspring from reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab. In mutant mice lacking HER2, embryos died in early gestation. Trastuzumab exposure was reported at delivery in offspring of cynomolgus monkeys treated during the early (Days 20-50 of gestation) or late (Days 120-150 of gestation) fetal development periods, at levels of 15 to 28% of the maternal blood levels. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning Cardiomyopathy]. • Advise pregnant women and women of childbearing potential that Herceptin exposure can result in fetal harm [see Warnings and Precautions and Use in Specific Populations]. • Advise women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Warnings and Precautions]. • Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother [see Use in Specific Populations]. • Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER- the Herceptin Pregnancy Registry (1-800-690-6720) [see Warnings and Precautions and Use in Specific Populations]. HERCEPTIN® [trastuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 Initial US Approval: September 1998 Revision Date: October 29, 2010 Herceptin® is a registered trademark of Genentech, Inc. HER0000111000 © 2010 Genentech, Inc.
TON_December 2010_FINAL_v2_TON 12/8/10 11:48 AM Page 4
Editorial Board EDITOR-IN-CHIEF
Sharon S. Gentry,
Kena C. Miller,
RN, MSN, AOCN
RN, MSN, FNP
OCN, PhD, RN
RN, MSN, APRN, BC, AOCN
Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC
Roswell Park Cancer Institute Buffalo, NY
Rush University College of Nursing Rush-PresbyterianSt. Luke’s Medical Center Chicago, IL
Cassandra J. Hammond, RN,
Karla Wilson, RN,
Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Elizabeth Bilotti, RN, MSN, APRN, BC, OCN
MS, RN, APN-C, AOCNS
MSN, FNP-C, CPON
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Avid Education Partners, LLC Sharpsburg, MD
Somerset Medical Center Somerville, NJ
City of Hope National Medical Center Duarte, CA
Catherine S. Bishop, DNP, NP,
Dolores “Jeff” Nordquist, RN, MS,
Pharmacy John F. Aforismo,
Novant Health Presbyterian Cancer Center Charlotte, NC
BSc Pharm, RPh, FASCP
Deena Damsky Dell, RN, MSN,
Patricia Irouer Hughes, RN, MSN,
Melinda Oberleitner, RN,
Nutrition Karen Connelly,
RN, BSN, OCN
Mayo Clinic Rochester, MN
R. J. Health Systems International, LLC Wethersfield, CT
DNS, APRN, CNS
Fox Chase Cancer Center Philadelphia, PA
Piedmount Healthcare Rex, GA
College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA
Somerset Medical Center Somerville, NJ
DNP, APRN, AOCN
NP, MSN, ACNP-C
Genentech New London, NH
University of Southern California Norris Cancer Center & Hospital Los Angeles, CA
MSN, ARNP, AOCN
Patient Advocate Peg Ford
Denice Economou, RN,
Sandra E. Kurtin,
Lori Stover, RN,
RN, MS, AOCN, ANP-C
MN, CNS, AOCN City of Hope National Medical Center Duarte, CA
Arizona Cancer Center Tucson, AZ
Constance Engelking, RN,
MS, CNS, OCN
Cleveland Clinic Taussig Cancer Institute Cleveland, OH
The CHE Consulting Group, Inc. Mt. Kisco, NY
NYU Cancer Institute New York, NY
Social Work Carolyn Messner,
Western Pennsylvania Cancer Institute Pittsburgh, PA
DSW, MSW, LCSW-R, BCD
Pamela Hallquist Viale, RN, MS,
Managed Care and Pharmaceutical Management Burt Zweigenhaft,
CS, ANP, AOCN Saratoga, CA
CancerCare New York, NY
BS BioPharma Partners LLC New York, NY
Amy Ford, RN,
Isabell Castellano, RN
MSN, RN, NP-C, OCN
RN, PhD, APRN
Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ
Innovex Dallas, TX
The Cancer Center at Hackensack University Medical Center Hackensack, NJ
University of Nebraska College of Nursing Omaha, NE
Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN
December 2010 I VOL 3, NO 8
TON_December 2010_FINAL_TON 12/6/10 11:19 AM Page 5
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TON_December 2010_FINAL_v2_TON 12/8/10 11:47 AM Page 6
FROM THE EDITOR PUBLISHING STAFF Publisher Philip Pawelko firstname.lastname@example.org
wo new reports call for changes in education to ensure that healthcare professionals have the competencies necessary to work in an increasingly complex healthcare system. Since oncology is one of the most complex and rapidly advancing areas of medicine, their recommendations have implications for oncology nurses Beth Faiman, RN, and our colleagues. In a report by the Lancet ComMSN, APRN, mission (Frenk J, et al. Lancet. Nov BC, AOCN 26, 2010. Epub ahead of print), the Editor-in-Chief authors propose a number of instructional and institutional reforms, including “team-based education to break down professional silos.” A report by the Institute of Medicine specifically addresses nursing education and practice (The Future of Nursing: Leading Change, Advancing Health; 2010). “Nurses’ roles, responsibilities, and education should change significantly
Editorial Director Karen Rosenberg email@example.com Associate Editor Dawn Lagrosa firstname.lastname@example.org Director, Client Services John W. Hennessy email@example.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto firstname.lastname@example.org Executive Administrator Andrea Boylston Circulation Department email@example.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938
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December 2010 I VOL 3, NO 8
to meet the increased demand for care that will be created by health care reform and to advance improvements in America’s increasingly complex health system,” the report states. Among the changes they recommend are removing scope of practice barriers and improving the education system to include the creation of a residency program. The report also calls for nursing associations, schools, and other organizations to “provide nurses greater opportunities to gain leadership skills and put them into practice.” In many ways, oncology nurses are ahead of the curve on these issues and are already putting some of these ideas into practice. Many of us have advanced education and credentials; we work closely with our colleagues in multidisciplinary teams; and we play an active role in patient and nursing education throughout the continuum of cancer care. Oncology nurses are well positioned to take a leadership role in advancing the profession and ensuring that patients receive the highest-quality care. The Oncology Nurse will continue to provide reports on the latest advances in nursing practice and cancer care to help our readers meet the challenges of practice in a changing healthcare environment. ●
CONFERENCE NEWS: ONS APN/IOL
8 Faces at the conference 9 Prophylactic minocycline keeps cetuximab-induced rash at bay 10 Collaborative program trains oncology specialist nurses 26 Telephone support increases adherence to IV chemotherapy for recurrent ovarian cancer 28 Survey shows gaps in oncology nurses’ knowledge about cardiotoxicity of cancer drugs
December 2010 • VOL 3, NO 8 45 PARP inhibitor improves survival in triple-negative breast cancer
24 36 46 49
International News Oncology Drug Codes Nursing Life Meetings
Journal of Oncology
16 Prompt pain relief for vertebral compression fractures with balloon kyphoplasty
NAVIGATION & SURVIVORSHIP
The Official Journal of the Academy of Oncology Nurse Navigators ®
Between pages 34 and 35 CARE COORDINATION
20 Stereotactic radiation may be as effective as surgery for some non–small-cell lung cancers
25 Fast neutron radiotherapy may be safe and effective for lung cancer patients 32 Low-dose CT screening found to reduce lung cancer deaths in large study
30 Maintenance therapy in patients with advanced non–small-cell lung cancer
44 Prolonging chemotherapy in metastatic breast cancer improves survival
44 Tamoxifen may confer a limited benefit in older women with early-stage breast cancer
1 City-wide patient navigation network coordinates Washington, DC, cancer care
1 Center provides platform for discussion of cancer survivorship, navigation, and policy
3 Most oncology nurses unfamiliar with IOM report on caring for the whole patient
4 Integrative psychooncology services: how the Cleveland Clinic did it
2 Patient navigation improves mammography rates in the inner city
4 Survivors often dissatisfied with breast-conserving treatment results www.TheOncologyNurse.com
TON_December 2010_FINAL_TON 12/6/10 11:19 AM Page 7
exhaust all possibilities.
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TON_December 2010_FINAL_v2_TON 12/8/10 11:46 AM Page 8
Faces at the Conference ONCOLOGY NURSING SOCIETY’S 11TH ANNUAL ADVANCED PRACTICE NURSING CONFERENCE/INSTITUTES OF LEARNING
Orlando, Florida, November 11-14, 2010.
Congratulations to Tanya Laudick of Greeley, Colorado, winner of our iPad giveaway.
Millie Toth celebrates breast cancer awareness with pink gloves.
Bobbie Piccolo checks out a contemporary infusion chair.
Michelle Blanca and Sylvia Robertson point out what they are learning.
Judy Sigmon catches up on the latest in mastectomy bras and prostheses.
Karen Stephenson stops by to chat with The Oncology Nurse-APN/PA Editor-in-Chief Beth Faiman.
Magda Ostos-Germain and Ali Khan pose for our camera.
Maureen Berry, Michael Rehbein, and Pamela Grant-Navarro take time out for coffee.
Ami Rowe tests state-of-the-art technology.
Photos by Mark Losh • For more photos go to www.TheOncologyNurse.com 8
December 2010 I VOL 3, NO 8
TON_December 2010_FINAL_TON 12/6/10 11:19 AM Page 9
Conference News ONS APN/IOL
Prophylactic Minocycline Keeps Cetuximab-induced Rash at Bay By Fran Lowry
ORLANDO—Breakthrough pain in cancer patients can be managed easily and effectively with fentanyl pectin nasal spray, according to new data. Minocycline, given before the start of treatment with cetuximab and chemoradiotherapy, plus topical pimecrolimus as needed, can reduce the severity of cetuximab-induced skin toxicity in patients with non–small-cell lung cancer (NSCLC), according to researchers from The Netherlands. Cetuximab, a chimeric monoclonal antibody that binds to the extracellular domain of the epidermal growth
patients received cetuximab once weekly for 6 weeks along with daily cisplatin and radiotherapy. The 12 patients in group 1 were treated on demand after the appearance of an
acneiform rash. The 14 patients in group 2 received prophylactic oral minocycline, 100 mg/day for 45 days, and, if necessary, topical pimecrolimus, 1%, twice daily.
Toxicity was scored according to the Common Toxicity Criteria for Adverse Events, version 3.0. In the first group, 11 of 12 patients Continued on page 10
Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens
Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2
“If we give minocycline prophylactically and do not wait for the rash to appear, we manage to reduce the skin toxicity to a maximum of grade 2.” —Wilma Uyterlinde, MANP
■ 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Important Safety Information factor receptor, has shown activity in patients with metastatic colorectal cancer, in addition to patients with NSCLC, but its potential for severe skin toxicity may cause some patients to abandon their treatment, said Wilma Uyterlinde, MANP, a nurse practitioner at the Netherlands Cancer Institute in Amsterdam. In 2008, oncologists at the institute began to test the feasibility of combining cetuximab with concurrent chemoradiation in their patients with locally advanced NSCLC. “We added cetuximab to our treatment because of the promising effects it was shown to have in colorectal cancer patients, and when we did so, we saw a lot of grade 3 skin toxicity, so we conferred with a dermatologist and an oncologist and we came up with a new protocol to see if we could reduce it,” said Uyterlinde, who specializes in thoracic oncology. To test their protocol, the researchers divided patients into two groups. All
Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo-treated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.
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Conference News Prophylactic Minocycline Keeps Cetuximab-induced... Continued from page 9 developed grade 2 or 3 acneiform rash, and one patient discontinued treatment because of the rash. In the second group, three of 14 patients developed grade 2 rash, and none of the patients developed grade 3 rash. This represents a significant difference between the groups (P = .001), Uyterlinde said. BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary: s 3PLENIC 2UPTURE ;3EE Warnings and Precautions] s !CUTE 2ESPIRATORY $ISTRESS 3YNDROME ;3EE Warnings and Precautions] s 3ERIOUS !LLERGIC 2EACTIONS ;3EE Warnings and Precautions] s 5SE IN 0ATIENTS WITH 3ICKLE #ELL $ISORDERS ;3EE Warnings and Precautions] s 0OTENTIAL FOR 4UMOR 'ROWTH 3TIMULATORY %FFECTS ON -ALIGNANT #ELLS ;3EE Warnings and Precautions] The most common adverse reactions occurring in r 5% of patients and with a between-group difference of r 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer
“In the cohort that did not get prophylactic treatment, we sometimes had to send patients to a specialized hospital for their skin toxicity because it was so bad, and we had to stop treatment with cetuximab because of the rash,” Uyterlinde noted. “If we give minocycline prophylactically and do not wait for the rash to receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term
Placebo (N = 461)
Neulasta 6 mg SC on Day 2 (N = 467)
Musculoskeletal and connective tissue disorders Bone pain
Pain in extremity
Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. 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) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta. Gastro-intestinal disorders: 3PLENIC RUPTURE ;SEE Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis ;SEE Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS ;SEE Warnings and Precautions] General disorders and administration site conditions: Injection site reactions Skin and subcutaneous tissue disorders: Allergic reactions/ hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and FLUSHING ;SEE Warnings and Precautions] DRUG INTERACTIONS No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting boneimaging results. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during
appear, we manage to reduce the skin toxicity to a maximum of grade 2.” She noted that controlling the acneiform rash did not compromise the effectiveness of cetuximab. “It has not been proven that developing a rash means that cetuximab is working,” she said. “This is what they pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/ developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
say, but it has never really been proven. That is a hypothesis. Controlling the rash works by a different mechanism and does not prevent the cetuximab from working on the tumor.” The protocol has now become the institute’s standard for use in patients with other types of cancer undergoing treatment with cetuximab, she said. ●
Collaborative Program Trains Oncology Specialist Nurses By Karen Rosenberg
Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.
ORLANDO—Despite the need for nurses with specialized oncology knowledge to care for the growing population of cancer patients and survivors, few graduate oncology nursing programs currently exist. A collaboration between The Ohio State University Comprehensive Cancer Center–The James Cancer Hospital (OSUCCC-James) and the university’s College of Nursing (CON) has been established to help fulfill the need for nurses with specialized oncology education. The collaboration between the cancer center and the college, described in a poster presented by Deborah Hanes, RN, CNS, and her colleagues, has re sulted in a graduate oncology nursing program and an oncology clinical nurse specialist internship. The graduate nursing program will provide curriculum and clinical practicum sites by the CON and OSUCCC-James. The internship will train registered nurses with at least 3 years of experience as a registered nurse to become oncology clinical nurse specialists. Interns will be full-time employees of OSUCCC-James and will pursue part-time study following the CON curriculum; program participants will receive tuition reimbursement. The framework for all educational experiences will be the cancer continuum, with emphasis on survivorship. Both the graduate program and the internship are based on adult learning theory. Students’ success rates on the Advanced Oncology Clinical Nurse Specialist examination will be one measure of the program’s success. The developers of the program anticipate that it will boost oncology recruitment and retention, and that patients will benefit from care based on graduate-level oncology nursing education. ●
Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard DEVIATION ;3$= SYSTEMIC EXPOSURE !5#0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.
Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2010 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 11.0
Conference News continued on page 26
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“After my balloon kyphoplasty, I’m walking pain-free again.” Tom Callaghan experienced debilitating pain due to spinal fractures caused by multiple myeloma. He underwent a minimally invasive procedure, Balloon Kyphoplasty, to treat the spinal fractures.
KYPHON® Balloon Kyphoplasty
To learn more about Balloon Kyphoplasty, visit our website at www.kyphon.com.
The complication rate with KYPHON® Balloon Kyphoplasty has been demonstrated to be low. As with all surgical procedures, there are risks associated with the procedure, including serious complications, and though rare, some of which can be fatal. For complete information regarding indications for use, contraindications, warnings, precautions, adverse events, and methods of use, please reference the devices’ Instructions for Use included with the product. © 2009 Medtronic Spine LLC. All Rights Reserved. 16003611_001 rev 1
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Multigene Signature Scores and Breast Cancer... demonstrated a consistent statistical link to distant breast cancer recurrence (Figure 1)2 as well as to the degree of response to chemotherapy (Figure 2).3 An algorithm is used to calculate a “recurrence score” (RS) from the expression results for each of 16 cancerrelated genes. The RS ranges from zero to 100. Cutoff points for RS risk groups are defined: low risk, <18; intermediate risk, 18 to 30; and high risk, ≥31. The RS provides information that is independent from age, size, and grade of the tumor.2 This information helps tailor treatment for the individual patient. In addition, the RS is a more significant predictor of distant recurrence-free survival independent of age and tumor size.2 Assigning Individualized Options for Treatment (Rx), a multi-institutional trial known as TAILORx, aims to determine, more specifically, how predictive the assay is for the intermediate-risk RS group.4 The manufacturer has Clinical Laboratory Improvement Amendments certification, and strictly
adheres to College of American Pathology standards. The 21-gene assay is for use in patients with stage I or II, node-negative, ER-positive breast cancer who will be treated with hormone therapy. In 2007, the assay was included in the 2007 American Society of Clinical Oncology clinical guidelines on the use of tumor markers in breast cancer.5 In 2008, the National Comprehensive Cancer Network incorporated the assay into its breast cancer clinical practice guidelines.6 These inclusions reinforce the significance of molecular diagnostics in breast cancer treatment planning and, in particular, the potential value of the individualized information provided. After the assay became available to clinicians, the manufacturer discovered that 4% to 6% of specimens sent for testing that were ER-positive on immunohistochemistry (IHC) staining were not ER-positive by RT-PCR. In addition, 9% to 20% of specimens that were ER-negative by IHC were ER-pos-
Distant Recurrence at 10 Years
Source: Reference 2. Reprinted with permission from Genomic Health.
Figure 1. Statistical link between recurrence score and distant breast cancer recurrence
n = 353 Low, RS <18
n = 134
n = 164 High, RS ≥31
Absolute Increase (%) in DRFS at 10 Years (mean ± SE) from Chemotherapy
40% Source: Reference 3. Reprinted with permission from Genomic Health.
DRFS indicates distant recurrence-free survival; RS, recurrence score; SE, standard error.
Figure 2. Statistical link between RS and the degree of response to chemotherapy
December 2010 I VOL 3, NO 8
Continued from cover
The researchers suggested that patients with a low RS might be candidates for a shorter course of chemotherapy. itive by RT-PCR. This raised concern: Are there women who could benefit from hormone therapy who are not being identified? To answer this question, the company started including individual quantitative ER, PR, and HER2 scores as part of its reports in 2008. It now offers an ER qualifier program to guide decisions on testing specimens, based on medical necessity as determined by the referring physician, if the ER status by IHC is in question. Recently presented information suggests increased applications for the 21gene assay. Three studies have shown that it is also informative for women with node-positive, hormone receptor (HR)-positive, invasive breast cancer. Goldstein and colleagues looked at the prognostic ability of the assay in HRpositive operable breast cancer with one to three positive nodes. They found that a low RS is predictive of an excellent outcome at 5 years, and that a low RS is a common finding in these patients (49%).7 The researchers suggested that patients with a low RS might be candidates for a shorter course of chemotherapy, plus hormonal therapy; and that a high score may be used to select patients who need more aggressive chemotherapy or who would be candidates for clinical trials evaluating novel agents.7 Dowsett and colleagues, on behalf of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group, presented a follow-up study referred to as transATAC at the San Antonio Breast Cancer Symposium in 2008.8 They looked at the risk of distant recurrence using the 21-gene assay in postmenopausal breast cancer patients with and without positive nodes who were treated with either tamoxifen or anastrozole, an aromatase inhibitor. Pre viously, the RS score had only been validated in patients treated with tamoxifen; in the present day, an aromatase inhibitor is usually the endocrine treatment of choice in postmenopausal women. The researchers evaluated 302 node-positive women and 872 node-negative women. They concluded that the RS for women treated with tamoxifen may be applied for those treated with anastrozole with adjustment for the lower risk of recurrence seen with aromatase inhibitors. They further concluded that the RS is an independent predictor of disease recurrence in node-positive as well as
node-negative HR-positive patients (Figure 3, page 14).8 Albain and colleagues, on behalf of the Breast Cancer Intergroup of North America, presented results of a retrospective analysis of a randomized study (SWOG 8814) of the prognostic and predictive value of the RS in postmenopausal women with node-positive, ERpositive breast cancer.9 They investigated specifically whether the RS was prognostic in women treated with tamoxifen alone and whether it identified women who could possibly avoid anthracyclinebased chemotherapy (cyclophosphamide/doxorubicin/fluorouracil [CAF]) despite higher risk of recurrence. This chemotherapy regimen is more “modern” than the regimen of cyclophosphamide/methotrexate/fluor ouracil used in earlier adjuvant studies. The researchers determined the RS for 367 specimens and found that the RS was prognostic for the group treated with tamoxifen alone. They also determined that CAF therapy had no benefit in patients with a low RS, but that there was an improvement in disease-free survival (DFS) for women with a high RS after adjustment for the number of positive nodes. An improvement in breast cancer–specific survival (BCSS) was also observed for women with a high RS treated with chemotherapy. The 10-year BCSS was 73% compared with 54% for the tamoxifen alone group in the high RS group. The predictive benefit of the RS was significant in the first 5 years only (P = .029); there was no additional prediction beyond this time (P = .58), although there was a cumulative benefit at 10 years (P = .053). The researchers concluded that a low RS identifies women who, despite positive nodes, might not benefit from CAF.9 Based on these results, the Centers for Medicare & Medicaid Services (CMS) extended coverage for Oncotype DX to ER-positive patients with micrometastases and one to three positive nodes.10 An editorial in Lancet Oncology states, “…the consistency across studies suggests that there is little risk of falsely concluding that there is no chemotherapy benefit in patients with low recurrence scores.”11 Small studies have been conducted to determine whether the 21-gene assay may help predict response to neoadjuvant therapy. Anderson and colleagues
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Genetic Testing compared RS, ER, PR, and HER2 scores from core biopsies to surgical specimens on more than 11,000 samples. They had a 92% correlative success rate.12 With the confidence that core biopsies provide accurate information, three small studies examined RS and response to neoadjuvant therapy.13-15 Two studies used chemotherapy; one used hormonal therapy. No patients with a low RS had a pathologic complete response (pCR) in the chemotherapy studies; however, these patients had a much better clinical response in the hormonal therapy group. Therefore, assay results may help physicians and patients assess the benefit of neoadjuvant therapy options. Finally, the usefulness of the 21-gene assay for both physicians and patients has been confirmed in several studies. Based on assay results in node-negative patients, physicians have reported changing their treatment recommendations 20% to 31.5% of the time. The most frequent change is to omit chemotherapy.16-18 At one comprehensive cancer center, the number of patients getting chemotherapy decreased from 55% to 25%.19 More than 80% of patients stated that the results influenced their decisions, and more than 90% were glad they took the test. Patients reported less anxiety and situational conflict.20 Oratz and colleagues polled more than 1000 physicians who ordered the assay for node-positive patients and found that there was a change in chemotherapy recommendation 42% of the time.21 70-gene prognostic signature Available in Europe since 2004, MammaPrint received US Food and Drug Administration (FDA) approval in February 2007. It was the first clearance issued by the FDA for a breast cancer recurrence test based on data that showed that the gene signature adds independent prognostic information to clinicopathologic risk assessment. The test was validated for use in patients less than 61 years of age with stage I or II, node-negative, ER-positive or ER-negative tumors. MammaPrint was developed in an untreated, heterogeneous patient population.22 In June 2007, Agendia also obtained FDA clearance for use of its tissue preservative (RNARetain). It should be noted that there is a difference in FDA approval and FDA clearance. Clearance provides marketing permission for a test that is considered to pose a low risk to public health and that has been shown to be substantially equivalent to another test. Formal approval provides marketing permission for a test that is new or may be of higher risk to the user; studies are evaluated that show the test does what it claims. This 70-gene prognostic signature became commercially available in the United States in 2008. Using a process called microarray
gene chip technology, the test identified 70 genes linked to the genomic pathways associated with breast cancer recurrence. An algorithm was used to establish two gene signatures (Figure 4, page 14). The test uses fresh-frozen tissue or tissue that must be put into a DNA preservative within an hour and then mailed to the manufacturer. It does not provide an individual RS, but rather
binary results. A “low-risk signature” or “good prognosis” means a woman has a 95% chance of DFS at 5 years, a 90% chance at 10 years, and a 99% BCSS rate at 5 years. A “high-risk signature” or “poor prognosis” means a woman has a 78% chance of DFS at 5 years, a 71% chance at 10 years, and an 80% BCSS rate at 5 years.22-24 The 70-gene prognostic signature has
been found to be of benefit in deciding prognosis in women with node-positive disease. In 2007, Mook and colleagues presented the results from 106 patients with one to three positive lymph nodes.25 They found that the 70-gene signature outperformed clinicopathologic prognostic factors. In patients with a good prognostic score, at 10 years, overall survival Continued on page 14
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December 2010 I VOL 3, NO 8
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Multigene Signature Scores and Breast Cancer... (OS) was 99.7% and DFS was 94%. In patients with a poor prognostic score, OS was 66% and DFS was 62%. Based on these results, patients with one to three positive nodes were incorporated into the Microarray in Node Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial to obtain prospective validation.25 MINDACT is a prospective, randomized trial being conducted by an international breast group (TRANSBIG) comparing the 70-gene signature with the common clinicopathologic criteria in selecting breast cancer patients with zero to three positive nodes for adjuvant chemotherapy.26 In addition, in 2009, Saghatchian and colleagues reported an analysis of frozen tumor samples from 519 node-positive patients followed for 10 years. They found the 70-gene signature to be a strong prognostic marker of disease recurrence and BCSS. Patients with a high genomic risk and elevated number of positive lymph nodes (more than three) have a very poor prognosis; therefore, the researchers suggested that these patients may want to consider more aggressive treatment.27 Based on these
results, CMS provides coverage for the 70-gene prognostic signature for all patients with stage I and II breast cancer, including those with one to three positive nodes.10 CMS coverage for the 70-gene signature has also been expanded to include all age groups. Bedard and colleagues looked at 204 women aged 65 years and older (median, 70 years). They found that the 70-gene signature remained an independent prognostic indicator in this group.28 Data were confirmed in a group of patients between 55 and 70 years of age.29 Finally, studies have been reported showing the predictive value of the 70gene signature. Although there has been no prospective analysis of the predictive value of this test in randomized, controlled, phase 3 trials, Knauer and colleagues presented data at the 2009 St. Gallen Breast Cancer Conference on a meta-analysis of 1637 tumor samples of women who received adjuvant chemotherapy plus hormonal therapy or hormonal therapy alone for T1-3, N0-1, M0 breast cancers. This was a heterogeneous group of women: ER-positive, ER-negative, HER2-positive, and HER2-nega-
4+ positive nodes
Continued from page 13
tive. Median follow-up was 7.1 years. Data on 167 neoadjuvant chemotherapy patients were also reviewed. The researchers found that the 70-gene prognostic signature was predictive of neoadjuvant and adjuvant therapy. For low-risk patients, chemotherapy plus hormonal therapy did not demonstrate a significant benefit compared with hormonal therapy alone; however, there was a clear benefit in high-risk patients. In patients who received neoadjuvant therapy, there was no pCR in low-risk patients, but there was a 20% pCR in high-risk patients.24,30,31 Agendia can also provide geneexpression levels of the ER, PR, and HER2 in freshly preserved tumor biopsies using a high-density microchip assay called TargetPrint. TargetPrint has been validated against FDA-approved IHC assays. It can be ordered with or without ordering MammaPrint. Conclusion The additional information about the clinical behavior of a patient’s cancer provided by these assays should help the clinician in personalizing a therapeutic program for patients. Hopefully, fewer patients who will not benefit from chemotherapy will be exposed to the toxicity of these agents. ● Disclosure Ms Dell is a member of Genomic Health’s speakers’ bureau. References
1-3 positive nodes Node negative
Source: Reference 8. Reprinted with permission from Genomic Health.
Figure 3. Risk of distant recurrence increases with the number of positive nodes for all recurrence scores
Source: Reference 23. Reprinted with permission from Agendia.
Threshold set with 10% false negatives (91% sensitivity, 73% specificity)
Figure 4. 70-gene prognostic signature, supervised analysis
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1. Edge S, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010. 2. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734. 4. Sparano JA. The TAILORx trial: individualized options for treatment. Commun Oncol. 2006;3:494-496. 5. Harris L, Fritsche H, Mennel R, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287-5312. 6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2010. www.nccn.org/professionals/physician_gls/PDF/breast. pdf. Accessed March 26, 2010. 7. Goldstein LJ, Gray R, Childset BH, et al. Prognostic utility of 21-gene assay in hormone receptor (HR) positive operable breast cancer and 0-3 positive axillary nodes treated with adjuvant chemohormonal therapy (CHT): an analysis of Intergroup Trial E2197. J Clin Oncol. 2007;25(18S):Abstract 526. 8. Dowsett M, Allred C, Knox J, et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol. 2008;26:1059-1065. 9. Albain KS, Barlow WE, Shak S, et al; for the Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogenreceptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010; 11:55-65.
10. Medicare Coverage Database. Baltimore, MD: Centers for Medicare & Medicaid Services; 2009. 11. Andre F, Delalage S. First generation genomic tests for breast cancer treatment. Lancet Oncol. 2010;11:6-7. 12. Anderson JM, Shak S, Millward C, et al; for Genomic Health Inc. Molecular characterization of breast cancer core biopsy specimens by gene expression analysis using standarized quantitative RT-PCR. San Antonio Breast Cancer Symposium. 2009:Abstract 6021. 13. Akashi-Tanaka S. Predicting responses to chemotherapy in breast cancer: from bench to bedside. Breast Cancer. September 30, 2009. Epub ahead of print. 14. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23:7265-7277. 15. Chang JC, Makris A, Gutierrez MC, et al. Gene expression patterns in formalin-fixed paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients. Breast Cancer Res Treat. 2008; 108:233-240. 16. Liang H, et al. A retrospective analysis of the impact of Oncotype DX low recurrence score results on treatment decisons in a single academic breast cancer center. San Antonio Breast Cancer Symposium. 2007:Abstract 2061. 17. Lo SS, Norton J, Mumby PB, et al. Prospective multicenter study of the impact of the 21 gene recurrence score (RS) assay on medical oncologist (MO) and patient (pt) adjuvant breast cancer (BC) treatment selection. J Clin Oncol. 2007;25(18S):Abstract 577. 18. Kamal AH, Loprinzi CL, Reynolds C, et al. How well do standard prognostic criteria predict Oncotype DX (ODX) scores? J Clin Oncol. 2007;25(18S): Abstract 576. 19. Erb C, Fox KR, Patel M, et al. Evaluation of practice patterns in the treatment of node-negative, hormonereceptor positive breast cancer patients with the use of the assay at the University of Pennsylvania. San Antonio Breast Cancer Symposium. 2007:Abstract 3082. 20. Mumby PB, Lo SS, Norton J, et al. Prospective multi-center study of the impact of the 21-gene recurrence score assay on patient satisfaction, anxiety and decisional conflict for adjuvant breast cancer treatment selection. San Antonio Breast Cancer Symposium. 2007:Abstract 1092. 21. Oratz R, Chao C, Skrzypczak S, et al; for Genomic Health Inc. Effect of 21-gene recurrence score results on treatment recommendations in patients with lymph node-positive, estrogen receptor-positive breast cancer. San Antonio Breast Cancer Symposium. 2009: Abstract 2031. 22. Buyse M, Loi S, van’t Veer L, et al; for the TRANSBIG Consortium. Validation and clinical utility of a 70gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98:1183-1192. 23. van’t Veer LJ, Dai H, van de Vijver MJ, He YD, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536. 24. Straver M, Glas AM, Hannemann J, et al. The 70gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119:551-558. 25. Mook S, Rutgers EJT, Peterse JL, et al. The Amsterdam 70-gene signature predicts outcome in breast cancer patients with 1-3 positive lymph nodes. San Antonio Breast Cancer Symposium. 2007:Abstract 1064. 26. EORTC Trial 10041 (BIG 3-04)—MINDACT. October 14, 2009. www.eortc.be/services/unit/mindact/ MINDACT_websiteii.asp. Accessed January 19, 2010. 27. Saghatchian M, Mook S, Pruneri G, et al. Combining genomic profiling (70 gene-MamaPrint) with nodal status allows to classify patients with primary breast cancer and positive lymph nodes (1-9) into very distinct prognostic subgroups that could help tailor treatment. San Antonio Breast Cancer Symposium. 2009: Abstract 102. 28. Bedard PL, Mook S, Knauer M, et al. The 70-gene profile (MammaPrint) is an independent predictor of breast cancer specific survival for women 65 years of age or older. San Antonio Breast Cancer Symposium. 2009:Abstract 4049. 29. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. October 13, 2009. Epub ahead of print. 30. Knauer M, Staver M, Rutgers E, et al. The 70-gene MammaPrint signature is predictive for chemotherapy benefit in early breast cancer. Breast. 2009;18(suppl 1):36. Abstract 73. 31. Albain K, Paik S, van’t Veer L. Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays. Breast. 2009;18(S3):S141-S145.
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In the fight against asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer...
Extends Survival PROVENGE® is the first FDA-approved autologous cellular immunotherapy—activating a patient’s own antigen-presenting cells to stimulate an immune response against prostate cancer. • Extended median survival beyond 2 years—25.8 months compared with 21.7 months for patients in the control group (P=.032) • Reduction in risk of death—22.5% (HR=0.775, 95% CI: 0.614, 0.979) • Most common adverse events—Chills, fatigue, fever, back pain, nausea, joint ache, and headache • Therapy complete in 3 cycles—3 infusions, at approximately 2-week intervals* *Each infusion is preceded by a standard leukapheresis procedure. The dosing interval ranged from 1 to 15 weeks in controlled clinical trials.
Now Available—To learn more about getting access to PROVENGE, call Dendreon ON Call at 1-877-336-3736. INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group are chills, fatigue, fever, back pain, nausea, joint ache, and headache. Please see Brief Summary of full Prescribing Information on the next page.
©2010 Dendreon Corporation. All rights reserved. November 2010. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation. P-A-11.10-072.00
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Prompt Pain Relief for Vertebral Compression Fractures with Balloon Kyphoplasty By Caroline Helwick
MILAN—Painful vertebral compression fractures can be promptly and effectively treated with balloon kyphoplasty, according to an international
study presented at the 35th European Society for Medical Oncology Congress. The Cancer Patient Fracture Evaluation (CAFE) study was the first to ran-
domize cancer patients with vertebral compression fractures to balloon kyphoplasty or standard nonsurgical treatment (controls). The results were reported by
PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion
BRIEF SUMMARY — See full Prescribing Information for complete product information INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION • For Autologous Use Only. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, conﬁrm that the patient’s identity matches the patient identiﬁers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction. (See Dosage and Administration  of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use. • Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the ﬁrst infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed. • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efﬁcacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The ﬁnal (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions  of full Prescribing Information.) ADVERSE REACTIONS 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 safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four
December 2010 I VOL 3, NO 8
Leonard Bastian, MD, of the Klinikum Leverkusen in Leverkusen, Germany. “We found that we can reduce pain immediately in these patients,” Bastian
randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor ﬂare. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)
Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Inﬂuenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot ﬂush Hematuria Muscle spasms
Control* (N = 303)
All Grades n (%)
Grade 3-5 n (%)
All Grades n (%)
591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)
186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)
291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)
Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)
(Table 1 continued on next page.)
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Cancer Complications said at a press conference. “Cancer patients with vertebral compression fractures having balloon kyphoplasty have a superior outcome.” Balloon kyphoplasty involves a 1-cm incision into the fractured vertebra through which a balloon is inserted and inflated to restore the shape and height of the vertebra. The balloon is then
deflated and removed, and quick-setting bone cement is injected into the vertebral body to maintain the shape. The study population included 134 patients with three or fewer vertebral compression fractures who were randomized to kyphoplasty (n = 70) or nonsurgical management (n = 64), mainly physical therapy, analgesics,
and sometimes braces and bed rest. Patients were followed for 1 year. After 1 month, the Roland-Morris Disability Questionnaire score dropped by 8.3 points in the kyphoplasty group but increased slightly by 0.1 point in the nonsurgical group. After just 1 week, the kyphoplasty group reported significant improvements in back pain,
Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)
Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor
Control* (N = 303)
All Grades n (%)
Grade 3-5 n (%)
All Grades n (%)
Grade 3-5 n (%)
45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)
3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)
14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)
0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)
37 (6.2) 36 (6.0)
0 (0.0) 2 (0.3)
22 (7.3) 23 (7.6)
1 (0.3) 2 (0.7)
35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)
0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)
17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)
0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)
*Control was non-activated autologous peripheral blood mononuclear cells.
Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.
Recent FDA Approval
(See Adverse Reactions  of full Prescribing Information.)
To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Trastuzumab for HER2-positive Metastatic Stomach Cancer The US Food and Drug Administration (FDA) has approved trastuzumab (Herceptin, Roche) in combination with chemotherapy (cisplatin plus either capecitabine or 5-fluorouracil) for human epidermal growth factor receptor type 2 (HER2)-positive metastatic cancer of the stomach or gastroesophageal junction in patients who have not received prior medicines for their metastatic disease. Approval was based on results of a phase 3 study (ToGA), which showed that patients who received trastuzumab plus chemotherapy had improved overall survival (HR, 0.73; 95% CI, 0.60-0.91; P = .0038). Median overall survival was 13.5 months for patients on combination therapy compared with 11 months for those on chemotherapy alone. An analysis based on an additional year of follow-up showed the numbers to be slightly lower (HR, 0.80; 95% CI, 0.67-0.97; P = .02; median overall survival, 13.1 vs 11.7 months).
Dendreon Corporation 3005 First Avenue Seattle, Washington 98121
©2010 Dendreon Corporation. All rights reserved. November 2010. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation. P-A-11.10-073.00
with a change in the numerical rating scale of -3.8 points, compared with virtually no change in the control group, and they used less analgesia. The difference between the groups in the two pain measurements was highly significant (P <.0001), Bastian noted. Patients receiving balloon kyphoplasty reported significantly fewer days with limited activity—6.2 days fewer per 2 weeks (P <.0001)—and greater improvements in quality of life as measured by an eight-point advantage in the SF-36 score (P <.0001). Crossover to kyphoplasty was allowed after 1 month, and the 38 patients who did so experienced similar benefits with regard to back pain relief, activity level, and quality of life. “All the balloon kyphoplasty patients reported sustained improvements throughout the 12-month period of the study,” Bastian said. Adverse events were similar except for the occurrence of one intraoperative non–Q-wave myocardial infarction that resolved in the kyphoplasty group and a cement leakage to the disc and adjacent fracture 1 day later in another patient. The indication for this procedure is virtually any painful vertebral compression fracture or multiple fractures. Bones that have been highly compromised due to metastases, however, may not be amenable to kyphoplasty. ●
December 2010 I VOL 3, NO 8
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Cancer Center Profile Geisinger Medical Center’s Cancer Institute Joins the NCCCP Continued from cover
Thanjavur Ravikumar, MD, FACS, performs surgery in Geisinger’s Center for Surgical Innovation.
Geisinger’s Cancer Institute, believes that serving this mix of patients marries well with the NCCCP’s mission of reducing cancer healthcare disparities. NCCCP cancer centers are directed to increase programs to reach the underserved in their communities more effectively, thus improving access to cancer screening, treatment, and research. Community outreach The centerpiece at Geisinger is value-based healthcare delivery, a philosophy evident in its advanced patientcentered medical home program, known as ProvenHealth Navigator. At Geisinger, medical homes are caregivers, such as primary care physicians or nurse case managers, who provide service excellence beyond just seeing patients in an acute-care setting. Their proactive approach to chronic diseases is recognized by the National Committee for Quality Assurance—all 40 facilities distributed throughout Geisinger’s community have been recognized as Level 3, the highest level awarded for the medical home model. This philosophy of managing patients through a disease continuum that is continued into wellness programs—a philosophy that is also practiced by Geisinger’s cancer specialists—parallels the NCCCP’s vision of cancer as a disease continuum, according to Ravikumar. NCCCP cancer centers are tasked with improving the quality of care at community hospitals by promoting datadriven, evidence-based, and coordinated cancer care. In addition, NCCCP cancer centers are working to enhance their cancer survivorship and palliative care services. With a $1.7-million award from the NCCCP, Geisinger hopes to reach these goals. To do so, Geisinger will use its
December 2010 I VOL 3, NO 8
medical home model to reach patients and physicians who are not members of the Geisinger system. “We need to provide the same services to both Geisinger patients and non-Geisinger patients in the 11 counties that surround us,” said Ravikumar in an interview with The Oncology Nurse. “Our plan through the NCCCP, our obligation, is to all patients in the counties that we serve.”
The centerpiece at Geisinger is value-based healthcare delivery, a philosophy evident in its advanced patientcentered medical home program. According to Ravikumar, Geisinger plans to reach out to area physicians who are not participants in the Geisinger system through the Keystone Health Information Exchange (KeyHIE) initiative. This initiative aims to provide healthcare professionals with the timely information they need to provide the best care possible for their patients. Through the initiative’s master patient list, patients’ charts and all medical information that reside at any participating hospital can be accessed through a secure web-based browser. Information technology GMC’s Cancer Institute also has “significant strength in information technology,” noted Ravikumar. This is another area that marries well with the NCCCP’s mission. NCCCP cancer centers are charged with exploring what is needed to adapt or adopt the tools of the National Cancer Institute’s (NCI)
cancer Bioinformatics Grid (caBIG) as well as to enhance their electronic health record (EHR) networks to support and link cancer patients and researchers nationwide. “What the NCCCP wants to do is connect all the cancer centers in the country through a grid called caBIG. They are trying to bring everyone up to speed. We are already advanced in that area, so perhaps the NCCCP thought that it would be a good thing for centers like ours to lead the way,” said Ravikumar. For the past 8 years, Geisinger has been recognized as one of the nation’s “100 Most Wired Hospitals and Health Systems” by Hospitals & Health Networks (H&HN), the journal of the American Hospital Association. As one of the most digitally advanced healthcare providers in the nation, Geisinger uses information technology to address safety and quality, customer service, business processes, workforce, and public health. Research In addition, Geisinger already has a very robust biospecimen initiative through MyCode. Currently, MyCode has 20,000 DNA samples from patients throughout Geisinger. Patients at all levels of health are asked to participate, provide a blood sample, and give consent for its use in research. “If any studies need to be done across the cancer research at the community level, we are well positioned to carry out the mission of the NCCCP,” explained Ravikumar. To help the NCCCP reach its goal of applying NCI Best Practices for Biospecimen Resources to enable all community cancer centers to contribute to the national biobank, Geisinger is expanding its specimen collection beyond Geisinger-affiliated cancer centers by “helping them retrieve the specimen when they operate on cancer patients,” Ravikumar said. As a member of the Community Clinical Oncology Program (CCOP), Geisinger already has 11 of the 15 NCCCP clinical trials open at its cancer centers. According to Ravikumar, Geisinger plans to expand those 11 trials and open the additional four trials to patients in its community. Because of its rural patient base, Geisinger will offer trials at multiple sites so, as Ravikumar explains, the patients “do not have to come to us in our main center.” In addition, Geisinger accrues to trials through other oncology groups including the Eastern Cooperative Oncology Group and the North Central Cancer Treatment Group. “Using the NCCCP mechanism, we are going to make these trials available to people in the community through outreach and navigators and transportation service,” explained
Ravikumar. “In addition, for clinical trials, we are going to enlist oncologists, radiation doctors, surgeons, and primary care physicians who are not Geisinger physicians and make sure that they have access to NCCCP clinical trials.” Quality care All of this, of course, is about the quality of care delivered. “We have some ideas of how we will use our EHR and our model of ProvenHealth to improve the quality of patient care, so every patient gets the same level of care,” said Ravikumar, a surgeon by profession. This care will continue through the disease continuum and include survivorship and palliative care. This past year, Geisinger has launched the Geisinger accelerated performance program (GAPP) initiative. “One of the central focuses of the GAPP initiative is palliative care, making sure that the patients that we cannot cure we offer palliation as a focus and that we keep their quality of life central to our mission.” GMC’s Cancer Institute will not be resting on its laurels. By becoming an NCCCP cancer center, Geisinger hopes to improve on its delivery of innovation and discovery and to enhance its diffusion of research and technology to positively influence cancer care today and tomorrow. Ravikumar looks forward to working with the other physician directors at the other sites. “We belong to the club. We may have one model. Others may other models. We will basically learn from each other,” Ravikumar said. ●
Recent FDA Approval Dasatinib for Ph+ CP-CML The US Food and Drug Administration (FDA) has approved a new indication for dasatinib (Sprycel, Bristol-Myers Squibb)—treatment of Philadelphia chromosome–positive chronic phase chronic myeloid leukemia (Ph+ CP-CML). This indication expands on the drug’s original approval in 2006 to treat adults with CP-CML with resistant disease or who were intolerant of prior therapies. An oral kinase inhibitor, dasatinib’s side effects can include de creased bone marrow activity, fluid retention, diarrhea, headache, muscle and bone pain, and rash. Because it was approved under the FDA’s accelerated approval program, the manufacturer is required to collect additional long-term efficacy and safety data.
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ALOXI provides powerful CINV prevention that canâ€™t be ignored. ÂŽ
Help support your patientsâ€™ chemotherapy treatment goals s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 s Lasts long against nausea following moderately emetogenic chemotherapy s Powerful acute CINV prevention following highly emetogenic chemotherapy 4 s %ISAI OFFERS A VARIETY OF SUPPORT PROGRAMS AND RESOURCES
Indication ALOXIÂŽ (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.
Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.
STARTS STRONG. LASTS LONG.
ALOXIÂŽ IS A REGISTERED TRADEMARK OF (ELSINN (EALTHCARE 3! 3WITZERLAND USED UNDER LICENSE $ISTRIBUTED AND MARKETED BY %ISAI )NC ÂĽ %ISAI )NC !LL RIGHTS RESERVED 0RINTED IN 53! !,/"