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MARCH/APRIL 2011

www.TheOncologyNurse.com

VOL 4, NO 2

The Official Publication for the Hem/Onc Nurse & Advanced Practitioner THE WHOLE PATIENT

CANCER CENTER PROFILE

St. Joseph Mercy Cancer Care Center A Cancer Hospital in a Small Community Has Big Plans By Dawn Lagrosa

Are You Talking to Patients About Smoking Cessation? By Christin Melton

D

espite aggressive campaigns to educate Americans on the lifethreatening risks of smoking, nearly 500,000 people die each year in the United States from smoking-related illness, according to a recent study in Epidemiology. Even patients with smoking-related cancers have trouble quitting, with about two-thirds of patients with lung cancer continuing to smoke.

At the annual meeting of the Hematology/Oncology Pharmacy Association, Jane Pruemer, PharmD, BCOP, FASHP, professor of clinical pharmacy practice at the University of Cincinnati’s James L. Winkle College of Pharmacy in Ohio, suggested clinicians have an obligation to encourage patients with cancer who smoke to give up the habit. “It is inconsistent to provide healthContinued on page 44

GUIDELINES

NCCN Updates Treatment Guidelines Revisions Expected to Change Practice By Audrey Andrews

A Clockwise from top left: Walter M. Sahijdak, MD; Philip J. Stella, MD; Lara Blair, RN; and Vita McCabe, MD; of the multidisciplinary lung clinic at St. Joseph Mercy Cancer Center.

ollowing a lung cancer diagnosis, patients typically embark on a dizzying journey that takes them from one waiting room to another, as they follow their treatment plan from the medical oncologist to the surgical oncologist to the radiation oncologist and back again. Coordinating these visits imposes yet another burden on the patient and often leads to delays in care. Six years ago, St. Joseph Mercy Cancer Center in Ypsilanti, Michigan, decided to simplify life for their patients by opening a multidisciplinary lung cancer clinic.

F

Continued on page 17

t the 16th Annual Conference of the National Comprehensive Cancer Network (NCCN), chairpersons of the various tumor panels presented updates to the NCCN Clinical Practice Guidelines and explained the reasoning behind these changes. We review the most important updates to the guidelines for breast, prostate, and lung cancer and for various hematologic malignancies, including non-Hodgkin lymphoma

©iStockphoto.com/Eduardo Jose Bernardino

COMPLIMENTARY CE

INSIDE ...........

32

Follow-up Management of Hodgkin Lymphoma Survivors ............

13

A Growing Crisis in Oncology

VISIT US

www.TheOncologyNurse.com

Breast Cancer Pivotal research and drug approvals in the past year led to changes that are immeContinued on page 39

DRUG SHORTAGES

For more CE Opportunities and to take the posttest for the CE article in this issue, visit

and chronic myelogenous leukemia (CML). This brief overview is for informational purposes and is not intended to guide treatment decisions. You are encouraged to visit www.nccn.org to review the complete guidelines and their respective references.

CONFERENCE NEWS

ASCO Gastrointestinal Cancers Symposium . . . . . . . . . . . . . . . . . . . . . 18 ASCO Genitourinary Cancers Symposium . . . . . . . . . . . . . . . . . . . . . 22

©2011 Green Hill Healthcare Communications, LLC

SUPPORTIVE CARE . . . . . . . . . . . .

28

Managing Anthracycline Extravasation THE WHOLE PATIENT . . . . . . . . . .

42

Cancer Treatment–Induced Diarrhea Elderly Patients with Comorbidities NEWS IN REVIEW

..............

Eribulin for Heavily Pretreated Metastatic Breast Cancer Axillary Lymph Node Dissection Unnecessary for Some

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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

13.5

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

11.7 0

3

6

9

12

15

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.

10581800

11/10






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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

In

d

B

Inflamm

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

Impairm N

P

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.

b

c

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

centages of

tin

ACb

3 n = 135

18%

4% 2%

9%

Grades 3/4

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)

_

15 (5)

_

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)

69 (23)

6 (2)

40 (14)

7 (2)

56 (19) 37 (13)

0 (0) 0 (0)

29 (10) 17 (6)

0 (0) 0 (0)

53 (18)

8 (3)

42 (15)

5 (2)

28 (10)

0 (0)

14 (5)

0 (0)

LVEF *10% *16% <50% decrease decrease

2%

29%

9%

7% 4 studies, a

and

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.

All Grades

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

17%

icin)

FC (N = 290) N (%)

Absolute LVEF Decrease <20% and *10% *20%

18.3% (294)

11.7% (188)

33.4% (536)

9.2% (148)

ACAT (n=1488)

9.1% (136)

5.4% (81)

2.2% (33)

18.3% (272)

2.4% (36)

Study 3 Herceptin (n=1678)

8.6% (144)

7.0% (118)

3.8% (64)

22.4% (376)

3.5% (59)

Observation (n=1708)

2.7% (46)

2.0% (35)

1.2% (20)

11.9% (204)

1.2% (21)

Study 4c TCH (n=1056)

8.5% (90)

5.9% (62)

3.3% (35)

34.5% (364)

6.3% (67)

ACATH (n=1068)

17% (182)

13.3% (142)

9.8% (105)

44.3% (473)

13.2% (141)

ACAT (n=1050)

9.5% (100)

6.6% (69)

3.3% (35)

34% (357)

5.5% (58)

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_April2011_v7_TON 4/7/11 10:47 AM Page 6

Editorial Board EDITOR-IN-CHIEF

Sharon S. Gentry,

Kena C. Miller,

Rita Wickham,

Beth Faiman,

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,

Patricia Molinelli,

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 Bishop,

Shannon Hazen,

DNP, NP, AOCNP

RN, BSN, OCN

Dolores “Jeff” Nordquist, RN, MS,

Pharmacy John F. Aforismo,

Virginia Cancer Care Lansdowne, VA

Novant Health Presbyterian Cancer Center Charlotte, NC

CS, FNP

BSc Pharm, RPh, FASCP

Deena Damsky Dell, RN, MSN,

Patricia Irouer Hughes, RN, MSN,

Melinda Oberleitner, RN,

Nutrition Karen Connelly,

MSN, CRNP

Mayo Clinic Rochester, MN

R. J. Health Systems International, LLC Wethersfield, CT

AOCN, BC

BSN, OCN

DNS, APRN, CNS

RD, CSO

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

Wendy DiSalvo,

Taline Khoukaz,

Gary Shelton,

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

BSN

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

Arizona Cancer Center Tucson, AZ

Constance Engelking, RN,

Elizabeth Lima,

MS, CNS, OCN

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

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

PA-C

Coronado, CA

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,

Ann McNeill,

Connie Visovsky,

Isabell Castellano, RN

BSN, OCN

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

6

March/april 2011 I VOl 4, NO 2

www.TheOncologyNurse.com


TON_April2011_v7_TON 4/7/11 10:47 AM Page 7

In multiple myeloma

The challenges of multiple myeloma need new approaches In multiple myeloma, median survival from the time of diagnosis has been significantly longer in the current decade than in previous years— 3.7 years vs 2.5 years.1 However, patients still face significant challenges. • Almost all patients eventually relapse2 • Patients may become refractory to multiple treatment options

Pursuing new treatment advances Onyx Pharmaceuticals is pursuing potential new options for the treatment of relapsed and refractory multiple myeloma, with the ultimate goal of extending patients’ lives.

©2011 Onyx Pharmaceuticals, Inc., South San Francisco, CA

1210-CARF-051-R1

December 2010

References: 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 2. Schwartz RN, Vozniak M. Current and emerging treatments for multiple myeloma. J Manag Care Pharm. 2008;14(suppl S):S12-S18.

4:31 PM


TON_April2011_v7_TON 4/7/11 1:18 PM Page 8

In This Issue 13 FEATURE

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com

32 COMPLIMENTARY CE

Drug Shortages: A Growing Crisis in Oncology

Editorial Director Christin Melton christin@greenhillhc.com

18 CONFERENCE NEWS

Follow-up Management of Hodgkin Lymphoma Survivors

42 THE WHOLE PATIENT

Highlights from the 2011 Gastrointestinal and Genitourinary Cancers Symposia

Associate Editor Dawn Lagrosa dawn@greenhillhc.com

• Considerations for Cancer Treatment–Induced Diarrhea • Managing Geriatric Patients

Quality Control Director Barbara Marino

• Balloon Kyphoplasty Reduces Vertebral Compression Pain

Director, Client Services John W. Hennessy john@greenhillhc.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com

In Advanced Renal Cell Carcinoma...

Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

GH Green Hill Healthcare Communications

, LLC ™

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The Oncology Nurse®-APN/PA, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse®-APN/PA logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be

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8

March/april 2011 I VOl 4, NO 2

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,”Section 5.1, in complete Prescribing Information. Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval,

and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. Hemorrhagic Events: Fatal hemorrhagic events have been reported (all grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. Hypertension: Hypertension has been observed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

www.TheOncologyNurse.com


TON_April2011_v7_TON 4/7/11 1:19 PM Page 9

In This Issue 48 NEWS IN REVIEW

60 NURSING LIFE

• Voluntary Recall of Irinotecan • Tamoxifen Protective 10 Years After Treatment • Medicare Plans to Cover Provenge

• Nursing By the Numbers • Do you Tweet? • Can Alternative Medicine Prevent Burnout?

58 NAVIGATION & SURVIVORSHIP

62 MEETINGS

• Azoospermic Survivors Not Necessarily Sterile • Navigators’ and Patients’ Perspectives on the Navigation Experience

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

9.2 months (95% CI, 7.4-12.9)

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 2,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 2,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 2,3

NCCN Guidelines Category 1 recommendation4 • First-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology

Proven safety profile1,2 • Most common adverse events observed with VOTRIENT (>20%) were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

Once-daily oral dosing1 • The recommended dosage of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal) • Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events • Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced VOTRIENT is a multitargeted tyrosine kinase inhibitor that is indicated for the treatment of patients with advanced RCC.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2010. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from ©National Comprehensive Cancer Network, Inc 2010. All Rights Reserved. NCCN Guidelines™: Kidney Cancer, V.1.2011. NCCN. org Accessed January 12, 2011. NCCN® and NCCN GUIDELINES™ are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com

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Need More CE Credits?

Y

ou can find them at www.TheOncologyNurse.com, by following the link to Continuing Education (CE). Topics range from supportive care issues, such as preventing neuropathy and thromboembolic disease; to treatment concerns, like KRAS mutations and colorectal cancer; to practice matters, including bar coding as a strategy to prevent medication errors.

BRIEF SUMMARY VOTRIENT™ (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

Additional CE is available at our preferred provider partner, Center of Excellence Media, LLC. At www.coexm.com, you will find a broad range of CE opportunities, on topics like multiple myeloma and metastatic breast cancer. If you have a CE topic you would like The Oncology Nurse-APN/PA to cover, forward your suggestion to us at editorial@greenhillhc.com with CE in the subject line. ●

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension: Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced.

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Don’t Forget to Vote at www.TheOncologyNurse.com/award. Polovich, PhD, RN, AOCN; Janet C. Stocker, RN, MS, NP-C, AOCNS, or Patricia Shearburn, RN, MSN, AOCN, to receive this award. If you no longer have the February issue available to read up on the nominees, you will find all their profiles at www.TheOncologyNurse.com/award. There are only a few more weeks left to make your selection, so don’t forget! ●

D

ue to the enthusiastic response our Oncology Nurse Excellence Award campaign has received, we have decided to extend voting until April 30. We will announce the winner in the June issue of The Oncology Nurse-APN/PA. If you have not voted already, we encourage you to visit the Website at the URL above and tell us whether you would like Lisa K. Rioux, RN, BSN, OCN; Martha

Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

41

<1

0

33

1

0

36

3

<1

10

1

<1

34

4

0

11

0

0

31

4

1

24

4

0

26

<1

1

14

0

0

17

0

<1

3

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension

were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.2).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.3).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.5).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any postbaseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.7).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/ kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was

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From the Editor

We Are All in This Together By Editor-in-Chief Beth Faiman, RN, MSN, APRN, BC, AOCN

T

he “Annual Report to the Nation on the Status of Cancer,” emerging from a collaboration of the North American Association of Central Cancer Registries, the National Cancer Institute (NCI), the Centers for Disease Control and Prevention, and the American Cancer Society, shows

declines in cancer rates and improved survival. It helps reassure us that the resources invested to fight cancer have not been misplaced. Yet those resources are threatened. Toward the end of the Bush administration, NCI funding flat-lined. In 2009, the American Recovery and

reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/ day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for

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March/april 2011 I VOl 4, NO 2

Reinvestment Act provided a welcome boost allocating millions for NCI research grants. Last month, the House passed a budget plan that would cut National Institutes of Health funding by $1.6 billion, leading to fewer grants from the NCI. In February, Stevens and colleagues wrote in the New England Journal of Medicine that 1 of 5 major medical advances approved by the US Food and Drug Administration between 1990 and

26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. • yellowing of the skin or the whites of the eyes (jaundice), • unusual darkening of the urine, • unusual tiredness, • right upper stomach area pain. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

©2010, GlaxoSmithKline. All rights reserved. VTR:3BRS

©2011 The GlaxoSmithKline Group of Companies. All rights reserved. Printed in USA. VOT234R0 January 2011

2007 originated in a federally funded laboratory. This includes more than 40 anticancer drugs, some of which you probably recognize: bortezomib, carboplatin, cisplatin, doxorubicin, imatinib, paclitaxel, sunitinib. How many lives have these drugs saved or prolonged? Not everyone agrees about what to leave in the federal budget and what to remove, but we healthcare workers tend to divorce spending on cancer research or patient programs from our political leanings. For us, it is an issue of protecting our patients, who are not just a number in a report. With so much promising research under way and such great need, it is painful to imagine what might be accomplished for the want of a sliver of the federal budget. Some say we have pushed billions at the cancer problem without solving it—but the money hasn’t been wasted. In the Journal of the NCI last month, Gambacorti-Passerini and associates wrote that patients with chronic myeloid leukemia (CML) in remission after imatinib therapy have a normal life expectancy. Before imatinib, life expectancy for patients with CML was 3 to 5 years. Last year, M. D. Anderson Cancer Center researchers reported that 3 of every 4 women diagnosed with breast cancer at their institution in 1944 died within 10 years. In 2004, 3 out of 4 patients diagnosed survived 10 years! The declines in cancer incidence and mortality are heartening, but as the proportion of our population aged ≥65 years grows, cancer rates will grow, too. Childhood cancers continue to increase. As nurses, we know cancer research is not only about helping patients live longer, but also about helping them live better. If everyone spent 1 week as a nurse on a pediatric cancer ward, we’d see a unanimous call to increase cancer research funding, with everyone agreed that curing cancer and stopping its burden outweighs anyone’s political points. Funding is, of course, only part of the equation for improving outcomes. Nurses are another important part. Our goal with every issue of The Oncology Nurse-APN/PA is to provide the information you need to play that part. This issue includes studies that had federal funding and others that were privately funded. All signal promise to improve care. We are also introducing two new departments: The Whole Patient, focusing on quality-of-life issues; and News in Review, keeping you current on prevalent research taking place outside the conference setting, along with regulatory and legislative news. We will still provide continuing education, conference highlights, and advice from peers. Please take a moment to let us know your thoughts about these changes! ●

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Drug Shortages

Drug Shortages: A Growing Crisis in Oncology By Christin Melton

D

rug shortages continue to plague the United States, compromising patient safety and placing additional strain on healthcare resources. The shortages encompass common drugs used to treat a range of conditions, from everyday infections to heart attacks. The problem has escalated in recent years, with the number of drugs deemed unavailable or scarce jumping from 74 in 2005 to more than 240 in 2010, according to the Drug Information Service (DIS) at the Uni versity of Utah Hospitals & Clinics. DIS, which started tracking drug shortages in January 2001, is among the first groups to recognize the problem. Erin Fox, PharmD, manages DIS and said in an interview, “I believe the current state of shortages is a crisis for the United States.” The shortages have hit oncology hard. “In so many cases there are no good alternative agents, particularly for chemotherapy agents. We have seen over 20 different chemotherapy drugs in short supply during 2010 and continuing into 2011,” Fox explained. The nonprofit Institute for Safe Medication Practices (ISMP) warns “there is little relief in sight.” Providers See the Effects of Drug Shortages Local news reports from Alaska, California, Maryland, Pennsylvania, Texas, Tennessee, Virginia, and elsewhere show that hospitals in virtually every state are struggling to manage the growing list of hard-to-get drugs. A hospital administrator in Tennessee told her local paper that drug shortages were “the new norm.” Small hospitals feel the burden more than large hospitals, which can use their purchasing power to stockpile drugs on the shortage list. Many hospitals in networks manage shortages by shifting supplies to whichever sister facility needs them. In 2010, ISMP surveyed 1800 pharmacists, physicians, nurses, and healthcare administrators at hospitals and long-term care facilities and found that nearly all had been affected by drug shortages. More than 80% complained that they were never warned of a looming drug shortage nor told how long it might last, and 82% said it required considerable resources to come up with a management plan. Shortages have also affected providers on a personal level, with 55% of physicians surveyed saying they felt anger toward other staff or the hospital when a drug was not available.

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Three-quarters of respondents told ISMP that drug shortages had cost their facility money. This corresponds with results of a survey by Premier, Inc, an alliance of 200 hospitals and health systems in the United States. From July to December 2010, Premier questioned 311 pharmacy experts about the effect of drug shortages on their practice. At least 98% acknowledged substituting a more expensive drug 1 or more times, and 40% said they had done so more than 21 times. Premier estimates oncology providers shelled out an additional $10.5 million in 2010 for the generic equivalents of drugs on the shortage list. Not every drug in short supply has a generic equivalent, and Premier says using the best therapeutic alternative increases treatment costs an average of 11%. Across all areas of care, hospitals paid an extra $200 million in 2010 for therapeutic substitutions. More than Dollars and Cents The highest costs of drug shortages have been borne by patients. Healthcare providers have only a few options when they are unable to give the patient the drug he or she needs: they can substitute an equivalent or nearequivalent agent, give nothing, or delay treatment until the drug becomes available. All these options could lead to worse outcomes. Respondents to the ISMP survey reported “more than 1000 near misses, errors, and adverse outcomes” attributable to drug shortages. Some errors led to a patient’s death. At one facility, hydromorphone was substituted for morphine, which was not available due to shortages. The provider administered the hydromorphone at the dose originally indicated for the morphine prescription, leading to the deaths of 2 patients and nonfatal overdose in another. Whenever a drug has been substituted for another, it is essential to ensure that the new drug is correctly dosed or that the correct infusion rate is used. Other dosing errors occur when the only way the hospital can get the drug is by ordering a different concentration. For example, when preloaded syringes of epinephrine were difficult to get, some hospitals ordered the drug in vials. Because epinephrine is typically used in emergencies, the nurse is pressured to draw the dose from the vial quickly, increasing the risk of delivering an underdose or overdose. Institutions might try to conserve supplies of a hard-to-get drug by using smaller doses. ISMP said attempts to

“Last year, acyclovir was virtually unavailable for a few months, which put our patients at risk to develop viral infections.” —Beth Faiman, RN, MSN, APRN, BC, AOCN

conserve propofol by cutting the dose at some hospitals led to inadequate sedation or anesthesia awareness. Some hospitals are shortening the duration of therapy when prescribing medications in short supply. For patients with cancer, both approaches could lead to worse outcomes. Substituting one drug for another compromises outcomes if the replacement drug proves to be less effective or less tolerable. Not every drug has a suitable replacement, such as amikacin and acyclovir. As Beth Faiman, RN, MSN, APRN, BC, AOCN, a nurse practitioner at the Cleveland Clinic Taussig Cancer Institute in Ohio and

editor-in-chief of The Oncology NurseAPN/PA, explained, “Last year, acyclovir was virtually unavailable for a few months, which put our patients at risk to develop viral infections.” In addition to the detrimental physical effects of drug shortages on patients with cancer, Catherine Bishop, DNP, NP, AOCNP, doctor of nursing practice and an oncology nurse practitioner at Virginia Cancer Care, Inc, pointed out that there are also psychological considerations. “Some of the issues patients face are the likelihood or need to discontinue a certain medication, such as leucovorin or etoposide. For patients in the metastaContinued on page 14

Common Cancer Drugs in Short Supply The following is a list of drugs commonly used for patients with cancer that the American Society of Health-System Pharmacists (ASHP) classified as being in short supply in March. For some drugs, only certain doses or preparations are unavailable. Most shortages are attributable to manufacturing delays and/or increased demand. In some cases, the manufacturer discontinued the drug or offered no explanation for the short supply. A couple (ie, capecitabine [Xeloda] tablets and dexamethasone sodium phosphate) have been voluntarily recalled because of contamination concerns. To alleviate the shortage of capecitabine, the US Food and Drug Administration has granted the manufacturer permission to import the drug from the European Union. The ASHP Website provides suggestions for managing care when your facility does not have one of the products listed below. • Acyclovir injection

• Etoposide injection

• Acyclovir capsules and tablets

• Fentanyl injection

• Amikacin injection

• Fludarabine injection

• Capecitabine tablets

• Granisetron hydrochloride injection

• Carboplatin

• Idarubicin hydrochloride injection

• Cisplatin injection

• Leucovorin calcium injection

• Cytarabine

• Melphalan injection

• Dacarbazine powder for injection

• Morphine injection

• Daunorubicin hydrochloride

• Vancomycin hydrochloride injection

• Dexamethasone sodium phosphate • Doxorubicin injection

• Vincristine injection

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Drug Shortages Drug Shortages: A Growing Crisis in Oncology Continued from page 13 tic setting, this can produce a great deal of anxiety,” she said. Talking to patients about drug shortages is also tough on the practitioner. “For any provider to tell a patient that the drug that may benefit them the most is not currently available is difficult and almost impossible to explain,” she said. Why Are So Many Drugs in Short Supply? The drug shortage crisis has emerged from a confluence of factors. “Our country depends on just a few generic manufacturers to make the majority of the critical drugs we need in our hospitals and operating rooms each day,” said Fox. A problem at one facility or a decision by one manufacturer to reduce production is ultimately felt at the clinic. The Pharmaceutical Research and Manufacturers of America (PhRMA) released a statement on drug shortages in March, noting that “according to the FDA [US Food and Drug Administration] and other experts, drug shortages can occur for any number of reasons.” PhRMA cited “natural disasters; shifts in clinical practices; wholesaler and pharmacy inventory practices; raw material shortages; changes in hospital and pharmacy contractual relationships with suppliers and wholesalers that can cause fluctuations in the availability of certain products; adherence to FDAmandated distribution protocols, which can impact patients’ timely access to medicines; individual company decisions to discontinue specific medicines; and manufacturing challenges” as some of the causes of the country’s drug shortage problem. In 2010, the FDA reported that 40% of drug shortages were caused by manufacturing issues, which includes difficulty obtaining the drug’s raw materials or containers and quality control issues. Another 20% of shortages

—Catherine Bishop, DNP, NP, AOCNP

occurred when the manufacturer decided to stop making the drug, often because it was no longer profitable, and 20% resulted from production delays. Premier notes that foreign companies provide nearly 80% of the raw materials for drug manufacture in the United States. In 2010, concerns over the integrity of ingredients from China led some drug companies to look for a new supplier, disrupting production for some drugs and landing them on the shortage list.

Clinicians should consider centralizing their supply of medications and tracking what they need based on their patient roster. At the Drug Shortages Summit convened in November 2010 by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists, the American Society of Clinical Oncology, and the ISMP, participants recognized that regulatory issues can cause shortages. As part of the 2006 Unapproved Drugs Initiative, the

Total drug shortages Drug shortages involving sterile injectables

175 150 125

Number

“Some of the issues patients face are the likelihood or need to discontinue a certain medication, such as leucovorin or etoposide. For patients in the metastatic setting, this can produce a great deal of anxiety.”

100 75

FDA is requiring manufacturers of drugs approved prior to the adoption of stricter drug regulations in 1938 to conduct trials and file a New Drug Application for their generic product. Some drug companies balked at the expense of complying with the initiative and instead elected to stop making the drug. A drugmaker must also file an application with the FDA when it wants to change suppliers for active ingredients, and several have complained that the agency is slow to approve these applications. Complex packaging requirements and demands for risk evaluation and mitigation strategies for certain drugs have also contributed to delays. Premier outlines other potential causes for drug shortages. When the economy was in recession, many companies in the drug production chain scaled down the quantity of supplies kept on hand. Any disruption in one company’s ability to restock supplies has a ripple effect on the manufacturer’s ability to get the drug to market. Some pharmacists complain that “gray market distributors” are causing artificial drug shortages by buying large quantities of important, inexpensive drugs and reselling them at greatly inflated prices once the drugs are difficult to obtain. This is a bit like when a ticket outlet purchases all the premium tickets for a major rock concert or popular Broadway show and offers them at a high markup once the show has sold out. Providers who stockpile drugs for fear that they might become hard to get also contribute to artificial shortages. Temporary shortages occur when one drug is discontinued, everyone switches to the same alternative, and the manufacturer cannot keep up with supply.

50 25 0 2005

2006

2007

Year Figure. Drug shortages per year.

14

March/april 2011 I VOl 4, NO 2

2008

2009

Is Anything Being Done? Fox expressed optimism about a few recent developments reguarding the drug shortage. “I am hopeful the problem may subside in part because 2 of the largest generic companies with multiple shortages seem to be resolving their manufacturing problems,” she said. If

this happens, Fox said the number of shortages might fall to 2009 levels, which she notes were still too high. Congressional legislators have introduced US Senate Bill 296, the Preserving Access to Life-Savings Medications Act. The bill requires drugmakers to notify the FDA at least 6 months before stopping or delaying production for a drug. Many in the medical community support the bill. “There is widespread belief by many in the medical community that there needs to be oversight and regulations, which should be strictly enforced, so manufacturers cannot just decide to stop the manufacturing of a drug without significant notice,” said Bishop. Bill 296 also requires the FDA to identify drugs vulnerable to shortages and take steps to ensure that the supply is not interrupted. “The bill won’t solve all shortage problems, but it is a great start,” said Fox. She encouraged clinicians to contact their congressional officials and urge them to support the bill. Some patients are not waiting for legislation to resolve the problem and have decided to head to court. Genzyme, which has been plagued with problems at its manufacturing facilities, has been named in a civil lawsuit by a group of patients with Fabry disease. Genzyme manufactures Fabrazyme, the primary drug used to treat the genetic disorder. In the past year, the company started rationing access to the drug and cutting dosages; the lawsuit claims at least 3 patients have died from this approach. Genzyme had similar manufacturing problems with Cerezyme, its drug for Gaucher disease, but believes it will soon have the situation corrected. As the Drug Shortages Summit participants pointed out, the FDA cannot require a drug manufacturer to keep making a product. They said Congress can and should, however, offer incentives to companies that manufacture life-saving generic medications, such as tax breaks and extended exclusivity rights. Taking Steps to Protect Patients Fox listed a few steps hospitals can take to minimize the effects of drug shortages on their patients. “Pharmacists can discuss shortages with clinicians as far ahead as possible.” She noted that sometimes this is not possible, but “as much advance notice as possible can help when decisions about therapy are being made, particularly if another treatment choice is available and will work well for the patient.” She recommended that clinicians Continued on page 16

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TON_April2011_v7_TON 4/7/11 10:48 AM Page 15

ALOXI provides powerful CINV prevention that canâ&#x20AC;&#x2122;t be ignored. ÂŽ

Help support your patientsâ&#x20AC;&#x2122; 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 %ISAIOFFERSAVARIETYOFSUPPORTPROGRAMSANDRESOURCES

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)ISCONTRAINDICATEDINPATIENTSKNOWNTOHAVEHYPERSENSITIVITYTOTHEDRUGORANY of its components s -OSTCOMMONLYREPORTEDADVERSEREACTIONSINCHEMOTHERAPY INDUCEDNAUSEAANDVOMITING 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.

ALOXIÂŽISAREGISTEREDTRADEMARKOF(ELSINN(EALTHCARE3! 3WITZERLAND USEDUNDERLICENSE $ISTRIBUTEDANDMARKETEDBY%ISAI)NC ÂĽ%ISAI)NC !LLRIGHTSRESERVED0RINTEDIN53!!,/"


TON_April2011_v7_TON 4/7/11 12:27 PM Page 16

Drug Shortages Drug Shortages: A Growing Crisis in Oncology Continued from page 14 consider centralizing their supply of medications and tracking what they need based on their patient roster. â&#x20AC;&#x153;This strategy is particularly helpful with chemotherapy shortages,â&#x20AC;? Fox said. â&#x20AC;&#x153;Track out the needs of the patients and then, if insufficient drug is available, the physicians can decide the best action.â&#x20AC;?

ALOXIÂŽ (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: L =23@/B3:G3;3B=53<711/<13@163;=B63@/>GK   >@3D3<B7=<=4/1CB3/<223:/G32</CA3//<2   D=;7B7<5/AA=17/B32E7B67<7B7/:/<2@3>3/B1=C@A3A L 756:G3;3B=53<711/<13@163;=B63@/>GK>@3D3<B7=<  =4/1CB3</CA3//<2D=;7B7<5/AA=17/B32E7B67<7B7/:  /<2@3>3/B1=C@A3A DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting =A/534=@2C:BA/A7<5:3  ;5)2=A3 /2;7<7AB3@32=D3@ A31=<2A=A7<5A6=C:2=11C@ />>@=F7;/B3:G ;7<CB3A034=@3B63AB/@B=4 163;=B63@/>G Instructions for I.V. Administration "+7AAC>>:732@3/2G4=@7<B@/D3<=CA7<831B7=< "+A6=C:2<=B03;7F32E7B6=B63@2@C5A:CA6 B637<4CA7=<:7<3E7B6<=@;/:A/:7<3034=@3/<2/4B3@ /2;7<7AB@/B7=<=4"+ #/@3<B3@/:2@C5>@=2C1BAA6=C:2037<A>31B32D7AC/::G 4=@>/@B71C:/B3;/BB3@/<227A1=:=@/B7=<034=@3 /2;7<7AB@/B7=<E63<3D3@A=:CB7=</<21=<B/7<3@>3@;7B CONTRAINDICATIONS "+7A1=<B@/7<271/B327<>/B73<BA9<=E<B=6/D3 6G>3@A3<A7B7D7BGB=B632@C5=@/<G=47BA1=;>=<3<BA [see Adverse Reactions (6) 7<4C:: >@3A1@707<57<4=@;/B7=< ] WARNINGS AND PRECAUTIONS Hypersensitivity G>3@A3<A7B7D7BG@3/1B7=<A;/G=11C@7<>/B73<BAE6= 6/D33F6707B326G>3@A3<A7B7D7BGB==B63@'

@313>B=@/<B/5=<7ABA ADVERSE REACTIONS 31/CA31:7<71/:B@7/:A/@31=<2C1B32C<23@E723:G D/@G7<51=<27B7=<A/2D3@A3@3/1B7=<@/B3A=0A3@D327< B631:7<71/:B@7/:A=4/2@C51/<<=B0327@31B:G1=;>/@32 B=@/B3A7<B631:7<71/:B@7/:A=4/<=B63@2@C5/<2;/G <=B@3J31BB63@/B3A@3>=@B327<>@/1B713 <1:7<71/:B@7/:A4=@B63>@3D3<B7=<=4</CA3//<2 D=;7B7<57<2C1320G;=23@/B3:G=@6756:G3;3B=53<71 163;=B63@/>G

 /2C:B>/B73<BA@3137D32>/:=<=A3B@=< 2D3@A3@3/1B7=<AE3@3A7;7:/@7<4@3?C3<1G/<2A3D3@7BG E7B6"+/<2=<2/<A3B@=<=@2=:/A3B@=<=::=E7<5 7A/:7AB7<5=4/::/2D3@A3@3/1B7=<A@3>=@B320Gâ&#x2030;Ľ =4 >/B73<BA7<B63A3B@7/:A'/0:3  Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies â&#x2030;Ľ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=194) (N=633) 3/2/163  



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  <=B63@ABC273A AC0831BA3F>3@73<132A3D3@3 1=<AB7>/B7=<4=::=E7<5/A7<5:3>/:=<=A3B@=<2=A3=4 />>@=F7;/B3:G ;5B6@33B7;3AB63@31=;;3<232 2=A3"<3>/B73<B@3137D32/ ;1595=@/:2=A37</ >=AB=>3@/B7D3</CA3//<2D=;7B7<5ABC2G/<2=<3 63/:B6GAC0831B@3137D32/ ;5)2=A37</ >6/@;/1=97<3B71ABC2G <1:7<71/:B@7/:AB634=::=E7<57<4@3?C3<B:G@3>=@B32 /2D3@A3@3/1B7=<A/AA3AA320G7<D3AB75/B=@A/A B@3/B;3<B@3:/B32=@1/CA/:7BGC<9<=E<=11C@@32 4=::=E7<5/2;7<7AB@/B7=<=4"+B=/2C:B>/B73<BA @3137D7<51=<1=;7B/<B1/<13@163;=B63@/>G /@27=D/A1C:/@ <=<ACAB/7<32B/16G1/@27/ 0@/2G1/@27/6G>=B3<A7=< 6G>3@B3<A7=< ;G=1/@27/:7A163;7/3FB@/AGAB=:3AA7<CAB/16G1/@27/ A7<CA/@@6GB6;7/AC>@/D3<B@71C:/@3FB@/AGAB=:3A/<2$' >@=:=<5/B7=<<;/<G1/A3AB63@3:/B7=<A67>B="+ E/AC<1:3/@ 3@;/B=:=571/: /::3@57123@;/B7B7A@/A6 3/@7<5/<2)7A7=< ;=B7=<A719<3AAB7<<7BCA 3G37@@7B/B7=</<2/;0:G=>7/ /AB@=7<B3AB7</:&GAB3; 27/@@63/ 2GA>3>A7/ /02=;7</:>/7<2@G;=CB66711C>A/<2J/BC:3<13

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March/april 2011 I VOl 4, NO 2

In some cases that might be not accepting a new patient, delaying treatment, or altering the treatment plan. ISMP recommends â&#x20AC;&#x153;establishing a shortage networkâ&#x20AC;? with other healthcare providers. The organization also suggests adopting strategies to prevent errors when using substitutes and con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ostmarketing Experience '634=::=E7<5/2D3@A3@3/1B7=<A6/D3033<723<B7I32 2C@7<5>=AB/>>@=D/:CA3=4"+31/CA3B63A3 @3/1B7=<A/@3@3>=@B32D=:C<B/@7:G4@=;/>=>C:/B7=< =4C<13@B/7<A7H37B7A<=B/:E/GA>=AA70:3B=@3:7/0:G 3AB7;/B3B637@4@3?C3<1G=@3AB/0:7A6/1/CA/: @3:/B7=<A67>B=2@C53F>=AC@3 )3@G@/@31/A3A   =46G>3@A3<A7B7D7BG@3/1B7=<A /<27<831B7=<A7B3@3/1B7=<A0C@<7<57<2C@/B7=< 27A1=;4=@B/<2>/7<E3@3@3>=@B324@=;>=AB;/@93B7<5 3F>3@73<13=4"+  ;57<B63>@3D3<B7=<=4 163;=B63@/>G7<2C132</CA3//<2D=;7B7<5 DRUG INTERACTIONS #/:=<=A3B@=<7A3:7;7</B324@=;B630=2GB6@=C560=B6 @3</:3F1@3B7=</<2;3B/0=:71>/B6E/GAE7B6B63:/BB3@ ;327/B32D7/;C:B7>:3,#3<HG;3AC@B63@7<D7B@= ABC273A7<271/B32B6/B>/:=<=A3B@=<7A<=B/<7<6707B=@ =4,#  ,# ,# ,# ,#  ,#  /<2,#  ,#  E/A<=B 7<D3AB75/B32<=@2=3A7B7<2C13B63/1B7D7BG=4,#   ,# =@,#  '63@34=@3B63>=B3<B7/:4=@ 1:7<71/::GA75<7I1/<B2@C57<B3@/1B7=<AE7B6 >/:=<=A3B@=</>>3/@AB=03:=E =/2;7<7AB@/B7=<=4  ;5)>/:=<=A3B@=</<2 ;5)23F/;3B6/A=<37<63/:B6GAC0831BA@3D3/:32 <=>6/@;/1=97<3B712@C57<B3@/1B7=<A03BE33< >/:=<=A3B@=</<223F/;3B6/A=<3 </<7<B3@/1B7=<ABC2G7<63/:B6GAC0831BAE63@3 >/:=<=A3B@=<  ;5)0=:CAE/A/2;7<7AB3@32=<2/G  /<2=@/:/>@3>7B/<B4=@ 2/GA ;5 ;5 ;5 B63>6/@;/1=97<3B71A=4>/:=<=A3B@=<E3@3<=B A75<7I1/<B:G/:B3@32(<=16/<53;/F 7<1@3/A3 ABC2G7<63/:B6GD=:C<B33@A7<D=:D7<5A7<5:32=A3 )>/:=<=A3B@=< ;5/<2AB3/2GAB/B3=@/: ;3B=1:=>@/;723 ;54=C@B7;3A2/7:G23;=<AB@/B32 <=A75<7I1/<B>6/@;/1=97<3B717<B3@/1B7=< <1=<B@=::321:7<71/:B@7/:A"+7<831B7=<6/A033< A/43:G/2;7<7AB3@32E7B61=@B71=AB3@=72A/</:53A71A /<B73;3B71A/<B7</CA3/<BA/<B7A>/A;=271A/<2 /<B716=:7<3@571/53<BA #/:=<=A3B@=<272<=B7<6707BB63/<B7BC;=@/1B7D7BG=4 B63ID3163;=B63@/>3CB71/53<BAB3AB3217A>:/B7< 1G1:=>6=A>6/;7231GB/@/07<32=F=@C0717</<2 ;7B=;G17<7<;C@7<3BC;=@;=23:A USE IN SPECIFIC POPULATIONS Pregnancy '3@/B=53<714431BA/B35=@G '3@/B=:=5GABC273A6/D3033<>3@4=@;327<@/BA/B =@/:2=A3AC>B= ;5952/G  B7;3AB63 @31=;;3<2326C;/<7<B@/D3<=CA2=A30/A32=<0=2G AC@4/13/@3//<2@/007BA/B=@/:2=A3AC>B= ;5 952/G B7;3AB63@31=;;3<2326C;/< 7<B@/D3<=CA2=A30/A32=<0=2GAC@4/13/@3//<2 6/D3@3D3/:32<=3D723<13=47;>/7@3243@B7:7BG=@6/@; B=B6343BCA2C3B=>/:=<=A3B@=<'63@3/@36=E3D3@ <=/23?C/B3/<2E3::1=<B@=::32ABC273A7<>@35</<B E=;3<31/CA3/<7;/:@3>@=2C1B7=<ABC273A/@3<=B /:E/GA>@3271B7D3=46C;/<@3A>=<A3>/:=<=A3B@=< A6=C:203CA322C@7<5>@35</<1G=<:G741:3/@:G<33232 Labor and Delivery #/:=<=A3B@=<6/A<=B033</2;7<7AB3@32B=>/B73<BA C<23@5=7<5:/0=@/<223:7D3@GA=7BA34431BA=<B63 ;=B63@=@167:2/@3C<9<=E< Nursing Mothers B7A<=B9<=E<E63B63@>/:=<=A3B@=<7A3F1@3B327< 6C;/<;7:931/CA3;/<G2@C5A/@33F1@3B327<6C;/< ;7:9/<2031/CA3=4B63>=B3<B7/:4=@A3@7=CA/2D3@A3 @3/1B7=<A7<<C@A7<57<4/<BA/<2B63>=B3<B7/:4=@ BC;=@753<717BGA6=E<4=@>/:=<=A3B@=<7<B63@/B 1/@17<=53<717BGABC2G/2317A7=<A6=C:203;/23 E63B63@B=27A1=<B7<C3<C@A7<5=@B=27A1=<B7<C3B63 2@C5B/97<57<B=/11=C<BB637;>=@B/<13=4B632@C5B= B63;=B63@

sulting the ethics committee about any decisions to prioritize or place limits on medications in short supply. Several online resources are available to identify ongoing and potential shortages and ways to manage a drug shortage. Fox recommended visiting www.ashp.org/shortage, which

Pediatric Use &/43BG/<234431B7D3<3AA7<>/B73<BA03:=EB63/53=4

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ALOXIÂŽ7A/@357AB3@32B@/23;/@9=43:A7<<3/:B61/@3 &&E7BH3@:/<2CA32C<23@:713<A3 7AB@70CB32/<2;/@93B320G7A/7<1*==21:744/93 !  O 7A/7<1 ::@756BA@3A3@D32#@7<B327<(&   

maintains a list of current shortages, resolved shortages, and drugs no longer available. The site also contains several resources on managing drug shortages and encourages clinicians to report possible shortages to ASHP. Because the vast majority of drugs in short supply or no longer available are injectables, nurses often have the final opportunity to ensure that the substitute drug provided is being used at the correct dose. The ASHP Website offers help with this, by highlighting the possibility of confusion or dosing errors with some substitute medications. For example, ASHP warns providers of the â&#x20AC;&#x153;potential for dosing errors when interchanging leucovorin and levoleucovorin (Fusilev),â&#x20AC;? noting that the levoleucovorin dose should be one-half the racemic leucovorin injection dose.

The pharmacy staff should also communicate with the nursing staff about alternative therapies and any special considerations. Etoposide for injection is another drug in short supply, and many hospitals are substituting oral etoposide. The oral version has only half the bioavailability of the injectable. This means that the oral dose needs to be double that of the intravenous dose. As the ISMP study indicates, problems have also occurred with epinephrine dosing. Miscalculations have been made when switching between the 1-mg/mL strength of epinephrine and the 0.1-mg/mL dose. In addition, some hospitals are using the 1-mg/mL syringe that has an intracardiac needle permanently affixed. The ISMP warns providers not to attempt to remove this needle. To prevent errors due to confusion about differences in dosing, activity, adverse effects, etc, between the intended drug and its substitution, ASHP recommends updating automated systems and order-entry systems. Pharmacy staff should also communicate with nursing staff about alternative therapies and any special considerations. Talking to patients or caregivers about why you have to delay their surgery, interrupt their treatment, or cannot give them the most effective drug for their disease is probably one of the greatest difficulties providers face in dealing with the shortages. It is also one problem for which the organizations advising hospitals on how to manage drug shortages have few suggestions. â&#x2014;?

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Cancer Center Profile St. Joseph Mercy Cancer Care Center... Continued from cover “They can come in the morning and see everybody and come out with a plan,” explained Philip J. Stella, MD, the clinic’s medical director and medical oncologist. The multidisciplinary approach seems to be working. Not only has the program shaved more than two-thirds off the time between when lung cancer is suspected to initiation of a treatment plan, “We have very high rates of satisfaction from the patients and their families,” said Stella. Patients are not the only ones who appreciate St. Joseph Mercy’s efforts. Primary care physicians in the region have shown their satisfaction with the program by referring more patients to the lung cancer clinic. “We try to make it easy for them, so [that] when they have a patient with lung cancer, they don’t have to call 3 different offices. … Just 1 call will get the patient seen in a timely fashion,” said Stella. The lung cancer clinic’s reputation continues to spread. Stella said the positive reception for the multidisciplinary approach has led to patient referrals from physicians outside the St. Joseph Mercy system and the need to expand. A Model in the Making Like other multidisciplinary clinics at St. Joseph Mercy, the lung cancer clinic is spearheaded by an advisory committee, which consists of physicians and other providers who tend to patients at the clinic and participate in tumor boards. Vita McCabe, MD, a cardiothoracic surgeon, chairs the committee and helps steer the program. McCabe described her philosophy of care: “When you are a cancer patient, you need to feel that you are in a highend department store, that you are completely cared for from every direction— [that] this is not a discount-shopping situation.” Department stores claim to operate according to the principle that the “customer is always right.” Although the patient might not always be right at St. Joseph Mercy, the lung cancer clinic’s multidisciplinary team factors the patient’s perspective into each decision. In developing the program from the perspective of the patient, it became clear that it would be important to assign each patient to a nurse navigator. The navigator serves as the point person for arranging visits and facilitating communication between the patient or the patient’s caregivers and the individuals on his or her care team. This is useful for coordinating not only anticancer treatment, but also support services. Along with medical oncologists, surgeons, and radiologists, many patients meet with researchers, social workers, and nutritionists at the clinic.

www.TheOncologyNurse.com

“They can come in the morning and see everybody and come out with a plan.” —Philip J. Stella, MD

Lara Blair, RN, is one of the program’s nurse navigators. “Even if someone just has a small question, when you have a team of 3 or 4 different doctors and other specialists, that can mean 20 phone calls,” said Blair. “One of my biggest jobs is cutting that process down and streamlining it for [the patients].” Benefits of this system are that “patients don’t have to wait for care, nor are they confused,” said McCabe. The clinic strives to stay at the forefront of lung cancer care, offering an array of advanced surgical and radiotherapy techniques. To handle growing demand, a second surgeon was recently added to the staff. With 2 surgeons onboard, the clinic has been able to expand the number of minimally invasive approaches available, to include video-assisted and robotic surgery and thoracoscopic procedures. St. Joseph Mercy became the first hospital in Michigan to offer the CyberKnife system for stereotactic body radiation therapy. As a result, “Medically inoperable patients are being treated for their lung cancers with a high degree of success and with minimal complications and side effects,” said Walter M. Sahijdak, MD, a radiation oncologist at the clinic. As a member of the Community Clinical Oncology Program (CCOP) network for the past 20 years, St. Joseph Mercy has actively recruited patients with cancer for a number of clinical trials. The CCOP affiliation allows patients treated at St. Joseph Mercy, including those seen in the lung cancer clinic, to enroll in trials conducted by major national research groups, such as the Mayo Clinic and the M. D. Anderson Cancer Center. The lung program currently has patients enrolled in several innovative studies its researchers are conducting, including trials comparing outcomes with CyberKnife versus standard resection in patients with solitary lung nodules. The lung cancer clinic recently moved into new space, which houses a nurse navigation office and the advisory committees for each of St. Joseph Mercy’s multidisciplinary clinics. Stella said the lung cancer program has been so successful he expects it to serve as a model for future multidisciplinary clinics focused on other tumor types.

Success Paves the Way The success of the lung cancer program no doubt factored into last year’s decision by the National Cancer Institute’s Community Cancer Centers Program (NCCCP) to designate St. Joseph Mercy as one of only 30 NCCCP sites in the nation. The NCCCP initiative seeks to develop a network of community hospitals tasked with researching ways to improve the quality of cancer care and prevention, as well as to reduce disparities in access to care and outcomes.

“Medically inoperable patients are being treated for their lung cancers with a high degree of success and with minimal complications and side effects.” —Walter M. Sahijdak, MD

An accompanying $2.5-million grant will allow St. Joseph Mercy to add several cancer specialists to its staff and develop new programs. In a press release announcing the designation, Stella, the

grant’s principal investigator, said, “This program allows St. Joseph Mercy Ann Arbor to accelerate the tempo of scientific research and advancement of cancer care. … St. Joe’s is already recognized for our cancer research; this contract allows us to take our program to the next level and expand other areas of research and care. It underscores our dedication to providing our patients with the latest and most state-of-the-art care.” The NCCCP contract calls for St. Joseph Mercy to develop a tissue bank. Stella said while St. Joseph Mercy typically submits tissue from patients in its clinical trials for translational research, the center will now be preserving tumor tissue samples for all their patients with cancer. “We are going to…be able to provide that to investigators at academic centers around the country that want access to fresh tissue or paraffin-embedded tissue to do their translational work,” said Stella. “This is a very important part of this grant and the network as a whole,” he explained. “So much of what we are going to be learning about cancer is going to be through translational research. Other plans include hiring a geneticist to counsel patients and evaluate those considered high risk and expanding outreach efforts to underserved communities. This will require hiring a minority coordinator to reach out to ethnic minority populations and adding a financial counselor to the staff to help low-income and indigent patients with obtaining oncologic care. “There is no way in this economic environment that the hospital would ever be able to provide these positions,” Stella said. “If it had not been for this grant, we absolutely would not be able to provide many of the services that I think we should be doing as a cancer program.” And had it not been for the stellar multidisciplinary lung cancer clinic at St. Joseph Mercy, it might have taken the NCCCP longer to recognize just how determined the center is to ensure that people with cancer have the best care possible. ●

Oncology News

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Conference News The following articles are based on presentations at the 2011 Gastrointestinal Cancers Symposium held January 20-22, 2011, in San Francisco, California.

Lanreotide Reduces Vomiting in Patients with Malignant Bowel Obstruction ©ASCO/Todd Buchanan 2011.

T

he somatostatin analog lanreotide (Somatuline) reduced the frequency of vomiting for patients with inoperable malignant bowel obstruction (MBO) in what presenter Pascale Mariani, MD, at the Institut Curie in Paris, France, called the first randomized, doubleblind, placebo-controlled study on palliative care in this patient population. “We showed that lanreotide may reduce the frequency of vomiting and allow for nasogastric tube [NGT] removal, which makes hospital discharge possible,” said Mariani, who presented the findings. Investigators at 22 European centers enrolled symptomatic patients with inoperable MBO who were experiencing ≥2 vomiting episodes per day or had an NGT. Most patients were severely impaired; 63.8% had an ECOG performance status of 3 or 4, and 80% were fed by central parenteral route. Patients were randomly assigned to receive 1 injection with 30 mg of lanreotide microparticles (n = 43) or placebo (n = 37). The trial’s primary end point was response rate (RR), defined as the proportion of patients at 7 days who, for 3 consecutive days, recorded ≤1 episode of vomiting or no vomiting after NGT removal.

By Caroline Helwick

In the intent-to-treat (ITT) population, RR was 41.9% for patients injected with lanreotide compared with 29.7% for those given placebo, a difference that was not significant (odds ratio [OR], 1.75; 95% confidence interval [CI], 0.684.49; P = .24). A per protocol analysis found a statistically significant benefit associated with lanreotide use, with an

On most secondary end points, no significant differences were observed between the groups. The mean number of days without vomiting and the mean change in episodes of nausea from baseline to day 7 were similar, as was the decline in the abdominal pain score. Well-being, which investigators assessed on day 7 using a visual analog scale,

“We showed that lanreotide may reduce the frequency of vomiting and allow for nasogastric tube removal, which makes hospital discharge possible.” —Pascale Mariani, MD

RR of 57.7% in the treatment arm versus 30.4% in the control group (OR, 3.60; 95% CI, 1.03-12.62; P = .045). Mariani said investigator assessment of data for the ITT population also found a significant difference in RR between the groups, favoring lanreotide over pla cebo (50.0% vs 28.6%, respectively; P = .0481). By day 7, the frequency of vomiting had declined by a median of 2.3 episodes for patients in the lanreotide group and 1.3 episodes for patients in the placebo arm (P = .4510).

was the only secondary end point that significantly favored lanreotide. Patients treated with lanreotide experienced significant improvement in well-being, which declined for patients given placebo. Mariani said treatment-emergent adverse events were similar in both groups and as expected for patients with inoperable MBO. None of the serious adverse events appeared to be treatment-related. Robert S. Krouse, MD, a surgery

professor at the University of Arizona and staff general and oncologic surgeon at Southern Arizona VA Health Care System in Tuscon, discussed the findings at the session. He observed how challenging it is to treat MBO, which occurs in approximately onequarter of patients with colorectal cancer and half of patients with ovarian cancer. “There is no defined algorithm for the management of these patients,” said Krouse, but he noted that somatostatin analogs are the standard of care, with multiple studies showing some benefit with octreotide (Sandostatin LAR) use. “This study suggests that lanreotide may also have a role in the treatment algorithm for MBO.” Krouse said medical treatment is often preferred to surgery even for patients with operable MBO because nearly 20% “just get postoperative pain without benefit.” The patients who undergo surgery have higher risks of morbidity and mortality and worse quality of life and up to 50% experience recurrence. Krouse said nearly one-third of patients with MBO benefit from nonsurgical interventions such as nasogastric compression and symptom management. ●

New Radiotherapy Technique Less Toxic for Patients with Anal Cancer

U

sing dose-painted intensitymodulated radiation therapy (DP-IMRT) to treat cancer in the anal canal reduces the risk of serious adverse events associated with standard radiation therapy without compromising survival according to data presented by Lisa Kachnic, MD, chief of radiation oncology at Boston Medical Center and an associate professor with Boston University School of Medicine, Massachusetts. She reported results from the phase 2 Radiation Therapy Oncology Group (RTOG)-0529 trial at a press briefing. Kachnic said although the study did not achieve its goal of a 15% reduction in the rate of gastrointestinal (GI) and genitourinary toxicities ≥grade 2 observed in RTOG-9811, which used standard external beam

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March/april 2011 I VOl 4, NO 2

radiation, DP-IMRT demonstrated enough benefit to become the “standard radiation technique in future RTOG anal cancer trials assessing novel agents in combination with radiation.” With DP-IMRT, the radiation dose is “painted” to conform to the shape of the targeted tissue and spares nearby healthy tissue. Investigators analyzed data for 52 patients with stage II and stage III anal cancer enrolled in RTOG-0529 who received standard 5-fluorouracil/mitomycin-C chemotherapy plus DPIMRT. Patients with T2 disease received a total radiation dose of 50.4 Gy targeted to the tumor and 42 Gy delivered to elective lymph nodes in 28 fractions over 5.5 weeks. Patients with T3 to T4 disease received 54 Gy to the tumor and 45 Gy to the nodes,

delivered in 30 fractions over 6 weeks. Findings were compared with results for the patients in RTOG-9811 who had received the same chemotherapy regimen plus conventional radiotherapy (n = 325). The RTOG-0529 patients had significantly lower rates of acute GI and dermatologic toxicities. Nearly 20% of patients given DP-IMRT developed GI toxicities ≥grade 3 versus 35% of the selected RTOG-9811 patients (P = .0082). Whereas skin toxicities ≥grade 3 were observed in ~50% of the RTOG-9811 patients, the rate dropped to ~20% for patients in the DP-IMRT group (P <.0001). Kachnic said investigators were surprised by the significant 10% reduction in hematologic toxicities ≥grade 2 seen with DP-IMRT (P = .032).

At median follow-up of 27 months, the trials demonstrated similar 2-year rates of locoregional and distant failure and survival outcomes, even though RTOG-0529 had a higher proportion of node-positive patients. The median duration of DP-IMRT was 43 days versus 49 days for the conventional arm, and patients in RTOG-0529 experienced fewer treatment breaks, which Kachnic said was an important benefit. Kachnic acknowledged DP-IMRT involved a learning curve and that “real-time quality assurance” is essential for safety and efficacy. She said the RTOG-0529 researchers concluded that “DP-IMRT is feasible with rigorous quality assurance and continued education...and may allow for further radiation dose escalation in advancedstage disease.” —CH ●

www.TheOncologyNurse.com


TON_April2011_v7_TON 4/7/11 10:48 AM Page 19

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE THE 5 - Y EAR SURV IVAL RATE IS 17 % F OR PATIENTS WITH METASTATIC SO F T TISSU E SA RC OMA , Y ET SIG NIF ICAN T THE RA PEU TIC ADVANCEM ENTS ARE L A GGIN G. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 21003100(5)-ARI


TON_April2011_v7_TON 4/7/11 10:49 AM Page 20

Conference News 2011 GASTROINTESTINAL CANCERS SYMPOSIUM

A Wealth of Targets Identified in Colorectal Cancer By Caroline Helwick

F

or patients with colorectal cancer (CRC), advances in molecular profiling have led to an explosion in novel agents specific for targets above and beyond the epidermal growth factor receptor (EGFR). Joseph Tabernero, MD, director of clinical research at Vall d’Hebron Institute of Oncology in Barcelona, Spain, previewed the future of treatment for CRC. “The good news is there are lots of new compounds. The challenge will be to profile patients accurately and to identify the gene signatures of those who will benefit from the individual drugs and combinations of agents,” said Tabernero.

EGFR Remains a Target Many patients with CRC are resistant to the currently approved EGFR inhibitors cetuximab (Erbitux) and panitumumab (Vectibix). The KRAS gene has already been identified as playing an important role in CRC, with constitutive mutations of KRAS serving as predictors of resistance to anti-EGFR monoclonal antibodies.

Novel Strategies for Treating CRC • More efficient anti-EGFR monoclonal antibodies • Monoclonal antibodies directed to other members of the EGFR/HER family • Monoclonal antibodies directed to other receptors (c-MET, IGF-1R) • Inhibitors of downstream effectors (MAPK/ERK) • Rationally based combinations • Identification of populations likely to benefit from specific therapies

Researchers are examining the role of genetic mutations associated with other signal transducer proteins, including mutations in BRAF, NRAS, PIK3CA, AKT, PTEN, and TP53. Tabernero said any of these might prove to be a useful “on/off” biomarker for EGFR expression in metastatic CRC. “More effective monoclonal antibodies are coming,” Tabernero promised. Encouraging results have been observed with the investigational compounds GA201 and SYM004, including seemingly durable responses. “Objective response rates have been achieved in very refractory patients,” he noted. HER3 is a new target in CRC. It has been implicated as a potential mechanism of resistance to EGFR inhibitors. A handful of anti-HER3 compounds are in development, including the monoclonal antibody MEHD7945A (a dual antiEGFR and HER3 inhibitor), MM121, and U3-1287-AMG888. Other Targets Under Study Researchers are developing monoclonal antibodies specific for receptors other than EGFR. One target is insulin-like growth factor-1 receptor (IGF-1R) protein, which is expressed in 90% of colon cancers but not found at all in normal mucosa. Expression levels correspond with proliferation and tumor stage. Overexpression of IGF-1R, observed in ~50% of patients, is an independent prognostic factor for worse survival. Research into therapeutics for this novel target took a step back when a randomized phase 2 clinical trial of IMCA12, an investigative inhibitor of IGF1R, failed to improve outcomes in patients with CRC refractory to EGFR inhibitors. Ongoing studies are attempting to refine the gene signature and develop effective agents.

Two possible new targets are the ligand of the c-Met receptor and hepatocyte growth factor (HGF) receptor. Both have been implicated in tumor invasiveness, metastasis, and proliferation; angiogenesis; and resistance to treatment. The HGF inhibitor rilotumumab (AMG102) showed promising efficacy in metastatic CRC when combined with panitumumab. Eric Van Cutsem, MD, University of Leuven, Belgium, presented data from an international, randomized, phase 1/2 trial involving 142 patients that compared panitumumab alone; rilotumumab plus panitumumab; and ganitumumab (AMG479), a novel IGF-IR inhibitor, plus panitumumab. Van Cutsem said the doublet of rilotumumab and panitumumab was promising, producing an overall response rate (ORR) of 31% compared with an ORR of 22% in the ganitumumab arm and 21% in the panitumumab monotherapy group. Median progression-free survival was 5.2 months with rilotumumab plus panitumumab, 5.3 months with the ganitumumab combination, and 3.7 months with panitumumab alone. Another avenue being pursued involves the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors. TRAIL inhibits the growth of colon cancer cells, and TRAIL-R1 expression correlates with improved disease-free survival. Conatumumab (AMG655) is a monoclonal antibody that binds to TRAIL-R2 and has produced partial responses in early trials. It is also being studied in combination with standard chemotherapy regimens. Looking at Downstream Pathways Some researchers are looking into inhibiting critical downstream pathways, such as the mitogen-activated protein kinase (MAPK)/extracellular

signal-regulated kinase (ERK) pathway. Protein kinases along this pathway regulate cell proliferation, differentiation, and survival and respond to external stimuli. Tabernero said investigators have identified at least 2 therapeutic targets in the MAPK/ERK pathway, namely RAF and MEK. Already more than a dozen inhibitors are in development. In 50% of patients with advanced disease, PIK3CA is dysregulated. PIK3CA activation triggers a signal transduction cascade that promotes cell growth and survival. Druggable targets in this pathway include PIK3CA, AKT, mTOR, TORC 1/2, and pS6K. Nearly 20 relevant compounds are being investigated, including some multikinase inhibitors. It is thought that many novel agents might be most effective when combined. Promising marriages are between 2 ERK pathway inhibitors (ie, a RAF inhibitor and a MEK inhibitor); 2 PIK3CA pathway inhibitors (ie, a dual PIK3CA inhibitor and a TORC 1/2 inhibitor); 1 ERK pathway inhibitor and 1 PI3K pathway inhibitor (ie, a MEK inhibitor with either an AKT, TORC 1/2, or PIK3CA inhibitor). Any of these agents could potentially be combined with a cytotoxic agent, as well. Despite an apparent plethora of opportunities for arresting proliferation of CRC cells, Tabernero cautioned that huge challenges lie ahead. The molecular profile of a specific cancer cell influences its behavior, and cancer cells operate under “plastic and evolutive phenomena” that extend to the gene level (expression, mutation, amplification/deletion, etc) and the proteomic level (activation, phosphorylation). “Cells change under the pressure of stress,” he said, noting that treatment induces stress. ●

Tissue of Origin Test Leads to Changes in Treatment By Christin Melton

I

n a study funded by Pathwork Diagnostics, Inc., researchers found that using the company’s tissue of origin test for patients with hard-toidentify primary cancers enabled accurate diagnosis of the tumor in several cases and led to changes in treatment. Patients whose diagnosis was confirmed appeared less anxious. Data were collected for 59 patients whose physician used the test to

20

March/april 2011 I VOl 4, NO 2

identify their primary cancers. The physicians (n = 48) completed an online survey about the patient’s diagnosis, diagnostic procedures used, and recommended treatments before and after tissue of origin testing. Responses were confirmed by telephone. The physicians indicated that prior to performing the test, patients underwent a median of 6 imaging

tests and 10 immunohistochemistry tests. In 54% of patients, the tissue of origin test results led to changes in diagnosis. Treatment changed for 68% of patients. Nearly two-thirds of physicians said the test was “clinically useful” in informing disease management. In addition, 62% patients were observed to have less anxiety after receiving results. The authors wrote, “In patients

with difficult-to-diagnose primary cancers, extensive baseline diagnostics is not uncommon and less than half of the patients have an established working diagnosis.” The test, which compares >2000 genes in the patient’s tumor against a control set of gene expression patterns from 15 tumor types, received clearance in 2010 from the US Food and Drug Administration. ●

www.TheOncologyNurse.com


TON_April2011_v7_TON 4/7/11 1:59 PM Page 21

ALIGN Pharmaceuticals Providing Supportive Care Solutions for Your Patients Xclair ® Cream, the preferred treatment option for radiation dermatitis by both physicians and patients.1 Numoisyn® Liquid and Numoisyn® Lozenges, for dry mouth relief with less side effects.

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www.alignpharma.com Customer Service: 908-834-0960 All three ALIGN Pharmaceuticals products are FDA approved prescription products and are available at your major wholesalers. For Direct Purchases, please call 866-231-5020. Xclair Cream

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Prescribing Information

Prescribing Information

Ingredients: Water, isohexadecane, butyrospermum parkii, pentylene glycol, ethylhexyl palmitate, glycyrrhetinic acid, cera alba, peg-30 dipolyhydroxystearate, bisabolol, polyglyceryl-6 polyricinoleate, tocopheryl acetate (antioxidant), hydrogenated castor oil, sodium hyaluronate nylon 12, butylene glycol, magnesium sulfate, piroctone olamine, allantoin, magnesium stearate, disodium EDTA, vitis vinifera, ascorbyl tetraisopalmitate, propyl gallate, and telmesteine.

Ingredients: Sorbitol (0.3 g per lozenge), polyethylene glycol, malic acid, sodium citrate, calcium phosphate dibasic, hydrogenated cottonseed oil, citric acid, magnesium stearate, and silicon dioxide.

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Contents: 75 mL per tube Therapeutic Group: Xclair Cream is formulated for symptom relief in radiation dermatitis. Indications: Xclair Cream is indicated to manage and relieve the burning, itching, and pain experienced with radiation dermatitis. Xclair Cream may be used to relieve the pain of firstand second-degree burns.

Contents: 100 lozenges per bottle. Net weight of 40 g (0.4 g per lozenge). Therapeutic Group: Numoisyn Lozenges are oral lozenges formulated to promote lubrication of oral mucosa that may be dry due to a variety of circumstances, including medication, chemotherapy or radiotherapy, Sj˙˙ogren’s syndrome, or oral inflammation.

How Supplied: 30 mL per bottle or 300 mL per bottle.

Indications: Numoisyn Liquid is indicated for the treatment of symptoms of dry mouth. Numoisyn Liquid relieves the symptoms of dry mouth by enhancing swallowing, improving speech mechanics, and lubricating the oral cavity like natural saliva. Numoisyn Liquid may be used to replace natural saliva when salivary glands are damaged or not functioning. The viscosity is similar to that of natural saliva.

Contraindications: Xclair Cream is contraindicated in patients with a known history of hypersensitivity to any of the ingredients.

Indications: Numoisyn Lozenges are indicated for the treatment of xerostomia (dry mouth). Numoisyn Lozenges provide temporary relief of dry mouth due to damaged salivary function. Numoisyn Lozenges are formulated to support the natural protection of teeth provided by saliva so that no damage occurs to teeth with repeated use of the lozenges.

Special Precautions for Use: Xclair Cream contains a nut oil, and patients with a known allergy to nuts or nut oils should consult their physician before using this topical preparation.

Contraindications: Numoisyn Lozenges are contraindicated in patients with fructose intolerance or a known history of hypersensitivity to any of the ingredients.

Special Precautions for Use: As Numoisyn Liquid contains linseed (flaxseed) extract, patients with irritable bowel syndrome or diverticular disease or those on a high linseed diet may experience abdominal discomfort.

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Warning: Federal law restricts Numoisyn Lozenges to sale by, or on the order of, a physician or properly licensed practitioner.

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Interactions: There are no known interactions between Xclair Cream and any medicinal or other products.

Interactions: There are no known interactions between Numoisyn Lozenges and any medicinal or other products.

Interactions: There are no known interactions between Numoisyn Liquid and any medicinal or other products.

Directions for Use: Apply Xclair Cream to the affected skin area 3 times per day (or as needed), and massage gently into the skin. If the skin is broken, cover the affected area with a sterile dressing after application of Xclair Cream.

Directions for Use: Let one Numoisyn Lozenge dissolve slowly in the mouth when needed. To obtain optimal effect, move the lozenge around in the mouth. Repeat as necessary. Do not exceed 16 lozenges in 24 hours.

Directions for Use: Shake bottle well. Take 2 mL (about 1/2 teaspoon) of Numoisyn Liquid and rinse around in the mouth before swallowing. Use as needed.

Storage: Store at room temperature. KEEP OUT OF REACH OF CHILDREN.

Side Effects: Excessive consumption can cause minor digestive problems. Storage: Store at room temperature. KEEP OUT OF REACH OF CHILDREN. Overdose: No overdoses have been reported to date.

Contraindications: Numoisyn Liquid are contraindicated in patients with a known history of hypersensitivity to any of the ingredients.

Side Effects: Patients may experience difficulty in swallowing, altered speech, and changes in taste. If side effects persist or become severe, patients should contact a physician. Storage: Store at room temperature. Do not refrigerate. Use within 3 months of first opening. KEEP OUT OF REACH OF CHILDREN. Please Note: Numoisyn Liquid is translucent and may contain some natural particles that do not affect the quality of the product.

Manufactured in Italy under license from Sinclair Pharmaceuticals Ltd., Godalming, Surrey GU7 1XW UK. Distributed by ALIGN Pharmaceuticals, LLC, Berkeley Heights, NJ 07922 USA www.alignpharma.com 1. Primavera G., et al. A double-blind, vehicle-controlled clinical study to evaluate the efficacy of MAS065D (Xclair), a hyaluronic acid-based formulation, in the management of radiation-induced dermatitis. Cutaneous and Ocular Toxicology, 25: 1–7, 2006. ©2011 ALIGN Pharmaceuticals, LLC All rights reserved.


TON_April2011_v7_TON 4/7/11 10:49 AM Page 22

Conference News The following articles are based on presentations at the 2011 Genitourinary Cancers Symposium held February 17-19, 2011, in Orlando, Florida.

Approved Sunitinib Dosing Schedule Recommended for Patients with Metastatic Renal Cell Carcinoma ©ASCO/Todd Buchanan 2011.

By John Schieszer

I

nvestigators of a phase 2 study comparing 2 dosing schedules of sunitinib (Sutent) as first-line therapy for patients with advanced renal cell carcinoma (RCC) concluded that clinicians should stay with the currently approved dosing regimen of 50 mg daily for 4 weeks followed by a 2-week break. Robert Motzer, MD, attending physician, Memorial Sloan-Kettering Cancer Center, New York, who presented the

findings, said the data add to a growing body of evidence favoring the dosing regimen that the US Food and Drug Administration approved for sunitinib. From January 2007 to June 2008, Motzer and colleagues recruited 292 patients (median age, 62 years) with locally recurrent or metastatic RCC of clear cell histology to participate in the phase 2 Renal EFFECT trial. Patients were assigned randomly to receive the

70 62

62

60

4/2 56

56

CDD

49

Patients, %

50 40

38 34

34

34

30 20 10 0 Fatigue

Nausea

Diarrhea

Dysgeusia

Vomiting

Adverse Event 4/2 indicates 50 mg daily for 4 weeks followed by a 2-week break; CDD, 37.5-mg continuous daily dosing.

Figure. Rate of Adverse Events

Novel Drugs in Prostate Cancer By Alice Goodman

I

nterim results of a randomized, controlled, phase 3 trial showed that abiraterone acetate significantly prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) who progressed after docetaxel-based chemotherapy. The survival benefit was consistent across all prespecified subgroups. Lead author Howard Scher, MD, Memorial Sloan-Kettering Cancer Center, New York, said abiraterone is poised to become a new standard of care. The study enrolled 1200 patients with metastatic CRPC who failed on

22

March/april 2011 I VOl 4, NO 2

docetaxel and ≤1 additional chemotherapy regimen. Patients were randomized to abiraterone and prednisone or prednisone and placebo. Groups were well balanced for demographic and disease characteristics. Patients on abiraterone achieved significantly superior median OS versus placebo (14.8 months vs 10.9 months; P <.001), representing a 35% reduction in the relative risk of mortality. Preplanned analyses found survival benefit consistent across all subgroups, regardless of prior chemotherapy lines, performance status, pain scores, and radiograph-

conventional 50-mg dose, 4 weeks on/ 2-weeks off (4/2) regimen of sunitinib or a 37.5-mg continuous daily dose (CDD). Treatment continued for up to 2 years, with patients who experienced disease progression or unacceptable toxicity discontinuing earlier. The study’s primary end point was time to tumor progression (TTP), with secondary end points of overall response rate (ORR), overall survival (OS), time to deterioration, and adverse events. Patients in the 4/2 group received a median of 5 months of treatment compared with 6 months in the CDD arm. On the primary end point of TTP, Motzer said, “There wasn’t a statistically significant difference between the 2 arms, but there was a strong trend favoring the 4/2 schedule over continuous dosing.” Median TTP was 9.9 months for patients treated with the 4/2 regimen compared with 7.1 months for those assigned to the CDD schedule (hazard ratio, 0.77; 95% confidence interval, 0.57-1.04; P = .090). ORR and OS were similar between the study arms. ORR in the 4/2 arm was 32.2% versus 28.1% in the CDD group (P = .044) and OS reached a median of 23.1 months in the 4/2 group compared with 23.5 months in the CDD arm. Time to deterioration and death were significantly improved with the 4/2 schedule versus the CDD regimen (4.0 months vs 2.9 months; P = .034).

No statistically significant difference was observed between the groups in the proportion of patients experiencing all-grade or grade 3/4 adverse events (P >.05). The most common drug-related adverse events overall were fatigue, nausea, diarrhea, dysgeusia, and vomiting (Figure). Hand-foot syndrome was the most frequent grade 3/4 adverse event, observed in 10% of patients in each arm. Motzer told The Oncology NurseAPN/PA that patient-reported outcomes suggested the regimens had an equal effect on quality of life and kidney cancer symptoms, but patients on the 4/2 schedule reported better quality of life during the 2 weeks off therapy. “I think this is important in counseling patients on the 4/2 schedule,” Motzer said. Although previous studies comparing these regimens have found them equally active, Motzer said those studies generally excluded patients with a poor performance score. This study allowed patients with a Karnofsky performance score as low as 70% and enrolled fewer patients (~80%) who had a nephrectomy. Based on these data, Motzer concluded, “The treatment goal, therefore, should be to adhere to the approved dose and schedule.” Motzer disclosed that funding for the study was provided by Pfizer and he has received compensation from Pfizer. ●

ic progression-free survival. The abiraterone group also had higher rates of total and confirmed responses according to prostate-specific antigen (PSA) testing. Rates of overall and serious adverse events were similar between both groups and considered manageable. Oliver Sartor, MD, Tulane University School of Medicine, New Orleans, Louisiana, moderated the prostate cancer session. “This is a game-changer. To me this will change practice,” he said. Positive 42-month data were also presented for MDV3100, a novel, tripleacting, oral androgen-receptor antagonist for CRPC. In a phase 1/2 study, MDV3100 demonstrated durable antitumor activity, based on median times to PSA and radiographic progression.

Higano and associates enrolled 140 men with progressive disease resistant to standard antiandrogen treatments, such as bicalutamide. As of the meeting, 18 men remained on active treatment. Median time to PSA progression was 316 days in the postchemotherapy group and not yet reached in the chemotherapynaïve cohort. Median time to radiographic progression was 392 days versus 175 days, respectively. Circulating tumor cell counts remained favorable for 91% of patients with favorable counts at baseline, and counts for 15 patients went from unfavorable to favorable. MDV3100 is currently being studied in the randomized phase 3 AFFIRM and PREVAIL trials. Both trials are actively recruiting patients. ●

www.TheOncologyNurse.com


TON_April2011_v7_TON 4/7/11 10:49 AM Page 23

Conference News

Prostate Cancer Therapies Cause Toxicities Up to 10 Years Later

S

ome men with prostate cancer who undergo external beam radiotherapy (EBRT), interstitial brachytherapy, or radical prostatectomy show evidence of toxicity for at least a decade after the procedure. Grant Hunter, MD, a third-year urology resident at the Cleveland Clinic in Ohio, led the retrospective study and presented findings at the meeting. He said all 3 modalities resulted in gastrointestinal (GI) and/or genitourinary (GU) toxicities up to 10 years later, with the most severe profiles observed in patients with diabetes mellitus (Table). “The findings from this study should be of special interest to oncology nurses,” said Hunter, who noted that many clinicians might not be aware of the potential for late-term effects related to these therapies. Hunter and colleagues reviewed records for 483 patients who received EBRT (36%), interstitial brachytherapy (24%), or radical prostatectomy (40%) for prostate cancer in 1999. They examined the incidences of late GI and GU treatment-related adverse effects during a mean follow-up of 8.6 years (range, 0.211.5 years) and graded their severity

Table Cumulative Rates of GI and GU Effects 5 and 10 Years After Therapy GI Toxicity ≥Grade 2, % Modality 5 Years 10 Years 7.8 7.8 EBRT 1.7 1.7 Brachytherapy

5 Years

10 Years

8.6 4.3

11.2 4.3

0

3.1

5.5

Prostatectomy

0

GU Toxicity ≥Grade 2, %

EBRT indicates external beam radiotherapy; GI, gastrointestinal; GU, genitourinary. Source: Hunter G, et al. J Clin Oncol. 2011;29(suppl 17):65.

according to the Radiation Therapy Oncology Group scoring criteria for acute and late effects. Other factors weighed in the analyses include patient’s age; body mass index; smoking history; and medical comorbidities, such as diabetes mellitus, peripheral vascular disease, and connective tissue disease. The rates of late GI and GU toxicities were low, which Hunter said was reassuring. A competing risk regression analysis found that patients who underwent EBRT were most likely to experience GU toxicities ≥grade 2 in 10 years of follow-up and patients who received brachytherapy were least likely (11.2% vs 4.3%, respectively). In the 10 years after radical prostatecto-

my, 5.5% of patients had GU toxicities ≥grade 2. The risk of GU toxicity ≥grade 2 was 2.35-fold greater for men with diabetes at treatment outset than men who did not have diabetes when beginning therapy (P = .043). Nobody in the radical prostatectomy group experienced late GI toxicity ≥grade 2, but the 10-year cumulative rate was 1.7 for patients in the brachytherapy arm and 7.8% for the EBRT group. According to Hunter, EBRT (P = .038) and diabetes (P = .008) were the only independent variables found to significantly increase patients’ risk of late GI toxicity of ≥grade 2. “This is the first study of this kind to look at all 3 treatment modalities

in patients treated for prostate cancer,” said Hunter in an interview with The Oncology Nurse-APN/PA. “We thought this was something to look at because patients treated for prostate cancer tend to live a very long time and so the potential toxicity profiles are relevant.” Hunter said it is important for oncology nursing professionals to be cognizant of the possibility for patients treated 7 or 8 years ago to experience late GI and GU toxicity. These patients have a “need for follow-up and need for care because of toxicity issues that are late, especially in patients who have diabetes when they undergo treatment,” he said.—JS ●

ADT for Intermediate-Risk Prostate Cancer Does Not Appear to Improve Overall Survival

A

dding androgen-deprivation therapy (ADT) to dose-escalated external beam radiotherapy (EBRT) for men with intermediate-risk prostate cancer improves biochemical failure-free survival but not overall survival (OS), according to a retrospective study. Researchers from Emory University School of Medicine and the Atlanta Veterans Administration in Georgia conducted the study. Although previous trials have found that combining ADT with EBRT improves biochemical failure-free survival and OS in men with high-risk prostate cancer, the dual therapy has never been thoroughly investigated in men with intermediaterisk disease. Using a database of 850 men treated at multiple institutions, investigators identified 251 with intermediate-risk prostate cancer, which they defined as stage ≥T2b disease or a prostate-specific antigen (PSA) level >10 ng/mL or a Gleason score (GS) of 7. Patients meeting any of the following criteria were excluded: stage ≥T3 disease, PSA level >20 ng/mL, GS ≥8, positive nodes, or distant metastases. All patients in the study had received EBRT to a dose ≥70 Gy but

www.TheOncologyNurse.com

none had undergone brachytherapy or prostatectomy; 87 were given ADT. Mean PSA score was higher for men in the ADT group than for those in the EBRT-only arm (12.0 ng/mL vs 8.9 ng/mL, respectively), and more men in the ADT group than the EBRT-only arm underwent pelvic radiography (49% vs 22%, respectively). The study arms were well balanced in terms of age, race, mean

compared with 76% of patients not given ADT (P = .028). Multivariate analyses found that ADT use and GS were the only significant independent predictors of biochemical failure-free survival and that PSA level and IMRT were the only significant independent predictors of OS. Adding ADT to EBRT did not increase the incidence or severity of gastrointestinal and genitourinary toxicities.

Edelman said the findings might reassure some men contemplating ADT, but they need to know about the significant side effects associated with the therapy before deciding on treatment.

EBRT dose, and the proportion of patients who had intensity-modulated radiation therapy (IMRT). Median follow-up was 47 months. The 5-year rate of biochemical failurefree survival was 80% for the ADT group compared with 76% for the EBRT-only group (P = .017). At 5 years, 84% of patients in the ADT group were alive

In an interview with The Oncology Nurse-APN/PA, lead investigator Scott Edelman, MD, assistant professor of radiation oncology at Emory University, said although the data support nurses counseling their patients with intermediate-risk prostate cancer that “if you take hormonal therapy [for 6 months], there is a really good chance

that 3 or 4 years down the road, your PSA will be under control,” it is premature to suggest adding ADT improves survival. Edelman said the findings might reassure some men contemplating it, but they need to know about the significant side effects associated with the therapy before deciding on treatment. “Hormonal therapy gives you hot flashes and breast tenderness. It may give you a little breast enlargement and may make you more emotional. It also may take away your sex drive in the short term and give you problems with erections, and increase your risk for osteoporosis and bone fractures,” he explained. Edelman said it comes down to what matters most to the patient. “If the patient is someone who wants a cure— based on his PSA level—and that is the most important thing for him, then he should go on hormonal therapy. However, if quality of life is the most important issue, then it would probably be best to tell them not to go on hormonal therapy.” A randomized trial is currently investigating combination therapy in men with intermediate-risk prostate cancer.—JS ●

March/april 2011 I VOl 4, NO 2

23


TON_April2011_v7_TON 4/7/11 10:49 AM Page 24

to drive outcomes in HER2+ adjuvant breast cancer

This is not an actual Herceptin patient.

Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer: As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel With docetaxel and carboplatin As a single agent following multi-modality anthracycline-based therapy *

High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages.


TON_April2011_v7_TON 4/7/11 10:49 AM Page 25

1 year of Herceptin plus standard adjuvant therapy significantly reduced the risk of disease recurrence1-4 Four pivotal trials involving more than 10,000 women demonstrated that 1 year of Herceptin therapy provided significant clinical benefit1-4 Clinical Benefit of 1 Year of Herceptin Study

Control Arm

Joint Analysis

AC´T

of NCCTG N9831 and NSABP B-31

Reduction in Relative Risk of Recurrence†

AC´TH

52%

(n=1872)

(n=1880) HR=0.48 (95% CI: 0.39-0.59), P≤0.0001

Observation only

HERA‡

Herceptin Arm

(n=1693)

Herceptin 1 year

46%

(n=1693) HR=0.54 (95% CI: 0.44-0.67), P≤0.0001

TCH

33%

(n=1075)

BCIRG 006

HR=0.67 (95% CI: 0.54-0.84), P=0.0006

AC´T (n=1073)

AC´TH

40%

(n=1074) HR=0.60 (95% CI: 0.48-0.76), P≤0.0001

AC=anthracycline (doxorubicin) plus cyclophosphamide. T=Taxotere® (docetaxel) (in BCIRG 006) or paclitaxel (in the Joint Analysis). C=carboplatin (in the TCH regimen). H=Herceptin. Taxotere is a registered trademark of sanofi-aventis U.S. LLC. † ‡

Recurrence was defined as any clinical or radiologic evidence of tumor recurrence. Patients were randomized upon completion of chemotherapy, surgery, and radiotherapy (if appropriate).

Boxed WARNINGS and Additional Important Safety Information 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 trial, one patient who developed CHF died of cardiomyopathy Evaluate cardiac function prior to and during treatment. For adjuvant therapy, also evaluate cardiac function after completion of Herceptin. 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 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 use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia References: 1. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684 and supplementary appendix. 2. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010. 3. Data on file. Genentech, Inc. 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.

©2010 Genentech USA, Inc.

So. San Francisco, CA

All rights reserved.

10606700

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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. b 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

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) Herceptin Single + Paclitaxel Herceptin ACb Agenta 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.


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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.

b

c

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

FC (N = 290) N (%)

All Grades

Grades 3/4

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)

_

15 (5)

_

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)

69 (23)

6 (2)

40 (14)

7 (2)

56 (19) 37 (13)

0 (0) 0 (0)

29 (10) 17 (6)

0 (0) 0 (0)

53 (18)

8 (3)

42 (15)

5 (2)

28 (10)

0 (0)

14 (5)

0 (0)

LVEF <50% and Absolute Decrease from Baseline LVEF *10% *16% <50% decrease decrease

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.

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

Studies 1 & 2b ACATH 22.8% (n=1606) (366)

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.

Absolute LVEF Decrease <20% and *10% *20%

18.3% (294)

11.7% (188)

33.4% (536)

9.2% (148)

ACAT (n=1488)

9.1% (136)

5.4% (81)

2.2% (33)

18.3% (272)

2.4% (36)

Study 3 Herceptin (n=1678)

8.6% (144)

7.0% (118)

3.8% (64)

22.4% (376)

3.5% (59)

Observation (n=1708)

2.7% (46)

2.0% (35)

1.2% (20)

11.9% (204)

1.2% (21)

Study 4c TCH (n=1056)

8.5% (90)

5.9% (62)

3.3% (35)

34.5% (364)

6.3% (67)

ACATH (n=1068)

17% (182)

13.3% (142)

9.8% (105)

44.3% (473)

13.2% (141)

ACAT (n=1050)

9.5% (100)

6.6% (69)

3.3% (35)

34% (357)

5.5% (58)

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.

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Guidelines for Managing Anthracycline Extravasation What Nurses Should Know By Marianne Bunce-Houston, RN, MS, AOCNS, CRNI Oncology Clinical Nurse Specialist, Contra Costa Regional Medical Center, Martinez, California

Marianne Bunce-Houston, RN, MS, AOCNS, CRNI

E

xtravasation is always a risk when administering medicines intravenously. This is when the infused drug infiltrates the tissue surrounding the injection site. The resulting injury can range from mild to lifethreatening, depending on whether the drug involved is classified as an irritant or a vesicant. The Infusion Nurses Society (INS) defines a vesicant as “an agent capable of causing injury when it escapes from the intended vascular pathway into the surrounding tissue.”1 Anthracyclines are vesicants commonly used to treat cancer. More than 500,000 doses of anthracyclines are administered intravenously in the United States each year,2 and an estimated 0.1% to 1.0% of doses involve extravasation.3 Although extravasa-

tion is rare, it is not always preventable. This is partly because many patients with cancer have thin, fragile, mobile veins, and multiple punctures are required to administer intravenous (IV) chemotherapy.4 The literature also documents unexpected extravasations via central venous catheters.5-8 Anthracycline extravasation re quires immediate attention to mitigate the risk of severe—even permanently disabling—tissue damage.9 The potential consequences underscore the need for nurses to know and adhere to national evidence-based practice guidelines for managing anthracycline extravasation. They should also use this knowledge to make the case to their employer for following best practices. How Anthracycline Extravasation Affects Patients Symptoms of anthracycline extravasation can be immediate or delayed and typically include swelling; redness; and pain, itchiness, or burning at the site of infusion.9 As damage progresses, skin discoloration, induration, and blistering are often observed. Sequelae of a minor extravasation sometimes heal without involved care. More extensive cases of extravasation can progress to ulcers, tissue necrosis, and infection. These patients might require plastic surgery, skin grafting, physical therapy, and other interventions over several months that leave them scarred or disfigured. In extreme

100 100%

90

19/19

97.4%

98.2%

37/38

56/57

80 Patients, %

70 60 50 40 30 20 10 Study 1

Study 2

Studies 1 and 2 combined

Source: Reference 13.

Figure. Proportion of patients in 2 prospective, multicenter trials of dexrazoxane who did not require surgical intervention for anthracycline-induced necrosis.

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cases, they might be left with permanent physical impairment, such as nerve damage, partial loss of hand function, or amputation.10 Extravasation sometimes leads to treatment delays, particularly for patients who develop ulcers. Because chemotherapy has a negative effect on fast-growing cells like those involved in healing, it might need to be withheld until the ulcer resolves, even if surgical treatment is not required. Treatment interruptions can reduce the overall effectiveness of anticancer therapy and contribute to poorer outcomes.9

I continue to be haunted by a case of anthracycline extravasation that occurred in the late 1980s, before an antidote existed.

Treatment Guidelines Improve Care The INS and the Oncology Nursing Society (ONS) have issued guidelines on chemotherapy administration that address treatment extravasation.1,11 Both sets of guidelines specify dexrazoxane for injection (Totect) as the only medical treatment approved by the US Food and Drug Administration to manage anthracycline extravasation.1,11 TopoTarget USA, which manufactures dexrazoxane, packages the antidote as part of a single-patient emergency treatment kit containing 10 vials of dexrazoxane and 10 vials of diluent.12 If there are symptoms or other signs of anthracycline extravasation (such as fluid leaking from the injection site or problems with the rate of infusion), guidelines call for stopping treatment, assessing the site, and cooling it with an ice pack for 15 to 20 minutes.1,11 The ice needs to be removed from the site for at least 15 minutes before administering dexrazoxane, which INS guidelines say should be initiated within 6 hours of extravasation.1 The drug is infused into a large vein in the unaffected arm. The guidelines cite evidence from 2 prospective multicenter studies in support of the dexrazoxane recommendation. The studies showed that dexrazox-

ane prevented tissue necrosis requiring surgical treatment in 98% of patients (Figure).13 The remaining 2% reflects the experience of 1 study participant who had experienced massive anthracycline extravasation, encompassing an area 253 cm2.13 Additionally, 74% of patients treated with dexrazoxane experienced no delay in chemotherapy.13 National treatment guidelines reflect the best practices according to evidence in the medical literature and outcomes observed in hospitals and in the community. They are useful tools that aid in decision making on effective care and promote patient safety. Guidelines also provide peace of mind for the nursing professional. In addition to caring for the patient at the bedside and responding to the patient’s needs, nurses usually bear the hefty responsibility of placing an IV line or catheter, each time putting their career, license, and heart on the line. When extravasation occurs, a nurse’s first impulse is to assume blame. Even if the pharmacy failed to place the antidote on the formulary or did not release an adequate supply of antidote, the nurse might still feel responsible. I continue to be haunted by a case of anthracycline extravasation that occurred in the late 1980s, before an antidote existed. The patient had a large doxorubicin extravasation through a vein in the upper arm that progressed to severe tissue necrosis and infection. Eventually, the patient’s arm was amputated. Fortunately, with national guidelines now in place on the proper placement of IV catheters and patency assessment during an infusion of vesicant therapy, extravasations are few and far between. When they do occur, the availability of an antidote and guidelines on its administration make severe extravasationrelated complications such as amputations far less likely. Spending Money to Save Money Although evidence-based medicine has gained widespread acceptance in medical and nursing circles, the call is growing for all clinicians and hospitals to adhere to national treatment guidelines. With Donald Berwick as the new administrator of the Centers for Medicare & Medicaid Services (CMS), there will likely be even more emphasis on patient-centered, evidence-based approaches to care. Berwick is the former president and chief executive officer of the Institute for Healthcare Im-

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Supportive Care provement, a nonprofit organization that worked to advance evidence-based medicine throughout the world. Berwick is expected to base CMS reimbursement and policy decisions partly on national treatment guidelines; private insurers are expected to follow the agency’s lead. At some point, reimbursement for treating complications like extravasation might depend on being able to show evidence of adherence to national guidelines. Although hospitals are loath to admit it, economic considerations have the potential to influence their degree of adherence to national guidelines. The current economy has led hospitals to become increasingly cost conscious and

sometimes tempts even those committed to evidence-based practice to replace a more expensive proven treatment specified by the guidelines with a less expensive unproven alternative. In the case of dexrazoxane for injection, some hospitals are pooling their resources to reduce their costs. Each emergency kit contains enough dexrazoxane to satisfy the full 3-day regimen required to treat anthracycline extrava-

Three hospitals, for example, will share the expense of a single kit, dividing the doses so that each hospital has a 1-day supply. sation.12 Three hospitals, for example, will share the expense of a single kit, dividing the doses so that each hospital has a 1-day supply. Such resource sharing

is potentially problematic, eroding a hospital’s control over supplies. What if a hospital is unwilling to hand over its supContinued on page 30

Case Report: Anthracycline Extravasation

A

call came from a nurse attending to 3 patients in the infusion clinic. One patient had received a full dose of doxorubicin (60 mg/m2) via the vein in the dorsum of her hand. Afterward, the nurse detected a trace of blood in the infusion tube. While administering post-dose hydration, she noticed that the patient’s hand was completely swollen. I concluded that a possible anthracycline extravasation had occurred. Dispersion of a vesicant drug into surrounding cells can damage tissue and vital structures outside the discrete area of intravenous (IV) placement. To mitigate possible damage, we needed to initiate the procedure for administering the antidote for anthracycline extravasation. I immediately went to the pharmacy department to request the dexrazoxane for injection (Totect) emergency kit used to treat anthracycline extravasation, which is stocked as part of our facility’s formulary. Over the course of 3 days, the patient received the full dose of dexrazoxane for injection as indicated. She did not experience any sequelae from the extravasation and was able to maintain her treatment schedule as planned. Before the existence of an evidence-based treatment plan, this patient might have developed ulceration of the hand, wrist, and upper forearm. Timely administration of the antidote prevented these complications. The patient later said, “I appreciate the nurse’s prompt response and the careful handling of my feelings. I was just grateful my hand was saved and that the antidote was available within minutes.”

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Guidelines for Managing Anthracycline Extravasation... Continued from page 29 ply or is unable to do so within the 6hour window for initiating dexrazoxane after suspected anthracycline extravasation? What if a second patient needs the antidote before the supply is restocked? Another concern is that one hospital might be less diligent than another in monitoring product expirations. Hospitals need to recognize that not having dexrazoxane readily available to treat a case of anthracycline extravasation will potentially be more costly for the hospital, particularly if a patient develops necrosis and infections (See Sidebar: Making the Case for Dexrazoxane). Insurers might also balk at paying to treat conditions that adherence to guidelines would likely have prevented. Best Practices: In Everyone’s Best Interest Nurses are often directly involved when anthracycline extravasation occurs, underscoring their important role in patient care. Evidence-based treatment guidelines are clear in recommending prompt administration of dexrazoxane for injection as an antidote to anthracycline extravasation; failure

Nurses are often directly involved when anthracycline extravasation occurs, underscoring their important role in patient care.

to adhere to these guidelines puts patients at risk of significant morbidity. A nurse who is aware of the availability of an antidote to complications associated with a specific caustic agent but fails to use it is open to potential legal liability as a named defendant in a malpractice lawsuit. Lack of control over supplies or pharmacy cost-cutting does not alleviate a nurse of this responsibility. A hospital administration that is familiar with the ONS and/or INS guidelines but does not make the antidote available faces similar liability risks. Nurses must therefore be more outspoken when it comes to advocating for best practices. This requires staying informed of available resources, which goes beyond specific medications to include individuals within the system who can offer support and

cooperation. Pharmacists typically hold the purse strings on pharmaceuticals in hospital systems. Oncologists might be supportive of nurses’ requests but ultimately defer to the pharmacists. This makes it even more important for nurses to speak up and outline the case for adhering to best practices on anthracycline extravasation. Begin by citing the emphasis of the national guidelines on timely and appropriate intervention as a means of providing quick resolution and preventing costly, debilitating complications. ● References 1. Alexander M, Corrigan A, Gorski L, et al, eds. Infusion Nursing: An Evidence-Based Approach. 3rd ed. Norwood, MA: Infusion Nurses Society; 2009:357-367. 2. TopoTarget launches Totect in the US [press release]. October 16, 2007. https://newsclient.omx group.com/cdsPublic/viewDisclosure.action?

disclosureId=240215&messageId=271989. Accessed April 1, 2010. 3. Buter J. Savene (dexrazoxane): an effective nonsurgical treatment for anthracycline extravasation. Hosp Pharm Eur. 2007;33:38-39. 4. Rudolph R, Larson DL. Etiology and treatment of chemotherapeutic agent extravasation injuries: a review. J Clin Oncol. 1987;5:1116-1126. 5. Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol. 2004;15:858-862. 6. Langstein HN, Duman H, Seelig D, et al. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg. 2002;49:369-374. 7. Langer SW, Sehested M, Jensen PB, et al. Dexrazoxane in anthracycline extravasation. J Clin Oncol. 2000;18:3064. 8. Langer SW. Treatment of anthracycline extravasation from centrally inserted venous catheters. Oncol Rev. 2008;2:114-116. 9. Langer SW. Extravasation of chemotherapy. Curr Oncol Rep. 2010;12:242-246. 10. Jordan K, Behlendorf T, Mueller F, Schmoll HJ, et al. Anthracycline extravasation injuries: management with dexrazoxane. Ther Clin Risk Manag. 2009;5:361-366. 11. Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society Publications; 2009:ix, 108. 12. Totect (dexrazoxane) for injection [package insert]. Rockaway, NJ: TopoTarget USA Inc. October 2007. 13. Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol. 2007; 18:546-550.

Making the Case for Dexrazoxane

C

ontra Costa Regional Medical Center is a public hospital with 167 beds. Despite our hospital’s cost-conscious approach to formulary management, it was one of the first in the area to add the dexrazoxane for injection (Totect) emergency treatment kit to its formulary. This addition predated the Oncology Nursing Society guidelines on managing anthracycline extravasation and followed a long process involving presentations to 4 hospital committees.

Day 1: redness and pain.

In a presentation for pharmacy staff, I incorporated several slides that graphically depicted the sequelae of anthracycline extravasation, essentially telling my audience, “This is what an extravasation looks like; this is what I’m afraid of.” Audience members were visibly affected by the graphic images. After I completed all 4 presentations, the hospital approved my request to add the dexrazoxane for injection emergency kit to the hospital formulary for the treatment of anthracycline extravasation.

Day 2: blistering.

My experience exemplifies how incorporating patient stories and photos in your presentation can help decision makers realize that looking out for the patients’ best interests is the fiscally responsible choice. Formulary managers, pharmacists, and other administrators need to understand that sometimes a financial outlay is needed if we are to adhere to best practices designed to protect our patients from avoidable complications associated with tremendous emotional, physical, and monetary costs.

Day 12: induration, necrosis.

Photo Credits: Oncology Nursing Society. Reproduced with permission via Copyright Clearance Center; January 16, 2010.

Figure. Sequelae of doxorubicin extravasation.

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ducational S ivision o ational P S TAT E ervices, a d harmacy T echnician A ssociation IInc., nc., iis sa ccredited b y tthe he A ccreditation C ouncil ffor or P harmacy E ducation ((ACPE) ACPE) a sap rovider o ontinuing STAT Educational Services, division off N National Pharmacy Technician Association accredited by Accreditation Council Pharmacy Education as provider off ccontinuing p harmacy e ducation. du pharmacy education. This knowledge-based program has been accredited for 1.0 contact hours of continuing education for pharmacists, pharmacy techni cians, nurses, and risk managers. technicians, Learning Obj Objectives: ectives: At the completion activity completion of this act activity,, the participant will be able to: - Describe the e evidence for the genotoxicity of anti-cancer chemotherapy in patients; - Relate the sp pecific chromosomal chromo osomal targets g assoc ciated with various chemotherapy py drug drug g classes; specific that have been associated - Discuss the suf fficiency ficiency of current c safe-handling policies in light of recent evidence of worker exposure; sufficiency - Identify the concerns associated with handling hazardous medications; - Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications; - Review future research opportunities around hazardous medications; - List ONS guidelines for safe handling; - Describe nursing basics for safe handling; - Describe proper donning of personal protective equipment (PPE).

Activity T Type: ype: Knowledge T arget Audience: Pharmacists, Pharmacy T Manage echnicians, Nurses, & Risk Managers Target Technicians, 1-002-C05-P Universal Activity Number (UAN): 0384-9999-1 0384-9999-11-002-C05-P 0384-9999-1 1-002-C05-T 0384-9999-11-002-C05-T The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center â&#x20AC;&#x2122;s Commission on Accreditation. Centerâ&#x20AC;&#x2122;s Provided under Iowa Provider #78. Provider approved by the California Board of Registered Nursing, Provider #13699.


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CONTINUING EDUCATION PROGRAM CE11 • RELEASE DATE: APRIL 15, 2011 • EXPIRATION DATE: APRIL 15, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYNURSE.COM

Follow-up Management of Hodgkin Lymphoma Survivors By David C. Hodgson, MD, MPH Associate Professor, Department of Radiation Oncology, University of Toronto Staff Radiation Oncologist, Department of Radiation Oncology Princess Margaret Hospital/University Health Network, Toronto, Ontario, Canada STATEMENT OF NEED Hodgkin lymphoma is a highly curable cancer that is most common in younger adults and children. Long after therapy completion, treatment-related toxicities are often evident and second malignancies can arise. Follow-up care for patients in remission involves monitoring them for recurrent disease and managing existing and emergent treatment-induced adverse effects. Although current guidelines outline appropriate surveillance measures for detecting recurrence and second malignancies, limited data are available on the quality of follow-up care being provided to survivors of Hodgkin lymphoma. TARGET AUDIENCE Advanced practice nurses, registered nurses, and other interested healthcare professionals, especially those caring for cancer patients LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Recognize the need for long-term follow-up to detect and manage delayed effects of treatment and second malignancies in patients with Hodgkin lymphoma. • Incorporate recommended interventions into practice for screening Hodgkin lymphoma survivors for cancer.

I

mproved cure rates across multiple types of cancer are spurring efforts to identify optimal follow-up care for cancer survivors. This is especially important for young cancer survivors, whose treatment-related adverse effects might not arise for years or even decades. Hodgkin lymphoma (HL) is a highly curable cancer that more commonly occurs in young adults and children. The risk of recurrence varies among HL survivors, but many experience treatment-related toxicity long after therapy completion1-7 and have an elevated risk of other medical problems, including second malignancies.1-4,6-9 Guidelines for follow-up care emphasize surveillance for recurrent disease and second cancers and managing treatment-induced ad verse effects.10-13 Few studies have examined the quality of follow-up care HL survivors receive or considered the relationship between follow-up care and outcomes.14,15 For example, it is uncertain whether HL survivors with low likelihood of relapsing benefit from routine follow-up computed tomography (CT) scanning. Growing concern about

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exposure to diagnostic radiation16 suggests a need for studies to evaluate the extent to which routine CT scanning improves patient outcomes. Previous studies have determined that many cancer survivors—especially survivors of childhood cancer—are not screened for second cancers in accordance with current guidelines for follow-up care.17-19 Some studies have been limited by a reliance on patient reporting or a decision to restrict data to patients aged ≥65 years.17-19 The objective of the current study was to evaluate the follow-up care HL patients receive and the degree to which this care incorporates routine imaging, standard healthcare interventions, and guideline recommendations for cancer screening in HL survivors.

Guidelines for follow-up care emphasize surveillance for recurrent disease and second cancers and managing treatment-induced adverse effects.

Study Population and Protocol We used the Ontario Cancer Registry to identify all patients in Ontario given an HL diagnosis from 1992 through 2000 (N = 2900). Excluding patients with a prior malignancy or those who developed a second malignancy within 12 months of diagnosis, patients who required chemotherapy for >1 year after diagnosis, and patients who died during the first year of follow-up left a total of 2071 HL survivors for study inclusion (median age, 35.4 years). To assess adherence to recommended routine and HLspecific cancer screening tests, we analyzed billing records for physician visits, imaging tests, and cancer screening for follow-up in years 2 through 15. Data for patients who died or left the Ontario Health Insurance Plan during the followup period were censored.

Results In years 2 through 5 after diagnosis, HL survivors averaged 4 visits annually to their primary care provider (PCP), with approximately 75% of patients overall making ≥1 PCP visit per year. During this same period, between 65% and 75% of patients each year made ≥1 visit to a medical oncologist and between 11% and 31% of patients each year saw a radiation oncologist at least once. In years 2 through 5, approximately 13% of patients visited a PCP but not an oncologist. For years 6 through 9, cumulatively, 87.4% of patients made ≥1 visit to their PCP. Although 86.7% of patients had ≥1 appointment with the medical oncologist during this 4-year interval, it is not clear whether the visits were for annual follow-up care or scheduled to address specific concerns. Overall, patients underwent a range of imaging tests, including chest radiCONTINUING NURSING EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT Science Care is approved by the California Board of Registered Nursing, Provider number 15559, for 1.0 Contact hour. METHOD OF PARTICIPATION 1. Read the article in its entirety 2. Go to www.TheOncologyNurse.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE Activity Evaluation 7. Print your Certificate of Credit This activity is provided free of charge to participants. FACULTY DISCLOSURES As a provider accredited by the California Board of Registered Nursing, Science Care must ensure balance, independence, objectivity, and scientific rigor in all its activities. All course directors, faculty, planners, and any other individual in a position to control the content of this educational activity are required to disclose to the audience any relevant financial relationships with any commercial interest. Science Care must determine if the faculty’s relationships may influence the educational content with regard to exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity.

ography, CT scanning, gallium scanning, magnetic resonance imaging (MRI), and ultrasound. Imaging tests completed >11 months after the previous imaging procedure were categorized as “annual” screening. In the second year of follow-up, 87.8% of patients had ≥1 chest radiographs and 66% had ≥1 CT scans. Rates steadily declined in each of the next few years; in year 5, 62.9% of patients had chest radiography and 31.8% received CT scanning. The rate for patients considered to have undergone annual CT scanning during the 4-year period held fairly constant at ~20% each year. During the first 4 years of follow-up, a cumulative 5352 CT scans were performed, with 125 patients receiving chemotherapy within 6 months of CT scanning. Although most HL survivors visited a PCP or an oncologist in the 14-year Disclosures are as follows: • David C. Hodgson, MD, MPH, has nothing to disclose. • Dawn Lagrosa has nothing to disclose. • Chistina A. Liebertz, APN, RN, has nothing to disclose. • Christin Melton has nothing to disclose. • Karen Rosenberg has nothing to disclose. The staff of Science Care have nothing to disclose. DISCLAIMER The opinions and recommendations expressed by faculty, authors, and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of Science Care or Green Hill Healthcare Communications, LLC. COPYRIGHT STATEMENT Copyright © 2011 Science Care. All rights reserved. EDITORIAL BOARD David C. Hodgson, MD, MPH Princess Margaret Hospital/ University Health Network 610 University Avenue Toronto, ON M5G 2M9 Canada Christina A. Liebertz, APN, RN Urology Outpatient Center Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10065

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Table Summary of NCCN Guidelines on Follow-up Care for HL Survivors When Years 1-2 Physical Years 3-5 exam/blood test (with oncologist) After year 5

Frequency Every 2-4 mo Every 3-6 mo Annually

Who All

Chest radiograph Years 2-5 After year 5 or CT

Every 6-12 mo Annually

All Patients with increased risk of lung cancera

Abdominal/pelvic Years 2-3 CT (category 2B)b Breast screeningb 8-10 years after therapy or age 40 years (whichever is first)

Every 6-12 mo

All

Annually

Women treated with chest/axillary RT

a

Optional after 5 years for patients treated with a nonalkylating agent, no chest RT, and no other risk factors.

b

Category 2B recommendations are based on lower-level evidence and there is nonuniform consensus (but no major disagreement).

c

Guidelines note that the American Cancer Society recommends breast MRI and mammography in women who received chest irradiation between 10 and 30 years of age.

HC Hodgkin Lymphoma; CT indicates computed tomography; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; RT, radiotherapy. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology for Hodgkin’s Lymphomas V.2.2010. ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

follow-up period, 62.5% of survivors aged 50 to 70 years never received standard colorectal cancer screening as recommended for this age demographic. Also in this period, 32.3% of women aged 50 to 69 years never underwent mammography to screen for breast cancer, and 19.9% of women aged 20 to 69 years never received cervical cancer screening. These screening rates were similar to rates of colorectal, breast, and cervical cancer screening among the general population of Ontario.20 Women aged 25 to 49 years who had received an HL diagnosis ≥9 years earlier and underwent mediastinal radiotherapy as part of initial treatment (n = 526) were considered eligible for early-onset breast cancer screening. Guidelines typically recommend women treated with irradiation to the chest or axillary undergo annual mammography starting 8 to 10 years after completion of therapy. During 14 years of follow-up, only 22% of eligible patients underwent HL-specific breast cancer screening. Those women who saw only their PCP and not an oncologist during follow-up were significantly less likely to get HL-specific screening (odds ratio, 0.14; 95% confidence interval, 0.03-0.64). Discussion We believe our study is the first to examine the provision of follow-up care to an unselected, population-based cohort of HL survivors. Although most patients with HL are completely cured and never relapse, treatment-related adverse effects often persist or arise long after treatment ends. Several studies have shown that long-term survivors have an increased risk of heart disease,2,3,6,8 second malig-

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nancy,4,7,9 thyroid dysfunction,1 and other medical problems resulting in part from therapy. In particular, HL survivors appear to have an increased risk of leukemia, non-Hodgkin lymphoma, and solid tumors of the breast, thyroid, colon, rectum, cervix, stomach, and lungs; the degree of increased risk varies according to age at diagnosis, stage of disease, and treatment received.4,7,9 For example, radiation therapy that includes the mediastinum and axillae is associated with an increased risk of breast cancer.21 Oncology experts have developed guidelines for follow-up care of HL survivors (Table). These guidelines generally emphasize detecting recurrence and managing residual and delayed effects of treatment.10,13 Use of Computed Tomography Scanning It is standard to use imaging to confirm remission status in HL patients who have completed therapy. Guidelines on the use of CT scanning for follow-up care differ between the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN). After confirming remission, ESMO recommends CT scanning only for patients with suspicious clinical symptoms.12 NCCN guidelines call for chest radiographs and CT scanning of the chest every 6 to 12 months during the first 2 to 5 years of follow-up and CT scanning of the abdominal/pelvic re gion every 6 to 12 months for the first 2 to 3 years of follow-up and then annually for the next 2 years. After 5 years, NCCN recommends annual radiographs or CT scans of the chest for

patients considered to have an increased risk of lung cancer and optionally for patients treated with a nonalkylating agent or who did not receive chest radiotherapy and have no other risk factors for lung cancer.13 The NCCN guidelines acknowledge that few data support these recommendations but state that they represent the “range of practice at NCCN institutions.” In follow-up years 2 through 5, HL survivors in the study received a total of 5352 CT scans—a rate more than 3 times greater than the rate of CT scanning in the general population of Ontario.22 Only 125 patients initiated chemotherapy within 6 months of undergoing CT scanning, which suggests that routine scanning is not an efficient way to detect treatable disease recurrence. This is supported by previous studies that found CT scanning to be no more effective than radiography at detecting asymptomatic HL recurrence23 and not cost-effective if it is assumed that only 8% of patients with recurrence are asymptomatic.24 Although use of CT scanning in this patient population was consistent with practices at NCCN institutions, the low recurrence rate suggests that it was likely overused in follow-up care. One limitation of this study was the inability to determine the reason for imaging tests using administrative data. Screening for Second Cancers Some HL survivors have a lifelong elevated risk of second cancers9 and require screening for certain cancers earlier and more frequently than the general population. A 2007 study concluded that the risk of colorectal cancer for individuals aged 35 to 40 years who survived HL as an adolescent or young adult was compa-

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breast cancer.4,7,25 Guidelines typically recommend that these survivors initiate breast cancer screening 8 to 10 years posttherapy. 10,13 Our findings indicate that screening guidelines for HL survivors are not being incorporated into clinical practice. Many HL survivors are also not receiving routine age-appropriate screening for breast cancer, cervical cancer, and colorectal cancer. Over the 14-year followup period in this study, nearly a majority of eligible survivors did not appear to undergo colorectal cancer screening and a substantial proportion of patients did not receive screening for cervical or breast cancer. Despite their personal history with cancer and frequent contact with physicians, HL survivors were no more likely than the general population in Ontario to undergo routine screening for these 3 cancers.20 Conclusion Our study indicates that the rates of cancer screening are too low for HL survivors and the rate of CT scanning is likely too high, particularly in light of emerging data on the contributing role of radiation exposure during CT scanning to cancer development.16 To improve follow-up care, patients and clinicians need to be educated on the latent health risks for HL survivors and their need for follow-up care.

Our study indicates that the rates of cancer screening are too low for Hodgkin lymphoma survivors and the rate of CT scanning is likely too high, particularly in light of emerging data on the contributing role of radiation exposure during CT scanning to cancer development. rable to the risk seen in the general population at age 50 to 54 years. The same study found that within 5 to 10 years of an HL diagnosis, the risk of breast cancer for young female survivors was similar to that of a typical 50-year-old woman.9 Although patients in our study made frequent visits to multiple physicians, many did not undergo cancer screening as advised by current guidelines for the follow-up care for HL survivors. Of particular concern is the large proportion of young women who received mediastinal radiotherapy for HL yet were never screened for

Improving communication between oncologists and PCPs on issues facing HL survivors would also likely lead to better care.24,26-28 The cancer care team should educate HL survivors on which symptoms require prompt medical attention from a physician, who will then determine whether further evaluation is warranted. Efforts should also be made to boost rates of posttreatment screening for second cancers in HL survivors, particularly breast cancer screening in women who undergo mediastinal radiotherapy, to facilitate earlier detection and treatment. Continued on page 34

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CONTINUING EDUCATION Continued from page 33

Follow-up Management of Hodgkin Lymphoma... Some cancer centers in North America have established structured clinics in an attempt to provide the growing number of cancer survivors with appropriate follow-up care. There is also growing emphasis on empowering survivors through education, encouraging them to take an active role in their healthcare. Although these are positive developments, evidence is lacking on how to structure effective survivorship programs and adapt them to patients. In addition to studying these issues, future research should determine the level of followup care from oncologists and PCPs needed to improve the quality of care and/or outcomes for HL survivors. ● Disclosure Funding for the study was provided by Cancer Care Ontario. The study was supported by the Institute for Clinical Evaluative Sciences, which is funded by the Ontario Ministry of Health and Long-Term Care. References 1. Acharya S, Sarafoglou K, LaQuaglia M, et al. Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer. 2003;97:2397-2403.

2. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22:3139-3148. 3. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:1878-1886. 4. Bhatia S, Yasui Y, Robison LL, et al; for the Late Effects Study Group. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. J Clin Oncol. 2003;21:4386-4394. 5. Mauch P, Ng A, Aleman B, et al. Report from the Rockefeller Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin’s disease. Eur J Haematol Suppl. 2005;66:68-76. 6. Swerdlow AJ, Higgins CD, Smith P, et al. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst. 2007;99:206-214. 7. van Leeuwen FE, Klokman WJ, Hagenbeek A, et al. Second cancer risk following Hodgkin’s disease: a 20year follow-up study. J Clin Oncol. 1994;12:312-325. 8. Myrehaug S, Pintilie M, Tsang R, et al. Cardiac morbidity following modern treatment for Hodgkin lymphoma: supra-additive cardiotoxicity of doxorubicin and radiation therapy. Leuk Lymphoma. 2008; 49:1486-1493. 9. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol. 2007;25:1489-1497. 10. Ralleigh G, Given-Wilson R. Breast cancer risk and possible screening strategies for young women following supradiaphragmatic irradiation for Hodgkin’s disease. Clin Radiol. 2004;59:647-650. 11. Children’s Oncology Group Nursing Discipline Clinical Practice Subcommittee/Survivorship in collaboration with the Late Effects Committee. Establishing and Enhancing Services for Childhood

Cancer Survivors: Long-Term Follow-Up Program Resource Guide. 2007. www.survivor shipguidelines.org/pdf/LTFUResourceGuide.pdf. Accessed December 22, 2010. 12. Engert E, Eichenauer DA, Dreyling M; ESMO Guidelines Working Group. Hodgkin’s lymphoma: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2010;21(suppl 5):168-177. 13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Hodgkin Lymphoma. V.2.2010. ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf. Accessed December 22, 2010. 14. Ng AK, Li S, Recklitis C, et al. Health practice in long-term survivors of Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2008;71:468-476. 15. Oeffinger KC, Ford JS, Moskowitz CS, et al. Breast cancer surveillance practices among women previously treated with chest radiation for a childhood cancer. JAMA. 2009;301:404-414. 16. Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med. 2007;357:2277-2284. 17. Snyder CF, Earle CC, Herbert RJ, et al. Trends in follow-up and preventive care for colorectal cancer survivors. J Gen Intern Med. 2008;23:254-259. 18. Snyder CF, Frick KD, Kantsiper ME, et al. Prevention, screening, and surveillance care for breast cancer survivors compared with controls: changes from 1998 to 2002. J Clin Oncol. 2009;27:1054-1061. 19. Nathan PC, Ness KK, Mahoney MC, et al. Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Ann Intern Med. 2010;153:442-451. 20. Cancer Care Ontario. Cancer in Ontario: Overview, A Statistical Report. Toronto, Canada, 2010. www.cancercare.on.ca/common/pages/UserFile. aspx?fileId=81843. Accessed December 22, 2010.

To Receive cRediT, compleTe The posTTesT aT TheOncologyNurse.com

21. Hodgson DC, Pintilie M, Yun L, et al. Cardiovascular morbidity following modern treatment for Hodgkin lymphoma: age- and sex-specific estimates of risk in the doxorubicin era. Int J Radiat Oncol Biol Phys. 2008;72:S122-S123. 22. Laupacis A, Przybysz R, Keller MA. CT and MRI scanning. In: Access to Health Services in Ontario. ICES Atlas. 2nd ed. 2006:149-164. 23. Dryver ET, Jernstrom H, Tompkins K, et al. Follow-up of patients with Hodgkin’s disease following curative treatment: the routine CT scan is of little value. Br J Cancer. 2003;89:482-486. 24. Guadagnolo BA, Punglia RS, Kuntz KM, et al. Cost-effectiveness analysis of computerized tomography in the routine follow-up of patients after primary treatment for Hodgkin’s disease. J Clin Oncol. 2006;24:4116-4122. 25. Ng AK, Bernardo MV, Weller E, et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood. 2002;100:1989-1996. 26. Oeffinger KC, Wallace WH. Barriers to follow-up care of survivors in the United States and the United Kingdom. Pediatr Blood Cancer. 2006;46:135-142. 27. Oeffinger KC, McCabe MS. Models for delivering survivorship care. J Clin Oncol. 2006;24:5117-5124. 28. Oeffinger KC, Robison LL. Childhood cancer survivors, late effects, and a new model for understanding survivorship. JAMA. 2007;297:2762-2764.

Acknowledgement Jill Stein contributed to the preparation of this article.

COMMENTARY

Importance of a Care Plan in the Follow-up Management of Hodgkin Lymphoma Survivors By Christina A. Liebertz, APN, RN Urology Outpatient Center, Memorial Sloan-Kettering Cancer Center New York, New York

T

his study found that computed tomography scans rarely led to active therapy, despite the fact that a high number of posttreatment scans were performed. In addition, the study validated the ambiguous screening value and cost-effectiveness of procedures other than the history, physical examination and, possibly, chest x-ray. The lack of screening these patients received posttreatment highlights the need for standardized survivorship care guidelines and education of practitioners and patients. It is alarming that many high-risk patients did not receive screening. How many of these patients could have found early, detectable, and treatable disease with simple screening and follow-up? One of the limitations to this study is that these patients were diagnosed and treated from 1992 to 2000, before the development and adoption of more

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standardized guidelines for surveillance and follow-up for cancer survivors. It would be interesting to see if these findings have changed and by how much with the advent of more educational and formal survivorship programs. Also, because this study was done in Canada, it is difficult to know how these findings would compare if a similar study were done within the US healthcare system. This study clearly supports the need for more research to establish evidence-based standards for follow-up and surveillance, along with methods to decrease posttreatment toxicities, morbidity, and mortality. We also need to evaluate the best, most efficient methods for providing this care and increasing patient adherence to recommendations. A limitation of this study is the lack of data about what other factors may have impacted

lack of screening. Besides practitioner recommendation, other potential barriers to screening may have included lack of insurance, decreased access to care, and/or psychosocial issues such as fear of recurrence. We have learned a lot about the needs of Hodgkin lymphoma survivors and survivorship care in general, but there is still much to learn about improving and providing that care. We need to develop methods to support more consistent, effective, and thorough follow-up care and communication. One method is developing posttreatment cancer care plans or summaries that not only educate each patient about individualized follow-up care, but also serve as a tool for all of that patient’s healthcare providers. Unfortunately, this is rarely provided. Regardless of the method used, there should be open and ongoing

communication between the oncologist and patient’s other healthcare practitioners. Recommendations from all of these providers should be consistent and based on best practices. They should include assessments for treatment-related toxicities; education for general health maintenance (eating habits, regular exercise, smoking cessation, vaccinations); appropriate follow-up and screening guidelines, especially for high-risk conditions and cancers; and appropriate, efficient, and individualized surveillance guidelines based on risks. Follow-up care should be clearly defined, not random. We have made many advances in survivorship care, but this study reinforces the need to continue to develop more efficient methods to provide optimal posttreatment care and improve patient outcomes and quality of life. ●

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: + :L6+ 

112 12

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THE PROMISE OF 1000 ORIGAMI CRANES The ancient Japanese tradition of senbazuru promises that anyone who folds 1000 origami cranes will be granted a wish, such as long life or recovery from illness — at Millennium, our wish is to cure cancer. We’re committed to patients and strive to make a difference in their lives. 1000 Cranes of Hope is an online monument that contains the collective wishes of patients, caregivers, healthcare providers and our employees who all stand together in the fight against cancer. Add your wish to create a new crane — and make a difference. For each crane created, Millennium will make a donation to benefit professional and charitable cancer organizations.

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Patient-Centered Outcomes Research

Making Cancer Drugs Worth the Cost By Christin Melton

A

s nations around the globe struggle to afford the growing cost of care for their citizens, more people are asking ‘how much is too much?’ when it comes to cancer. Although the John G. Kuhn Keynote Lecture delivered at the annual meeting of the Hematology/ Oncology Pharmacy Association was titled “The Cost of Cancer Therapy,” speaker Tito Fojo, MD, PhD, with the medical oncology branch of the National Cancer Institute (NCI), says cost is not the real issue. “If you frame the argument in terms of cost, you’re going to lose it,” he told the audience of pharmacists. Fojo said the real issues are “how effective drugs are and how toxic drugs are.” Fojo offered examples of drugs used in clinical practice that he believes not only fail to improve survival but actually harm patients, including cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and bevacizumab (Avastin) in breast cancer. He noted that controversy surrounds these examples and not everyone shares his views—including Giuseppe Giaccone, his supervisor at the NCI and a member of the American Society of Clinical Oncology (ASCO)

panel responsible for adding the combination of cetuximab and paclitaxel to the ASCO guidelines for first-line therapy of mCRC. The examples Fojo cites are also found in the National Comprehensive Cancer Network (NCCN) treatment guidelines.

“Delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms.” —Tito Fojo, MD, PhD

Even if one disagrees with Fojo’s conclusions, his review of the pivotal trials used to support approval of cetuximab in mCRC and bevacizumab in breast cancer underscores important considerations for stakeholders when deciding how

How Costly Is Cancer Care in the United States?

T

he National Cancer Institute set out to answer this question last year and published results of their investigation in the January 2011 issue of the Journal of the National Cancer Institute. The study’s authors point to flaws in previous cancer cost estimates, many of which did little more than take figures from 15 years ago and adjust them for inflation. When one considers the major transformations in cancer care in just the past decade, it is not hard to see why these earlier estimates are unreliable. Using the Surveillence, Epidemiology, and End Results database to obtain incidence rates and Medicare records for medical expenses, Mariotto and colleagues estimated the following: US Cancer Care Costs in 2010: $124.57 billion Projected US Cancer Costs in 2020: $157.77 billion-$207 billion*

*Lowest figure assumes constant incidence, survival, and cost; highest figure assumes increase for greater use of targeted therapies.

Most expensive Breast: Colorectal: Lymphoma: Lung: Prostate:

cancers in 2010 (in billions): $16.50 $14.14 $12.14 $12.12 $11.85

For men and women whose deaths were caused by cancer in 2010, costs were highest in the first 12 months after diagnosis and the last 12 months of life across all malignancies. The greatest increase in cost from the first year to the last year was for melanoma. For example, a woman aged <65 years accumulated $6057 in medical costs in the year of diagnosis and $85,175 in the final year of life. Source: Mariotto AB, et al. Projectons of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103(2):117-128.

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anticancer drugs should be developed, evaluated, and used. “Our drug development, drug approval, and drug consumption strategies need better focus,” said Fojo, who lamented that despite the decade that has elapsed since imatinib (Gleevec) ushered in the “targeted therapy revolution,” too many treatments are still used indiscriminately in broad patient populations. Fojo sees room for improvement at all levels: academia, the pharmaceutical industry, government agencies like the US Food and Drug Administration (FDA), and clinicians caring for patients with cancer. All are responsible for “our failure to deliver on the promise of personalized medicine.” The experience with cetuximab in mCRC supports Fojo’s contention that researchers need to analyze drugs prospectively, identifying predictive markers before initiating trials. Four years after cetuximab’s 2004 approval, investigators reported in the New England Journal of Medicine that it was ineffective in patients with mutated KRAS. In 2009 ASCO issued its Provisional Clinical Opinion recommending KRAS testing before prescribing cetuximab but called compliance with the opinion voluntary. Fojo said a prospective investigation might have uncovered the KRAS issue before trials were initiated. Cetuximab inhibits epidermal growth factor receptor (EGFR), and Fojo said, “As early as 1990, Bert Vogelstein at Hopkins had reported that as many as 50% of colorectal patients harbored KRAS.” In 1998, KRAS was reported to be in the EGFR signaling pathway. “Despite this, we went ahead and conducted studies without looking at this prospectively.” Continued investigation into the causes of poor response to cetuximab among some patients with wild-type KRAS will likely whittle the viable patient population down even further. “Eventually, we’ll be able to identify the 80% of patients that do not benefit and give it only to the 20% who benefit substantially, and a drug that was marginal to begin with will become highly effective,” explained Fojo. Fojo said he is concerned that “increasingly, therapies that demonstrate at best marginal improvement are being used in the treatment of cancer.” With breast cancer, we might even be going backwards he said, pointing to the controversy over bevacizumab. He emphasized that his views did not represent those of the NCI or anyone else. Fojo faulted the decision to approve bevacizumab based on data from the

Eastern Cooperative Oncology Group (ECOG) 2100 study, which suggested adding it to paclitaxel significantly prolonged progression-free survival (PFS) but not overall survival (OS). Although the study showed nonsignificant improvement in OS favoring bevacizumab, Fojo said, “Nonsignificant improvement is no improvement.” He added that it was unusual for a study to reflect major discordance between PFS and OS. Fojo and other researchers published a report in Lancet Oncology last year that reviewed major studies published since 1996 with a statistically significant PFS or OS and found “tight correlation between the two.” He therefore believes ECOG 2100 is an outlier. Even if bevacizumab does improve PFS, in Fojo’s opinion, PFS on its own is not an important end point. “Delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms,” he said. Studies need to focus more on whether the regimens used are harming patients. Fojo noted that in ECOG 2100, patients treated with bevacizumab experienced more than twice as many adverse events as the control group. Given its failure to improve OS and its cost, Fojo said the toxicity is unacceptable, but he acknowledged that many breast cancer specialists disagree. The FLEX trial, investigating cetuximab in mCRC, also found high rates of serious grade 3 and 4 toxicities related to cetuximab, particularly skin reactions that are sometimes disfiguring. With the growing use of oral treatments, Fojo said it is important that studies not overlook the grade 1 and 2 toxicities. “The scale was developed for chemotherapy, but when you are taking a drug every day for months on end, a grade 1 or 2 event can be very difficult.” While cost is relevant for drugs that cause serious adverse effects but demonstrate minimal efficacy, Fojo said it comes down to the notion that you do not harm patients for little improvement in survival. Various attempts to combine therapies have hurt patients without helping them, and Fojo called for an end to this “incremental approach” to treatment. Finding better treatments requires determining the settings in which the drugs work best but also the ones in which they do not work. Fojo said this would require major journals to give greater weight to negative studies, which are often relegated to second- and thirdtier journals. It also requires expanding incentives for pharmaceutical companies to take a more personalized approach to drug development, where rewards are likely to be less lucrative. ●

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YOU INFUSE ANTHRACYCLINES, BUT ARE YOU PREPARED FOR AN EXTRAVASATION? TWO PRICE OPTIONS AVAILABLE

Totect® Kit (dexrazoxane) for injection is for intravenous infusion only. Totect is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

First and only FDA approved treatment for anthracycline extravasation. Supplied as a convenient and accessible complete three day treatment kit for single patient use, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation. Demonstrates 98% overall efficacy based on two biopsy-confirmed clinical trials1,2 in reducing or avoiding surgical intervention (i.e., surgical debridement, plastic surgery and their related costs), thereby reducing postponement of a patient’s chemotherapy treatments and the avoidance of long-term consequences. Cited in nursing guidelines.3,4 Extravasation management is now a chemotherapy administration safety standard.5

For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors. ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply US Oncology (800) 746-6273 (866) 677-4844 (800) 482-6700 (800) 633-7555 (888) 987-6679 1

Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. 2 Totect® package insert. 3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009. 4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009. 5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658. © 2010 Topotarget USA. All rights reserved. TOT0112/7-10 Totect and its logo mark are registered trademarks of Topotarget A/S 10:55:02 AM


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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Totect is a cytotoxic drug. Vial contents must be mixed and diluted before use. Totect should not be mixed or administered with any other drug during the infusion. Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.3-5 Direct contact of Totect® with the skin or mucous membranes prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water. Contraindications: None. Warnings and Precautions: Myelosuppression: treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Use in Pregnancy: Pregnancy Category D. Totect can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions: The most common adverse reactions (≥ 16%) are nausea, pyrexia, injection site pain and vomiting.

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Rx only

Totect® is a registered trademark of Topotarget A/S US Patent No. 6,727,253B2 NDC 38423-110-01

TOT0112/7-10 © 2010 Topotarget USA

Drug Interactions: No drug interactions have been identified. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Specific Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and effectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Hameln Pharmaceuticals GmbH 31789 Hameln Germany

Manufactured for: Topotarget A/S Fruebjergvej 3 DK-2100 Copenhagen Denmark


TON_April2011_v7_TON 4/7/11 10:50 AM Page 39

Guidelines NCCN Updates Treatment Guidelines... Continued from cover diately applicable to clinical practice for patients with breast cancer, announced Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Palo Alto, California, who served as chair of the breast cancer panel. Some of the leading cancer institutions that inform the NCCN guidelines have already implemented many of these recommendations. Despite the recent controversy regarding decision by the US Food and Drug Administration (FDA) to rescind the indication for bevacizumab (Avastin) in patients with metastatic breast cancer (MBC), the NCCN reaffirmed its support for using a doublet of bevacizumab and paclitaxel for this population. Carlson said the panel decided to keep the combination of bevacizumab and paclitaxel in the guidelines as a treatment option based on the fact that the data had not changed. “If the data were compelling 2 years ago, [they are] compelling enough today,” he said. The panel added a footnote acknowledging that the use of this regimen does not improve overall survival (OS) and only “modestly improves time to progression and response rates.” Carlson said panel members were less confident of the data on combining bevacizumab with other approved chemotherapy agents. The updated guidelines also reflect recent FDA approvals of eribulin (Halaven) monotherapy for women with MBC who have received at least 2 prior chemotherapy regimens, including a taxane and an anthracycline, and denosumab (Xgeva) to help prevent skeletal-related events in patients with solid tumors that have metastasized to the bone. Eribulin, a cytotoxic agent, became a “preferred” agent in MBC based on final data from the EMBRACE study, in which 762 patients were randomized to eribulin or treatment of physician’s choice (TPC). Median OS was 13.1 months in the eribulin arm versus 10.6 months in the TPC arm, representing a 19% reduction in risk with the new agent (P = .041). The rate of 1-year OS was 53.9% in the eribulin arm compared with 43.7% for the TPC arm. Significantly more patients in the eribulin arm experienced grade 3/4 neutropenia, leukopenia, and peripheral neuropathy, but study investigators described adverse events as manageable. The inclusion of denosumab was based on its approval following phase 3 trial data showing that patients randomized to denosumab experienced 23% fewer skeletal-related events (SREs) than patients given zoledronic acid (Zometa; P = .001). Denosumab also delayed the time to first onstudy SRE by 18% versus zoledronic acid

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issue. Oncologists should interpret this as a recommendation not to perform CYP2D6 testing at this time,” said Carlson.

Robert W. Carlson, MD

(P = .001). Rates of OS and diseasefree survival (DFS) were similar in the study arms. Translational Findings The panel recommended that any work-ups for metastatic lesions seek to determine the hormonal and HER2 status of the metastases “if unknown, originally negative, or not over-expressed.” This was based on a growing body of data showing discordance between hormonal status of the primary tumor and metastases. For example, a study presented at the American Society of Clinical Oncology annual meeting in 2010 identified several cases in which the hormonal status of the patient’s liver metastases did not match the hormonal status of her primary tumor. The findings resulted in treatment changes for >12% of patients. “This recommendation is likely to get stronger as these data are formally published,” Carlson said. Representing a significant change in current clinical practice, the NCCN guidelines now advise against complete axillary lymph node dissection for women with clinically node-negative T1-T2 breast tumors and fewer than 3 involved sentinel lymph nodes who undergo surgery and radiation therapy. Carlson said the recommendation is based on data from a single randomized trial, the landmark ACOSOG Z0011 study. Investigators found no difference in rates of locoregional recurrence, DFS, and OS between patients who underwent complete axillary lymph node dissection and those who had sentinel lymph node dissection. The recommendation applies only to patients who match the well-defined characteristics observed in the subset of patients who formed the study population. The panel considered whether to recommend clinicians test patients for the CYP2D6 polymorphism prior to prescribing tamoxifen but decided against it. Panel members noted significant discrepancies between major studies investigating whether this mutation is associated with tamoxifen resistance. “The current NCCN guidelines are silent on this

Prostate Cancer In updating guidelines for prostate cancer, the panel reportedly spent considerable time weighing whether the data favor active surveillance or immediate treatment for certain patient populations. James L. Mohler, MD, Roswell Park Cancer Institute, Buffalo, New York, discussed the NCCN’s recommendation to monitor more rigorously men who opt for active surveillance. “The NCCN remains concerned about overdiagnosis and overtreatment of prostate cancer, as growing evidence suggests that overtreatment commits too many men to side effects that outweigh a very small risk of prostate cancer death,” he said. He also reviewed new treatment options for advanced prostate cancer.

New Therapeutic Options: Sipuleucel-T, Cabazitaxel, Denosumab For men with advanced metastatic castration-resistant prostate cancer (CRPC), the panel voted to add sipuleucel-T (Provenge) and cabazitaxel (Jevtana) as new therapeutic options. The FDA approved both treatments in 2010, after studies showed they improved OS.

James L. Mohler, MD

Active Surveillance OK—for Some Active surveillance, also termed watchful waiting, is a viable option for patients whose risk of progression is low to very low. The “very low risk” category is reserved for men with clinically significant prostate cancer, and the 2010 guidelines incorporated strict criteria for determining which patients meet this designation. Per 2010 guidelines, active surveillance was considered suitable for men identified as “very low risk” and men considered “low risk” who have a life expectancy <10 years. The 2011 updates to the guidelines increase the level of monitoring recommended for men in the “very low risk” category whose life expectancy is <20 years. Men who elect this approach should receive the following: • Prostate-specific antigen (PSA) tests every 6 months • A digital rectal examination at least every 12 months • Repeat biopsies as often as every 12 months. Mohler outlined challenges in determining whether some men with prostate cancer should get active surveillance rather than treatment. Large clinical studies examining this question have applied different criteria for active surveillance and disease progression, making it difficult to reconcile findings between series. Concerns also remain about overtreatment rates and the clinical risks associated with biopsies. “Ultimately, this decision must be based on careful, individualized weighting of a number of factors and is an option that needs to be thoroughly discussed,” he said. Mohler added that more clinical research is required to answer this question definitively.

Sipuleucel-T, an autologous cellular immunotherapy, is classified as a category 1 recommendation, which means the evidence is strong and panel members concurred on including the drug. “It is appropriate as salvage treatment for patients with CRPC who have minimally symptomatic disease, a performance status of 0 or 1, and a life expectancy of at least 6 months,” Mohler said. The relative risk for death with sipuleucel-T was 22%, according to a study by Kantoff and colleagues published in the New England Journal of Medicine last year (P = .03). It did not improve disease progression. Serious adverse effects were minimal, but many patients had immune-modulated reactions. Cabazitaxel, a taxane, was approved in conjunction with prednisone as a second-line option for men with metastatic CRPC that recurred following therapy with a docetaxel (Taxotere)based chemotherapy regimen. In the TROPIC study, men who received cabazitaxel plus prednisone saw a 2.4month improvement in OS compared with men treated with mitoxantrone (P <.001). As was the case with the breast cancer guidelines, the NCCN added denosumab as an alternative to zoledronic acid for the prevention of SREs in patients with bone metastases. Mohler said selecting an agent for bone protection depends on whether the patient has underlying comorbidities or has received zoledronic acid previously. Denosumab did not improve OS in men with prostate cancer but did demonstrate superiority to zoledronic acid on Continued on page 40

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Guidelines NCCN Updates Treatment Guidelines... Continued from page 39 multiple end points, including delaying time to first onstudy SRE.

PIK3CA, 1%

FGFR4, 2%

BRAF, 2%

HER2, 2%

R, 1

%

EGF

5 K, AL

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L4

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EM

Non–Small Cell Lung Cancer The guideline updates provide recommendations on the need to determine the histologic subtype of non–small-cell lung cancer (NSCLC) tumors and conduct genetic tests in some patients before selecting a therapeutic regimen. David S. Ettinger, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, Baltimore, Maryland, described the changes as pivotal. “We are heading toward the era of mutation driving the therapy, and it’s extremely important for our patients,” said Ettinger. In 2011, he added, “Histology matters and NOS [not otherwise specified] is unacceptable.” When evaluating patients with recurrent or metastatic NSCLC for systemic therapy, the molecular diagnostics section of the 2011 guidelines recommends establishing the histologic subtype before testing for genetic mutations (Figure). Ettinger said all patients with adenocarcinoma should undergo molecular testing. Testing for epithelial growth factor receptor (EGFR) is a category 1 recommendation for patients with adenocarcinoma or tumors of large cell histology and patients with NSCLC NOS. EGFR testing is not recommended in cases of squamous cell carcinoma. In addition to updating information on EGFR and KRAS gene status, the guidelines discuss the EML4-ALK gene translocation. It is estimated that aberrations of EGFR, KRAS, and ALK drive >60,000 new cases of NSCLC in the United States each year, and each is an important predictor of response to various targeted therapies. Crizotinib, a novel agent that targets EML4-ALK, has been submitted to the FDA for approval. It has the potential to improve prognosis for the 5% to 10% of patients positive for the EML4-ALK translocation. A recent phase 2 clinical trial of EML4-ALK–positive patients with adenocarcinoma found robust, durable responses to crizotinib, and Ettinger said updated findings from this study will be important. No standard method exists to detect the EML4-ALK translocation, but he said studies are looking at polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization. For patients with adenocarcinoma who progress or are resistant to first-line therapy with erlotinib (Tarceva), the guidelines have added bevacizumab (Avastin) plus a platinum doublet as a treatment option. Ettinger said combining bevacizumab with paclitaxel and carboplatin might be effective for patients

MEK, 1%

5%

Unknown, 42%

KRAS, 30%

Figure. Frequency of Oncogene Mutations in Non–Small Cell Lung Cancer

with tumors of nonsquamous histology but should not be used for squamous cell carcinoma. He noted that bevacizumab is changing the landscape of treatment for stage IV NSCLC. Non-Hodgkin Lymphoma A new guideline on diagnosing and treating posttransplant lymphoproliferative disease (PTLD) and the reclassification of 2 therapies as category 1 recommendations in follicular lymphoma (FL) are central to the guideline updates for non-Hodgkin lymphoma (NHL). Andrew D. Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, chaired the NHL panel and discussed the revisions. New Guidelines for Transplant Complication “PTLD has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation,” said Zelenetz. Advances in our understanding of the pathogenesis of PTLD and improvements in detection strategies are allowing clinicians to identify patients at high risk of the disease earlier. “The single biggest risk factor for PTLD is the presence of an Epstein-Barr virus [EBV] mismatch between the recipient and the donor,” he said. “The time from organ transplant is critically important, with most of these lesions developing within the first year.” The NCCN guidelines specify tests for PTLD and designate them as “essential” or “useful in selected cases.” Essential tests include histopathology, immunophenotyping, and the EBVencoded RNA in situ hybridization assay. EBV viral load is deemed “useful in selected cases.”

Depending on PTLD subtype, recommended treatment options include reducing immunosuppression, which is effective in 23% to 64% of patients; single-agent rituximab (Rituxan), associated with a response rate as high as 90% in patients with early and polymorphic lesions; and gancyclovir or another antiviral prophylaxis for EBV-positive patients. Although chemoimmunotherapy is also an option, Zelenetz said, “I would reserve chemoimmunotherapy for patients in whom other, simpler maneuvers have failed.” Stronger Evidence for Follicular Lymphoma Regimens In the FL section of the guidelines, the combination of bendamustine (Treanda) and rituximab (B-R) was upgraded to a category 1 recommendation for first-line treatment. A pivotal trial compared B-R with standard therapy using cyclophosphamide, doxorubicin, vincristine, prednisone, and ri tuximab (CHOP-R). B-R was associated with significant improvement in progression-free survival (PFS) and the rate of complete response versus CHOP-R; OS was similar in both trial arms. Consolidation with 90Y ibritumomab tiuxetan (Zevalin), a radiotherapy agent, followed by rituximab maintenance therapy was also reclassified as a category 1 recommendation for treatment after first remission. Patients on this regimen had prolonged PFS but no improvement in OS. Because “no maintenance strategy in FL has yet demonstrated a benefit in OS,” Zelenetz said observation remains an appropriate option in the NCCN algorithm for initial treatment of the disease. He emphasized the importance

of individualized treatment planning for patients with FL. Chronic Myelogenous Leukemia Two newer tyrosine kinase inhibitors (TKIs) received new indications as first-line treatment options for chronic myelogenous leukemia (CML) in the past year. Susan O’Brien, MD, the University of Texas M. D. Anderson Cancer Center, Houston, said the NCCN panel updated guidelines to include nilotinib (Tasigna) and dasatinib (Sprycel) as options for patients with newly diagnosed Philadelphia chromosome–positive CML. Studies show dasatinib and nilotinib are associated with significantly higher response rates than imatinib (Gleevec) at 12 months and fewer patients treated with these agents progressed to accelerated phase or blast crisis. Data from the ENESTnd study, reported at the 2010 annual meeting of the American Society of Hematology, showed that >60% of patients with newly diagnosed CML had achieved major molecular response at 24 months with nilotinib compared with 37% of patients treated with imatinib. Less than 2% of nilotinib-treated patients progressed to accelerated phase or blast crisis, experienced by 4% to 6% of patients in the imatinib arm. “This is the most clinically relevant data in the short-term, because transformation heralds a very poor prognosis,” said O’Brien. The phase 3 DASISION study compared dasatinib, an SRC inhibitor, with imatinib in patients with newly diagnosed CML in the chronic phase. At a median of 12 months’ follow-up, patients in the dasatinib arm were more likely to have experienced major molecular response and complete cytogenetic response than patients treated with imatinib. O’Brien said trials indicate these newer agents offer nearly identical improvements in short-term end points, although their ultimate effect on PFS and OS has not been determined. Adverse effects with both agents are considered manageable. With 3 approved first-line agents, oncologists have the option of starting patients on one of the newer drugs at diagnosis or initiating treatment with imatinib and switching to nilotinib or dasatinib in the secondline. Both have proven highly effective in patients resistant to or intolerant of imatinib who do not have the T315I mutation, which renders patients resistant to all available TKIs. ●

These and other guidelines are available free of charge to registered users of the NCCN Website at www.nccn.org.

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Your goal is to give him a cancer treatment that’s right for him. When you choose a Lilly Oncology product, our goal is to make sure he has access to it.

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The Whole Patient

Considerations for Cancer Treatment–Induced Diarrhea By Christin Melton

C

ancer treatment–induced diarrhea (CTID) occurs in 50% to 80% of patients receiving chemotherapy and 50% of patients undergoing radiotherapy. Older patients, women, patients on an irinotecan-containing regimen, and patients treated in the adjuvant setting are at higher risk of CTID, reported Kelly Markey, PharmD, BCOP. Markey is a clinical pharmacist with the gastrointestinal tumor program at Moffitt Cancer Center in Tampa, Florida, and discussed CTID at the annual meeting of the Hematology/Oncology Pharmacy Association. “There are many different sources for diarrhea in this patient population,” she said. It can be caused by surgery, nosocomial infection, treatment, graft-versus-host disease, and the patient’s malignancy. A diagnostic work-up for diarrhea requires obtaining a clinical history and a description of the stool. “Stool description is especially important, including not only the number of stools but the composition,” said Markey. “Are they watery or bloody? Did they occur nocturnally?” Patients should be checked for fever and asked if they have experienced dizziness, cramping, pain, or weakness.

“Sometimes fever can indicate infection or even bowel obstruction,” she noted. Current medications or diet might also contribute to diarrhea. Persistent diarrhea requires a stool work-up, complete blood count, and assessment of electrolyte levels. Markey said an abdominal examination is also necessary, as is an endoscopy in some cases, to check for Clostridium difficile or inflammatory bowel disease. “Nosocomial infections are most often associated with C difficile,” she said. Other culprits include Salmonella, Shigella, Campylobacter, and Escherichia coli. For diarrhea lasting >7 days, “You need to start thinking about your protozoa.” Patients meeting National Cancer Institute criteria for grade 1/2 persistent diarrhea but who do not have fever, dehydration, neutropenia, or blood in their stool can be seen at the office. Patients with grade 3/4 diarrhea require hospital admittance, even if they have no other symptoms. Markey said probiotics, which contain live bacteria or yeast, secrete acids that lower the pH level in the gastrointestinal (GI) tract, which thwarts the growth of pathogenic bacteria. “They also secrete toxins to these bacteria, such as hydrogen perox-

ide, and they inhibit the binding of these bacteria to the GI tract,” she explained. Caution is recommended when using probiotics in patients who are immunocompromised or have central venous devices. Probiotics should not be used in patients on an antifungal agent. A concern with probiotics is that they are not quality controlled by the US Food and Drug Administration. Several antimotility agents are used in the initial treatment of CTID. “Many times I find my patients haven’t maximized use of their first-line agents, such as loperamide, and we prematurely move them to a second-line agent,” said Markey. “You want to make sure you’re maximizing your dosing.” For patients with persistent diarrhea, long-acting and short-acting octreotide are available. “Long-acting wouldn’t be used in the refractory-treatment population, but it is being investigated as a prophylactic, particularly in the radiationinduced population,” she said. One study found continuous octreotide infusion effective in patients with colorectal cancer who were receiving 5-fluorouracil. Diphenoxylate, opium tincture, budesonide, and cholestyramine resin are other options for CTID.

If C difficile is the culprit, metronidazole or vancomycin are standard first-line options. “The problem with these agents is they can be efficacious up front, but 20% to 30% of patients are going to recur within 60 days...the majority recur within 2 weeks,” said Markey. Several new drugs for C difficile are on the market. In 2010, a small study by Basu and colleagues reported that 73% of pa tients who were refractory to metronidazole responded to rifamycin (Xifaxan). A 2011 study by Louie and associates determined that fidaxomicin (not yet approved) was noninferior to vancomycin as initial therapy for C difficile; it was associated with a lower rate of recurrence. Nitazoxanide (Alinia) is used against protozoa with similar effectiveness to vancomycin. It is also active against norovirus and rotavirus. Persistent diarrhea can be a lifethreatening complication of anticancer therapy. Even low-grade persistent diarrhea has a negative effect on quality of life. Persistent diarrhea requires prompt investigation, particularly when accompanied by fever. It is important to let patients with cancer know when diarrhea warrants calling their healthcare provider or seeking hospitalization. ●

Managing Elderly Patients Who Have Comorbidities

T

he median age for someone to receive a cancer diagnosis is 67 years according to the Sur veillance, Epidemiology, and End Results database and even higher for certain malignancies. For example, many gastrointestinal cancers are diagnosed in septuagenarians. With the advancing age and expanding waistlines of the US population, the number of patients seen at oncology clinics who have multiple chronic conditions is also expanding. Said Rowena Schwartz, PharmD, BCOP, director of oncology pharmacy at Johns Hopkins Hospital in Balti more, Maryland, and president of the Hematology/Oncology Pharmacy Association, “We know that as patients age, there are more comorbidities; and as patients age, the instance of cancer increases, so it makes sense that those go together.” Schwartz said elderly patients with comorbidities often have worse outcomes with anticancer therapies and said no one is certain why. “Is it because they have high comorbidities and they don’t tolerate treatments, or is it because we dose-modify to deal with the comorbidities? Is it because they don’t present until their disease is advanced because their

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“I like to do phone follow-ups because you can do it every day and get a better picture.” —Rowena Schwartz, PharmD, BCOP

cancer symptoms are confused with the comorbidities?” she asked. “We don’t know why. The data in comorbidities and the data in geriatrics are not really plentiful,” explained Schwartz. The COPIT (Cancer in the Oldest: Prevalence, Related-Illnesses, and Treatment Modalities) study looked at records for 194,797 US military veterans aged >70 years with cancer (99.6% were men) to assess the rates of various comorbidities in this aged population. The researchers found that 70% had hypertension, >50% had hyperlipidemia, 40% had heart disease, 25% had diabetes, 21% had osteoarthritis, 17% were medically frail, 10% had depression, and 6% had dementia. Some patients fell into more than 1 of these categories. A single-institution study by Wedding and colleagues found a high rate of comorbidity in adult patients with

cancer in all age demographics. Comorbidities were severe in approximately three-quarters of the elderly patients compared with half of the younger patients. The rate of severe comorbidities was similar in the cohort of elderly patients without cancer (79%). Schwartz said a 2010 literature review by Lee and associates looked at 34 studies and concluded that clinicians used chemotherapy less often or at lower doses for patients who had comorbidities, regardless of the type or stage of cancer. More than two-thirds (69%) of the 29 studies to report on overall survival found it was diminished in patients with cancer who had comorbidities. The prevalence, range of comorbid conditions, and their effects on treatment and outcomes point to the need for clinicians to consider comorbidities when caring for patients with cancer. Schwartz

believes this is something that must be done on an individual basis, but also at the clinical trial level. “There are no clinical trials that look at comorbidities and look at treatment in individual populations,” Schwartz said. “We may need to look at specific comorbidities in specific populations with specific types of disease.” Monitoring patients with comorbidities involves more than asking questions at a follow-up visit. Schwartz prefers to telephone patients, particularly when prescribing anticoagulation therapies. “I like to do phone followups because you can do it every day and get a better picture.” That daily interaction is important for some of the highest risk patients because “people’s memories just don’t jive with what actually happens,” she said. This is especially true for elderly patients, who, weeks later, might not remember to tell their clinician about a symptom that seemed important at the time. Schwartz said monitoring an elderly patient with comorbidities also requires engaging the people in their lives who provide support. “Figure out where they live and who provides that overview of care.” —CM ●

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VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright Š 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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The Whole Patient Are You Talking to Patients About Smoking Cessation? Continued from cover care and, at the same time, remain silent about a major health risk,” she said. Studies show intervention from a clinician nearly doubles the chances of a patient succeeding in his or her attempt to quit smoking compared with pharmacologic interventions alone or self-help materials. Although medical oncologists often tell smokers they should quit, Pruemer said they do not always explain why. “Patients may think, ‘I’ve already got cancer, what’s the reason to quit?’” She rattled off several: Smoking and nicotine exposure decrease the effectiveness of certain anticancer therapies, particularly erlotinib (Erbitux); tobacco use impairs wound healing after surgery and increases the risk of infection; and for patients receiving radiotherapy, smoking is associated with greater epithelial damage in irradiated tissue and a higher incidence of mucositis. Perhaps the most important reason to quit is that patients who continue smoking have a higher risk of second cancers, shorter survival, and worse quality of life.

cians must dispel these myths and describe how cigarettes operate on them physiologically. Another component of behavioral modification is identifying their smoking triggers. “Make sure they understand the difference between a physical craving and habit.”

Before selecting a pharmacologic aid, Pruemer recommended working with the patient to establish their goals, such as relieving withdrawal symptoms, controlling urges, and abstinence. Most patients have tried quitting before, so she recommended finding out what

worked and what did not work in those attempts. The pharmacologic options are essentially equal in effectiveness, and which one to use is primarily a matter of preference. Nicotine replacement therapy (NRT) comes in various forms and is a popular

Healthcare providers need to be understanding when patients seem reluctant to discuss their tobacco use.

The first step in getting a patient to quit is finding out how much they smoke, which is not always easy. “Do you know that 1 in 6 smokers really doesn’t tell the truth about how much they smoke?” Pruemer asked. Healthcare providers need to be understanding when patients seem reluctant to discuss their tobacco use. Pruemer recommended highlighting the link between smoking and their cancer to motivate them to take the next steps. “If you don’t have a [tobacco cessation] program, refer them to one you know about. They are out there.” A successful program addresses the physiological and behavioral aspects of dependence. “These two have to work together. ...We can’t just hand the patient a box of patches and expect them to be able to quit,” said Pruemer. People highly dependent on cigarettes find it harder to quit. This includes someone who smokes >1 pack a day or who lights up within 30 minutes of waking. People with psychiatric disorders or a history of chemical dependency also struggle. Some patients are convinced that cigarettes have positive effects, like keeping them calm or preventing weight gain. Pruemer said clini-

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The Whole Patient option, but it should be used with caution in patients with underlying cardiovascular disease. Pruemer said the standard dose might not work for heavier smokers. “I have a lot of patients that come in and they smoke 3 or 4 packs a day—I had a lady who smoked 5 packs a day. If you give them the equivalent of 1 pack of nicotine, they’re not going to quit,” she

explained. A Mayo Clinic study in 1995 demonstrated higher quit rates at end points of 8 weeks, 6 months, and 1 year in patients using a 44-mg patch compared with the 11-mg or 22-mg patches. Although researchers have not found an increase in adverse effects when using the dose equivalent of 2 patches, Pruemer said, “I would not do this unless patients

are under the guidance of a physician that you’re working with.” Prescription options consist of bupropion SR (Zyban) and varenicline. “Bupropion works by increasing the central nervous system levels of dopamine, which makes patients feel better.” The drug is started 1 week prior to the scheduled quit date. Patients take

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What happens to the patient caught in the complications of chemotherapy-induced neutropenia? Consider your last patient with neutropenia

Figure. Overall survival by average relative dose intensity (ARDI)

Did your patient experience any consequences from severe or febrile neutropenia? According to a prospective registry study of 2,692 patients encompassing major tumor types, 29.3% overall were impacted by severe or febrile neutropenia in the first 3 cycles of chemotherapy, leaving a large opportunity for risk assessment intervention. This study also showed that the risk of severe or febrile neutropenia was greatest in the first cycle. That risk continued in subsequent cycles.*1

1.0

In a retrospective database analysis (N = 41,779), the inpatient mortality rate for febrile neutropenia–related hospitalization was 9.5%. This inpatient mortality rate was directly related to the number of major comorbidities present at the time of admission. Major comorbidities were defined as any major organ dysfunction requiring diagnostic or therapeutic intervention. Inpatient mortality ranged from 2.6% (556/21,386) for patients with no comorbidities to over 50% (181/358) for those with 4 or more.2

Optimal chemotherapy delivery was shown to improve survival in some tumor types Retrospective studies have shown that dose delays and reductions due to severe or febrile neutropenia may impact treatment plans and result in unfavorable outcomes for some diagnoses.3-7 While there are inherent risks associated with chemotherapy treatment, landmark studies in both non-Hodgkin’s lymphoma (NHL) and early-stage breast cancer have shown that closer adherence to standard doses is one factor that was associated with increased survival rates.8-11 A retrospective analysis demonstrated significantly longer median survival (7.08 years) for patients with NHL who received > 90% average relative dose intensity of CHOP-21 compared with those who received ≤ 90% (N = 210; P = 0.002) (see Figure).12 Multivariate analyses have identified several independent risk factors for reduced relative dose intensity. The risk factors for relative dose intensity < 85% among early-stage breast cancer patients included age, weight, and three-drug regimens (CAF or CMF).3

0.8 Estimated survival

Febrile neutropenia–related hospitalization can lead to mortality

0.9

0.7 0.6

ARDI: ≤ 85%

0.5

ARDI: 86% to ≤ 90%

0.4 ARDI: > 90%

0.3 0.0 0

1

2

3 4 5 Years post-chemotherapy

6

7

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Retrospective chart data of overall survival in 210 patients treated with CHOP-21 according to average relative dose intensity (ARDI). CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone.

For patients with NHL, age > 60 years, advanced disease stage and poor performance status were associated with relative dose intensity < 85%.4

You can intervene for your next patient A comprehensive risk assessment protocol is critical to helping you identify patients at risk for clinically significant febrile neutropenia.

Consider the risk of the chemotherapy regimen ie, chemotherapeutics administered, alone or in combination

Assess patient risk factors eg, age ≥ 65 years, poor performance status

Risk increases with more comorbidities eg, COPD, cardiovascular disease, diabetes mellitus

Evaluate each patient prior to every cycle To request a febrile neutropenia Risk Assessment Checklist, email: FNchecklist@amgen.com.

Assess the risk.

References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Kuderer N, et al. Cancer. 2006;106:2258-2266. 3. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 4. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 5. Lyman G, et al. J Natl Compr Canc Netw. 2009;7:99-108. 6. Link B, et al. Cancer. 2001;92:1354-1367. 7. Picozzi V, et al. Oncology. 2001;15:1295-1306. 8. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 9. Bonadonna G, et al. BMJ. 2005;330:217-222. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Kwak L, et al. J Clin Oncol. 1990;8:963-977. 12. Bosly A, et al. Ann Hematol. 2008;87:277-283.

MC49941

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Patients unable to quit on a single-agent option might be candidates for therapy that combines NRT agents or uses an NRT agent with bupropion.

Adapted from Bosly A, et al. Ann Hematol. 2008.

*Crawford J, et al. J Natl Compr Canc Netw. 2008. Nationwide, prospective registry study conducted in 115 community-based, randomly selected, IRB-approved sites, evaluating the incidence and timing of neutropenia and neutropenic events in the first cycle and in cycles 2–3 across major tumor types.

© 2010 Amgen. All rights reserved.

150 mg once daily for 3 days and then increase to twice-daily dosing for the remaining 7 to 10 weeks of therapy. The drug increases the risk of seizures, and Pruemer advised extreme caution for patients with a history of brain surgery or trauma, patients taking medications that increase seizure risk, and patients with severe cirrhosis. Bupropion is contraindicated in patients with bulimia, anorexia nervosa, or seizure disorders, and in those who are abruptly quitting alcohol or sedatives. Varenicline binds to nicotine receptors, blocking the usual dopaminergic boost patients get from smoking. It also helps alleviate withdrawal symptoms. As with bupropion, patients should start the drug 1 week prior to their quit date; it should be taken with food. The dose is titrated to 1 mg twice daily by the start of the second week. This dosing is continued for 10 weeks. Pruemer cautioned that varenicline increases the risk of depression.

Patients unable to quit on a singleagent option might be candidates for therapy that combines NRT agents or uses an NRT agent with bupropion. Varenicline should not be used as part of a combination regimen. Another option is to continue on pharmacologic therapy beyond the standard treatment period. During the question and answer session, Pruemer was asked whether patients with rapidly progressive disease or in palliative care should quit. “Even those patients are going to have a higher risk of pneumonia and more complications at the end of life, and their quality of life is going to be poorer. There’s plenty of data that still recommends they should be quitting,” she responded. The benefits of smoking cessation are immediate and long-term for patients with cancer, and Pruemer said, “It can be one of the single most effective strategies to improve outcomes for our patients.” Individuals who work at places that do not offer smoking cessation programs can still help their patients who smoke by initiating the conversation and then referring them to an established program. ●

March/april 2011 I VOl 4, NO 2

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The Whole Patient

Managing Geriatric Patients By Christin Melton

G

eriatric case management should always begin with a Comprehensive Geriatric Assessment, said Demetra Antimisiaris, PharmD, GCP, FASCP, assistant professor with the Department of Family Medicine & Geriatrics and director of Geriatric Pharmacotherapy at the University of Louisville School of Medicine in Kentucky. In a presentation at the 2011 annual meeting of the Hematology/ Oncology Pharmacy Association, Antimisiaris said many criteria must be considered when assessing a patient’s functionality: nutritional status, activity levels, medical and psychological states, environment, and gait and balance. Obtaining this baseline measure is critical because commonly prescribed and over-the-counter medications often have unanticipated effects on an elder’s behavior or function. Antimisiaris said medications—even run-of-the-mill drugs like ibuprofen— were never tested in this demographic prior to approval. “Older adults are underrepresented in clinical trials,” she said, adding that exclusions for comorbidities prevent many elderly patients from participating. “Data is especially sparse for individuals 75 and older.” Antimisiaris cited an Alzheimer’s drug trial as an example of how drugs wind up being used in patients for whom they were never tested. This particular trial limited enrollment to individuals with Alzheimer’s and “no other neurodegenerative disease,” she said. Because an Alzheimer’s diagnosis is typically only confirmed at autopsy, Antimisiaris said the drug is likely going to be used in patients with other types of dementia, causing unexpected toxicities. Even if more drug trials included the oldest patients, applying the results would be challenging. “We become more diverse as we age,” she said, explaining that “a pediatric kidney is a pediatric kidney, but a 65-year-old’s kidney might be different from another 65-year-old’s kidney depending on how they lived their life as they aged.” Complicating the ability to recognize when an elderly patient is having a negative response to a drug or combination of drugs is the range of nonspecific signs and symptoms they exhibit. “Elderly people don’t present with the classic symptoms you might expect,” said Antimisiaris. One reason is that, as people age, protein levels diminish and the blood-brain barrier becomes increasingly porous. As a result, many patients will exhibit psychological changes, like “agitation, manic behavior, change in effect, confusion, not eating, or not sleeping.”

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“Being strong in geriatric medication management requires knowing how unnecessary medication use happens and how to recognize when a medication is causing problems.” —Demetra Antimisiaris, PharmD, GCP, FASCP

Guidelines in hand, a physician might respond to a complaint of insomnia with a prescription for zolpidem (Ambien), when replacing or discontinuing a drug in the patient’s current regimen could have resolved the problem. “Being strong in geriatric medication management requires knowing how unnecessary medication use happens and how to recognize when a medication is causing problems,” said Antimisiaris. “We’re so guidance driven [that] we’ve kind of lost the part about being able to see toxicities when they’re right in front of us.” She described a huge gap between “the bench science and the bedside” and said providers must exercise clinical judgment when caring for elders. “Polypharmacy is prevalent among elderly patients,” Antimisiaris said, noting that guidelines often fail to address how drugs interact. Studies show total drug burden is important for this patient population, and she pointed to a 2007 study by Garfinkle and colleagues. They found that cutting the number of drugs given to a group of geriatric patients in palliative care by an average of 2.8 improved outcomes compared with a control group of patients whose drug regimens stayed the same. The 1-year mortality rate was 21% in the study group versus 45% in the control arm, and only 11.8% of patients in the study group needed referrals to acute care each year compared with 30% of patients in the control group. Drug burden affects quality of life, Antimisiaris said, with each additional unit negatively affecting physical function and cognitive task performance. “Keep what you need, lose what you want. … Keep the warfarin, lose the Ambien.” Antimisiaris outlined important considerations when medicating elderly patients: • Elders have decreased total body water, so use “baby doses” of watersoluble drugs to prevent excessive drug concentrations. • Elders typically have more body fat

and thus an increased risk of toxicity when using fat-soluble or lipophilic drugs (psychotropics, vitamins A and E, some statins), which are slow to activate and accumulate. • Elders have decreased serum protein levels and consequently a higher rate of free drug, so treat to efficacy and not to levels. • Almost 50% of elders are slow metabolizers, associated with an increased risk of adverse effects and toxicity; don’t just assume the drug is not working and then increase the dose. • Watch for drug–drug interactions and toxicities in patients treated with 1 or more drugs metabolized along the CYP3A4 pathway. • Elders, especially those aged >85 years, frequently have impaired kidney and renal function, so evaluate total drug burden. • Try to elicit from the patient information about changes in behavior or mood by asking questions like “Are you sleeping?” or “Are you still doing [a favorite activity]?”; responses might indicate an adverse drug reaction. Prescribing the right drugs is only one component of drug management for geriatric patients; adherence is another. With the typical physician’s office visit lasting only 7 minutes, Antimisiaris said, “nobody is testing [elderly patients’] literacy or cognitive function” to assess whether they are capable of managing their drug regimen. “Have the patient draw a clock,” she suggested. “That will tell you whether they can handle taking an aspirin a day,” she said. Antimisiaris warned that the coming years are likely to bring an influx of elderly patients to oncology clinics. “The elders are coming…they’re sicker, more frail, and harder to manage,” she said. Before that happens, we must do more to learn about needs specific to elderly patients and to educate care teams on what we already know. ●

Balloon Kyphoplasty Reduces Pain from Vertebral Compression Fractures

I

n a randomized trial of patients with cancer who were suffering from vertebral compression fractures (VCFs), balloon kyphoplasty was associated with greater pain relief and better quality of life than nonsurgical care. According to the authors, patients who received kyphoplasty relied significantly less on pain medication, bed rest, and walking assistance 1 month after undergoing the procedure. James Berenson, MD, founder and president of the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, led the multinational Cancer Patient Fracture Evaluation (CAFE) study, and results were published online in Lancet Oncology. In an interview with The Oncology Nurse-APN/PA, Berenson said, “Any cancer patient with a vertebral compression, whether the cancer in volves the vertebral body or not, would be a candidate for this procedure.” He said balloon kyphoplasty should be performed “without delay” as soon as a symptomatic VCF is diagnosed. Balloon kyphoplasty might be contraindicated, however, in patients with advanced disease who are not expected to survive long or those who are considered poor surgical risks. The study enrolled 134 adults with cancer, each of whom had suffered 1 to 3 VCFs. More than half the patients (60%) had a diagnosis of multiple myeloma or breast cancer, both of which are associated with bone complications. Investigators randomized 70 patients to undergo the balloon kyphoplasty procedure, along with the option to use nonsurgical care for pain as needed. The remaining 64 patients made up the control group, and these patients could only use nonsurgical methods of relieving pain. All patients were allowed to continue their cancer treatments as prescribed. To measure improvement in backspecific functionality, the research team administered the RolandDisability Questionnaire (RDQ) at baseline and repeated it at a 1-month follow-up appointment. Using the RDQ scale, 0 indicates no disability and 24 indicates a maximum level of disability. At baseline, the mean RDQ score for patients in the kyphoplasty group was 17.6 compared with 18.2 for the control

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The Whole Patient group. At 1-month follow-up, RDQ scores for the kyphoplasty group declined by a mean of 8.3 points to 9.1 (P <.0001). In contrast, RDQ scores only declined a mean of 0.1 points for the control arm, falling to 18.0 (P <.0001). Other standardized tests were used to measure pain, physical and mental health, and performance status. The 10point pain scale reflected a significant drop of 3.8 points in pain levels for the kyphoplasty group at 7 days postprocedure; this compared with a 0.3-point drop in pain levels for the control arm (P <.0001). At 1 month, end points continued to favor balloon kyphoplasty. At 1 year, pain assessments for the groups began to converge, and no significant difference in pain levels was observed between the 2 arms. Berenson said data at the end of the trial were biased because “only a small minority of patients made it to that time point.” He noted that those patients in the study who were alive at 1-year followup likely had better quality of life in general, particularly regarding pain levels, compared with the study population as a whole.

Balloon kyphoplasty is associated with few adverse effects.

uncommon in patients who have cancer. “A procedure that effectively treats VCFs for patients with cancer might confer clinical and quality-of-life benefits beyond treatment of the fracture itself,” they wrote. Balloon kyphoplasty is associated with few adverse effects. Berenson said, “Very rarely, there can be significant extravasation of the cement outside of the cavity in which it is intended.”

The study was limited by its short duration and its open-label design. In an accompanying editorial, David Schiff, MD, and Mary E. Jensen, MD, University of Virginia, Charlottesville, said because of the study design, a placebo effect could not be ruled out. They said additional trials should be conducted before adopting the costly surgical procedure as standard practice. Medtronic, which makes the Kyphon

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Berenson and colleagues noted that 94% of patients treated with kyphoplasty had been taking pain medications prior to the procedure. At a follow-up assessment 1 month after undergoing the procedure, in vestigators found the proportion of patients using pain medication had declined to 52%. In the control arm, however, the use of pain medication remained consistent. After 1 month, patients initially randomized to the control group were permitted to cross over into the kyphoplasty group, and 38 patients decided to do so. This subgroup of 38 patients experienced improvement in pain and function at similar rates and levels to the patients assigned to the original kyphoplasty group. One-year assessments of patients in the initial kyphoplasty group and patients in the kyphoplasty crossover group showed that they had maintained their 1-month improvements in pain and function. The authors hypothesized that the improved function afforded by balloon kyphoplasty might contribute to a reduction in the risk of events such as decubitus ulcers and pneumonia, which are not

www.TheOncologyNurse.com

balloon kyphoplasty device used in the study, provided funding. Berenson and other authors have received consulting fees, honoraria, and research funding from Medtronic. Several authors were Medtronic employees, and one disclosed relationships with Synthes, Orthofix, and Alphtec. Schiff has received consulting fees from Genentech, and Jensen acknowledged consulting fees from Kuros Biosurgery.—CM ●

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News in Review

Radiation Therapy for Initial Cancer Causes Relatively Few Second Cancers By Christin Melton

R

esearchers from the National Cancer Institute report that radiation therapy for a first cancer is unlikely to lead to a second cancer diagnosis later in life. Berrington de Gonzalez and associates conducted a retrospective review of data from the Surveillance, Epidemiology, and End Results cancer registry for nearly 650,000 adults who received a cancer diagnosis between 1973 and 2002 and survived at least 5 years. Approximately 50% of patients received radiation, and only 8% of these (n = 3266) developed a second malignancy considered attributable to the therapy (95% confidence interval [CI], 7%-9%). Almost all 650,000 patients were at least 20 years of age at diagnosis and had 1 of 15 tumor types commonly treated with radiation: rectal, lung, breast, prostate, cervical, testicular, endometrial, brain, central nervous system, ocular and orbital, laryngeal, salivary gland, oropharyngeal, and soft tissue tumors. An estimated 60,000 patients, including 42,000 given radiotherapy, developed a second primary cancer, suggesting that the overall rate of second primary cancers is low. The authors said at 15 years’ followup, 5 excess cancers occurred per every

Voluntary Recall of Irinotecan Announced By Dawn Lagrosa

Factors associated with increased risk of a second cancer included a younger age at diagnosis of the first cancer and greater radiation exposure (>5 Gy) during therapy.

1000 patients whose initial cancers were treated with radiotherapy (median follow-up, 12 years). Among patients who received radiation, secondary cancer risk varied according to the initial type of cancer. The relative risk was lowest for women treated for breast cancer, at 1.10 (95% CI, 1.07-1.13). Men treated for testicular cancer had the highest relative risk, at 1.43 (95% CI, 1.13-1.84). Factors associated with increased risk of a second cancer included younger age at diagnosis of the first cancer and greater radiation exposure (>5 Gy) during therapy. The risk increased as the patients aged. The authors ruled out second cancers that occurred within 5 years of radiation therapy as being treatment related. They noted that patients often have more fol-

low-up care in the first 5 years after treatment and were concerned that including cancers diagnosed during this time frame might bias results. The investigators did not assess whether the patients had other known risk factors for cancer, such as smoking history, hormonal therapy, obesity, and exposure to carcinogenic chemotherapy drugs. They did a subanalysis of patients who did not receive chemotherapy, however, and found consistent results. Most patients in the study received radiotherapy prior to widespread use of intensitymodulated radiotherapy, but the authors believe studies will continue to show that the benefits of radiotherapy outweigh the risk of second cancers. The study was published online in Lancet Oncology in March. ●

A

PP Pharmaceuticals has issued a voluntary recall of 5 lots of irinotecan hydrochloride injection (Camptosar) as a precautionary measure. No adverse events related to the recalled products have been reported. The following lots have been recalled: • 870DE00301 • 870CZ00301 • 870DE00101 • 870DE00201 • 870DE00401 APP issued the recall after receiving customer complaints associated with lot 870DE00301, in which particulates were observed in the product solution. An investigation of the vials returned to the manufacturer established that the particulate matter was a fungal microbial contaminant. After consulting with the US Food and Drug Administration, and as a precautionary measure, all lots produced immediately before and after lot 870DE00301 are being recalled. For complete details, visit www.apppharma.com. ●

Variation in Prescribing Instructions Confuses Patients on Multidrug Regimens

E

very physician has a preferred way of writing prescription instructions, and pharmacists differ in how they translate those instructions to the pill bottle. A study published in the Annals of Internal Medicine by Wolf and associates found that the lack of a universal medication schedule (UMS) to standardize how prescriptions are written and filled contributes to poor patient adherence and increases safety concerns. Elderly patients or those with low health literacy are more prone to confusion when trying to follow a multidrug regimen. In a 2008 report, “Standardizing Medication Labels,” the Institute of Medicine (IOM) recommended implementing a UMS to reduce misunderstandings related to medication use. Noting that 90% of prescriptions require no more than 4 daily doses, the IOM called for delineating 4 standard dosage times—morning, noon, evening, and bedtime—to help patients taking multiple drugs to consolidate doses. Reception

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to the proposal was mixed, with calls for more research. To determine whether a UMS was needed, investigators assessed the ability of 464 patients aged 55 to 74 years to adhere to a hypothetical 7-drug prescription regimen. The patients were part of a broader study that incorporated a 2-hour interview to evaluate their adeptness at performing everyday health tasks. Most (84%) had at least 1 chronic health condition; approximately 61% were college educated and an equal proportion had household incomes >$50,000. Researchers gave every patient prescription bottles containing fake pills and mock labels for 7 retired drugs; dosing instructions varied between the drugs. Patients also received a pill box with 24 slots marked with consecutive 1-hour intervals, going from 12:00 AM to 11:00 PM. Each patient was verbally instructed to “imagine that your doctor has prescribed you these medications. I would like you to please show me when you would take these medicines over the

course of 1 day,” and offered additional instruction as needed. Although the drugs could be neatly consolidated into 4 dosing intervals, participants sorted them into an average of 6 slots. Some consolidated the regimen into as few as 3 dosing periods, whereas others used as many as 14 slots. One-third of patients indicated 7 intervals each day for taking drugs; 14.9% indicated 4 times or fewer. Labels for 3 drugs had identical dosing instructions and could therefore have been taken simultaneously, yet one-third of patients failed to do so. Another 2 drugs required thrice-daily dosing, with 1 stipulating to take it with food and water. Only 50.5% of participants scheduled them to be taken together. Another 2 drugs needed to be taken twice a day; the label for one said “twice daily” and the other said “every 12 hours.” In all, 79% of patients failed to consolidate them into concurrent dosing intervals. For drugs calling for twice-daily dosing, an average of 10.3 hours elapsed

between doses (range, 1 hour to 18 hours). For thrice-daily dosing, a mean of 5.4 hours elapsed between the first and second doses and 6.5 hours between the second and third doses. Low health literacy—ascribed to 20.7% of patients—was the only factor that independently predicted a greater likelihood of taking medications more than 7 times per day. Patients with low health literacy and no chronic conditions had the worst rate of efficient consolidation. The authors said strategies are needed to help patients understand how to take prescriptions and how to consolidate multiple prescriptions. They said adopting a UMS could “unite medical and pharmacological practice” and suggested that an electronic health records system could be used to facilitate standardization in prescribing. They also recommended educating providers on how to identify patients likely to have trouble adhering to a complicated regimen.—CM ●

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News in Review

Eribulin Improves Overall Survival in Women with Heavily Pretreated Metastatic Breast Cancer By Christin Melton

D

ata published in the Lancet in March support the effectiveness of eribulin mesylate (Halaven)â&#x20AC;&#x201D;a microtubule inhibitorâ&#x20AC;&#x201D; in women with advanced breast cancer that has progressed after several treatments. The US Food and Drug Administration approved eribulin in November 2010 for metastatic breast cancer patients treated with at least 2 chemotherapy regimens (an anthracycline and a taxane). As EMBRACE investigator Chris Twelves, MD, said last year at the American Society of Clinical Oncology annual meeting, this is the first evidence that a chemotherapeutic agent can improve overall survival (OS) in a heavily pretreated population.

TPC arm received chemotherapy and continued treatment for a median of 2.1 months; 9 patients took hormonal agents for a median of 1.0 month.

During the study, fewer deaths occurred in the eribulin arm than in the TPC group (54% vs 58%, respectively), and more patients in the

eribulin arm than in the TPC arm survived 1 year (53.9% vs 43.7%, respectively). Independent review found progression-free survival (PFS) slight-

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The primary end point of EMBRACE was a significant increase in OS, and this was met, with eribulin improving survival by 2.5 months. Median OS was 13.1 months in the eribulin arm versus 10.6 months in the treatment of physicianâ&#x20AC;&#x2122;s choice (TPC) group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-0.99; P = .041). Following eribulinâ&#x20AC;&#x2122;s demonstrated activity against breast cancer in phase 1 and phase 2 studies, investigators enrolled 762 women from 19 countries for this phase 3 trial. All participants had locally advanced or recurrent metastatic breast cancer and had completed 2 to 5 chemotherapy regimens. In the study, 16% of women were HER2-positive and 19% had triple-negative disease, but results were not stratified according to cancer subtype. Investigators randomized patients at a 2:1 ratio to eribulin (n = 508; 1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle) or TPC (n = 254). Median duration of treatment was 3.9 months in the eribulin group, with 59% of patients receiving at least 5 cycles. Most (96%) patients in the

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March/april 2011 I VOl 4, NO 2

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he addition of new biomarkers for available establishing a prognosis in the United States: for pa- DX (Genomic Oncotype tients with breast Health) and MammaPrint cancer has been recommended in (Agendia). the 2010 American Joint Committeeedition of the of Cancerâ&#x20AC;&#x2122;s 21-gene Cancer Staging Handbook.1 recurrence score Human epiderassay mal growth factor Available since 2004, Oncotype (HER2) status and receptor type 2 uses a process called reverse-transcrip DX multigene signature â&#x20AC;&#x153;scoresâ&#x20AC;? have been tase polymerase chain added to estrogen reaction (RT-PCR) receptor (ER) and to progesterone receptor look at 21 genes: 16 are linked to breast (PR) determinations.1 cancer and five are reference genes used regarding multigene So, where are we for normalizing the expression of the signature scores? At this time, two tests cancer-related genes. The chosen genes are commercially have Continued on page

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NAVIGATION & SURVIVORSHIP The Official Journal of

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Pamela Matten, RN, BSN, OCN St. Joseph Hospital Orange, California Elaine Sein, RN, BSN, OCN, CBCN Fox Chase Cancer Center Rockledge, Pennsylvania Partners Tricia Strusowski, MS, RN Helen F. Graham Cancer Christiana Care Health Center System Newark, Delaware Linda Fleisher, MPH, PhD(c) Fox Chase Cancer Center Cheltenham, Pennsylvania Susan M. Gardner, RN, Valley Medical Center CBEC, CBCN Renton, Washington Jay R. Swanson, RN, Saint Elizabeth Cancer BSN, OCN Institute Lincoln, Nebraska Carol Lewis, RN, BSN, OCN, CRNI Memorial Hermann The Woodlands, Texas

AONN Staff Sean T. Walsh Executive Director sean@AONNonline.org

VOL 1, NO 7

Continued on page

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Nurse Navigators ÂŽ

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he George Washington Cancer the network, Institute (GWCI) recently re- embedded and patient navigators are and a secure ceived a $2.4 million at every site, said Steven tion process, Internet-based data collecthe DC Cancer Consortiumgrant from Patierno, PhD, which allows the navigators executive director to estab- the GWCI. lish and coordinate of to upload their a City-wide Patient navigation logs and Navigation Network their patient interactions in real time. (CPNN) in Washington, DC. The CPNN will create a seamless, cohesive framework for â&#x20AC;&#x153;The CPNN will cancer care throughout coordination of create that all city residents the city to ensure cohesive framework a seamless, get appropriate canfor cer screening and treatment regardless cancer care throughout coordination of of their ability to pay. the city. â&#x20AC;? The help patients identify network will also â&#x20AC;&#x201D;Steven Patierno, PhD throughout the cancer support services cluding posttreatment continuum, insurvivorship. Twenty-five separate institutions, including hospitals, The program, he cancer explained, provides community organizationscenters, and training once a He gave an example month to every navigator of how coordinain the and every Washington, DC, tion of care works. navigatorâ&#x20AC;&#x2122;s supervisor. area are members â&#x20AC;&#x153;If a patient is seen It also a community of provides a central advocacy group that at communications portal does

NAVIGATION

Center Provides Platform for Discussion Cancer Survivorship, of Navigation, and Policy

Journal of Oncology Navigation & Survivorshipâ&#x201E;˘

2

By Karen Rosenberg

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he Center for the Advancement policy analysis, and of Cancer Survivorship, education. NavicaSNP grew out of gation, and Policy the understanding (caSNP), a that collaboration of the there is â&#x20AC;&#x153;overlap George Cancer Institute (GWCI) Washington navigation, survivorship,between patient and the uni- both and policy and versityâ&#x20AC;&#x2122;s School of of these intersect Public with local and Health Services DepartmentHealth and national healthcare policy,â&#x20AC;? explained of Health Steven Policy, was established Patierno, PhD, executive in 2009 with of director support from Pfizer the GWCI. â&#x20AC;&#x153;We wanted to create and the Pfizer Foundation. The a platform to talk about centerâ&#x20AC;&#x2122;s navigation and suradvance patient navigationgoals are to vivorship in the context of policy and cancer united in a survivorship efforts program.â&#x20AC;? both locally and nationally through The center offers training training, research, programs at three levels:

â&#x20AC;˘ Navigation training is navigators, including designed for nurses, social workers, and lay persons. Trainees from institutions across try learn about barriers the counthat affect their patients, are trained to launch or improve programs, gain tools for implementing and institutional change. â&#x20AC;˘ Executive level training is designed for chief executive officers, chief financial officers, hospital adminis-

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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

Breast Cancer Prolonging Chemotherapy Breast Cancer Improves in Metastatic Survival

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TON_April2011_v7_TON 4/7/11 12:30 PM Page 51

News in Review ly better with eribulin, at a median of 3.7 months versus 2.2 months when taking TPC (HR, 0.87; 95% CI, 0.71-1.05; P = .137) in the intent-to-treat (ITT) population. Investigator assessment found significantly improved PFS for the eribulin arm of the ITT population (HR, 0.76; 95% CI, 0.64-0.90; P = .002). In this heavily pretreated population, 12% of patients given eribulin demon-

strated objective response compared with only 5% of patients receiving TPC (P = .002). The median duration of response was shorter with eribulin than with TPC (4.2 vs 6.7 months, respectively; P = .159), but the clinical benefit rate for the eribulin arm was higher than for the TPC arm due to eribulin’s improvements in OS and response (23% vs 17%, respectively).

In this heavily pretreated population, 12% of patients given eribulin demonstrated objective response compared with only 5% of patients receiving TPC. Most patients experienced 1 or more adverse events, most of which were grade 1/2. In the eribulin arm,

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Who Should Attend All clinical and nonclinical professionals involved or interested in patient navigation and survivorship. This conference will enhance the skills and knowledge of: • Oncology Nurse Navigators • Administrators • Patient Navigators • Oncology Social Workers • Oncology Nurses & • Case Managers Nurse Practitioners • Practice Managers

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99% (503) of patients suffered an adverse event, which was serious in one-quarter of patients. In the TPC arm, 93% (230) of patients had an adverse event, with 26% experiencing a serious adverse event. Compared with the TPC group, the eribulin arm had higher rates of grade 3/4 neutropenia (21% vs 45%, respectively), leukopenia (6% vs 14%, respectively), and peripheral neuropathy (2% vs ~9%, respectively). Patients taking eribulin who had grade 1/2 neuropathy at the start of the study were no more likely to develop grade 3/4 neutropenia than patients starting the study with no signs of neuropathy. Hypersensitivity reactions were uncommon, reported in only 1% of patients taking eribulin. In each study arm, 1% of patients suffered fatal adverse events due to treatment. The 5 eribulin-related deaths were attributed to febrile neutropenia, lung infection, bronchopneumonia, and dyspnea (2 cases). Treatment-related deaths in the TPC arm consisted of 1 case of febrile neutropenia and 1 case of aspergillosis. After the study’s conclusion, a requested updated analysis of OS rates found that 76% of patients in the eribulin arm had died compared with 80% of patients in the TPC group (HR, 0.81; 95% CI, 0.67-0.96; P = .014). Investigators said this showed eribulin’s survival advantage persisted over time. An ongoing study is comparing eribulin with cap ecitabine in women with previously treated metastatic breast cancer in an effort to assess quality of life. Although the authors concede that the range of agents used in the TPC group could be considered a limitation of the study, they counter that their protocol better reflects “real-life choices made by oncologists and their patients.” They recommend that eribulin be considered a new standard of treatment for heavily pretreated women with metastatic breast cancer. The authors disclosed that the study was funded by Eisai and Eisai employees took part in analyzing the data. ●

Questions or comments about this issue? E-mail us at editorial@greenhillhc.com.

March/april 2011 I VOl 4, NO 2

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TON_April2011_v7_TON 4/7/11 12:30 PM Page 52

News in Review

Axillary Lymph Node Dissection Unnecessary for Some Early-Stage Patients with Breast Cancer By Christin Melton

D

ata published in the Journal of the American Medical Association in March indicate that for 20% of women with early-stage breast cancer, removing malignant lymph nodes from the armpit does not improve survival or prevent recurrence. Women in the phase 3 trial who underwent complete axillary lymph node dissection (ALND) had higher rates of lymphedema than those who had sentinel lymph node dissection (SLND) alone (P <.001). They also had higher rates of wound infection, axillary seromas, and paresthesias (70% vs 25%, respectively; P <.001). The study, known as the American College of Surgeons Oncology Group Z0011 trial, was conducted at 115 sites from May 1999 to December 2004 to assess whether SLND was noninferior to ALND. In total, 891 women with similar clinical and disease characteristics were randomized to ALND or SLND and followed for a median of

6.3 years with regular physical examinations and annual mammograms. All women enrolled in the study had stage T1-T2 noninvasive tumors (5 cm or less), with no more than 2 positive sentinel lymph nodes at biopsy, no palpable axillary nodes, and no metastatic spread. Initial treatment consisted of lumpectomy, and 605 underwent wholebreast radiation; women who had received neoadjuvant hormonal therapy or chemotherapy were ineligible. Following surgery, 403 women in the ALND group and 423 in the SLND-only arm received adjuvant systemic therapy, with the types of therapy given fairly well balanced between the study arms. Women in the ALND group had an average of 17 nodes removed compared with 2 in the SLND arm. At a median of 6.3 years after enrollment, 52 women in the ALND group had died compared with 42 in the SLND group, for an unadjusted hazard ratio of

Tamoxifen Protective 10 Years After Treatment

A

new study shows that tamoxifen protects high-risk women against breast cancer for as long as a decade after treatment ends. Joyce Noah-Vanhoucke, PhD, Archimedes Inc, San Francisco, California, and colleagues conducted the metaanalysis and found that using tamoxifen to prevent breast cancer in postmenopausal women aged <55 years was cost-effective and saved lives. The researchers created a virtual clinical trial filled with simulated patients based on breast cancer incidence and survival rates from the Surveillance, Epidemiology, and End Results registry. Treatment in the mathematical model followed protocols used in 4 randomized, placebo-controlled trials that evaluated the effectiveness of 5 years of tamoxifen at preventing breast cancer. All women in the simulation were aged <55 years when treatment started and postmenopausal, and all had a Gail risk score of 1.66% or greater, indicating a high risk for breast cancer. The study population was restricted to women aged <55 years to allow a more accurate assessment of tamoxifen’s contribution to reducing breast cancer risk or increasing the risk of events such as endometrial cancer and blood clots, which are more common in older women. In the article, published in Cancer, the authors said previous studies that

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March/april 2011 I VOl 4, NO 2

found tamoxifen was not cost-effective due to its side effects profile had based their calculations on the assumption that tamoxifen’s prophylactic benefit ended when the drug was stopped. The studies selected for the meta-analysis had extended follow-up that showed benefits did not end with treatment but persisted for another 10 years. For every 1000 women treated with tamoxifen in the original trials, 36 lifeyears were saved or 29 quality-adjusted life-years (QALYs), at a cost of $11,530 per QALY. In evaluating results for the subpopulation of women aged <55 years used in the model, the authors said, “Tamoxifen use in this population is forecast to save 85 QALYs per 1000 postmenopausal women age <55 with cost savings of $47,580 compared with no treatment over lifetime follow-up.” A total of 69 life-years were also saved. Stratifying women according to risk scores showed that as breast cancer risk increased, years saved and QALYs increased while the cost per QALY decreased. Tamoxifen’s use as a chemopreventive has been limited because of side effects. The authors said the study showed that the benefits of tamoxifen prophylaxis in this patient population compensated for the risks and costs of managing adverse events, even though some were serious.—CM ●

0.79 (90% confidence interval, 0.561.10), which the authors said demonstrated the noninferiority of SLND alone (P = .008). The 5-year overall survival rates were also similar between the groups, at 92.5% in the SLND-only arm and 91.8% in the ALND group. No statistically significant difference in survival rates was observed when stratifying the patients according to estrogen- or progesterone-receptor status. In the SLND-only arm, 83.9% of women had no recurrence at 5 years compared with 82.2% of women in the ALND group (P = .14). The 5-year rate of local recurrence was 1.6% in the SLND-only arm versus 3.1% in the ALND group, supporting the conclusion that ALND does not prevent recurrence. The authors concluded that “the only rationale for ALND in these patients would be if the finding of additional nodal metastases would result in changes in systemic therapy.” Because current

treatment guidelines generally call for the same adjuvant therapy regimen regardless of nodal status, the authors said “ALND does not appear to be warranted in this patient population.” For women with early-stage breast cancer similar to the women in this study, foregoing ALND offers the potential to improve quality of life significantly. Armando E. Giuliano, MD, chief of surgical oncology at the John Wayne Cancer Institute at St. John’s Health Center, Santa Monica, California, was lead author of the study. He presented preliminary findings last year at the annual meeting of the American Society of Clinical Oncology and noted then that it might be hard for some physicians to abandon ALND, which has been standard practice for at least a century. Additional studies will need to determine whether women with more than 2 positive sentinel nodes or matted nodes can safely forego ALND. ●

Marijuana Ingredient Improves Eating and Sleeping

A

small Canadian study found that patients who took delta-9tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, slept better and derived more enjoyment from eating than patients given a placebo. The University of Alberta investigators, led by associate professor Wendy Wismer, recruited terminal patients with advanced cancer who were randomly assigned to take 2.5 mg of dronabinol (a pill form of THC) or placebo twice daily for 18 days. Afterward, the participants completed questionnaires to assess whether their quality of life improved during the study. Chemotherapy, along with certain types of cancer, often affects the senses of smell and taste and leads to anorexia in some patients. Helping patients maintain a healthy weight and nutritional status is challenging, which was the impetus for the study. All the participants underwent chemotherapy prior to enrollment, and approximately two-thirds reported mild to moderate changes in their sense of taste. Although 73% of the THC group found food more appealing and 55% said food tasted better while taking the

drug, overall calorie intake was similar between the 2 groups. Patients in the THC group did increase their consumption of meat, a food that commonly induces nausea during chemotherapy and tends to be avoided. The investigators said patients taking THC reported improvement in their sleeping habits. A 2009 study by Palesh and associates appearing in the Journal of Oncology observed that more than three-quarters of patients with cancer experience sleep disorders during chemotherapy, and 43% meet the criteria for a diagnosis of insomnia. Palesh and colleagues found a correlation between sleep disorders and depression, and the authors of this Canadian study speculated that THC might help alleviate sleep disorders and depression. They said it might also reduce pain, inflammation, and anxiety. The THC and control arms had similar rates of adverse events, which were minimal overall. The study by Wismer and associates is limited by its small study size and did not analyze the effects of smoking marijuana for medicinal purposes. The complete findings are available in the March issue of the Annals of Oncology.—CM ●

www.TheOncologyNurse.com


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News in Review

FDA Panel Recommends Stricter Process for Accelerated Approval of Cancer Drugs By Christin Melton

T

he US Food and Drug Administration (FDA) held a public meeting in February to assess whether stricter criteria are needed when considering oncology drugs for accelerated approval. Measures enacted in 1992 allow the FDA to grant accelerated approval for drugs targeted at unmet needs in cancer based solely on data from single-arm studies and relying on end points other than the standard metric of overall survival. At the meeting, experts with the FDA’s Oncologic Drugs Advisory Committee (ODAC) criticized the FDA, with Silvana Martino, DO, who directs the Breast Cancer Program at the Angeles Clinic and Research Institute in Santa Monica, California, calling its actions “ignorant.” Gary Lyman, MD, MPH, professor of medicine and director of comparative effectiveness and outcomes research at Duke University School of Medicine and the Duke Comprehensive Cancer Center in Durham, North Carolina, sat on the ODAC panel and discussed the hearing with The Oncology NurseAPN/PA. “The major concern of the ODAC is that accelerated approval has been granted on the basis of a single-arm study in more than half of instances,

which limits a full comparative look at efficacy and safety,” he explained. Lyman said relying on such limited evidence might be appropriate in exceptional cases, such as for drugs to treat rare tumors or when a drug has very strong, observable treatment effects, but “the default recommendation is that this conditional approval be based on at least one well-designed randomized, controlled trial [RCT] reporting significant improvement in an outcome measurement likely to convey clinically meaningful benefit.” In every case, approval should be “based on the robustness of the results in terms of a strong treatment effect and a very favorable risk-to-benefit ratio,” said Lyman. On the rare occasions when accelerated approval is granted without data from an RCT, Lyman said ODAC recommends that the FDA require the drug’s maker to have an RCT under way or imminent. The FDA should review plans for the trial to ensure that its design allows for reliable results, suitable to support licensing approval. The review of the accelerated approval process was prompted by the FDA’s controversial decision in December to withdraw approval of

bevacizumab (Avastin) in breast cancer, which Lyman said was the first time the agency had rescinded an approved indication of a drug brought to market under this mechanism. “There are a number of others—including 6 that we reviewed yesterday—that have not fulfilled their postmarketing requirements and may be vulnerable,” he added. The drugs in question include Erbitux by Eli Lilly, Bexxar and Arranon by GlaxoSmithKline, Clolar by Genzyme, Vectibix by Amgen, and Gleevec by Novartis for its indication in gastrointestinal stromal tumors. At the meeting, the panel questioned manufacturers about their failure to submit requisite follow-up data for these 6 drugs, but the FDA gave no indication that their approval status is in jeopardy. Most of the manufacturers cited difficulty recruiting enough patients for clinical trials to produce meaningful results as the primary reason for the delays. Amgen’s representative told the committee the company was confident it had complied with the FDA requirements. Whereas most companies that receive accelerated approval for a drug show due diligence in complying with

follow-up requirements, Lyman said a few have taken a decade or longer to submit the requested data. “The ODAC members [believe] that plans for more frequent updates—perhaps annually—of studies with outstanding validation or postmarketing requirements would help shorten the time interval to completion and consideration for full approval.” Members of the ODAC panel also voiced concern that the FDA had occasionally granted full approval to a cancer drug without requiring solid data from an RCT. “The ODAC believes that, with few exceptions, such approval should be based on at least 2 well-done RCTs with consistent or robust results,” said Lyman. Lyman acknowledged that patients with cancer and advocacy groups have complained in the past that strict standards delay access to lifesaving medications. “It will be important that no unnecessary delays occur,” he said. If drug companies are pushed to fulfill their postmarketing requirements more promptly, Lyman said he expects it to shorten the time to full approval and decrease how long an ineffective or unsafe drug remains on the market. ●

Ipilimumab (Yervoy) Is First Melanoma Drug Approved in a Decade

P

atients with inoperable metastatic melanoma now have another treatment option as ipilimumab becomes the second immunotherapy drug approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Fortunately for clinicians, ipilimumab also has a new, easier-to-pronounce name—Yervoy. Specifically, Yervoy is indicated for patients with unresectable metastatic melanoma that is newly diagnosed or progresses despite prior therapy. Ipilimumab is a recombinant, human monoclonal antibody. It works by in hibiting cytotoxic T-lymphocyte anti gen-4 (CTLA-4), a protein that is involved in downregulating T-cells, to keep the immune system from attacking healthy tissue. Ipilimumab blocks CTLA-4 so that the T-cells remain active and the patient’s immune system continues to fight the cancer as long as he or she is receiving treatment. Data from a pivotal phase 3 trial of ipilimumab, which were published in

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the New England Journal of Medicine in 2010, show that patients who received ipilimumab alone or in combination with gp100 had better survival outcomes than patients treated only with gp100. Median overall survival (OS) for patients in the ipilimumab trial arms reached 10 months compared with 6 months for patients in the gp100 monotherapy arm. The rate of 1-year survival was 46% for patients treated with ipilimumab versus 25% for patients on gp100 monotherapy. Investigators estimated the 2-year survival rate at 24% for the ipilimumab group and 14% for the gp100 arm. Ipilimumab was associated with a 34% reduction in risk of death (hazard ratio, 0.66; P = .0026). The overall response rate (ORR) was only 10.9% for patients receiving ipilimumab, but this was significantly higher than the ORR seen in the combination arm and the gp100 monotherapy group (5.7% vs 1.5%, respective-

ly). The authors reported that the mean duration of response was 11.5 months for the group that received ipilimumab and gp100 combined but had not been reached in the other groups because >50% of patients who experienced complete or partial responses had not relapsed. Approximately 10% of patients discontinued ipilimumab because of treatment-related adverse events. Among patients receiving ipilimumab alone, the most common adverse events (all grades) were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). Some patients treated with ipilimumab did have severe or fatal immune-mediated adverse reactions, including enterocolitis (7%), endocrinopathy (4%), dermatitis (2), hepatitis (1%), neuropathy (1%), nephritis (1%), and eosinophilia (1%). Some of these can be treated with corticosteroids, according to researchers practicing at one of the institutions that conducted phase 3 ipilimumab trials.

In a review article on the drug, published in Seminars in Oncology in 2010, Boasberg and colleagues warn that “colonic perforation can occur” and call for patients who develop diarrhea to be monitored carefully, “with strict adherence to treatment algorithms.” The researchers note that if adverse effects are caught promptly and managed properly, “Ipilimumab is an extremely safe drug to administer.” Bristol-Myers Squibb, which manufactures the drug, has worked with the FDA to develop a Risk Evaluation and Mitigation Strategy for ipilimumab in an effort to help clinicians manage or prevent the most serious treatmentrelated adverse events. The company announced that it has launched a copayment program to assist “eligible, commercially insured patients who have been prescribed ipilimumab” in line with its FDA-approved indication. Information on ipilimumab and the REMS program is available at www.yervoy.com. —CM ●

www.TheOncologyNurse.com


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News in Review

Study Shows Patients in Clinical Trials Receptive to Most Testing By Christin Melton

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ecruiting adults with cancer to take part in clinical trials is an ongoing challenge in the United States, but the growing number of studies for targeted therapeutics and the positive news emerging from these studies might help turn that around. Trials of targeted agents depend heavily on pharmacokinetic and pharmacodynamic testing to assess outcomes, prompting a team of researchers to investigate how willing patients are to undergo various testing procedures in the trial setting. Raoul Tibes, MD, PhD, associate director of the Acute and Chronic Leukemia Program at the Mayo Clinic in Scottsdale, Arizona, led the collaborative study, which he describes as the first of its kind. “This has never been asked in a prospective and such a systematic way,” he said in an interview. Tibes and his colleagues from Scottsdale Healthcare and the Translational Genomics Research Institute believe that the results will be useful in planning future clinical trials, particularly of molecular-targeted therapies. “Looking at data in detail, it may inform what specific tests are easier tolerated by patients and those can be incorporated preferentially in trials over others,” explained Tibes.

“If tests and procedures are explained to a patient, most patients are willing and agreeable to have these performed.” —Raoul Tibes, MD, PhD

The researchers analyzed the willingness of 61 patients with advanced cancer to submit to various pharmacodynamic and pharmacokinetic tests, including imaging, while participating in a clinical trial. Perhaps not unexpectedly, the patients were more willing to undergo noninvasive tests, such as

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urine and blood testing, than they were to submit to invasive procedures like tumor and skin biopsies. When it came to imaging, patients were more receptive to getting ultrasounds, radiographs, echocardiograms, computed tomography scans, and positron-emission tomography scans than they were to undergoing magnetic resonance imaging. Although the study found that some patients were less willing to have a biopsy during a trial than some of the other tests, “Skin biopsies did not pose great burden on patients,” Tibes noted. More reluctance was observed when it came to tumor biopsies, but nearly all the patients consented to at least 1 tumor biopsy and several agreed to repeat the procedure. Patients who found an invasive test inconvenient or had negative feelings about the experience were somewhat less willing to repeat the test. Tibes said, “This tells us that researchers can ask for tumor biopsies but need to be mindful of the number to ask for.” The study included 39 men and 22 women, but the data show “gender was not a major determining factor” of a patient’s willingness to undergo testing. “Demographics, overall, had little influence,” said Tibes. The investigators did find that “college graduates and patients with higher income had a higher positive association with willingness to undergo most tests.” Patients with insurance coverage were also more likely to agree to requested procedures. Tibes said the study “supports clinical trials that have frequent biomarker collection and imaging studies and gives clinical researchers the data on hand to support this.” He said this is important in an era where many of the newer drugs are targeted therapies, requiring complex analyses of molecular factors to assess matters like cancer origin, disease progression, and treatment response. Having information about how a drug is expected to work for a particular patient provides that patient with greater reassurance about participating in a trial for a novel drug. “The more scientifically rational and the more data, including molecular data—even data that is still experimental—the more support it lends to participate in a particular study,” said Tibes. In most trials involving a novel drug, a lot of unknowns remain, but Tibes believes this does not deter most patients. “New agents and drugs can work even without us understanding why and still offer great clinical bene-

“New agents and drugs can work even without us understanding why and still offer great clinical benefit.” —Raoul Tibes, MD, PhD

fit,” he pointed out. “Patients that have few treatment options left are willing to try these options.” Although the study did not attempt to measure whether explaining a test helped elicit the patient’s cooperation, Tibes said his involvement conducting trials indicates, “If tests and procedures are explained to a patient, most patients are willing and agreeable to have these performed.” He added that patients in phase 1 trials are generally more willing to undergo procedures than suggested by experts and others

who have never been directly in volved in early oncology trials beyond talking about how much is reasonable to ask of patients. “In my experience, patients in a phase 1 setting understand the limitations of clinical research, but it still gives patients and their loved ones hope that something can be done!” said Tibes, who then added, “Hope dies last.” The study by Tibes and associates appears online in the journal Cancer and is scheduled for inclusion in the July 15, 2011, print edition. ●

Medicare Plans to Cover Provenge

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he Centers for Medicare & Medicaid Services (CMS) has released a proposed decision memo that suggests it will cover the cost of sipuleucel-T (Provenge), the immunotherapy vaccine approved in April 2010 for men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer, for on-label use. CMS contractors will have discretion as to whether they will cover it for off-label use. To date, no studies have been published that support off-label use of sipuleucel-T, but CMS decided to leave the coverage question open so that patients in clinical trials investigating off-label indications might have access to the drug. The agency noted that it does not expect clinicians to prescribe sipuleucel-T for indications unsupported by evidence, but if this occurs regularly, CMS said it would reconsider the ruling. When sipuleucel-T was first approved, CMS took the unusual step having the Medicare Evidence Development and Coverage Ad visory Committee (MEDCAC) review the clinical trial data before agreeing to cover the drug’s estimated $93,000 cost. The committee completed its review in November 2010, and panel members rated the

drug an average of 3.6 for effectiveness despite concerns about flaws in the trials’ protocols and analyses. CMS also asked the Blue Cross & Blue Shield Technology Evaluation Center to conduct an independent investigation of the evidence for its effectiveness. The center concluded it had “moderate” efficacy. During an initial 30-day public comment period, 620 (94.4%) of the 657 comments received by CMS expressed support for covering sipuleucel-T. CMS also reviewed national guidelines and met with officials from Dendreon to discuss the trials. In issuing its proposed coverage decision, CMS noted the underrepresentation of non-white men in the trials and “encourage[d] researchers to take appropriate steps to assure that clinical trials enroll subject populations that reflect the distribution of patients affected by the disease.” Black men are more than twice as likely to die from prostate cancer as white men. CMS has initiated another call for public comments on its proposed determination. The agency says it will review these comments and issue its final ruling by June 30, 2011.—CM ●

www.TheOncologyNurse.com


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International News

Reports from the Netherlands and the United Kingdom Timing of Hormonal Replacement Therapy Affects Breast Cancer Risk

What Women Need to Know About Mammography LONDON—False-positive mammography results increase anxiety and decrease quality of life (QOL) for some women, negative effects that persist for 1 year or longer. Lideke van der Steeg,

www.TheOncologyNurse.com

“Cancer screening is intuitively appealing, and common sense dictates that early detection is good and without risk,” van der Steeg and her team wrote in the article appearing in the British Journal of Surgery, noting that most breast cancer screening programs have been shown to reduce breast cancer–related deaths. Many women, however, overestimate their odds of breast cancer and the benefits of mammography, and they are unaware of the falsepositive risk. This rate is typically said to hover around 6% in the United States, but varies according to region, clinician experience, and patient characteristics; the risk of a false positive increases with successive mammograms. The authors add that women are also not aware of potential dangers of receiving a false-positive mammography result, such as the need for additional tests and the associated increase in anxiety and diminished QOL. This information is not touted in campaigns promoting routine mammography screening, and van der Steeg and colleagues urge clinicians to provide women with balanced information about breast cancer screening, addressing the benefits and risks of the procedure.

Prevalence of Depression in Breast Cancer Patients Overestimated ©Copyright Bigstock.com/monkeybusinessimages

LONDON—New data by a group from Oxford University in England show that women who wait ≥5 years after menopause to start hormone replacement therapy (HRT) are less likely to get breast cancer than women who initiate HRT almost as soon as they experience menopause. The authors note that multiple studies have demonstrated an increased risk of breast cancer for women taking HRT after menopause, but they said few have considered whether the interval between onset of menopause and start of HRT influences risk. In conducting the retrospective analysis, Valerie Beral, FRS, and associates relied on data for 1.13 million postmenopausal women (median age, 56.6 years) recruited in 1996-2001 to participate in the United Kingdom’s Million Women Study. Investigators estimated the adjusted relative risk (RR) of breast cancer for current HRT users (n = 394,697), past users (n = 221,056), and never-users (n = 513,272). Women in the HRT group were further stratified according to time elapsed between menopause and initiation of HRT, type of hormone used, and duration of HRT. A total of 15,759 cases of breast cancer were reported, with 9632 (61%) incidents in women currently or previously on HRT. RR was significantly greater in women who started HRT before or within 5 years of menopause (RR, 1.43; 95% confidence interval [CI], 1.35-1.51; P <.001) than for women who waited at least 5 years after menopause to begin HRT (RR, 1.05; 95% CI, 0.891.24; P = .6). Women who did not begin HRT until ≥5 years after menopause had nearly the same risk of breast cancer as women who never used HRT. The breast cancer risk was lower for women who waited ≥5 years after menopause to begin HRT regardless of type or duration of HRT and body mass index. Complete findings were published in the Journal of the National Cancer Institute.

PhD, and colleagues from St. Elisabeth Hospital in Tilburg, the Netherlands, say their findings suggest that clinicians need to do a better job of informing women before breast cancer screening about the pros and cons of the procedure. Over a 5-year period, women who received abnormal mammography results at 1 of 3 Dutch hospitals were invited to enroll in the study. In vestigators administered questionnaires that assessed QOL in various areas. Of the 385 women who completed the surveys, 152 had a breast cancer diagnosis and 233 received a false-positive result following mammography. Medical records showed that women in the false-positive group often underwent more tests to rule out a breast cancer diagnosis than women confirmed to have breast cancer. Only 14% of women with confirmed breast cancer had ≥4 diagnostic procedures compared with 32% of women eventually found not to have breast cancer. More than half (54.9%) of women in the false-positive group had to go back to the outpatient clinic for additional work-up within the first year of initial screening, with some women returning as many as 8 times.

Clinicians need to do a better job of informing women before breast cancer screening about the pros and cons of the procedure. The researchers believe the multiple screenings and procedures to rule out breast cancer, which included biopsies in some cases, gave rise to the women’s anxiety and negatively affected their QOL. For some women, particularly those prone to anxiety, the reduction in QOL was significant.

LONDON—A British study published in Lancet Oncology undermines the widely held belief that depression is endemic in patients with cancer. Investigators for the meta-analysis found that 30% to 40% of patients seen in oncologic, hematologic, and palliative-care settings suffered from a combination of mood disorders. As a result, “Clinicians should remain vigilant for mood complications, not just depression,” said the authors of the study, led by Alex J. Mitchell, MRCPsych, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicestershire Partnership Trust, United Kingdom. The research team looked at data from 94 studies encompassing 14,078 adults in 14 countries who were screened for depression, anxiety, and adjustment disorders in the first 5 years after cancer diagnosis. The prevalence of mood disorders, including depression, was assessed using criteria from the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases.

©Copyright Bigstock.com/Savol_67

By Jill Stein

Clinicians need to to remain vigilant for signs of a number of mood disorders in patients. Overall, 29.0% of patients in palliative-care settings (n = 4007) and 38.2% of patients in oncologic and hematologic settings (38.2%) experienced mood disorders. Rates of depression were similar between patients in palliative-care settings and those in oncologic and hematologic settings (16.5% vs 16.3%, respectively). Compared with patients in the palliativecare setting, patients in the oncologic and hematologic setting were slightly more likely to have an adjustment disorder (15.4% vs 19.4%, respectively) and clinically significant anxiety (9.8% vs 10.3%, respectively). Mitchell and associates emphasized that although patients with cancer experience depression less often than commonly thought, it “remains an important and overlooked complication of cancer.” According to the authors, studies suggest patients with depression are less likely to remain active in their medical care, have longer hospital stays, and have significantly worse quality of life and survival outcomes. The authors added that their study highlights the need for clinicians to remain vigilant for signs of a number of mood disorders in patients. They recommended using simple screening tools to evaluate patients for distress, declines in quality of life, unmet needs, and a desire for help. Although the rates of mood disorders and depression remained fairly consistent when stratifying data by age, sex, and clinical setting, the investigators said the studies did not provide sufficient information for them to assess results by cancer type or duration of illness. ●

March/april 2011 I VOl 4, NO 2

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Navigation & Survivorship

Brought to you by

Azoospermic Survivors Not Necessarily Sterile

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or the up to two-thirds of men with azoospermia after chemotherapy, microdissection testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) can salvage fertility, according to the largest reported series of postchemotherapy microdissection TESE-ICI to date. Although prechemotherapy sperm banking remains a recommended part of any treatment plan, researchers from Weill Cornell Medical College in New York City demonstrated that assisted reproductive techniques should be offered to patients who did not preserve sperm. Hsiao and colleagues analyzed 84 TESE procedures performed in 73 patients with persistent postchemotherapy azoospermia (mean time since treatment, 18.6 years). Of the 61 patients who underwent testicular biopsy, 90.2% showed a Seroli-cell–only pattern and 9.8% showed hypospermatogenesis. Surgeons retrieved sperm from 37% of patients, which equated to 42.9% of procedures. From these sperm, a 57.1% fertilization rate per injected oocyte was achieved, resulting in a 50% clinical pregnancy rate (confirmed by fetal

heartbeat 32 days postprocedure) and a 42% live birth rate. Sperm retrieval rates differed by disease site, with the highest rate (85%) seen in men who were treated for testicular cancer and the lowest rate (14%) in men treated for sarcoma. The researchers speculated that these rates correlate not

with the cancer site but with the therapy commonly used for these cancers, that is, low gonadotoxic platinum-based chemotherapy and high rates of exposure and higher doses of alkylating agents, respectively. Retrieval success was found to associate with exposure to an alkylating agent,

www.AONNonline.org

with exposure associated with less success than no exposure (21.4% vs 45.7%, respectively). On multivariate analysis, however, this association did not reach significance. Testicular histopathology pattern correlated with retrieval rates as well. Hypospermatogenesis was uniformly associated with successful sperm retrieval (100%), whereas a Seroli-cell– only pattern correlated with a lower rate of success (38.2%). Some factors did not affect retrieval rates. Testicular volume, follicle-stimulating hormone, time since chemotherapy, age at TESE, and luteinizing hormone use were not found to correlate with TESE outcome. The researchers noted that because this was not a retrospective trial, it is difficult to determine the impact of a single agent when analyzed as part of a chemotherapy regimen. In addition, the small study did not accrue enough patients who received gonadal radiation treatment for the researchers to analyze the data. The complete study is published online in the Journal of Clinical Oncology (March 14, 2011). ●

Navigators’ and Patients’ Perspectives on the Navigation Experience

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mbalanced investment and relational amelioration emerged as areas of care that were viewed differently by navigators and their patients in an analysis of perspectives from each group. Researchers from the University of Rochester interviewed 18 pairs of patients and navigators as part of a larger randomized controlled trial. In doing so, Yosha and colleagues identified struggles the navigators, in this study well-trained lay community health workers supervised by social workers, were experiencing but to which the patients were unaware. Most noticeably, navigators expressed tension from their dual responsibilities of advocacy for their patients’ autonomy in decision making and their desire to promote decisions consistent with guideline-concordant care. Patients not only expressed comfort with their decisions but also, when asked, noted that they were unaware of the navigators’ struggle regarding this issue. Another significant struggle for navigators was improving, and not worsen-

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ing, any relationship difficulties between a patient and other members of the healthcare team. Navigators expressed discomfort in having to support a patient without passing judgment on medical providers when there was an adversarial relationship between that patient and provider. Navigators noted that not making the situation worse was an important goal in these situations.

as a main part of their job function. Patients generally did not expect emotional support but found it beneficial as time progressed. Most patients expressed appreciation for their navigators in the interviews conducted after acute treatment. They appreciated not only the help they received but the help their family members received from the navigation intervention.

Most noticeably, navigators expressed tension from their dual responsibilities of advocacy for their patients’ autonomy in decision making and their desire to promote decisions consistent with guideline-concordant care. There was consensus on patient needs identified. Emotional support, informational support, and accompaniment emerged as important for both groups. These needs, however, were viewed differently by navigators and patients. Navigators often saw emotional support

The researchers concluded that as patient navigation programs continue to evolve, instruction on the imbalanced investment in the relationship between patient and navigator can be used to improve navigator training. Training programs should educate navigators to

anticipate these struggles and offer navigators methods to help manage them. “This study clearly identifies some of the unique issues that navigators deal with every day, especially in the 3 complex ‘struggles’ explained in the findings. These issues can be very time-consuming in a patient–navigator meeting,” noted Frank delaRama, RN, MS, AOCNS, a practicing navigator and clinical nurse specialist at the Palo Alto Medical Foundation Cancer Care Clinic. “Healthcare these days often seems to be occupied with patient satisfaction, dashboard measures, and other stats. Provider perspectives could easily identify an area of need, or even validate aspects of current practice, as well as help support the amount of time/resources allocated to navigator services.” Published study results are available in: Yosha AM, Carroll JK, Hendren S, et al. Patient navigation from the paired perspectives of cancer patients and navigators: a qualitative analysis. Patient Educ Couns. 2001;82:396-401. ●

www.TheOncologyNurse.com


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Newsletter Series

YOUR QUESTIONS ANSWERED

         

        

Editor in Chief

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkin Lymphoma â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

    

   

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

            Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEKsize40611MM


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Nursing Life

Nursing by the Numbers

Do You Tweet?

E

very year, the demand for healthcare services grows in the United States and more responsibilities for providing that care are shifted to nurses. While NursingSchool.org reports that the country has at least 5.5 million nurses and nursing aides, this number is not nearly high enough to keep pace with the rising number of patients. The resulting shortage leaves many nurses feeling overworked and underpaid. Nurses’ wages vary according to certification and region (Figure). The most qualified nurses make good money—the average annual salary for a certified registered nurse anesthetist is $129,530. But is this enough when you consider that 2.5 million regis-

A nurse suffers more injuries than a construction worker and is more likely to be physically assaulted than your average prison guard.

tered nurses plus the 2.3 million nursing aides and 750 thousand licensed practical nurses spend a cumulative 11 billion hours working each year? And the job is not always pleasant. Nurses get yelled at (and not just by patients!) and come into close contact with the full spectrum of bodily

45.00 RN 40.00

LPN

Hourly Wage, $

35.00 30.00 25.00 20.00 15.00 10.00 5.00 0.00 USA

AL

AZ

CA

CT

FL

IN

MS

MT

NY

TX

Region Source: United States Department of Labor, Bureau of Labor Statistics.

Figure. Median Hourly Wage for LPNs and RNs (May 2009)

fluids on a regular basis. Nursing also has its dangers. A nurse suffers more injuries than a construction worker and is more likely to be physically assaulted than your average prison guard. Is it any surprise that 1 out of 5 emergency department nurses meets the criteria for posttraumatic stress disorder? After reading these statistics, you might wonder why those who go into nursing stick with the job. A 2010 survey of 1399 registered nurses by AMN Healthcare suggests at least one-third say they might not! The survey found 29% of nurses overall plan to reduce their role in nursing or leave nursing and 6% of hospital nurses plan to retire in the next 1 to 3 years. The survey also found that most nurses are satisfied with their careers and that 59% of nurses would select nursing again if they had to do it all over and 64% would advise young people to consider nursing as a career. Most nurses say they are in the job because they like helping people and being in a position to make a valuable contribution to society. In the end, nurses save lives, and that is something you can’t put a price tag on. ●

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hen it comes to social media, some studies indicate that nurses have bounded ahead of other healthcare professionals in embracing the digital platform. A 2010 survey of 292 nurses by Nicholson Kovac Inc found that 65% said they “would engage in social media for reasons of professional development.” Slightly more than threequarters (77%) acknowledged visiting Facebook and 11% said they use Twitter. More than 80% of nurses responded that they access Websites to find healthcare information, and 41% said they visit Websites of manufacturers to learn more about products and services. Now a new book, The Nurse’s Social Media Advantage by Robert Fraser, BScN, RN (Sigma Theta Tau International), instructs nursing professionals on how to harness social media to improve their nursing practice. The book addresses various issues in a Q&A format and reviews a range of topics the author believes are important for social media users working in healthcare, including how to assess your legal risks. Fraser is a nurse in Canada and describes himself as being passionate about “how technology can change the way we share information.” He encourages nurses to be at the forefront of technology and become part of a global nursing network. The book costs $24.95 and is available through www.nursingknowledge.org or at www.amazon.com. ●

Can Alternative Medicine Prevent Burnout?

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©Copyright Bigstock.com/NejroN

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urnout is a common problem among nurses. A 2008 study in the Online Journal of Issues in Nursing reported that 44% of nurses aged <30 years and 38% of nurses aged ≥30 years experience “acute” burnout. In the hopes of reducing job-related stress, Kent State University’s College of Nursing has joined forces with the Urban Zen Foundation, run by fashion designer Donna Karan, to implement a program that teaches nurses to care for themselves using principles of alternative medicine. Karan’s foundation operates the Urban Zen Integrative Therapy (UZIT) program, which integrates various holistic practices designed to help

heal the mind and body. UZIT incorporates yoga, essential oil therapy, Reiki, nutrition, and contemplative caregiving.

The College of Nursing launched the UZIT “Care for the Caregiver” class as a pilot program in September 2010, enrolling 30 advanced nursing students. The class met monthly in person and then provided weekly online Webinars. Students were required to document their progress with the Eastern techniques in a journal. Kent State University College of Nursing is one of the largest nursing schools in the country. Laura Dzurec, dean of the college, believes these efforts to teach nursing students how to manage work-related stress and head off burnout could have a lasting effect on the profession and ultimately lead to better patient care. The college is offering the class

again this semester and eventually hopes to make it available to all its nursing students. You can learn more about UZIT at www.urbanzen.org.—CM ●

Going to the ONS Meeting? If you are attending the 2011 Oncology Nursing Society Annual Congress in Boston, we would like to hear from you. Email editorial@greenhillhc.com and share your experiences at the conference in 500 words or fewer. We will select the best emails to published in an upcoming issue of The Oncology Nurse-APN/PA and on our Website.

www.TheOncologyNurse.com


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THANK YOU FOR MAKING US

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In a recent survey, oncology nurse parctitioners (NPs) ranked The Oncology Nurse-APN/PA their favorite tabloid publication in the oncology nursing market. *Source: Š Kantar Media, custom study of Oncology Nursing publications among The Oncology Nurse-APN/PA circulation (December 2010).

ad e R 1 # e Th ng i s r u N y Oncolog blication* u Tabloid P

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TON_April2011_v7_TON 4/7/11 10:54 AM Page 62

Meetings JULY 2011

MAY 2011

AUGUST 2011

SEPTEMBER 2011

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21-24 CARLSBAD, CA 15 -17 LAS VEGAS, NV 8-10 SAN FRANCISCO, CA

12th International Lung Cancer Congress www.cancerlearning.com

5-7 BRUSSELS, BELGIUM IMPAKT Breast Cancer Conference www.esmo.org

International Conference and Exhibition on Cancer Science & Therapy http://omicsonline.org/cancerscience 2011/

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

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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.

8-12 LONDON, UNITED KINGDOM European Society for Therapeutic Radiation and Oncology International Oncology Forum www.estro-events.org

JUNE 2011

DOSAGE AND ADMINISTRATION  Å&#x2DC;For Autologous Use Only.  Å&#x2DC;7KHUHFRPPHQGHGFRXUVHRIWKHUDS\IRU3529(1*(LVFRPSOHWHGRVHV given at approximately 2-week intervals.  Å&#x2DC;3UHPHGLFDWHSDWLHQWVZLWKRUDODFHWDPLQRSKHQDQGDQDQWLKLVWDPLQHVXFK as diphenhydramine.  Å&#x2DC;%HIRUHLQIXVLRQFRQŵUPWKDWWKHSDWLHQWÅ&#x2018;VLGHQWLW\PDWFKHVWKHSDWLHQWLGHQWLŵHUV on the infusion bag.  Å&#x2DC;Do Not Initiate Infusion of Expired Product.  Å&#x2DC;,QIXVH3529(1*(LQWUDYHQRXVO\RYHUDSHULRGRIDSSUR[LPDWHO\PLQXWHV Do Not Use a Cell Filter.  Å&#x2DC;,QWHUUXSWRUVORZLQIXVLRQDVQHFHVVDU\IRUDFXWHLQIXVLRQUHDFWLRQVGHSHQGLQJ on the severity of the reaction. (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS  Å&#x2DC;PROVENGE is intended solely for autologous use.  Å&#x2DC;Acute infusion reactions UHSRUWHGZLWKLQGD\RILQIXVLRQ LQFOXGHGEXW ZHUHQRWOLPLWHGWRIHYHUFKLOOVUHVSLUDWRU\HYHQWV G\VSQHDK\SR[LDDQG EURQFKRVSDVP QDXVHDYRPLWLQJIDWLJXHK\SHUWHQVLRQDQGWDFK\FDUGLD,Q FRQWUROOHGFOLQLFDOWULDOVRISDWLHQWVLQWKH3529(1*(JURXSGHYHORSHG an acute infusion reaction.

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  ,QFRQWUROOHGFOLQLFDOWULDOVVHYHUH *UDGH DFXWHLQIXVLRQUHDFWLRQVZHUHUHSRUWHGLQ RISDWLHQWVLQWKH3529(1*(JURXS5HDFWLRQVLQFOXGHGFKLOOVIHYHUIDWLJXH DVWKHQLDG\VSQHDK\SR[LDEURQFKRVSDVPGL]]LQHVVKHDGDFKHK\SHUWHQVLRQ PXVFOHDFKHQDXVHDDQGYRPLWLQJ7KHLQFLGHQFHRIVHYHUHHYHQWVZDVJUHDWHU IROORZLQJWKHVHFRQGLQIXVLRQ YVIROORZLQJWKHŵUVWLQIXVLRQ DQG GHFUHDVHGWRIROORZLQJWKHWKLUGLQIXVLRQ6RPH  SDWLHQWVLQWKH 3529(1*(JURXSZHUHKRVSLWDOL]HGZLWKLQGD\RILQIXVLRQIRUPDQDJHPHQWRI DFXWHLQIXVLRQUHDFWLRQV1R*UDGHRUDFXWHLQIXVLRQUHDFWLRQVZHUHUHSRUWHGLQ patients in the PROVENGE group.

3-7 CHICAGO, IL American Society of Clinical Oncology Annual Meeting www.asco.org

 &ORVHO\PRQLWRUSDWLHQWVZLWKFDUGLDFRUSXOPRQDU\FRQGLWLRQV,QWKHHYHQWRI DQDFXWHLQIXVLRQUHDFWLRQWKHLQIXVLRQUDWHPD\EHGHFUHDVHGRUWKHLQIXVLRQ VWRSSHGGHSHQGLQJRQWKHVHYHULW\RIWKHUHDFWLRQ$SSURSULDWHPHGLFDOWKHUDS\ should be administered as needed.

Breast Cancer Symposium www.breastcasymposium.org

results become positive for microbial contamination after PROVENGE has been DSSURYHGIRULQIXVLRQ'HQGUHRQZLOOQRWLI\WKHWUHDWLQJSK\VLFLDQ'HQGUHRQZLOO DWWHPSWWRLGHQWLI\WKHPLFURRUJDQLVPSHUIRUPDQWLELRWLFVHQVLWLYLW\WHVWLQJRQ UHFRYHUHGPLFURRUJDQLVPVDQGFRPPXQLFDWHWKHUHVXOWVWRWKHWUHDWLQJSK\VLFLDQ'HQGUHRQPD\UHTXHVWDGGLWLRQDOLQIRUPDWLRQIURPWKHSK\VLFLDQLQRUGHU to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS %HFDXVHFOLQLFDOWULDOVDUHFRQGXFWHGXQGHUZLGHO\YDU\LQJFRQGLWLRQVDGYHUVHUHDFWLRQ 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. 7KHVDIHW\HYDOXDWLRQRI3529(1*(LVEDVHGRQSURVWDWHFDQFHUSDWLHQWVLQWKH PROVENGE group who underwent at least 1 leukapheresis procedure in four UDQGRPL]HGFRQWUROOHGFOLQLFDOWULDOV7KHFRQWUROZDVQRQDFWLYDWHGDXWRORJRXV peripheral blood mononuclear cells. 7KHPRVWFRPPRQDGYHUVHHYHQWVUHSRUWHGLQSDWLHQWVLQWKH3529(1*(JURXS DWDUDWHŰZHUHFKLOOVIDWLJXHIHYHUEDFNSDLQQDXVHDMRLQWDFKHDQGKHDGDFKH 6HYHUH *UDGH DQGOLIHWKUHDWHQLQJ *UDGH DGYHUVHHYHQWVZHUHUHSRUWHGLQ DQGRISDWLHQWVLQWKH3529(1*(JURXSFRPSDUHGZLWKDQGRI SDWLHQWVLQWKHFRQWUROJURXS)DWDO *UDGH DGYHUVHHYHQWVZHUHUHSRUWHGLQRI SDWLHQWVLQWKH3529(1*(JURXSFRPSDUHGZLWKRISDWLHQWVLQWKHFRQWUROJURXS 6HULRXVDGYHUVHHYHQWVZHUHUHSRUWHGLQRISDWLHQWVLQWKH3529(1*(JURXS DQGRISDWLHQWVLQWKHFRQWUROJURXS6HULRXVDGYHUVHHYHQWVLQWKH3529(1*( group included acute infusion reactions (see Warnings and Precautions)FHUHEURYDVFXODUHYHQWVDQGVLQJOHFDVHUHSRUWVRIHRVLQRSKLOLDUKDEGRP\RO\VLVP\DVWKHQLDJUDYLV P\RVLWLVDQGWXPRUŶDUH 3529(1*(ZDVGLVFRQWLQXHGLQRISDWLHQWVLQ6WXG\ 3529(1*(JURXSQ  &RQWUROJURXSQ  GXHWRDGYHUVHHYHQWV6RPHSDWLHQWVZKRUHTXLUHGFHQWUDO YHQRXVFDWKHWHUVIRUWUHDWPHQWZLWK3529(1*(GHYHORSHGLQIHFWLRQVLQFOXGLQJVHSVLV $VPDOOQXPEHURIWKHVHSDWLHQWVGLVFRQWLQXHGWUHDWPHQWDVDUHVXOW0RQLWRULQJIRU LQIHFWLRXVVHTXHODHLQSDWLHQWVZLWKFHQWUDOYHQRXVFDWKHWHUVLVUHFRPPHQGHG (DFKGRVHRI3529(1*(UHTXLUHVDVWDQGDUGOHXNDSKHUHVLVSURFHGXUHDSSUR[LPDWHO\ GD\VSULRUWRWKHLQIXVLRQ$GYHUVHHYHQWVWKDWZHUHUHSRUWHGůGD\IROORZLQJD OHXNDSKHUHVLVSURFHGXUHLQŰRISDWLHQWVLQFRQWUROOHGFOLQLFDOWULDOVLQFOXGHGFLWUDWH WR[LFLW\  RUDOSDUHVWKHVLD  SDUHVWKHVLD  DQGIDWLJXH   7DEOHSURYLGHVWKHIUHTXHQF\DQGVHYHULW\RIDGYHUVHHYHQWVUHSRUWHGLQŰRI SDWLHQWVLQWKH3529(1*(JURXSRIUDQGRPL]HGFRQWUROOHGWULDOVRIPHQZLWKSURVWDWH FDQFHU7KHSRSXODWLRQLQFOXGHGSDWLHQWVZLWKPHWDVWDWLFFDVWUDWHUHVLVWDQWSURVWDWH FDQFHUDQGSDWLHQWVZLWKQRQPHWDVWDWLFDQGURJHQGHSHQGHQWSURVWDWHFDQFHUZKR ZHUHVFKHGXOHGWRUHFHLYHLQIXVLRQVRI3529(1*(DWDSSUR[LPDWHO\ZHHNLQWHUYDOV 7KHSRSXODWLRQZDVDJHWR\HDUV PHGLDQ\HDUV DQGRISDWLHQWV were Caucasian.

 Å&#x2DC;Handling Precautions for Control of Infectious Disease. PROVENGE is notURXWLQHO\WHVWHGIRUWUDQVPLVVLEOHLQIHFWLRXVGLVHDVHV7KHUHIRUHSDWLHQW leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

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 Å&#x2DC;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 VWXGLHG3529(1*(LVGHVLJQHGWRVWLPXODWHWKHLPPXQHV\VWHPDQGFRQFXUUHQW XVHRILPPXQRVXSSUHVVLYHDJHQWVPD\DOWHUWKHHIŵFDF\DQGRUVDIHW\RI3529(1*( 7KHUHIRUHSDWLHQWVVKRXOGEHFDUHIXOO\HYDOXDWHGWRGHWHUPLQHZKHWKHULWLVPHGLFDOO\ appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. 

23-25 ATHENS, GREECE Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium www.mascc2011.org

62

March/april 2011 I VOl 4, NO 2

Å&#x2DC;Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination GHWHUPLQDWLRQE\*UDPVWDLQHQGRWR[LQFRQWHQWDQGLQSURFHVVVWHULOLW\ZLWKD GD\LQFXEDWLRQWRGHWHUPLQHDEVHQFHRIPLFURELDOJURZWK7KHŵQDO GD\LQFXEDWLRQ VWHULOLW\WHVWUHVXOWVDUHQRWDYDLODEOHDWWKHWLPHRILQIXVLRQ,IWKHVWHULOLW\

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TON_April2011_v7_TON 4/7/11 10:54 AM Page 63

Meetings SEPTEMBER 2011

DECEMBER 2011

23-27

16-18

6-11

10-13

STOCKHOLM, SWEDEN European Society for Medical Oncology European Multidisciplinary Cancer Congress www.esmo.org

SAN ANTONIO, TX Academy of Oncology Nurse Navigators Second Annual Navigation and Survivorship Conference www.aonnonline.org

SAN ANTONIO, TX 34th Annual San Antonio Breast Cancer Symposium www.sabcs.org

SAN DIEGO, CA American Society of Hematology Annual Meeting and Exposition www.hematology.org

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever %DFNSDLQ Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting $QHPLD Constipation Pain Paresthesia oral Pain in extremity 'L]]LQHVV 0XVFOHDFKH $VWKHQLD 'LDUUKHD ,QĹśXHQ]DOLNHLOOQHVV 0XVFXORVNHOHWDOSDLQ '\VSQHD Edema peripheral Hot flush Hematuria 0XVFOHVSDVPV Hypertension $QRUH[LD %RQHSDLQ Upper respiratory tract infection ,QVRPQLD 0XVFXORVNHOHWDO chest pain Cough Neck pain Weight decreased Urinary tract infection Rash 6ZHDWLQJ Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3)  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

186 (30.9)  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

291 (96.0)  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

97 (32.0)  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Grade 3-5 n (%)

Cerebrovascular Events.,QFRQWUROOHGFOLQLFDOWULDOVFHUHEURYDVFXODUHYHQWV LQFOXGLQJKHPRUUKDJLFDQGLVFKHPLFVWURNHVZHUHUHSRUWHGLQRISDWLHQWV LQWKH3529(1*(JURXSFRPSDUHGZLWKRISDWLHQWVLQWKHFRQWUROJURXS (See Adverse Reactions [6] 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.

Dendreon Corporation 3005 First Avenue Seattle, Washington 98121

*Control was non-activated autologous peripheral blood mononuclear cells.

k'HQGUHRQ&RUSRUDWLRQ $OOULJKWVUHVHUYHG1RYHPEHU3ULQWHGLQWKH86$ 'HQGUHRQWKH'HQGUHRQORJRDQG3529(1*(DUHUHJLVWHUHG WUDGHPDUNVRI'HQGUHRQ&RUSRUDWLRQ P-A-11.10-073.00

www.TheOncologyNurse.com

March/april 2011 I VOl 4, NO 2

63


TON_April2011_v7_TON 4/7/11 10:54 AM Page Cov4

In asymptomatic or minimally symptomatic metastatic castr castrate ate resistant resistant prostate prostate cancer

Before, Frank's immune cells could barely recognize a prostate cancer cell.

Now, they are focused on it.

PROVENGE is the first in a new class of therapy that is designed to activate a patient antigen-presenting cells patient’s’s own antigen-presenting to stimulate an immune rresponse esponse against prostate prostate cancer. cancer. 

«Extends 25.8 months compar ed Extends median survival beyond 2 years— years—25.8 compared with 21.7 months for patients in the contr ol* gr oup ((P=.032) P=.032) control* group «Reduction in risk of death—22.5% (HR=0.775, 95% CI: 0.614, 0.979) « 3 infusions, at approximately approximately 2-week intervals† «Therapy completed in 3 cycles— cycles—3 e primarily mild or moderate— «Most Most common adverse events ar are chills, fatigue, pain, nausea, joint ache, and headache ue, fever, feverr,, back pain *

Contr Control ol was nonactivated, autologous autologous,, peripheral blood mononuclear cells. The dosing interval ranged fr from om 1 to 15 weeks in controlled controlled clinical trials.

INDICATION: ICATION: PROVENGE® treatment of (sipuleucel-T) is an autologous cellular immunotherapy immunotherapy indicated for the treatment PROVENGE® (sipuleucel-T) IND castrate asymptomatic or minimally symptomatic metastatic castr ate resistant resistant (hormone refractory) refractory) prostate prostate cancer. cancer. IMPORTANT INFORMATION: TANTT SAFETYY INF INFORMA FORMA ATTION: PROVENGE IMPOR PROVENGE is intended solely for autologous use and is not routinely routinely tested for transmissible diseases. tr ansmissible infectious dise diseases. In controlled controlled clinical trials, serious adverse events reported reported in the PROVENGE PROVENGE group group include acute infusion reactions reactions (occurring within 1 day of infusion) and cerebrovascular cerebrovascular events. Severe Severe (Grade (Grade 3) acute infusion reactions reactions were were rreported eported in 3.5% of patients in the PROVENGE PROVENGE group. group. Reactions Reactions included chills, fever, fever, fatigue, asthenia, dyspnea, dyspnea, hypoxia, hypoxia, bronchospasm, br onchospasm, dizziness, dizziness, headache, headache, hypertension, muscle ache, nausea, nausea, and vomiting. No Grade Grade 4 or 5 acute infusion weree rreported PROVENGE rreactions eactions wer eported in patients in the PRO PROVENGE group. group. fever, back pain, TThe he most common adverse events (incidence ≥15%) reported reported in the PROVENGE PROVENGE group group are are chills, fatigue, fever, nausea, nause a, joint ache, and headache. headache. PPlease lease see Brief Summary of full PPrescribing rescribing Information on the adjacent page.

©2011 Dendr eon Corporation. Corporation. Dendreon All rights rreserved. eserved. February February 2011. Printed Printed in the U.S.A. U.S.A. Dendr eon, the Dendr eon logo, logo, and PROVENGE PROVENGE are are registered registered Dendreon, Dendreon tr ademarks of Dendreon Dendreon Corporation. Corporation. trademarks P-A-02.11-007.00

www www.PROVENGE.com .PROVENGE.com

Stimulate a Response


MARCH/APRIL 2011, VOL 4, NO 2