June 2011, Vol 4, No 4

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JUNE 2011

www.TheOncologyNurse.com

VOL 4, NO 4

The Official Publication for the Hem/Onc Nurse & Advanced Practitioner GENETIC COUNSELING

CANCER CENTER PROFILE

Identifying Endometrial Cancer Survivors with Lynch Syndrome

Ella Millbank Foshay Cancer Center

The Role of Immunohistochemistry

Research Nurse Provides Clinical Care that Helps Find a Cure

By Dawn Lagrosa

By Cristi Radford, MS, CGC Sarasota Memorial Health Care System, Sarasota, Florida

L

ynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is the most common cause of hereditary endometrial cancer. It accounts for at least 2% to 3% of all endometrial cancer cases and 9% to 10% of endometrial cancer cases in women

diagnosed younger than 50 years of age.1-3 Women with Lynch syndrome have a high lifetime risk for colorectal (30%52%)4 and endometrial (20%-71%)5 cancer. Risks for other cancers associated with Lynch syndrome are lower and include stomach, ovary, hepatobiliary Continued on page 30

CONFERENCE NEWS

36th Annual Congress of the Oncology Nursing Society Boston, Massachusetts, April 28-May 1, 2011 Complete coverage: page 10

Clinical Research Nurse, Jeanine Secor, RN, BSN, discusses a trial’s protocol with her patient.

upiter Medical Center’s Ella Millbank Foshay Cancer Center offers cancer trials in and for its Florida community. But providing care close to home is just part of the oncology clinical research nurse’s role in the clinical trials unit.

As a clinical research nurse, Jeanine Secor, RN, BSN, educates patients about the clinical trial, consents the patients, and oversees their chemotherapy, radiation therapy, hormone treatment, or surgery. “We really are a liaison between the study, the doctor, and the patient,” she tells The Oncology Nurse-APN/NP, adding that she

J

Continued on page 19

INSIDE COMPLIMENTARY CE

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PROSTATE CANCER

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34

Systemic Treatment Options in Advanced Melanoma

Translating Basic Science into the Clinic: Approval of Abiraterone

SUPPORTIVE CARE

NAVIGATION & SURVIVORSHIP

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Palliation of Severe Dysphagia Hepatitis B Screening and Chemotherapy Rise in Invasive Fungal Infections

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Reducing Barriers to Care PA LIFE

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A Nurse on the “Other Side of the Job”

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You voted for the

Oncology Nurse Excellence Award

©2011 Green Hill Healthcare Communications, LLC

Find Out Who Won! Page 24

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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 cancer1 †

Trastuzumab for 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)

r

*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.

©2011 Genentech USA, Inc.

So. San Francisco, CA

All rights reserved.

HER0000330201

3/11

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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 d

B

In

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.

Im N

For 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

ges of

= 135

8%

6%

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%

9%

9%

7% udies, a

Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of * 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

LVEF <50% and Absolute Decrease from Baseline

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

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

7%

and

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.

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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

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JuNe 2011 I VOL 4, NO 4

www.TheOncologyNurse.com

TON_June2011_7_TON 6/16/11 3:46 PM Page 7

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Taking a broader view — charting a unique course in cancer care

At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community.

A commitment to patients — We created Genentech BioOncology™ Access Solutions®, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care.

Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card Program and ongoing charitable donations to various independent, nonprofit organizations in support of co-pay assistance.

A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $2.3 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs.

Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.

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TON_June2011_7_TON 6/17/11 10:38 AM Page 8

From the Editor

A

t this year’s ONS Annual Congress, we had the opportunity to network with our peers and discuss aspects of care that are part of our daily lives as oncology nurses: pain management, quality-oflife interventions, adherence, and survivorship. This opportunity to learn from one another helps not only our patients but also ourselves, Beth Faiman, RN, MSN, as advanced practice nurses demonstrated their role in our practice.

APRN, BC, AOCN Editor-in-Chief Then, there was ASCO. With all the big news coming out at the American Society of Clinical Oncology annual meeting—vemurafenib and ipilimumab for melanoma, exemestane for breast cancer prevention, bevacizumab for ovarian cancer—smaller studies tend to be overlooked, at least at first. But for nurses, their results are no less important. These studies expand on our knowledge of supportive care treatments, quality-of-life interventions, and psychosocial issues, and provide us with a

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com

point of view that is not nurse-specific (see below).

Amidst all the big news, everyday practice continues.

With this issue of The Oncology Nurse-APN/PA, we discuss 2 new drugs approved by the US Food and Drug Administration. Our continuing education article provides an overview of recent advances in immunotherapy and the development of novel BRAF- and KIT-targeted agents for stage IV melanoma, including ipilimumab, the newly approved immunotherapy monoclonal antibody.

Dr William Figg, a pharmacist with the National Cancer Institute, describes the mechanism of action for abiraterone acetate, and TON board member Gary Shelton explains the implications of this recent approval on nursing practice.

In addition, this issue announces the winner of the inaugural Oncology Nurse Excellence award: Janet C. Stocker, RN, MS, NP-C, AOCNS, an oncology clinical nurse specialist and an oncology adult nurse practitioner at Wentworth Douglass Hospital in Dover, New Hampshire. Please join me in congratulating her for her hard work and dedication to oncology nursing and oncology patients. ●

Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

Abstracts of Interest

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Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

Please convey any errors to the Editorial Director.

BPA Worldwide membership applied for April 2011.

8

JuNe 2011 I VOL 4, NO 4

2011 Annual Meeting of the American Society of Clinical Oncology NEUROPAIN-01: A Phase 2 Study of Oxycodone and Pregabalin In a comparison of 2 strategies involving the combination of oxycodone and pregabalin, researchers found that a fixed dose of oxycodone with an increasing dose of pregabalin provided better neuropathic pain control than a fixed dose of pregabalin with an increasing dose of oxycodone. In addition, the “increasing pregabalin” group experienced less frequent side effects. Garassino MC, et al.

Abstract 9028.

ARNP-Directed Palliative Care Intervention for Patients with Metastatic Cancer A prospective randomized study identified an advanced registered nurse practitioner (ARNP)-directed intervention that improved patients’ emotional quality of life, as assessed by the FACT-G tool. For the study, ARNPs discussed the benefits of hospice and advanced directives with patients and assessed their quality of life soon after an advanced diagnosis. Control patients received usual care.

Patients in the intervention arm found the intervention useful, and the researchers found the intervention a costeffective strategy. Dyar SH, et al. Abstract 9097.

5HT3 Antagonist plus Dexamethasone with or without Aprepitant in Multiple-Day Cisplatin Regimens Aprepitant combined with a 5HT3 antagonist and dexamethasone improved control of emesis in germ cell tumor patients receiving a 5-day course of treatment containing cisplatin. This double-blind, placebo-controlled, crossover phase 3 study randomized patients to aprepitant 125 mg on day 3 with 80 mg on days 4 to 7 or to placebo. All patients received a 5HT3 antagonist on days 1 to 5 and dexamethasone 20 mg on days 1 and 2. Patients crossed over for the second cycle of treatment. Blinded dexamethasone 8 mg twice daily or 4 mg twice daily was added in the placebo group, as was dexamethasone 4 mg twice daily on day 8 in the aprepitant group. Brames MJ, et al. Abstract 9013.

Patient Perspectives on Maintenance Therapy Patients are amenable to maintenance therapy as long as they experience no or mild side effects, according to this semistructured survey during patients’ fourth or subsequent cycle of chemotherapy. Patients with low-grade Hodgkin lymphoma, lung cancer, or colorectal cancer were surveyed regarding their preferred route of administration and willingness to tolerate side effects for hypothetical maintenance therapy. Patients identified oral therapy as their preferred route of administration.

Unexpectedly, researchers found that patients anticipated an unrealistic prolongation of overall survival, prompting them to conclude that open and precise information on benefits and side effects is essential. Frank S, et al. Abstract e19653.

Acupuncture and Sham Acupuncture Equally Reduce Fatigue For postchemotherapy chronic fatigue, a randomized sham-controlled trial found that both acupuncture and sham acupuncture reduced Brief Fatigue Inventory scores by approximately 1 point. Both treatments were given once weekly for 6 weeks. Based on their results, the researchers concluded that acupuncture did not have much effect above placebo. Deng GE, et al.

Abstract 9029.

YOCAS Yoga Favorably Affects Circadian Rhythm in Survivors Participants in a yoga intervention exhibited a more favorable circadian rhythm than survivors randomized to standard care in a phase 3 trial. Survivors with nonmetastatic disease (96% female; 75% breast cancer) attended 4 weeks of Yoga for Cancer Survivors (YOCAS) twice a week. The program consisted of breathing exercises, gentle Hatha and Restorative yoga postures, and meditation. The researchers found that the altered circadian rhythms led to improved anxiety and mood among participant survivors. Mustian KM, et al. Abstract 9034. ●

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TON_June2011_7_TON 6/16/11 3:47 PM Page 9

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Conference News 2011 ONS ANNUAL CONGRESS

Breakthrough Cancer Pain Remains a Challenge Proper Assessment and Treatment Are Key

By Christin Melton

BOSTON—As every oncology nurse knows, pain is no stranger to patients with advanced cancer. Even if background pain appears under control, studies show 23% to 89% of patients experience intermittent bouts of pain known as breakthrough cancer pain (BTCP).

Variation in the incidence rates reflects variation in the definition of BTCP. Jeannine M. Brant, PhD, APRN, AOCN, oncology clinical nurse specialist and research scientist, Billings Clinic Cancer Center, Montana, who copresented a satellite symposium on challenges in managing BTCP, described BTCP thusly: “A transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.” Brant said BTCP episodes can be as brief as 1 second to as long as 30 minutes and range from moderate to severe.

She divided BTCP into incident pain, which occurs after voluntary or involuntary movement, and idiopathic pain, which arises spontaneously.

Patients often have a mix of both types. Patients who have no background pain also experience BTCP. Prostate, head and neck, genitourinary, breast, uterine, and pancreatic cancers are the most painful malignancies.

Bone metastases also cause pain.

Assessment BTCP seriously impairs the patient’s physical and psychological well-being, said Carol P. Curtiss, MSN, RN, BC, clinical nurse specialist, Curtiss Consulting, Greenfield, Massachusetts.

Properly assessing pain is crucial to providing proper treatment. Curtiss said nurses must question patients often about their pain and believe their responses. She recommended asking questions such as: • Do you have periods during the day when your pain is uncontrolled?

• How long is it from when you noticed the pain to when it is at its worst?

• Describe it to me.

• Does it interfere with your ability to do the things you like to do or that

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JuNe 2011 I VOL 4, NO 4

I’m asking you to do?

• Does anything lessen its severity?

She advised doing separate assessments for breakthrough pain and background pain.

Nurses should work with patients to establish realistic goals for pain control.

She suggested asking the patient to identify on a scale of 1 to 10 the level of pain they consider acceptable. The primary goal in managing BTCP is to provide quick pain relief that persists for the duration of pain and rapidly dissipates afterward.

Curtiss warned against confusing aberrant behavior (taking an extra pill or requesting another dose of pain medication before it is due) with addiction. Aberrant behavior typically results when pain is not properly controlled. “99% of the time, it’s the plan, not the patient,” she said.

Assessing pain in nonverbal patients is difficult, requiring careful observation.

Curtiss said to watch for changes in facial expression, verbalizations or vocalizations, mental status changes, body move-

ments, differences in activities or routine, and other subtle cues.

Treatment Options Medications to treat BTCP should have rapid onset and control pain effectively but also have a short halflife to prevent accumulation and oversedation. Brant said the drug should be simple to use and acceptable to the patient.

Morphine is the gold standard.

Opiates are highly effective, but growing restrictions sometimes make it hard to deliver the drug quickly. Commonly used opiates are oxycodone, hydromorphone, oxymorphone, and fentanyl in various preparations.

Immediate-release oral agents typically take 15 minutes to work. Brant warned they are absorbed in the gastrointestinal mucosa and must be swallowed to be effective. They often do not act fast enough to address idiopathic BTCP and sometimes peak after the incident resolves. Many last up to 6 hours, increasing the risk of oversedation.

Several rapid-onset fentanyl prepa-

rations are available, including transmucosal fentanyl citrate, fentanyl buccal tablets, fentanyl buccal soluble film, and sublingual fentanyl. An aerosolized version and a nasal spray are being studied. Fentanyl preparations tend to have a quicker onset, ranging from 1 to 15 minutes. This is because they are lipophilic and absorbed by the buccal mucosa. Their duration ranges from 1 to 3 hours, allowing them to clear the system faster than many other opiates.

The US Food and Drug Administration has mandated Risk Evaluation and Mitigation Strategies (REMS) for all rapid-acting opioids, which may require prescribers to receive special training and to provide additional education to patients. The goal is to prevent misuse and abuse. Curtiss advised oncology nurses to become familiar with the REMS for the various opioids used. ● The educational symposium was presented by Meniscus Educational Institute and sponsored by Cephalon.

Oncology Nurses Best Positioned to Talk to Patients About Lymphedema Patients Can Learn Techniques for Reducing Their Risk and Managing Symptoms—If They Know About Them BOSTON—Many patients are unaware of their risk of cancer-related lymphedema, and oncology nurses can be instrumental in raising consciousness about this debilitating adverse effect. Of breast cancer survivors, 22% to 66% develop lymphedema, said Jane Armer, PhD, RN, FAAN, Sinclair School of Nursing, University of Missouri, in her poster presentation. Approximately 15% of nonbreast cancer patients also develop lymphedema. This chronic condition is optimally managed by a lymphedema therapist.

Armer and colleagues with the American Lymphedema Framework Project (ALFP) surveyed 419 lymphedema therapists in 46 states and found that only 2% were nurses. Most were physical (48%) or occupational (33%) therapists, with anywhere from 1 day to 135 hours of training in lymphedema

management. Complete decongestive therapy (CDT) remains the gold standard of care for lymphedema, but patients can also learn other techniques for reducing their risk and managing symptoms—if they know about them.

At enrollment, 40% were found to have mild lymphedema and 10% had severe lymphedema.

Yet, none had received a diagnosis.

The Need for Education Women with lymphedema feel neglected by the healthcare system, discovered Mei R. Fu, PhD, RN, ACNS-BC, assistant

professor of nursing at New York University, who presented 2 posters on lymphedema. Fu believes simply discussing lymphedema risks and prevention with patients improves outcomes because it improves their mental outlook.

Her team enrolled 136 breast cancer patients (median age, 54 years) who had an average of 12 lymph nodes removed; 1 patient had no lymph nodes removed.

Half were mastectomy patients, and all had unilateral lymph node surgery.

Three-quarters were white.

At enrollment, 40% were found to have mild lymphedema and 10% had severe lymphedema. Yet, none had received a diagnosis. This patient population was highly educated, with 44% having a graduate degree. “This tells us even with this highly educated, high middle class population, there is a strugContinued on page 12

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SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T H E 5- YEAR S UR VIVAL RATE I S 17 % F OR PATIENTS WITH M E TAS TATIC S OF T TISSUE SA RC OMA , Y E T S IG NIF ICANT THERA PEUTIC A D VA NCEM ENTS AR E LA GGING. 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.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001

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Conference News Oncology Nurses Best Positioned to Talk... Continued from page 10 gle. What about our minorities, our lower socioeconomic income population?” Fu asked.

Slightly more than half (53%) of patients had some information on lymphedema, mostly from pamphlets provided by the American Cancer Society. “The second source, I am proud of this, are nurses,” said Fu. However, 53% said their nurse never told them how to protect themselves from lymphedema, and 47% received no information from anyone.

Those who had some information, such as “don’t use blood pressure readers on that arm” and “no injections,” reported significantly fewer lymphedema symptoms than those who had no information (2.5 vs 4, respectively). They took at least 10 protective measures compared with 7 for uninformed patients.

“Most doctors and nurses don’t know how to educate this population,” said Fu. “We need to have specialized training for nurses who are going to do

53% said their nurse never told them how to protect themselves from lymphedema, and 47% received no information from anyone.

the risk-reduction education; maybe not 135 hours, but a 1-day course, talking about the physiology of lymphedema and what you should do.”

Risk Factors Women with a body mass index (BMI) ≥25 had a higher rate of lymphedema than women with a BMI <25 (27.4% vs 16.7%, respectively), in a study by Marybeth Singer, NP, Tufts Medical Center, Boston, and colleagues who assessed the effect of BMI on lymphedema risk in 399 women with unilateral breast cancer.

Although most surgeons say sentinel lymph node (SNL) biopsy is less likely to

cause lymphedema than axillary lymph node dissection, Singer said 50% of lymphedema sufferers in the BMI ≥25 group had undergone SNL biopsy.

Overall, 12 patients with no lymph nodes removed developed lymphedema, of which 10 were in the BMI ≥25 group.

“We don’t think of those patients of being at risk,” Singer observed.

“We need to look at what role heart disease, diabetes, or other proinflammatory conditions might play in the underlying biology of lymphedema,” she said, adding that genetics should also be considered.

The researchers agreed that nurses are in the optimal position to talk to patients

about lymphedema and counsel them on the benefits of lifestyle changes, such as weight loss and exercise. Patients who are not educated sometimes take treatment into their own hands, increasing the damage. Fu did a longitudinal study examining the behaviors of 13 ChineseAmerican breast cancer survivors with undiagnosed lymphedema. After hearing that massage might help, some sought heat massage or vigorous Thai massages, which exacerbated their lymphedema.

Secondary lymphedema seriously compromises quality of life, and Singer said, “Many patients don’t seek treatment until they’ve had edema for some time—meaning months or years.” Fu observed this in her study, with 1 woman suffering from undiagnosed lymphedema for 8 years.

Armer recommended downloading guidelines on evaluating patients for lymphedema from the ALFP website (www.alfp.org). Updated guidelines are now available. ● —CM

Nurses Can Help with Poor Adherence to Oral Oncolytics Teaching Sessions and Motivation Technology Offer Assistance BOSTON—The growing use of oral oncolytics corresponds to a growing challenge with poor adherence to therapy. With more than 40 oral oncolytics available and dozens in the pipeline, “the issue is not going to fade away,” said Susan Moore, RN, MSN, ANPBC, AOCN, MCG Oncology, Chicago.

Moore, who spends much of her time studying the problem of medication adherence, defined adherence as “the degree or extent of conformity to provider recommendations about dayto-day treatment with respect to timing, dosage, and frequency.” Poor adherence can also mean taking more than what is prescribed. The few studies in the literature on adherence are all over the map regarding the percentage of patients who fail to take their oral drugs as prescribed, but Moore said everyone nonetheless recognizes it as a serious problem.

“Patients have a variety of reasons for becoming nonadherent,” said Moore, but the most common is adverse effects.

Other causes are psychologic issues, cognitive or physical impairment, skepticism about treatment benefits, and poor understanding of the disease process. She mentioned a mastectomy patient who skipped hormonal therapy in the mistaken belief that without breasts, she could not get breast cancer

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again. Other patients, particularly those with chronic myeloid leukemia (CML), feel better and stop taking their pills.

With oral drugs, patients are ultimately in charge. “We don’t know what’s going on at home,” said Moore.

Educating patients taking oral therapies on the importance of adherence is essential. A 2010 study by Simchowitz and colleagues showed most patients want more education on how to take their drugs and what to expect.

Teaching sessions should always be individualized, not rehearsed, and a family member or friend should accompany the patient.

But whose job is it to provide that education wondered Debra Winkeljohn, RN, MSN, AOCN, CNS, Hematology Oncology Associates of New Mexico, Albuquerque. “Is it the physician, the oncology nurse, or the pharmacist?”

She said oncology nurses must become more involved in dealing with oral oncolytics.

A 2008 survey of 1116 oncology

nurses in 15 countries by Sultan and associates found that 47% had no formal education on oral therapies.

Winkeljohn said her clinic’s nurses “do great with IV therapy but when asked to do some of the teaching, they said we don’t really know much about these oral therapies.” She described it as a big hole in oncology nursing.

Never attempt to educate patients on their treatment plan at diagnosis. “Bring them back for a second visit,” said Winkeljohn. Teaching sessions should always be individualized, not rehearsed, and a family member or friend should accompany the patient, advised Winkeljohn. That person or another caregiver can be enlisted to help the patient stay adherent.

Motivating patients to remain adherent is difficult, and several techniques have been investigated with marginal success. Diaries and pill counts work for some, said Moore, but others hide poor adherence out of embarrassment. Contracts sometimes work but are obviously not enforceable. A 2003 study found mail reminders somewhat effective, but these would not work for patients on daily oral therapy. She proposed researching the effectiveness of daily cell phone reminders.

One study used an automatic voice response system to call patients each

day. Patients left a message confirming whether they had taken their drug or indicating any problems. Nurses followed up with those who were not adherent, and rates of adherence improved. With multidrug regimens, which are especially problematic, one trial found using a 31-day blister pack with each day’s drugs contained in a blister raised adherence from 61% to 98% at a cost of only 14 cents per card.

Another approach under investigation is measuring metabolite in the patient’s blood levels or molecular response. Abstract 1053269 at the ONS Congress by Romvari and associates analyzed claims for CML patients and concluded that BCR-ABL counts were an effective tool for assessing adherence.

Nonadherence has serious consequences. For CML patients, decreasing levels of adherence correspond with lower rates of major molecular response. Poor adherence might lead to multidrug resistance or symptoms of recurrence mistaken as adverse effects.

Moore begged oncology nurses to do more research on this issue, such as looking at the effect of language barriers, health literacy, and economic status on adherence. She also proposed future studies incorporate adherence as an end point. ● —CM

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Conference News

Can Nurse Practitioners Solve the Looming Oncologist Shortage?

Two NPs—One Outpatient and One Inpatient—Discuss How They Are Getting It Done BOSTON—Practices, community cancer centers, and hospitals are looking at supplementing physicians’ services with nurse practitioners (NPs), who can handle many aspects of care. To demonstrate how this model can work, Melanie Maze, RN, MSN, ANPBC, OCN, and Jean Treacy, APRN, BC, AOCNP, shared their experiences as NPs in oncology nursing from different sides of the spectrum.

are supervised by a medical director and a nursing director, with an attending as primary backup.

The NPs serve as the responding clinician. They meet with families, order and interpret laboratory reports, order

consults, and confer with specialists.

“We are responsible for admitting as well as discharge, and we do documentation,” said Treacy.

The model has decreased the length of hospitalization, saving the hospital money and improving quality of life for patients. The program has increased satisfaction among patients and families, who have greater access to the NPs than they would with physicians. ● —CM

Missouri Cancer Care Maze said outpatient oncology practices that hire NPs benefit in several ways, including financially. Patients also benefit, because on average NP visit lasts 30 minutes compared with 15 minutes for physicians. Maze said much of her visits are spent on education and symptom management. Her day comprises 4 hours providing direct patient care and 4 hours handling tasks such as triaging issues in the treatment room and discussing laboratory results.

Maze administers chemotherapy while the physicians are making their rounds. Her ability to prescribe medications and handle a range of patient concerns frees physicians up to take on new patients. She also sees patients when the physicians are away, allowing the office to remain open all 52 weeks in the year.

Since Maze was hired, staff overtime has declined, relieving stress and reducing overhead expenses, because the office now generally closes on time.

“If you look at independent billing versus incident-to billing, it won’t take long to see how soon you recoup your salary. After that, everything made is revenue for that practice,” said Maze.

Within 6 months of starting, her practice hired another NP. “I was able to show them how valuable it was to the practice to have an NP.” Maze said her practice previously relied on primary care nurses, and it took time for her to gain everyone’s trust.

Massachusetts General Hospital For Treacy, the physicians were used to working with NPs and knew what NPs could handle. When the Accreditation Council for Graduate Medical Education recommended leaving 14 oncology beds uncovered to reduce demands on existing staff, the optimal solution was to create an NP oncology unit. The beds were split between medical oncology and thoracic oncology and staffed with 11 NPs who work 24 to 39 hours per week, and 3 per diem NPs are on the floor 24/7. All

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Conference News

A View from the Floor ONS Annual Congress draws more than 3000 nurses from all 50 states and several countries.

Photos by Michael J. Molfetto

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Conference News d ay an a iP aw er OCN Michig ve inn s, RN,apids, i G W eter d R l D ran ta G ys in Cr lth a He ta

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Conference News

Having Evidence-Based Discussions on CAM Nurses Can Help Patients Assess CAM Therapies and Practices

By Christin Melton

BOSTON—With complementary and alternative medicine (CAM) becoming increasingly popular among patients with cancer, it is important for oncology nurses to familiarize themselves with the evidence for and against various CAM therapies. As a nurse involved with CAM for more than 30 years, Judith Fouladbakhsh, PhD, APRN, AHN-BC, believes these therapies can be used to promote health and wellness.

Fouladbakhsh, who is assistant professor, Wayne State University, Detroit, Michigan, said it is important for nurses to stay educated on CAM therapies because many patients are using them when they present for care. “Cancer patients and survivors are among the highest users of CAM therapies,” she said, “and we have seen the growth of integrative medicine within cancer centers where these therapies are offered.”

A University of Pennsylvania School of Medicine study published in the March issue of the Journal of Cancer Survivorship backs this up. The survey showed that 65% of cancer survivors had used CAM during their lifetime versus 53% of patients without cancer. Patients offer various reasons for using CAM, including a desire to improve their quality of life or provide a greater sense of control over their disease, cultural reasons, dissatisfaction with conventional care, and the desire for natural treatment options.

Some oncologists are not well informed on CAM therapies and avoid discussing them with patients. Oncology nurses, who typically play an active role in educating patients, might hesitate to

broach the topic of CAM out of concern that their employer does not consider it within the scope of their services. As evidence emerges that CAM therapies benefit certain patients, attitudes have begun to shift.

“Oncologists have become more open to the therapies that have an evidence base as they seek means of symptom management for their patients,” said Fouladbakhsh. “I was recently contacted by an oncologist interested in the physiological mechanism of yoga, and several others have joined my yoga research team.”

Symptom management is an area where certain CAM therapies show tremendous promise. Many people— with and without cancer—turn to CAM therapies to relieve pain. “Several CAM therapies have established evidence supporting use for pain management and relief,” Fouladbakhsh said, singling out acupuncture, yoga for low back pain, and chiropractic services.

Preserving or enhancing the wellbeing of patients is an important element of nursing. Shutting the door on dialogue about CAM therapies can hinder the nurse’s ability to provide patients with the best care. Some CAM therapies are harmful or become harmful when used with conventional treatment, others are ineffective but costly, and still others provide much-needed relief. Patients need guidance on determining into which category a CAM therapy they are using or would like to use falls.

Before nurses have these conversations with patients and their families, they need to be knowledgeable about

Trusted Sources of CAM Evidence Publications Journal of Complementary and Integrative Medicine European Journal of Integrative Medicine

Memorial Sloan-Kettering Cancer Center Herbs & Botanical Database www.mskcc.org/mskcc/html/ 11570.cfm

Websites American Botanical Council www.herbalgram.org

Natural Medicines Comprehensive Database www.naturaldatabase.com

The Cochrane Library www.thecochranelibrary.com M. D. Anderson Cancer Center Complementary/Integrative Medicine Education Resources www.mdanderson.org/CIMER

the evidence surrounding various CAM therapies and practices. After becoming educated on CAM therapies, Fouladbakhsh said, “nurses must assess use and may be able to incorporate appropriate therapies into the plan of care.” During the educational session, Lynda Balneaves, RN, PhD, associate professor, and her colleague, Tracy Truant, RN, MSN, professional practice leader, both from the University of British Columbia School of Nursing, Vancouver, suggested using a customized version of the Situation, Choices, Objectives, People, Evaluation, Decision (SCOPED) decision-support tool and provided an example available for download at www.ons.org/CNECentral/ Conferences/Congress/2011.

Important factors to consider in helping the patient assess a CAM therapy or practice are its effects on quality of life,

Natural Standard www.naturalstandard.com NCI Office of Cancer Complementary and Alternative Medicine www.cancer.gov/cam PubMed (CAM on PubMed) www.nccam.nih.gov/research/ camonpubmed

relationships, and overall health; the patient’s ability to commit the time, cost, and energy needed to pursue the therapy or practice; and whether it is compatible with the patient’s overall objectives.

CAM education is never completed.

Data are released regularly that update what is known about existing practices or that propose new ones. Word-of-mouth CAM therapies routinely surface in the media and on the Internet. To continue helping patients make safe, educated decisions on CAM use requires nurses to remain proactive in keeping abreast with the evidence. ● This educational session involved collaboration between the Oncology Nursing Society Complementary & Integrative Therapies Special Interest Group (SIG) and the Canadian Association of Nurses in Oncology CAM SIG.

Advanced Practice Nurses Forge New Ground in Radiation Oncology Units RadOnc APNs Explain Their Roles and Share Their Experiences BOSTON—Nurses have been involved in radiation oncology since the early 1940s, but as nursing roles in general have evolved over time, so has the role of these nurses. A group of advanced practice nurses (APNs) shared how they came to be part of their facility’s radiation oncology department and how the increased strain on healthcare is opening opportunities in this field for APNs. The role of a RadOnc APN is multifaceted. They provide patient education, participate in consultations and

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treatment visits, administer follow-up care and symptom management, handle inpatient admissions, mentor staff, and participate in research.

Elene Viscosi-Spieler, APRN, BC, is a RadOnc nurse in the head and neck department at Massachusetts General Hospital (MGH) in Boston.

“Nurse practitioners [NPs] are vital to the multidisciplinary team,” she said.

“I am often the first person the patient sees.”

Viscosi-Spieler’s team includes radiation oncologists, residents and fellows,

radiation registered nurses (RNs), therapists, physicians/dosimetrists, and research and administrative staff. Her input is sought on developing plans for treatment and follow-up care. As part of a multidisciplinary team, she attends tumor boards and newpatient conferences. “Once treatment is established, my role is one of a navigator, an educator for the patient and family, and a patient care provider to help them get through their symptoms.” She also makes appropriate referrals to other team members.

The greatest benefit in adding an APN/NP to the radiation oncology staff is their ability to manage adverse effects promptly and effectively.

“There are many early toxicities as a result of radiation that have to be dealt with to avoid treatment interruptions,” Viscosi-Spieler explained.

After therapy’s acute effects diminish, she watches for late effects and addresses quality-of-life concerns.

Diane Doyle, MS, APRN, BC, AOCN, is an NP at MGH who was at Boston’s Brigham and Women’s

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Conference News Hospital (BWH) in 2005 when it became one of the first institutions to incorporate NPs in radiation oncology.

Realizing how effective NPs were in medical oncology, Doyle said it was a natural decision to use them in radiation oncology, starting with units whose patients need more intense symptom management because of cancer type or concomitant therapies.

At MGH, Doyle works with radiation patients with thoracic and central nervous system malignancies.

Doyle said, “The physicians were a little hesitant at first, but they’ve come on board nicely.” Now every radiation oncology team wants an NP. MGH recently created a position for a palliative care NP in radiation oncology.

Doyle said APN/NPs in radiation oncology sometimes feel isolated from other NPs, and joked that it is not because they are locked away in the hospital basement all day. “There just aren’t that many of us out there,” she said. “Networking is important to bridge this isolation.”

Allison Taylor, MSN, APRN, BC, AOCNP, an NP affiliated with BWH, noted that the Oncology Nursing Society has a special interest group for radiation oncology nursing.

She also praised the American Society for Therapeutic Radiology and Oncology for being supportive of NPs in this specialty.

Cost is a major obstacle to using APNs/NPs in radiation oncology or in small clinics such as the one Taylor has worked at for 4 years. “We are only able to bill right now for our follow-up visits,” said Taylor. “We cannot bill for status checks and outpatient or inpatient consultation or hospital admissions.” Her clinic collects a lump sum at the outset of treatment that incorporates the expense of the NP. Another challenge is defining the role of the RadOnc APN/NP, broadly as a career and specifically for fellow nurses, physicians, and patients. Physicians might not understand the level of care an APN/NP is capable of furnishing, radiation RNs might fear that the APN/NP will replace them, and patients find it “hard to accept they aren’t seeing the physician at first,” said Taylor. “But [after that] they may want to see just you.” The radiation oncologist should explain to patients how the APN/NP fits into their care.

The speakers called for changes in American College of Radiology guidelines to reflect the growing involvement of NPs in caring for radiation oncology patients. Taylor said research is needed to assess the effects of APNs on the quality of patient care and healthcare costs. ● —CM

www.TheOncologyNurse.com

Preventing Skeletal-Related Events in Patients with Cancer Clinicians Need to Do a Better Job BOSTON—Bone loss and related complications are common in patients with cancer. And the problem is growing, with more patients with cancer aged 65

years and older and increased use of newer treatments that compromise bone mineral density (BMD). “As nurses, we have a very significant role to play in

both prevention and management of [bone loss] problems,” said Carrie Tompkins Stricker, PhD, RN, oncology nurse practitioner, Abramson Cancer

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Conference News Center, Philadelphia, Pennsylvania.

Osteoporosis is a systemic skeletal disease characterized by low BMD and deterioration of bone microarchitecture on dual-emission x-ray absorptiometry (DXA) scanning and/or bone fragility and susceptibility to fracture.

Approximately 80% of people with osteoporosis are women, but men are also at risk. At the time cancer is diagnosed, many patients already have osteopenia, a precursor to osteoporosis.

Certain cancer treatments and their physiologic effects exacerbate bone loss. Primary breast cancer therapy, for example, often induces premature menopause and resulting loss of BMD. Androgen deprivation therapy, aromatase inhibitors (AIs), certain chemotherapeutics, and radiotherapy to the pelvis also cause bone deterioration.

Stricker said seeing these in the treatment history should raise flags.

Oncology organizations offer guidance on when to screen patients with cancer for bone loss. DXA scans mea sure BMD at the hip, femoral neck, and lumbar spine and are recommended for at-risk patients. “The best predictor of fracture is the value the hip…it is most preferential for decision making,” said Stricker. The spine shows the first evidence of BMD loss, and T scores help track bone loss over time.

“The best predictor of fracture is the value at the hip… it is most preferential for decision making.”

—Carrie Tompkins Stricker, PhD, RN

Studies show breast and prostate cancer patients are not getting recommended DXA screening for osteoporosis. “We need to be doing a better job,” Stricker said, especially for patients with bone metastases.

Treatment depends on BMD and history of fracture. Nutritional and behavioral strategies are often started before osteopenia. Beth Faiman, RN, MSN, APRN-BC, AOCN, oncology nurse practitioner with the Cleveland Clinic, Ohio, and editor-in-chief of The Oncology Nurse-APN/PA, recommended supplementation with calcium and vitamin D3 and weight-bearing exercise.

Supplements should be taken in 2 daily doses. “You get better absorption.”

Faiman cautioned that proton pump inhibitors, protein, and coffee interfere with calcium absorption.

Pharmacologic options for antiresorptive therapy in cancer patients include bisphosphonates, selective estrogen receptor modulators (eg,

raloxifene), serum calcitonin, and denosumab. Stricker said raloxifene can lead to cross-resistance with tamoxifen and should not be used in breast cancer patients.

Bisphosphonates have long been the standard of care, with pamidronate and zoledronic acid (ZA) the most common.

The Z-FAST study showed initiating ZA at the start of AI therapy improved BMD, whereas waiting until osteopenia developed led to greater BMD loss. Both approaches were equally effective at preventing fractures.

Denosumab, essentially deactivates osteoclasts and is approved to prevent bone loss in patients with solid tumors but is not recommended for multiple myeloma patients. It is administered subcutaneously every 6 months. Victoria Sinibaldi, MS, CRNP, AOCN, nurse practitioner and program coordinator for genitourinary research, Johns Hopkins Medical Institutions in Baltimore, Maryland, said, whereas

both drugs greatly increase time to first and subsequent skeletal-related events (SREs) compared with placebo, a headto-head comparison of ZA and denosumab found that denosumab significantly delayed time to first and subsequent on-study SREs. Neither drug appears to improve survival.

Bisphosphonates cause significant gastrointestinal disturbance, hypo calcemia, increased parathyroid hormone, skin rash, and bone pain.

Intravenous formulations are associated with fatigue, nausea, vomiting, myalgia, and osteonecrosis of the jaw (ONJ). ZA requires renal monitoring and management of acute-phase reactions. Faiman suggested premedicating patients with acetaminophen or a nonsteroidal antiinflammatory agent and having them drink ample fluids.

Denosumab causes fatigue, asthenia, hypophosphatemia, nausea, dyspnea, hypocalcemia, and ONJ. Hypocalcemia is sometimes severe. Sinibaldi said, “We need to make sure baseline calcium levels are within a normal range prior to initiating denosumab.”

Faiman said preventing bone loss and fracture helps maintain the patient’s quality of life. “Preventing SREs is integral to the patient’s well-being,” said Faiman, adding that nurses are central to effective patient management. ● —CM

Changing the Paradigm of Care for Dying Patients Oncology Nurses Can Help Relieve Physical Symptoms and Psychosocial Concerns BOSTON—Where most people see the end of life for a patient with cancer as a time of grief and suffering, “the final chapter…also holds the opportunity for profound healing, comfort, and growth,” believes Betty Ferrell, PhD, RN, who was honored with the Mara Mogensen Flaherty Memorial Lectureship Award.

She further believes that, through compassionate and competent psychical and psychosocial care, oncology nurses can be instrumental in brightening the darkest days for patients.

The modern hospice movement took root in the 1970s and it continues to evolve and spread, said Ferrell, who is a nursing research scientist with the City of Hope Comprehensive Cancer Center in Duarte, California. Although nursing practices vary according to a region’s resources and customs, Ferrell said she has come to recognize common elements in all nursing efforts to relieve the burden on patients in the later stages of life (Table).

Ferrell said she made these observations during 34 years of oncology nursing experience and through her involvement in the End of Life Nursing Education Consortium (ELNEC) proj-

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Table Elements to Relieve the Burden on Patients in the Later Stages of Life • Challenging the paradigm of care • Creating expertise and knowledge in palliative care • Fostering nursing presence • Expertly attending to the body and relief of symptoms • Envisioning the end of life as a spiritual experience ect. The launch of ELNEC’s palliative care training program in 2001 has brought her together with oncology nurses from all 50 states and 69 coun-

The nurse’s presence is comforting even if she is unable to provide direct relief of the patient’s suffering.

tries. “From Japan to Tajikistan, from Kenya to Russia, Romania to South Korea, nurses around the globe are improving the care of cancer patients at the end of life.”

Oncology is largely focused on curing

disease or prolonging cancer. Meeting the psychosocial needs of those patients who are beyond saving requires challenging this paradigm, said Ferrell. She cited nurses in Veterans Affairs (VA) hospitals as an example of individuals challenging the way their institutions handle death.

VA hospitals have progressed from quickly, silently, and secretly moving the dead from their beds to the morgue to announcing each veteran’s death over the hospital’s audio system and inviting visitors and other patients to “join in the recognition of a life ending.” Each veteran is draped in a US flag and saluted as his or her body is escorted in dignity to the morgue. As part of its effort to transform how death is viewed, the VA also has expanded its commitment to educating its nursing staff on palliative care through the ELNEC project.

Despite the increased attention to palliative care concerns over the decades, Ferrell said her research has identified several areas where it consistently falls short, including the relief of physical symptoms and help for psychosocial concerns such as anxiety, depression, distress, and uncertainty.

Multidisciplinary teams need to adopt aggressive strategies for preventing and alleviating symptoms in patients with cancer and to screen patients for psychosocial issues, rather than waiting to respond when they escalate to a crisis.

One of the most important steps to being a skilled provider of palliative care is showing up. Many patients and families crave the presence of another person as they deal with their grief, and the nurse’s presence is comforting even if she is unable to provide direct relief of the patient’s suffering. Ferrell said in today’s culture of “technology-driven healthcare,” death is viewed as a physiologic experience that represents failure. Nurses must continue to change this paradigm for patients with cancer and work to “create an alternate vision that the end of life is a spiritual experience,” said Ferrell. ● —CM

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Cancer Center Profile Ella Millbank Foshay Cancer Center... Continued from cover also collects data and forwards them to each study’s sponsor.

These studies vary by disease site— breast, lung, ovaries, skin—and by type—clinical trials groups or pharmaceutical trials. As an affiliate of Mt. Sinai Medical Center’s Community Clinical Oncology Program (CCOP), Jupiter Medical Center offers trials from the Radiation Therapy Oncology Group, the Gynecological Oncology Group, the Cancer and Leukemia Group B, the Eastern Cooperative Group, and the American College of Surgeons Oncology Group.

Keeping track of patients in approximately 30 open trials, Secor acts “almost like a navigator through the trial or treatment regimen.” She coordinates each patient’s laboratory testing, chemotherapy, and office visits as well as scans and surgeries. And depending on the trial, patients can be followed for 5 years or longer; some for a lifetime, says Secor. “The patients really look to the oncology clinical research nurse as their primary resource.”

As this resource, Secor coordinates her patients’ supportive care needs as well. If a patient is experiencing certain limitations, she can connect that patient

“I think that helping to find a cure is just so rewarding.

Hopefully, 10 years from now there will be a cure for a specific cancer, because maybe a little part of what I did with my patients helped.”

—Jeanine Secor, RN, BSN

with the center’s physical or occupational therapist. If a patient is experiencing fatigue or wound care issues, she can connect that patient with the sleep center or hyperbaric wound care department. All the hospital’s resources are available to her patients, according to Secor. This includes programs meeting psychosocial needs, such as support groups and the center’s Look Good…

Feel Better program.

In addition, like all clinical research nurses, she follows US Food and Drug Administration (FDA) regulations for clinical trials, which include adherence to the principles of good clinical practices and adequate human subject

protection. Secor also follows policies designed by the Institutional Review Board (IRB), which reviews and monitors research involving human subjects to ensure protection of the patients’ rights, welfare, and privacy.

For example, at Jupiter Medical Center, all trials are designed to meet FDA regulations as well as go through an IRB affiliated with Mt. Sinai Medical Center’s CCOP and an IRB affiliated with Jupiter Medical Center.

This process ensures that even if the research is performed in the physician’s office, the clinical research nurse provides care in keeping with government standards.

The Call Even with her demanding job, Secor loves the oncology field and taking care of cancer patients. “It’s a mutual admiration between patient and nurse. And the patient, I have found, is so appreciative of everything I do.” Her previous work as a director of nursing, an acute care nurse, and a nurse manager on an oncology unit prepared her to work as a clinical research nurse. “Because of my background, administratively and clinically it was a good fit for me. With research nursing, it’s extremely detail oriented and it fits well with a bit of a type A personality,” says Secor.

Working as a clinical research nurse can be approached from many paths.

Nurses can migrate to the work from other specialties or take courses in clinical research from an associate, undergraduate, or graduate degree program. For those interested, the Society of Clinical Research Associates provides educational programs, certification, and a forum for professionals to exchange information.

“I think that helping to find a cure is just so rewarding. Hopefully, 10 years from now there will be a cure for a specific cancer, because maybe a little part of what I did with my patients helped.” ●

Supportive Care

For Palliation of Severe Dysphagia, Small-Caliber Stents Work Well with Fewer Complications

By Caroline Helwick

SAN FRANCISCO—A novel smallcaliber metal stent can provide a low-risk means of palliation for severe malignant dysphagia, according to investigators who have created these stents and are now testing them in trials. The results were presented at the 2011 Gastrointestinal Cancers Symposium by Stephen Kucera, MD, of H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, where he is an interventional endoscopy fellow.

Self-expandable covered metal stents are an important component of palliative care for malignant dysphagia, but significant complication rates have been associated with large-diameter stents, Kucera noted.

“We hypothesized that small-caliber, fully covered self-expandable metal stents [sccSEMS] would provide adequate palliation of dysphagia but carry less risk for major complications,” he said at a poster session.

He and his colleagues conducted a prospective observational study of 2

www.TheOncologyNurse.com

See also pages 36 and 40. patients presenting with severe malignant dysphagia between December 2008 and August 2010. They placed 38 sccSEMS in 23 patients with esophageal cancer. The prestent luminal diameter was <8 mm in 187 patients and 8 to 10 mm in 5 patients. All stents were placed under direct endoscopic vision without fluoroscopy. Dysphagia scores, migration rates, and complication rates were recorded.

Stent Specifications sccSEMS are made of nitinol (nickel titanium). Their shaft diameter varies depending on the placement location: 12 to 16 mm for esophageal placement, 14 to 16 mm for tracheal-bronchial placement, and 8 to 10 mm for biliary placement.

“One of the problems with our current stents is the shaft diameter,” he said. “The smallest we have is 20 mm.

It makes no sense to put something this size when there is a residual luminal diameter of 8 mm, for example,

The poststent median dysphagia score decreased from 3 to 2 (P <.0001). Median duration of first stent placement was 71 days (range, 7-139).

because you can get fistulas, perforations, bleeding, and severe chest pain.

This often means we have to remove the stents.”

Efficacy of Novel Stents The poststent median dysphagia score decreased from 3 to 2 (P <.0001).

Median duration of first stent placement was 71 days (range, 7-139). The overall migration rate was 31.6%, most of which was anticipated because of chemotherapy or radiotherapy; for only 2 patients did migration occur in the absence of treatment.

He acknowledged these small stents “may migrate more,” but noted that they are small and easy to remove. “We were able to remove all the migrated stents endoscopically without complication,” Kucera reported. “We will accept more migration at the expense of less complications and pain.”

Complications included chest pain in 3 (7.9%) patients. No major complications occurred. ● The Alimaxx-ES stents are being manufactured by Merit Medical. Dr Kucera reported no relevant conflicts of interest.

JUNE 2011 I VOL 4, NO 4

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A TREATMENT STRATEGY BUILT FOR YOUR PATIENTS. ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ALIMTA is available in 100 mg and 500 mg vials.

Important Safety Information for Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia).

Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency

PM70409

0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED. ® ALIMTA is a registered trademark of Eli Lilly and Company.

(creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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ALIMTAÂŽ (pemetrexed for injection) Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence)â&#x20AC;&#x201D; 1st-line NSCLC The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/ pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/ heartburn (5 vs 6).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent pages.

PM_HCP_ISI_NSCLC1_04052011

insideALIMTA.com

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ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities 75% of previous dose (pemetrexed and Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin).

50% of previous dose (pemetrexed and Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials.

Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reactionb (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. 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.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal — colitis General Disorders and Administration Site Conditions — edema

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

a

NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose b

PV 5209 AMP

5.2

PV 5209 AMP

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Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal.

7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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 use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse 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. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3)].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-to-treat population.

8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay).

Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

PV 5209 AMP

Literature revised March 17, 2011

Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 2004, 2011, Eli Lilly and Company. All rights reserved.

PM_HCP_BS_NSCLC1_04052011 PV 5209 AMP

PRINTED IN USA PV 5209 AMP

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the

ONE Award

New Hampshire Nurse Janet Stocker Wins the Oncology Nurse Excellence Award

By Daniel Denvir

“

I’m extremely passionate about oncology, particularly palliative care, and dealing with patients’ fears and anxieties—just making sure the patients and their families have the support they need.”

—Janet C. Stocker, RN, MS, NP-C, AOCNS

T

he Oncology Nurse-APN/PA congratulates Janet C. Stocker, RN, MS, NP-C, AOCNS, on being chosen by more than 400 of her peers to be this year’s winner of the Oncology Nurse Excellence award.

“I’m extremely passionate about oncology,” says Stocker, “particularly palliative care, and dealing with patients’ fears and anxieties—just making sure the patients and their families have the support they need.”

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Wearing 2 hats at the Seacoast Cancer Center, part of Dover, New Hampshire’s Wentworth Douglass Hospital—an oncology adult nurse practitioner and a clinical nurse specialist—Stocker notes that her days can be hectic. She has to look out for both patients and fellow nurses. But the variety of her workday is what keeps her engaged. Things are never boring.

“I get to flex between educating patients and educating nursing staff, which is a nice mix for me,” says Stocker. “It’s a little bit crazy, but it gives me great job satisfaction.”

“Janet exemplifies the role of an oncology nurse in our community hospital–based outpatient cancer center,” says Alice Tansey, RN, BSN, a medical oncology nurse manager and colleague of Stocker’s at Wentworth Douglass Hospital. She gives Stocker plaudits for taking on so many different tasks. “Janet seamlessly moves back and forth from presenting evidence on personal protection for staff in the infusion room, to mentoring staff, to conferring on patient care, to researching admissions for neutropenia.”

Though Stocker is a highly capable educator, she is deeply committed to providing patient care and says that she chose oncology because it provided a unique opportunity to connect to patients.

“I completed my nursing rotations, and these were patients that I seem to take care of a lot,” she tells The Oncology Nurse-APN/PA. “I just seemed to connect with them, so when I went looking for a job, I looked for work in oncology.”

The Call to Nursing Stocker grew up in Pen Argyl, Pennsylvania, a small borough in the Lehigh Valley just north of Allentown. After receiving her associate’s degree, she started work as a medical secretary. Stocker grew bored, however, sitting behind the desk, and became increasingly interested in what was going on in the office around her. Convinced that she wanted to learn more about medicine, she lasted all of 3 months on the job.

“I worked and quickly decided that this was not for me, to be behind a desk doing administrative work. I sincerely wanted connectivity to the patient,” she says. “I knew I wanted to be in some therapeutic profession as a child. I always liked helping people.”

By age 22, she was employed as a licensed practical nurse at a community hospital just across the Delaware River in New Jersey. She started working on her associate’s degree in nursing, but had to take a slight detour when diagnosed with ovarian cancer.

After treatment, she married and moved to New Hampshire with her husband, and completed her registered nurse degree.

The traumatic experience was exhausting, however. And Stocker decided that she needed a “personal and professional break” from oncology. She spent the next 5 years working as an emergency room nurse.

But when a position for an assistant manager in the hospital’s oncology unit opened up, she knew that she should apply. “I was missing it, and I knew that I needed that connectivity again.”

Stocker says that she usually does not tell patients that she is a fellow survivor. She only tells her story if she thinks that sharing a personal experience will be of some value to them. Sometimes she can make a patient’s fear less scary by saying, “I’ve been there, I understand.” Although she and her patients have suffered, she finds the job deeply fulfilling. It truly makes her happy.

“There are times when it’s sad,” she says. “But on the other side, there are times of great joy. There’s a

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the

ONE Award

“

She is comforting to patients as she makes treatment decisions in addition to supporting their symptoms as they go through treatment.”

—Alice Tansey, RN, BSN, in her nomination of Stocker

balance that happens there—just knowing that I’m helping that person not only in his or her really happy times, but to help manage and get through some of those sad moments in life. Whether that’s being told that you have cancer or telling someone that their life is limited. How do you help them do what they want to do before they die?”

Walking alongside of that patient and his or her family, guiding them through this detour in their lives, this is the piece that oncology nurses facilitate every day.

And that’s the joy and comfort she finds in her role.

Looking to the Future When she started at Wentworth Douglass 4 years ago, Stocker worked a 40-hour week as a clinical nurse specialist, and as an oncology nurse practitioner at a separate physician-based office and infusion center once per week. Now, she transitions between both roles at Wentworth Douglass, providing care for a few hours and then doing rounds of inpatient units to support staff. Sometimes, she’ll “teach a class and address a patient prescription need during a class break.”

Stocker has played a lead role in introducing new procedures and technologies to the cancer center, and she is a stickler for evidence-based procedures. She created a checklist to streamline the delivery of chemotherapy and improve safety for employees and patients alike. She also developed care plans for the center’s electronic health record (EHR) based on National Comprehensive Cancer Network guidelines.

“Prior to implementing the EHR, Janet ensured that all steps of the delivery of chemo were safe,” says Tansey. “All of this is done within a supportive, mentoring, and empathetic atmosphere, which enhances the experience of our patients.”

She is part of the team implementing the center’s Elekta Impac software and Mosaiq EHR system.

Stocker also developed a protocol for the insertion of vascular access devices, which has been implemented hospital-wide.

Oncology has changed a lot over the past decades, from new antiemetic and growth factors for managing side effects to new targeted treatment therapies. And Stocker has changed too. She says that it is important to grow and learn throughout your career, to keep up with and successfully implement advances in the field.

“Oncology nursing has changed immensely

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through the years,” she says. “How and where chemotherapy is delivered, for example. When I began working, chemotherapy was mostly given on an inpatient basis. Now chemo is mostly given on the outpatient basis, so patients can go home to their families. Go home to their own pillows.”

The biggest and most important change in oncology over the past decades is that cancer is being treated with increasing success, and patients are living longer. This gives Stocker a new, but good, problem to deal with: patients facing a lifetime of survivorship. She says that nurse specialists and nurse practitioners are well positioned to deliver this long-term survivorship care, taking on matters like counseling a patient on obtaining appropriate screening such as a mammogram or a colonoscopy.

There are a declining number of physicians available to deal with the skyrocketing number of survivors, and oncology providers must think creatively about delivering treatment.

“

All of Janet’s work is done with in a supportive, mentoring, and empathetic atmosphere that enhances the experience of our patients.”

—Alice Tansey, RN, BSN, in her nomination of Stocker

“Because we’ve done such a great job treating cancer, we will have more patients who you’re going to find that they had a history of cancer, or at least a family member who does,” she says. “With healthcare looking at a limited number of physicians, there are important disease management and survivorship roles that nurse practitioners can fill very confidently, guiding the patients through what they need to do for just good sound healthcare after a diagnosis of cancer. That’s just one part of what you gain as an oncology nurse.” ●

A Commitment to Helping Those with Cancer

A

s the Oncology Nurse Excellence award winner, Janet C. Stocker, RN, MS, NP-C, AOCNS, chose 2 local cancer charities to receive donations—Amy’s Treat and the New Hampshire Prostate Cancer Coalition.

Amy’s Treat Janet chose Amy’s Treat because it provides solutions to the day-to-day difficulties of living with cancer and offers unexpected “treats” to renew the spirit to patients at the Seacoast Cancer Center of New Hampshire. This all-volunteer organization funds fun activities when they are needed the most.

As a collaboration between a cancer center and its community, Amy’s Treat works to meet the requests of patients with cancer, whether in an outing to the ballpark or a trip to a country inn.

“A contribution to Amy’s Treat ends up exactly where the donor meant it to be—in the hands of those who need it most,” according to the organization, which acts as the go-between for the donor to an individual with cancer.

The organization launched in 2007 as a legacy foundation honoring the memory of Amy Maliszewski. If you wish to help, Amy’s Treat accepts online donations at www.FirstGiving.com or through the mail: Amy’s Treat PO Box 2234 Dover, NH 03821

New Hampshire Prostate Cancer Coalition Janet also chose the New Hampshire Prostate Cancer Coalition because of its work to significantly reduce prostate cancer deaths in the state.

This all-volunteer organization, almost all of whom are survivors, spreads awareness of this disease through appearances at service clubs and community organizations. The group also offers brochures and PowerPoint presentations through its website, and publishes a monthly newsletter that is e-mailed to hundreds of subscribers.

Through its partnerships with the local medical community, the New Hampshire Prostate Cancer Coalition encourages informed decision making regarding detection and treatment. Another set of partnerships, with New Hampshire’s 6 prostate cancer support groups, helps the organization reach newly diagnosed men.

If you would like to help the New Hampshire Prostate Cancer Coalition raise the quality of life for men and their loved ones, donations can be made online at www.FirstGiving.com or through the mail: The New Hampshire Prostate Cancer Coalition 9 Fernwood Drive Merrimack, NH 03054

JUNE 2011 I VOL 4, NO 4

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CONTINUING EDUCATION PROGRAM CE18 • RELEASE DATE: JUNE 15, 2011 • EXPIRATION DATE: JUNE 15, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYNURSE.COM

An Update on Systemic Treatment Options in Advanced Melanoma

By Suzanne McGettigan, MSN, CRNP, APRN-BC, AOCN Oncology Nurse Practitioner, Abramson Cancer Center at the University of Pennsylvania, Philadelphia

STATEMENT OF NEED Patients with metastatic melanoma historically have had few therapeutic options, but there have been recent advances in immunotherapy and the development of novel BRAF- and KIT-targeted agents for those with stage IV disease. This year ipilimumab, an immunotherapy monoclonal antibody, was FDA-approved for late-stage metastatic melanoma. Nurses now need to understand how these agents work, their efficacy, and their adverse event profiles. In addition, nurses will need to comprehend better the molecular changes that occur in relation to certain melanomas.

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: • Compare/contrast therapeutic options for patients with metastatic melanoma.

• Discuss efficacy rates and adverse event profiles for newly approved agents and those in the late-stage pipeline.

M

elanoma is the most severe form of skin cancer and contributes to more life-years lost than any other cancer type. Melanoma detected in its earliest stages is associated with a 5-year survival rate of 97%.1 The prognosis for patients with metastatic stage IV melanoma, however, is poor, with a 1-year survival rate of 33% to 62% and an average life expectancy of 6 to 12 months. Patients with metastatic melanoma historically have had few therapeutic options, but recent advances in immunotherapy and the development of novel BRAFtargeted agents have generated optimism that someday we may see improvement in survival outcomes for those with stage IV disease.

Systemic chemotherapy remains the mainstay of treatment for stage IV disease despite its limited effectiveness. It is important to remember that when evaluating therapy options in meta static melanoma, metastatecomy seems to provide the best progression-free survival (PFS) and overall survival (OS) outcomes for a single site of metastatic disease, although randomized clinical trials have not been performed in this setting.2 In addition, for patients with metastatic melanoma involving the brain, therapy to manage

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the central nervous system should be the priority.

Chemotherapy and immunotherapy are used widely for treating stage IV melanoma, but only a small proportion of patients demonstrate long-term response. Guidelines from the National Comprehensive Cancer Network cite enrollment in a clinical trial as the preferred option for patients with metastatic melanoma,3 but few agents studied in large clinical trials have demonstrated efficacy. Until this year, none of these investigational drugs had consistently demonstrated improvement in OS. Better understanding of the molecular changes that occur in relation to certain melanomas has made developing oncogene-targeted therapy a research priority. Several molecular targets have been identified, and large clinical trials are investigating promising therapies.

Immunotherapy The US Food and Drug Administration (FDA) approved interferon alpha-2b in 1995 as an adjuvant treatment for metastatic melanoma and interleukin-2 in 1998 for advanced melanoma. The first treatment to gain approval since then is ipilimumab, an immunotherapy monoclonal antibody approved by the FDA in March 2011 for patients with late-stage, metastatic melanoma.

The cytotoxic T-lymphocyte antigen (CTLA)-4 signaling pathway plays an important role in T cell production and activation. Costimulatory signaling between B7 and CD28 initiates T cell production. CTLA-4 selectively binds to B7 to signal T cell production to stop. Preventing CTLA-4 from binding to B7 allows continued T cell activation. Ipilimumab (formerly MDX-010) and the novel agent tremelimumab (also known as CP-675206 and previously known as ticilimumab) are both monoclonal antibodies designed to target CTLA-4 that have been investigated in melanoma.

Studies suggest they have similar efficacy rates and toxicity profiles.

Ipilimumab. This fully humanized IgG1 monoclonal antibody specific for CTLA-4 is FDA-approved for the treatment of unresectable and meta-

static melanoma. As part of approval, the FDA required the manufacturer to implement a Risk Evaluation and Mitigation Strategy. Approval was based on a phase 3 clinical trial (N = 676), in which Hodi and colleagues demonstrated an approximately 3.6-month improvement in OS associated with ipilimumab therapy.4 Patients with previously treated metastatic melanoma were randomized at a 1:1:3 ratio to receive ipilimumab alone, a glycoprotein 100 (gp100) peptide vaccine alone, or a combination of the gp100 vaccine and ipilimumab. Ipilimumab was administered at a dose of 3 mg/kg every 3 weeks for a total of 4 treatments, but patients who experienced progression after induction with ipilimumab had the option of receiving additional treatment. Response was assessed at 12 weeks, 24 weeks, and every 3 months thereafter.

The best overall response rate (ORR) in the combination arm was 5.7% compared with 10.7% in the ipilimumab-only arm and 1.5% in the CONTINUING 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

gp100 monotherapy arm. The disease control rate in the ipilimumab-only group was 28.5% compared with 20.1% for the combination arm and 11% for the gp100 monotherapy group.

At 2 years, 60% of patients treated only with ipilimumab and 17.4% of patients given ipilimumab/gp100 maintained their responses. The median duration of response was 10 months in both ipilimumab-containing arms and 6 months in the gp100 arm.4 Ipilimumab also was studied in the first-line setting in patients with metastatic disease. In a phase 2 trial, patients received ipilimumab plus dacarbazine. Fischkoff and associates reported that 5.4% of patients obtained a partial response (PR) and 10.8% experienced stable disease.5 The study demonstrated complete responses (CRs) in 5.7% of patients durable at 17+ and 20+ months, PRs in 11.4% at 3 months up to 21+ months, and stable disease in 11.4% lasting for 4 to 8 months. Another phase 2 trial adminresolve any conflicts of interest prior to the commencement of the educational activity.

Disclosures are as follows: • Dawn Lagrosa has nothing to disclose.

• Christin Melton has nothing to disclose.

• Suzanne McGettigan, MSN, CRNP, APRN-BC, AOCN, is on the speakers’ bureau for Bristol-Myers Squibb and Merck and Co. The staff of Science Care have nothing to disclose.

UNLABELED OR UNAPPROVED USE OF DRUGS OR DEVICES It is the policy of Science Care to require the disclosure of all references to unlabeled or unapproved uses of drugs or devices prior to the presentation of educational content. The audience is advised that this CE activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. Please consult the prescribing information for full disclosure of approved uses.

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.

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istered ipilimumab alone or in combination with dacarbazine in the firstline metastatic setting, with a median OS for all patients of 368.5 days, 351 days and 386 days for the monotherapy and combination groups, respectively.6 Tremelimumab. This fully humanized IgG2 monoclonal antibody to CTLA-4 has been studied in a multitude of phase 1 to 3 clinical trials, both alone and in combination with other agents. In the initial dose-escalation study, 29 of 39 study participants had metastatic melanoma. Of these, 2 patients experienced CRs maintained for 34+ and 25+ months, and 2 patients experienced PRs at 26+ and 25+ months.7 A dose of 15 mg/kg every 3 months for tremelimumab was selected for use in subsequent trials.8 A phase 3 open-label, randomized, comparative study of tremelimumab and chemotherapy (temozolomide or dacarbazine) administered in the first-line setting in patients with metastatic disease was halted early by the data safety monitoring board, who at the second interim analysis determined no difference in OS between the tremelimumab and chemotherapy arms. At that time, 6 to 11 months into treatment, median OS was 11.8 months in the tremelimumab arm and 10.7 months in the chemotherapy arm. The final analysis of this trial has yet to be completed.9 Treatment with anti–CTLA-4 therapies has forced clinicians to re-evaluate the criteria by which patient response typically is gauged; with traditional chemotherapy, Response Evaluation Criteria In Solid Tumors are used effectively. Many patients treated with anti– CTLA-4 agents who appear to have stable disease or even progressive disease at the initial analysis go on to have tumor regression on subsequent evaluations at much later time periods than typically would be expected from traditional chemotherapy. New guidelines for evaluation of patient response to these therapies, Immune-Related Response Criteria (irRC), measure re sponse to therapy based on overall tumor burden.10 Following CTLA-4–induced upregulation of T cells, immune-mediated adverse reactions can occur, many of which can be life-threatening. These immune-mediated reactions may involve any organ system, but the most common reactions are dermatitis, colitis, hypophysitis, hepatitis, and neuropathy. These toxicities can be severe and even fatal, with grade 3/4 toxicity occurring in 10% to 15% of patients.

Immune-mediated adverse reactions must be managed aggressively, with steroidal therapy playing a major role.

Most reactions occur during active therapy with ipilimumab, but can occur at any time following therapy.

www.TheoncologyNurse.com

Interferon alpha-2b. This adjuvant therapy is FDA-approved for the treatment of high-risk stage II and III melanomas following surgical resection of known disease. The first clinical trial in melanoma demonstrating an improvement in both disease-free survival and OS was Eastern Cooperative Oncology Group (ECOG) 1684.

Overall relapse-free survival was improved in the treatment arm from 0.98 years to 1.72 years, and an OS benefit of 9% was observed.11 Subsequent trials consistently have demonstrated an impact on PFS, but OS has remained more evasive. In addition, the toxicities commonly associated with this therapy make it a challenging therapy for use in all patients. Interferon therapy is associated with flu-like symptoms, fever, chills, myalgias, nausea, vomiting, diarrhea, fatigue, depression, anorexia, elevation in liver function tests, and myelosuppression. Improvements in toxicity management have led to greater numbers of patients completing a full year of high-dose therapy, making effective and proactive management of these toxicities a priority.

Many patients treated with anti–CTLA-4 agents who appear to have stable disease or even progressive disease at the initial analysis go on to have tumor regression on subsequent evaluations.

Interleukin-2. This immune-modulating agent is FDA-approved for the treatment of stage IV melanoma.

Response rates range from 12% to 20%, with complete regression reported for 6.6% of the 409 patients treated.12,13 The median duration of response is 8.9 months. In patients achieving CR or PR, durable responses have been observed to last for up to 10 years.

Interleukin-2 must be administered by a team of highly qualified and experienced individuals. It is administered in a specialized acute care setting because of its toxicities, which include capillary leak syndrome, hypotension, arrhythmias, pulmonary complications, renal dysfunction, flu-like symptoms, and rash, among others.

Chemotherapy Dacarbazine, an intravenous chemotherapy, was FDA-approved for the treatment of metastatic melanoma in 1975. Other chemotherapeutics, used off-label, have

been shown to have an effect on melanoma.

Dacarbazine has been studied in numerous clinical trials with response rates ranging from 5% to 28%, with a median response rate of 15%.

Temozolomide, an oral agent, demonstrates similar response rates to dacarbazine, with no significant difference noted in PFS or OS.14 Temozolomide offers patients a convenient oral treatment regimen. Both agents are associated with hemopoietic suppression.

Nitrosureas have a response rate ranging from 10% to 20%, cisplatin 14% to 29%, paclitaxel 14%, and vincristine 12%.15 Combination regimens, the most promising of which have been cisplatin/vinblastine/dacarbazine and carboplatin/dacarbazine/carmustine/ tamoxifen, have not been demonstrated to be superior to single-agent dacarbazine in clinical trials.16-18 In addition, the combination paclitaxel/carboplatin was demonstrated to have a clinical benefit in a phase 2 trial, with a disease control rate of >60% and toxicities consisting of myelosuppression, fatigue, alopecia, and peripheral neuropathy.18 Subsequent reports have demonstrated disease control rates of 16% to 74%.18,19 Biochemotherapy regimens, the combination of chemotherapeutic with immune-modulating agents, have been studied extensively in metastatic melanoma. Although these combinations have been shown to improve response rates, no benefit in OS has been observed. Side effects of biochemotherapy include severe and prolonged myelosuppression, flu-like syndrome, capillary leak syndrome, renal and hepatic dysfunction, and severe nausea/vomiting.20 Adoptive Immunotherapy Adoptive immunotherapy is being studied extensively in patients with metastatic melanoma. Most of this research involves investigating adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) or T-cell receptor (TCR)-transduced lymphocytes and interleukin-2 with a nonmyeloablative conditioning regimen. Objective tumor regression rates have been reported as high as 49% to 72% of patients with many long-term durable responses; however, patients must have a resectable tumor from which TIL can be generated that exhibit tumor-specific reactivity. A recent publication described a 5-year period in which 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 (27%) patients, with viable TILs generated in 376 (94%) patients, and active, specific TILs identified in 269 (67%) patients.21-24

To Receive cRediT, compleTe The posTTesT aT TheOncologyNurse.com

Objective responses also have been seen in central nervous system–based disease with ACT.25 Forty-one percent of patients treated with TIL-based therapy achieved a CR in the brain and a PR in systemic disease. Median survival for these 17 patients was 8.5 months, with an estimated actuarial 2-year survival of approximately 40%. Twentytwo percent of patients treated with TCR-based therapy achieve a CR in the brain, with a median OS of these 9 patients equaling 15 months. In patients who achieved response in the brain lesions, these responses endured for 4+ to 43+ months in TIL group and 8 to 25+ months in the TCR group.25 Clinical trials are ongoing to improve the technique and examine response in larger groups of patients.

Although the field has enormous promise, it is a complex and expensive approach to therapy.

BRAF-Targeted Agents BRAF is a member of the MAP kinase pathway, a mediator of growth-factor signaling in cell division, including cancer. Mutations in BRAF have been identified in several types of cancer.

Activating mutations in the BRAF oncogene have been reported in up to 60% of melanomas.26 The most common of these mutations is in the BRAF protein V600E. In primary melanomas, clinicopathologic features consistently reported to be associated with mutant BRAF include younger age, fewer markers of chronic sun damage in surrounding skin, higher total body nevus counts, specific histopathologic findings (superficial spreading melanoma, nodular melanoma), truncal location of primary, and the presence of mitoses; however, BRAF-mutation status does not appear to have an impact on the disease-free interval, measuring from time of melanoma diagnosis to time of metastatic disease.27 Sorafenib. One of the first BRAF-targeting agents in clinical development was sorafenib, currently FDA-approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. It is an orally administered bi-aryl urea originally designed as an inhibitor of BRAF and RAF1, with additional activity against vascular endothelial growth factor receptors 2 and 3 (VEGFR2 and VEGFR3), the tyrosine kinase FLT3, the cytokine receptor KIT,

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An Update on Systemic Treatment Options in Advanced Melanoma and platelet-derived growth factor receptor (PDGFR). Despite extremely encouraging results in early clinical trials, in phase 3 trials for melanoma, sorafenib demonstrated only moderate inhibition when combined with chemotherapy and no clinical efficacy as a single agent.28-31 Agents in development. Two BRAFtargeting agents currently undergoing clinical trials are RG7204 (formerly RO5185426, PLX 4032) and GSK211 8436. In the phase 1 clinical trial with RG7204, patients with BRAF-mutant melanoma tolerated the therapy well at a dose of 960 mg twice daily, and 60% of these heavily pretreated patients demonstrated disease stabilization and shrinkage with a PFS of 8.5 months.32 The extension phase of this trial demonstrated a response rate of 81%, with most patients experiencing PRs and 2 of 32 achieving a CR. PFS was greater than 7 months. The main toxicities experienced were rash, fatigue, arthralgias, photosensitivity, and the development of squamous cell carcinomas and keratocanthomas.33 The BRAF Inhibitor in Melanoma (BRIM3) phase 3 multicenter trial, in which untreated patients with BRAFmutant melanoma were randomized to receive either RG7204 or dacarbazine, has completed accrual; preliminary results demonstrate an improvement in OS and longer time to disease progression with RG7204.

GSK2118436 has been evaluated in a phase 1 clinical trial. The most common toxicities included pyrexia, fatigue, rash, and the development of squamous cell carcinomas and keratocanthomas. The ORR was 63%, with PRs seen in most patients treated; in addition, patients with asymptomatic, untreated brain metastases experienced regression in those lesions.

Although these responses occurred quickly, often within 1 to 2 weeks of initiation, they were short-lived.34 There are several theories on the mechanisms of resistance, and combinations with other agents are being investigated.

KIT-Targeted Therapies KIT mutations have been identified in 39% of mucosal, 36% of acral, and 28% of chronically sun-damaged melanomas.35 Multiple phase 2 studies have been conducted in nonselected patients using imatinib alone or in combination with temozolomide, with limited clinical responses. 36 Several clinical trials, enrolling patients with known KIT-mutated melanoma, have demonstrated more promising results. Another study

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Ipilimumab is associated with immune-related response patterns and immune-mediated adverse reactions, both of which require a new approach for optimal management.

investigating the use of imatinib in metastatic melanoma demonstrated a 60% disease control rate, with 20% achieving a PR.37 Dasatinib inhibits c-KIT, PDGFβR, and EPHA2, and the SRC kinases cSRC, c-YES, LCK, and FYN. A phase 2 trial conducted in nonselected patients demonstrated low response rates in KITmutated and nonmutated patients.38 Nilotinib is a second-generation tyrosine kinase inhibitor of KIT, PDGFR, and BCR-ABL, with a similar potency in vitro and selectivity profile to that of imatinib; however, based on positive responses in gastrointestinal tumors, nilotinib is currently being studied in imatinib-resistant melanoma.36

Based on positive responses in gastrointestinal tumors, nilotinib is currently being studied in imatinibresistant melanoma.

Conclusions Metastatic melanoma is associated with poor clinical outcomes. Being an immunogenic cancer, many of the mainstays of therapy for melanoma involve manipulation of the immune system, including the newest agent, ipilimumab. Ipilimumab is associated with immune-related response patterns and immune-mediated adverse reactions, both of which require a new approach for optimal management.

Better understanding of the genomic character of melanoma has led to the development of many new targeted approaches to treatment. Clinical trials continue to investigate the therapeutic benefit of these agents and ways to combine these therapies to optimize patient outcomes. ●

References 1. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199-6209.

2. Young SE, Martinez SR, Essner R. The role of surgery in treatment of stage IV melanoma. J Surg Oncol.

2006;94:344-351.

3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma. V.4.2011. www.nccn.org/professionals/physician_gls/pdf/melano ma.pdf. Accessed May 9, 2001.

4. Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

5. Fischkoff SA, Hersh E, Weber J, et al. Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma. J Clin Oncol. 2005;23(16S Pt I):Abstract 7525.

6. Hersh EM, Weber SJ, Powderly JD, et al. Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab (MDX- 010) with or without dacarbazine. J Clin Oncol. 2008;26(May 20 suppl):Abstract 9022.

7. Ribas A, Camacho LH, Lopez-Berestein G, et al.

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyteassociated antigen 4 monoclonal antibody CP-675,206.

J Clin Oncol. 2005;23:8968-8977.

8. Gomez-Navarro J, Sharma A, Bozon V, et al. Dose and schedule selection for the anti-CTLA4 monoclonal antibody ticilimumab in patients (pts) with metastatic melanoma. J Clin Oncol. 2006;24(18S Pt I): Abstract 8032.

9. Ribas A, Hauschild A, Kefford R, et al. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma. J Clin Oncol. 2008;26(15S):Late Breaking Abstract 9011.

10. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.

11. Kirkwood JM, Stawdeman MH, Ernstoff MS, et al.

Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol. 1996;14:7-17.

12. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228:307-319.

13. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:21052116.

14. Quirt I, Verma S, Petrella T, et al. Temozolomide for the treatment of metastatic melanoma: a systematic review. Oncologist. 2007;12:1114-1123.

15. Wolchok JD, Saenger YM. Current topics in melanoma. Curr Opin Oncol. 2007;19:116-120.

16. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-2751.

17. Hauschild A, Schadendorf D. Working group of the dermatologic oncology [in German]. J Dtsch Dermaol Ges. 2009;7:726-727.

18. Hodi FS, Soiffer RJ, Clark J, et al. Phase II study of paclitaxel and carboplatin for malignant melanoma.

Am J Clin Oncol. 2002;25:283-286.

19. Pflugfelder A, Eigentler TK, Keim U, et al.

Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma. PloS One. February 16, 2011. Epub ahead of print.

20. Atkins MB, Lee S, Flaherty LE, et al. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): an ECOG-coordinated intergroup trial. J Clin Oncol. 2003;22:Abstract 2847.

21. Goff SL, Smith FO, Klapper JA, et al. Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. J Immunother.

2010;33:840-847.

22. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma.

J Immunother. 2002;25:243-251.

23. Dudley ME, Wunderlich JR, Yang JC, et al.

Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346-2357.

24. Heemskerk B, Liu K, Dudley ME, at el. Adoptive cell therapy for patients with melanoma, using tumorinfiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther. 2008;19:496510.

25. Hong JJ, Rosenberg SA, Dudley ME, et al.

Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res. 2010; 16:4892-4898.

26. Curtin JA, Fridyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.

27. Long GV, Menzies AM, Nagrial AM, et al.

Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol.

2011;29:1239-1246.

28. Amaravadi RK, Schuchter LM, McDermott DF, et al. Phase II trial of temozolomide and sorafenib in advance melanoma patients with or without brain metastases. Clin Cancer Res. 2006;15:7711-7718.

29. Flaherty KT, McArthur G. BRAF, a target in melanoma: implications for solid tumor drug development. Cancer. 2010;116:4902-4913.

30. Hauschild A, Agarwala SS, Trefzer U, et al.

Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823-2830.

31. Jilaveanu L, Zito C, Lee SJ, et al. Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib. Clin Cancer Res. 2009;15:1076-1085.

32. Flaherty K, Puzanov I, Sosman J, et al. Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer.

J Clin Oncol. 2009;27(15S):Abstract 9000.

33. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma.

N Engl J Med. 2010;363:809-819.

34. Flahery KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. April 1, 2011. http://f1000.com/reports/m/3/8/. Accessed May 9, 2001.

35. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-4346.

36. Romano E, Schwartz GK, Chapman PB, et al.

Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol.

February 22, 2011. Epub ahead of print.

37. Kong Y, Si L, Zhu Y, et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma.

Clin Cancer Res. 2011;17:1684-1691.

38. Kluger HM, Dudek AZ, McCann C, et al. A phase 2 trial of dasatinib in advanced melanoma. Cancer.

2011;117:2202-2208.

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Genetic Counseling Identifying Endometrial Cancer Survivors... Continued from cover tract, urinary tract, small As Lynch syndrome is an bowel, and brain/central autosomal dominant cancer nervous system, as well as syndrome, offspring, siblings, sebaceous neoplasms. The and parents of probands have a average age of onset for 50% chance of carrying the endometrial cancer associatfamilial mutation. Not only does ed with Lynch syndrome is testing endometrial cancer sur54 years.1 Among women vivors provide more useful inforwith Lynch syndrome who mation for family members with Cristi Radford, develop colon and gyneconegative germline results, it also MS, CGC logic malignancies in their can reduce the cost of germline lifetime, approximately 50% present first analysis substantially, from several thouwith a gynecologic cancer. Further, the sand dollars to several hundred dollars median number of years between diag- per individual tested. nosis of gynecologic cancer and colLynch syndrome is associated with orectal cancer is estimated to be 11.6 mutations in the mismatch repairs Identifying survivors of endometrial (MMR) genes: MLH1, MSH2, MSH6, cancer with Lynch syndrome is impera- and PMS2. Mutations in EPCAM also tive in medical management. Survivors have been demonstrated to cause Lynch are at an increased risk of developing a syndrome by affecting the ability of second primary cancer, especially colo- MSH2 to function. Given mutations in 5 rectal cancer. Individuals with Lynch genes are associated with Lynch synsyndrome need colonoscopies every 1 to drome, the average age of onset for 2 years beginning at age 25.7 Each colo- endometrial cancer is older than 50 years, rectal cancer survivor with Lynch syn- and the syndrome has a variable phenodrome has at least 3 relatives also with type, diagnosing an individual with Lynch syndrome.8 It is likely this number Lynch syndrome can be challenging. is similar for endometrial cancer surTypically, identification of individuvivors. Identifying “previvors” with als with Lynch syndrome has depended Lynch syndrome allows for tailored med- on clinical guidelines, such as the ical management that prevents cancer or Amsterdam and Bethesda criteria. catches it in its earliest, most treatable These criteria rely on young age at diagstage. In addition, after a mutation for nosis, history of colorectal cancer, Lynch syndrome has been identified, at- and/or detailed family history. Such risk family members can be tested for the approaches fail to identify up to 70% of particular mutation in the family.

Lynch syndrome cases—missed oppor-

tunities for reducing morbidity and mortality in survivors, as well as their children, siblings, and extended relatives.1 Many centers have implemented routine screening of colorectal and endometrial cancer tissue via immunohistochemistry (IHC) analysis. IHC is a cost-effective pathology technique used to triage patients at risk for Lynch syndrome.9 The results help provide a road map for additional genetic analysis.

Most cases of loss of staining are associated with a germline mutation; however, in up to 30% of cases it is a result of hypermethylation of the MLH1 promoter, an epigenetic event.10 In cases not caused by promoter hypermethylation, loss of expression can be correlated with single-gene analysis for the gene most likely to harbor a mutation, including EPCAM. Patients with loss of expression then are referred to an expert in genetics for genetic counseling and possible germline testing.

A normal IHC result suggests that the 4 MMR proteins are expressed normally.

As with any test, the quality of IHC results can vary by sample and/or laboratory performing the analysis. In addition, some mutations associated with Lynch syndrome make a protein that can be visualized on staining; however, the protein does not work correctly in the body.11 Therefore, although a normal IHC result in an endometrial cancer survivor greatly reduces the chance of

Lynch syndrome, individuals with a personal and/or family history that is highly suspicious for a hereditary syndrome should be further evaluated by an expert in genetics. It is possible that a woman could have a mutation not detected by IHC or in a gene associated with a different hereditary cancer syndrome. ● References 1. Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810-7817.

2. Lu KH, Schorge JO, Rodabaugh KJ, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol.

2007;25:5158-5164.

3. Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993; 71:677-685.

4. Watson P, Vasen HF, Mecklin JP, et al. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med. 1994;96:516-520.

5. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129:415-421.

6. Lu KH, Dinh M, Kohlmann W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol.

2005;105:569-574.

7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening.

V.2.2001. www.nccn.org/professionals/physi cian_gls/pdf/ colorectal_screening.pdf. Accessed May 12, 2011.

8. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783-5788.

9. Resnick K, Straughn JM, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol. 2009; 114:530-536.

10. Modica I, Soslow RA, Black D, et al. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol.

2007;31:744-751.

11. Boland C, Koi M, Chang K, Carethers J. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer. 2008; 7:41-52.

Applying Knowledge to Clinical Practice A Case Example for Nurses Is Jane a candidate for genetic services, such as genetic counseling? Why or why not?

Jane is a 54-year-old woman recently diagnosed with an endometrial adenocarcinoma. Her only paternal aunt was diagnosed with endometrial cancer at age 56. Family history also includes a father who died in a car accident at age 31 and a paternal grandfather diagnosed with colorectal cancer at age 60. Per Jane’s report, her grandfather has had colon polyps removed since his diagnosis. In addition, she has zero paternal cousins and paternal uncles. Her pathology report indicates that expressions of MLH1, MSH2, MSH6, and PMS2 were normal. Maternal family history is negative for malignancy.

While interacting with Jane, she expresses that she has 3 children, 2 daughters aged 30 and 25 years and 1 son aged 28 years. She is concerned about their chance of developing a

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“female” cancer and inquires what tests their doctors should order. She also expresses that she is relieved she doesn’t have to have another colonoscopy until age 62, because her screening colo noscopy at age 52 was normal.

As the number of centers implementing routine screening of endometrial cancer tissue via immunohistochemistry (IHC) increases, it is likely oncology nurses will encounter patients who have undergone IHC analysis for the mismatch repairs proteins. Understanding the benefits and limitations of IHC in identifying endometrial cancer survivors with Lynch syndrome is essential in assessing the appropriateness of genetic services and in educating patients. Many of the competencies stated in the Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators apply to Jane’s case. Three of these include the ability to1: • Identi(fy) clients who may benefit

from specific genetic and genomic information and/or services based on assessment data • Facilitate referrals for specialized genetic and genomic services for clients as needed • Use health promotion/disease prevention practices that incorporate knowledge of genetic and/or genomic risk factors.

Jane is a candidate for referral to genetic counseling by an expert in genetics, such as a certified genetic counselor or advanced practice nurse with training in genetics. You know that most but not all cases of Lynch syndrome are identified by IHC. Jane’s personal and family history of cancer is suspicious for Lynch syndrome, especially because she has a small family size and her paternal grandfather has had colon polyps removed—which may have prevented a second, primary colon cancer. Genetic counseling can help address Jane’s questions about cancer

risks for other family members and medical management options.

Further, endometrial cancer survivors with Lynch syndrome are at high risk of developing colorectal cancer. By having colonoscopies every 1 to 2 years, individuals with Lynch syndrome significantly reduce their risk of developing colorectal cancer. Thus, if Jane has Lynch syndrome, she would need a colonoscopy before the age she plans to undergo screening, 62 years. By having a basic understanding of IHC and Lynch syndrome, oncology nurses can identify individuals who may benefit from genetic services, encourage referral to local genetic providers, and educate patients about health promotion/disease prevention practices associated with genetic knowledge. ● Reference

1. Consensus Panel on Genetic/Genomic Nursing Competencies. Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators. 2nd ed. Silver Spring, MD: American Nurses Association; 2009.

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For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

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reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information.

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.

In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm3 <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

0

10.2

0

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

TON_June2011_7_TON 6/16/11 3:49 PM Page 33

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

12

0

0

4

0

0

19

2

0

14

<1

0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

18

0

0

12

0

0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. 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.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

TM

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

TON_June2011_7_TON 6/16/11 3:49 PM Page 34

Prostate Cancer

Translating Basic Science into the Clinic: Approval of Abiraterone

By William D. Figg, PharmD Molecular Pharmacology Section and the Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

O

n April 28, 2011, the US Food and Drug Administration (FDA) approved abiraterone acetate (Zytiga, Johnson & Johnson) for the treatment of metastatic castration-resistant prostate cancer (CRPC) for patients who have failed docetaxel therapy. Prostate cancer is a leading cause of cancer mortality and morbidity in the United States.1,2 Each year approximately 215,000 men are diagnosed and 32,000 men die of the disease. Androgen ablation is the cornerstone for the treatment of metastatic prostate cancer, as a result of Huggins and Hodges’ Nobel Prize– winning work published in 1941.

Depletion of circulating androgens either through surgical or medical castration is the first therapeutic maneuver for men failing definitive therapy (radical prostatectomy or external beam radiation). For several decades it was believed that the progression following androgen-deprivation therapy

The benefit was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received.

(ADT) was resistant to further hormonal manipulations.3 This paradigm started to change when prostate cancer gene–expression studies found that androgen-receptor– activated genes, which are normally downregulated during ADT, become reactivated on transition to CRPC.4,5 Furthermore, ADT strategies resulted in castrate concentrations of testosterone; however, it was found that low levels of circulating androgen persisted (mainly through peripheral conversion of adrenal steroids). In addition, gene

upregulation is involved in androgen biosynthesis, including CYP 17.6-8 Intratumoral enzymes involved in the conversion of upstream precursors of testosterone and dihydrotestosterone became a molecular target.

Clinical Trials Cytochrome p450c17 is involved in androgen biosynthesis by 17-alphahydroxylation of C21 steroids and cleavage of C17,20 bond of C21 steroids.3,9 These reactions are critical in the biosynthesis of dehydroepiandro-

sterone and androstenedione. Abiraterone is a potent, selective, irreversible inhibitor of CYP 17A1.10 In the initial phase 1 trial of abiraterone conducted in chemotherapy-naïve CRPC patients, the drug was well tolerated. The dose (1000 mg/day) used in the phase 2 trial was determined after a plateau in the pharmacodynamic effects was observed.

When compared with baseline values during an additional phase 1/2 trial of abiraterone in chemotherapy-naïve patients, 67% of the patients achieved a decline in prostate-specific antigen (PSA) ≥50% and the median time to PSA progression (TTPP) on abiraterone alone for all phase 2 patients was 225 days.11 Toxicities observed were attributed to changes in mineralocorticoid, which were manageable with lowdose corticosteroids.11,12 The pivotal trial for abiraterone was conducted in the postchemotherapy setting for men with CRPC. In COUAA-301, a large randomized, double-

NURSING COMMENTARY

Patient Education for Abiraterone

By Gary Shelton, MSN, NP, ANP-BC, AOCNP Oncology Clinical Nurse Specialist and Adult Nurse Practitioner, New York University Cancer Institute, New York, New York

W

ith the addition of agent has been anticipatabiraterone acetate ed with great interest from as a treatment option all fronts. for metastatic castration-resistant Depleting circulating prostate cancer (CRPC), healthandrogens with various care providers have more to talk hormonal manipulations about when planning or outlinhas been the mainstay of ing management strategies for treatment, after curative men as they progress through efforts have failed or been hormonal ablations and beyond. Gary Shelton, MSN, unreachable. And al For men with prostate cancer, NP, ANP-BC, AOCNP though these medications they now have more to think have all come with a cost, about when sitting before us, as we dis- men generally have accepted the side cuss treatments. effects and alterations with their masAbiraterone has been in the press and culinity/sexuality due, in large part, to on the tongue of patients’ questions for the ease of taking oral medication. a number of months and now will Although as healthcare providers, we require concentrated efforts, such as dis- may debate these merits, patients have cussing the approval profile and the been generally more accepting of theraappropriate population of men for pies that can be held than those requirwhom the US Food and Drug Admin- ing giving up an arm and a vein for infuistration has approved this new com- sions. Abiraterone acetate is, therefore, pound. Whether we have taken part in an attractive addition to treatment opclinical trials offering abiraterone or tions, and creates a new niche or an responding to patients’ requests of com- opportunity for an oral intervention in a passionate use of abiraterone, this oral new setting, for men with CRPC.

34

June 2011 I VOL 4, nO 4

Always welcoming of educational opportunities, we now are aware of changes in the androgen receptor milieu that can be reactivated after prostate cancer cells become castration resistant. Abiraterone acetate is a potent inhibitor, both selective and irreversible, of CYP 17, the enzyme responsible for androgen biosynthesis.

This enzyme is expressed in testicles, in adrenals, and within prostate cancer tumor tissue. Abiraterone, therefore, can be effective even with chemical or surgical castration.

As with all oral therapies, patients are on their own to be compliant, making proper patient selection key to efficacy and identification of tolerability.

Abiraterone is taken on an empty stomach because of its affinity to protein binding. Instruct men to wait at least 1 hour after taking this medication before eating. Also impress upon patients the importance of waiting at least 2 hours after eating before swallowing abiraterone. Men also should understand

that their dosing (approved at four 250mg tablets) needs to be taken with a large glass of water.

The current approval and treatment indication of abiraterone acetate is for use in combination with prednisone, for the treatment of patients with metastatic CRPC who have failed prior chemotherapy containing docetaxel. Although abiraterone has been/is being investigated in both postchemotherapy and the chemotherapy-naïve populations, this initial indication is specific to docetaxel failures. As is common in practice settings, men wish to hold off on starting chemotherapy regimens until all oral options have been exhausted.

Until study data mature from the chemotherapy-naïve populations, there is no label use of abiraterone in the prechemothearapy arena. Patients unready for chemotherapy already are calling for prescriptions. For now, we educate and offer options based on the evidence, and label; don’t we? ●

www.TheOncologynurse.com

TON_June2011_7_TON 6/16/11 3:49 PM Page 35

Prostate Cancer blind, placebo-controlled phase 3 study, chemotherapy-refractory metastatic patients were treated with either abiraterone plus low-dose prednisone (n = 797) or prednisone plus placebo (n = 398). The median overall survival, the primary end point for this study, was 15.8 months and 11.2 months, respectively, after 775 events (hazard ratio, 0.740; 95% confidence interval, 0.638-0.859), and the benefit was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received.

Other trial end points, including PSA change, TTPP, and radiographic progression-free survival (PFS), also resulted in superior outcomes. Patients on abiraterone achieved a PSA decline of >50% in 38% of the patients compared with 10% for placebo (P <.0001), had a significant delay in TTPP (10.2 vs 6.6 months, P <.0001), and radiographic PFS (5.6 vs 3.6 months, P <.0001).

Although the incidence of adverse events was higher in patients receiving placebo, there were more patients who experienced grade 3 and 4 toxicities on the treatment arm (fluid retention, hypokalemia, and hypertension).13

5. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol.

2005;23:8253-8261.

6. Chung BC, Picado-Leonard J, Haniu M, et al.

Cytochrome P450c17 (steroid 17 alpha-hydroxylase/ 17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad Sci U S A. 1987;84:407-411.

7. Picado-Leonard J, Miller WL. Cloning and sequence of the human gene for P450c17 (steroid 17 alphahydroxylase/17,20 lyase): similarity with the gene P250c21. DNA. 1987;6:439-448.

8. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.

Cancer Res. 2006;66:2815-2825.

9. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17.

Endocrinol Metab Clin North Am. 2001;30:101-119, vii.

10. Barrie SE, Potter GA, Goddard PM, et al.

Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/ C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50:267273.

11. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-3748.

12. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol.

2008;26:4563-4571.

13. Pal SK, Sartor O. Phase III data for abiraterone in an evolving landscape for castration-resistant prostate cancer. Maturitas. 2011;68:103-105.

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: Q 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 80% reduction in febrile neutropenia–

With this addition, we now have 5 FDAapproved regimens for the treatment of this disease.

An Additional Option Treatment options for men with CRPC are limited, but abiraterone/prednisone is a welcomed addition to the armamentarium. With this addition, we now have 5 FDA-approved regimens for the treatment of this disease (sipuleucel-T, docetaxel plus prednisone, cabazitaxel plus prednisone, and mitoxantrone plus prednisone). The real question is whether clinicians will move this treatment to the prechemotherapy setting. Abiraterone is a novel agent that inhibits androgen synthesis by selectively blocking CYP 17.

The role of prednisone is of some concern, especially with prolonged use.

Nonetheless, this is a true example of translating basic laboratory observations into clinic advances. ● References 1. Howlader N, Noone AM, Krapcho M, et al; eds.

SEER cancer statistics review, 1975-2008. April 15, 2011. www.seer.cancer.gov/csr/1975_2008/index.html.

Accessed May 3, 2011.

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300.

3. Mohler JL, Pantuck AJ. Use of abiraterone for prostate cancer. J Urol. 2011;185:783-786.

4. Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011;185:787-794.

www.TheOncologyNurse.com

related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

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

Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebotreated patients.

Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

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Supportive Care

Hepatitis B Screening and Chemotherapy

By Audrey Andrews

HOLLYWOOD, FL—Patients receiving chemotherapy are at risk for reactivation of the hepatitis B virus (HBV), and this can have a significant negative impact on the outcomes, including

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

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

See also pages 19 and 40. death from liver failure. According to Emmy Ludwig, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), New York, one-third of the world has been exposed to HBV, “mak-

(n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder: Sickle cell crisis and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, Sweet’s and Precautions] syndrome, generalized erythema and flushing [see Warnings • Potential for Tumor Growth Stimulatory Effects on Malignant and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity.

Skin and subcutaneous tissue disorders: Cutaneous vasculitis Clinical Trials Experience Because clinical trials are conducted under widely varying DRUG INTERACTIONS conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice.

Neulasta clinical trials safety data are based upon 932 patients these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The USE IN SPECIFIC POPULATIONS population was 21 to 88 years of age and 92% female. The Pregnancy ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy Category C 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant tumors (n = 53) and lymphoma (n = 56) received Neulasta women. Pegfilgrastim was embryotoxic and increased after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative received a single 100 mcg/kg (n = 259) or a single 6 mg doses approximately 4 times the recommended human dose (n = 546) dose per chemotherapy cycle over 4 cycles. (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta

ing it an enormous problem.”

Fortunately, HBV reactivation can be prevented with the prophylactic use of effective antiviral agents, for which recommendations were presented by

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 12.0

MC45288-B

Ludwig at the 2011 National Com prehensive Cancer Network (NCCN) annual conference.

Although reactivation can occur spontaneously, it typically occurs as a result of immunosuppressive therapies in cancer, autoimmune disease, and organ transplantation. The risk does not end when chemotherapy is completed, but persists for at least 6 months, possibly longer in stem cell transplant patients and in those receiving rituximab. The risk of liver failure from HBV reactivation has been linked to the use of rituximab—precipitating a black-box warning for these patients.

The risk does not end when chemotherapy is completed, but persists for at least 6 months, possibly longer.

Recommendations for Screening and Prophylaxis Antiviral prophylaxis can prevent chemotherapy-related HBV reactivation. A systematic review of 14 studies (Loomba R, et al. Ann Intern Med. 2008;148:519-528) evaluated the use of lamivudine in patients with chemotherapy who tested positive for the hepatitis B surface antigen (HBsAg). Of 108 patients who received lamivudine prophylactically, none developed HBV reactivation or HBV-related liver failure.

Other studies made similar findings among patients with cancer.

Lamivudine was used in many of the earlier studies and is effective; however, most patients will become resistant to lamivudine at 5 years, Ludwig noted. “We do not recommend lamivudine because of the high resistance rate,” she said.

Newer agents such as entecavir are extremely effective, have less propensity for resistance, and are less likely to interact with other medications.

Entecavir, therefore, is the preferred antiviral at MSKCC, she said.

In March 2009, MSKCC initiated HBV screening of all new patients receiving immunosuppressive therapy.

Among 4065 patients screened from May 2009 to September 2010, almost 10% tested positive for either the HBsAg or the hepatitis B core antibody (HBcAb). All of these patients were Continued on page 44

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June 2011 I VOL 4, nO 4

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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Navigation & Survivorship

Brought to you by

Reducing Barriers to Care: Patient Navigators in the Field

www.AONNonline.org

By Dawn Lagrosa

N

avigators in the Tampa Bay area facilitate the provision of individualized care to help patients receive timely diagnostic resolution of abnormal breast and/or colorectal cancer screenings and get timely treatment.

They address a multitude of issues related to transportation, insurance, family support, fear, and other emotions involved with a cancer diagnosis as well as the complexities of the healthcare system, said Ercilia R. Calcano, administrator of the Patient Navigator Research Program (PNRP) at H. Lee Moffitt Cancer

Center in Tampa, Florida. The Moffitt PNRP, 1 of 8 programs funded by the National Cancer Institute, is evaluating the use of patient navigators to reduce delays to diagnosis and treatment of breast and colorectal cancers. The choice of using lay navigators from the community was based on feedback from a community advisory board and participating primary care clinics, as well as formative research with community members using focus groups. It was felt that patient navigators hired from the community would build trust and meet

A navigator arranges transportation for a patient, using a community clinic’s shuttle van.

A navigator arrives at a patient’s home.

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June 2011 I VOL 4, nO 4

Most of the barriers, such as assisting patients in scheduling appointments or helping them apply for insurance or financial assistance, require attention outside the clinical environment, before patients arrive at the diagnostic and treatment facilities. literacy, communication, and cultural needs of patients in the project.

The 7 community clinics where patients received patient navigation are located in a large geographic area and included the following populations: African-Americans, Hispanics (primarily migrant farm workers), and rural whites. At each community clinic, the PNRP supplied a trained lay patient navigator who had deep knowledge of the community. Most navigators were Spanish–English bilingual, thus enhancing the ease of communication. The clinics “really had to be involved in this project to make it work. They had to do quite a bit, but at the same time their patients were going to benefit from having a navigator,” explained Calcano.

Each clinic provided space for a navigator to use approximately 3 days per week, where she picked up the referrals from clinic staff and contacted patients. After making contact with a patient, the navigator met with the patient at his or her home or in the clinic during an appointment to assess the patient’s needs and strengths, Calcano told the Academy of Oncology Nurse Navigators. After identifying the patient’s barriers to diagnosis or care, the navigator worked closely with the patient to address them.

Much of the program’s success is credited to its use of a lay navigation model. “The strength of this model is that the navigators go out to the patients, they see them in their own familiar environment to help address barriers, whatever they are,” said Calcano. Most of the barriers, such as assisting patients in scheduling appointments or helping them apply for insurance or financial assistance, require attention outside the clinical environment, before patients arrive at the diagnostic and treatment facilities. “Lay navigators,” continued Calcano, “can complement the services provided by nurse navigators whose skills are especially valuable when patients have complex medical and psychosocial needs.”

Many patients experienced transportation barriers. Calcano gave these examples: “If there was only one car in

the patient’s home and one of the patient’s daughters or sons needed that car to go to work, then the patient had no way to get to their appointment. Or if the community clinic had a van that drove patients to the diagnostic or care facility every Monday morning and the patient was not scheduled on a Monday morning, then the patient did not have transportation.” The navigators efficiently worked with different community services to create linkages between patients and services. This included finding solutions such as partnering the patient with a community agency, a friend, or a church member to obtain transportation.

Patients also faced communication barriers. “One of the other issues we face, especially with the migrant farm worker community, is that patients change their telephone numbers often as they migrate,” shared Calcano. “So, when a staff member tries to follow up on an appointment, he or she can’t find them.” As the navigators often live in the community, they are much more adept at locating the patient through a family member.

The study is now in its last year and, therefore, the navigation phase has ended. To help the patients from the participating clinics, however, the program disseminated the patient navigation model by “working with each clinic by asking them to identify some key people for the navigators to train to do basic navigation activities.” It also created a resource guide for the participating clinics, and established strong linkages between the clinics and the cancer center. Those linkages, training, and resources have helped the clinics to better assist their patients in identifying where the resources are, facilitating patients’ access to follow-up care, and obtaining some of the basic skills needed to navigate the patients. Also, thanks largely to the efforts of these navigators, funding was obtained to implement another navigation program with the Tampa Bay Community Cancer Network, to address cervical cancer disparities. ●

www.TheOncologynurse.com

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Supportive Care

Are You Prepared for the Rise in Invasive Fungal Infections?

costeroids. Whenever granulocytes or lymphocytes are prolonged excessively, you’re going to find problems with invasive fungal infections.

We also have seen an increase in different varieties of fungal diseases. We’ve had a shift from Candida infections that are usually relatively easy to treat to Aspergilli infections that are more difficult to manage.

See also pages 19 and 36.

A

s the incidence of invasive fungal infections has risen over the past 20 years, so has the level of concern among oncology nurses. In an interview with The Oncology Nurse-APN/PA, Brenda Shelton, MS, RN, CCRN, AOCN, clinical nurse specialist, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, discusses who is at risk, how nurses can identify them, and steps nurses can take to help these patients.

Why is it necessary for oncology nurses to revisit their knowledge of invasive fungal infections?

Brenda Shelton (BS): Over the years, we have perfected a large number of cancer treatment regimens. We now have people surviving first-line regimens and moving on to second- and third-line ones, creating added toxicity. This means, we now see patients undergoing therapy who have more prolonged neutropenia and comorbid health conditions, such as autoimmune diseases for which they receive corticosteroids. They are coming to us with multiple risk factors for infections in general as well as fungal infections.

optimal organ function receiving an allogeneic transplant. Now we have many variations of allogeneic transplants, including mini-transplants and haplotype transplants and mixed,

unrelated donor transplants.

Additionally, there are new monoclonal antibodies that induce immune suppression and more patients are on high-dose or extended courses of corti-

JOIN THE LARGEST Nurse & Patient Navigator Association BLOGS Experts from various disciplines will be featured in blog segments over the course of the year, allowing members to interact with their colleagues on multiple subject areas.

RESOURCES Informational/educational resources to help you and your patients navigate their cancer treatment and improve their quality of life.

*

Member Benefits Include: • Best Practices • Continuing Education • Networking “We’ve had a shift from Candida infections that are usually relatively easy to treat to Aspergilli infections that are more difficult to manage.”

—Brenda Shelton, MS, RN, CCRN, AOCN

What factors have led to the growing incidence of invasive fungal infections?

BS: One factor is the resurgence of transplant as a therapeutic option. We really have perfected this treatment and many more patients receive a transplant. We used to have only those patients with

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June 2011 I VOL 4, nO 4

• Expert Opinion Blogs

PUBLICATIONS DECEMBER 2010

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By Dawn Lagrosa s. Regardles through to track guiding patients as they present themselve of the Year— of the Year you will need Navigator ARNP, impact of coming barriers you are using, Navigator MAS Lung Cancer ll, RN, MSN, n model , RN, BS, (VA) investand the financial of the navigatio Lillie ShockneyBreast Center Laura Hunnibe Veterans Affairs West a return on Most clinical outcomes the n. have to show Johns Hopkins University and report AOCN, of Healthcare System and n. You will and patient satisfactio making n is ility develop Johns Hopkins patient navigatio Connecticut works to Medicine as sustainab that navigatio School of r role, and ment, as well will need to show Haven Campus , Maryland the navigato g the Baltimore line. were presented improvin important—you AOCN, implement n program on the bottom facility in patients with RN, MSN, annual an impact to justify a navigatio ators at the third assists her for Sharon Gentry, and at diagnosis administr College of Oncology Strategies nationally and stage CBCN of nurses She speaks Davis Forsyth position n program the American by a panel Derrick L. lung cancer. standard Update of each presenter’s navigatio Cancer CenterCarolina in the outcomes develop a Regional Oncology needs, the group to Because tors/navigators alem, North advisory ty’s specific Winston-S care coordina Administrators. so vary. leads an its communi 2 doing cancer for of page for on RN was designed Continued description re System. and the methods Nicole Messier, Center r of measures tracked VA Healthca Cancer Navigato Vermont Cancer of , Vermont RN, BSN, Gastrointestinal Burlington ES lie Pope, OCN RN, BSN, the Year—JuL. Davis Forsyth Regional CHALLENG Pamela Matten, Salem, North FINANCIAL the Derrick Hospital Winstontheir St. Joseph Cancer Center, patients and their Orange, California empowers Mammography e about OCN, CBCN Carolina, technologist knowledg she RN, BSN, Partners In addition, and disciplinary breast cancer Jessica Davis, RT(R) (M), is part of Elaine Sein, families with Cancer Center a multiresources. care team working caring screening, treatment, Fox Chase nia care and to improve access through her and research. , Pennsylva to Rockledge supports them his past April, Geisinger i, MS, RN compassion.

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By Karen and issue for patients opportunity to expand of community cancer centers ania, Wellspan offers GMC the s are a key t protocols MPH, PhD(c) MSW, of York, Pennsylvnearly northeast Pennsylvania.its state-of-the-art cancer care with treatmen presented at the Linda Fleisher, inancial challenge r for and research in Cancer Center, interfere Cancer Center g to a study nurse navigato ion, sup-GMC is a part of Geisinger and can Clinical a Fox Chase Pennsylvania of cer been Accordin e. has m, informat Society Health System (Geisinger), mostly rural population Cheltenha She offers CBCN patient adherenc of the American of patients turn to tion for aher which 10 years. and has cancer RN, CBEC, meeting Barre, her State College, one third centers in Danville, serves Gardner, clinical coordina these barriers. and Hazleton. Geisinger 2010 annual only about Susan M. Wilkesport, and also extended overcome Center tive approach to however, takes pride in its She has by develhelp them Los Angeles, , healthcare to care Valley Medical Oncology, n innovapatients. delivery to this Research workers includes many survivorship their lifelong population, (AOSW), elderly Renton, Washingto oncology social tive project by Kelton role into with OCN underserved because patients. In addition, a significant which also Social Workers diagnosed survivors RN, BSN, In a collabora on of Oncology portion is of socioeconomic on page 2 m to support surveyed newly about the Jay R. Swanson,Cancer Institute Continued problems. Thanjavur status and transportation a curriculu Ravikumar, MD, and the Associatiand his associates oping members d Saint Elizabeth Surgical FACS, AOSW director of the Center Innovation, and process. complete Martin Eichholz caregivers, and co-chair of the recovery for Lincoln, Nebraska . Surveys were oncology service OCN, CRNI cancer patients, of cancer treatment line at on page 2 RN, BSN, Continued Carol Lewis, financial impact Continued on page Hermann 18

By Dawn

• Publications

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Multigene Signature Breast Cancer 2010 Scores and

By Deena Damsky Dell, Clinical Nurse Specialist,MSN, RN-BC, AOCN Fox Chase Cancer Philadelphia Center,

Y

Social OncologyCan Help Workers with Financial Patients es of Treatment Challeng

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he addition of new biomarkers for available in the United establishing a prognosis States: Oncotype for pa- DX (Genomic tients with breast Health) and MammaPrint cancer has been recommended in the (Agendia).

2010 American Joint Committeeedition of the of Cancer’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-transcriptDX multigene signature “scores” have been ase 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 So, where are we for normalizing are reference genes used regarding multigene the expression of the signature scores? At canthis time, two tests cer-related genes.

The chosen genes are commercially have

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Orlando, Florida, November 11-14, 2010.

See who was there: page 8.

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F

Memorial s, Texas The Woodland

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NAVIGATION & SURVIVORSHIP

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The Official Journal of

DECEMBER 2010

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

Healthcare Communications,

VOL 1, NO 7

Continued on page

TRAINING

™

Nurse Navigators ®

T

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 establish and coordinate of to upload their a City-wide Patient the GWCI. navigation logs and Navigation Network their patient interactions (CPNN) in in real time.

Washington, DC. The CPNN will create a seamless, cohesive framework for “The CPNN will cancer care throughout coordination of create a seamless, that all city residents the city to ensure cohesive framework get appropriate canfor cer screening and treatment regardless cancer care throughout coordination of of their ability to pay. the city. ” The help patients identify network will also —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. navigator’s supervisor. area are members “If a patient is seen It also of provides a central communications portal a community advocacy group that at does

NAVIGATION

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

Journal of Oncology Navigation & Survivorship™

2

By Karen Rosenberg

T

he Center for the Advancement policy analysis, and of Cancer Survivorship, education.

Navigation, and Policy caSNP grew out of the understanding (caSNP), a that collaboration of the there is “overlap George Cancer Institute (GWCI) Washington navigation, survivorship,between patient and the university’s School of both of these intersect and policy and Public with local and Health Services DepartmentHealth and national healthcare policy,” explained of Health Steven Policy, was established Patierno, PhD, in 2009 with support from Pfizer of the GWCI. “We executive director and the Pfizer wanted to create Foundation. The a platform to talk about center’s navigation and suradvance patient navigationgoals are to vivorship in the context of policy and cancer united in a survivorship efforts program.” both locally and nationally through The center offers training, research, training programs at three levels:

• 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.

• Executive level training is designed for chief executive officers, chief financial officers, hospital adminis-

GUIDE OUR PATH Start a Local, State, or Regional Join a Committee Affiliate,

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City-wide Patient Navigation Network Coordinates Washington, DC, Cancer Care

By Karen Rosenberg

Leadership Council Lillie Shockney, RN, BS, MAS Johns Hopkins Breast Center Johns Hopkins University School of Medicine Baltimore, Maryland Sharon Gentry, RN, MSN, AOCN, CBCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, North Carolina Nicole Messier, RN Vermont Cancer Center Burlington, Vermont

Breast Cancer Prolonging Chemotherapy Breast Cancer Improves in Metastatic Survival

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TON_June2011_7_TON 6/16/11 3:50 PM Page 41

Supportive Care What are the signs and symptoms of invasive fungal infections? How do they differ from those of viral and bacterial infections?

BS: It is sometimes very hard to tell bacterial and fungal infections from each other. Look at the risk profile. If a patient is at risk for both bacterial and fungal infections, nurses tend to think bacterial first, and that makes

sense early during the immune compromise. Many times, a patient is treated for a bacterial infection, and if he or she does not rapidly respond, a fungal infection is suspected. It is so difficult to sort out, and I recently read that up to 67% of patients are only discovered on autopsy to have had a fungal infection as opposed to the bacterial one being treated.

A few very subtle things can help identify a patient with a fungal infection. Mucositis is high on my list of identifiers for probable fungal infection. I also always look at a patient’s skin to see if there are any clues that perhaps signal an untreated fungal infection that has become systemic.

In addition, I look for high spikes in fevers or continuous fevers, but it’s

Do these infections occur in hospitalized patients or outpatients or both?

BS: Both. Many patients on immunesuppressing therapy for leukemia, lymphoma, or myelodysplastic syndrome (MDS) are outpatients. Transplant patients are inpatients at least initially, but become outpatients if not actively infected. These patients need to come to the clinic frequently and be evaluated thoroughly. We are seeing most of these infected patients start antifungal therapy in the hospital but, because it may require many weeks of treatment, they are at home for part of that time.

If they get resistant fungus or if they get a second fungus, those would only be observed at a home visit or when they come into the outpatient area. Caregiver and patient education, therefore, is very important.

Second Annual Navigation and Survivorship Conference

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September 16-18, 2011 - San Antonio, Texas

Register Online at

www.AONNonline.org/conference Conference Overview AONN’s second annual conference will further advance navigation and survivorship in cancer care through the addition of a variety of sessions, topics, and networking events. Attendees will receive a thorough understanding of the state of navigation and survivorship in today’s evolving healthcare system.

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not like you can use fevers exclusively because patients on steroids may not have a fever. You should look for thrush, look for fungal infections of the skin, or Candida in the urine, all clues of a possible systemic fungal infection. Lastly, I just recently saw an individual with a systemic fungal infection that had small, hard, and red nodules all over their body.

What actions can high-risk patients take?

BS: We advise patients to use standard anti-infection precautions. Fungi are opportunistic and not usually considered contagious. For example, Aspergilli are soil organisms and, when you stir up the soil, whether gardening or traveling through a construction area, you’re going to breathe soil contaminants and increase the risk of Aspergillus sinusitis or an Aspergillis lung infection. We instruct patients to wear high-particulate filtration masks on their way to the hospital because we’re constructing new buildings, and the ground is disturbed with dust and dirt. We tell patients to put on their air conditioners, put up their car windows, and wear the masks from their car into the hospital.

For inpatients, especially high-risk transplant patients, we advise them to stay in the HEPA filtration area.

The best defense against an oral infection with fungus is really good mouth care. This is frequent, high-quality mouth care.

For skin infections, we advise keeping the skin dry and clean, especially recleaning those areas that are in skin folds or become moist, because that’s where fungus likes to grow. Any fungal infection can become systemic in the immune-compromised patient.

What agents are available for prophylaxis?

BS: The azole agents, in general, are a class of medication that has been used

JUNE 2011 I VOL 4, NO 4

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Supportive Care for a number of years. Resistance is developing to some of the early-generation azole agents.

So in fact, at this point in time we have posaconazole, voriconazole, itraconozole, and fluconazole. The specifics about how to use these agents are available in their package inserts. That information also is available in the National Comprehensive Cancer Network guide-

lines. Plus, there is some information sharing about the indications in the Oncology Nursing Society preventing infection guidelines.

It is important to know which infection you are worried about the patient having: is it Aspergilli or Candida, because your choice of agents might vary. In addition, you have to look at the specifics of the patient: their ability to take the drug

without drug–food or drug–drug interactions. Each patient may require something a little bit different based on these variables.

Are nurses at risk, and do they have to take any precautions when treating patients with invasive fungal infections?

BS: Nurses are not usually at risk,

because, for the most part, they have healthy immune systems. It’s really during times of high life stress that nurses are most compromised. And all of us are always at some risk. We’re all colonized with Candida, but that isn’t a problem for most of us. However, if a nurse has an autoimmune disease, has diabetes, or is on corticosteroids, he or she needs to be careful. ●

CASE STUDY

Respiratory Fungal Infection in a Patient with MDS

By Brenda Shelton, MS, RN, CCRN, AOCN The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

M

K is a 65-year-old man diagnosed 9 months ago with refractory anemia with excess blasts (RAEB type of myelodysplastic syndrome [MDS]). He has required intermittent biweekly red blood cell and platelet transfusions. Two months ago, he developed oral thrush that was treated with nystatin swish and swallow.

The infection cleared over a 2-week period, and he had no further complaints until the past 3 weeks. He had described progressive fatigue and some breathlessness, but displayed normal vital signs and resting oxygen saturation. His lab results showed lower than usual anemia and thrombocytopenia requiring more frequent transfusions.

Today MK presented for an unscheduled nurse visit with a new fever and cough.

• Temperature: 38.2°C • Heart rate: 122 beats/min • Respiratory rate: 30 breaths/min • Blood pressure: 102/56 mm/Hg (normally 130/70) • Oxygen saturation: 90% on room air.

His assessment showed use of accessory muscles for breathing with exertion, diminished bibasilar breath sounds with crackles in the right lung, and new petechiae and red nodules on the lower extremities. Blood was drawn for hematology, chemistry with hepatic profile, and bacterial/mycology/viral cultures. A second set of cultures from the Hickman catheter was drawn.

Suspected Clinical Complications and Immediate Interventions Given MK’s diagnosis of MDS with blasts, he had been experiencing dysfunctional white blood cells (WBCs) for the past 9 months. His oral thrush provided evidence that his leukopenia with WBC dysfunction recently had become more symptomatic. In a patient with prolonged neutropenia, infection with opportunistic microbes,

42

June 2011 I VOL 4, nO 4

fungal organisms, or viral organisms is more common than experienced by other patients. Although the initial presentation clearly showed infection, this patient also should be considered high risk for all common and unusual infectious organisms. In addition, because patients with in- dwelling venous catheters are at high risk for bloodstream infections, it is reasonable to draw cultures from the intravenous line as well as peripherally. A shorter time to positivity of the line-drawn blood cultures is one clue that the infection may involve the catheter.

Based on the presenting symptoms, it was highly likely that MK was experiencing a respiratory infection. It was also worrisome that MK was showing more depressed blood counts with peteichiae. This could mean the systemic infection and inflammatory process are further depleting his limited blood cells. In addition, it could indicate a more serious complication of infection: disseminated intravascular coagulation. Further hematologic testing with fibrinogen level, prothrombin time, fibrin degradation products, and D-dimer were obtained to detect this complication. The red nodular lesions were particularly concerning given his recent history of a Candida infection. Septic emboli from systemic candidiasis may present as red, nodular skin lesions.

MK needed immediate antimicrobials, such as antipseudomonal penicillins, extended-spectrum cephalosporins, or carbapenems, to cover common bacterial pathogens. Because of the risk of Staphylococcus aureus related to the indwelling venous catheter, vancomycin also was recommended while awaiting results of the blood cultures. Given this patient’s chronic immune suppression, respiratory symptoms, recent oral fungal infection, and skin lesions, most clinicians also would prescribe an anti-

fungal agent that could treat either aspergillus or candidiasis.

MK was placed on oxygen 4L by nasal cannula. A chest x-ray was ordered and vital signs taken every 30 minutes, including oxygen saturation.

Intravenous fluids 0.9% normal saline were started through the patient’s Hickman catheter at 100 mL/hr.

According to the febrile neutropenia protocol, MK was started on imipenem every 6 hours and admission planned.

An infectious disease consult also was requested.

MK was admitted and his temperature spiked to 39.0°C with chills and hypotension (88/50 mm Hg) later that evening. Three liters of fluid were given with resolution of the blood pressure (100/60 mm Hg), but his oxygen requirements increased to 50% by face mask to maintain an oxygen saturation at 92%. All cultures were negative to this point, but vancomycin was added to the antibiotic regimen to cover a potential line infection. Significant lab values were: • Hemoglobin: 8.0 g/dL • Platelets: 20,000/µL • WBC: 550/mm3 • Blood urea nitrogen: 22 • Creatinine: 1.8, K+ 5.4, Phos++ 2.0 • Lactate dehydrogenase: 440 IU/L. In addition, chest x-ray showed diffuse lower lung infiltrates, and a follow-up computed tomography (CT) scan was ordered but had not yet been completed.

The infectious disease consultant saw the patient and requested the CT scan be performed immediately, as well as drawing of b-D-glucan and galactomannan levels and the addition of antifungal coverage with caspofungin.

Rationale for Recommendations The additional recommendations were made because of concern that an invasive fungal infection was the etiology of MK’s symptoms of sepsis. The CT scan

is a more sensitive diagnostic test for aspergillus than a chest x-ray, and the presence of lesions suspicious for aspergillus may alter the choice of antifungal agent. The b-D-glucan serum level is a nonspecific blood test that may be elevated in patients with invasive fungal infection. The galactomannan assay is also a potential marker of fungal infection, but is specific for aspergillus.

The prescribers chose an antifungal agent with known efficacy against both fungal organisms, a tolerable adverse profile, and availability in intravenous form, so as not to interfere with immediate treatment.

Could This Infection Have Been Prevented?

MK has a disease known to cause significant immunosuppression, placing him at high risk for infections. There are several subtypes of MDS, and not all carry the same concerns with WBC dysfunction. It is essential for clinicians to recognize these at-risk patients and consider early oral antifungal prophylaxis with an azole. It also could have been presumed that the oral fungal infection, although it appeared to resolve with topical therapy, required systemic antifungal therapy as a result of this patient’s severity of immunosuppression. Oral prophylaxis for fungal infection may include fluconazole, itraconazole, voriconazole, or posaconazole. Once the patient had symptoms of oral thrush, the agent could have been changed to andulafungin, caspofungin, or micafungin; or the patient could have changed to a therapeutic dose of voriconazole or posaconazole. Given the severity of symptoms and length of immunosuppression, if there was concern for infection with other more unusual fungal organisms, it would have been reasonable to prescribe amphotericin or one of its liposomal derivatives. ●

www.TheOncologynurse.com

TON_June2011_FINAL_TON 6/20/11 12:41 PM Page 43

THANK YOU FOR MAKING US

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TON_June2011_FINAL_TON 6/20/11 12:48 PM Page 44

PA Life

A Nurse on the “Other Side of the Job”

I

n December of 2009, Lisa M. Schnabel’s husband was diagnosed with glioblastoma, after 20 years of marriage with 3 teenaged children. Schnabel began working as a physician’s assistant in oncology the month she got married in 1989 and has been in her same position since. Her husband had been involved in medicine for as many years. He supported me through long hours and nursing children without a complaint. He even took a research job at the National Institutes of Health in pediatric oncology, so they would have lots to talk about over the dinner table.

After the diagnosis, the family suffered a miserable year, especially for Schnabel and her husband, now being on the other side of the job. In 1 week, they knew they were dealing with a terminal prognosis.

To help her “shake the dread,” Schnabel did some soul-searching, going from clinician to caregiver. She wrote this poem to express her emotional rollercoaster and her love of her husband. She also still loves her career in oncology, helping others. That is why she hopes her poem can remind others why we do what we do even if it hurts sometimes—we are committed and caring. ●

Caregiving to Caregiver: A Personal Journey

By Lisa M. Schnabel, PA-C

SUPPORTIVE CARE

Hepatitis B Screening...

Continued from page 36

treated with antiviral prophylaxis, and none experienced HBV reactivation.

The evidence of potential benefit has led many medical groups to endorse HBV screening for patients receiving immunosuppressive therapy, including the American, European, and Asian-Pacific Associations for the Study of Liver Diseases; the Infectious Diseases Society of America; the American Gastroenterology Association; the American College of Rheumatology; and the Centers for Disease Control and Prevention.

The NCCN suggests that antiviral therapy “be strongly considered in patients with acute HBV infection undergoing hematopoietic stem cell transplant or other intensive immunosuppression,” although this is based on limited data, the group acknowledged. Also in its Clinical Practice Guidelines for Non-Hodgkin’s Lymphomas (V.2. 2011), the NCCN recommends HBsAg and HBcAb screening for all patients receiving rituximab.

But such recommendations are not universal, most notably, routine screening is not recommended by the American Society of Clinical Oncology (ASCO). ASCO deems the evidence to be “insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in individuals with cancer who are about to receive cytotoxic or immunosuppressive therapy or who are already receiving therapy” (Artz AS, et al. J Clin Oncol. 2010;28:3199-3202).

Ludwig said that despite the reservations in ASCO’s Provisional Clinical Opinion, she personally recommends universal screening. “The data, honestly, are imperfect, and there are no large, randomized trials. However, if I had hepatitis B and were getting chemotherapy, I would put myself on an antiviral,” she commented. “Screening is straightforward and cost-effective, antiviral prophylaxis for HBV works, and prevention is better than treatment,” she pronounced. ●

44

June 2011 I VOL 4, nO 4

When I was young and naïve, Oncology was a very scary word Twenty plus years ago my thoughts turned to death, vomiting and pain is all I heard.

So imagine my chagrin in taking the first job offered me when my husband and I moved out of state as man and wife All I had seen before of Oncology were inpatients that were sick or worse— previously I had said “not in this life!”

Never say never has always been one of my favorite mottos to live by So there I was finding myself learning compassion with conversations about death and dying, I’m pretty good, I won’t lie.

“Live every day and make them all count” was another phrase frequently heard from the mouth of a young well-meaning physician assistant Until one day those words turned on me, mocked me, shaking my whole world and I looked at living different.

My loving husband of twenty years was suddenly struck like lightening out of the blue Amazing how in just one week our lives seemingly normal almost boring went to frantic and scary, just like that—who knew?

For a few short hours I was almost thankful the ER thought he had a stroke But when I returned the next morning and saw one of my docs at his door I knew That what I feared the most was not a joke.

I was numb and furious with little faith to draw on right then and there I conversed with God please let it not be a Glioblastoma or I surely would quit Oncology, that wouldn’t be fair.

I presumed all my devotion to helping others would count—I made promise after promise in true desperate fashion.

Alas my prayers went unanswered as I turned to the role of caregiver with all my heart, soul and passion I was afraid my spirit was broken—it wasn’t easy to return day after day where so many memories stirred inside me just walking the halls For a while my life seemed chaotic, falling down around me like I had been personally hit by a huge wrecking ball.

My friends, my support, my lifeline are all in one place They know my strengths, my weaknesses and recognize the pain on my face Leon would not want me to quit my career choice, he was so very proud of me He loved my people, and he knew this was where I belonged and where I should be.

My heart breaks a little more each day you have been away I miss you, I love you, and that is all I have to say!

www.TheOncologynurse.com

TON_June2011_7_TON 6/16/11 3:51 PM Page 45

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BRIEF SUMMARY â&#x20AC;&#x201D; See full Prescribing Information for complete product information INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION Å&#x2DC; For Autologous Use Only. Å&#x2DC; 7KH UHFRPPHQGHG FRXUVH RI WKHUDS\ IRU 3529(1*( LV FRPSOHWH GRVHV given at approximately 2-week intervals. Å&#x2DC; 3UHPHGLFDWH SDWLHQWV ZLWK RUDO DFHWDPLQRSKHQ DQG DQ DQWLKLVWDPLQH VXFK as diphenhydramine. Å&#x2DC; %HIRUH LQIXVLRQ FRQŵUP WKDW WKH SDWLHQWÅ&#x2018;V LGHQWLW\ PDWFKHV WKH SDWLHQW LGHQWLŵHUV on the infusion bag. Å&#x2DC; Do Not Initiate Infusion of Expired Product. Å&#x2DC; ,QIXVH 3529(1*( LQWUDYHQRXVO\ RYHU D SHULRG RI DSSUR[LPDWHO\ PLQXWHV Do Not Use a Cell Filter. Å&#x2DC; ,QWHUUXSW RU VORZ LQIXVLRQ DV QHFHVVDU\ IRU DFXWH LQIXVLRQ UHDFWLRQV GHSHQGLQJ 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 UHSRUWHG ZLWKLQ GD\ RI LQIXVLRQ LQFOXGHG EXW ZHUH QRW OLPLWHG WR IHYHU FKLOOV UHVSLUDWRU\ HYHQWV G\VSQHD K\SR[LD DQG EURQFKRVSDVP QDXVHD YRPLWLQJ IDWLJXH K\SHUWHQVLRQ DQG WDFK\FDUGLD ,Q FRQWUROOHG FOLQLFDO WULDOV RI SDWLHQWV LQ WKH 3529(1*( JURXS GHYHORSHG an acute infusion reaction. , Q FRQWUROOHG FOLQLFDO WULDOV VHYHUH *UDGH DFXWH LQIXVLRQ UHDFWLRQV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS 5HDFWLRQV LQFOXGHG FKLOOV IHYHU IDWLJXH DVWKHQLD G\VSQHD K\SR[LD EURQFKRVSDVP GL]]LQHVV KHDGDFKH K\SHUWHQVLRQ PXVFOH DFKH QDXVHD DQG YRPLWLQJ 7KH LQFLGHQFH RI VHYHUH HYHQWV ZDV JUHDWHU IROORZLQJ WKH VHFRQG LQIXVLRQ YV IROORZLQJ WKH ŵUVW LQIXVLRQ DQG GHFUHDVHG WR IROORZLQJ WKH WKLUG LQIXVLRQ 6RPH SDWLHQWV LQ WKH 3529(1*( JURXS ZHUH KRVSLWDOL]HG ZLWKLQ GD\ RI LQIXVLRQ IRU PDQDJHPHQW RI DFXWH LQIXVLRQ UHDFWLRQV 1R *UDGH RU DFXWH LQIXVLRQ UHDFWLRQV ZHUH UHSRUWHG LQ patients in the PROVENGE group. &ORVHO\ PRQLWRU SDWLHQWV ZLWK FDUGLDF RU SXOPRQDU\ FRQGLWLRQV ,Q WKH HYHQW RI DQ DFXWH LQIXVLRQ UHDFWLRQ WKH LQIXVLRQ UDWH PD\ EH GHFUHDVHG RU WKH LQIXVLRQ VWRSSHG GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ $SSURSULDWH PHGLFDO WKHUDS\ should be administered as needed. Å&#x2DC; Handling Precautions for Control of Infectious Disease. PROVENGE is not URXWLQHO\ WHVWHG IRU WUDQVPLVVLEOH LQIHFWLRXV GLVHDVHV 7KHUHIRUH SDWLHQW leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product.

Universal precautions should be followed. 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 VWXGLHG 3529(1*( LV GHVLJQHG WR VWLPXODWH WKH LPPXQH V\VWHP DQG FRQFXUUHQW XVH RI LPPXQRVXSSUHVVLYH DJHQWV PD\ DOWHU WKH HIŵFDF\ DQG RU VDIHW\ RI 3529(1*( 7KHUHIRUH SDWLHQWV VKRXOG EH FDUHIXOO\ HYDOXDWHG WR GHWHUPLQH ZKHWKHU LW LV PHGLFDOO\ appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE.

Å&#x2DC; Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination GHWHUPLQDWLRQ E\ *UDP VWDLQ HQGRWR[LQ FRQWHQW DQG LQ SURFHVV VWHULOLW\ ZLWK D GD\ LQFXEDWLRQ WR GHWHUPLQH DEVHQFH RI PLFURELDO JURZWK 7KH ŵQDO GD\ LQFXEDWLRQ VWHULOLW\ WHVW UHVXOWV DUH QRW DYDLODEOH DW WKH WLPH RI LQIXVLRQ ,I WKH VWHULOLW\

results become positive for microbial contamination after PROVENGE has been DSSURYHG IRU LQIXVLRQ 'HQGUHRQ ZLOO QRWLI\ WKH WUHDWLQJ SK\VLFLDQ 'HQGUHRQ ZLOO DWWHPSW WR LGHQWLI\ WKH PLFURRUJDQLVP SHUIRUP DQWLELRWLF VHQVLWLYLW\ WHVWLQJ RQ UHFRYHUHG PLFURRUJDQLVPV DQG FRPPXQLFDWH WKH UHVXOWV WR WKH WUHDWLQJ SK\VLFLDQ 'HQGUHRQ PD\ UHTXHVW DGGLWLRQDO LQIRUPDWLRQ IURP WKH SK\VLFLDQ LQ RUGHU to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQ 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.

7KH VDIHW\ HYDOXDWLRQ RI 3529(1*( LV EDVHG RQ SURVWDWH FDQFHU SDWLHQWV LQ WKH PROVENGE group who underwent at least 1 leukapheresis procedure in four UDQGRPL]HG FRQWUROOHG FOLQLFDO WULDOV 7KH FRQWURO ZDV QRQ DFWLYDWHG DXWRORJRXV peripheral blood mononuclear cells.

7KH PRVW FRPPRQ DGYHUVH HYHQWV UHSRUWHG LQ SDWLHQWV LQ WKH 3529(1*( JURXS DW D UDWH Ű ZHUH FKLOOV IDWLJXH IHYHU EDFN SDLQ QDXVHD MRLQW DFKH DQG KHDGDFKH 6HYHUH *UDGH DQG OLIH WKUHDWHQLQJ *UDGH DGYHUVH HYHQWV ZHUH UHSRUWHG LQ DQG RI SDWLHQWV LQ WKH 3529(1*( JURXS FRPSDUHG ZLWK DQG RI SDWLHQWV LQ WKH FRQWURO JURXS )DWDO *UDGH DGYHUVH HYHQWV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS FRPSDUHG ZLWK RI SDWLHQWV LQ WKH FRQWURO JURXS 6HULRXV DGYHUVH HYHQWV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS DQG RI SDWLHQWV LQ WKH FRQWURO JURXS 6HULRXV DGYHUVH HYHQWV LQ WKH 3529(1*( group included acute infusion reactions (see Warnings and Precautions) FHUHEURYDVFXODU HYHQWV DQG VLQJOH FDVH UHSRUWV RI HRVLQRSKLOLD UKDEGRP\RO\VLV P\DVWKHQLD JUDYLV P\RVLWLV DQG WXPRU Ŷ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ů GD\ IROORZLQJ D OHXNDSKHUHVLV SURFHGXUH LQ Ű RI SDWLHQWV LQ FRQWUROOHG FOLQLFDO WULDOV LQFOXGHG FLWUDWH WR[LFLW\ RUDO SDUHVWKHVLD SDUHVWKHVLD DQG IDWLJXH

7DEOH SURYLGHV WKH IUHTXHQF\ DQG VHYHULW\ RI DGYHUVH HYHQWV UHSRUWHG LQ Å° RI SDWLHQWV LQ WKH 3529(1*( JURXS RI UDQGRPL]HG FRQWUROOHG WULDOV RI PHQ ZLWK SURVWDWH FDQFHU 7KH SRSXODWLRQ LQFOXGHG SDWLHQWV ZLWK PHWDVWDWLF FDVWUDWH UHVLVWDQW SURVWDWH FDQFHU DQG SDWLHQWV ZLWK QRQ PHWDVWDWLF DQGURJHQ GHSHQGHQW SURVWDWH FDQFHU ZKR ZHUH VFKHGXOHG WR UHFHLYH LQIXVLRQV RI 3529(1*( DW DSSUR[LPDWHO\ ZHHN LQWHUYDOV 7KH SRSXODWLRQ ZDV DJH WR \HDUV PHGLDQ \HDUV DQG RI SDWLHQWV were Caucasian.

TON_June2011_7_TON 6/16/11 3:51 PM Page 47

Table 1 Incidence of Adverse Events Occurring in â&#x2030;¥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever %DFN SDLQ Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting $QHPLD Constipation Pain Paresthesia oral Pain in extremity 'L]]LQHVV 0XVFOH DFKH $VWKHQLD 'LDUUKHD ,QŶXHQ]D OLNH LOOQHVV 0XVFXORVNHOHWDO SDLQ '\VSQHD Edema peripheral Hot flush Hematuria 0XVFOH VSDVPV Hypertension $QRUH[LD %RQH SDLQ 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 (%)

Grade 3-5 n (%)

591 (98.3)

186 (30.9)

291 (96.0)

97 (32.0)

Cerebrovascular Events. ,Q FRQWUROOHG FOLQLFDO WULDOV FHUHEURYDVFXODU HYHQWV LQFOXGLQJ KHPRUUKDJLF DQG LVFKHPLF VWURNHV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS FRPSDUHG ZLWK RI SDWLHQWV LQ WKH FRQWURO JURXS (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.

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TON_June2011_FINAL_TON 6/20/11 12:41 PM Page 48

In asymptomatic or minimally symptomatic metastatic castrate resistant 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’s own antigen-presenting cells to stimulate an immune response against prostate cancer.

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

Control was nonactivated, autologous, peripheral blood mononuclear cells.

The dosing interval ranged from 1 to 15 weeks in controlled clinical trials.

†

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group are chills, fatigue, fever, back pain, nausea, joint ache, and headache.

Please see Brief Summary of full Prescribing Information on the adjacent page.

©2011 Dendreon Corporation.

All rights reserved. February 2011. Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-02.11-007.00

www.PROVENGE.com

Stimulate a Response