October 2011, Vol 4, No 7

TON_October 2011_FINAL_TON 10/27/11 10:49 AM Page 1

OCTOBER 2011

www.TheOncologyNurse.com

VOL 4, NO 7

Breast Cancer Awareness Month BREAST CANCER

CANCER CENTER PROFILE

The Cleveland Clinic Taussig Cancer Institute Patient Education Translates into Better Outcomes

Bevacizumab in Metastatic Breast Cancer: Is This the End of the Line?

By Joanna Schwartz, PharmD, BCOP Assistant Professor, Albany College of Pharmacy and Health Science Colchester, Vermont Maggie Charpentier, PharmD, BCPS Clinical Associate Professor, College of Pharmacy University of Rhode Island, Kingston

B

evacizumab (Avastin; Genentech) for metastatic breast cancer may be one of the most widely debated, media-reported, and editorialized agents in oncology. This is certainly understandable in an era when targeted therapy such

as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, holds high expectations to provide a much-needed treatment option for thousands of women with metastatic breast cancer. It is currently the best-sellContinued on page 12

NAVIGATION & SURVIVORSHIP Staff of the Cancer Answer Line at the Cleveland Clinic Taussig Cancer Institute: from left: Debbie Kantzes, Josette Snyder, Patricia Fields, and Debbie Petish.

TNo Now N ow

AONN Conference Helps Advance the Patient Navigation Profession

Approved A Ap Appr oved ed

he Cleveland Clinic was founded in 1921 in Cleveland, Ohio, by 4 physicians. At that time, it was one of the few group practices in the United States. This group practice model was very familiar to 3 of the founders—George Crile Sr, Frank Bunts, William Lower—as they served together in military hospitals near the front lines in World War I. These 3 colleagues were determined to establish a not-for-profit clinic that combined the best of military and civilian medical practices. Joined by a fourth physician—John Phillips—they set about building a practice Continued on page 30

SAN ANTONIO—More than 300 oncology nurse and patient navigators discussed the advancement of their profession at the Second Annual Navigation and Survivorship Conference, a forum for navigators to connect with one another and discuss the changing landscape of patient navigation and survivorship care

for patients with cancer. “Ultimately, the networking of these professionals is so important to patient care, because it enables a forum for the sharing of ideas and experiences to impact practice,” said Sean T. Walsh, executive director, Academy of Oncology Nurse Navigators (AONN).

Continued on page 28

CONFERENCE NEWS: ASCO BREAST

Chemoprevention in Breast Cancer: Which Agents for Which Patients?

Complimentary Ce

Choice of Agent Depends on Patient Variables

Exercise Across the Cancer Continuum

By Caroline Helwick

SAN FRANCISCO—A number of interventions can help reduce breast cancer among women at high risk, but ADCETRIS and the ADCETRIS logo are trademarks uptakeandisSeasluggish, ttle Genetics and and there are US regcan isteredbe conofwhich Seattle Genetics, Inc. to prescribe fusiontrademarks about agent © 2011 Seattle Genetics, Inc., Bothell, WA 98021 to a given patient.

Seema MD, All rights reser ved. Printed in USA Khan, US/BV/2011/0029 professor of surgery at Northwestern

INSIDE

Best praCtiCes

...........

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

24 22

Nurses’ Uniforms Often Contain Dangerous Bacteria High Eye, Skin Exposure to Chemotherapy Reported

ConferenCe news

European Multidisciplinary Cancer Congress . . . . . . . . . . . . . . . . . 32 American Association for Cancer Research . . . . . . . . . . . . . . . . . 44

University Feinberg School of MedBreast CanCer . . . . . . . . . . . . . . 38 icine, Chicago, addressed the topic of Regional Lymph Node Irradiation pharmacologic risk reduction at the Indicated for Early Breast Cancer 2011 Breast Cancer Symposium. pharmaCoeConomiCs . . . . . 21 the patient’s VoiCe . . . . . . . . . 40 “It’s clear that selective estrogen Please see page 51 forFinancial Brief Summary ofEncourage full Prescribing Information.

Incentives receptor modulators [SERMs; tamoxSurvivors Teaching Students: Please see full Prrescribing escribing Information ADCETRIS.c om.

Patients to ChooseatLess Expensive ifen and raloxifene] reduce risk, but Saving Women’s Lives Regimens Continued on page 36 ©2011 Green Hill Healthcare Communications, LLC

TON_October 2011_FINAL_TON 10/26/11 12:10 PM Page 1

OCTOBER 2011

www.TheOncologyNurse.com

VOL 4, NO 7

Breast Cancer Awareness Month BREAST CANCER

CANCER CENTER PROFILE

The Cleveland Clinic Taussig Cancer Institute Patient Education Translates into Better Outcomes

Bevacizumab in Metastatic Breast Cancer: Is This the End of the Line?

By Joanna Schwartz, PharmD, BCOP Assistant Professor, Albany College of Pharmacy and Health Science Colchester, Vermont Maggie Charpentier, PharmD, BCPS Clinical Associate Professor, College of Pharmacy University of Rhode Island, Kingston

B

evacizumab (Avastin; Genentech) for metastatic breast cancer may be one of the most widely debated, media-reported, and editorialized agents in oncology. This is certainly understandable in an era when targeted therapy such

as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, holds high expectations to provide a much-needed treatment option for thousands of women with metastatic breast cancer. It is currently the best-sellContinued on page 12

NAVIGATION & SURVIVORSHIP Staff of the Cancer Answer Line at the Cleveland Clinic Taussig Cancer Institute: from left: Debbie Kantzes, Josette Snyder, Patricia Fields, and Debbie Petish.

he Cleveland Clinic was founded in 1921 in Cleveland, Ohio, by 4 physicians. At that time, it was one of the few group practices in the United States. This group practice model was very familiar to 3 of the founders—George Crile Sr, Frank Bunts, William Lower—as they served together in military hospitals near the front lines in World War I. These 3 colleagues were determined to establish a not-for-profit clinic that combined the best of military and civilian medical practices. Joined by a fourth physician—John Phillips—they set about building a practice

T

Continued on page 30

AONN Conference Helps Advance the Patient Navigation Profession SAN ANTONIO—More than 300 oncology nurse and patient navigators discussed the advancement of their profession at the Second Annual Navigation and Survivorship Conference, a forum for navigators to connect with one another and discuss the changing landscape of patient navigation and survivorship care

for patients with cancer. “Ultimately, the networking of these professionals is so important to patient care, because it enables a forum for the sharing of ideas and experiences to impact practice,” said Sean T. Walsh, executive director, Academy of Oncology Nurse Navigators (AONN).

Continued on page 28

CONFERENCE NEWS: ASCO BREAST

Chemoprevention in Breast Cancer: Which Agents for Which Patients?

Complimentary Ce

Choice of Agent Depends on Patient Variables

Exercise Across the Cancer Continuum

By Caroline Helwick

SAN FRANCISCO—A number of interventions can help reduce breast cancer among women at high risk, but uptake is sluggish, and there can be confusion about which agent to prescribe to a given patient. Seema Khan, MD, professor of surgery at Northwestern

INSIDE

Best praCtiCes

University Feinberg School of Medicine, Chicago, addressed the topic of pharmacologic risk reduction at the 2011 Breast Cancer Symposium.

“It’s clear that selective estrogen receptor modulators [SERMs; tamoxifen and raloxifene] reduce risk, but

...........

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

24 22

Nurses’ Uniforms Often Contain Dangerous Bacteria High Eye, Skin Exposure to Chemotherapy Reported pharmaCoeConomiCs

.....

21

Financial Incentives Encourage Patients to Choose Less Expensive Regimens

Continued on page 36 ©2011 Green Hill Healthcare Communications, LLC

ConferenCe news

European Multidisciplinary Cancer Congress . . . . . . . . . . . . . . . . . 32 American Association for Cancer Research . . . . . . . . . . . . . . . . . 44 Breast CanCer

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

38

Regional Lymph Node Irradiation Indicated for Early Breast Cancer the patient’s VoiCe

.........

Survivors Teaching Students: Saving Women’s Lives

40

TON_October 2011_v8_TON 10/18/11 11:02 AM Page 2

Your inspiration, You guide your HER2+ breast cancer patients through their course of treatment with care and support. The HER Connection program can provide some extra help, including:

Text tips and email tailored to HER journey Live outreach call program Live 24/7 support line

Boxed WARNINGS and Additional Important Safety Information s Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant trial, one patient who developed CHF died of cardiomyopathy

s Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death

s Evaluate cardiac function prior to and during treatment. For adjuvant therapy, also evaluate cardiac function after completion of Herceptin.

Discontinue Herceptin for cardiomyopathy

s Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy

s Exacerbation of chemotherapy-induced neutropenia has also occurred

s Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome

Š2011 Genentech USA, Inc.

6391928 Onc Nurse Jrnl Ad AUG M01 indd 1-2

s The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia

So. San Francisco, CA

All rights reserved.

HER0000422100

6/11

TON_October 2011_v8_TON 10/18/11 11:02 AM Page 3

HER commitment

Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or nodenegative (ER/PR-negative or with one high-risk feature*) breast cancer:

s As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel s With docetaxel and carboplatin s As a single agent following multi-modality anthracycline-based therapy *High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

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

8/3/11 3:02 PM

TON_October 2011_v8_TON 10/18/11 11:02 AM Page 4

HERCEPTINÂŽ (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 s AS PART OF A TREATMENT REGIMEN consisting of doxorubicin, cyclophosphamide, and either PACLITAXEL OR DOCETAXEL s WITH DOCETAXEL AND CARBOPLATIN s AS A SINGLE AGENT FOLLOWING MULTI MODALITY ANTHRACYCLINE based therapy. Metastatic Breast Cancer Herceptin is INDICATED s )N COMBINATION WITH PACLITAXEL FOR lRST LINE TREATMENT OF (%2 OVEREXPRESSING METASTATIC BREAST CANCER s !S A SINGLE AGENT FOR TREATMENT OF (%2 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 mUOROURACIL 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 4â&#x2C6;&#x2019;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 â&#x2030;Ľ 16% absolute decrease in LVEF from PRE TREATMENT VALUES OR AN ,6%& VALUE BELOW INSTITUTIONAL limits of normal and â&#x2030;Ľ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration]. The safety of continuation or resumption of Herceptin in patients WITH (ERCEPTIN INDUCED LEFT VENTRICULAR CARDIAC DYSFUNCTION has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, AND DETERMINATION OF ,6%& BY ECHOCARDIOGRAM OR -5'!

SCAN 4HE FOLLOWING SCHEDULE IS RECOMMENDED s "ASELINE LVEF measurement immediately prior to initiation of Herceptin s ,6%& MEASUREMENTS EVERY MONTHS DURING AND UPON COMPLETION OF (ERCEPTIN s 2EPEAT ,6%& MEASUREMENT AT WEEK INTERVALS IF (ERCEPTIN IS WITHHELD FOR SIGNIlCANT LEFT VENTRICULAR cardiac dysfunction [see Dosage and Administration= s ,6%& measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. )N 3TUDY OF PATIENTS DISCONTINUED (ERCEPTIN due to clinical evidence of myocardial dysfunction or SIGNIlCANT DECLINE IN ,6%& )N 3TUDY THE NUMBER OF PATIENTS who discontinued Herceptin due to cardiac toxicity was 2.6% )N 3TUDY A TOTAL OF PATIENTS IN THE TCH arm (1.5% during the chemotherapy phase and 1.4% DURING THE MONOTHERAPY PHASE AND PATIENTS IN THE !# 4( ARM DURING THE CHEMOTHERAPY PHASE AND 4.2% during the monotherapy phase) discontinued Herceptin DUE TO CARDIAC TOXICITY !MONG 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 !PPROXIMATELY HALF OF THE SURVIVING PATIENTS HAD RECOVERY TO A NORMAL ,6%& DElNED AS â&#x2030;Ľ 50%) on continuing MEDICAL MANAGEMENT AT THE TIME OF LAST FOLLOW UP )NCIDENCE of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with (ERCEPTIN INDUCED LEFT VENTRICULAR CARDIAC DYSFUNCTION HAS not been studied.

Table 1 )NCIDENCE OF #ONGESTIVE (EART &AILURE IN !DJUVANT "REAST #ANCER 3TUDIES Study 1 & 2a

4

a

Regimen !#bâ&#x2020;&#x2019;Paclitaxel+ (ERCEPTIN #HEMOâ&#x2020;&#x2019;(ERCEPTIN !#bâ&#x2020;&#x2019;Docetaxel+ (ERCEPTIN Docetaxel+Carbo+ (ERCEPTIN

Incidence of CHF Herceptin Control

Includes 1 patient with fatal cardiomyopathy. !NTHRACYCLINE DOXORUBICIN AND CYCLOPHOSPHAMIDE

b

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic "REAST #ANCER 3TUDIES

Study 5 !# b 5 (paclitaxel) 6

Incidence .9(! )Â&#x2013;)6 .9(! )))Â&#x2013;)6 Herceptin Control Herceptin Control

Event Cardiac $YSFUNCTION

Cardiac Dysfunction 11% 1% 4% 1% Cardiac c Dysfunction . !

. ! a #ONGESTIVE HEART FAILURE OR SIGNIlCANT ASYMPTOMATIC decrease in LVEF. b !NTHRACYCLINE DOXORUBICIN OR EPIRUBICIN AND cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy. )N 3TUDY THE INCIDENCE OF .#) #4# 'RADE CARDIAC ischemia/infarction was higher in the Herceptin containing REGIMENS !# 4( AND 4#( AS COMPARED TO NONE IN !# 4 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 SIGNIlCANT 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 IDENTIlCATION 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 (ERCEPTIN DURING PREGNANCY resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal ABNORMALITIES AND NEONATAL DEATH !DVISE 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 INlLTRATES PLEURAL EFFUSIONS

NON CARDIOGENIC PULMONARY EDEMA PULMONARY INSUFlCIENCY and hypoxia, acute respiratory distress syndrome, and PULMONARY lBROSIS 3UCH 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 .#) #4# 'RADE Â&#x2013; 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 BENElT HAS BEEN SHOWN $UE TO DIFFERENCES IN TUMOR HISTOPATHOLOGY USE &$!

APPROVED TESTS FOR THE SPECIlC TUMOR TYPE BREAST OR GASTRIC gastroesophageal adenocarcinoma) to assess HER2 protein OVEREXPRESSION AND (%2 GENE AMPLIlCATION 4ESTS SHOULD BE PERFORMED BY LABORATORIES WITH DEMONSTRATED PROlCIENCY IN THE SPECIlC TECHNOLOGY BEING UTILIZED )MPROPER ASSAY PERFORMANCE INCLUDING USE OF SUBOPTIMALLY lXED TISSUE

FAILURE TO UTILIZE SPECIlED REAGENTS DEVIATION FROM SPECIlC assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several &$! APPROVED COMMERCIAL ASSAYS ARE AVAILABLE TO AID IN THE selection of breast cancer and metastatic gastric cancer patients for Herceptin therapy. Users should refer to the PACKAGE INSERTS OF SPECIlC ASSAY KITS FOR INFORMATION ON THE Intended Use, and the validation and performance of each assay. Limitations in assay precision make it inadvisable to RELY ON A SINGLE METHOD TO RULE OUT POTENTIAL (ERCEPTIN BENElT Treatment outcomes for adjuvant breast cancer (Studies AND AND FOR METASTATIC BREAST CANCER 3TUDY AS A FUNCTION OF )(# AND &)3( TESTING ARE PROVIDED IN 4ABLES AND !SSESSMENT OF (%2 PROTEIN OVEREXPRESSION AND (%2 GENE AMPLIlCATION IN METASTATIC GASTRIC CANCER SHOULD BE PERFORMED USING &$! APPROVED TESTS SPECIlCALLY 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.

3TUDY DEMONSTRATED THAT GENE AMPLIlCATION AND PROTEIN overexpression were not as well correlated as with breast cancer. Treatment outcomes for metastatic gastric cancer 3TUDY BASED ON (%2 GENE AMPLIlCATION &)3( 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 s #ARDIOMYOPATHY ;see Warnings and Precautions= s )NFUSION REACTIONS ;see Warnings and

Precautions= s %MBRYO FETAL 4OXICITY ;see Warnings and Precautions= s 0ULMONARY TOXICITY ;see Warnings and Precautions= s %XACERBATION 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 !DVERSE REACTIONS REQUIRING interruption or discontinuation of Herceptin treatment include #(& SIGNIlCANT 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 (â&#x2030;Ľ 10%) that were increased (â&#x2030;Ľ 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 INmAMMATION NASOPHARYNGITIS AND DYSGEUSIA 4HE MOST common adverse reactions which resulted in discontinuation OF TREATMENT ON THE (ERCEPTIN CONTAINING ARM IN THE ABSENCE of disease progression were infection, diarrhea, and febrile neutropenia. Clinical Trials Experience "ECAUSE 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 REmECT THE RATES OBSERVED in practice. Adjuvant Breast Cancer Studies The data below REmECT EXPOSURE TO (ERCEPTIN ACROSS THREE RANDOMIZED OPEN LABEL STUDIES 3TUDIES

AND WITH N OR WITHOUT N TRASTUZUMAB IN THE ADJUVANT TREATMENT OF BREAST CANCER 4HE DATA SUMMARIZED IN 4ABLE BELOW FROM 3TUDY REmECT EXPOSURE TO (ERCEPTIN IN PATIENTS THE median treatment duration was 51 weeks and median number OF INFUSIONS WAS !MONG THE PATIENTS ENROLLED IN 3TUDY THE MEDIAN AGE WAS YEARS RANGE TO YEARS

OF PATIENTS WERE #AUCASIAN AND WERE !SIAN Table 3 !DVERSE 2EACTIONS FOR 3TUDY !LL 'RADESa :

!DVERSE 2EACTION

1 Year Herceptin Observation N N

Cardiac (YPERTENSION

$IZZINESS

%JECTION &RACTION $ECREASED

0ALPITATIONS

#ARDIAC !RRHYTHMIASb

#ARDIAC &AILURE #ONGESTIVE

#ARDIAC &AILURE

#ARDIAC $ISORDER

Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders #OUGH

)NmUENZA

$YSPNEA

52)

2HINITIS

0HARYNGOLARYNGEAL 0AIN

3INUSITIS

Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders $IARRHEA

.AUSEA

6OMITING

#ONSTIPATION

$YSPEPSIA

5PPER !BDOMINAL 0AIN

Musculoskeletal & Connective Tissue Disorders !RTHRALGIA

"ACK 0AIN

-YALGIA

"ONE 0AIN

-USCLE 3PASM

Nervous System Disorders (EADACHE

0ARAESTHESIA

Skin & Subcutaneous Tissue Disorders Rash 70 (4%) .AIL $ISORDERS

Pruritis 40 (2%) General Disorders Pyrexia 100 (6%) %DEMA 0ERIPHERAL

#HILLS

!ESTHENIA

)NmUENZA LIKE )LLNESS

Sudden Death 1 (0.06%) Infections .ASOPHARYNGITIS

54)

Immune System Disorders Hypersensitivity 10 (0.6%) !UTOIMMUNE 4HYROIDITIS

0 (0%)

1 (0.06%) 0 (0%) 0 (0%)

10 (0.6%)

10 (0.6%) 6 (0.4%)

0 (0%)

1 (0.06%)

4HE INCIDENCE OF 'RADE ADVERSE REACTIONS WAS IN both arms for each listed term. b Higher level grouping term.

4HE DATA FROM 3TUDIES AND WERE OBTAINED FROM PATIENTS OF WHOM RECEIVED (ERCEPTIN THE MEDIAN treatment duration was 50 weeks. The median age was YEARS RANGE Â&#x2013; OF PATIENTS WERE 7HITE

"LACK (ISPANIC AND !SIAN )N 3TUDY ONLY 'RADE Â&#x2013; ADVERSE EVENTS TREATMENT RELATED 'RADE EVENTS AND 'RADE Â&#x2013; DYSPNEA WERE COLLECTED DURING AND FOR UP TO MONTHS FOLLOWING PROTOCOL SPECIlED TREATMENT 4HE FOLLOWING NON CARDIAC ADVERSE REACTIONS OF 'RADE Â&#x2013; OCCURRED AT AN incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy ALONE ARTHRALGIA VS FATIGUE VS INFECTION VS HOT mASHES VS ANEMIA VS 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia VS 4HE MAJORITY OF THESE EVENTS WERE 'RADE a

2 in severity. In Study 2, data collection was limited to the FOLLOWING INVESTIGATOR ATTRIBUTED TREATMENT RELATED ADVERSE REACTIONS .#) #4# 'RADE AND HEMATOLOGIC TOXICITIES

'RADE Â&#x2013; NON HEMATOLOGIC TOXICITIES SELECTED 'RADE Â&#x2013; toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1â&#x2C6;&#x2019;5 cardiac toxicities occurring during chemotherapy and/ OR (ERCEPTIN TREATMENT 4HE FOLLOWING NON CARDIAC ADVERSE reactions of Grade 2â&#x2C6;&#x2019;5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: ARTHRALGIA VS MYALGIA VS NAIL CHANGES VS AND DYSPNEA VS 4HE MAJORITY OF THESE events were Grade 2 in severity. Safety data from Study 4 REmECT EXPOSURE TO (ERCEPTIN AS PART OF AN ADJUVANT TREATMENT regimen from 2124 patients receiving at least one dose of STUDY TREATMENT ;!# 4( N 4#( N = 4HE OVERALL MEDIAN TREATMENT DURATION WAS WEEKS IN BOTH THE !# 4( and TCH arms. The median number of infusions was 26 in the !# 4( ARM AND IN THE 4#( ARM INCLUDING WEEKLY INFUSIONS during the chemotherapy phase and every three week dosing IN THE MONOTHERAPY PERIOD !MONG THESE PATIENTS THE MEDIAN AGE WAS YEARS RANGE TO YEARS )N 3TUDY THE TOXICITY PROlLE WAS SIMILAR TO THAT REPORTED IN 3TUDIES

AND WITH the exception of a low incidence of CHF in the TCH arm.

Metastatic Breast Cancer Studies 4HE DATA BELOW REmECT EXPOSURE TO (ERCEPTIN IN ONE RANDOMIZED OPEN LABEL STUDY

3TUDY OF CHEMOTHERAPY WITH N OR WITHOUT N trastuzumab in patients with metastatic breast cancer, and one SINGLE ARM STUDY 3TUDY N IN PATIENTS WITH METASTATIC breast cancer. Data in Table 4 are based on Studies 5 and 6. !MONG THE PATIENTS TREATED IN 3TUDY THE MEDIAN AGE WAS YEARS RANGE Â&#x2013; YEARS %IGHTY NINE PERCENT WERE 7HITE "LACK !SIAN AND OTHER RACIAL ETHNIC GROUPS !LL PATIENTS RECEIVED MG KG INITIAL DOSE OF (ERCEPTIN FOLLOWED by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for â&#x2030;Ľ 6 months and â&#x2030;Ľ 12 months were AND RESPECTIVELY !MONG THE PATIENTS TREATED IN SINGLE AGENT STUDIES PATIENTS FROM 3TUDY THE MEDIAN AGE WAS YEARS RANGE Â&#x2013; YEARS WERE 7HITE

WERE "LACK WERE !SIAN AND 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 â&#x2030;Ľ 6 months and â&#x2030;Ľ MONTHS WERE AND RESPECTIVELY Table 4 0ER 0ATIENT )NCIDENCE OF !DVERSE 2EACTIONS /CCURRING in â&#x2030;Ľ 5% of Patients in Uncontrolled Studies or at Increased )NCIDENCE IN THE (ERCEPTIN !RM 3TUDIES AND

Herceptin 3INGLE

0ACLITAXEL (ERCEPTIN !#b a !GENT 0ACLITAXEL !LONE !#b !LONE N N N N N

"ODY AS A 7HOLE Pain 47% 61% 62% 57% 42% !STHENIA

&EVER

#HILLS

(EADACHE

!BDOMINAL PAIN

"ACK PAIN

)NFECTION

Flu syndrome 10% 12% 5% 12% 6% !CCIDENTAL INJURY

!LLERGIC REACTION

Cardiovascular Tachycardia 5% 12% 4% 10% 5% #ONGESTIVE

heart failure Digestive .AUSEA

$IARRHEA

6OMITING

Nausea and VOMITING

!NOREXIA

Heme & Lymphatic !NEMIA

,EUKOPENIA

Metabolic Peripheral edema 10% 22% 20% 20% 17% %DEMA

Musculoskeletal "ONE PAIN

!RTHRALGIA

Nervous )NSOMNIA

$IZZINESS

0ARESTHESIA

$EPRESSION

Peripheral NEURITIS

.EUROPATHY

Respiratory Cough INCREASED

Dyspnea 22% 27% 26% 42% 25% Rhinitis 14% 22% 5% 22% 16% 0HARYNGITIS

3INUSITIS

Skin 2ASH

Herpes SIMPLEX

!CNE

Urogenital Urinary tract INFECTION

a Data for Herceptin single agent were from 4 studies, INCLUDING PATIENTS FROM 3TUDY b !NTHRACYCLINE DOXORUBICIN OR EPIRUBICIN AND cyclophosphamide.

M

I

TON_October 2011_v8_TON 10/18/11 11:02 AM Page 5

Metastatic Gastric Cancer The data below are based on THE EXPOSURE OF PATIENTS TO (ERCEPTIN IN COMBINATION WITH A mUOROPYRIMIDINE CAPECITABINE OR &5 AND CISPLATIN (Study 7). In the Herceptin plus chemotherapy arm, the initial DOSE OF (ERCEPTIN MG KG WAS ADMINISTERED ON $AY PRIOR to chemotherapy) followed by 6 mg/kg every 21 days until DISEASE PROGRESSION #ISPLATIN WAS ADMINISTERED AT MG M2 ON $AY AND THE mUOROPYRIMIDINE WAS ADMINISTERED AS EITHER capecitabine 1000 mg/m2 ORALLY TWICE A DAY ON $AYS OR mUOROURACIL MG M2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for SIX DAY CYCLES -EDIAN DURATION OF (ERCEPTIN TREATMENT WAS WEEKS MEDIAN NUMBER OF (ERCEPTIN INFUSIONS ADMINISTERED was eight.

"ODY 3YSTEM !DVERSE %VENT

Grades

FC .

N (%) !LL Grades Grades

?

17%

Time 0 is the date of randomization.

Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of â&#x2030;Ľ 0ERCENTAGE 0OINTS FROM "ASELINE AND TO "ELOW 50% with Death as a Competing Risk Event

0 (0)

0 (0)

Time 0 is the date of randomization.

,6%& AND !BSOLUTE $ECREASE FROM "ASELINE

!BSOLUTE ,6%& $ECREASE

LVEF â&#x2030;Ľ10% â&#x2030;Ľ DECREASE DECREASE

AND â&#x2030;Ľ10% â&#x2030;Ľ20%

!#â&#x2020;&#x2019;4 N

Study 3 (ERCEPTIN N

/BSERVATION N

Study 4c 4#( N

!#â&#x2020;&#x2019;4( N

!#â&#x2020;&#x2019;4 N

&OR 3TUDIES AND EVENTS ARE COUNTED FROM THE BEGINNING of Herceptin treatment. For Study 4, events are counted from the date of randomization.

a

Figure 2 3TUDY #UMULATIVE )NCIDENCE OF 4IME TO &IRST ,6%& Decline of â&#x2030;Ľ 0ERCENTAGE 0OINTS FROM "ASELINE AND TO "ELOW WITH $EATH AS A #OMPETING 2ISK %VENT

â&#x2030;¤1)

Studies 1 & 2b !#â&#x2020;&#x2019;4(

N

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

The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, METASTATIC BREAST CANCER METASTATIC GASTRIC CANCER OR POST marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the ADJUVANT TREATMENT OF BREAST CANCER )N 3TUDY THE MEDIAN DURATION OF FOLLOW UP WAS MONTHS MONTHS IN THE OBSERVATION ARM MONTHS IN THE YEAR (ERCEPTIN ARM AND IN 3TUDIES AND MONTHS IN THE !# 4 ARM MONTHS IN THE !# 4( ARM )N 3TUDIES AND OF PATIENTS WERE NOT PERMITTED TO INITIATE (ERCEPTIN FOLLOWING COMPLETION OF !# CHEMOTHERAPY DUE TO CARDIAC DYSFUNCTION ,6%& OR â&#x2030;Ľ POINT DECLINE IN ,6%& FROM BASELINE TO END OF !# 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 3TUDY SEE 4ABLE &IGURES AND Table 6a 0ER PATIENT )NCIDENCE OF .EW /NSET -YOCARDIAL $YSFUNCTION BY ,6%& 3TUDIES

AND

6%

!LL Grades

Investigations .EUTROPENIA

(YPOKALEMIA

!NEMIA

4HROMBOCYTOPENIA "LOOD !ND ,YMPHATIC System Disorders &EBRILE .EUTROPENIA ?

Gastrointestinal Disorders $IARRHEA

3TOMATITIS

$YSPHAGIA

"ODY AS A 7HOLE &ATIGUE

&EVER

Mucosal )NmAMMATION

#HILLS

â&#x2030;¤1) -ETABOLISM !ND Nutrition Disorders 7EIGHT $ECREASE

)NFECTIONS !ND Infestations Upper Respiratory 4RACT )NFECTIONS

.ASOPHARYNGITIS

2ENAL !ND 5RINARY Disorders Renal Failure and )MPAIRMENT

Nervous System Disorders $YSGEUSIA

Herceptin +FC .

N (%)

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of â&#x2030;Ľ 0ERCENTAGE 0OINTS FROM "ASELINE AND TO "ELOW WITH $EATH AS A #OMPETING 2ISK %VENT

Table 5 3TUDY 0ER 0ATIENT )NCIDENCE OF !DVERSE 2EACTIONS OF !LL 'RADES )NCIDENCE â&#x2030;Ľ BETWEEN !RMS OR 'RADE )NCIDENCE BETWEEN !RMS AND (IGHER )NCIDENCE IN (ERCEPTIN !RM

3 TUDIES AND REGIMENS DOXORUBICIN AND CYCLO PHOSPHAMIDE FOLLOWED BY PACLITAXEL !#â&#x2020;&#x2019;T) or paclitaxel PLUS (ERCEPTIN !#â&#x2020;&#x2019;TH). c Study 4 regimens: doxorubicin and cyclophosphamide FOLLOWED BY DOCETAXEL !#â&#x2020;&#x2019;T) or docetaxel plus Herceptin !#â&#x2020;&#x2019;4( DOCETAXEL AND CARBOPLATIN PLUS (ERCEPTIN 4#( b

The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was CLASSIlED FOR SEVERITY USING THE .EW 9ORK (EART !SSOCIATION CLASSIlCATION SYSTEM )Â&#x2013;)6 WHERE )6 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 â&#x2030;Ľ 10% absolute decrease in LVEF from pretreatment values.

Infusion Reactions $URING THE lRST INFUSION WITH (ERCEPTIN 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 (ERCEPTIN INFUSION PERMANENT DISCONTINUATION OF (ERCEPTIN FOR INFUSIONAL TOXICITY WAS REQUIRED IN 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 OF PATIENTS AND WAS SEVERE IN AND of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with CHEMOTHERAPY RESPECTIVELY )N 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 VS ;3TUDY = OF SELECTED .#) #4# 'RADE 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 .#) #4# 'RADE ANEMIA WAS )N 3TUDY (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm the overall INCIDENCE OF ANEMIA WAS COMPARED AND OF .#) #4# 'RADE ANEMIA WAS COMPARED TO Neutropenia In randomized controlled clinical trials in the adjuvant setting, THE INCIDENCE OF SELECTED .#) #4# 'RADE Â&#x2013; NEUTROPENIA vs. 0.7% [Study 2]) and of selected Grade 2â&#x2C6;&#x2019;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 .#) #4# 'RADE NEUTROPENIA VS AND OF FEBRILE NEUTROPENIA VS 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 .#) #4# 'RADE NEUTROPENIA WAS COMPARED TO FEBRILE NEUTROPENIA COMPARED TO Infection The OVERALL INCIDENCES OF INFECTION VS ;3TUDY = OF SELECTED .#) #4# 'RADE Â&#x2013; INFECTION FEBRILE NEUTROPENIA

VS ;3TUDY = AND OF SELECTED 'RADE Â&#x2013; INFECTION FEBRILE NEUTROPENIA VS ;3TUDY = 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 (ERCEPTIN TO !# 4 BUT NOT TO 4#( ; !# 4( 4#(

!# 4 = 4HE INCIDENCES OF .#) #4# 'RADE Â&#x2013; INFECTION WERE SIMILAR ; !# 4( 4#( !# 4 = ACROSS THE three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile NEUTROPENIA WAS HIGHER VS IN PATIENTS RECEIVING (ERCEPTIN IN COMBINATION WITH MYELO SUPPRESSIVE CHEMO therapy as compared to chemotherapy alone. Pulmonary Toxicity !DJUVANT "REAST #ANCER !MONG WOMEN RECEIVING adjuvant therapy for breast cancer, the incidence of selected .#) #4# 'RADE Â&#x2013; PULMONARY TOXICITY VS ;3TUDY = AND OF SELECTED .#) #4# 'RADE Â&#x2013; PULMONARY TOXICITY AND SPONTANEOUS REPORTED 'RADE DYSPNEA VS ;3TUDY = was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common PULMONARY TOXICITY WAS DYSPNEA .#) #4# 'RADE Â&#x2013; VS ;3TUDY = .#) #4# 'RADE Â&#x2013; VS ;3TUDY = 0NEUMONITIS PULMONARY INlLTRATES OCCURRED IN OF PATIENTS RECEIVING (ERCEPTIN COMPARED WITH OF THOSE RECEIVING CHEMOTHERAPY ALONE &ATAL RESPIRATORY FAILURE OCCURRED IN PATIENTS RECEIVING (ERCEPTIN ONE AS A COMPONENT OF MULTI organ system failure, as compared to 1 patient receiving CHEMOTHERAPY ALONE )N 3TUDY THERE WERE CASES OF INTERSTITIAL PNEUMONITIS IN (ERCEPTIN TREATED PATIENTS COMPARED TO NONE IN THE CONTROL ARM -ETASTATIC "REAST #ANCER !MONG WOMEN RECEIVING (ERCEPTIN 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 INlLTRATES 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 VS ;3TUDY = AND VS ;3TUDY = AND VS ;3TUDY = Diarrhea !MONG WOMEN RECEIVING ADJUVANT THERAPY FOR BREAST CANCER THE INCIDENCE OF .#) #4# 'RADE Â&#x2013; DIARRHEA VS ;3TUDY = AND OF .#) #4# 'RADE Â&#x2013; DIARRHEA VS ;3TUDY = AND OF 'RADE Â&#x2013; DIARRHEA VS ;3TUDY = were higher in patients receiving Herceptin as compared to CONTROLS )N 3TUDY THE INCIDENCE OF 'RADE Â&#x2013; DIARRHEA WAS HIGHER ; !# 4( 4#( VS !# 4= AND OF 'RADE Â&#x2013; WAS HIGHER ; !# 4( 4#( VS !# 4= AMONG women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, EXPERIENCED DIARRHEA !N 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 (ERCEPTIN CONTAINING ARM AS COMPARED TO THE chemotherapy alone arm the incidence of renal impairment WAS COMPARED TO 3EVERE 'RADE RENAL FAILURE WAS ON THE (ERCEPTIN CONTAINING ARM COMPARED TO on the chemotherapy only arm. Treatment discontinuation for RENAL INSUFlCIENCY FAILURE WAS ON THE (ERCEPTIN CONTAINING ARM AND ON THE CHEMOTHERAPY ONLY ARM )N 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 MONTHS FROM INITIATION OF (ERCEPTIN THERAPY 0ATHOLOGIC lNDINGS INCLUDED MEMBRANOUS GLOMERULONEPHRITIS FOCAL GLOMERULOSCLEROSIS AND lBRILLARY GLOMERULONEPHRITIS Complications included volume overload and congestive heart failure. Immunogenicity !S WITH ALL THERAPEUTIC PROTEINS THERE IS A POTENTIAL FOR IMMUNOGENICITY !MONG WOMEN WITH METASTATIC BREAST CANCER HUMAN ANTI HUMAN ANTIBODY (!(!

TO (ERCEPTIN WAS DETECTED IN ONE PATIENT USING AN ENZYME LINKED IMMUNOSORBENT ASSAY %,)3! 4HIS PATIENT DID NOT experience an allergic reaction. Samples for assessment of (!(! WERE NOT COLLECTED IN STUDIES OF ADJUVANT BREAST CANCER The incidence of antibody formation is highly dependent on THE SENSITIVITY AND THE SPECIlCITY OF THE ASSAY !DDITIONALLY THE observed incidence of antibody (including neutralizing ANTIBODY POSITIVITY IN AN ASSAY MAY BE INmUENCED 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 IDENTIlED DURING POST APPROVAL USE OF (ERCEPTIN "ECAUSE 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 s )NFUSION REACTION ;see Warnings and Precautions] s /LIGOHYDRAMNIOS OR OLIGOHYDRAMNIOS SEQUENCE INCLUDING pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions= s 'LOMERULOPATHY ;see Adverse Reactions] DRUG INTERACTIONS In Study 5, the mean serum trough concentration of trastuzumab WAS CONSISTENTLY ELEVATED APPROXIMATELY 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 )N POST marketing 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 mUID INDEX INCREASED AFTER (ERCEPTIN was stopped. In one case, Herceptin therapy resumed after THE AMNIOTIC mUID 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.

4HE EFlCACY OF )6 HYDRATION IN MANAGEMENT OF OLIGOHYDRAMNIOS DUE TO (ERCEPTIN EXPOSURE IS NOT KNOWN !DVISE WOMEN OF THE potential hazard to the fetus resulting from Herceptin exposure during pregnancy. Encourage pregnant women with breast CANCER WHO ARE USING (ERCEPTIN TO ENROLL IN -OT(%2 THE (ERCEPTIN 0REGNANCY 2EGISTRY PHONE ;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 $AYS OF GESTATION OR LATE $AYS OF GESTATION FETAL DEVELOPMENT PERIODS AT LEVELS OF TO 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 MONTHS OF AGE HOWEVER

trastuzumab levels in animal breast milk may not accurately REmECT HUMAN BREAST MILK LEVELS "ECAUSE 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 (ERCEPTIN HAS BEEN ADMINISTERED TO PATIENTS WHO WERE YEARS OF AGE OR OVER IN THE ADJUVANT TREATMENT AND 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 PROlLE OF (ERCEPTIN IN OLDER PATIENTS IS different from younger patients. The reported clinical EXPERIENCE IS NOT ADEQUATE TO DETERMINE WHETHER THE EFlCACY improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients YEARS OF AGE FOR METASTATIC DISEASE AND ADJUVANT TREATMENT )N 3TUDY METASTATIC GASTRIC CANCER OF THE PATIENTS TREATED WITH (ERCEPTIN WERE YEARS OF AGE OR OLDER WHILE WERE AND OVER .O OVERALL differences in safety or effectiveness were observed.

OVERDOSAGE There is no experience with overdosage in HUMAN CLINICAL TRIALS 3INGLE DOSES HIGHER THAN MG KG HAVE not been tested. PATIENT COUNSELING INFORMATION s !DVISE 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= s !DVISE PREGNANT WOMEN and women of childbearing potential that Herceptin exposure can result in fetal harm [see Warnings and Precautions and Use in Specific Populations= s !DVISE WOMEN OF CHILDBEARING potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Warnings and Precautions= s !DVISE 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= s %NCOURAGE women who are exposed to Herceptin during pregnancy to ENROLL IN -OT(%2 THE (ERCEPTIN 0REGNANCY 2EGISTRY ;see Warnings and Precautions and Use in Specific Populations].

HERCEPTINÂŽ [trastuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group $.! 7AY 3OUTH 3AN &RANCISCO #!

)NITIAL 53 !PPROVAL 3EPTEMBER 2EVISION $ATE /CTOBER

HerceptinŽ is a registered trademark of Genentech, Inc. HER0000111000 Š 2010 Genentech, Inc.

3:02 PM

TON_October 2011_v8_TON 10/18/11 11:02 AM Page 6

Editorial Board EDITOR-IN-CHIEF

Cassandra J. Hammond, RN,

Melinda Oberleitner, RN,

Karla Wilson, RN,

MSN, CRNP

DNS, APRN, CNS

Avid Education Partners, LLC Sharpsburg, MD

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

City of Hope National Medical Center Duarte, CA

Elizabeth Bilotti,

Shannon Hazen,

Jayshree Shah, NP

RN, MSN, APRN, BC, OCN

RN, BSN, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP Virginia Cancer Care Lansdowne, VA

Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

MSN, FNP-C, CPON

Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP

Gary Shelton,

BSN, OCN

MSN, ARNP, AOCN

Piedmount Healthcare Rex, GA

NYU Cancer Institute New York, NY

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

Nutrition Karen Connelly, RD, CSO

Deena Damsky Dell, RN, MSN,

Taline Khoukaz,

Lori Stover, RN,

NP, MSN, ACNP-C

BSN

AOCN, BC

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

Western Pennsylvania Cancer Institute Pittsburgh, PA

Wendy DiSalvo,

Sandra E. Kurtin,

DNP, APRN, AOCN

RN, MS, AOCN, ANP-C

Joseph D. Tariman, PhD,

Fox Chase Cancer Center Philadelphia, PA

Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

APRN, BC

Arizona Cancer Center Tucson, AZ

Northwestern University Myeloma Program Chicago, IL

Ann McNeill,

Jacqueline Marie Toia, RN, MS, DNP

MSN, RN, NP-C, OCN

Northwestern University Myeloma Program Chicago, IL

Somerset Medical Center Somerville, NJ

Patient Advocate Peg Ford Ovarian Cancer Advocacy Alliance Coronado, CA

Social Work Carolyn Messner,

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Constance Engelking, RN,

Kena C. Miller,

MS, CNS, OCN

Roswell Park Cancer Institute Buffalo, NY

Saratoga, CA

Managed Care and Pharmaceutical Management Burt Zweigenhaft,

Amy Ford, RN,

Patricia Molinelli,

Connie Visovsky,

BS

BSN, OCN

MS, RN, APN-C, AOCNS

RN, PhD, APRN

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

Innovex Dallas, TX

RN, MSN, FNP

Somerset Medical Center Somerville, NJ

DSW, MSW, LCSW-R, BCD CancerCare New York, NY

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN

BioPharma Partners LLC New York, NY

University of South Florida College of Nursing Tampa, FL

Isabell Castellano, RN Sharon S. Gentry, RN, MSN, AOCN Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

6

OcTOber 2011 I VOL 4, NO 7

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

CS, FNP

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Mayo Clinic Rochester, MN

PhD, RN, AOCN

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Jeanne Westphal, RN Meeker County Memorial Hospital Litchfield, MN

www.TheOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:03 AM Page 7

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TON_October 2011_v8_TON 10/18/11 1:04 PM Page 8

From the Editor

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com

O

n this 25th anniversary of Breast Cancer Awareness Month, we celebrate all you do to help educate and treat those with or at risk for breast cancer. Our pink-labeled articles highlight the latest information on breast cancer and its treatments. The good news is that for the past decade the incidence rate has dropped by 2.2% and Beth Faiman, RN, MSN, the instances of death from breast cancer continue to drop, especially APRN, BC, AOCN Editor-in-Chief for those younger than 50 years.

However, from the current dialogue regarding bevacizumab to recent advances in chemoprevention, there is a lot to take in on this disease. So, as always, The Oncology Nurse-APN/PA strives to provide you information you can use. We highlight not only current studies on treatments and regimens, but also how the breast cancer experience affects women throughout all the phases along the continuum—such as treatment effects on hot flashes and future fertility.

And the need for information goes beyond just the breast.

All cancer patients and survivors deserve our best care and

Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@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 Editorial Contact: Telephone: 732.992.1891 Fax: 732.656.7938

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the benefit of our up-to-date education. As Drs Calys and VanHoose discuss in their article, exercise can improve quality of life. Their step-by-step guide can be adapted for any patient requiring oncologic rehabilitation. Dr Wickham clarifies the recommendations regarding use of vitamin D in cancer. Her findings may not be what you think.

And in San Diego, survivors are flipping the educational coin, by teaching our future oncology professionals. Ms Ford and Ms Silver illustrate some shortcomings of our profession, while working to help tomorrow’s nurses overcome them.

The San Diego chapter of the Ovarian Cancer National Alliance’s Survivors Teaching Students: Saving Women’s Lives initiative presents the patient’s perspective of ovarian cancer care at medical, nursing, and physician assistant schools throughout their metropolitan area.

This month, we also continue our new series. Ms Connelly combines seasonal recipes with quality nutrition for us and our patients, with the autumn classic—pumpkin. Dr Wickham answers your questions and you tell us your feelings about the term “mid-level provider.” I enjoyed reading your passionate responses and invite you to continue your involvement (see this month’s question, page 18).

As always, I hope this issue benefits your practice. We look forward to hearing from you. ●

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8

OcTOber 2011 I VOL 4, NO 7

Recent FDA Approvals Denosumab to Increase Bone Mass The US Food and Drug Administration (FDA) has approved denosumab (Prolia, Amgen) to increase bone mass in patients at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer.

This monoclonal antibody that binds to RANKL was approved based on results of 2 randomized, double-blind, placebo-controlled trials. One trial randomized 1468 men with prostate cancer. Men aged younger than 70 years were required to have either a baseline bone mineral density (BMD) T score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or history of osteoporotic fracture. The other trial randomized 252 women with breast cancer. Women were required to have a baseline BMD T score at the lumbar spine, total hip, or femoral neck between -1.0 and -2.5 and to have not experienced fracture after age 25.

Denosumab use resulted in changes in lumbar spine BMD of +5.6% at 24 months in men and +4.8% at 12 months in women. Those on placebo experienced changes of -1.0% and -0.7%, respectively.

Common adverse reactions included arthralgia and back pain. Pain in extremity and musculoskeletal pain were also noted. Hypocalcemia (serum calcium <8.4 mg/dL) was observed only in denosumab-treated patients (2.4%) at the month 1 visit.

In Vitro Diagnostic Assay for Change in ProstateSpecific Antigen Over Time The FDA has granted 510k marketing clearance to an invitro diagnostic assay (NADiA ProsVue, Iris International) for determining rate of change of serum total prostate-specific antigen over a period of time. A slope of 3 assays is indicated for use as a prognostic marker in conjunction with clinical evaluation to aid in identifying those patients at reduced risk for recurrence of prostate cancer for the 8-year period following prostatectomy.

This nucleic acid detection immunoassay identifies

extremely low concentrations of proteins that have not been routinely used as a diagnostic or prognostic aid. Clearance was based on a retrospective study of 304 patients that evaluated the slope of 3 successive tests over a period of at least 10 months after prostatectomy to identify patients with no evidence of disease or clinical progression. The assay correctly identified 92.7% of stable patients and 78.0% of patients with recurrence.

Bevacizumab Label Changes The FDA issued a statement warning physicians of changes in the package insert for bevacizumab (Avastin, Genentech) regarding newly identified risks.

• Increased risk for ovarian failure. New cases of ovarian failure were identified in 34% of women receiving bevacizumab in combination with chemotherapy compared with 2% of women receiving chemotherapy alone. After discontinuation of bevacizumab, recovery of ovarian function was demonstrated in 22% of these women.

• Osteonecrosis of the jaw. Postmarketing, osteonecrosis of the jaw was reported in patients receiving bevacizumab but not bisphosphonates. The pathogenesis is unclear, but it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis.

• Venous thromboembolic event (VTE) and bleeding in patients receiving anticoagulation therapy after first VTE event. In patients with metastatic colorectal cancer, prospective evaluation found the overall incidence of first VTE was higher with bevacizumab (13.5%) than with chemotherapy alone (9.6%). Among patients treated with anticoagulants following an initial VTE event, the overall incidence of subsequent VTEs was also higher among those treated with bevacizumab (31.5% vs 25.6%, respectively) and the overall incidence of bleeding was higher in the bevacizumab group (27.4% vs 20.9%, respectively). ●

www.TheOncologyNurse.com

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Do you recognize these patients?

Before Cycle 1, identify your patients’ individual risk factors for CINV s In addition to the emetogenic potential of a chemotherapy regimen, consider a patient’s additional risk factors for emesis.1 — Female, age <50 years, history of low alcohol intake (<1.5 oz/day), history of morning or motion sickness, and preexisting anxiety or nausea1,2 s Because with every additional risk factor, the risk of emesis increases.1,2. s Because a 5-HT3 antagonist and a corticosteroid alone may not be enough to prevent CINV for 5 days.

Motion sickness Younger than age 50 ✔ Anxiety ✔

Female ✔ Light drinker ✔

✔

An antiemetic regimen with a 5-HT3 antagonist, a corticosteroid, and

EMEND—Helps provide superior CINV prevention for 5 days.

References: 1. Navari RM. Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting—two new agents.

J Support Oncol. 2003;1(2):89–103. 2. Osoba D, Zee B, Pater J, et al; for Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Determinants of postchemotherapy nausea and vomiting in patients with cancer. J Clin Oncol. 1997;15(1):116–123.

EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Selected Important Safety Information (continued)

EMEND has not been studied for treatment of established nausea and vomiting.

Chronic continuous administration of EMEND is not recommended.

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

Selected Important Safety Information EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

EMEND should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine.

Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle.

Merck Oncology Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1001721-0004 emend.com

The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND.

In clinical trials of EMEND in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10% were asthenia/fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%).

In clinical trials of EMEND in patients receiving moderately emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy were alopecia (12.4% EMEND vs 11.9% standard therapy), dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia (5.8% vs 5.6%), asthenia (4.7% vs 4.6%), and stomatitis (3.1% vs 2.7%).

In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. EMEND increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND. Please see Brief Summary of Prescribing Information on the following pages. For copies of the Prescribing Information, call 800-672-6372, visit emend.com, or contact your Merck representative.

CINV=chemotherapy-induced nausea and vomiting.

Persons depicted are for illustrative purposes only and are not actual patients.

An antiemetic regimen including

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Brief Summary of the Prescribing Information for

INDICATIONS AND USAGE Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV): EMEND, in combination with other antiemetic agents, is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses CAPSULES of moderately emetogenic cancer chemotherapy (MEC).

Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative nausea and vomiting.

Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting.

Chronic continuous administration is not recommended.

CONTRAINDICATIONS EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions].

WARNINGS AND PRECAUTIONS CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications.

Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree.

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was coadministered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions].

Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of EMEND with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting [see Drug Interactions].

Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions].

Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (ChildPugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients.

Chronic Continuous Use: Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

ADVERSE REACTIONS The overall safety of aprepitant was evaluated in approximately 5300 individuals.

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

Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, 3.1 Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1 Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 Hemic and lymphatic system: neutropenia: 3.1, 2.9 Metabolism and nutrition: anorexia: 10.1, 9.5 Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 Respiratory system: hiccups: 10.8, 5.6 In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy.

In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy (n=846), respectively: Blood and lymphatic system disorders: neutropenia: 5.8, 5.6 Metabolism and nutrition disorders: anorexia: 6.2, 7.2 Psychiatric disorders: insomnia: 2.6, 3.7 Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9 General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar in the 2 treatment groups.

Highly and Moderately Emetogenic Chemotherapy: The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen in either HEC or MEC studies: Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection Neoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinoma Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia Psychiatric disorders: anxiety disorder, confusion, depression Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor Eye disorders: conjunctivitis Cardiac disorders: myocardial infarction, palpitations, tachycardia Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia Renal and urinary disorders: dysuria, renal insufficiency Reproductive system and breast disorders: pelvic pain General disorders and administrative site conditions: edema, malaise, pain, rigors Investigations: weight loss Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Laboratory Adverse Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Proteinuria: 6.8, 5.3 ALT increased: 6.0, 4.3 Blood urea nitrogen increased: 4.7, 3.5 Serum creatinine increased: 3.7, 4.3

EMEND® (aprepitant) capsules AST increased: 3.0, 1.3 The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The adverse-experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively: Infections and infestations: urinary tract infection: 2.3, 3.2 Blood and lymphatic system disorders: anemia: 3.0, 4.3 Psychiatric disorders: insomnia: 2.1, 3.3 Nervous system disorders: headache: 5.0, 6.5 Cardiac disorders: bradycardia: 4.4, 3.9 Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2 Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4 General disorders and general administration site conditions: pyrexia: 5.9, 10.6 The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: Infections and infestations: postoperative infection Metabolism and nutrition disorders: hypokalemia, hypovolemia Nervous system disorders: dizziness, hypoesthesia, syncope Vascular disorders: hematoma Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia Skin and subcutaneous tissue disorders: urticaria General disorders and administrative site conditions: hypothermia, pain Investigations: blood pressure decreased Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: Nervous system disorders: dysarthria, sensory disturbance Eye disorders: miosis, visual acuity reduced Respiratory, thoracic, and mediastinal disorders: wheezing Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant.

Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).

Other Studies: In addition, 2 serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: 1 case of constipation, and 1 case of subileus.

Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect.

As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy-induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended.

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended.

Chemotherapeutic agents: [see Warnings and Precautions] Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce the metabolism of S(–) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as international normalized ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In

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EMENDÂŽ (aprepitant) capsules addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND. Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (eg, elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy-induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).

Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND. Additional Interactions: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.

Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once-daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C max by approximately 20% of both aprepitant and paroxetine.

USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC 0â&#x20AC;&#x201C;24hr >5 <26M7A <$ 01>DC C8<4B C74 7D<0= 4G?>BDA4 0C C74 A42><<4=343 3>B4 0=3 8= A0118CB 0C >A0; 3>B4B up to 25 mg/kg/day (plasma AUC 0â&#x20AC;&#x201C;24hr >5 <26M7A <$ 01>DC C8<4B C74 7D<0= 4G?>BDA4 0C C74 A42><<4=343 3>B4 0=3 70E4 A4E40;43 no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of EMEND in pediatric patients have not been established.

Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out.

Dosage adjustment in the elderly is not necessary.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC 0â&#x20AC;&#x201C;24hr ) of 0.7 to 1.6 times the human exposure (AUC 0â&#x20AC;&#x201C;24hr <26M7A <$ 0C the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test.

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia.

Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting.

Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND. For detailed information, please read the Prescribing Information.

Rx only

Copyright Š 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1001721-0004

Noteworthy Numbers

T

hanks to medical research, there are nearly 12 million cancer survivors living in the United States today. And the research continues: There are approximately 400 new cancer therapies in preclinical and clinical development. As progress continues to treat those with cancer, letâ&#x20AC;&#x2122;s examine the statistics related to clinical trial participation.

From 1996 through 2002, National Cancer Institute (NCI)-sponsored cooperative group nonsurgical treatment trials for breast, colorectal, lung, and prostate cancers enrolled 75,215 patients: â&#x20AC;˘ 85.5% white â&#x20AC;˘ 9.2% black â&#x20AC;˘ 3.1% Hispanic â&#x20AC;˘ 1.9% Asian/Pacific Islander â&#x20AC;˘ 0.3% American Indian/Alaskan Nativeâ&#x20AC;Ś Cancer incidence was divided evenly among 3 participating age-groups (30-64, 65-74, â&#x2030;Ľ75 years) in the NCI-sponsored treatment trials; however, trial participant representation was heavily skewed toward the youngest age-group (68%).

Fewer than 5% of cancer patients participate in clinical trialsâ&#x20AC;Ś If 10% participated, studies potentially could be completed in 1 year, instead of the current 3 to 5 years.

â&#x20AC;˘ Potential side effects â&#x20AC;˘ Treatments under study are not the best option.

Unfortunately, fewer than 4% of US physicians participate in clinical trialsâ&#x20AC;Ś Therefore, although most trial participants are highly satisfied with their experience, 8 of 10 cancer patients may be unaware that a clinical trial was a possible option.

After identifying an appropriate trial, 40% of cancer patients either enroll or try to enrollâ&#x20AC;Ś Furthermore, most adult cancer patients who participate in clinical trials say a physician greatly influenced their decision to participate.

For those wishing to enroll, only 40% meet eligibility requirements and participate in clinical trials.

Most (91%) participants said they would recommend clinical trial participation to a friend or family member diagnosed with cancer.

Common cancer patient concerns regarding joining a clinical study include: â&#x20AC;˘ Fear of a reduction in quality of life â&#x20AC;˘ Reluctance to accept the possibility of receiving a placebo

Sources: The Center for Information & Study on Clinical Research Participation; National Cancer Institute.

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OctOber 2011 I VOL 4, NO 7

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Breast Cancer Bevacizumab in Metastatic... Continued from cover ing anticancer drug in history, even with its high price tag—the annual sales have exceeded $6 billion, with $1 billion per year used in breast cancer.1 The main sources of controversy leading to the US Food and Drug Administration’s (FDA) reversal of its approval for this indication, as outlined in the timeline (Table 1), surround several very important as yet unanswered questions that may determine the fate of many investigational agents in the future. The most important and most contested question concerns what is an appropriate, clinically significant end point in clinical trials of new agents to decide their FDA approval: progressionfree survival (PFS) or overall survival (OS). Further, when considering the adverse event profile in relation to any apparent benefit, what is an acceptable risk-to-benefit ratio? Adding to the controversy is the valid arguments on both sides of the issues, with breast cancer experts, organizations, and even mem-

Joanna Schwartz, PharmD, BCOP

Maggie Charpentier, PharmD, BCPS

bers within organizations such the FDA and its Oncologic Drugs Advisory Committee (ODAC) appear to be split on these issues. ODAC is a committee that consists of members representing cancer and statistics experts, industry, and the public that is charged by the

FDA to evaluate study data and to make recommendations to the FDA about the approval of new cancer medications.

Initial Study Achieves Accelerated Approval The historical timeline of bevacizumab

Table 1 Timeline of Bevacizumab for Metastatic Breast Cancer Date

Action

December 2005

The randomized, phase 3 E2100 trial presented at a national meeting, showing a 5.5-month increase in median PFS with the addition of bevacizumab to paclitaxel for metastatic breast cancer.a (Results published in the New England Journal of Medicine in 2007.b)

December 2007

ODAC recommends against approval of bevacizumab for metastatic breast cancer to FDA, citing the lack of OS benefit in the E2100 study.

February 2008

FDA grants conditional accelerated approval for bevacizumab with paclitaxel as first-line therapy for metastatic breast cancer contingent upon confirmatory trials to further define benefits.

July 2010

ODAC meets to review the 2 confirmatory trials,c,d and recommends to FDA to remove the breast cancer indication from the label, citing an unfavorable risk-tobenefit profile.

September 2010

FDA announces it will delay its decision regarding converting the accelerated approval to a full approval or removing the breast cancer indication.

December 2010

FDA proposes removing the metastatic breast cancer indication from bevacizumab label.

January 2011

The manufacturer (Genentech) files an appeal with FDA and requests an administrative hearing that is open to the public.

June 28, 2011

FDA and ODAC conduct 2-day public hearing involving data presentations from the manufacturer and testimonials from patients and physicians, accompanied by expansive media coverage and patient advocacy group demonstrations.

June 30, 2011

ODAC votes unanimously against allowing the breast cancer indication to remain on the label; however, the FDA allows public comments to be submitted until July 28, 2011.

August 5, 2011

The manufacturer files an appeal of decision in its posthearing summary, with proposed labeling changes.

September 2011

A final decision is awaited from FDA Commissioner.

a

Miller KD, Wang M, Gralow A, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, TX. b Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676. c Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247. d Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260.

FDA indicates US Food and Drug Administration; ODAC, Oncologic Drugs Advisory Committee; OS, overall survival; PFS, progression-free survival.

12

OctOber 2011 I VOL 4, NO 7

for metastatic breast cancer starts in 2005 when the Eastern Cooperative Oncology Group (ECOG, or E) 2100 study was presented amid much excitement at a large international meeting2 and was subsequently published in the New England Journal of Medicine in 2007.3 The E2100 study was a multicenter, randomized, clinical trial of bevacizumab as initial therapy in metastatic breast cancer. This open-label trial enrolled 722 patients with treatmentnaïve metastatic breast cancer to either weekly paclitaxel 90 mg/m2, or to weekly paclitaxel plus bevacizumab 10 mg/kg every 2 weeks until progression.

The primary end point was PFS; secondary end points included objective response rate, toxic effects, OS, and quality of life. Patients with HER2-positive breast cancer were eligible, provided they had received trastuzumab.

Ultimately, few patients with HER2positive disease were enrolled. Patients who received previous taxane therapy as adjuvant or neoadjuvant therapy were required to have received their last dose at least 12 months before enrollment.

Results demonstrated a significant improvement in median PFS with the addition of bevacizumab (11.8 months vs 5.9 months; hazard ratio [HR], 0.60; P <.001). Median OS, however, was similar between groups (25.2 months in the paclitaxel-alone group vs 26.7 months in the combined therapy group; HR, 0.88; P = .16). On subgroup analysis, no subgroup was identified as most likely to benefit from the combination therapy.

Grade 3 and 4 toxicities were more frequent in the combination group than in the paclitaxel-alone group, including neuropathy, infection, and fatigue; hypertension, cerebrovascular ischemia, and headaches were all more frequent in the combination arm. Treatment-related deaths were similar in both groups.

Table 2 summarizes trial-related serious adverse events.

The debate began in December 2007 when ODAC recommended, in a split decision, against approval of bevacizumab. The FDA, in a move rare in its history, overrode its own committee in granting conditional accelerated approval on the basis of the pivotal E2100 study in 2008. This suggested that the FDA accepted the end point of improvement in PFS, even with a lack of OS benefit, as observed in the E2100 study, for approval of an oncology agent, although most ODAC members appeared to disagree with this decision.

Confirmatory Studies Arrive Amid End Point Controversy The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it consid-

www.theOncologyNurse.com

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Your determination to educate patients on how they can benefit from therapy is what makes you a vital part of the treatment team DISCOVER THE MANY WAYS TREANDAÂŽ SUPPORTS NURSES IN THE CONTINUED FIGHT AGAINST CANCER. Patient brochures and treatment diaries t Everything patients need to know about their disease and treatment in an easy-to-read format t Patients can track their progress, blood counts, and report side effects

Cephalon Oncology Reimbursement Expertise (CORE) t A service that helps patients and providers with the reimbursement process and accessing TREANDA CephalonCaresÂŽ Foundation t A program that provides patients who qualify with FDA-approved Cephalon products free of charge Additional disease education tools and useful patient resources We want to hear about your patientsâ&#x20AC;&#x2122; success with TREANDA. Help them share their story today! t From Where I Stand is a program in which patients who have benefitted from treatment with TREANDA share their experiences t 7JTJU XXX 53&"/%" DPN 8IFSF*4UBOE GPS NPSF QSPHSBN JOGPSNBUJPO

Real Patients. Real Passions. Real Practices.

Learn more about all of these resources at www.TREANDA.com.

Indications TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkinâ&#x20AC;&#x2122;s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information t Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur t Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment t TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol.

Women should be advised to avoid becoming pregnant while using TREANDA t The most common non-hematologic adverse reactions associated with TREANDA (frequency â&#x2030;Ľ15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities associated with TREANDA (frequency â&#x2030;Ľ15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia

Š2011 Cephalon, Inc. All rights reserved. TRE-2354 August 2011 Printed in USA.

TON_October 2011_v8_TON 10/18/11 11:03 AM Page 14

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

TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression.

Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration].

Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions.

A number of skin reactions have been reported in clinical trials and post-marketing safety reports.

These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

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

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53)

13 (7)

0

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

TON_October 2011_v8_TON 10/18/11 11:03 AM Page 15

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration.

M D6AE:42==J C64@?DE:EFE6 6249 ,* & G:2= 2D 7@==@HD M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used.

M D6AE:42==J H:E95C2H E96 G@=F>6 ?66565 7@C E96 C6BF:C65 5@D6 32D65 @? >8 >$ 4@?46?EC2E:@? and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture D9@F=5 36 2 4=62C 2?5 4@=@C=6DD E@ D=:89E=J J6==@H D@=FE:@? M -D6 +E6C:=6 /2E6C 7@C "?;64E:@? -+( for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown E@ 36 4@>A2E:3=6 M (2C6?E6C2= 5CF8 AC@5F4ED D9@F=5 36 :?DA64E65 G:DF2==J 7@C A2CE:4F=2E6 >2EE6C 2?5 discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability.

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

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

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial.

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

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat.

Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing.

These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50

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

Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates.

TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

March 2011 All rights reserved.

TON_October 2011_v8_TON 10/18/11 12:57 PM Page 16

Breast Cancer ers a “gold standard” study end point for FDA approval; however, the role of conditional or provisional accelerated approval, as opposed to full approval, must be put in perspective. Introduced in 1992, the accelerated approval process was originated so the FDA could grant marketing authorization, or provisional approval based on surrogate end points such as PFS, conditional on additional studies to further define clinical benefit, for agents that fulfill unmet medical needs, such as for HIV/AIDS and cancer.

This process provides for more rapid access of these medications to populations with few treatment options, but does not guarantee a conversion to full approval after further studies are complete. An agent that was available, therefore, could be later taken off the market when its approval is rescinded, such as the case with the antileukemia agent gemtuzumab ozogamicin.4 For bevacizumab, not only was full approval not granted, but also withdrawal of approval was determined. This decision was based on 2 factors: an unclear clinical benefit when evaluating the end point of PFS compared with OS; and concern about the benefit-to-risk ratio. These evaluations were based on the release of 2 manufacturersponsored confirmatory trials: Avastin and Docetaxel (AVADO) and Regimens in Bevacizumab for Breast Oncology (RIBBON)-1.

The randomized, double-blind, phase 3 AVADO study evaluated the use of bevacizumab in patients with HER2negative breast cancer who were treatment-naïve for metastatic disease.5 A total of 736 patients were enrolled into 1 of 3 treatment arms: docetaxel (100 mg/m2 every 3 weeks) plus placebo every 3 weeks; docetaxel plus 7.5 mg/kg beva-

cizumab every 3 weeks; or docetaxel plus 15 mg/kg bevacizumab every 3 weeks.

Entry criteria were similar to the E2100 trial. Unlike the E2100 trial, however, patients whose disease progressed were given the option to receive bevacizumab in combination with second-line chemotherapy; approximately 34% of the docetaxel-alone group received bevacizumab after progression.

The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it considers a “gold standard” study end point for FDA approval.

There was significant improvement in PFS in the docetaxel plus bevacizumab 15-mg/kg arm (8.1 months vs 10.1 months; HR, 0.77; P = .006), although the PFS was nonsignificant in the docetaxel plus bevacizumab 7.5-mg/kg arm (9.0 months vs 8.1 months; HR, 0.86, P = .12). OS was not statistically different among treatment groups: 31.9 months in the docetaxel plus placebo group; 30.8 months in the docetaxel plus bevacizumab 7.5-mg/kg group; and 30.2 months in the docetaxel plus bevacizumab 15-mg/kg group.

Similar to the E2100 trial, more patients in the bevacizumab arms experienced grade 3 and 4 toxicity, especially neutropenia, febrile neutropenia, and hypertension (Table 2).

Table 2 Serious Adverse Events (Grade 3-5) with Bevacizumab Total Control Group, %

Total Bevacizumab Group, %

Number of patients

980

1681

Fatal adverse events

1.5

1.1

Hypertension

0.7

8.8

Thrombosis Sensory neuropathy

3 7.8

3.4 7.1

Neutropenia

5.3

7.9

Proteinuria

0

3.4

Left ventricular dysfunction

0.7

1.8

Bleeding events Febrile neutropenia Gastrointestinal perforation

0.3 3.4 0.3

1.2 6.3 0.5

Total serious adverse events

27.6

43.8

Data compiled from: Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676; Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247; Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol.

2011;29:1252-1260.

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OcTOber 2011 I VOL 4, NO 7

The second trial, RIBBON-1, was an international, phase 3, multicenter, placebo-controlled study in treatmentnaïve patients.6 Before enrollment, the investigators selected the chemotherapy regimen of either capecitabine, or taxane/anthracycline. Patients then were randomized 2:1 to bevacizumab or placebo. The bevacizumab dose was 15 mg/kg every 3 weeks. Patients in this trial were permitted to receive open-label bevacizumab 5 mg/kg per week as secondline therapy after progressive disease.

The RIBBON-1 trial used the same primary and secondary end points as the E2100, along with similar schedules and criteria to assess patients.

RIBBON-1 enrolled a total of 1237 patients, 615 in the capecitabine arm and 622 in the taxane/anthracycline arm. The PFS was 5.7 months in the capecitabine plus placebo arm and 8.6 months in the capecitabine plus bevacizumab arm (HR, 0.69; P <.001). In the taxane/anthracycline plus placebo arm, median PFS was 8 months compared with 9.2 months in the bevacizumab group (HR, 0.64; P <.001).

When evaluating a planned subset of taxane versus taxane plus bevacizumab, the PFS was 8.2 months compared with 9.2 months, respectively; the PFS of anthracycline versus anthracycline plus bevacizumab was also significant, 7.9 months compared with 9.2, respectively (HR, 0.55; P <.001).

Again, the OS was not statistically significant among groups. In the capecitabine group, the HR for OS was 0.85 (P = .27), whereas in the taxane/ anthracycline cohort, the HR for OS was 1.03 (P = .83). Of note, after progression, 54.4% of the capecitabinealone patients and 50.7% of the taxane/anthracycline patients received open-label bevacizumab.

Similar to AVADO and E2100, grade 3 and 4 adverse events in the RIBBON1 trial were significantly higher in the bevacizumab arms. Hypertension and proteinuria were increased with bevacizumab. There were more treatment discontinuations resulting from adverse effects in the bevacizumab arm. Deaths related to treatment were similar among groups.

Both RIBBON-1 and AVADO did not appear to confirm the impressive 5.5-month median PFS increase seen in E2100 and confirmed a lack of OS benefit. In July 2010, therefore, ODAC met to consider these 2 trial results to recommend to the FDA either the conversion to full approval or withdrawal of approval. The committee voted 12:1 to recommend that the FDA remove the indication for metastatic breast cancer from the label, citing that the data demonstrated that PFS did not appear to act as a surrogate for OS and, therefore, a lack of favorable risk-to-benefit profile.

Approval Review Following an extended review period by the FDA, which heightened expectations and resulted in emotionally charged media coverage of the impending decision, the FDA announced its plan to withdraw approval in December 2010. However, the manufacturer soon appealed by filing an opposition petition to request an administrative hearing open to the public. The focus of the appeal was mainly contingent upon the increase in PFS shown in the E2100 trial, although that trial had been criticized for being open label, making quality-of-life data less meaningful.7 Also, they argued E2100, RIBBON-1, and AVADO used PFS as the primary end point based on the assumption that the FDA accepted this end point for approval and, therefore, the trials may have been underpowered to address OS. Furthermore, PFS may be considered an important end point for patients, because it may delay symptoms and improve quality of life.

In addition, in metastatic colorectal cancer, PFS is considered a valid end point for drug approval. Additional points outlined in the appeal were that the large difference observed in PFS in the E2100 trial was not replicated in subsequent trials because of the lower dose intensity of docetaxel compared with the E2100 paclitaxel trial, which resulted from increased toxicity of docetaxel, and that there is a potentially synergistic effect between paclitaxel and bevacizumab that may not occur with other combinations. There are no data to substantiate these claims, however.

The confusion by the public over the seeming back and forth on bevacizumab’s efficacy is certainly understandable when many experts, organizations, and agencies—not just the FDA and ODAC—remain divided on many issues. Other agents for metastatic cancers have been FDA-approved on the basis of a median PFS increase alone.

Indeed, bevacizumab remains approved for breast cancer in several European countries and remains on the list of preferred regimens (with paclitaxel) for HER2-negative breast cancer by the National Comprehensive Cancer Network (NCCN) 2011 breast cancer guidelines, albeit with a statement that it does not increase OS.8 Additional debate also concerns whether OS is measurable in future metastatic breast cancer trials. This is especially challenging, because patients have several options for treatment of refractory disease that cannot be standardized in trials, as well as the crossover or access to the study agent after trial completion. Another valid argument is that sponsors should still be encouraged to design studies to address this very important end point. Despite these con-

www.TheOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:04 AM Page 17

In relapsed and refractory disease

The complications of multiple myeloma present clinical challenges The care of patients with relapsed and refractory multiple myeloma can be complicated by a number of factors related to the patient, prior therapies, stage of disease, and comorbidities.1 • 65% of patients with multiple myeloma are 65 years of age or older2 • Cumulative toxicities from prior therapies can impact treatment options1 • Multiple myeloma itself can damage the patient’s organs and nervous system3

Seeking a new approach to your patients’ needs Onyx Pharmaceuticals is committed to pursuing advances to address the unmet needs of patients with relapsed and refractory multiple myeloma.

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

1210-CARF-052

August 2011

References: 1. Richardson P, Mitsiades C, Schlossman R, et al. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program. 2007;317-323. 2. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology Am Soc Hematol Educ Program.

2009;566-577. 3. Munshi NC, Anderson KC. Plasma cell neoplasms.

In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:2305-2342.

TON_October 2011_v8_TON 10/18/11 11:04 AM Page 18

Breast Cancer cerns, the recent FDA approvals of other agents for metastatic breast cancer, such as eribulin, were approved on the basis of statistically significant increases in OS.9 Unlike metastatic breast cancer, PFS recently has been validated statistically as a surrogate end point for OS in metastatic colorectal cancer.10 In addition, not all regimens recommended in NCCN guidelines for every cancer site and stage, or treatment line, are FDAapproved regimens. Unfortunately, there are not strong data to support the connection between quality-of-life data and extension of PFS in breast cancer, although this should be a research focus of the near future.

Certainly the patient’s perspective about the understandable desire to access alternative treatment options should be considered strongly; and it was considered by the FDA and ODAC officials, during the 2-day public hearing in June 2011. This hearing not only included the manufacturer’s as well as patient perspectives, but also provided for physician testimonials along with much media interest.

The ODAC opinion regarding the lack of OS benefit and the questionable PFS benefit in light of the risk of serious adverse effects remained unchanged as the FDA members voted unanimously against allowing the breast cancer indication to remain on the label. Again, the manufacturer soon appealed, this time proposing labeling changes to enable a

Even the definitions of serious adverse events and “unmet medical need” are now a source of debate.

continuation of the conditional accelerated approval until a confirmatory trial of paclitaxel plus bevacizumab—the apparent preferred combination—powered to assess OS can be completed.11 The proposal includes revising the labeling to restrict treatment to women with an “unmet medical need, that have fewer treatment options,” which is detailed in their proposal as women with triple receptor (estrogen/progesterone receptor [ER/PR] and HER2 receptor)-negative breast cancer, or ER-positive women with aggressive (rapidly progressing) disease with symptomatic visceral metastases. They also propose to restrict bevacizumab use to be with paclitaxel only, with updated trial data about differing efficacy with other chemotherapy partners, and to commence a Risk Evaluation and Mitigation Strategy that would require distribution of a medication guide to every physician and patient containing detailed safety information, including serious adverse events.

An Unknown Future The final chapter of this controversy is not written yet, as the FDA Com-

missioner has not made a final decision on the process of withdrawal of the breast cancer indication, and the date of this decision remains unknown. Even the definitions of serious adverse events and “unmet medical need” are now a source of debate—the manufacturer argues that the risks appear manageable, whereas others report that bleeding and thrombotic events carry significant risks.

Experts continue to argue that there are other treatment options for metastatic breast cancer; therefore, bevacizumab is not fulfilling an unmet need. The highrisk subpopulations as defined previously have not been identified statistically to have greater responses to bevacizumab in the clinical trials. Certainly, there is an argument made by patients who have had a good response to this treatment and want to continue to have access to as many options as possible for the treatment of a serious, incurable disease.

The impact of this decision also remains unknown and leaves many questions unanswered.

• What is the gold standard study end point required by the FDA: PFS or OS?

Reader Poll ©iStockphoto.com/Nathan Maxfield

Have patients asked you about the situation with bevacizumab and the FDA? To weigh in on this question, please log on to www.TheOncologyNurse.com.

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OctOber 2011 I VOL 4, NO 7

• Should PFS be considered a clinically meaningful end point and, if so, what is an appropriate risk-tobenefit ratio?

• How will the decision impact insurance coverage for women already on bevacizumab for metastatic breast cancer and, until this is known, should any new patients be started on this regimen?

• Will this decision impact accrual to clinical trials in breast cancer using bevacizumab?

Clearly studies need to continue to clarify whether PFS may be a surrogate for OS in metastatic breast cancer, and whether an increased PFS confers any benefit on quality of life. Ultimately, the goal would be to identify women through genetic or other markers who will most benefit from treatment. Until then, questions remain regarding the use of bevacizumab, including is this the end of the line for this agent in breast cancer? ● References 1. Goren M. Roche may keep some Avastin sales if US breast cancer label lost. Wall Street Journal. June 27, 2011. http://online.wsj.com/article/BT-CO-20110627704044.html. Accessed September 8, 2011.

2. Miller KD, Wang M, Gralow A, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, TX. 3. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.

4. US Food and Drug Administration. FDA: Pfizer voluntarily withdraws cancer treatment Mylotarg from U.S. market. June 21, 2010. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm216448.htm. Accessed September 1, 2011.

5. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247.

6. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260.

7. Horning SJ, Labson MS, Schmidt PW. Submission of Genentech, Inc. in response to the Food and Drug Administration’s Notice of Opportunity for a hearing and proposal to withdraw approval of AVASTIN® (bevacizumab) in combination with weekly paclitaxel for the first-line treatment of patients with metastatic breast cancer. Docket No. FDA-2010-N-0621. January 16, 2011. www.gene.com/gene/news/news-events/avastin/ documents/NOOH-Prim-Sub-Doc_FINAL_ 16JAN2011.pdf. Accessed September 10, 2011.

8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2011. www.nccn.org/professionals/physician_gls/pdf/breast. pdf. Accessed September 5, 2011.

9. US Food and Drug Administration. Eribulin mesylate.

November 23, 2010. www.fda.gov/AboutFDA/Centers Offices/CDER/ucm234527.htm. Accessed September 23, 2011.

10. Grothey A, Hedrick EE, Mass RD, et al. Responseindependent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107.

J Clin Oncol. 2008;26:183-189.

11. Horning SJ, Labson MS, Schmidt PW. Post-hearing submission of Genentech, Inc. in support of maintaining the accelerated approval of AVASTIN® (bevacizumab) in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer.

Docket No. FDA-2010-N-0621. August 4, 2011. www.cancerletter.com/downloads/20110812_1/down load. Accessed August 30, 2011.

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:04 AM Page 19

A S T HE C OMP L E X I T Y O F H E ALT H C AR E E V OLV ES , HOS PIR A G E M C I TAB I N E I N J E C T I O N D ELIV ER S ON E S O L UT I O N F O R AL L .

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Warnings and Precautions Patients receiving therapy with Gemcitabine Injection should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

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Hematologic Malignancies

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

Multiple Myeloma Treatments Are Moving Rapidly from Bench to Bedside

Gemcitabine Injection For Intravenous Infusion Only.

Must Be Diluted Before Use. Initial U.S. Approval: 1996 CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter.

Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8) ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

By Wayne Kuznar

Courtesy of ASCO/GMG/Phil McCarten 2011

CHICAGO—Treatments for multiple myeloma have advanced rapidly over the past 15 years as research has fostered an improved understanding of the mechanisms of the disease. These discoveries have been translated into effective drugs, most notably bortezomib, thalidomide, and lenalidomide.

“Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma,” was the title of the Karnofsky Lecture delivered

by Kenneth C. Anderson, MD, Kraft Family Professor of Medicine, Harvard Medical School, and Director, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Institute, Boston. Anderson was awarded the David A. Karnofsky Memorial Award to recognize his outstanding achievements over 3 decades in multiple myeloma research at the annual meeting of the American Society of Clinical Oncology.

“Multiple myeloma represents a new paradigm in drug development, due to the remarkable therapeutic efficacy of targeting tumor cells in their microenvironment.”

—Kenneth C. Anderson, MD

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Combination therapy with melphalan and prednisone was long the standard of care for the treatment of multiple myeloma, with stem-cell transplant reserved for select patients.

Advances beyond these therapies have emerged rapidly as the research by Anderson broadened beyond the myeloma cell surface to the bone marrow microenvironment as a driver of disease pathogenesis.

“Multiple myeloma represents a new paradigm in drug development, due to the

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remarkable therapeutic efficacy of targeting tumor cells in their microenvironment,” he said. Newly discovered agents interfere with the mechanisms by which myeloma cells grow, survive, develop resistance, and migrate within the bone marrow.

Rapid Drug Development and Approval for Myeloma The proteasome inhibitor bortezomib is an example of a new therapy for multiple myeloma that progressed from bench to bedside rapidly (<3 years). The drug, which has an action that targets multiple myeloma cells in the bone marrow macroenvironment, was approved as initial therapy for multiple myeloma after demonstrating an improvement in median survival from 3 to 7 years.

The immunomodulatory drug lenalidomide, which directly induces apoptosis but also targets cells in the tumor microenvironment, was another result of Anderson’s work.

Lenalidomide also progressed rapidly from bench to bedside and was approved in 2006 for use with dexamethasone for the treatment of relapsed multiple myeloma.

Along with thalidomide and bortezomib, lenalidomide is used routinely in conventional cytotoxic and transplant regimens for multiple myeloma.

Novel Classes in the Pipeline Nevertheless, the need for more effective and tolerable drugs remains, said Anderson.

Second-generation proteasome inhibitors include carfilzomib, which is associated with less neuropathy than bortezomib, and oral chymotryptic inhibitors, which appear more potent at inhibiting myeloma cell growth.

Pomalidomide, another immunomodulatory agent currently under development, has shown good activity in patients resistant to lenalidomide and bortezomib.

Other novel classes of drugs are histone deacetylase inhibitors (eg, panobinostat), heat shock protein 90 inhibitors, and the alkylphospholipid AKT inhibitor perifosine. Some of these are being explored as a part of rational combinations of therapies.

For example, the combination of bor tezomib and panobinostat is synergistic, as panobinostat blocks ubiquitinated protein via the aggresomal pathway and bortezomib blocks these same proteins via the proteasomal pathway.

The use of genomics to personalize approaches to the treatment of multiple myeloma is another research interest of Anderson’s.

Genetic profiling is identifying genes that are upregulated or downregulated in the progression to multiple myeloma. ●

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Pharmacoeconomics

Financial Incentives Encourage Patients to Choose Less Expensive Regimens

By Caroline Helwick

F

or antiemetic prophylaxis, a model of shared cost-savings using incentives such as cash rebates might reduce the high cost of some pharmaceuticals while maintaining patient access to optimal care, according to oncologists from Michigan.

The investigators wanted to determine whether patients receiving chemotherapy could be enticed to choose a less expensive antiemetic regimen if given a choice. “We considered using a ‘carrot’ instead of a ‘stick’—a cash rebate earned by choosing less costly care,” said Emily Z. Touloukian, DO, an oncologist at Providence Hospital, Southfield, Michigan.

“We were greatly surprised that as many as 38% of patients who had trouble with prior nausea still chose the less effective program.”

—Emily Z. Touloukian, DO

Although costly copays serve as disincentives for patients to ask for more costly regimens, the potential cost-saving impact of this is often thwarted by manufacturers’ patient assistance programs, Touloukian noted. She and her colleagues chose antiemetic regimens for the model, because choice does not affect patient survival, but her findings could have implications for other types of treatment choices.

Of the 162 study participants, 80% were women, 75% had cancer, and 50% had received previous chemotherapy.

All participants completed a survey that portrayed 2 antiemetic programs.

Program A would have a 60% chance of completely eliminating nausea/vomiting at a cost of $200 per cycle. Program B would have 80% efficacy at a cost of $800 per cycle. If program A was ineffective, the patient could switch to program B at any time.

Both programs were described as covered by insurance; however, patients who selected program A would participate in the savings by receiving 50% of the cost difference, a $300 rebate per cycle.

More patients (58%) chose program A than program B (42%). Neither a previous history of cancer nor previous receipt of chemotherapy significantly affected program selection. Within the cohort who had previously received

See also pages 51 & 54. chemotherapy, 63% of patients who had experienced mild or no nausea in the past chose program A compared with 38% with moderate-to-severe nausea, “but we were greatly surprised that

as many as 38% of patients who had trouble with prior nausea still chose the less effective program,” she said.

If all patients received 6 cycles of program B, the cost would be $777,600. By

giving the patients a choice and reassigning the theoretical 40% of patients whose nausea was ineffectively controlled by program A to program B after 1 cycle, the cost dropped to $556,820.

This represented a savings of $220,780, or 28% of the total cost of the program, without limiting access to effective antiemetic care. One half of the savings went to the patients and half was saved by the payers, Touloukian said. ●

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY INCLUSION CRITERIA* PRIMARY ENDPOINT • Advanced NSCLC

• Overall survival

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Best Practices

Nurses’ Uniforms Often Contain Dangerous Bacteria

By John Schieszer

M

any oncology nurses may be wearing uniforms that contain harmful bacteria, including drug-resistant organisms. A new study has found that more than 60% of hospital staff’s uniforms are colonized with potentially pathogenic bacteria. The study, which was published in the September issue of the American Journal of Infection Control (Wiener-Well Y, et al. 2011;39:555-559), suggests that physicians and nurses may be transferring pathogens that could cause clinically relevant infection.

The investigators isolated antibioticresistant bacteria from samples from 14% of nurses’ uniforms and 6% of physicians’ uniforms in a single institution. A total of 135 nurses and physicians from the medical and surgical wings were included in the study.

“The study was well done and found some interesting results,” said Russell Olmsted, MPH, president of the Association for Professionals in Infection Control and Epidemiology.

“The study is of interest to oncology nurses in that we have pathogens that cause healthcare-associated infection on a wide range of surfaces, and this

A new study has found that more than 60% of hospital staff’s uniforms are colonized with potentially pathogenic bacteria.

study is a reminder that they have to have good hand hygiene.”

He said this study points to ways nurses may be able to lower their risk of inadvertently transferring pathogens to patients. “Because it shows articles we touch certainly can result in contamination of our hands. The hands are the mode or mechanism to get the pathogen to patients,” Olmsted said in an interview with The Oncology Nurse-APN/PA. In recent years, studies have shown physicians’ white coats and ties, medical students’ coats, and nurses’ uniforms have been colonized with pathogenic organisms and could be potential sources of cross-infection. It is believed that the greatest amount of contamination may occur in areas of greatest hand contact, such as pockets and cuffs, allowing recontamination of already

washed hands. In the current study, researchers at the Shaare Zedek Medical Center in Jerusalem, Israel, collected swab samples from 3 parts of the uniforms of 75 registered nurses (RNs) and 60 medical doctors (MDs) by pressing standard blood agar plates at the abdominal zone, sleeves’ ends, and pockets.

The researchers found that half of all the cultures taken (65% of the RN uniforms and 60% of the MD uniforms) harbored pathogens. Of those, 21 cultures from RN uniforms and 6 cultures from MD uniforms contained multidrug-resistant pathogens, including 8 cultures that grew methicillin-resistant Staphylococcus aureus. Although the uniforms themselves may not pose a direct risk of disease transmission, these results indicate a prevalence of antibiotic-resistant strains in close

proximity to hospitalized patients.

The study was conducted at a 550bed, university-affiliated hospital. It is unknown how widely applicable these findings are to community hospitals and cancer centers in the United States.

Olmsted noted that any clothing that is worn by humans will become contaminated with microorganisms. According to the World Health Organization, the risk of healthcare-associated infection (HAI) in some developing countries is as much as 20 times higher than in developed countries. Even in hospitals in developed countries such as the United States, HAIs occur too often, can be deadly, and are expensive to treat.

A previous study conducted at a burn unit demonstrated the possibility of transferring S aureus from nurses’ gowns to patients and bed sheets. In this current study, researchers say the high prevalence of contaminated uniforms may be related to inadequate compliance with hand hygiene. However, that still needs to be further studied. Overall, they found no significant differences between nurses and physicians or between staff from medical departments and surgical departments. ●

High Eye, Skin Exposure to Chemotherapy Reported in Study

By Caroline Helwick

A

lmost 1 of 5 oncology nurses is unintentionally exposed to chemotherapy agents, according to an article published online August 16 in BMJ (British Medical Journal) Quality & Safety.

Christopher Friese, RN, PhD, and colleagues reported that the overall rate of exposure to the skin or eyes in the past year among nurses working in an outpatient setting was 16.9%. Such “secondhand chemo” can have immediate effects on the nervous system and acute and long-term reproductive effects (infertility, miscarriage), and may place individuals at risk for hematologic malignancies.

In the study, 1339 oncology nurses working in an ambulatory care setting were sent questionnaires; 402 (30.5%) responded. The survey examined the likelihood of self-reported exposure to chemotherapy as “a function of perceived quality of the practice environment,” nursing workload, and 7 ambulatory chemotherapy administration

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safety standards adapted from those issued by the Oncology Nursing Society (ONS) and the American Society of Clinical Oncology (ASCO).

Nursing leadership could help protect nurses from harm by distributing nursing workloads more evenly, assuring the availability of adequate time, space, and personnel for chemotherapy verification.

Nurses reporting exposure had lower (worse) scores on several of the subscales of the Practice Environment Scale of the Nursing Work Index, reporting less participation in practice

affairs and less adequate staffing and resources. In particular, chemotherapyexposed nurses claimed to have higher workloads: an average assignment of 11.1 patients per shift compared with 8.4 per shift for nurses not reporting exposures (P = .02). Because of the substantial variation in workload, however, the authors cautioned against overinterpretation. And although there was no significant difference between the percentage reporting a “favorable” practice environment, a numerical difference favored the nonexposed group.

Chemotherapy orders were verified by 2 or more nurses on a frequent or very frequent basis 94.5% of the time for the whole cohort; however, only 82.9% of the chemotherapy-exposed nurses said this held true for them, compared with 96.9% of those not exposed (P <.01). The authors called this finding “intriguing” and suggested “it may serve as a proxy for various processes to protect patients and nurs-

es.” They noted that centers adhering to the ONS/ASCO-recommended safety practices “likely are predisposed to a positive safety culture.”

Number of years of nursing employment did not differ by exposure status, nor did race, oncology certification status, or education level.

According to the authors, this study is one of the few to evaluate chemo therapy safety among oncology nurses in an ambulatory care setting, and the first to assess the impact of organizational structures and processes on exposure risk. In addition to strengthening the safety culture within their institution, nursing leadership could help protect nurses from harm by distributing nursing workloads more evenly, assuring the availability of adequate time, space, and personnel for chemotherapy verification, and guaranteeing that requisite resources are available to administer chemotherapy in ways that minimize occupational exposure, they suggested. ●

www.theOncologyNurse.com

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www.BioOncology.com

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.

© 2011 Genentech USA, Inc. All rights reserved. BIO0000330901 Printed in USA.

TON_October 2011_v8_TON 10/18/11 1:02 PM Page 24

CONTINUING EDUCATION PROGRAM CE27 • RELEASE DATE: OCTOBER 16, 2011 • EXPIRATION DATE: OCTOBER 15, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYNURSE.COM

Exercise Across the Cancer Continuum

Mary Calys, DPT, PT, MS, BSW Cancer Rehabilitation and Fatigue Management North Kansas City Hospital Kansas City, Missouri

STATEMENT OF NEED Mounting evidence continues to underscore the importance of exercise during and after cancer treatment as a way to promote quality of life, improve function, and potentially reduce comorbidities. In the past 2 decades, it has become increasingly clear that exercise also plays a vital role in cancer prevention and control. Exercise may decrease the risk of many cancers; extend survival for breast and colon cancer survivors; and prevent, attenuate, treat, or rehabilitate many of the psychological and physiological challenges faced by survivors. Because many oncology nurses practice in a location that lacks formal oncology rehabilitation services, they may be the primary providers for exercise prescription. For these situations, nurses can introduce early exercise intervention and help patients’ exercise regimens progress as they traverse along the cancer continuum.

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: • Discuss the role of exercise throughout the phases along the cancer continuum • Prepare an exercise prescription that meets individual patient needs and limitations

T Lisa VanHoose, PhD, PT, CLT-LANA, WCC Department of Physical Therapy and Rehabilitation Science University of Kansas Medical Center Kansas City, Kansas

he new buzzword in cancer survivorship is exercise. Cancer is the primary cause of impairment or dysfunction in the United States because of long- and late-term effects of treatment.1 The primary comorbidities include obesity, diabetes, osteoporosis, integumentary conditions, cardiovascular disease, and psychosocial impairments. Research has suggested that every cancer survivor will have at least one primary comorbidity and this interaction increases with age.2 Mounting evidence continues to underscore the importance of exercise during and after cancer treatCONTINUING 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.

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OctOber 2011 I VOL 4, NO 7

ment as a way to promote quality of life,3 improve function,4,5 and potentially reduce comorbidities.6,7 In the past 2 decades, it has become increasingly clear that exercise also plays a vital role in cancer prevention and control.8 Exercise may decrease the risk of many cancers; extend survival for breast and colon cancer survivors; and prevent, attenuate, treat, or rehabilitate many of the psychological and physiological challenges faced by survivors.9 The Call to Action On national and global levels, clinicians are being challenged to address the long- and late-term effects of cancer diagnosis and treatment in the context of the whole person (Table). Although we understand the importance of exercise in the prevention and management of cancer and its related complications, it has been difficult to merge theory and practice. Many nurses and other healthcare professionals struggle to create a viable structure that integrates the recommended exercise guidelines into their patients’ comprehensive oncology survivorship plans of care.

The Cancer Continuum Traditionally, exercise has been studied either during the “treatment period” or “posttreatment period” (formerly referred to as the “survivorship period”).

More recently, the definition of cancer survivorship has broadened to include the individual from the time of diagnosis through the balance of his or her life.10 Courneya and Friedenreich proposed a framework that outlines 6 phases of the cancer continuum.11 Exercise is appropriate at any of these phases with a thorough evaluation of the patient FACUlTy DISClOSURES As a provider accredited by the California Board of Registered Nursing, Science Care must ensure balance, independence, objectivity, and scientific rigor in all its activities. All course directors, faculty, planners, and any other individual in a position to control the content of this educational activity are required to disclose to the audience any relevant financial relationships with any commercial interest. Science Care must determine if the faculty’s relationships may influence the educational content with regard to exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity.

Disclosures are as follows: • Mary Calys, DPT, PT, MS, BSW, has nothing to disclose.

and appropriate modifications. This article will limit discussion to the role of exercise throughout the final 4 phases of this framework, using diagnosis as the threshold point in the continuum. The first 2 phases, prescreening and screening, occur before diagnosis. The pretreatment, treatment, survivorship, and end-of-life phases occur after diagnosis. The International Classification of Functioning, Disability, and Health (ICF) provides a framework for healthcare professionals to identify impairments, limitations, and restrictions resulting from cancer, its treatment, and related comorbidities.12 After identifying these areas, an appropriate exercise plan can be added to the survivorship plan of care.

The World Health Organization endorsed the ICF in 2001. The model addresses the physical, psychologic, and social needs of the cancer patient through an analysis of the body, individual, and societal domains. These domains intermingle in determining one’s quality of life and, thereby, offer a working structure to assess and treat the needs of the whole person (Figure). Nurses may use this model as a springboard for collaboration with other healthcare and community professionals to develop meaningful exercise interventions for cancer survivors.

Prescribing Exercise Along the Cancer Continuum After identifying the impairments, limitations, and restrictions related to the health condition, the healthcare provider can develop an appropriate exercise plan. Therapeutic exercise is prescribed similarly to medication dosing and takes into consideration the status of • Dawn Lagrosa has nothing to disclose.

• Kristen Olafson has nothing to disclose.

• Kristin Siyahian has nothing to disclose.

• Lisa VanHoose, PhD, PT, CLT-LANA, WCC, has nothing to disclose.

The staff of Science Care have nothing to disclose.

DISClAIMER The opinions and recommendations expressed by faculty, authors, and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of Science Care or Green Hill Healthcare Communications, LLC. COPyRIGHT STATEMENT Copyright © 2011 Science Care. All rights reserved.

www.theOncologyNurse.com

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CONTINUING EDUCATION in combination with a physical assessment by the nurse or healthcare provider.

Table Goals for Treating the Whole Cancer Patient Organization American Cancer Society 2015

Goal a

Accomplish measurable improvement in quality of life from the time of diagnosis and for the balance of life of all cancer survivors

Healthy People 2020b

Increase the proportion of cancer survivors who report physical health–related quality of life similar to the general population

LIVESTRONG National Action Plan Cancer Survivorshipc

Minimizing preventable pain, disability, and psychosocial distress for those living with, through, and beyond cancer

World Cancer Declarationd

Access to accurate cancer diagnosis, appropriate cancer treatments, supportive care, rehabilitation services, and palliative care will be improved for all patients worldwide

2. Breathing retraining15 An emotionally stressful period often produces an altered breathing pattern, in which diaphragmatic function is reduced and an anxiety-linked, upperchest pattern evolves. Early recognition and correction of dysfunctional breathing patterns may improve anxiety levels, postural control, and somatic complaints.

a

2010 Strategic Progress Report. Atlanta, GA: American Cancer Society; 2010.

Healthy People 2020 objective topic areas. HealthyPeople.gov.

National Action Plan for Cancer Survivorship: Advancing Public Health Strategies. Lance Armstrong Foundation, US Centers for Disease Control and Prevention; 2004. d Union for International Cancer Control. World Cancer Declaration: targets. 2011. www.uicc.org/declaration/targets/. b c

the individual, mode of exercise, intensity, frequency, duration, and safe progression. Treatment goals may be preventive, restorative, supportive, or palliative and address complications that may occur along the cancer continuum.13 Preventive exercise. Preventive exercise is prescribed before the development, or to lessen or shorten the duration, of disability.13 For example, preoperative education and training may prepare a client for postoperative range-of-motion limitations and prevention of lymphedema after breast surgery. Preoperative training is not affected by normal postoperative pain and/or postanesthesia symptoms. Preventive measures also may include approaches to improve a client’s physical functioning and general health status, that is, a program to provide clients with knowledge and skills to reduce their risk for developing osteoporosis after cancer treatments.

Restorative exercise. Restorative exercise is indicated when the return to previous levels of physical, psychologic, social, and vocational functioning is expected, without the presence of handicap or residual disease.13 Postoperative range-of-motion exercises for clients undergoing mastectomy or head and neck resection are examples of interventions included in this category.

Cardiopulmonary conditioning and mobility training after surgery, chemotherapy, or radiation also is considered restorative care.

Supportive exercise. Supportive exercise is dosed when ongoing disease is controlled or slowly progressing, to maintain a degree of function and independence.13 The focus may in clude identifying ways to accommodate existing disabilities. Instruction in the use of adaptive equipment may be provided to assist in self-management, self-care abilities, and independent functioning. Interventions to improve memory and complex cognitive processing may be prescribed after brain tumor resection. Education and

www.TheOncologyNurse.com

training regarding prosthetic devices may occur after amputation.

Palliative exercise. Palliative exercise is prescribed to prevent or reduce complications when increasing disability is expected from relentless disease progression.13 Maintaining a balance between optimal function and comfort becomes a key issue. Goals include pain control, prevention of contractures and pressure sores, prevention of unnecessary deterioration from inactivity, and energy conservation. The inclusion of family, friends, and caregivers is important when establishing an exercise prescription.

In all cases, the needs and goals of the patient are the primary foundation of exercise prescription, and the intent is to encourage meaningful and selfdirected health-related behaviors, that may be modified and adapted to the changing needs of the patient.

Positive outcomes are motivating to survivors and nurses.

The Role of Rehabilitation Therapists Individualized treatment plans and outcome goals are the hallmark of oncology rehabilitation. Patients may present with complex comorbidities and side effects of surgery, chemotherapy, and radiation that may require a referral to a rehabilitation therapist, such as a speech pathologist, physical therapist, or occupational therapist. The role of oncology rehabilitation, therefore, has expanded to encompass a wide range of conditions and functional concerns, including, but not limited to, cancerrelated fatigue, chemotherapy-induced peripheral neuropathy, balance/coordination deficits, lymphedema, radiation fibrosis, postoperative limitations, cardiopulmonary deconditioning, difficul-

ty swallowing, weight loss/weight gain, muscle weakness and pain, cognitive changes, depression, body image changes, and hormonal side effects.

The impact of such an intervention to the survivorship care plan may be physically, psychologically, and socially profound. The case study illustrates this point (Sidebar).

Nurses and Exercise Prescription Positive outcomes are motivating to survivors and nurses. Many oncology nurses, however, are challenged by a lack of formal oncology rehabilitation services in their specific care setting. Nurses may be the primary providers for exercise prescription. In these situations, early exercise intervention can be introduced and progressed by the nurse along with other strategies taught in nursing education along the cancer continuum.

1. Medical clearance The American College of Sports Medicine risk stratification tool is a resource that allows healthcare professionals to identify individuals who may need additional supervision during exercise or possibly medical clearance.14 The risk tool can be used

Awareness of faulty breathing patterns.

With the patient in a semireclined position, have him or her place one hand on the stomach and the other on the upper chest. Ask the patient to take a deep breath. Chances are he or she will take a big breath instead, through the mouth, inflating the upper chest only. Cue the patient to inhale gently through the nose, involving the upper chest, lower chest, and finally activating the diaphragm at the peak of inspiration. Using his or her hands as guides, the patient can appreciate the difference between vigorous big and gentle deep breathing.15 Relaxation of the upper chest, shoulders, and accessory muscles. In the same position, have the patient clasp his or her hands on top of the head. This helps put the upper chest muscles into “neutral,” and usually the patient immediately can feel the diaphragm recruited into action. The diaphragm descends as the patient breathes in and the stomach gently rises, then relaxes as he or she exhales. Bending the knees will help the patient loosen tense abdominal muscles.15 Abdominal/low-chest breathing pattern retraining. Concentrate on low-chest breathing, with gentle inhales dissolving into the exhale without

Health Condition (disorder/disease)

Structure & Function BODY (Impairment)

Participation SOCIETY (Restriction)

Activities INDIVIDUAL (Limitation)

Environmental Factors

Personal Factors

Figure. International Classification of Functioning, Disability, and Health Model Reprinted with permission from the American Physical Therapy Association Oncology Section Research Committee.

OcTOber 2011 I VOL 4, NO 7

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CONTINUING EDUCATION pause, until the end of the exhale is reached. Cue the patient to exhale twice as long as the inhale. The patient may practice in a semireclined, seated, or standing position. Aim at getting the number of breaths down to 6 to 8 breaths per minute. This should be

practiced for 10 minutes, a minimum of 3 to 4 times per day.15 Awareness of normal breathing rates and rhythms. Restoring an energy-efficient, low-chest, nose-breathing pattern, with a relaxed pause at the end of the

Case Study: Can MT benefit from an exercise intervention?

MT is a 58-year-old woman diagnosed with stage III colon cancer 1 year ago.

She underwent colon resection, lymph node dissection (3+/24 nodes), and completed chemotherapy (leucovorin/fluorouracil/oxaliplatin and leucovorin/ fluorouracil/irinotecan) 6 months ago. She has a history of 2 failed coronary artery bypass grafts, 5 cardiac stents, a pacemaker, and right knee osteoarthritis with a previous ligament repair.

MT is a concert violinist and music teacher. At the height of her career, she was groomed for the position of concert mistress of her metropolitan symphony.

She presents to the clinic with severe chemotherapy-induced peripheral neuropathy in the hands and feet. She has been unable to play her violin for 1 year because of pain. Because of loss of income from teaching, she was forced to sell 2 violins to pay for cancer treatment.

Physical Therapy Intervention Using the International Classification of Functioning, Disability, and Health model, the various domains of MT’s quality of life are considered (Figure). MT was prescribed individualized exercise interventions that directly addressed physiologic structure and function, activities of daily living, and social participation.

At the impairment level, reducing her neuropathy symptoms from proximal to distal was facilitated by exercises and kinesiotaping to desensitize pain receptors.

At the limitation level, pain-free ambulation was achieved through the use of Nordic walking poles, redistributing weight-bearing forces through all 4 extremities. Balance training using the Nintendo Wii Fit program provided re-education of damaged proprioceptive nerves in the feet. Finger dexterity drills using the Wii Fit and other various media were progressed gradually to “fingering” on the violin, followed by timed intervals of “fingering and bowing” on the violin.

After 2 months of intensive physical therapy, MT was able to play her violin for 30 minutes without fingertip pain. She independently completed a home exercise program on her own Nintendo equipment and adhered to a routine Nordic pole walking program. At 4 months, MT obtained gainful employment outside the home and was ready to start teaching violin on a part-time basis.

Disorder/Disease Colon cancer

BODY Impairment Chemotherapy-induced peripheral neuropathy

INDIVIDUAL Limitation Painful ambulation High fall risk Manual dexterity

Environmental Loss of employment Loss of personal identity

SOCIETY Restriction Unable to play violin Loss of livelihood

Personal factors Knee osteoarthritis Pacemaker 2 coronary artery bypass grafts 5 cardiac stents

Figure. International Classification of Functioning, Disability, and Health Model Applied to MT’s Case

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OctOber 2011 I VOL 4, NO 7

exhale often restores normal breathing rates. Ultimately, the patient should integrate corrected breathing patterns, both at rest and during activity.15 3. Postural correction Kyphosis. This commonly observed exaggeration warrants treatment in the oncology population, as it augments the flexion moment on the vertebral bodies, thus rendering the patient more vulnerable to vertebral compression fracture. Altered alignment of the body may lead to postural pain syndrome and increase the propensity for falls because of the forward shift in the center of gravity.16 Observe and cue patients to correct faulty postures such as forward head, downward gaze, rounded shoulders, and a flexed or slumped spine.

Change sitting posture often. Inactivity can be one of the biggest culprits in back, neck, and shoulder pain after sitting for long periods. Continually shifting the pelvis and doing a few chair exercises may help reduce muscle tension.

Use of lumbar support. Advise the patient regarding purchase of a lumbar support cushion or use of an improvised form, such as a small pillow or rolled towel.

4. Scar management As soon as the physician will allow, the patient should be instructed in scar management, and multiple techniques and treatments are available.17 Gentle stretching of the scar will reduce contractures, which may decrease range of motion and/or function.

5. Self manual lymph drainage Proper diaphragmatic breathing. Deep breathing helps to empty the larger lymphatic ducts. The en hanced clearance of the lymphatic system may reduce lymphedema risk or assist in the management of lymphedema. Have the patient perform 5 to 10 repetitions before the warm-up.

Lymph node bed stimulation. Instruct the patient to move his or her hands in circular motions over the lymph node bed, using the palm of the hand.

The stroke should be firm enough to stretch the skin, but not cause discomfort or a rubbing sensation. In the groin, the motion should be toward the greater trochanter, not the genitals. The patient should perform 5 to 10 repetitions over each lymph node bed (axilla and inguinal).

Self manual lymph drainage before exercising. By performing the drainage procedure before exercise, the patient may

prepare the body for the increased lymph flow associated with exercise.18 6. Warm-up Gradual increases in activity over 5 to 10 minutes. Preferably, the warm-up should include the same exercise mode that the patient will use for training.

The warm-up increases body temperature and allows the body to acclimate to higher metabolic demands.

Monitor vital signs for abnormal changes in heart rate or blood pressure.

Stretching after the warm-up may reduce muscle injury.19,20 Stretching should account for an additional 5 to 10 minutes of the total warm-up time to reduce muscle stiffness and injury.

7. Physical activity Adapted, slowly progressive aerobic and resistance training. Encourage these activities for survivors in any of the 6 phases of the cancer continuum.

Aerobic exercise 5 times per week. The American College of Sports Medicine suggests at least 150 minutes per week of aerobic exercise.9 Remember, your patient may need to work up to this level slowly.

Interval training. Training in intervals has been shown to be less stressful on the cardiopulmonary system.21 Intervals can be divided into 30 or 60 seconds of activity.

Progressive resistance training. Resistance training should progress very slowly.9 If your patient reports increased pain or fatigue with progression, then return to the prior amount of resistance or no weight, until symptoms resolve. Assess for deep-vein thrombus. Then, slowly progress the patient, watching for any adverse symptoms.

Balance training. Include balance training to address the increased fall risk related to cancer treatment.22 8. Lymphedema prevention Exercise has been shown not to increase the risk of lymphedema.23,24

Patients with lymphedema slowly should progress physical activity and weight lifting.23 Assess limb changes over 24 hours after initiating new modes of physical activity or increasing resistance with weight training. Assess for deep-vein thrombus if the client complains of pain and/or increased limb girth.

Some patients will need to wear a garment when exercising to control the increased lymph flow that occurs during exercise.

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9. Cool-down Gradual declines in activity for 5 to 10 minutes. End the cool-down with gentle stretches with holding times of at least 30 seconds. Monitor vital signs for a return to baseline values.

Measuring Outcomes Baseline physical activity measures can be collected during any phase of the cancer continuum. An earlier understanding of physical activity levels, however, allows the healthcare provider to quickly identify declines and be proactive in identifying appropriate interventions. Multiple selfreport questionnaires and physical activity barriers are available. Commonly used tools include the SF-36 health survey, 25 Disabilities of the Arm, Shoulder, and Hand questionairre,26 the Functional Assessment of Cancer Therapy,27 the Timed Get-Upand-Go test,28 and the Short Physical Performance Battery. 22 These tools allow the provider to assess baseline status and changes in quality of life and physical performance after the initiation of exercise training.

Disease-Specific Exercise Prescription Each cancer has specific exercise considerations related to the site of the tumor and/or the treatment. An exercise program for a survivor of breast cancer should include range-of-motion exercises for the shoulder, but also include abdominal and scapular exercises. Of particular interest are exercises focused on the serratus anterior, because it commonly is affected by sur-

gical interventions. Gynecologic and prostate cancer survivors may benefit from pelvic floor exercises. Survivors of lung cancer and multiple myeloma may require more attention on endurance-building tasks. The exercise plan, however, should be individualized to the client and his/her limitations, barriers, and restrictions as outlined in the ICF model.

The American College of Sports Medicine suggests at least 150 minutes per week of aerobic exercise.

Conclusion Exercise plays a role in healthy living throughout the cancer continuum.

Exercise training can reduce cancer risk, as well as strengthen the body and mind before treatment. With our increasing understanding of the physiologic benefits of exercises, we now are encouraging survivors to exercise during treatment to attenuate the side effects of cancer treatment. After treatment, exercise has been shown to improve quality of life, physical function, and survival. The goals of exercise need to be individualized for each survivor.

We have introduced the ICF model as a framework to develop an exercise program along with general recommendations, which can be used across multiple disease sites. This information will provide additional resources for nurses in their endeavors to address the indi-

vidualized survivorship care plans for the patients they serve. ● References 1. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011.

2. Extermann M. Interaction between comorbidity and cancer. Cancer Control. 2007;14:13-22.

3. Mock V, Pickett M, Ropka ME, et al. Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract. 2001;9:119-127.

4. Schwartz AL, Mori M, Gao R, et al. Exercise reduces daily fatigue in women with breast cancer receiving chemotherapy. Med Sci Sports Exerc. 2001;33:718-723.

5. Mutrie N, Campbell AM, Whyte F, et al. Benefits of supervised group exercise programme for women being treated for early stage breast cancer: pragmatic randomised controlled trial. Br Med J. 2007;334:517-520.

6. Galvão DA, Spry N, Taaffe DR, et al. A randomized controlled trial of an exercise intervention targeting cardiovascular and metabolic risk factors for prostate cancer patients from the RADAR trial. BMC Cancer.

2009;9:419.

7. Wonders KY, Reigle BS. Trastuzumab and doxorubicin-related cardiotoxicity and the cardioprotective role of exercise. Integr Cancer Ther. 2009;8:17-21.

8. Campbell KL, McTiernan A. Exercise and biomarkers for cancer prevention studies. J Nutr. 2007;137(1 suppl):161S-169S. 9. Schmitz KH, Courneya KS, Matthews C, et al.

American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-1426.

10. Twombly R. What’s in a name: who is a cancer survivor? J Natl Cancer Inst. 2004;96:1414-1415.

11. Courneya KS, Friedenreich CM. Physical activity and cancer control. Semin Oncol Nurs. 2007;23:242-252.

12. International Classification of Functioning, Disability and Health (ICF). Geneva, Switzerland: World Health Organization; 2001.

13. Fitzpatrick T. Principles of physical and occupational therapy in cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation: Principles and Practices. New York, NY: Demos Medical; 2009:785-796.

14. Scherer S. Addressing cardiovascular risk as part of physical therapist practice—what about practice recommendations for physical therapists? Cardiopulm Phys Ther J. 2009;20:27-29.

15. Chaitow L, Bradley D, Gilbert C. Multidisciplinary Approaches to Breathing Pattern Disorders. London: Churchill Livingstone; 2002:182-184.

16. Farooki A, Rimner HC. Osteoporosis in cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation: Principles and Practice. New York, NY: Demos Medical; 2009:753-772.

To Receive cRediT, compleTe The posTTesT aT TheOncologyNurse.com

17. Mustoe TA, Cooter RD, Gold MH, et al; International Advisory Panel on Scar Management.

International clinical recommendations on scar management. Plast Reconstr Surg. 2002;110:560-571.

18. Desai P, Williams AG Jr, Prajapati P, Downey HF. Lymph flow in instrumented dogs varies with exercise intensity. Lymphat Res Biol. 2010;8:143-148.

19. Nall R. How to warm up before stretches. www.live strong.com/article/325618-how-to-warm-up-beforestretches/. Updated December 5, 2010. Accessed September 12, 2011.

20. Herbert RD, Gabriel M. Effects of stretching before and after exercising on muscle soreness and risk of injury: systematic review. Br Med J. 2002;325:468.

21. Meyer K, Samek L, Schwaibold M, et al. Interval training in patients with severe chronic heart failure: analysis and recommendations for exercise procedures.

Med Sci Sports Exerc. 1997;29:306-312.

22. Bylow K, Dale W, Mustian K, et al. Falls and physical performance deficits in older patients with prostate cancer undergoing androgen deprivation therapy.

Urology. 2008;72:422-427.

23. Schmitz KH, Ahmed RL, Troxel A, et al. Weight lifting in women with breast-cancer–related lymphedema. N Engl J Med. 2009;361:664-673.

24. Bicego D, Brown K, Ruddick M, et al. Exercise for women with or at risk for breast cancer–related lymphedema. Phys Ther. 2006;86:1398-1405.

25. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. Br Med J. 1992;305:160-164.

26. Gummesson C, Atroshi I, Ekdahl C. The disabilities of the arm, shoulder and hand (DASH) outcome questionnaire: longitudinal construct validity and measuring self-rated health change after surgery. BMC Musculoskelet Disord. 2003;4:11.

27. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol.

1993;11:570-579.

28. Wall JC, Bell C, Campbell S, et al. The Timed Getup-and-Go test revisited: measurement of the component tasks. J Rehabil Res Dev. 2000;37:109-113.

Readers Survey

Do you think “mid-level provider” is an accurate term or an insult?

I

n the September issue, we published an editorial entitled “I Am a Nurse Practitioner, NOT a Mid-Level Provider,” in which author Alison Moriarty Daley provided an argument against this phrase. We asked our online reading community what they think about “mid-level provider.”

• 17% accepted mid-level provider as an accurate term • 50% agreed with Ms Daley that it is an insult • 33% didn’t think it mattered since nobody knows what the term means

©iStockphoto.com/Sean Locke

Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 18 for details.

www.TheOncologyNurse.com. www.TheoncologyNurse.com

ocTobeR 2011 I vol 4, No 7

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Navigation & Survivorship

Brought to you by

Photo by: JOWDY Photography

AONN Conference Helps Advance... Continued from cover

Interactive sessions focused on how to make certain your cancer program will meet the recently released Cancer Program Standards 2012: Ensuring Patient-Centered Care from the Commission on Cancer, specifically sections 3.1 (Patient Navigation Process), 3.2

(Psychosocial Distress Screening), and 3.3 (Survivorship Care Plan). Navigators also discussed practical ways to use the National Cancer Institute Community Cancer Centers Program’s Navigation Matrix to identify and remove patient care barriers, to collaborate with other

professionals for optimal patient care, and to develop best practices within the navigator community.

Highlights included the patient advocacy keynote given by Andy Miller, MHSE, CHES, executive vice president of mission for LIVESTRONG,

and the poster podium sessions moderated by Lillie Shockney, RN, BS, MAS, CBCN, CBPN-IC. The 5 posters presented were chosen from more than 2 dozen displayed at the conference, and they illustrated the great research and endeavors of nurse and patient navigators.

Survivorship sessions provided a road map of how to set up and grow a program, as well as examples of successful programs at the George Washington Cancer Institute at George Washington University Medical Center in Washington, DC; St. Mary’s Regional Cancer Center in Grand Junction, Colorado; and John Muir Cancer Institute in Walnut Creek, California. Survivorship keynote speaker Lillie Shockney shared her personal history with cancer from childhood through her own encounter with the disease and how she has persevered as a survivor. ●

Academy Honors Excellence in Navigation

Gastrointestinal Cancer Navigator of the Year Coralyn Martinez, RN, of the Lack Cancer Center in Grand Rapids, Michigan, provides coordinated care for patients dealing with the chaos of cancer. In her position, she is responsible for coordinating the Multi disciplinary Clinic, which consists of the many specialists responsible for a patient’s care, including surgery, medical oncology, radiation oncology, social work, and other areas. Coralyn provides quality patient-centered care, and her compassion is something all healthcare professionals should strive to attain.

Lung Cancer Navigator of the Year This year’s Lung Cancer Navigator of the Year, Cynthia Smart, RN, OCN, of the Derrick L. Davis Forsyth Regional

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OctOber 2011 I VOL 4, NO 7

in Newton, Massachusetts, is a great example of the importance of navigation as the glue of the many professionals and departments required for optimal patient care across the cancer continuum. Through her efforts, the navigator program has instituted several clinical and patient services, including increased nutrition and psychosocial support, the growth of a genetic counseling program for high-risk patients, and survivorship plans and services. Cindy strikes the important balance of advocacy, empathy, and perseverance, with the end result of greatly improved communication and patient care.

Photo by: JOWDY Photography

SAN ANTONIO—In conjunction with the Second Annual Navigation and Survivorship Conference, the Academy of Oncology Nurse Navigators (AONN) presented the Second Annual Excellence in Navigation and Survivorship Awards. Recognizing excellence in patient navigation and survivorship care, 5 recipients were selected from more than 60 nominations in a variety of categories. “All of these award winners represent a great example for those just starting in this profession to emulate, whether they are navigators or administrators responsible for developing these patient services at their center,” said Sean T. Walsh, executive director of AONN.

Cancer Center in Winston-Salem, North Carolina, has been a lung cancer navigator for 7 years. Her compassion and dedication for the patients she guides, as well as their families, has had a tremendous impact in a community of patients faced with a disease often in its later stages. In addition, Cynthia has taken time to mentor other navigators, work in the community on various events, advocate for and empower her patients, as well as develop support groups for patients and their families dealing with the reality of a lung cancer diagnosis.

Breast Cancer Navigator of the Year Although not in attendance, Carol G. Boyer, MSN, APN-C, CBPN-IC, of Summit Medical Group in Summit,

New Jersey, was awarded the Breast Cancer Navigator of the Year award.

Nominated by several colleagues, Carol helped to establish the breast cancer navigator program, as well as many other extended patient services, such as targeted support groups and exercise classes. Carol also was key in Summit Medical Group earning a designation of Certified Quality Breast Center of Excellence through the National Consortium of Breast Centers.

Multisite Tumor Navigator of the Year Recognizing that many navigators are responsible for guiding patients with a variety of diagnoses, AONN created the Multisite Tumor Navigator of the Year award. Cindy Krasnecky, BSN, OCN, of Newton-Wellesley Hospital

Administrator of the Year The inaugural Administrator of the Year award was presented to a group of 8 navigators from the Derrick L. Davis Forsyth Regional Cancer Center in Winston-Salem, North Carolina, on behalf of Sharon K. Murphy, MBA, MHA, a pioneer, true believer, and early adopter of the navigation profession. Under her guidance, the program has grown from a single breast cancer navigator to 6 disease site–specific programs. By encouraging the strengths of each navigator, Sharon has been able to make an enormous impact on the community, one patient at a time, by ensuring that each patient’s voice is heard. ●

In-depth coverage of the material presented will be available in the November issue of the Journal of Oncology Navigation & Survivorship and at www.AONN online.org.

www.theOncologyNurse.com

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Cancer Center Profile The Cleveland Clinic Taussig Cancer Institute where medical specialists worked together to achieve the best outcomes in patient care, while furthering the goals of research and education.

From the beginning, the mission of the Cleveland Clinic has been: “Better care of the sick, investigation into their problems, and further education of those who serve.” To help ensure the success of their mission, the 4 founders decided to commit 25% of their net income to an endowment that supported medical research, education, and care of the indigent. Today, the Cleveland Clinic has facilities throughout Ohio, as well as in Florida, Nevada, Canada, and Abu Dhabi.

In the field of oncology, the Cleveland Clinic has a distinguished history.

George Crile Jr, MD, the son of one of the founders, was a pioneer in establishing alternatives to radical mastectomy to treat breast cancer. His book, Cancer and Common Sense, was written for the public and endorsed conservative treatment for cancer while railing against what Dr Crile called “the unnecessarily mutilating results of the surgery being done at some of the socalled cancer centers.” These were controversial ideas in 1955, and Life magazine published excerpts from his book. Today, the Cleveland Clinic Taussig Cancer Institute is internationally recognized for its clinical, translational, and basic cancer research and is a National Cancer Institute–designated cancer center, as part of the Case Comprehensive Cancer Center.

To continue the mission of its founders, the Cleveland Clinic offers a variety of programs and provides outreach to people with cancer, regardless of where they may receive their med-

Continued from cover

“We also take the patients on a tour of our center. It is heart warming to see the change of expression from the ‘deer in headlights’ to the more confident ‘I can do this.’”

—Josette Snyder, RN, MSN, AOCN

ical treatment. Josette Snyder, RN, MSN, AOCN, a clinical nurse specialist, answered our questions about the Cleveland Clinic and some of these programs.

What is your hospital doing that is different from other cancer centers?

Josette Snyder (JS): Twenty years ago we started the Cancer Answer Line, which answers patients’ questions about cancer. We receive questions from around the country and around the world. To those who choose to have treatment at our facility, we triage and assist with navigating patients through the system so they are seeing the appropriate specialist or specialists for their cancer diagnosis.

Through the support of the Scott Hamilton CARES (Cancer Alliance for Research, Education and Survivorship) Initiative, we have been able to launch some very unique programs. The website Chemocare.com helps patients better understand their chemotherapy experience. Available in both English and Spanish, it is the first of its kind in the United States and helps patients navigate complex chemotherapy infor-

mation using easy-to-understand language. This is available not only to our cancer patients but also to all with Internet access.

The 4th Angel Patient & Caregiver Mentoring Program offers free, one-toone, confidential outreach and support by matching cancer patients with volunteers who are cancer survivors. The program is telephone-based, so connections can be made regardless of where someone lives or receives his or her medical care.

The Reflections wellness program offers complementary esthetic services designed to reduce anxiety and promote healing and well-being. Services include Reiki therapy, guided imagery, reflexology treatments, facial treatments, and makeovers.

How do these translate to better outcomes for your patients?

JS: When patients are better informed about their disease from the outset, set up with the correct specialist, assisted

in navigating the complex healthcare system, and supported in their disease from diagnosis through treatment and beyond, patients are better able to complete their treatment. And this translates into better outcomes.

The Cleveland Clinic believes in educating the patient and his or her family about cancer as a means of increasing the chance for a better outcome of therapy. Can you share a patient success story that illustrates this belief?

JS: I have been very fortunate to witness many success stories; however, from my perspective of patient education, I would like to note the success of our patient chemotherapy orientation classes in general. We offer this 1-hour class to our patients, optimally attended between the time that they have been scheduled to receive treatment and their first treatment appointment. We give a brief overview of our cancer center, services offered, and what to expect. Then, we educate them about chemotherapy in general, especially side effects, and provide helpful hints for the first day of treatment. We also take the patients on a tour of our center. It is heartwarming to see the change of expression from the “deer in headlights” to the more confident “I can do this.” When the patients have been to class and show up for their first treatments, our treatment nurses see a tremendous difference. This difference has been noticed by management, and with that support, we have been able to offer these classes twice daily.

How has your educational role changed in the past 5 years?

JS: There have been so many new therapies approved, and many are oral medications. Patient education takes on a whole new perspective, because patients are not coming to the outpatient setting for their treatment. We have needed to make adjustments in our education of patients as well as our follow-up and monitoring, so they continue to feel supported and connected with the team, even if they are not physically seeing us.

What is in the future for the Cleveland Clinic?

The Cleveland Clinic Taussig Cancer Institute provides world-class care to patients with cancer and is at the forefront of new and emerging clinical, translational, and basic cancer research.

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OCTOBER 2011 I VOL 4, NO 7

JS: Providing superior patient care within a cooperative, compassionate, and innovative healthcare practice is a founding principle of the Cleveland Clinic. As we move into the future, we will see changes in technology as well as ways of communicating with our patients; however, the founding principles won’t change. ●

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Specifically, this conference is intended for: â&#x20AC;˘ Medical Oncologists and Hematologists â&#x20AC;˘ Pathologists â&#x20AC;˘ Geneticists â&#x20AC;˘ Advanced Practice Oncology Nurses â&#x20AC;˘ Research Nurses â&#x20AC;˘ Clinical Oncology Pharmacists â&#x20AC;˘ Genetic Counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

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TON_October 2011_v8_TON 10/18/11 11:05 AM Page 32

Supportive Care

Effects of Chemotherapy on Fertility May Be Underestimated Significantly

By John Schieszer

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any cancer survivors who thought they were fertile now may be finding that is not the case. New research is suggesting that current estimates of the impact of chemotherapy on women’s reproductive health are too low.

Researchers at the University of California San Francisco (UCSF) say their analysis of the age-specific, longterm effects of chemotherapy provides new insights that will help patients and clinicians make more informed decisions about future reproductive options, such as egg harvesting (Cancer. September 1, 2011. Epub ahead of print).

The investigators adopted a more tailored investigation into chemotherapy-related infertility and found estimates may have been far too low. They say these findings will now change how oncology nurses counsel their patients.

“The nurses play a pivotal role here,” said study investigator Mitchell Rosen, MD, assistant professor in the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences. “Nurses are the most important. Most of the time, referrals are generated and initiated by the nurse.”

He said that oncology nurses need to be aware of the new study findings and consider them when educating patients.

Rosen said even though an oncologist mentions that fertility may be affected, many patients simply don’t comprehend

new findings, which also take into account cancer type and age, hopefully will enable clinicians to offer more strategic and personalized counseling.

The researchers used the California Cancer Registry (a statewide population-based cancer surveillance system) to ask women about their reproductive “We found chemotherapy essentially narrows a history before and after cancer treatwoman’s reproductive window by causing a range of ment. Survey questions addressed acute ovarian failure (cessation of menses damage to the ovaries, even if her menses resume after treatment), early menopause after chemotherapy.” (menopause before 45 years of age), —Mitchell Rosen, MD and infertility (failed conception).

A total of 1041 women diagnosed with 1 of 5 targeted cancers (leukemia, fully what that means because they are education and awareness,” said Rosen. Hodgkin disease, non-Hodgkin lymfocused more on their current treatment Previous studies largely have focused phoma, breast cancer, and gastroinoptions to enhance survival. “They forget on amenorrhea, the lack of menstrua- testinal cancers) between the ages of 18 about the one sentence from the oncolo- tion shortly after treatment, as the pri- and 40 years responded, and 620 gist,” said Rosen in an interview with The mary reproductive side effect of chemo - reported having been treated with only Oncology Nurse-APN/PA. “I think every- therapy. Analyzing retrospective survey chemotherapy. one who is taking care of patients diag- responses from women who were diagThe researchers found the percentage nosed with cancer needs to be educated nosed between 18 and 40 years, the of women reporting acute ovarian failure about it. There are still not enough refer- researchers focused on longer-term, was 8% (Hodgkin disease), 10% (nonrals going to the fertility specialists. The age-specific outcomes associated with Hodgkin lymphoma), 9% (breast canmore awareness we can do, and the more chemotherapy, including infertility and cer), and 5% (gastrointestinal cancers). people that are involved, the better.” early menopause. Their analysis sug- In women without acute ovarian failure, He said many men and women gests that the younger a woman is when the incidence of infertility increased sigundergoing chemotherapy are not get- diagnosed with cancer, the more likely nificantly with age at diagnosis. ting enough information about how she will experience early menopause.

In addition, the estimated probabilitheir future fertility may be affected by “We found chemotherapy essentially ty of early menopause increased signifithe various treatments they may be narrows a woman’s reproductive win- cantly with younger age at diagnosis. receiving. “At every center there is a dow by causing a range of damage to When counseling patients, focusing difference in who is involved when a the ovaries, even if her menses resume solely on short-term outcomes like loss patient is getting treated, so the more after chemotherapy,” said Rosen. of menses may give women unrealisti[nurses] are involved the better. It Many of the women who responded cally low assessments of their risks, needs to be standard of care for both to the survey had been told that as long because they could experience infertilimen and women. Only 10% to 30% of as their periods returned, they would ty or early menopause years to decades men bank sperm, and that is easy. It is have no negative impact from treat- after treatment. Rosen noted that more much more complicated with women. ment, he said. Making recommenda- research is needed because this study Yet 10% to 30% do it, and the main tions on preserving fertility currently is did not include genetics or variations reason for [the low numbers] is a lack of based on rather limited data. These in individual cancer treatments. ●

Conference News The following articles are based on presentations at the European Multidisciplinary Cancer Congress, held in Stockholm, Sweden, September 23-27, 2011.

Gastrointestinal Symptoms After Pelvic Radiotherapy Should Be Explored Patients Often Suffer in Silence and Never Receive Help

By Caroline Helwick

STOCKHOLM—After radiation to the pelvic area, gastrointestinal symptoms are common and can be severe. Jervoise Andreyev, MD, consultant gastroenterologist in pelvic radiation disease at the Royal Marsden Hospital in the United Kingdom, maintained that such patients are not given the attention

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they deserve, leading to unnecessary suffering.

“Curing patients inevitably risks damage to the normal tissue. Your job is to actively seek out these problems, identify patients, and develop pathways for referral to a gastroenterologist,” Andreyev told attendees. “It’s time for a

culture change. We must start offering solutions to these patients.”

Typical Aftereffects of Pelvic Radiotherapy Take the case of Sarah, a 38-year-old diagnosed with cervical cancer in 2001.

She underwent surgery and radiotherapy

and had 5 different clinicians involved in her care, yet she was left with nearly incapacitating symptoms. Her bowels moved up to 12 times a day, including several times during the night. She had liquid stool, urgency, and daily incontinence with intermittent steatorrhea, plus subacute obstructive symptoms

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TON_October 2011_v8_TON 10/18/11 11:05 AM Page 34

Conference News every 6 weeks. She had lost 35% of her body weight by the time she saw Andreyev and had repeatedly been told there was no treatment for her condition.

Sarah is typical of patients who undergo radiotherapy for pelvic cancer, he said. In surveys, physicians estimate that moderate-to-severe toxicity occurs in 5% to 15% of patients, but, in patient surveys, 90% report a permanent change in bowel habits, 50% say their daily activities are impacted, 30% report that symptoms are moderate to severe, and 15% eventually resort to surgery for these problems.

In the United States, some 5 million cancer survivors have undergone pelvic radiotherapy; these statistics mean that nearly 2 million have moderate-to-severe symptoms such as Sarah’s, Andreyev said.

Symptoms “Mean Very Little” After pelvic radiotherapy, men report an average of 6 symptoms and women report 11. An incomplete list includes

“Many patients have more than one cause for each symptom, and different causes can produce the same symptom.”

—Jervoise Andreyev, MD

diarrhea, bleeding pain, urgency, frequent defecation, loss of rectal sensation, incontinence, and weight loss. Andreyev uses a comprehensive checklist and asks patients about each possible symptom.

But Andreyev cautioned that such

symptoms should never be assumed to be caused by the cancer treatment. “Why do patients get symptoms? It depends on where the physiologic damage occurs,” he said. “Many patients have more than one cause for each symptom, and different causes can produce the same symptom. If you can identify the symptoms accurately, you can arrange for appropriate testing, diagnosis, and treatment.”

For example, the potential causes of chronic loose stool are numerous: bile acid malabsorption, large bowel strictures, bacterial overgrowth, diverticular disease, lactose intolerance, pelvic sepsis, irritable bowel disease, proctopathy, new neoplasia or disease relapse, and drugs.

For Sarah, the case he described, testing revealed bile acid malabsorption, which was treated with colesevelam (oral bile acid sequestrant); small bowel bacterial overgrowth, which responded to ciprofloxacin; and free fatty acid mal-

absorption, which was managed with a diet containing 50 g of fat.

Within 4 days, she formed stool twice a day, had no more urgency or fecal incontinence, and no further obstructive episodes. Within 3 weeks, she felt completely normal, and declared her new health to be “a miracle.”

“It was not a miracle. It was pathetic she had put up with these symptoms for such a long time,” he commented.

Andreyev did not suggest that oncology clinicians manage these patients themselves—just that they become aware of the frequency with which side effects of pelvic radiotherapy occur and to ask patients about them.

“Identify patients in trouble and refer them to an expert,” he advised.

“And be aware that most of these patients have urinary and sexual problems as well. These are global issues that need to be addressed.” ●

Nurses Should Be Proactive in Recognizing Bowel Problems After Rectal Surgery Physical and Psychosocial Components Will Need to Be Overcome

By Caroline Helwick

STOCKHOLM—Oncology nurses can take simple measures to help patients manage incontinence related to surgery for rectal cancer.

Restoration of intestinal continuity and preservation of the anal sphincter is now done via an ultralow anterior resection, but this can leave patients with functional problems that need attention, said Claire Taylor, RN, a lecturer at the Burdett Institute of Gastrointestinal Nursing at St. Mark’s Hospital in London.

“First, make the problem known,” she said. This means overcoming the taboo surrounding defecation, encouraging patients to talk about their problem, and dispelling the myths that the condition is ‘normal,’ ‘will get better soon,’ or is something the patient must ‘learn to cope with,’” she said.

Although permanent stomas are used less frequently now, rectal cancer patients often receive temporary loop ileostomies and at least 40% of them will get a temporary stoma. In 30% of these cases the stoma becomes permanent due to functional changes, delays in treatment, and other issues. Bowel symptoms will occur in most of these patients, including urgency, frequency, erratic bowel habits, incontinence, tenesmus, and evacuation difficulty.

“These patients feel very tied to

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“I suggest a nurse-led intervention that occurs early in the treatment course, rather than a wait-and-see approach.”

—Claire Taylor, RN

the toilet, and this has a psychosocial component,” she said. Nurses can help these patients regain confidence, she suggested.

Recommendations for Treatment Patients with fecal incontinence should be assessed thoroughly before any treatments are considered and should be managed appropriately with conservative measures before specialized treatments are initiated.

“For this, I suggest a nurse-led intervention that occurs early in the treatment course, rather than a wait-andsee approach,” Taylor said. Symptoms improve in most patients by 1 year, although they remain more prevalent than in the healthy population.

Even if they are better by the end of the first postoperative year, “this is a year of symptoms in which we could have been helping the patients, stopping them from slipping into a vicious circle of fear of incontinence leading to behavioral change.”

Taylor described the first steps to take for patients to experience an improvement in symptoms and sense of control over their bowels.

The first is self-management. PaTable Guidelines for Perianal Skin Soreness • Keep area clean and dry • Use moist toilet paper • Avoid rubbing area • Avoid excessive moisture • Avoid perfumed talcum powder • Wear cotton underwear • Avoid tight clothing • Avoid excessive use of ointments and creams • Consider antidiarrheal medication • When wiping anal area, wipe away from anus • Consider change in diet

tients should receive written information and be referred to websites and support groups. Nurses should manage expectations, which are an important determinant of long-term health status. Studies have shown that 50% of patients are unhappy with the information they received with regard to wind/gas, difficult evacuation, medications, use of pads, and unspecified other bowel problems. Nurses can provide better education.

Perianal skin soreness should be addressed (Table). Nurses should re view and adjust diet and fluid intake (caffeine, alcohol, fiber) and medications, consider prescribing an antidiarrheal (loperamide, titrated closely) and glycerin suppositories (to aid in complete evacuation), and address toilet access.

Behavioral techniques can be very helpful. Patients should train themselves to wait at least 5 minutes before toileting when they feel the urge, and to perform “control” exercises 10 times a day.

Referral to a specialist may be necessary when conservative interventions fail and more complex, longer-term input is required: biofeedback, bowel retraining, electrical stimulation, or rectal irrigation, she said. “The goal is to empower patients, but nurses can also do more to assess and help them manage this condition,” Taylor concluded. ●

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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 The following articles are based on presentations at the American Society of Clinical Oncology Breast Cancer Symposium 2011 held September 8-10 in San Francisco, California.

Chemoprevention in Breast Cancer... Continued from cover uptake is poor. High on our priority list is better risk assessment of women at sufficiently high risk to benefit from such preventive therapy,” she said.

Even in high-risk women, fewer than 15% use any means of chemoprevention, and this rate falls to about 5% when patients in clinical trials are excluded.

But many women could benefit. An example is a 45-year-old woman with 1 first-degree relative with breast cancer and 1 biopsy showing atypical hyperplasia. Her 5-year risk is almost 5% (compared with 1% for an average-risk peer) and her lifetime risk is 37% (vs 12%), Khan noted.

Choosing an Agent For such women, the type of pharmacologic intervention depends on menopausal status and age, hysterectomy status, bone mineral density status, mutation carrier status, and whether ductal carcinoma in situ (DCIS) has been found (Figure).

For premenopausal women, tamoxifen is the preferred agent. Tamoxifen has been shown to cut risk by at least two thirds in women with lobular carcinoma in situ or atypical hyperplasia. For postmenopausal women, raloxifene or the aromatase inhibitor exemestane are

recommended (based on recent data); patients who have had a hysterectomy also may consider tamoxifen (because adverse effects on the uterus are moot).

“Women at risk for sporadic breast cancer are most likely to benefit from SERMs, and BRCA2 carriers are more likely to benefit than BRCA1 carriers.

Data also are emerging to suggest that estrogen receptor (ER)-positive patients are more likely to benefit than ER-negative ones and, for women with DCIS, tamoxifen is marginally better than raloxifene,” she said.

A recent analysis determined the relative risks and benefits of tamoxifen and raloxifene in a variety of clinically relevant scenarios (Freedman AN, et al. J Clin Oncol. 2011;29:2327-2333).

Over a 5-year period, postmenopausal women with an intact uterus had a better benefit–risk ratio for raloxifene than with tamoxifen, but for those without a uterus the ratio was similar.

In particular, the analysis showed that regardless of ethnicity, older women (aged 70-79 years) with a lower risk of breast cancer seem to derive little benefit from either agent.

Non-Hispanic white women aged 50 to 70 years at high risk, with an intact uterus, have a more favorable benefit– risk ratio with raloxifene. In the ab-

High Risk Premenopausal

Postmenopausal

Tamoxifen Surgical prevention

Uterus intact

Hysterectomized

Osteoporotic

Osteoporotic No

No

Yes

Yes Exemestane Tamoxifen

Exemestane

Raloxifene

Figure. Summary of Pharmacologic Agents to Prevent Sporadic Breast Cancer

sence of a uterus, both tamoxifen and raloxifene are reasonable options in many scenarios. In black women, the pattern is similar.

Freedman and colleagues summarized the benefits and risks into an index, which can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen.

Based on recent data showing a 65% risk reduction for ER-positive breast

cancer, “exemestane can certainly be introduced into the category of drugs to consider for chemoprevention,” Khan added, but she had concerns about adverse effects and short follow-up in the MA.3 trial (Goss PE, et al. N Engl J Med. 2011;364:2381-2391).

In the future, other options may prove effective for chemoprevention, she said, including low-dose tamoxifen, tamoxifen gel, the bisphosphonates, metformin, fenretinide, and poly [ADP-ribose] polymerase (PARP) inhibitors. ●

Managing Hot Flashes in Breast Cancer Patients Still Trial and Error, Says Survivorship Specialist Who Is Also a Gynecologist

By Caroline Helwick

SAN FRANCISCO—One of the most perplexing issues for healthcare providers caring for breast cancer patients is the management of hot flashes, both natural and induced by treatment, because estrogen replacement therapy is not considered wise.

“The consequences of estrogen deprivation are complex, and its symptoms are significant, debilitating, and can directly impact quality of life,” said Michael Krychman, MD, a gynecologist, certified sex therapist, and cancer survivorship specialist who is executive director of the Southern California Center for Sexual Health and Survivorship Medicine in Newport Beach.

“Comprehensive care of these symptoms will enhance quality of life and increase medication compliance for breast cancer patients,” Krychman said at the 2011 Breast Cancer Symposium,

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where he shared practice advice on managing hot flashes.

Severe hot flashes are reported by over half of all breast cancer patients and are most common among younger patients

Young patients tend to be “hit hard” by treatment-induced menopause.

and those who take tamoxifen. Young patients tend to be “hit hard” by treatment-induced menopause, not only with the physical symptoms themselves but the idea they are “growing older prematurely,” he noted.

Take a “Conservative Aggressive” Approach First Treatment options are plentiful, but few are based on evidence. Krychman starts with counseling and education, instructing patients in nonmedication interventions—behavioral, lifestyle, and commonsense approaches—and adding medications as needed.

Observational and nonrandomized studies show benefits for exercise, smoking cessation, cooler ambient temperatures (drinking cold water, air conditioning, fans), the “chillow” (a cooling pillow), and “menopausal pajamas.”

Some women respond to dietary interventions: avoiding caffeine, alcohol, and spicy foods and adding basic vitamin and mineral supplements.

Pharmacologic Aids “Estrogen is not my treatment of choice, though I do prescribe it to a

few select patients and follow them closely,” Krychman said. For most patients, he tries the following nonhormonal agents, often in low doses and in combination: antihypertensives (clon idine and methyldopa), megestrol acetate (synthetic progestin), antidepressants, and antiepileptics.

Randomized trials have shown benefits for clonidine and megestrol acetate. A Cochrane review concluded that clonidine, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, and gabapentin all have mild-to-moderate effects on reducing hot flashes in breast cancer patients.

“Many women find the SSRI paroxetine very helpful in small doses,” Krychman observed, “but others who may be very sensitive to this class of drugs may have negative sexual side

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Conference News effects. This is concerning because their baseline sexuality may already be in a fragile state due to the breast cancer diagnosis.”

The SSRI escitalopram, however, is not effective in treating hot flashes, he added. There are also concerns that SSRIs interfere with CYP2D6 metabolism, which could affect the efficacy of tamoxifen. “I advise you to continue to exercise caution with regard to the use of potent CYP2D6 inhibitors in women on tamoxifen,” he said.

A newer SNRI, desvenlafaxine, is showing promise and is under review by the US Food and Drug Administration.

“Because this medication is nonhormonal and has no effect on the CYP2D6 system, it may offer breast cancer survivors a novel treatment,” he said.

herbs and supplements as a treatment for hot flashes.

Two new compounds are touted as being less estrogenic and possibly of some help. A novel serum estrogen receptor modulator, DT56a (Femarelle, Tofupill) is thought to affect the estro-

gen receptor only in specific sites and has relieved hot flashes in 75% of users. AUS 131, a synthetic S-equol, is a soy isoflavone that is a nonhormonal selective estrogen receptor agonist being evaluated for hot flashes as well.

Efficacy and safety data on these are

limited and should “be taken with a grain of salt,” he said.

Mindfulness training and acupuncture are both backed by randomized trials, and may have health effects that extend beyond a reduction in hot flashes, Krychman added. ●

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

“Many women find the SSRI paroxetine very helpful in small doses, but others who may be very sensitive to this class of drugs may have negative sexual side effects.”

—Michael Krychman, MD

Herbs and Supplements Not Backed by Data Complementary medicine and alternative therapies are popular, but few are supported by evidence. The Cochrane review did not find efficacy for vitamin E, soy isoflavones, or black cohosh. The American College of Obstetricians and Gynecologists Task Force on Hormone Therapy also examined the scientific evidence for soy, black cohosh, red clover, and Mexican progesterone yam cream and found no significant effects on hot flashes.

Other compounds have been studied even less, and some may “act like estrogens,” which is undesirable, he advised.

Altogether, the medical literature does not conclusively support the use of

www.TheOncologyNurse.com

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. © 2011 Amgen. All rights reserved.

60070-R1-V1

08-11

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OcTOber 2011 I VOL 4, NO 7

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Breast Cancer

Regional Lymph Node Irradiation Indicated for Early Breast Cancer

By Audrey Andrews

CHICAGO—In the National Cancer Institute of Canada Clinical Trials Group MA.20 trial, regional nodal

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.

irradiation (RNI) added to whole breast irradiation (WBI) improved disease-free survival (DFS), with a trend

(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, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders: Sweet’s syndrome, are bone pain and pain in extremity.

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

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toward improved overall survival (OS), reported Timothy Whelan, MD, of McMaster University and the

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.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

60070-R1-V1

Juravinski Cancer Centre in Hamilton, Ontario.

Locoregional recurrences were reduced by 42% and distant recurrences by 36%. “Results from MA.20 suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities,” Whelan said at the American Society of Clinical Oncology annual meeting.

Specialty guidelines recommend locoregional radiation after mastectomy for women with tumors >5 cm or those who have >3 positive axillary lymph nodes. The benefit in women with 1 to 3 positive nodes has been unclear.

WBI may involve radiation to the lower axillae and some of the internal mammary nodes; RNI to the internal mammary, supraclavicular, and high axillary lymph nodes may provide added benefits to WBI, but it can be more toxic.

The trade-off for a clinical improvement was an increased toxicity with the combined radiotherapy approach.

The MA.20 trial, therefore, evaluated the benefit of RNI added to WBI after breast-conserving surgery for women with node-positive or high-risk nodenegative early breast cancer. The study randomized 1832 patients to WBI or to WBI plus RNI. At a median follow-up of 62 months, the addition of RNI to WBI significantly improved DFS—preventing locoregional recurrences and, more surprisingly, recurrences elsewhere in the body. A nonsignificant trend toward improved OS was also seen.

DFS at 5 years, defined as any recurrence, contralateral breast cancer, or breast cancer death, was 84.0% in the WBI arm and 89.7% in the WBI/RNI arm, a significant 33% reduction in events. Locoregional DFS was 94.5% with WBI and 96.8% with WBI/RNI, a 42% reduction in risk.

The protection against distant recurrences was an unexpected benefit of the approach, Whelan said. Distant DFS was 87.0% with WBI and 92.4% with WBI/RNI, representing a 36% risk reduction. At 5 years, 90.7% of the patients in the WBI group were alive compared with 92.3% in the WBI/RNI group, a 23% reduction in mortality.

The trade-off for a clinical improvement was an increased toxicity with the combined radiotherapy approach. Com-

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Breast Cancer pared with WBI alone, the combination of WBI/RNI was associated with more episodes of radiation dermatitis (50% vs 40%, respectively; P <.001), pneumonitis (1.3% vs 0.2%; P = .01), and lymphedema (7% vs 4%; P = .004).

Although cosmetic outcomes were similar at 3 years, more of the RNI group considered the outcome “fair or poor” at 5 years (36% vs 29%, respectively).

Findings Are Practice-Changing Thomas Buchholz, MD, of The University of Texas M. D. Anderson Cancer Center, Houston, commented that the findings “add to the conclusive evidence that radiation eradication of local-regional microscopic disease reduces subsequent distant metastases and can improve survival.” He said that the benefits of adding regional irradiation “now clearly outweigh the risks.”

“I agree with the investigators’ conclusions,” Buchholz said. “We should offer RNI for higher-risk patients with 1 to 3 positive lymph nodes, but we should await additional data for lowrisk patients with 1 to 3 nodes.” ●

Patients Discovering BreastCancer Trials.org

By Caroline Helwick

SAN ANTONIO—A rapidly growing, nationwide clinical trial matching service that is user-friendly for patients is enabling more patients to learn about and enroll in clinical trials, said Ellie Cohen, PhD, the program’s director.

Cohen described the success of her program at the 33rd annual San Antonio Breast Cancer Symposium.

BreastCancerTrials.org is designed to empower patients and increase trial participation.

BreastCancerTrials.org is a web-based clinical trials matching service designed to empower patients and increase trial participation. Patients find trials looking for participants with their medical situation and connect with research sites. The site was launched in 2008 by the Carol Franc Buck Breast Care Center at the University of California San Francisco National Center of

www.TheOncologyNurse.com

Excellence in Women’s Health in collaboration with Quantum Leap Healthcare Collaborative.

“Thousands of patients have adopted BreastCancerTrials.org and they use it to monitor trial opportunities. Our portfolio of breast cancer trials is diverse and growing,” Cohen said. “The purpose is to help patients who might not hear about trials from their doctors.”

The total number of visitors to date is more than 35,000. Of patients who start a health history, 61% complete it and are matched to trials and, of this group, 41% find at least one trial interesting enough to view the site contact information.

Cohen does not have information as to how many patients actually enroll, and the numbers reflect only users who complete the application in one visit.

What the Site Offers The online forms are customized depending on whether the user is recently diagnosed, managing metastatic disease, or has completed treatment.

Women can choose whether to use the service anonymously or to save their health history by providing an e-mail address. They are matched with trials Continued on page 42

Nurse & Patient Navigator Association Best Practices A selection of member-submitted best practices for others to learn from and comment on.

Continuing Education Learn how to advance your understanding of the complexities of cancer care through our live, online, and printed educational activities.

Networking Opportunities Coordinated events throughout the year both in person and online to help you connect with members and leaders.

Community Resources A collection of resources to help you and your patients better navigate their cancer treatment.

Expert Opinion Blogs Thought-provoking articles from the leaders in navigation and survivorship on various subject areas.

Publications Subscriptions to the Journal of Oncology Navigation & Survivorship® and The Oncology Nurse®-APN/PA.

AONNKsize_81911

www.AONNonline.org OcTOber 2011 I VOL 4, NO 7

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The Patient’s Voice Since we first reported on the Ovarian Cancer National Alliance and its Survivors Teaching Students: Saving Women’s Lives initiative (September/October 2009), the San Diego chapter has expanded its program into nursing schools and further empowered a research patient advocate. Nationally, the program currently presents in 140 medical, nursing, and physician assistant schools and reaches more than 5000 students annually. In their own words, founder of the San Diego chapter, Peg Ford, and presenter Cindy Silver detail how and why the program flourished. For more information on the Ovarian Cancer National Alliance, visit www.ovariancancer.org.

From Patient to Research Patient Advocate

By Peg Ford

M

y life has changed drastically in many ways since being diagnosed with ovarian cancer in early 2007. Before my encounter with ovarian cancer, I had embraced alternative healing methods. This was to change, however, when a relationship with Western medicine was needed to save my life. In a short time, I discovered how fortunate I was to be referred quickly to a gynecologic oncologist. Although most women diagnosed with ovarian cancer are diagnosed at stage III or IV, my cancer was caught at stage I, before it had spread. After my surgeon removed a huge mass that completely filled my

abdomen, concern regarding recurrence led him to prescribe chemotherapy as a precautionary measure.

What awaited me in the “cure” was to put my body at greater risk. I did not tolerate chemotherapy well. In the early morning hours of day 5 of the first series of treatments my pulse rate suddenly dropped to 29 bpm. All chemo therapy was stopped. Then, the next morning my pulse rate dropped again, to 34 bpm. I spent an additional 4 days in the hospital for testing and monitoring. The findings indicated that the chemotherapy regimen, in particular cisplatin, could be the source of the problem, causing the slow heart action I experienced. Two years later, this severe adverse reaction had a name, platinum hypersensitivity reaction. For me, chemotherapy was discontinued.

Luckily, my tumor was a very rare type, a sex-cord stromal tumor, and removed at stage I, so changing to observation (or watchful waiting) was an option.

While doing research to understand the disease that engulfed me, I discov-

ered Survivors Teaching Students (STS): Saving Women’s Lives, an ovarian cancer education program for medical students that is sponsored by the Ovarian Cancer National Alliance

“Very valuable and emotional experience.

A good reminder of why we went into the medical field.”

—Third-Year Medical Student, University of California San Diego School of Medicine

(OCNA). OCNA is a survivor-led, national umbrella organization that unites cancer activists, women’s health advocates, healthcare providers, and researchers in the battle against ovarian cancer.

Knowing how fortunate I was to

Figure. Third-year medical students participate in a Survivors Teaching Students: Saving Women’s Lives session at University of California San Diego School of Medicine

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have the opportunity and realizing the important role advocates can play, I launched an STS chapter at the University of California San Diego (UCSD) School of Medicine in December of 2008. The goal was to address the issue of early detection and the urgent need for women to be referred to a gynecologic oncologist when ovarian cancer is first suspected.

STS San Diego brings ovarian cancer survivors into the classroom to share their stories.

In the 1-hour presentation, 3 women of diverse backgrounds illustrate the difficulty of early diagnosis and what happened to them as a result. They give ovarian cancer a human face and voice.

This August, we started our fourth school year, presenting once every 6week obstetrician (OB)/gynecologist (GYN) rotation for third-year medical students at UCSD. We also present to the OB/GYN and family medicine residency programs at UCSD. In May 2011, the program expanded, now including Azusa Pacific University School of Nursing. So far, we have presented to the medical-surgical class and the women’s health and maternity class.

Plans are under way to implement the program in the remaining 8 nursing schools in San Diego County.

I also saw the need to reach practicing physicians who have been out of medical school for 10 years or more.

This led to my collaboration with a well-known Southern California gynecologic oncologist, Afshin Bahador, MD, who presents CME Grand Rounds at major hospital campuses for Scripps Health and Sharp Healthcare. Bahador presents the clinical information, and our group presents the human side. This successful team effort has presented 6 Grand Rounds reaching 353 medical doctors and healthcare providers in the past 2 years.

In addition, I launched the Ovarian Cancer Advocacy Alliance of San Diego, an organization that participates on the local, state, national, and international level in research patient advocacy, incorporating the STS program as the flagship educational arm. ●

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save the date - April 20-22, 2012 Le Westin Montreal, Montreal, QC, Canada You are invited to join us at this multiday forum designed to inform, educate, and exchange clinically relevant ideas in the field of cutaneous malignancies.

CONFERENCE CHAIR Kim A. Margolin, MD Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, WA

SESSION CHAIRS Sanjiv Agarwala, MD Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Aleksandar Sekulic, MD, PhD

A Focus on Melanoma, Basal Cell Carcinoma, and Cutaneous T-Cell Lymphoma

Assistant Professor, Dermatology Integrated Cancer Genomics Division Mayo Clinic Scottsdale, AZ

Francine Foss, MD Professor of Medicine (Hematology) and Dermatology Yale Cancer Center New Haven, CT

About the World Cutaneous Malignancies Congress

Who should attend

The World Cutaneous Malignancies Congress is a 2-day forum dedicated to inform, educate, and exchange clinically relevant ideas in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, and cutaneous T-cell lymphoma including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Management of less common cutaneous malignancies • Future strategies in management based on translational data from current clinical trials and basic research

All healthcare professionals who are involved in the management of patients with cancer are invited to join this exciting forum.

Specifically, this conference is intended for: • Medical and Surgical Oncologists • Dermatologists • Radiation Oncologists involved in the treatment of patients with cutaneous malignancies.

• Fellows • Nurse Practitioners • Nurses • Physician Assistants • Clinical Oncology Pharmacists • Researchers • Other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to participate.

For more information and to register, please visit www.cutaneousmalignancies.com

TON_October 2011_v8_TON 10/18/11 12:59 PM Page 42

The Patient’s Voice

From Survivor to Teacher

By Cindy Silver

A

fter a long series of treatments for stage IV ovarian cancer, I finished my last chemotherapy session in March 2010. About 2 months later, I realized I missed the camaraderie and friendships I had developed during the hours of waiting for the chemotherapy to be administered. I looked for a support group and soon joined the Scripps GYN Support Group that meets twice monthly. By that point, I had started sharing the story of my journey with ovarian cancer, finding that others were helped when they heard it.

Like so many others, my journey started with a doctor completely ignoring my symptoms and ended with me being treated professionally by a gynecologic oncology team. In telling my story, I found myself becoming more passionate about sharing that part of my journey, because I didn’t want other women to go through what I went through, especially the part where my primary care doctor ignored and patronized my symptoms, even though I sensed something was very wrong.

“That was an excellent educational presentation. We are very thankful of your time and commitment to bring awareness of the existence of such a silent killer. It should not take a celebrity to make that stride. You all did it in such a very classy, heartwarming, and passionate fashion.”

—Lourdes Deperio, MSN, RN, Adjunct Nursing Instructor, Azusa Pacific University

At the support group, I realized that most women who shared their stories had encountered a similar journey. I just couldn’t imagine how to get that message where it would really matter.

In the support group, I learned about a group of survivors who talked to medical students about their experiences. I was fascinated immediately and excited about the idea, as medical students would be the future doctors who cared for women like me. One member of

Breast Cancer Patients Discovering... Continued from page 39 appropriate for their disease and can view research site information, including the closest research site and distance from the patient’s home.

The trial portfolio includes 450 trials, including 275 treatment trials, 84 psychosocial/supportive trials, 32 evaluating diagnosis/screening, 22 assessing preventive approaches, and 37 in other categories.

“Trials are for all patients,” Cohen stressed. “There is a big myth that they are only for patients who run out of options, but 40% of our trials are in the neoadjuvant and adjuvant setting.

Wherever you are on the cancer journey, there is an opportunity to participate in a clinical trial. We want patients to consider trials as a routine option for their breast cancer care.”

Users can share their BreastCancer Trials.org history with participating research sites through the Secure Connnect message service. This enables the first screening interview to be simplified as well as efficient, and the user can leave a personal message for the research site, such as, “I don’t have health insurance. Can I still enroll?”

The website now also has a weekly trial alert service that informs users when newly listed trials match their health his-

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tory. The service has more than 1600 subscribers, and 85% of users who have a BreastCancerTrials.org history sign up for these alerts, she said.

“The trial alert service has been responsible for a 68% increase in users,” according to Cohen. “It’s prompting users to log in and view newly posted trials.”

During the first year, there were 4587 returning users and this increased to 7736 in year 2 after the trial alert service was launched.

Who Is Using BreastCancerTrials.org?

By disease stage, 440 of 1814 users (who saved their history) were stage 0 to III and recently diagnosed; 746 had completed treatment for stage 0 to III disease; and 628 were living with metastatic disease.

Most current users are 50 to 69 years of age, with women aged 40 to 49 a close second. Most users have been white (non-Hispanic) women with some college education. Fewer than 10% have no more than a high school degree. “Our early adopters are educated and white, but we hope to change this through outreach to underserved populations,” Cohen said. ●

Survivors Teaching Students (STS): Saving Women’s Lives informed me that she not only shared her story with medical students but also spoke at CME Grand Rounds, where her story was shared with practicing medical doctors in major hospitals. I couldn’t wait to make contact to see if I could be a part of the group. I thought this might be the perfect situation to get my message to future doctors.

“I didn’t have very much background knowledge, which this presentation certainly provided.”

—Second-Year Nursing Student, Azusa Pacific University’s School of Nursing

In early September, I exchanged emails with the group’s leader, Peg Ford, expressing my interest in joining.

During a long phone conversation/ interview about what her group does, we shared personal things about our lives and our cancer journeys. Definitely wanting to be part of the program, I attended the next STS training session.

At Peg’s suggestion, I prepared by writing the story of how I was diagnosed and what happened next.

While awaiting the training session, I had an appointment with my gynecologic oncologist, at which I informed him that I had contacted STS and would be attending the training class. He was thrilled and gave me a big hug. He talked about doing Grand Rounds with Peg and the importance of the STS message.

In January 2011, a group of survivors met for our training session. There were 8 trainees, plus Peg and Naomi Whiteacre, a fellow presenter, who was preparing to become an onsite facilitator. Peg shared the story of STS, what the group stood

for, what it hoped to accomplish, and was accomplishing. It was very inspirational. She had us read our personal stories. I volunteered to be first, just to get it over with. When I finished she gave me some great feedback. In a wonderful supportive way, she told me how to reduce the story so it would fit into a 5minute timeframe.

After tightening my story, I was thrilled to be chosen to present it at the next STS session at the University of California San Diego. I felt somewhat desperate about wanting the main point of my story to be heard and understood.

I wanted these medical students to be so moved that they literally would remember the gist of my story as they became practicing doctors. I hoped they would be inspired to really listen to their patients and understand that they know when something is wrong. As the time approached for our presentations, I felt a little calmer. I thought to myself, “look what you’ve overcome the last few years, this will be a piece of cake.” I was very grateful to be able to read my story though, and not have to memorize it. I thought I managed to get through it pretty well. I got emotional near the end, but didn’t lose control. When I finished, I looked over at Peg. I think she gave me a thumbs up, and I relaxed. It was over.

I was surprised that after our presentations there didn’t seem to be questions from the students. But then after they turned in their questionnaires and some left, others made a real point to come back and thank us for sharing with them. A couple actually came up to me with tears in their eyes (one young lady was really crying) telling me how touched they were by my story. We talked more in depth with a couple of the students about our experiences. In reading the comments about our presentations, I realized that many were moved, indicating that what they saw and heard would make a difference in the way they would one day treat their patients. This is exactly what I hoped this experience would be like. My message was heard. It had to have been one of the most rewarding days of my life.

Meanwhile, over the past few months, our group of STS presenters lost 2 members. Their ovarian cancer recurred, and they lost their courageous battles. Two wonderful women whose courage took my breath away. Although it’s been devastating and heartbreaking losing these wonderful women, it has made us realize even more how important a program like STS can make a difference to save more women’s lives. ●

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Overall Survival Advantage Sustained at 3-Year Median Follow-up In Previously Untreated Multiple Myeloma (MM) VISTTA* OVERALL VISTA* OVER RALL SURVIV SURVIVAL VAL AL (OS) ANAL ANALYSIS: LY YSIS: VcMP† vs MP (36.7-month median follow-up)

MEDIAN OS NOT REACHED FOR VcMP

100 90

% PPatients atients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP ■ VE LCADE+MP (n=344) ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); PP=0.00084 =0.00084 =

0 0

3

6

9

12

15

18

21

24

Months Kaplan-Meier Kaplan-Meier estimate. estimate.

▼ ▼

▼

27

30

33

36

39

42

45

48

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Conference News The following articles are based on presentations at the Fourth American Association for Cancer Research Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved held September 18-21, 2011, in Washington, DC.

Secondary Breast Cancer Rates Higher in African-American Women

By John Schieszer

WASHINGTON, DC—The overall incidence of breast cancer is generally higher among white women than black women. The incidence of a second breast cancer in the opposite breast,

however, is higher among black women, according to new data.

Researchers have found that, when cancer is diagnosed in women aged younger than 45 years, the incidence of

primary breast cancer is higher among blacks than among whites. And “when the disease does occur in blacks early on, it tends to be more aggressive, more likely to be estrogen-receptor negative, and

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

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Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at www.VELCADE.com

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. V-11-0041 All rights reserved.

Printed in USA

04/11

it is more likely to cause death,” said lead researcher Nsouli-Maktabi Hala, who is a PhD graduate of George Washington University, Washington, DC. She and her colleagues found that when cancer is diagnosed at an older age, the incidence is higher among white women. Because most breast cancers are diagnosed in older women, the overall incidence is higher in whites.

“While the incidence of breast cancer is generally higher among whites for first-time diagnosis, we found the incidence of the second contralateral diagnosis was higher among blacks,” said Hala. “This was unexpected.

Blacks usually have a higher mortality rate than whites from the first cancer, so you would expect blacks to have lower rates of second cancers.” She said usually about 4% of all breast cancer patients will present with a second primary cancer contralaterally.

The researchers used Surveillance, Epidemiology, and End Results Registry 9 data to evaluate breast cancer incidence among 415,664 white women and 39,887 black women diagnosed with primary breast cancer aged 19 years or older and possible development of a second cancer in the opposite breast. Results showed that 22,290 (40.7%) developed a second primary breast cancer, of which 18,142 (4%) occurred in the opposite breast. Incidence of second primary cancers of the opposite breast was higher among black women, and 15,101 (83.2%) of second contralateral cancers developed in those who were diagnosed with first breast cancer at age 45 or older.

The researchers also found that the average age of the second primary contralateral cancer diagnosis tended to be lower in blacks (59 years of age) than in whites (67 years of age). Contralateral breast cancer tended to occur within the first 2 years of the primary breast cancer diagnosis. “This should alert the physician to watch patients very carefully,” Hala said.

Study coinvestigator Donald Henson, MD, who is with George Washington Cancer Institute, said these findings should be of particular interest to oncology nurses. “African-American women need to be more closely followed and longer than what we usually do. So they need to be followed past 6 years,” said Henson. “I think these data are something that you need to know as an oncology nurse and counsel your patients about. It is important to know some statistics about this so the nurses can better counsel their patients.” ●

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 12:59 PM Page 45

Conference News

Stress Linked to Breast Cancer Aggressiveness Association More Pronounced in Blacks and Hispanics WASHINGTON, DC—Psychosocial stress may play a role in the etiology of breast cancer aggressiveness, particularly among minority populations, according to study results. In a cross-sectional study, greater levels of fear, anxiety, or isolation were found to be associated with more aggressive breast cancer; however, no clear driver for the association is yet identified.

“We found that after diagnosis, black and Hispanic breast cancer patients reported higher levels of stress than whites, and that stress was associated with tumor aggressiveness,” said study investigator Garth Rauscher, PhD, associate professor of epidemiology in the division of epidemiology and biostatistics at the School of Public Health, University of Illinois at Chicago.

Rauscher and his colleagues studied patient-reported perceptions of fear, anxiety, and isolation, together referred to as psychosocial stress, and associations with breast cancer aggressiveness.

The patients’ stress levels were examined 2 to 3 months after diagnosis. The study included 989 breast cancer patients who were recently diagnosed (411 were non-Hispanic black, 397 were non-Hispanic white, and 181 were Hispanic).

Results showed that psychosocial stress scores were higher for both black and Hispanic patients compared with white patients. “Those who reported higher levels of stress tended to have more aggressive tumors. However, what we don’t know is if we had asked them the same question a year or 5 years before diagnosis, would we have seen the same association between stress and breast cancer aggressiveness?” said Rauscher. “It’s not clear what’s driving this association. It may be that the level of stress in these patients’ lives influenced tumor aggressiveness. It may be that being diagnosed with a more aggressive tumor, with a more worrisome diagnosis and more stressful treatments, influenced reports of stress. It may be that both of these are playing a role in the association. We don’t know the answer to that question.”

Patient-reported psychosocial stress was one-third of a standard deviation higher for patients with receptor-negative versus -positive disease, and higher for patients with high- versus low- or intermediate-grade disease (difference = 0.17). Compared with whites, psychosocial stress scores were higher for black patients (difference = 0.22), and higher for Hispanic patients (difference = 0.44).

“There are reasons that the breast may be more vulnerable to effects of

www.TheOncologyNurse.com

stress. Stress increases certain hormone levels in the body and hormones affect breast cancer risk,” Rauscher said in an interview with The Oncology Nurse-

APN/PA. “Stress may be an important prognostic factor, but it is not clear what the process is. We need to figure out what we need to do to intervene. There

What’s Hot in

SEPTEMBER 2011

are all kinds of reasons to help people lower their stress, and this study suggests there may be a benefit in terms of breast cancer.” ● —JS

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© 2011 Green Hill Healthcare Communications, LLC

Current Issue • Seasons of Survival: Redefining the Paradigm for Cancer

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TON_October 2011_v8_TON 10/18/11 2:02 PM Page 46

Noteworthy

Loretta C. Ford Inducted into the National Women’s Hall of Fame

T

he National Women’s Hall of Fame recently inducted Loretta C. Ford, RN, EdD, PNP, FAAN, FAANP, along with 10 other American women who have made valuable and enduring contributions to our nation.

These women were formally inducted on September 30 and October 1, 2011, in Seneca Falls, New York, the birthplace of the American Women’s Rights Movement.

The National Women’s Hall of Fame is the nation’s oldest membership organization recognizing the achievements of great American women.

Inductees are selected every 2 years based on their lasting contributions to society through the arts, athletics, business, education, government, humani-

ties, philanthropy, and science. From a group of over 200 completed nominations, a national panel of judges conducted a rigorous scoring process and selected 11 women for induction.

The National Women’s Hall of Fame 2011 inductees are: Loretta C. Ford (1920-). An internationally renowned nursing leader, Dr Loretta C. Ford has devoted her career to practice, education, research, consultation, and the delivery of health services. Ford is best known for cofounding the nurse practitioner model through her studies on the nurse’s expanded scope of practice in public health nursing. In 1972, Ford became the founding dean of the University of Rochester School of Nursing, where she imple-

mented the unification model. Ford is the author of more than 100 publications and has served as a consultant and lecturer to multiple organizations and universities.

St. Katharine Drexel (1858-1955).

A missionary who dedicated her life and fortune to aid Native Americans and African Americans, St. Katharine Drexel is only the second recognized American-born saint.

Dorothy Harrison Eustis (18861946). A philanthropist, Dorothy Harrison Eustis combined her love of animals and her passion for helping others to cofound the nation’s first dog guide school, The Seeing Eye. Abby Kelley Foster (1811-1887). A major figure in the national antislavery

and women’s rights movements, Abby Kelley Foster is remembered for her roles as a lecturer, fundraiser, recruiter, and organizer. In 1850, Foster helped develop plans for the National Women’s Rights Convention in Massachusetts, and later, in 1868, she was among the organizers of the founding convention of the New England Woman Suffrage Association.

Helen Murray Free (1923-). A pioneering chemist, Helen Murray Free, BA, MA, conducted research that revolutionized diagnostic testing in the laboratory and at home. Free is the codeveloper of Clinistix, the first dip-and- read diagnostic test strips for monitoring glucose in urine. Along Continued on page 52

St. Katharine Drexel

Dorothy Harrison Eustis

Abby Kelley Foster

Helen Murray Free

Loretta C. Ford

46

OctOber 2011 I VOL 4, NO 7

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TON_October 2011_v8_TON 10/18/11 11:07 AM Page 47

Now Approved

Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 These indications are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A new therapeutic alternative for relapsed patients

73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for neuropathy and institute dose modifications accordingly.1

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be discontinued immediately and appropriate medical management instituted.1

Please see Brief Summary of full Prescribing Information on the last page of this ad.

Please see full Prescribing Information at ADCETRIS.com.

003153 sgn35 na oncnu fa3 indd 1

10/7/11 11:28 AM

TON_October 2011_v8_TON 10/18/11 12:59 PM Page 48

ADCETRIS is the first approved CD30-directed antibody-drug conjugate (ADC)

Antibody The antibody, brentuximab, specific for CD301

Cytotoxic agent

Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1

The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1

CD30 is prevalent in both HL and sALCL2 • ADCETRIS is an ADC designed to target cells expressing CD301 • Binding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1

Neutropenia Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials:

Monitor complete blood counts prior to each dose of ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1

• 102 patients with HL who relapsed after ASCT1

Tumor lysis syndrome

• 58 patients with relapsed sALCL1 ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1 Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1

Stevens-Johnson syndrome Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.1

Progressive multifocal leukoencephalopathy (PML) A fatal case of PML has been reported in a patient who received four chemotherapy regimens prior to receiving ADCETRIS.1

Please see Brief Summary of full Prescribing Information on the last page of this ad.

Please see full Prescribing Information at ADCETRIS.com.

TON_October 2011_v8_TON 10/18/11 3:06 PM Page 49

ADCETRIS induced complete and partial remissions in clinical trials1 Efficacy and safety in relapsed patients1 Relapsed HL

Relapsed sALCL

(N = 102)

(N = 58)

Median treatment duration: 27 weeks

Median treatment duration: 24 weeks

Duration of response in months

Response, % (95% CI)

Median (95% CI)

Range

Response, % (95% CI)

32

20.5

1.4-21.9+

(23-42)

(12.0-NE*)

Complete remission (CR) Partial remission (PR)

40

3.5

(32-49)

(2.2-4.1)

Objective response rate (ORR)

1.3-18.7

73

6.7

(65-83)

(4.0-14.8)

1.3-21.9+

Duration of response in months Median (95% CI)

Range

57

13.2

0.7-15.9+

(44-70)

(10.8-NE*)

29

2.1

(18-41)

(1.3-5.7)

86

12.6

(77-95)

(5.7-NE*)

0.1-15.8+ 0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.

• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4

Adverse reactions occurring in ≥20% of patients regardless of causality1

Adverse Reaction

Neutropenia Peripheral sensory neuropathy Fatigue Nausea Anemia Upper respiratory tract infection Diarrhea Pyrexia Rash Thrombocytopenia Cough Vomiting

HL (N = 102)

sALCL (N = 58)

% of patients

% of patients

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

54 52 49 42 33 47 36 29 27 28 25 22

15 8 3 8 1 2 7 -

6 2 2 -

55 53 41 38 52 12 29 38 31 16 17 17

12 10 2 2 2 3 2 5 3

9 2 5 -

• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

TON_October 2011_v8_TON 10/18/11 11:07 AM Page 50

Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1 Recommended ende dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes nu es every 3 weeks1 • P Patients ent who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete C blood counts should be monitored prior to each dose of ADCETRIS1

Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 - 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 - 3% discontinued due to peripheral motor neuropathy1

Monitor patients for PN and institute dose modification accordingly1 New or worsening Grade 2 or 3

• Hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg

Grade 4

• Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors

• Hold dose until resolution to baseline or Grade 2 or lower • Consider growth factor support for subsequent cycles • Discontinue or reduce dose to 1.2 mg/kg

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

Please see full Prescribing Information at ADCETRIS.com.

REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2011. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood.

1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.

4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504.

855.4SEAGEN (855.473.2436) SeaGenSecure.com

TON_October 2011_v8_TON 10/18/11 12:58 PM Page 51

Pharmacoeconomics

Value of Targeted Therapies in Patients Lacking a Molecular Target Questioned See also pages 21 & 54.

By Caroline Helwick

CHICAGO—Targeted drugs are very effective in patients with a well-specified molecular target. Examples include imatinib in patients with chronic myelogenous leukemia and trastuzumab in HER2-positive breast cancer.

Evidence, however, has shown only

modest improvements in outcomes when targeted agents are given to “unselected patients,” that is, those lacking a tumor characteristic (or mutation) that is specifically addressed by a given drug.

“Little data exist regarding the true impact of targeted therapy in routine

clinical practice,” said Janakiraman Subramanian, MD, of Washington University School of Medicine, St. Louis, Missouri, at the annual meeting of the American Society of Clinical Oncology.

“Intolerable side effects are infre-

Drug interactions (see Package Insert for full Prescribing Information)

In vitroo data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Indications and usage

Effect of other drugs on ADCETRIS

These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS.

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications: None.

Warnings and precautions Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions.

Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Effect of ADCETRIS on other drugs Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specifi fic populations Pregnancy Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

The safety and effectiveness of ADCETRIS have not been established in the pediatric population.

Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Stevens-Johnson syndrome

Geriatric use

Tumor lysis syndrome

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Progressive multifocal leukoencephalopathy

Renal impairment

A fatal case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient who received 4 chemotherapy regimens prior to receiving ADCETRIS.

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Use in pregnancy

Hepatic impairment

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Adverse reactions

General dosing information

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritis, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

www.TheOncologyNurse.com

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Dose modification Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BV/2011/0029

quent with targeted drugs, and discontinuation is primarily due to progressive disease,” he noted. “Identifying the proportion of patients who are ‘minimum users,’ defined as those who failed to refill their prescription more than once, would be one way of assessing treatment efficacy in routine practice.”

“Targeted therapy for cancer in unselected patients leads to very high rates of early discontinuation.”

—Janakiraman Subramanian, MD

Subramanian and his colleagues used studied claims in the Express Scripts pharmacy claims database from 2007 to 2009 for imatinib, lapatinib, erlotinib, sorafenib, sunitinib, and everolimus.

Each patient’s age, sex, and duration of prescription were identified; the database does not include information on diagnosis and outcomes.

Prescription claims for 14,300 patients were examined; most prescriptions were for erlotinib (43%), followed by imatinib (28%).

A surprising proportion of patients did not refill their prescription after 60 days, including approximately 10% for imatinib, 21% for lapatinib, 31% for erlotinib, 38% for sorafenib, 44% for sunitinib, and 56% for everolimus.

The proportion of prescription claims that were not filled past 60 days significantly differed between drugs prescribed to biomarker-selected patients (ie, imatinib and lapatinib) and drugs prescribed for nontargeted (unselected) patients (ie, erlotinib, sunitinib, sorafenib, and everolimus).

Among the biomarker-selected patients, only 12% failed to refill prescriptions compared with 34% of the unselected patients (P <.001). “Targeted therapy for cancer in unselected patients leads to very high rates of early discontinuation,” Subramanian observed.

In light of the frequent treatment discontinuation among unselected patients, the cost of the initial prescriptions (claims ≤60 days) may appear unjustifiably high in these drugs, resulting in the following rates: $2,695,945 for imatinib; $1,534,059 for lapatinib; $12,878,656 for erlotinib; $4,937,772 for sorafenib; $9,280,050 for sunitinib; and $218,916 for everolimus. ●

OcTOber 2011 I VOL 4, NO 7

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Noteworthy Loretta C. Ford Inducted... Continued from page 46 with her husband, Alfred Free, she also developed additional strips for testing levels of key indicators for other diseases.

Today, dip-and-read strips make testing for diabetes, pregnancy, and other conditions available in underdeveloped regions of the United States and in foreign countries. Free is the recipient of numerous awards, including the National Medal of Technology and Innovation and the American Chemical Society’s 66th National Historic Chemical Landmark designation (2010).

Billie Holiday (1915-1959). Considered by many to be one of the greatest jazz vocalists of all time, Billie Holiday forever changed the genres of jazz and pop with her unique style.

Coretta Scott King (1927-2006).

One of the most celebrated champions of human and civil rights, Coretta Scott King, BA in partnership with her husband, Dr Martin Luther King, Jr, ignit-

52

ed democracy movements worldwide.

Lilly Ledbetter (1938-). For over a decade, Lilly Ledbetter has fought to achieve equal pay for men and women; her efforts proved successful when President Obama signed the Lilly Ledbetter Fair Pay Act into law in 2009.

In 1972, Ford became the founding dean of the University of Rochester School of Nursing, where she implemented the unification model.

Barbara Mikulski (1936-). The first female Democratic United States senator elected in her own right, Barbara Mikulski, BA, MSW, has been a political trailblazer for more than 30 years.

Donna Shalala (1941-). A groundbreaking educator and politician, Donna Shalala, PhD, has more than 25 years of experience as an accomplished scholar, teacher, and administrator.

Shalala is recognized as the longest serving United States Secretary of Health and Human Services (1993-2001) and is the current president of the University of Miami.

Kathrine Switzer (1947-). As the first woman to officially enter the Boston Marathon (1967), Kathrine Switzer broke the gender barrier and paved the way for women in running.

“From an early suffragist to a civil rights pioneer; from a university president to trailblazers in health and science; each of these women have demonstrated fortitude, perseverance, intelligence, and hope. Their experiences provide both an example for each of us to emulate and a challenge for each of us to embrace.

What began in Seneca Falls came full circle this October, when this phenomenal group of inductees convened in the birthplace of women’s rights,” said Christine Moulton, Executive Director of the National Women’s Hall of Fame.

The National Women’s Hall of Fame, founded in 1969, has inducted 236 women since its inception. This year’s inductees join a notable group that includes Susan B. Anthony, Dorothy Height, Maya Lin, Sandra Day O’Connor, and Rosa Parks.

“We congratulate this year’s inductees and are excited to welcome them to Seneca Falls,” said Beverly P. Ryder, the Hall’s President, from Los Angeles.

The National Women’s Hall of Fame recently launched its new website, www.greatwomen.org. The site allows visitors to read about this year’s inductees, view a complete list of all Hall inductees, and make plans to visit. ●

Billie Holiday

Coretta Scott King

Lilly Ledbetter

Barbara Mikulski

Donna Shalala

Kathrine Switzer

OctOber 2011 I VOL 4, NO 7

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:08 AM Page 53

Lung Cancer Diagnosis? We are here to help.

Question.

Prepare.

Learn.

Hope.

Being diagnosed with lung cancer can be overwhelming. Who to turn to for answers? For information about the KPZLHZL& ;V Ã&#x201E;N\YL V\[ ^OH[ [V KV UL_[& ;V RUV^ [OLYL PZ hope?

3\UN *HUJLY (SSPHUJL PZ OLYL [V OLSW >P[O V]LY `LHYZ VM L_WLYPLUJL Z\WWVY[PUN WH[PLU[Z JHYLNP]LYZ Z\Y]P]VYZ OLHS[O HUK WZ`JOVZVJPHS WYVMLZZPVUHSZ HUK HU`VUL JVUJLYULK HIV\[ S\UN JHUJLY [OLYL PZ UV VUL IL[[LY [V provide answers ;OYV\NO V\Y 0UMVYTH[PVU 3PUL ^L WYV]PKL \W [V KH[L PUMVYTH[PVU HUK YLZV\YJLZ ;OYV\NO V\Y Phone Buddy Program and online support JVTT\UP[` ¶ 3\UN3V]L3PUR ¶ ^L JVUULJ[ WLVWSL ^OV OH]L ILLU [V\JOLK I` S\UN JHUJLY ;OYV\NO V\Y TH[LYPHSZ HUK ^LIZP[L ^L WYV]PKL ^OH[ WH[PLU[Z ULLK [V RUV^ HIV\[ [OL diagnosis and can connect them with clinical trials.

Call us at 1-800-298-2436 LTHPS support@lungcanceralliance.org VY ]PZP[ www.lungcanceralliance.org [V Ã&#x201E;UK V\[ OV^ ^L JHU OLSW `V\ 3*( PZ H J UVU WYVÃ&#x201E;[ IHZLK PU >HZOPUN[VU +* ^OVZL TPZZPVU PZ [V YL]LYZL KLJHKLZ VM Z[PNTH HUK ULNSLJ[ I` LTWV^LYPUN [OVZL ^P[O VY H[ YPZR MVY [OL KPZLHZL LSL]H[PUN H^HYLULZZ HUK JOHUNPUN OLHS[O WVSPJ`

TON_October 2011_v8_TON 10/18/11 1:04 PM Page 54

Pharmacoeconomics

HBV Screening Before Lymphoma Treatment Improves Outcomes, Is Cost-Effective See also pages 21 & 51.

By Wayne Kuznar

CHICAGO—Screening all patients for hepatitis B surface antigen (HBsAg) before initiating chemotherapy for lymphoma is associated with improved clinical outcomes and is economically favorable, according to an analysis presented

by researchers at the University of Toronto and St Michael’s Hospital, Toronto, Ontario, at the annual meeting of the American Society of Clinical Oncology.

Reactivation of the hepatitis B virus

(HBV) during chemotherapy may lead to disruption of chemotherapy, hospitalization for HBV infection, and even death. Screening for HBV is often recommended but is not always performed, although effective prophylactic therapy

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: • Newly Diagnosed Patients • Maintenance Therapy • Transplant-Eligible Patients • Retreatment • Transplant-Ineligible Patients • Cytogenetics • Side-Effect Management • Bone Health

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

Topics include: • Hodgkin Lymphoma • Follicular Lymphoma • Mantle Cell Lymphoma • Waldenstrom’s Macroglobulinemia • Diffuse Large B-Cell Lymphoma • T-Cell Lymphoma

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 Credit™ (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.

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OctOber 2011 I VOL 4, NO 7

in the form of lamivudine is available.

Whether screening justifies the additional cost has not been investigated.

The researchers developed a decisionanalytic model for patients with lymphoma undergoing chemotherapy with R-CHOP (rituximab, cyclophospha mide, hydroxydaunorubicin, vincristine, prednisone). Three HBV screening strategies were evaluated: screen all patients, screen only those at high risk, and screen nobody. Patients who tested positive for HBsAg received lamivudine until 6 months after the completion of chemotherapy. Unscreened patients received lamivudine only if they developed HBV-related hepatitis.

Screening all patients resulted in a net savings of $62 per patient versus not screening and of $8 per patient versus screening only high-risk patients.

The risks of HBV-related hepatitis recovery, HBV-related death, and lymphoma outcomes were derived from a systematic literature review.

The following cost estimates (in Canadian dollars) were used in the model: HBV DNA test, $133; HBsAg test, $13; lamivudine, $180 per month; R-CHOP, $35,704 per cycle; end-of-life care, $46,465 hepatitis-related and $42,632 lymphoma-related.

Screening all patients was the dominant strategy. It was both the least costly and the most effective in increasing the 1-year survival rate. One-year survival was 85.0% with the screen-all strategy versus 84.96% with the highrisk patient–only strategy and 84.86% with the screen-nobody strategy. The number of HBV-related hepatitis hospitalizations per 1000 patients was 0.1 with the screen-all strategy, 0.9 with the high-risk patient–only strategy, and 3.0 with the screen-nobody strategy.

Screening all patients resulted in a net savings of $62 per patient versus not screening and of $8 per patient versus screening only high-risk patients, presuming that all high-risk patients were correctly identified.

A second analysis presented at the meeting by researchers from the University of Texas M. D. Anderson Cancer Center showed that HBV screening before chemotherapy for nonhematologic tumors is not cost-effective. ●

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:08 AM Page 55

BUILDING

pillars of knowledge

IN SUPPORTIVE CARE NEUTROPENIA

LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace06 Release Date: August 8, 2011 Expiration Date: August 7, 2012

TARGET AUDIENCE The educational series is intended for nurses, pharmacists, and others with clinical, research, and management interests of neutropenia management

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: â&#x20AC;˘ Outline the risk factors for neutropenia in patients with cancer undergoing chemotherapy â&#x20AC;˘ Review advances in the prevention and management of neutropenia, including updated evidence-based guidelines â&#x20AC;˘ Examine approaches for improving patient outcomes by identifying patients at risk and preventing or reducing the incidence of neutropenia

ACCREDITATION STATEMENTS Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This knowledge-based activity has been assigned ACPE # 0245-000011-017-H01-P and will award 1.0 contact hour (0.10 CEUs) of continuing pharmacy education credit. CEC complies with the Criteria for Quality for continuing education programming.

NURSING Creative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centerâ&#x20AC;&#x2122;s Commission on Accreditation.

FACULTY LeAnne Kennedy, PharmD, BCOP Pharmacy Clinical Coordinator Hematology and Oncology Wake Forest Baptist Health Winston-Salem, NC

Kathleen Colson, RN, BSN, BS Clinical Research Nurse Multiple Myeloma Dana Farber Cancer Institute Boston, MA

Regina Cunningham, PhD, RN, AOCN Senior Director, Oncology The Tisch Cancer Institute Mount Sinai Medical Center New York, NY

For further information and to participate, please go to: www.coexm.com/ace06

CEC provides this activity for 1.0 contact hour.

Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.

This activity is supported by an educational grant from Amgen Inc.

Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form. # (

TON_October 2011_v8_TON 10/18/11 12:58 PM Page 56

Answered!

Your FAQs...

Q:

A:

I am reading so much about vitamin D and cancer. How much daily vitamin D should we recommend to patients?

Although there is no straightforward answer to this question, the 6 or 12 months to make certain they have not become deficient. current recommended daily allowances for adults—600 IU for Vitamin D3 is an over-the-counter product available in several dosages (ie, 500 IU, 1000 IU, 2000 IU), whereas D2 is a prescription agent. D3 is more potent children and adults, and 800 IU for those older than 70 years— than D2, but adherence to a planned dosing schedule is probare probably too low.1,2 To provide a little background, vitamin D should be considably most important. Daily doses of 1000 to 2000 IU (or You will need to ered a prohormone rather than a vitamin (a greater) are considered safe, and deficient patients might need substance humans need in small amounts and usually canhigher doses. Maximum daily doses should not exceed 10,000 incorporate not synthesize).3 Animals convert 7-hydrocholesterol to IU, as higher doses taken for several months may lead to vitacalciferol (D3) in the dermis via a photochemical reaction knowledge regarding min D toxicity in some people.9 So, how much vitamin D should we tell our patients to with ultraviolet B (UVB) sunlight. Similarly, plants conthe multiple take? It depends on clinical judgment. You will need to incorvert sterols to ergocalciferol (D2). Humans convert both D3 physiologic roles of porate knowledge regarding the multiple physiologic roles of and D2 to calcidiol by hepatic hydroxylation.4 Serum calvitamin D, the cidiol is a relatively stable, measurable intermediate vitamin D, the potential negative effects of deficiency in canmetabolite. In the kidneys and other tissues, calcidiol is furpotential negative cer occurrence and mortality, each patient’s calcidiol level, ther hydroxylated to calcitriol, the active metabolite of and the “optimal” level for that patient. ● vitamin D. Calcitriol is short-lived and is synthesized as nec- effects of deficiency essary to bind with vitamin D receptors (VDRs) in the nucle- in cancer occurrence References 1. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for us of most cells. VDR binding ultimately affects many critical Calcium Vitamin D. Washington, DC: The National Academies Press; 2010. and mortality, each cell and tissue functions. For instance, calcitriol influences cell 2. Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much is necessary? Best Pract Res Clin Rheumatol. 2009;23:789-795. patient’s calcidiol supplementation division, differentiation, and apoptosis—functions that are 3. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66(10 important in cancer occurrence, invasion, and metastasis. suppl 2):S73-S87. level, and the 4. Wang S. Epidemiology of vitamin D in health and disease. Nut Res Rev. 2009; Calcitriol also facilitates absorption of dietary calcium in the “optimal” level for 22:188-203. gut and influences synthesis and secretion of insulin and 5. Bordelon P, Ghetu MV, Langan R. Recognition and management of vitamin D parathyroid hormone, calcium regulation, immune function, deficiency. Am Fam Physician. 2009;80:841-846. that patient.

6. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: how and when bone homeostasis, and other important functions.3,4 to treat. Mayo Clin Proc. 2010;85:752-758.

UVB sunlight is the major source of vitamin D, and most 7. Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Endocrinol Metab Clin North Am. 2010;39:401-418.

American diets provide only 150 to 200 IU per day. However, avoidance of sun 8. Wang-Gillam A, Miles DA, Hutchins LF. Evaluation of vitamin D deficiency in breast cancer patients on exposure, living in latitudes north of 37 degrees (an imaginary line extending bisphosphonates. Oncologist. 2008;13:821-827. from Santa Rosa, California, to Cape Hatteras, North Carolina), increasing age, 9. Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern Med Rev. 2008;13:6-20.

10. Garland CF, Grant WB, Mohr SB, et al. What is the dose-response relationship between vitamin D and darker skin color, obesity, and other factors decrease D3 formation.5 At least 50% cancer risk? Nutr Rev. 2007;65(8 pt 2):S91-S95. of Americans are vitamin D–insufficient or –deficient, which has been associated with some cancers (ie, colon, prostate, ovary, pancreas, lymphomas, and others), as well as decreased cancer survival.6,7 Deficiency also may exacerbate treatment-related bone loss and the risk for osteoporosis, and increase the likelihood of bisphosphonate-related hypocalcemia and renal dysfunction.8 Drawing a serum calcidiol level is the only way to assess nutritional vitamin D status. A level of 32 to 100 ng/mL is considered normal, whereas 15 to 31 ng/mL is considered insufficiency, and <15 ng/mL deficiency. Optimal levels to prevent particular diseases, however, are not known but may be 40 to 70 ng/mL—levels in people living close to the equator or working as lifeguards.9 Northern Michigan University It would be prudent to check the serum calcidiol level in all cancer patients (and perhaps all Americans) once a year. There are no guideline recommendaIndependent Oncology & Palliative tions regarding the optimal calcidiol level for cancer patients, so clinicians need Care Consultant to individualize patient management. Garland and colleagues suggest that maintaining a calcidiol level of ≥34 ng/mL would decrease the risk for colon cancer Marquette, Michigan by 50%, but a consistent level of ≥52 ng/mL would be necessary to decrease the risk for breast cancer by 50%.10 The calcidiol level should be rechecked every 1 Do you have a question you’d like answered? to 2 months after starting supplemental vitamin D to assess response. The level may plateau and the dose may need to be titrated up (or down) to maintain the E-mail us at editorial@greenhillhc.com target level. In addition, patients with a normal level should be evaluated every

This Month’s FAQ

Answered by:

Rita Wickham, PhD, RN, AOCN

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OctOber 2011 I VOL 4, NO 7

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:08 AM Page 57

Pushing Your Limits

Scan Here to Register.

Current activities at www.COEXM.com include:

To use 2D barcodes, download the ScanLife app: â&#x20AC;˘ Text â&#x20AC;&#x153;scanâ&#x20AC;? to 43588 â&#x20AC;˘ Go to www.getscanlife.com on your smartphoneâ&#x20AC;&#x2122;s web browser, and select â&#x20AC;&#x153;Downloadâ&#x20AC;? â&#x20AC;˘ Visit the app store for your smartphone

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Nutri ion

Karen

with

Pumpkin Power

By Karen Connelly, RD, CSO

©iStockphoto.com/Skip ODonnell

he cool, crisp air and the vibrant sea of red, vent oxidative damage from occurring and, therefore, orange, and yellow that decorate our landscapes protect cells and/or repair those that have been damare the inviting signs that fall has arrived. aged. Foods high in beta carotene and other carotenoids Among the most common symbols of fall is the pump- act as functional foods in their ability to offer protection kin. At this time of year, this winter squash is usually against heart disease, cancer, and age-related illnesses.2 adorned with a spooky face and potato ears—however, The ideal way to consume these antioxidant-rich the jack-o-lantern is not the pumpkin’s only claim to carotenoids is through diet. High-dose supplemental fame. Pumpkins are nutrient packed and provide forms of beta carotene or vitamin A can be toxic and numerous health benefits. Therefore, it is time to move increase the risk of lung cancer.

Winter squash has a combination of antioxidant and this jack-o-lantern from the porch to the kitchen.

Pumpkins are a nutrient powerhouse. They contain a antiinflammatory properties. Many research studies conducted on the functional variety of vitamins, including aspects of winter squash have been the antioxidant vitamins A, C, A study examined done on a cellular level, but the and E, B vitamins, and minerals the impact of a outcomes are exciting and promissuch as calcium, potassium, ing. Pumpkin belongs to the magnesium, and phosphorus.1 cucurbitacin comThe high potassium content is Cucurbita genus, and foods in this pound, the glycoside beneficial in maintaining heart genus contain compounds called health and stable blood prescucurbitacins. Cucurbitacins are molecule found in sure. In contrast, there may be glycoside molecules that are effecpumpkin and other a need to limit the intake of tive as antiviral, antibacterial, and pumpkin, because of its abuntypes of winter squash, antiinflammatory substances.3 An interesting study measured the dant potassium content (eg, in on the effectiveness of antioxidative activity of specific cases of end-stage renal disease components of pumpkins.4 The or hyperkalemia). It is always chemotherapy in researchers found that the cell important to review current pancreatic cancer. wall polysaccharides, the main medications and their possible source of fiber in pumpkins, have dietary interactions to avoid any adverse outcome. Pumpkins are also a fiber-rich powerful antioxidant properties. They also found that, food. Fiber is important in maintaining healthy choles- as the pumpkin ripens, the sugar content also changes, terol levels, glycemic control, weight management, and which may impact the degree of antioxidant activity. in the prevention of cancer, especially of the colon and This study suggests that plant foods may contain many rectum. Incorporating pumpkin into the diet is an components that provide significant health benefits excellent way to obtain a variety of nutrients from just that have yet to be discovered.

A study examined the impact of a cucurbitacin one modest vegetable.

The pumpkin’s deep orange color comes from its high compound, the glycoside molecule found in pumpkin carotenoid content. Carotenoids, or plant pigments, are and other types of winter squash, on the effectiveness found in orange, yellow, red, and many dark green leafy of chemotherapy in pancreatic cancer.5 The revegetables. These carotenoids found in plant foods are searchers found that, based on in vivo and in vitro converted by the body into vitamin A. Pumpkins con- results, combined therapy with the cucurbitacin comtain a variety of carotenoids, such as beta carotene, pound and the chemotherapy agent gemcitabine lutein, zeaxanthin, and retinol. Beta carotene and these resulted in the inhibition of tumor growth. Pumpkins other carotenoids also act as antioxidants in the body. and their active components have also been the focus Antioxidants are dietary substances that slow or pre- of studies on the prevention as well as management of cancers of the breast, colon, lung, and central nervous system.6 The result of this research is promising, but more human trials need to be conducted. Another Ms Connelly is a Registered important factor in translating research into practice Dietitian and Certified Specialist in Oncology Nutrition at the is to determine how much of the actual whole food Steeplechase Cancer Center in item is needed to produce the same results found in a Somerville, New Jersey. As study, which often utilizes isolated and concentrated part of her responsibilities, she forms of a particular dietary compound. These are the provides nutrition counseling, challenges health professionals face when communigroup classes, and monthly cating these exciting findings into practical advice for cooking classes to patients our clients and patients. and families.

In today’s fast-paced lifestyle, it may not be con-

T

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OctOber 2011 I VOL 4, NO 7

venient for some people to prepare and cook a fresh pumpkin. Therefore, it is just as beneficial to get your daily serving of pumpkin from a can. In fact, canned pumpkin is higher in certain nutrients than fresh, boiled pumpkin. Canned pumpkin is higher in vitamin A, iron, and carbohydrate. The higher carbohydrate content, possibly caused by varying degrees of ripening before canning or differences in water content, may impact glycemic control. The increased carotenoid content of canned pumpkin suggests that it also will have powerful antioxidant and antiinflammatory benefits. The canned version can also be easily substituted for fresh pumpkin in a recipe. Canned pumpkin does contain added sodium; therefore, be sure to factor this into your daily intake. A serving size of canned or fresh boiled pumpkin is one half cup.

Add pumpkin to chili, baked goods, pancakes, shakes, and soups. The possibilities are endless.

Pumpkin can be very useful to patients on active cancer treatment. Because of its the high fiber content, pumpkin can help with maintaining bowel regularity, especially for those patients on opioids or who experience opioid-induced constipation. Often patients experience electrolyte abnormalities, and a serving of pumpkin mixed into a shake is a great way to increase the potassium and magnesium content of their diet. Fresh pumpkin does not have as intense a flavor as canned pumpkin, the sweetness is mild and the texture is smooth, which makes it a perfect food for those patients suffering from taste changes, nausea, mucositis, xerostomia, and stomatitis. Adding pumpkin to a variety of foods can help restore nutrients that have been depleted as a result of cancer treatment, lack of appetite, and poor oral intake. For just one-half-cup serving of pumpkin, patients can receive a variety of vitamins, minerals, safe levels of antioxidants, and cancer-fighting compounds. Adequate nutritional status during treatment as well as in survivorship is paramount in helping our patients improve the day-to-day quality of their lives. As health professionals, having the opportunity to guide patients toward the foods that will improve their overall health is priceless. ● References 1. Wolford R, Banks D; University of Illinois Extension. Pumpkin nutrition. http://urbanext.illinois.edu/pumpkins/nutrition.cfm. Accessed October 7, 2011.

2. Duyff RL. American Dietetic Association Complete Food and Nutrition Guide. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:76-78, 87-88.

3. Duangmano S, Dakeng S, Jiratchariyakul W, et al. Antiproliferative effects of cucurbitacin B in breast cancer cells: down-regulation of the cMyc/hTERT/telomerase pathway and obstruction of cell cycle. Int J Mol Sci. 2010;11:5323-5338.

4. Nara K, Yamaguchi A, Maeda N, Koga H. Antioxidative activity of water soluble polysaccharide in pumpkin fruits (Cucurbita maxima Duchesne).

Biosci Biotechnol Biochem. 2009;73:1416-1418.

5. Iwanski GB, Lee DH, En-Gal S, et al. Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer. Br J Pharmacol. 2010;160:998-1007.

6. Jayaprakasam B, Seeram NP, Nair MG. Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett.

2003;189:11-16.

www.theOncologyNurse.com

TON_October 2011_v8_TON 10/18/11 11:09 AM Page 59

Nutri ion

Recipes ■ Sweet Potato and Pumpkin Chowder Ingredients 4 slices bacon, diced 1 tablespoon olive oil ½ cup onion, diced ¼ cup celery, diced ¼ cup carrot, diced 1 tablespoon chopped garlic 2 tablespoons flour 4 cups low-sodium vegetable stock 3 cups sweet potatoes, diced ½ cup whole milk 1 bay leaf 1 teaspoon thyme, chopped 1 cup canned pumpkin

1. Heat a medium saucepan, and add diced bacon. Cook for 5 minutes or until fully rendered. Add olive oil.

©iStockphoto.com/Sarah Lee

■ Pumpkin Chili Ingredients ¼ cup canola oil 1 red pepper, diced 4 garlic cloves, chopped 1 cup onion, diced 2 cups cooked kidney beans 2 cups cooked white beans 2 cups cooked garbanzo beans 1 pound cooked pumpkin 2 quarts low-sodium vegetable stock 2 tablespoons cumin 2 tablespoons chili powder 1 teaspoon salt 1 tablespoon cocoa powder 1 teaspoon nutmeg ½ chipotle pepper

1. Heat pan and add oil.

2. Cook onions, pepper, and garlic together until soft.

3. Add remaining ingredients and stir.

4. Simmer for 20 minutes to combine flavors.

Nutritional Information Serves 16; serving size 8 ounces 130 calories; 4.5 g total fat, 0.5 g saturated fat; 5 mg cholesterol; 240 mg sodium; 16 g total carbohydrate; 5 g dietary fiber; 2 g sugars; 7 g protein

www.TheOncologyNurse.com

Karen

with

Courtesy of Peter Pascale, Executive Chef, CCC, Somerset Medical Center, Somerville, New Jersey. Bon Appetit!

2. Add onions, carrots, celery, and garlic. Cook for 5 more minutes or until soft.

3. Stir in flour.

4. Add in vegetable stock and sweet potatoes. Simmer until potatoes are tender.

5. Add milk, bay leaf, and thyme.

Simmer for 10 minutes.

6. Whisk in pumpkin and bring to a boil.

7. Can be garnished with toasted pumpkin seeds.

®

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SANCUSO® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

DOSAGE AND ADMINISTRATION The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm.

SANCUSO should not be placed on skin that is red, irritated or damaged. Each patch is packed in a pouch and should be applied directly after the pouch has been opened. The patch should not be cut into pieces.

Adults Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate. Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.

DOSAGE FORMS AND STRENGTHS SANCUSO is a 52 cm2 patch containing 34.3 mg of granisetron. The patch releases 3.1 mg of granisetron per 24 hours for up to 7 days.

CONTRAINDICATIONS SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.

WARNINGS AND PRECAUTIONS Gastrointestinal The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition.

Skin Reactions In clinical trials with SANCUSO, application site reactions were reported which were generally mild in intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with placebo. If severe reactions, or a generalized skin reaction occur (e.g. allergic rash, including erythematous, macular, papular rash or pruritus), the patch must be removed.

Exposure to Sunlight Granisetron may be affected by direct natural or artificial sunlight. Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal because of a potential skin reaction.

ADVERSE REACTIONS Clinical Trials Experience The safety of SANCUSO was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with patch treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days.

Adverse reactions considered by the investigators as drug-related occurred in 8.7% (35/404) of patients receiving SANCUSO and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the SANCUSO group and 3.0% of patients in the oral granisetron group.

Table 1 lists the treatment emergent adverse reactions that occurred in at least 3% of patients treated with SANCUSO or oral granisetron.

Nutritional Information Serving size 8 ounces 180 calories; 4.5 g fat, 1 g saturated fat; 5 mg cholesterol; 540 mg sodium; 29 g total carbohydrate; 5 g dietary fiber; 9 g sugars; 6 g protein

Renal Failure or Hepatically-Impaired Patients Although no studies have been performed to investigate the pharmacokinetics of SANCUSO in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron.

OVERDOSAGE There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache. In clinical trials there were no reported cases of overdosage with SANCUSO. HOW SUPPLIED/STORAGE AND HANDLING SANCUSO (Granisetron Transdermal System) is supplied as a 52 cm2 patch containing 34.3 mg of granisetron.

Each patch is printed on one side with the words “Granisetron 3.1 mg/24 hours”. Each patch is packaged in a separate sealed foil-lined plastic pouch.

SANCUSO is available in packages of 1 (NDC 42747-726-01) patch.

Store at 20˚-25˚C (68˚-77˚F); excursions permitted between 15˚-30˚C (59˚-86˚F). [see USP Controlled Room Temperature].

SANCUSO should be stored in the original packaging.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

Gastrointestinal Because the use of granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition, patients should be instructed to tell their physician if they have pain or swelling in their abdomen.

Skin Reactions Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus). When patients remove the patch, they should be instructed to peel it off gently.

Exposure to Sunlight Granisetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity.

Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal.

FDA-Approved Patient Labeling Rx Only Manufactured by: Aveva Drug Delivery Systems Inc., Miramar FL 33025

Manufactured for: ProStrakan Inc., Bedminster NJ 07921 Copyright ©2008, ProStrakan Inc. All rights reserved.

SANCUSO and ProStrakan are trademarks owned by the ProStrakan group of companies

Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (Events ≥ 3% in either group) Body System Preferred Term

SANCUSO TDS N=404 (%)

Oral granisetron N=406 (%)

5.4

3.0

0.7

3.0

Revised: 08/2008

Gastrointestinal disorders Constipation Nervous system disorders Headache

DRUG INTERACTIONS Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug-interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with SANCUSO. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, about 24 times the recommended human dose delivered by the SANCUSO patch, based on body surface area) and oral doses up to 125 mg/m2/day (750 mg/m2/day, about 326 times the recommended human dose with SANCUSO based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m2/day, about 16 times the human dose with SANCUSO based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m2/ day, about 167 times the human dose with SANCUSO based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SANCUSO should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SANCUSO is administered to a nursing woman.

Pediatric Use Safety and effectiveness of SANCUSO in pediatric patients under 18 years of age have not been established.

Geriatric Use Clinical studies of SANCUSO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OcTOber 2011 I VOL 4, NO 7

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CONTINUOUS COVERAGE THAT STICKS

Prevent CINV. No pills.

Nothing to swallow.

Continuous protection from nausea and vomiting With the SANCUSO Transdermal System, your patients don’t have to accept chemotherapy side effects. SANCUSO gives patients continuous protection against nausea and vomiting by providing consistent delivery of medication.1 Important safety information SANCUSO® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.1 SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.1 Granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition.1 Mild application site reactions have occurred; remove the patch if severe reaction or a generalized skin reaction occurs.1 Patients should avoid direct exposure of application site to natural or artificial sunlight by covering with clothing while wearing the patch and for 10 days after removing it.1 The most common adverse reaction in patients receiving SANCUSO is constipation (5.4%).1 SANCUSO contains granisetron.1 Healthcare professionals should avoid prescribing any additional products that contain granisetron. No clinically relevant drug interactions have been reported in clinical studies with SANCUSO.1 Reference: 1. SANCUSO [package insert]. Bedminster, NJ: ProStrakan, Inc; 2008.

(not actual size)

Visit www.sancuso.com to learn more about the only transdermal antiemetic available.

www.prostrakan-usa.com www.sancuso.com

SANCUSO is a registered trademark of ProStrakan, Inc. ©2011 ProStrakan, Inc. Bedminster, NJ 07921 All rights reserved. Printed in U.S.A. SAN-2011-070 08/2011