December 201, Vol 4, No 8

TON_December 2011_FINAL_TON 12/22/11 6:30 AM Page 1

DECEMBER 2011

www.TheOncologyNurse.com

VOL 4, NO 8

GENETIC COUNSELING

CANCER CENTER PROFILE

Breastlink Medical Center A Team-Based Approach to Patient Care

How Comprehensive Is Comprehensive BRACAnalysis?

The Story of Kathleen Maxian

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

Y

ou may or may not have heard the name Kathleen Maxian, but it is likely you have encountered women like her in your practice without knowing it. Kathleen has been featured in several news stories lately, including in the New York Times and on CNN. Her sister, Eileen Kelly, was diagnosed with breast cancer at age 40 and underwent testing for BRCA1 and BRCA2 (BRCA1/2) gene mutations. She was found to be negative.

Two years later, Kathleen was diagnosed

with ovarian cancer. Ultimately, Eileen and Kathleen were found to carry a BRCA mutation that is only detected by BART, a test that looks for large genomic rearrangements in BRCA1/2. According to Maxian’s surgeon, “If BART had been done from the beginning, it could have saved Kathleen from getting ovarian cancer.”1 So why wasn’t BART performed on Eileen’s initial genetic test? To understand the science behind Kathleen’s story, the Continued on page 12

SIDE EFFECT MANAGEMENT James Waisman, MD, a breast oncologist with Breastlink, confers with a patient.

reastlink is a network of comprehensive breast centers that specifically focuses on providing treatment and care to women with breast cancer. The Breastlink Medical Group was founded in 1995 by John Link, MD, and now operates 5 breast cancer centers in California (4 in Southern California). Today, Breastlink offers a team-based, patient-centered approach to care, as well as a focus on research into the causes of and the cure for breast cancer. Lori Kells-Rezabek, NP, PhD, of the Manhattan Beach, California, center tells us how Breastlink’s multidisciplinary team works and what is happening in the areas of breast cancer prevention, care, and research.

B

Continued on page 54

Management of RadiationInduced Skin Reactions Up to Individual Practices

By Alice Goodman

A

lthough cancer patients who undergo radiation therapy frequently have acute and chronic skin reactions, there are no hard and fast guidelines on management of radiationinduced skin reactions or the best prod-

ucts to use. Each center or practice should develop its own clinical guide about how patients should manage skin reactions and which products are recommended for patient use, said Maureen McQuestion, RN, Princess Margaret Continued on page 16

CONFERENCE NEWS: ASTRO

Higher Radiation Doses May Not Help Lung Cancer Patients Live Longer

A

Complimentary Ce

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34

Metastatic Breast Cancer: Advances in Treatment and Management

By John Schieszer

higher dose of radiation (74 Gy) does not improve overall survival for non–small cell lung cancer (NSCLC) that has spread to the lymph nodes compared with the standard radiation dose (60 Gy), according to a new study presented at the 53rd Annual Meeting of the American Society for Radiation Oncology.

INSIDE

“Most radiation oncologists and lung cancer specialists are surprised by this finding. Although the optimal radiation dose for lung cancer patients has not been tested in a randomized phase 3 trial for over 30 years, most believed that higher doses of radiation cured more patients with lung cancer,” said study investigator Jeffrey Bradley,

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noteworthy numbers

Healthcare Literacy Rates ConferenCe news

Oncology Nursing Society Institutes of Learning

Continued on page 26 ©2011 Green Hill Healthcare Communications, LLC

CliniCal trials

Clinical Trials Awareness, Confusion, and Clarity . . . . . . . . . . 28 Participation of Older Cancer Patients in Clinical Trials . . . . . . . . . 33 your faQs…answered . . . . .

40

Types of Amyloidosis and Available Treatment Options nutrition with Karen

Bountiful Beets

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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_December 2011_v3_TON 12/21/11 11:24 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

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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_December 2011_v3_TON 12/21/11 11:24 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_December 2011_v3_TON 12/21/11 11:24 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, BSN, OCN Piedmount Healthcare Rex, GA

MSN, FNP-C, CPON

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

Gary Shelton,

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

MSN, NP, ANP-BC, AOCNP NYU Clinical Cancer Center New York, NY

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

University of South Florida College of Nursing Tampa, FL

BioPharma Partners LLC New York, NY

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

6

December 2011 I VOL 4, NO 8

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_December 2011_FINAL_TON 12/22/11 10:15 AM Page 7

Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®.

Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

© 2011 Genentech USA, Inc. All rights reserved. ACS0000716800 Printed in USA.

TON_December 2011_v3_TON 12/21/11 12:41 PM Page 8

From the Editor

A

s 2011 comes to an end, I have great news for readers of The Oncology NurseAPN/PA (TON). It is my pleasure to announce that in 2012 we will begin publishing 11 issues a year instead of the current 8 issues a year. This will allow us to bring you even more of the information you need and want. In each issue, we Beth Faiman, RN, MSN, will continue to present articles related to all aspects of oncology APRN, BC, AOCN nursing—results of the latest cliniEditor-in-Chief cal studies, management strategies, palliative and survivorship care, and professional considerations. We will address the issues that affect us as oncology nurses, including the drug shortage situation, the expanding use of oral oncolytics, and the increasing role of personalized medicine in oncology.

We at TON work hard to help keep you up-to-date about what is happening in the world of oncology and to bring you information you can use in your day-to-day nursing practice. In this issue, Cristi Radford gives an overview of BRCA1/2 testing and discusses how comprehensive this analysis is. Peg Ford tells us what she has learned about the levels of participation in clinical trials and

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@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

what she didn’t know when she was a patient being treated for ovarian cancer. We also report on some of the therapies on the horizon for treating breast cancer and provide information about how you and your colleagues can help patients manage radiation-induced skin reactions. Take note of the statistics presented in Noteworthy Numbers about overall healthcare literacy and its connection to a patient’s health status—a good reminder that we need to do everything we can to make sure patients understand all of the information we give them.

Please be sure to visit our Web site, www.TheOncology Nurse.com. Answer this month’s reader question about the drug shortage issue and tell us how your patients are reacting. Submit a question to our column, Your FAQs…Answered! Let us know what you like (or don’t like), and tell us what issues you want to see us cover. We want to hear from you!

All of us at TON wish you the best in the new year. ●

Correction In the October issue of The Oncology Nurse-APN/PA, the name of Josette Snyder, RN, MSN, AOCN, was misspelled several times in the Cancer Center Profile.

We sincerely regret the error.

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

Please convey any errors to the Editorial Director.

BPA Worldwide membership applied for April 2011.

8

Recent FDA Approvals

Your Innovative Partners in Medical Media

December 2011 I VOL 4, NO 8

Bortezomib Median Overall Survival Update for Previously Untreated Multiple Myeloma The US Food and Drug Administration (FDA) has approved a supplemental new drug application for Velcade (bortezomib) for Injection (Millennium: The Takeda Oncology Company) that updates the label to include additional longterm (median follow-up 60.1 months) overall survival (OS) data from the VISTA trial. The VISTA trial examined the use of bortezomib-based therapy in patients with previously untreated multiple myeloma (MM).

The 5-year follow-up data demonstrated that patients treated with bortezomib, melphalan, and prednisone (VcMP) continued to have a statistically significantly longer OS (median OS 56.4 vs 43.1 months, P <.05) than those treated with melphalan and prednisone (MP) alone, a recognized standard of care. These results translated into a 43.9% improvement in OS when patients received the bortezomibcontaining regimen. A complete data set from the trial was presented at the December 2011 meeting of the American Society of Hematology.

An earlier analysis (median follow-up of 36.7 months) demonstrated that starting with the bortezomib combination (VcMP) provided a statistically significant OS advantage over MP that was not regained despite the use of subsequent therapies including bortezomib-based regimens.

The VISTA trial is the largest phase 3 registration study to

report long-term OS in previously untreated MM patients.

This multicenter, international, 682-patient clinical trial compared VcMP to MP in patients with previously untreated MM who were not eligible for stem cell transplantation.

The safety profile of bortezomib in combination with MP was consistent with the known safety profiles of both bortezomib and MP. The prescribing information is also being updated to provide the information that the concomitant use of strong CYP3A4 inducers with bortezomib is not recommended.

In VISTA, the most commonly reported adverse events for bortezomib in combination with MP versus MP, respectively, included 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%), and peripheral edema (20% vs 10%). Other noted adverse events for both combinations were rash, back pain, pneumonia, dizziness, dyspnea, headache, pain in extremity, abdominal pain, paresthesia, herpes zoster, bronchitis, hypokalemia, hypertension, upper abdominal pain, hypotension, dyspepsia, nasopharyngitis, bone pain, arthralgia, and pruritus. ●

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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 atients may not understand the information medical care providers give them for a number of reasons, but significant among them is poor healthcare literacy, which is the ability to understand health information and to use that information to make good decisions about health and medical care. Unfortunately, about 33% of the adult population in the United States has limited healthcare literacy. Yet, the need for this proficiency is greater than ever because medical care has become progressively more complex. Let us take a look at healthcare literacy facts and figures:

P

In addition to basic literacy skills, healthcare literacy requires understanding of health topics and number skills.1 Healthcare literacy is one of the strongest predictors of health status. In fact, studies of the issue show literacy as a stronger predictor of an individualâ&#x20AC;&#x2122;s health status than income, employment status, education level, and racial or ethnic group.2 Healthcare literacy influences peopleâ&#x20AC;&#x2122;s ability to: â&#x20AC;˘ Participate in the healthcare system (fill out complex forms, locate providers and services, etc) â&#x20AC;˘ Communicate information, such as health history, with providers â&#x20AC;˘ Manage self-care and chronic disease â&#x20AC;˘ Understand mathematical concepts (ie, probability and risk)1 The 2003 National Assessment of Adult Literacy, issued by the US Department of Education, estimated the healthcare literacy skills of adults based on the following categories: Below Basic, Basic, Intermediate, and Proficient. The study findings include: â&#x20AC;˘ Proficient health literacy was present in only 12% of adults www.TheOncologyNurse.com

â&#x20AC;˘ Nearly 9 of 10 adults may lack the necessary skills to manage their health and prevent disease â&#x20AC;˘ In the US, 14% of adults (30 million people) have Below Basic health literacy â&#x20AC;˘ Adults with Below Basic health literacy were more likely to report their health as poor (42%) and are more likely to lack health insurance (28%) compared to adults with Proficient health literacy â&#x20AC;˘ Lower average healthcare literacy was found among adults aged 65 and older compared to adults in younger age groups1,3 Strategies for improving patient communication and understanding include: â&#x20AC;˘ Using plain, nonmedical language â&#x20AC;˘ Showing or drawing pictures to enhance understanding â&#x20AC;˘ Encouraging questions2 Sources 1. US Department of Health and Human Services. http://www.health.gov/com munication/literacy/quickguide/factslit eracy.htm.

2. Weiss BD. Health literacy and patient safety: help patients understand.

American Medical Association. http:// www.ama-assn.org/ama1/pub/upload/ mm/367/healthlitclinicians.pdf.

3. National Coalition for Literacy. http:// www.ncladvocacy.org/HealthLiteracyFac tst2009/HealthLiteracyFactst2009.pdf.

December 2011 I VOL 4, NO 8

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Genetic Counseling How Comprehensive Is Comprehensive BRACAnalysis? Continued from cover history of clinical BRCA testing needs to be examined.

Overview of BRCA1/2 Testing The majority of hereditary breast and ovarian cancer is linked to 2 genes, BRCA1 and BRCA2. A woman with a BRCA1/2 mutation has up to an 87% chance of developing breast cancer and up to a 40% chance of developing ovarian cancer in her lifetime. Other cancers associated with mutations in the genes include male breast cancer, prostate cancer, pancreatic cancer, and melanoma.

The genes were first identified in the early 1990s, and patents followed. In 1996, Myriad opened a $30 million laboratory and began marketing 3 tests for BRCA1/2 analysis.2 Some of Myriad’s patents will expire in 2014; however, the company believes patent protection should last at least until 2018.3 Today, Myriad Genetics offers several versions of the BRCA1/2 test: Single Site BRACAnalysis, Multisite 3 BRACAnalysis, Comprehensive BRACAnalysis, and BRACAnalysis Rearrangment Test (BART). The Single Site test is used to test for a known mutation in a family, while the Multisite 3 test looks for the 3 most common BRCA mutations in individuals of Ashkenazi Jewish descent.

Myriad’s standard test, Comprehensive BRACAnalysis, consists of sequencing of exons and flanking regulatory regions, as well as a panel for 5 rearrangements in BRCA1. The 5 rearrangements in BRCA1 were added to the test on August 12, 2002. Of interest, the first large rearrangements in BRCA1 began appearing in the literature in 1997.4,5 As the 5 rearrangements do not account for all large deletions and duplications in BRCA1/2, BART was launched in 2006. BART utilizes quantitative multiplexed fluorescent polymerase chain reaction to detect genomic rearrangements in BRCA1/2 that are typically missed by traditional sequencing.

Cristi Radford, MS, CGC

In August 2006, Myriad began performing BART as a reflex test on individuals meeting their defined clinical criteria.

On May 14, 2007, Myriad converted from a reflex test to a concurrent test. For individuals who do not meet Myriad’s defined criteria (Table), the BART component can be added for a fee. As of November 2011, most insurance companies do not cover the cost of the BART component.

How Common Are Mutations Detected by BART? It is difficult to assess the frequency of large genomic rearrangements in families at risk for BRCA1/2 mutations, as most studies have focused on families at the highest risk of carrying a mutation.

BRCA2 rearrangements are reported to be less common than BRCA1 rearrangements. Depending on ethnic background, studies report 0% to 36% of BRCA1 mutations are genomic rearrangements; however, these studies do not necessarily exclude the genomic rearrangements found by the BRCA1 large rearrangement panel.5 In 2006, Walsh and colleagues reported that 12% of families with 4 or more cases of breast and/or ovarian cancer

Table Criteria for Inclusion of BART Testing at No Additional Charge as Part of Comprehensive BRACAnalysis 8 Patient Affected With: Breast cancer before age 50

Additional Family History Required: 2 or more diagnoses of breast cancer before age 50* and/or ovarian cancer at any age†

Ovarian cancer at any age

2 or more diagnoses of breast cancer before age 50* and/or ovarian cancer at any age†

Male breast cancer at any age

2 or more diagnoses of breast cancer before age 50* and/or ovarian cancer at any age†

Breast cancer at or after age 50 1 or more diagnosis of breast cancer before and ovarian cancer at any age age 50* and/or ovarian cancer at any age† Breast cancer before age 50 and No additional relatives required ovarian cancer at any age *Male breast cancer qualifies at any age. † At least 1 relative must be a first- or second-degree relative, and qualifying cancers must be on the same side of the family.

Note: For these criteria, “breast cancer” includes ductal carcinoma in situ and invasive breast cancers.

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December 2011 I VOL 4, NO 8

found to be negative by BRCA1/2 sequencing harbored a large genomic deletion or duplication in BRCA1/2.6 A recent retrospective chart review conducted at Massachusetts General Hospital of patients undergoing BART analysis demonstrated 2 in 5 individuals with a mutation did not meet Myriad’s defined criteria and 1 in 5 only met criteria because information on thirddegree relatives was obtained. They suggest that “when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR [large genomic rearrangements] testing so that the results are the most comprehensive and reliable.”7 According to Myriad Genetics, “there is, on average, a less than 1% chance that BART will identify a mutation in a patient who has already had a negative result from Comprehensive BRACAnalysis.”8 BART currently detects approximately 7.5% of mutations, while Comprehensive BRACAnalysis detects 92.5% of all mutations. However, the ancestry of the patient is also important.

For patients of Latin American/ Caribbean ancestry, Myriad Genetics states that 20% of the mutations found were detected by BART.9 However, it is important to note, ancestry is not taken into account in Myriad’s defined clinical criteria for complimentary BART.

A woman with a BRCA1/2 mutation has up to an 87% chance of developing breast cancer and up to a 40% chance of developing ovarian cancer in her lifetime.

Applying Knowledge to Clinical Practice Take-home messages regarding BART testing: • Not every individual with a BRCA mutation detectable only by BART will meet Myriad’s defined clinical criteria for complimentary BART (eg, Kathleen Maxian) • Family history and genetic testing options are dynamic. Patients should be encouraged to alert healthcare providers about changes in their family history. Additionally, they should be encouraged to contact their genetic provider on an annual basis as genetic testing options may change—even for the same gene (case 2) • Familial mutations should be con-

firmed via a test report. Although a family may meet Myriad’s defined criteria for BART analysis, not every individual in the family may meet criteria for concurrent BART analysis (case 1) Case 1 A 68-year-old female presents for genetic counseling due to her history of breast cancer at age 65 and family history of breast cancer. Family history includes a sister diagnosed with bilateral breast cancer at age 35 and 42, mother diagnosed with breast cancer at age 90, maternal aunt diagnosed with colon cancer in her 60s, maternal first cousin diagnosed with breast cancer at age 45, a maternal first cousin who underwent risk-reducing mastectomies, and maternal first cousin diagnosed with ovarian cancer in her 40s. Additionally, the patient tells you that her nieces had some genetic testing based on the cousins, and results were negative.

Comprehensive BRACAnalysis is performed, and the patient is asked to contact her family members to obtain additional information about cancers and possible genetic testing results.

The patient is found to be negative via Comprehensive BRACAnalysis.

However, she was able to obtain additional information. Her maternal aunt, diagnosed with colon cancer in her 60s, actually had ovarian cancer. Ad ditionally, the cousin who underwent the risk-reducing mastectomies and her sister did carry a mutation in the BRCA1 gene. The patient brings copies of various family members’ results to the counseling session. The mutation in the family is a large deletion of the BRCA1 gene, which is only detected by BART. Her test result and the test results of the nieces did not include this component, as they did not meet Myriad’s defined criteria for complimentary BART. Ultimately, the patient is found to carry the familial mutation in the family and states she plans on contacting her nieces to alert them to the fact that their test result did not include testing for the familial mutation.

Case 2 Sandy was diagnosed with breast cancer at age 32, and was recently diagnosed with ovarian cancer at age 58. Her family history includes a mother, 2 maternal aunts, 2 maternal cousins, and a maternal grandmother with breast cancer, all diagnosed at younger than 50 years of age. Because of this extensive family history with cancer, Sandy underwent genetic counseling in 2000. She sought it for her own risk assessment as well as Continued on page 16

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:25 AM Page 13

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_December 2011_v3_TON 12/21/11 11:25 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_December 2011_v3_TON 12/21/11 11:25 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_December 2011_v3_TON 12/21/11 12:44 PM Page 16

Side Effect Management GENETIC COUNSELING

How Comprehensive Is Comprehensive BRACAnalysis?

Continued from page 12

Management of Radiation-Induced Skin... Continued from cover Hospital, Toronto, Ontario, Canada.

She spoke at a symposium called “New Perspectives in Oncology Practice” held in conjunction with The Chemotherapy Foundation Symposium.

“Your practice should be consistent regarding recommendations for products, so that the oncologist, nurses, and nurse practitioner are all telling patients the same thing,” she said.

Pharmacists should also be included in the discussion about product recommendations.

Radiation techniques have evolved over the past few decades, and now

for her 3 daughters. At that time, testing consisted of sequencing of BRCA1/2, and she was found to be negative. In 2002, Sandy underwent 5-site testing and was again found to be negative. Her daughters are managed as having high risk, and 1 daughter opted to proceed with risk-reducing mastectomies. Upon Sandy’s diagnosis of ovarian cancer, this daughter contacted her certified genetic counselor (CGC) for guidance on her ovarian cancer risk.

The CGC explained that there is a new component of the BRCA test called BART and suggested that her mother consider having the test performed.

Sandy opted to pay out-of-pocket for the test as her insurance carrier did not cover the test and she was not eligible for Myriad’s complimentary BART analysis. Sandy was found to carry a large genomic rearrangement in BRCA1. ● References 1. Cohen E. When breast cancer tests get it wrong.

CNN Health. http://www.cnn.com/2011/10/27/ health/brca-genetic-testing-ep/index.html. Updated October 27, 2011. Accessed November 23, 2011.

2. Gold ER, Carbone J. Myriad Genetics: In the eye of the policy storm. Genet Med. 2010;12(4 suppl): S39-S70.

3. Pollack A. Despite gene patent victory, Myriad Genetics faces challenges. New York Times. Published August 24, 2011. http://www.nytimes.com/2011/ 08/25/business/despite-gene-patent-victory-myriadgenetics-faces-challenges.html?_r=2&pagewanted= all. Accessed November 23, 2011.

4. Puget N, Torchard D, Serova-Sinilnikova OM, et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 1997;57:828-831.

5. Petrij-Bosch A, Peelen T, van Vliet M, et al.

BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet.

1997;17:341-345.

6. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295:1379-1388.

7. Shannon KM, Rodgers LH, Chan-Smutko G, et al.

Which individuals undergoing BRACAnalysis need BART testing? Cancer Genet. 2011;204:416-422.

8. Myriad Genetics. BART Brochure. Fact sheet 02/11. http://www.myriad.com/lib/brac/BART%20 one%20sheet.pdf.

9. Myriad Genetics. BART Prevalence Table and FAQ. http://www.myriad.com/lib/brac/BART-tablefaq.pdf.

Did You Know?

Prospective data from the Nurses’ Health Study indicates that drinking at least 4 cups of coffee daily is associated with a lower risk of endometrial cancer. Researchers speculate that the link may be related to the role of caffeine, which has been reported to lower the levels of estrogen and insulin.

—Cancer Epidemiol Biomarkers Prev.

2011 Nov 22. [Epub ahead of print]

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December 2011 I VOL 4, NO 8

www.TheOncologyNurse.com

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Side Effect Management most patients receive targeted therapy with conformal radiation delivered to the tumor cells, sparing more healthy tissue than in the past. Nevertheless, skin reactions do occur, and some are quite severe and painful.

“Acute reactions are worse at the end

of radiation, but they will improve 2 to 3 weeks later,” said McQuestion.

Acute reactions can include mild erythema, dry desquamation, moist desquamation, alopecia, pruritus, altered pigmentation, and fibrosis. She said that reactions can be mixed, with

both wet and moist desquamation in the radiated area.

Patient factors that affect skin reaction include older age, nutritional status, comorbidities, hygiene, and chronic sun exposure. Treatment-related factors include the area radiated and the total dose

ADVERTISEMENT

What happens to the patient caught in the complications of chemotherapy-induced neutropenia?

Consider your last patient with neutropenia

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

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

1.0

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

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

0.9 0.8 Estimated survival

Febrile neutropenia–related hospitalization can lead to mortality

Patient factors that affect skin reaction include include older age, nutritional status, comorbidities, hygiene, and chronic sun exposure.

0.7 0.6

ARDI: ≤ 85%

0.5

ARDI: 86% to ≤ 90%

0.4 ARDI: > 90%

0.3 0.0 0

1

2

4 3 5 Years post-chemotherapy

6

7

8

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

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

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

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

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

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

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

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

Assess the risk.

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

References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Kuderer N, et al. Cancer. 2006;106:2258-2266. 3. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 4. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 5. Lyman G, et al. J Natl Compr Canc Netw. 2009;7:99-108. 6. Link B, et al. Cancer. 2001;92:1354-1367. 7. Picozzi V, et al. Oncology. 2001;15:1295-1306.

8. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 9. Bonadonna G, et al. BMJ. 2005;330:217-222. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Kwak L, et al.

J Clin Oncol. 1990;8:963-977. 12. Bosly A, et al. Ann Hematol. 2008;87:277-283.

© 2010 Amgen. All rights reserved.

MC49941-D

06-10

and fraction size. Hyperfractionated treatment twice a day increases the chances of more severe skin reaction.

Patients can experience pain, difficulty ambulating and sitting, discomfort wearing clothes, impaired body image, increased urination and bowel movements, loss of independence with decreased ability for self-care, and they have to bear the cost of products to take care of skin reactions.

“Dressings and creams are typically not covered by drug plans,” McQuestion told the audience.

The goal of management of radiation-induced skin reaction is healing, and the principles are similar to general ones for wound healing. Promoting moisture is important, “but some patients think they should dry the affected area,” she noted.

Patients should be instructed to gently wash the affected area with a mild soap such as Dove and not to rub or abrade the skin. They should not use cornstarch or talc, but they can use deodorants that do not contain aluminum. Although a multitude of creams and lotions can be purchased over the counter, McQuestion said that at her center they have found that hyaluronic acid cream and calendula cream can be helpful. Cavilon No Sting Barrier Film prevents moisture loss. Antimicrobials are not needed if the patient is practicing good hygiene.

“Corticosteroids are not recommended unless the patient has pruritus or documented folliculitis,” she stated.

Other recommendations for patients include avoiding swimming in chlorinated water or hot tubs and keeping the skin area well moisturized, especially if the patient has moist desquamation. ●

Did You Know?

The American Association of Clinical Oncology has published an update to its clinical practice guideline on the use of antiemetics for the prevention of nausea and vomiting in patients treated with radiation and/or chemotherapy. The last update was published in 2006.

—J Clin Oncol. 2011;29:4189-4198

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December 2011 I VOL 4, NO 8

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Hematologic Malignancies

Ruxolitinib Tablets: A New Oral Option for the Treatment of Patients With Intermediate- or High-Risk Myelofibrosis Disorders

By Rhonda Williams

yeloproliferative neoplasms (MPNs) are a group of closely related hematologic malignancies that arise from abnormal development and function of the body’s bone marrow cells. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) comprise the Philadelphia chromosome (Ph)-negative MPNs.1 Myelofibrosis (MF) can arise on its own, which is called PMF, or it can result from the progression of other MPNs, such as postpolycythemia vera MF (PPVMF) and postessential thrombocythemia MF (PET-MF).1

M

The Burden of Disease and Its Impact MF is characterized by cytopenias, splenomegaly, poor quality of life, and shortened survival.1 Because chronic MPNs previously were not classified as hematologic malignancies, limited epidemiologic studies are available to estimate the incidence of MF. Multiple regional studies suggest that an estimated 6328 new cases of chronic myeloproliferative disorders (CMPDs as they were previously known) occurred in the US population in 2004.2 Of these patients, 45% had PV, 24% had ET, and 10% had PMF.2 The average annual age-adjusted

incidence in the United States between 2001 and 2003 was 2.1 per 100,000 persons, with rates ranging among states from a low of 0.8 per 100,000 persons in Delaware to as high as 4.1 per 100,000 persons in Idaho.2 The incidence was significantly higher in males (2.6 per 100,000) than in females (1.8 per 100,000; P <.05).2 In addition, the incidence increased significantly with age, reaching 13.3 per 100,000 persons among individuals aged ≥80 years.2

In November 2011, the FDA approved Jakafi (ruxolitinib) tablets for the treatment of patients with intermediate- or high-risk MF, including PMF, PPVMF, and PET-MF. Although appropriate treatment of patients with ET and PV is associated with prolonged survival, patients with symptomatic forms of PMF have a median survival of <5 years.1 The prognosis of MF is quite variable; however, those who develop anemia generally have a poorer prognosis. Patients with a

Table 1 Baseline Characteristics of Patients in Study 1 and Study 2 Baseline Characteristic

Study 1 (N = 309)

Study 2 (N = 219)

Median age, yrs (range)

68 (40-91)

66 (35-85)

Patients aged >65 yrs, %

61

52

Male patients, %

54

57

Primary myelofibrosis, %

50

53

Postpolycythemia vera myelofibrosis, %

31

31

Postessential thrombocythemia myelofibrosis, %

18

16

10.5

10.4

251

236

16

15

Disease state

Hematologic value Median hemoglobin, g/dL 9

Median platelet count, × 10 /L Median palpable spleen length below the costal margin, cm Median spleen volume, cm3 (range) Source: Reference 10.

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December 2011 I VOL 4, NO 8

2595 (478-8881) 2381 (451-7765)

good prognosis can live for many years without experiencing major symptoms, whereas those with a poor prognosis may have a significantly shorter survival. A small percentage of patients with MF can transform to acute myeloid leukemia, which is often difficult to treat and can be fatal.

Few treatment options exist for patients with MF. Until recently, the choice of treatment was often dictated by a patient’s symptoms and specific circumstances. Some patients with MF may remain symptom-free for many years, without undergoing treatment; however, monitoring for any signs or symptoms that may suggest worsening of the disease is required. For patients who require symptomatic treatment, chemotherapeutic agents, immunomodulatory drugs, and biological response modifiers (eg, hydroxyurea, androgen therapies, corticosteroids, thalidomide, lenalidomide, and interferon) are often used.

It is important to note that these therapies are not always directed to the biological processes that underlie the origin of disease or lead to progression of PMF. Therefore, these strategies are often primarily palliative in nature, and their effect on survival is uncertain.

Finally, surgery or radiation therapy may also be used in those who fail to respond to other treatments. For many patients with MF, however, available treatments may be ineffective and allogeneic stem cell transplantation may be the only potential known cure.

A decisive advance in our understanding of the underlying molecular mechanisms of MPNs has been the discovery of a somatic gain-of-function point mutation in the Janus kinase (JAK) 2 gene, which is a common clinical feature in patients with ET, PV, and PMF.3,4 We now know that approximately 50% of patients with MF have a gain-of-function mutation in the JAK2 gene.5,6 Discoveries in the molecular pathogenesis of PV, ET, and PMF enabled the genetic classification and molecular diagnosis of these neoplasms. The World Health Organization diagnostic criteria, which were based largely on clinical and pathologic descriptions, were subsequently revised for PV, ET, and PMF to include the incorporation of testing for JAK2 and other genetic mutations.7 In addition to modifying the criteria for diagnosing, monitoring, and assessing patients with ET, PV, and PMF, the

discovery of JAK2 involvement in patients with MF also led to the development of small-molecule inhibitors that specifically target JAK2. Although JAK2 mutations are responsible for the majority of dysregulated signaling in Ph-negative MPNs, JAK1 and JAK2 may interact, resulting in their transactivation.8,9 Armed with this information and a greater understanding of the cellular and molecular events that lead to the development of PMF, the possibility of more targeted and effective therapies for this disorder has become a reality.

In November 2011, the US Food and Drug Administration (FDA) granted marketing approval of oral Jakafi (ruxolitinib; Incyte) tablets for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF.10 Clinical Pharmacology Mechanism of Action Ruxolitinib, a kinase inhibitor, inhibits the Janus-associated kinases JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.10 MF is known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617Fpositive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutated cells in the spleen, and decreased circulating inflammatory cytokines (eg, tumor necrosis factor– alpha and interleukin-6).10 Pharmacodynamics. In healthy persons and in patients with MF, ruxolitinib inhibited cytokine-induced STAT3 phosphorylation in whole blood. The maximal inhibition of STAT3 phosphorylation occurred 2 hours after dosing, returning to nearbaseline levels by 10 hours in both groups of people.

Pharmacokinetics. Maximal plasma concentration (Cmax) of ruxolitinib occurred 1 to 2 hours after oral administration. Pharmacokinetic studies demonstrated no evident food effect on the absorption of ruxolitinib; when

www.TheOncologyNurse.com

TON_December 2011_FINAL_TON 12/22/11 10:16 AM Page 19

The Oncology Nurse-APN/PA is pleased to announce the Second Annual Oncology Nurse Excellence award sponsored by TREANDA.

Who Will Be the

ONE?

The Oncology Nurse Excellence Award Winner The Oncology Nurse-APN/PA Nurse Excellence award will recognize an oncology nurse nominated by his/her peers for an outstanding contribution to oncology nursing practice, patient care, research, or education in 2011.

The four leading nominees will be profiled in the February issue of The Oncology Nurse-APN/PA. Readers will have an opportunity to vote for the winner online at www.TheOncologyNurse.com/award or by visiting The Oncology Nurse-APN/PA booth at the 2012 ONS Congress. The winner will be announced in the June issue of The Oncology Nurse-APN/PA.

TREANDA is manufactured by Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.

Nomination forms are available at

www.TheOncologyNurse.com/award

TON_December 2011_FINAL_TON 12/22/11 6:33 AM Page 20

Hematologic Malignancies administered with a high-fat meal, the mean Cmax decreased moderately (24%) and the area under the curve remained nearly unchanged (ie, 4% increase). In early clinical trials, the volume of distribution at steady state was between 53 L and 65 L in patients with MF.10

Trial Designs Study 1 was a randomized, double-blind trial that compared ruxolitinib with placebo in patients with MF who were refractory to or were not candidates for available therapy. The primary end point was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT). Secondary end points included the duration of ≥35% reduction in spleen volume from baseline and the proportion of patients with a ≥50% reduction in Total Symptom Score from baseline to week 24. The latter was

Phase 3 Clinical Trials Jakafi was approved by the FDA based on the results of 2 randomized, phase 3 trials (Study 1 and Study 2) conducted in patients with MF.10 These trials are described in detail in the product prescribing information, with key data highlighted in this article.

Table 2 Percentage of Patients With ≥35% Reduction in Baseline Spleen Volume Study 1 (24 wks) Ruxolitinib (N = 155)

Placebo (N = 154)

41.9%

0.7%

Study 2 (48 wks)

P Value

Ruxolitinib (N = 146)

Best Available Treatment (N = 73)

P Value

<.001

28.5%

0%

<.001

Source: Reference 10.

Adverse Reactions and Laboratory Abnormalities Reported in Study 1: Table 3 Ruxolitinib Versus Placebo Ruxolitinib (N = 155) Reported Outcomes

Placebo (N = 151)

All grades, Grade 3, Grade 4, All grades, Grade 3, % % % % %

Grade 4, %

Adverse reaction Bruisinga

23.2

0.6

0

14.6

0

0

Dizzinessb

18.1

0.6

0

7.3

0

0

Headache

14.8

0

0

5.3

0

0

Urinary tract infectionc

9.0

0

0

5.3

0.7

0.7

Weight gaind

7.1

0.6

0

1.3

0.7

0

Flatulence

5.2

0

0

0.7

0

0

Herpes zostere

1.9

0

0

0.7

0

0

Laboratory abnormalityf Thrombocytopenia

69.7

9.0

3.9

30.5

1.3

0

Anemia

96.1

34.2

11.0

86.8

15.9

3.3

Neutropenia

18.7

5.2

1.9

4.0

0.7

1.3

Elevated ALT

25.2

1.3

0

7.3

0

0

Elevated AST

17.4

0

0

6.0

0

0

a

Includes contusion, ecchymosis, hematoma, injection-site hematoma, periorbital hematoma, vessel puncture-site hematoma, increased tendency to bruise, petechiae, and purpura. b Includes dizziness, postural dizziness, vertigo, balance disorder, Ménière disease, and labyrinthitis. c Includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, and nitrite urine present. d Includes weight increased and abnormal weight gain. e Includes herpes zoster and postherpetic neuralgia. f Worst grade values are presented, regardless of baseline.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.

Source: Reference 10.

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December 2011 I VOL 4, NO 8

measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.10 Study 2 was a randomized, open-label trial that compared ruxolitinib with the best available therapy in patients with MF. The study investigators selected the best available therapy on a patient-bypatient basis, with the most frequently used agents, including hydroxyurea (N = 47%) and glucocorticoids (N = 16%).

The primary end point of this trial was similar to that in Study 1—the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline, but at week 48 (as measured by MRI or CT). The secondary end point of Study 2 was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to week 24.10 In both trials, patients were required to have palpable splenomegaly >5 cm below the costal margin, as well as an MF risk category of intermediate-2-risk (2 prognostic factors) or high-risk (>3 prognostic factors).10 Dosing in these trials was based on platelet counts. The starting dose of ruxolitinib was 15 mg administered orally twice daily in patients with baseline platelet counts of 100 to 200 x 109/L and 20 mg administered orally twice daily in patients with baseline platelet counts >200 x 109/L. The doses of ruxolitinib were then adjusted during the course of therapy based on efficacy and tolerability. Maximum doses based on platelet counts were as follows10: • Platelet count 100 to ≤125 x 109/L: 20 mg twice daily • Platelet count 75 to ≤100 x 109/L: 10 mg twice daily • Platelet count 50 to ≤75 x 109/L: 5 mg twice daily.

Patient Populations Baseline characteristics of patients enrolled in Study 1 and Study 2 are shown in Table 1. The 2 patient populations were very similar in terms of demographics and the extent of disease before study treatment.10 Efficacy The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2 (Table 2). A significantly greater percentage of ruxolitinib-treated patients achieved this magnitude of reduction in baseline spleen volume compared with either placebo (41.9% vs 0.7%, respectively; P <.001) or best available therapy (28.5% vs 0%, respectively; P <.001).10 In Study 1, a secondary end point was improvement in symptoms, as measured by the MFSAF v2.0. This scale captures MF-related symptoms, including abdominal discomfort, pain under the left ribs,

night sweats, itching, bone or muscle pain, and early satiety. A higher proportion of ruxolitinib-treated patients experienced a ≥50% reduction in Total Symptom Score compared with placebo (45.9% vs 5.3%, respectively; P <.001).

The median time to symptom response was <4 weeks.10 Safety Profile Because clinical trials are conducted under widely varying conditions, rates of adverse reactions observed in the clinical trials of a particular drug cannot be compared directly with rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ruxolitinib was assessed in 617 patients in 6 clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in 2 phase 3 studies. In these 2 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range, 0.5-17 months), with 88.7% of patients treated for >6 months and 24.6% treated for >12 months. A total of 111 patients started treatment at 15 mg orally twice daily and 190 patients started at 20 mg orally twice daily.10 The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.9 A total of 11.0% of patients receiving ruxolitinib and 10.6% of patients receiving placebo discontinued therapy because of adverse events.9 The rates of adverse reactions and laboratory abnormalities reported in Study 1 are summarized in Table 3.

The median time to onset of grade 2 or higher anemia was approximately 6 weeks. Mean decreases in hemoglobin of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy were reported in ruxolitinib-treated patients, recovering gradually to reach a new steady state of approximately 1.0 g/dL below baseline.10 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks. Patients with baseline platelet counts of 100 to 200 x 109/L experienced a higher incidence of grade 3 or 4 thrombocytopenia than did those with baseline platelet counts >200 x 109/L.10 Dosing Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.

When discontinuing ruxolitinib therapy for reasons other than thrombocytopenia, gradual tapering of the dose may be considered—for example, by 5 mg twice daily each week.10

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VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 *The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

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Hematologic Malignancies In patients who are unable to ingest tablets, ruxolitinib can be administered through a nasogastric tube (8 French or greater) by suspending 1 tablet in approximately 40 mL of water and stirring for approximately 10 minutes.

Within 6 hours after the tablet has dispersed, the suspension can be administered via a nasogastric tube using an appropriate syringe. After use, the tube should be rinsed with approximately 75 mL of water. The effect of tube-feeding preparations on ruxolitinib exposure during administration through a nasogastric tube has not been evaluated.10 The recommended starting dose of ruxolitinib is based on platelet count (Table 4). A complete blood count (CBC) and platelet count must be performed prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.10 Treatment with ruxolitinib should be interrupted in patients with platelet

of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts <100 x 109/L.10

The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.

counts <50 x 109/L. Once the platelet count recovers to >50 x 109/L, dosing may be restarted or increased following recovery of platelet counts to acceptable levels. Table 5 shows the maximum allowable dose that may be used when restarting ruxolitinib therapy following a previous interruption.10 Patients who develop anemia may require blood transfusions. Dose modifications of ruxolitinib in patients who develop anemia may also be consid-

Table 4 Proposed Ruxolitinib Starting Doses Platelet Count, × 109/L

Starting Oral Dose

>200

20 mg twice daily

100 to 200

15 mg twice daily

Source: Reference 10.

Table 5 Maximum Restarting Doses for Ruxolitinib After Safety Interruption Current Platelet Count, × 109/L

Maximum Restarting Dosea

≥125

20 mg twice daily

100 to <125

15 mg twice daily

75 to <100

10 mg twice daily for at least 2 wks; if patient is stable, may increase to 15 mg twice daily

50 to <75

5 mg twice daily for at least 2 wks; if patient is stable, may increase to 10 mg twice daily

<50

Continue hold

a

When restarting therapy, begin with a dose at least 5 mg twice daily below the dose at interruption.

Source: Reference 10.

Table 6 Dosing Recommendations for Thrombocytopenia Dose at Time of Platelet Decline Platelet Count, × 109/L

25 mg twice 20 mg twice 15 mg twice 10 mg twice 5 mg twice daily daily daily daily daily New Dose

100 to <125

20 mg twice 15 mg twice No change daily daily

No change

No change

75 to <100

10 mg twice 10 mg twice 10 mg twice No change daily daily daily

No change

50 to <75

5 mg twice daily

5 mg twice daily

5 mg twice daily

5 mg twice daily

No change

Hold

Hold

Hold

Hold

Hold

<50

Source: Reference 10.

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December 2011 I VOL 4, NO 8

ered.10 Neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) was generally reversible and was managed by temporarily withholding ruxolitinib. CBCs should be monitored as clinically indicated, with dosing adjusted as required.10 Dose Modification Based on Response If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5-mg twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more often than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement is observed since initiation of ruxolitinib therapy.10 Based on limited clinical data, longterm maintenance with a 5-mg twicedaily dose has not demonstrated responses, and continued use of this dose should be limited to patients in whom the benefits outweigh the potential risks.10 Dose increases may be considered in patients who meet all of the following criteria10: • Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume, as measured by CT or MRI • Platelet count >125 x 109/L at 4 weeks and platelet count never <100 x 109/L • ANC >0.75 x 109/L. Dose Adjustment, Concomitant Strong CYP3A4 Inhibitors On the basis of pharmacokinetic studies in healthy volunteers, when administering ruxolitinib along with strong cytochrome (CY)P3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose is 10 mg twice daily for patients with platelet counts ≥100 x 109/L. Additional dose modifications should be made with careful monitoring of safety and efficacy. Concurrent administration

Contraindications, General Warnings, and Precautions

There are no black box warnings or contraindications associated with the use of ruxolitinib. Warnings and precautions associated with use of the agent include such hematologic adverse reactions as thrombocytopenia, anemia, and neutropenia. As indicated earlier, a CBC and platelet count must be performed prior to initiating therapy with ruxolitinib.

In clinical trials, patients with platelet counts <200 x 109/L at the start of therapy were more likely to develop thrombocytopenia during treatment.

Thrombocytopenia was generally reversible, however, and was usually managed by modifying or interrupting the dose of ruxolitinib in clinical trials.

Patients may also require a platelet transfusion, if clinically indicated. Dose reductions should be considered if platelet counts decrease, with the goal being to avoid dose interruptions for thrombocytopenia (Table 6).10 Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Active serious infections should have resolved prior to initiating ruxolitinib therapy.

Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection, and should initiate appropriate treatment promptly.

Physicians should inform patients about early signs and symptoms of herpes zoster, and should advise patients to seek treatment as early as possible. ● References 1. Verstovsek S, Kantarjian H, Mesa R, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010; 363:1117-1127.

2. Rollison DE, Howlader N, Smith MT, et al.

Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52.

3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397.

4. Kralovics R, Passamonti F, Buser AS, et al. A gainof-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.

5. Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood.

2010;115:1131-1136.

6. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.

7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009; 113:2895-2901.

8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131:612.e1.

9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1:979-993.

10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2011.

www.TheOncologyNurse.com

TON_December 2011_FINAL_TON 12/22/11 11:48 AM Page 23

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T H E 5 - Y EAR S UR V IVAL 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

TON_December 2011_v3_TON 12/21/11 11:26 AM Page 24

Conference News

A View From the Floor The 12th Annual Oncology Nursing Society Institutes of Learning was held in Salt Lake City on November 4-6, 2011.

The Oncology Nurse-APN/PA was thereâ&#x20AC;Ś

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December 2011 I VOL 4, NO 8

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Conference News s oi y in d l l I N a a iP aw er N, AOCckford, ve inn N, MSter, Ro i G W , AP Cen on al

F

OS

www.TheOncologyNurse.com

rls ic Ca Med e li y Ju hon t An St

December 2011 I VOL 4, NO 8

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Conference News The following articles are based on presentations at the 53rd Annual Meeting of the American Society for Radiation Oncology held October 2-6, 2011, in Miami Beach, Florida.

Higher Radiation Doses May Not Help Lung Cancer... Continued from cover MD, radiation oncologist at the Washington University School of Medicine in St. Louis.

The goals of the current phase 3 trial were to find out if high doses of radia-

tion improved survival and also if the chemotherapy drug cetuximab increased survival among patients with stage III NSCLC. Investigators randomized 423 patients to different doses of

radiation therapy and concurrent chemotherapy of paclitaxel and carboplatin with or without cetuximab.

Patients received 1 of 4 treatments: standard-dose (60 Gy) or high-dose (74 Gy)

BUILDING

pillars of knowledge IN SUPPORTIVE CARE

NEUTROPENIA

radiation therapy and to chemotherapy with or without cetuximab.

Two types of external beam radiation therapy were used during the trial: three-dimensional conformal radiation therapy (3D-CRT), and intensity-modulated radiation therapy (IMRT), a newer, specialized form of 3D-CRT that further limits the radiation dose to the healthy tissues.

The researchers found that the patients who received the higher dose of radiation (74 Gy) did not have better survival rates than those receiving the standard dose (60 Gy). Subsequently, the 2 arms of the trial that used high-dose radiation therapy were closed to patient accrual.

LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace06

Bradley noted that these findings are important because this is an area that had not been carefully studied in more than 20 years.

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: • Outline the risk factors for neutropenia in patients with cancer undergoing chemotherapy • Review advances in the prevention and management of neutropenia, including updated evidence-based guidelines • 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 # 02450000-11-017-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 Center’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

Did You Know?

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.

Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form.

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December 2011 I VOL 4, NO 8

Bradley said the trial provides pivotal evidence that the standard dose of radiation therapy for stage III lung cancer should remain at 60 Gy, as doses as high as 74 Gy do not achieve better outcomes in stage III lung cancer. He said it is uncertain why this is the case. The data are still being carefully reviewed.

Bradley noted that these findings are important because this is an area that had not been carefully studied in more than 20 years. He noted that it has been 30 years since the radiation dose of 60 Gy was established. However, the techniques of radiation therapy have improved a great deal. “This is the largest study to look at this question, and it is a definitive study for stage III lung cancer,” said Bradley. ●

This activity is supported by an educational grant from Amgen Inc.

Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, expressed cautious hope for the future of personalized drug therapy, acknowledging that “we’re now out of the general skepticism phase [and] into the long slog phase.” Woodcock spoke at a conference hosted by the FDA and the Drug Information Association in October.

—American Society of Health-System Pharmacists

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Conference News

Chemo Plus Radiation Prior to Surgery May Increase Tumor Response for Rectal Cancer

By John Schieszer

P

atients with rectal cancer who receive a combination of chemotherapy (capecitabine) and 5 weeks of radiation (50 Gy) prior to surgery may have an 88% chance of surviving the cancer 3 years after treatment.

“The results of the trial allow us to recommend a new preoperative treatment, the Cap50 regimen, in locally advanced rectal cancer. It’s safe and reduces the risk of the cancer coming back to less than 5%,” said study investigator Jean-Pierre Gérard, MD, radiation oncologist at Centre AntoineLacassagne in Nice, France.

Currently, the primary treatment for cancer of the rectum (the lower 15 cm of the bowel) is surgery. However, there is a risk of cancer recurrence within the bowel and the surrounding tissue. In the majority of cases, this recurrence is incurable. Depending on the location and stage of the cancer, physicians usually recommend radiation therapy and chemotherapy before surgery. However, the optimal regimen is still unknown.

This current study involved 598 patients with locally advanced rectal cancer who were diagnosed and treated in 50 hospitals in France between 2005 and 2008. Researchers wanted to find the most effective and safe preoperative treatment for rectal cancer by comparing a combination of 2 different chemotherapies and 2 different radiation doses.

Patients were randomized to receive either Cap45 (capecitabine and radiation treatment to 45 Gy) or Capox50 (capecitabine plus oxaliplatin and radiation to 50 Gy).

At 3 years after treatment, the researchers found that the Capox50 regimen did not have a significantly lower rate of local recurrence compared with the Cap45 treatment.

Oxaliplatin, given as part of the Capox50 treatment, was shown to immediately increase side effects, including severe diarrhea, and was not effective in increasing the chance of local tumor sterilization. However, the increase of the radiation dose from 45 to 50 Gy over 5 weeks was effective, well tolerated, and did not extend the duration of treatment.

Gérard said the Cap50 regimen should be the standard treatment for locally advanced rectal cancer. He noted that using capecitabine avoids the intravenous injection of fluorouracil, while a radiation dose to 50 Gy in 25 fractions over 5 weeks increases the chance of tumor sterilization and limits the risk of local recurrence to 5% or less. “We

know now that if we add chemotherapy before surgery, you can improve survival,” said Gérard.

He and his colleagues are now devising new guidelines for the management of rectal cancer patients. Gérard

said that currently there is a wide variety in practice patterns in the treatment of these patients.

“Many patients are getting neoadjuvant therapy in the United States, but it is not considered the standard care of yet.

This study may change that,” said Tim Williams, MD, medical director of radiation oncology at Boca Raton Regional Hospital in Florida. ●

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

• Receiving 1st-line chemotherapy

SECONDARY ENDPOINTS

• Hemoglobin (Hb) ≤ 11 g/dL

• Progression-free survival • Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

Darbepoetin alfa 500 mcg Q3W 2:1 Randomization

End of Investigational Product

(darbepoetin alfa: placebo)

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria can be found in the protocol.

For more information, please visit www.782study.com or call 1-866-965-0782 (US and Canada only).

© 2010 Amgen. All rights reserved.

MC45038-D-6

04-10

2:29:08 PM

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December 2011 I VOL 4, NO 8

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Clinical Trials

Clinical Trials Awareness, Confusion, and Clarity

By Peg Ford

A

fter launching the Survivors Teaching Students program of the Ovarian Cancer National Alliance (OCNA) in 2008, and this year organizing the Ovarian Cancer Advocacy Alliance (OCAA) of San Diego, I have focused on 3 aspects of advocacy: 1) Effect change in the way medical doctors approach diagnosis and treatment of ovarian cancer by educating the medical community, patient organizations, and the community at large to achieve early diagnosis and improved treatment options; 2) Advance ovarian cancer research toward early diagnosis and improved quality of care; and 3) Address legislative issues that affect ovarian cancer care and research.

My first research effort was as a consumer reviewer for the Congressionally Directed Medical Research Program (CDMRP) of the Department of

Resources for clinical trials • Cancer Information Service 1-800-4-CANCER (www.cancer.gov) • American Cancer Society 1-800-ACS-2345 (www.cancer.org) • Ovarian Cancer National Alliance Clinical Trials Matching Service 1-800-535-1682 (http://www.ovariancancer.org/ clinical-trials/find-a-clinical-trial/)

Patient resources • Patient Advocate Foundation (PAF) 1-800-562-5274 (www.patientadvocate.org) • Cancer Legal Resource Center 1-866-999-DRLC (3752)

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December 2011 I VOL 4, NO 8

Defense (DOD) for the Ovarian Cancer Research Program (OCRP). The DOD OCRP is the second-leading federal funding agency for ovarian cancer research in the United States. It was an amazing experience to participate in the first tier of evaluation, which is a scientific peer review of proposals measured against established criteria for determining scientific merit. From my perspective as an ovarian cancer survivor, I was able to give voice to how the research would impact the community while interacting with the scientists as an equal voting member. Without a doubt, it was an outstanding opportunity to learn about, as well as to support with my vote, pioneering research that demonstrated the quality and commitment of researchers in our country.

Thus began another phase of advocacy, legislative action to lobby Congress for funding to support ovarian cancer research. With the task of developing a screening test for ovarian cancer extremely important to my community, the funding for research is paramount.

Without it, the devastatingly dismal statistic of a 45% 5-year survival rate will continue to haunt us. Having participated on the fiscal year 2009 and fiscal year 2010 DOD OCRP Peer Review Panels, I was able to share my experience and the importance of funding research with legislators. Attending OCNA’s national conference in Washington, DC, for the past 4 years, I felt privileged to participate in their “Advocacy Day” each year, during which a group of survivors visited “the Hill” to call on members of Congress. I feel sharing our personal experiences made quite an impact in the meetings.

This was just the beginning, as we continue the effort to represent the patient’s voice locally.

Attending scientific conferences, including those of the American Society of Clinical Oncology, the American Association for Cancer Research, and the Gynecologic Oncology Group, as an advocate has given me insight on the complex and elusive challenges facing researchers.

Yes, some advances have been made, but there is still, unfortunately, a long way to go. There is no way to know if a woman will get ovarian cancer.

However, there are several factors that may increase the chances. For example, having tested positive for a genetic abnormality, BRCA1 or BRCA2, can increase the chance that a woman will

get ovarian cancer. Having had breast, uterine, or colorectal cancer are also factors that could increase the risk of ovarian cancer. Also, having firstdegree female family members (mother, sister, aunt, or grandmother on either a mother’s or father’s side) who have had ovarian cancer may increase the risk.

Participation in clinical trials is essential to continuing to see advances in cancer treatment, but with so little participation, overall progress is slow.

Another vital factor is clinical trials.

I knew virtually nothing about them— how important they are to research.

What I did hear from researchers at the conferences was the need for more patients to participate. Why was this not happening? Why did I know so little about them? Initially I thought it was because my personal involvement with Western medicine was quite limited prior to my health crisis with ovarian cancer in 2007. But, I was in for a surprise. Desiring to increase my knowledge and awareness of cancer clinical trials, I started a new search. The statistics proved I was not alone, as less than 3% of all adults with cancer take part in clinical trials. Participation is even less among patients from racial and ethnic minority groups, those who are over 65, or those with low income. For all groups, there is a major lack of knowledge about cancer clinical trials—few people know about them. I also think that the average person does not realize the link between evidence-based medicine and clinical trials. I know I did not.

Participation in clinical trials is essential to continuing to see advances in cancer treatment, but with so little participation, overall progress is slow. With this new understanding, how could I assist in a solution by advocating for cancer clinical trials in my community?

My search proved instructive, as I recently participated in an educational program provided by the California Ovarian Cancer Awareness Program (COCAP) (www.calovarian.ning.com) to strengthen the capacity of ovarian cancer advocates to encourage wider

clinical trials participation by women diagnosed with ovarian cancer. The training was conducted by the Education Network to Advance Cancer Clinical Trials (ENACCT) (www.enac ct.org). ENACCT is the only national organization devoted solely to evidence-based, community-centered approaches to cancer clinical trials education. Its mission is to improve access to cancer clinical trials through education and collaboration with communities, healthcare providers, and research staff.

Specifically, the Community Leader Training Program empowers community members to spread the message about the importance of cancer clinical trials to their peers in brief presentations with a call to action to “spread the word.” I found the training intense, educational, and thorough in preparation to inform people in my community of this important option in cancer treatment and care. See the box for a list of resources.

As well, the current issue surrounding drug shortages is weighing heavily on people’s minds. Researching and participating in webinars about this issue from the FDA, OCNA, and others is also important. The Executive Order, signed by the president on October 31, 2011, is only one step in addressing the widespread issue of drug shortages. The Executive Order does not change any law, but it directs the FDA to use existing powers to reduce the impact and duration of shortages. This problem, however, is not a simple one. An article

by Jim Koeller in the October 2011 issue of The Oncology Pharmacist, “Will Anybody Be Making Cancer Drugs in the Future?,” sheds some light on important factors in this matter.

Yes, we have challenges, but as a research advocate, I am becoming fully aware of the importance of clinical trials and, in particular, ovarian cancer clinical trials in the effort to eradicate this lethal gynecologic cancer and other cancers. Research is the only avenue where a potential screening test for ovarian cancer will emerge, and clinical trials are the avenue to bring this life-saving result to reality.

Reaching out to inform patients and other individuals of the importance of clinical trials is one way I envision patient advocates as the bridge between the patient community and the scientific/medical world, working hand-in-hand to advance research and impact changes to better serve both communities. ●

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:27 AM Page 29

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_December 2011_v3_TON 12/21/11 11:27 AM Page 30

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_December 2011_v3_TON 12/21/11 11:27 AM Page 31

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_December 2011_v3_TON 12/21/11 11:27 AM Page 32

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_December 2011_FINAL_TON 12/22/11 6:39 AM Page 33

Clinical Trials

Participation of Older Cancer Patients in Clinical Trials

By John Schieszer

O

lder cancer patients are significantly underrepresented in clinical trials, and it may be time to rethink eligibility for oncology clinical trials, according to Martine Extermann, MD, PhD, professor of

oncology at the University of South Florida in Tampa.

Extermann, who spoke on improving research for older patients at the 53rd Annual Meeting of the American Society for Radiation Oncology

(ASTRO), said it is time to require large phase 3 trials to oversample older cancer patients (60 years of age and older) in order to reach a meaningful percentage of their cohorts. She said that by doing this it may be possible to

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

achieve clinical trial results that are specific and pertinent to this population.

Extermann said another good approach that should be adopted is to extend phase 2 and 3 trials to patients with high levels of comorbidities or functional impairment with stratified accruals or extension cohorts.

“We can give these older patients the same treatments and then watch these patients more carefully, and then analyze the efficacy and side effects separately,” said Extermann in an interview with The Oncology Nurse-APN/PA. “With this approach, the main reason for the trial would not be affected, but we would still learn about these patients. Another way to do this may be to say if the patient may not be able to tolerate the main treatment of the trial, then we can do a dose escalation in these patients who have poor function.”

There is currently a significant role that oncology nurses can play in removing the barriers that older cancer patients now face in trying to enter clinical trials.

She said that in addition there should be trials that are specifically designed for older cancer patients.

Extermann said there needs to be a new emphasis on minimizing exclusions in cancer clinical trials. In addition, parallel trials need to be considered whenever possible, with one trial including only older cancer patients.

According to Extermann, there is currently a significant role that oncology nurses can play in removing the barriers that older cancer patients now face in trying to enter clinical trials.

“The nurses can be very valuable in doing the assessments in these trials,” she said. “They can provide screening and the assessments that look at how radiation therapy may affect these older patients. We need a lot more research into how well older patients functionally tolerate chemotherapy and radiation therapy.”

She noted that there are significant barriers to addressing this issue because of financial constraints. However, she said it is time to look at funding issues when it comes to older adults, since 50% of cancers are now occurring in adults 70 and older. The latest statistics from the National Cancer Institute suggest that the number of people over age 65 with cancer will rise by about 42% over the next 10 years. ●

December 2011 I VOL 4, NO 8

33

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CONTINUING EDUCATION EXPIRATION DATE: FEBRUARY 4, 2012 • ESTIMATED TIME TO COMPLETE: 1.0 HOUR COMPLETE THE POSTTEST AT WWW.THEONCOLOGYNURSE.COM

Metastatic Breast Cancer: Advances in Treatment and Management TARGET AUDIENCE This activity was developed for oncology nurses and pharmacists who wish to enhance their competence concerning the treatment of patients with metastatic breast cancer.

LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Discuss the impact of metastatic breast cancer and key parameters for disease stratification • Describe the role of prognostic/genetic markers and tumor histology in classifying breast cancer subtypes and predicting treatment response • Review advances in the treatment of metastatic breast cancer, including the role of endocrine therapy, chemotherapy, targeted therapy, and bisphosphonates, with emphasis on targeted therapies • Examine effective patient-tailored treatment approaches, based on recent data and clinical practice guidelines

A

lthough an estimated 207,090 cases of breast cancer will be diagnosed in the United States in 2010,1 mortality rates from the disease have been on the decline since 1990, especially in women younger than 50 years of age.2 This decrease is likely attributable to early detection through screening, increased general awareness, and improved therapies.2 Nevertheless, breast cancer remains the second leading cause of cancer-related death in women, and is responsible for more than 40,000 deaths a year in the United States alone.1,2 The majority of breast cancer–related deaths are a result of complications from recurrent or metastatic disease.

Metastatic breast cancer (MBC) is uncommon at initial presentation, occurring in only about 6% of newly diagnosed cases.2,3 However, approximately 30% of women initially diagnosed with earlier stages of breast cancer eventually develop recurrent advanced or metastatic disease.3,4 The 5-year relative survival rate for patients with MBC is only 23%.1 Given this poor prognosis, researchers continue to focus their efforts on the development of more effective and tolerable treatments that may provide prolonged survival and improved quality of life.

Investigators are also striving to more clearly identify biomarkers in breast cancer that can be used to assess prog-

34

December 2011 I VOL 4, NO 8

SPONSOR This activity is jointly sponsored by Medical Learning Institute, Inc., a non-profit medical accreditation company, and Center of Excellence Media, LLC. INSTRUCTIONS fOR CREDIT 1. Read the article in its entirety 2. Log on 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 Statement of Completion For questions regarding the accreditation of this activity, please contact Medical Learning Institute at (609) 333-1693 or cgusack@ mlicme.org.

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. Provider approved by the California Board of

nosis and guide the selection of therapies, in the hopes of offering more individualized treatment. As integral members of the oncology team, it is essential that nurses and pharmacists are aware of the latest advances in the treatment and management of MBC, including safety and efficacy data from clinical trials evaluating novel biologic and cytotoxic agents, as well as administration guidelines and side-effect management strategies pertaining to these therapies.

Breast Cancer Disease Stratification: Predictive and Prognostic Markers Advances have recently been made in the area of molecular profiling, which may help clinicians more accurately classify subtypes of breast cancer, as well as predict risk of recurrence and response to therapy.5 A number of genes have been identified as important predictive markers of chemotherapeutic and targeted therapy efficacy, and may be used to guide more patient-specific treatment. The technology of DNA microarray gene expression profiling has led to a system of classifying breast cancer into the following major subtypes: estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (luminal A and B subtypes); ER-negative/HER2-negative (basal subtype); HER2-positive; and tumors that are similar to normal breast

Registered Nursing, Provider Number 15106, for 1.5 contact hours. fACULTy DISCLOSURES Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial products(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions.

Peer reviewers—Jayshree Shah, RN, APN-C, MSN, BSN, BS, is on the speakers’ bureau for Bristol-Myers Squibb, Celgene, Merck, and Novartis, and is on the advisory board for Bristol-Myers Squibb and Novartis. Nancy Nesser, JD, PharmD, has nothing to disclose.

• Joanna Schwartz, PharmD, BCOP, has nothing to disclose.

• Georgia Litsas, MSN, ANP-BC, AOCNP, is on the speakers’ bureau for Genentech, Novartis, and Pfizer.

tissue (normal breast-like).6 Retro spective analyses have shown that characteristic relapse-free survival and overall survival (OS) are associated with these gene expression subtypes.6 Key tumor markers and their role in the management of breast cancer are shown in Table 1.7 Additional gene-based approaches have been developed for prognostic and predictive purposes. OncotypeDX is a 21-gene assay used to estimate the risk of recurrence in patients with earlystage, ER-positive, node-negative breast cancer, and to identify patients who may be successfully treated with tamoxifen alone (without chemotherapy).6,7 This test uses reverse transcription polymerase chain reaction on RNA isolated from paraffin-embedded breast cancer tissue. MammaPrint is an assay that uses microarray technology to analyze a 70gene expression profile from frozen breast tumor tissue of patients with early-stage, node-negative disease to determine their risk of developing distant metastases.6,8 Both of these multigene expression tests are commercially available and have been incorporated into several diagnostic protocols. It is important to note, however, that results from prospective trials evaluating the clinical value of these assays have yet to be reported, although 2 such trials (TAILORx and MINDACT) are currently under way.

The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months.

DISCLAIMER The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Trade names used in this article are for the learner’s reference only.

No promotion of or bias toward any product should be inferred.

COMMERCIAL SUPPORT ACkNOwLEDGMENT This activity is supported by an educational grant from Eisai, Inc.

Current Management Strategies for Patients With MBC Although survival rates for MBC have improved over the past 20 years, the primary goal of treatment is still palliation.

The decision-making process regarding the choice of agents and the sequencing and duration of therapy for metastatic disease is complex, and requires consideration of numerous key factors, including the pathology, histology, and clinical characteristics of the tumor(s), axillary node status, hormone receptor (HR) and HER2 status, and patientrelated factors (eg, age, menopausal status, and comorbid conditions).6

HR-Positive MBC The goals of systemic therapy for recurrent or metastatic disease are prolonging survival and improving quality of life.

Therefore, treatments with minimal toxicity are usually preferred and often include endocrine therapies (as opposed to cytotoxic therapies). Patients with HR-positive MBC (ie, those with tumors that are ER- and/or progesterone receptor [PR]-positive) may benefit from initial endocrine therapy. Recent data support treatment with a selective aromatase inhibitor (AI) for postmenopausal women with previous antiestrogen therapy who are within 1 year of antiestrogen exposure.6 For postmenopausal women who are antiestrogen naïve or more than 1 year from pre-

www.TheOncologyNurse.com

TON_December 2011_FINAL_TON 12/22/11 6:39 AM Page 35

vious treatment with an antiestrogen, tamoxifen or an AI is an appropriate therapeutic option.6 In this setting, AIs have shown a modestly superior outcome compared with tamoxifen.6 Sequential treatment with endocrine therapy may be beneficial at the time of disease progression.6 Subsequent endocrine therapy may include nonsteroidal AIs (anastrozole or letrozole); a steroidal AI (exemestane); fulvestrant; tamoxifen or toremifene; megestrol acetate; fluoxymesterone; or ethinyl estradiol.6 For women with HR-positive metastatic disease who have been previously treated with an AI or antiestrogen, fulvestrant is an option that appears to be well tolerated as a monthly injection, with an efficacy profile similar to anastrozole and a longer duration of response.6

ER-Negative MBC Both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines indicate an absence of benefit with endocrine therapy in women with ER-negative, invasive breast cancer, based on large, randomized, clinical trials.6,9 Chemotherapy has been shown to be more effective in the treatment of patients with this type of breast cancer (compared with adjuvant endocrine therapy),6,10 with a dosedense regimen of doxorubicin, cyclophosphamide, and paclitaxel showing the greatest benefit in terms of reducing the risk for recurrence and death.11 HER2-Positive MBC HER2 protein overexpression occurs in 20% to 25% of breast tumors, often leading to aggressive disease and poor outcomes.12 Consequently, successful targeting of HER2-positive tumors is an important therapeutic goal. Patients with this type of MBC may benefit from treatment with trastuzumab as monotherapy or in combination with select chemotherapy agents; or with a combination of capecitabine plus lapatinib for patients who are refractory to treatment with an anthracycline, a taxane, and trastuzumab. The preferred firstline agents for treating HER2-positive disease are listed in Table 2.6 Trastuzumab, a recombinant human anti-HER2 monoclonal antibody, specifically targets signaling mechanisms of HER2, which inhibits the growth of tumor cells that overexpress the receptor.

The addition of trastuzumab to anthracycline or taxane chemotherapy in patients with HER2-positive breast cancer has been shown to significantly improve time to progression, rate of objective response, and median survival.13 Trastuzumab combined with other chemotherapeutic agents is also a viable option, and a number of combinations are available.6 Clinical trials evaluating trastuzumab combined with other targeted agents,

www.TheoncologyNurse.com

Table 1 Key Tumor Markers in Breast Cancer7 Tumor Marker

Role

Estrogen receptor (ER)

Determine whether the cancer is likely to be successfully treated with hormone therapy, such as tamoxifen.

Progesterone receptor (PR) Human epidermal growth factor receptor 2 (HER2)

Cancer antigen 15-3 (CA 15-3) Cancer antigen 27.29 (CA 27.29) Carcinoembryonic antigen (CEA) Urokinase plasminogen activator (uPA) Plasminogen activator inhibitor (PAI-1)

including pertuzumab and lapatinib, are currently under way.12 Cardiac toxicity is a concern with trastuzumab treatment, particularly when this agent is combined with an anthracycline.6,14 According to NCCN guidelines, trastuzumab should not be administered concurrently with an anthracycline because of the risk of cardiac toxicity, except as part of the neoadjuvant regimen of trastuzumab plus paclitaxel followed by cyclophosphamide/epirubicin/fluorouracil.6 Close monitoring of cardiac function is advised for patients receiving trastuzumab therapy.6 Less serious side effects associated with this agent include nausea, vomiting, hot flashes, and joint pain.14,15 Resistance to trastuzumab often develops over time.16 One strategy for overcoming this resistance involves switching patients to lapatinib, a dual tyrosine kinase inhibitor that blocks HER2 signaling through an alternative mechanism.16 Lapatinib was approved by the US Food and Drug Administration (FDA) in 2007 for use in combination with capecitabine for the treatment of patients with advanced or metastatic disease whose tumors overexpress HER2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab.17,18 In February 2010, lapatinib received approval for an expanded indication in combination with letrozole for the treatment of postmenopausal women with HR-positive/HER2-positive MBC for whom hormonal therapy is indicated.17,18 The approved labeling includes a caution stating that hepatotoxicity is a potentially serious adverse effect associated with lapatinib.18

HR-Negative MBC and HR-Positive, Endocrine-Refractory MBC Cytotoxic chemotherapy is recommended for patients with HR-negative MBC

Determines whether the cancer can be treated with an anti-HER2 treatment, such as trastuzumab; in some cases, may indicate whether additional treatment with chemotherapy may be beneficial.

Found in 50% to 90% of patients with metastatic disease, these tumor markers may point to early recurrence or indicate whether the cancer is responding to treatment.

High levels of these markers may indicate that the cancer is aggressive; these markers may guide the use of chemotherapy after surgery for patients with node-negative disease. as well as HR-positive disease refractory to endocrine treatment. The NCCN guidelines recommend first-line singleagent chemotherapy until progression of disease.6 However, the adverse events associated with this therapy may necessitate dose reductions or treatment cessation.6 Preferred single-agent and combination chemotherapy regimens for HR-negative and HR-positive, endocrine-refractory breast cancer, as outlined in these guidelines, are shown in Table 3.6 Recent Advances in the Treatment of MBC Treatment options for patients with MBC continue to expand as investigators learn more about the biology of the disease and the process of metastasis.

Recent advances in treatment include the development of novel targeted agents, new formulations of existing drugs, and more effective combination regimens.

Microtubule-Targeting Agents

Eribulin Mesylate Eribulin mesylate, a nontaxane microtubulin, was highlighted as a “notable advance” in the treatment of breast cancer in ASCO’s annual report titled Clinical Cancer Advances 2010.19 Representing a new class of agents, eribulin is an analog of a chemical derived from a marine sponge. This drug was approved by the FDA in November 2010 for the treatment of patients with MBC who previously received at least 2 chemotherapy regimens. This decision was based on preliminary results of the pivotal phase 3 EMBRACE trial (N = 762), in which a significant improvement in OS (median of 2.47 months) was seen with eribulin compared with treatment of physician’s choice (TPC).20 Results from an updated analysis of this trial, presented at the 2010 San

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Antonio Breast Cancer Symposium, were consistent with these earlier findings, with a median OS of 13.2 months for eribulin versus 10.5 months for TPC.21 The most recently updated NCCN practice guidelines list eribulin as a preferred single agent for recurrent or metastatic disease.6 The most common adverse events (incidence ≥25%) associated with this agent include neutropenia, asthenia/ fatigue, anemia, peripheral neuropathy, nausea, and constipation.22

Ixabepilone Ixabepilone, a semisynthetic analog of epothilone B, received FDA approval in 2007 as both a single agent and in combination with capecitabine for the treatment of locally advanced and metastatic disease.6 Phase 2 clinical trials evaluating ixabepilone monotherapy in the first-line setting have reported significant activity in patients who have received prior therapy with anthracyclines and taxanes.23 In a pivotal phase 3 trial comparing ixabepilone plus capecitabine versus capecitabine alone in patients with resistance to previous anthracycline and taxane therapy, a significant improvement in progression-free survival (PFS) was seen with the combination regimen (6.2 months vs 4.4 months, respectively; P = .0005).24 The most common adverse events (≥20% incidence) associated with Table 2 NCCN Guidelines: Preferred First-Line Therapies for HER2-Positive Breast Cancer6 Preferred First-Line Agents Trastuzumab with: • Paclitaxel + carboplatin • Docetaxel • Vinorelbine • Capecitabine Preferred Chemotherapy Agents for Trastuzumab-Exposed HER2Positive Breast Cancer Lapatinib plus capecitabine • Trastuzumab plus other first-line agents • Trastuzumab plus capecitabine • Trastuzumab plus lapatinib (without cytotoxic therapy) HER2 indicates human epidermal growth factor receptor 2; NCCN, National Comprehensive Cancer Network.

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CONTINUING EDUCATION ixabepilone include peripheral neuropathy, fatigue/asthenia, myalgia/ arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.24

Nab-paclitaxel Nanoparticle albumin-bound (nab)paclitaxel is a solvent-free, albuminbound 130-nm particle form of paclitaxel that was developed to avoid toxicities associated with the cremophor vehicle used in solvent-based paclitaxel. This agent was approved by the FDA in January 2005 for the treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.25 A phase 3 trial (N = 454) compared nab-paclitaxel with a conventional formulation of the drug in MBC, showing a higher target-lesion response and objective response rates with nabpaclitaxel.25 In a separate phase 2 trial (N = 302) in previously untreated MBC, nab-paclitaxel demonstrated significantly longer PFS than docetaxel by both independent radiologist assessment (12.9 vs 7.5 months, respectively; P = .0065) and investigator assessment (14.6 vs 7.8 months, respectively; P = .012).26 Novel Combinations for HER2Positive MBC In a recent phase 3 trial, dual HER2targeted therapy with lapatinib and trastuzumab showed an increase in PFS compared with lapatinib alone (12 weeks vs 8.1 weeks; P = .008) in patients with heavily pretreated MBC and disease progression on trastuzumab therapy.27 In addition, according to recent data, the combination of lapatinib, trastuzumab, and paclitaxel was associated with a significant improvement in tumor response rate compared with individual agents in patients with HER2-positive disease.28 According to preliminary findings

Table 3 NCCN Guidelines: Preferred First-Line Chemotherapies for Patients With HR-Negative or HRPositive, Endocrine-Refractory Breast Cancer6 Single Agents Anthracyclines • Doxorubicin • Epirubicin • Pegylated liposomal doxorubicin Taxanes • Paclitaxel • Docetaxel • Albumin-bound paclitaxel Antimetabolites • Capecitabine • Gemcitabine Nontaxane Microtubule Inhibitors • Eribulin • Vinorelbine Combination Regimens Cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF) Fluorouracil, epirubicin, cyclophosphamide (FEC) Doxorubicin, cyclophosphamide (AC) Epirubicin, cyclophosphamide (EC) Doxorubicin in combination with either docetaxel or paclitaxel (AT) Cyclophosphamide, methotrexate, fluorouracil (CMF) Docetaxel, capecitabine Gemcitabine, paclitaxel HR indicates hormone receptor; NCCN, National Comprehensive Cancer Network.

from a phase 1b/2 trial, trastuzumabDM1 (T-DM1) plus pertuzumab demonstrated encouraging safety and efficacy in women with HER2-positive, locally advanced or metastatic disease who were previously treated with trastuzumab.29 T-DM1, an HER2-targeted

antibody-drug conjugate, is composed of the cytotoxic agent DM1, an antimicrotubule agent, conjugated to the monoclonal antibody trastuzumab.29,30 Pertuzumab, a humanized monoclonal antibody, is the first HER2-directed dimerization inhibitor for the treatment of HER2-positive breast cancer. T-DM1 and pertuzumab bind to different HER2 receptors; combining these agents has shown synergistic antitumor activity in HER2-positive xenograft models.29,30 Emerging Therapies for TripleNegative Disease Triple-negative breast cancer (TNBC) is a term used to describe tumors that lack expression of ER, PR, and HER2.

This type of breast cancer is associated with rapid disease progression and poor prognosis. Therefore, advances in treatment for this subtype of disease are particularly noteworthy. A recent study found that TNBC patients with BRCA1/BRCA2 mutations appear to have better survival than patients without these mutations.31

PARP Inhibitors Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors appear to have clinical activity in BRCA1-/ BRCA2-associated cancer. Results from a phase 2 study (N = 123) showed that the PARP inhibitor, iniparib, plus chemotherapy was associated with significantly prolonged OS in TNBC, compared with chemotherapy alone (12.3 months vs 7.7 months, respectively; hazard ratio for death, 0.57; P = .01).32 In addition, another PARP inhibitor, olaparib, is being investigated for its potential activity when combined with paclitaxel.33 In a small study (N = 10), 4 patients achieved a partial response with this combination; however, acceptable dose intensity was delayed or not achieved because neutropenia was reported in a number of patients.34 In another small study (N = 24), no

responses were observed in patients with TNBC treated with olaparib plus paclitaxel.33

Cetuximab Cetuximab, an antibody that targets epithelial growth factor receptor, is being studied for its potential role in treating TNBC. Based on results of a recent phase 2 trial (N = 173), adding cetuximab to cisplatin chemotherapy in heavily pretreated patients with TNBC resulted in twice the response rate and twice the time to progression compared with patients who received cisplatin alone.35 Bone Disease in Patients With MBC Bone metastasis, which occurs in approximately 70% of patients with advanced breast cancer,36 can lead to significant skeletal morbidity, including bone pain, pathologic fracture, hypercalcemia of malignancy, and spinal cord compression.36 Patients with breast cancer who are treated with AIs (eg, anastrozole, letrozole, exemestane) are at increased risk for bone loss and fractures.37 Bisphosphonates have demonstrated efficacy in delaying the onset and reducing the incidence of skeletalrelated events (SREs) associated with bone metastasis.38 The recently approved agent, denosumab, has also been shown to be effective in preventing these events in patients with bone metastases from solid tumors.39

Bisphosphonate Therapy The use of bisphosphonates is considered a palliative care measure in patients with MBC; these agents may also play a role in preventing skeletal complications associated with bone loss.6 The 2 intravenous (IV) bisphosphonates approved by the FDA for the treatment of bone metastases are zoledronic acid and pamidronate. Both of these agents have been studied in numerous clinical trials, and zoledronic

Update on Bevacizumab Use in Breast Cancer

I

n February 2008, the FDA granted accelerated approval of bevacizumab in combination with paclitaxel for the first-line treatment of HER2negative MBC. This approval was based on results of E2100, a phase 3 trial in which initial treatment with this combination almost doubled PFS compared with paclitaxel alone in women with recurrent or metastatic disease (11.8 months vs 5.9 months, respectively; P <.001).1 Subsequent phase 3 trials also demonstrated longer PFS when bevacizumab was added to various first-line chemotherapeutic regimens for MBC, but these gains were not as clinically significant as those seen in the E2100 trial.2,3 A recent meta-analysis of these trials failed to show an improvement in OS with the addition of bevacizumab.4 Given the fact that bevacizumab use has been associated with serious adverse events, including

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hypertension, bleeding, and febrile neutropenia,2,3,5 the FDA is now questioning whether the benefits of this drug outweigh the risks for women with MBC.6 After consideration of the data, the agency’s review panel announced that it was revoking this indication.6 The manufacturer of bevacizumab has requested a hearing to maintain their drug as a treatment option for HER2-negative MBC.7 It should be noted, however, that the European Medicines Agency and the National Comprehensive Cancer Network have both indicated that bevacizumab plus paclitaxel should remain a therapeutic option for women with this type of breast cancer.8 References 1. 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.

2. 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.

3. Robert NH, Dieras V, Glaspy J, et al. RIBBON-1: randomized, doubleblind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15 suppl).

Abstract 1005.

4. O’Shaughnessy J, Miles D, Gray RJ, et al. A meta-analysis of overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC). J Clin Oncol. 2010;28(15 suppl). Abstract 1005.

5. Avastin [package insert]. South San Francisco, CA: Genentech, Inc; December 2010.

6. U.S. Food and Drug Administration. FDA begins process to remove breast cancer indication from Avastin label. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm237172.htm? Accessed January 3, 2011.

7. Rohrer MH. Request for hearing (letter). www.gene.com/gene/news/ news-events/avastin/documents/avastin_use.pdf. Accessed January 3, 2011.

8. FDA revokes bevacizumab’s breast cancer indication. http://ascopost. com/articles/january-15-2011/fda-recommends-removal-of-bevacizum ab’s-breast-cancer-indication. Accessed January 13, 2011.

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acid appears to be superior to pamidronate in patients with lytic breast metastasis.6 Recent data also suggest that zoledronic acid may have antitumor properties.40 Zoledronic acid and pamidronate may help to decrease the pain related to bone metastasis, thereby reducing the need for supplemental analgesics in some patients.41 Generally, IV bisphosphonates are well tolerated. However, osteonecrosis of the jaw (ONJ), a rare but serious complication, may occur.6 Most reported cases of ONJ during bisphosphonate therapy have been associated with dental procedures such as tooth extractions.

A dental examination is recommended prior to treatment, and invasive procedures during therapy should be avoided whenever possible.6 In addition, serum creatinine should be monitored prior to each dose of zoledronic acid or pamidronate. According to recent data, short-term use (≤12 months) of these agents is associated with a low risk of renal dysfunction.41 However, the effects of extended therapy have not been studied extensively.41

Denosumab Denosumab, a fully human monoclonal antibody, was approved by the FDA in November 2010 for the prevention of SREs in patients with bone metastases from solid tumors.39 This novel agent inhibits bone resorption by specifically targeting the receptor activator of nuclear-factor kappa beta ligand (RANKL) and its receptor, RANK, key mediators of osteoclast formation and function.42 Phase 3 data presented at the 2010 San Antonio Breast Cancer Symposium showed that denosumab was superior to zoledronic acid in delaying the time to first on-study SREs by 18%, and denosumab delayed the time to first-

and-subsequent on-study event by 22%.43 Moreover, in patients with advanced breast cancer and bone metastases who were at risk, the median time to first on-study SRE was 5 months longer in the denosumab group compared with the zoledronic acid group. Denosumab was also associated with less pain, less interference with daily functioning, and improved health-related quality of life, based on other data presented at this meeting.43 In general, the rate of adverse events associated with denosumab was similar to the rate observed with zoledronic acid; cases of ONJ were rare, and hypocalcemia was more frequent in the denosumab arm.39 Calcium levels must be monitored in patients receiving denosumab, and administration of calcium, magnesium, and vitamin D may be required.39 The most common adverse events associated with denosumab were fatigue/asthenia, hypophosphatemia, and nausea; dyspnea was the most common serious adverse event.39 Conclusion Extended survival and improved quality of life are of paramount importance in patients with MBC. Advances in systemic, hormonal, and targeted therapies are yielding novel approaches and protocols that hold promise for improving clinical outcomes. Addressing pain and other disease-related comorbidities and preventing SREs are also key aspects of managing patients with MBC. The approach to treatment continues along the path of personalized care plans that are based on tumor/disease profile, patient-specific factors, and patient and physician preferences. Increasing attention is being directed toward the use of genetic markers and other tools that help clinicians stratify patients who will receive maximal benefit from a specific

therapy while sparing those patients who may not benefit from such regimens. Research continues to focus on the development of novel therapies that increase response and survival time for patients with MBC, while minimizing toxicity and other adverse events. ●

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References 1. Surveillance, Epidemiology, and End Results (SEER) Stat Fact Sheets—Cancer Statistics: Breast. http:// seer.cancer.gov/statfacts/html/breast.html.

Accessed December 28, 2010.

2. American Cancer Society. Breast cancer—what are the key statistics about breast cancer? Reviewed September 17, 2010. http://www.cancer.org/cancer/breastcancer/ detailedguide/breast-cancer-key-statistics. Accessed December 28, 2010.

3. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005; 10(suppl 3):20-29.

4. MBC Advocacy Working Group. Metastatic breast cancer patients: addressing their unmet needs-Special Report. Commun Oncol. 2008;5:645-647.

5. Moulder S, Hortobagyi GN. Advances in the treatment of breast cancer. Clin Pharmacol Ther.

2008;83:26-36.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Breast Cancer, V.2.2011. December 16, 2010. http://www.nccn. org/professionals/physician_gls/PDF/breast.pdf. Accessed December 29, 2010.

7. American Society of Clinical Oncology. What to know: ASCO’s guideline on tumor markers for breast cancer. Updated October 6, 2010. http://www.cancer. net/patient/Publications+and+Resources/What+to+Kn ow%3A+ASCO%27s+Guidelines/What+to+Know%3 A+ASCO%27s+Guideline+on+Tumor+Markers+for+ Breast+Cancer?sectionTitle=Introduction&sectionId=1 02827&vgnextrefresh=1. Accessed December 29, 2010.

8. Knauer M, Rutgers EJ, Mook S, et al. Evaluation of the 70-gene prognosis MammaPrint signature for the prediction of prognosis of breast cancer independently from histologic grade. J Clin Oncol. 2010;28:15(suppl).

Abstract 561.

9. Hammond ME, Hayes DF, Dowsett M, et al.

American Society of Clinical Oncology—College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol.

2010;28:2784-2795.

10. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet.

2005;365:1687-1717.

11. Berry DA, Cirrincione C, Henderson IC, et al.

Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. 2006;295:1658-1667.

12. Brufsky A. Trastuzumab-based therapy for patients with HER2-positive breast cancer: from early scientific development to foundation of care [abstract]. Am J Clin Oncol. Epub August 11, 2009 [ahead of print].

13. Cobleigh MA, Vogel CL, Tripathy D, et al.

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

J Clin Oncol. 1999;17:2639-2648.

14. Herceptin (trastuzumab) [package insert]. San Francisco, CA: Genentech, Inc; 2010.

15. National Cancer Institute. US National Institutes of Health. Adjuvant and neoadjuvant therapy for breast cancer. Rev June 16, 2009. http://www.cancer.gov/ cancertopics/fact sheet/Therapy/adjuvant-breast.

Accessed December 29, 2010.

16. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743.

17. Tykerb (lapatinib). Rxlist. http://www.rxlist.com/ tykerb-drug.htm. Accessed December 29, 2010.

18. Tykerb (lapatinib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.

19. Clinical cancer advances 2010—ASCO’s annual report on progress against cancer. J Clin Oncol. Epub ahead of print. November 8, 2010. http://www.can cer.net/patient/Publications%20and%20Resources/ Clinical%20Cancer%20Advances/CCA_2010.pdf.

Accessed December 10, 2010.

20. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. Presented at the 2010 annual meeting of the American Society of Clinical Oncology.

June 4-8, 2010. Chicago, IL. Abstract CRA 1004.

21. Twelves C, Loesch D, Blum J, et al. Updated survival analysis of a phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in subjects with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane.

Presented at the 33rd annual San Antonio Breast Cancer Symposium. December 8-12, 2010. San Antonio, TX. Poster P6-14-18.

22. Halaven (eribulin mesylate) [package insert].

Woodcliff Lake, NJ: Eisai Inc; and Nerviano, Italy: NerPharMa; 2010.

23. Vahdat L. Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms. Oncologist. 2008;13:214-221.

24. Sparano JA, Vrdolja E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

J Clin Oncol. 2010;28:3256-3263.

Continued on page 38

Improving Care for Patients With Metastatic Breast Cancer

By Georgia Litsas, MSN, ANP-BC, AOCNP Dana-Farber Cancer Institute, Boston, MA

M

etastatic breast cancer (MBC), although very treatable, is generally considered incurable. Consequently, key goals of treatment are prolonging survival, palliating symptoms, and increasing the time to disease progression. These objectives are often used as end points in clinical trials evaluating new therapies for MBC. It is imperative that the patient and the oncology team engage in detailed discussions regarding treatment goals, as this will ensure that the patient’s preferences are understood and

www.TheoncologyNurse.com

the appropriate course of therapy is undertaken. Nurses play a critical role in the care of patients with MBC and must be aware of the latest advances in treatment and symptom management.

Balancing Safety and Efficacy in the Treatment of MBC Decisions regarding the treatment of MBC are influenced by several factors, including estimates of prognosis. In addition, it is necessary to strike a balance between physician and patient preferences regarding the efficacy and

toxicity of various treatment options.1 Ultimately, the benefits of therapy must justify associated risks and toxicities, and the impact of treatment should be measured in relation to specified goals.

Some patients are willing to accept a high burden of toxicity for small survival benefits, whereas others may only desire treatment if toxicity is minimal.

Both physician and patient perspectives are essential in establishing the objectives of treatment, and this process must be an interactive and ongoing process throughout the course of the disease.

Current treatment options for MBC include hormonal therapies, chemotherapies, and novel targeted agents, used alone or in combination regimens.

Numerous disease- and patient-related factors must be considered when determining the choice of therapy, including the characteristics of the tumor, the site(s) of disease involvement, previous treatment, and response to that treatment (Table). In patients with hormone receptor (HR)-positive disease, hormonal agents are often recommendContinued on page 38

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CONTINUING EDUCATION Metastatic Breast Cancer: Advances in Treatment and Management Continued from page 37 25. Robinson DM, Keating GM. Albumin-bound paclitaxel: in metastatic breast cancer. Drugs. 2006;66:941-948.

26. Gradishar WJ, Krasnojon D, Cheporov S, et al.

Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol.

2009;27:3611-3619.

27. Blackwell KL, Burstein HJ, Storniolo AM, et al.

Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124-1130.

28. Combination therapy reduced HER2-positive breast cancers. Medical News Today. December 11, 2010. http://www.medicalnewstoday.com/articles/211172.php.

Accessed December 29, 2010.

29. Miller K, Gianni L, Andre F, et al. A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treat-

ed with trastuzumab (T). J Clin Oncol. 2010;28(suppl).

Abstract 1012.

30. Susman E. ASCO: new agents show promise in HER2-positive breast cancer [press release]. Medpage Today. Released June 8, 2010. http://www.medpageto day.com/tbprint.cfm?tbid+20550. Article 20550.

31. University of Florida—Shands Cancer Center.

BRCA1/2 mutations linked with better outcome in triple-negative breast cancer. Breast cancer news. http://cancer.ufl.edu/2010/10/13/brca12-mutationslinked-with-better-outcome-in-triple-negative-breastcancer/. Accessed December 30, 2010.

32. O’Shaughnessy J, Osborne C, Pippen JE, et al.

Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. Epub ahead of print. January 5, 2011.

33. Susman E. Olaparib may have promise in breast cancer. Medpage Today. June 8, 2010. http://www.medpage today.com/MeetingCoverage/ASCO/ 20546. Accessed December 30, 2010.

34. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the firstor second-line treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol.

2010;28:15s(suppl). Abstract 1018.

35. Triple-negative breast cancer responds well to cetuximab addition to chemotherapy [press release]. Medical News Today. October 12, 2010. http://www.medicalnew stoday.com/articles/204334.php. Accessed December 30, 2010.

36. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

37. Cancer treatment may result in bone loss [press release]. Medical News Today. November 16, 2008. http://www.medicalnewstoday.com/articles/129429.php.

Accessed December 8, 2010.

38. Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007;(3)Suppl;S21-7.

Epub November 7, 2007. Review.

39. FDA approves Amgen’s Xgeva (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Medical News Today.

November 19, 2010. http://www.medicalnewstoday. com/articles/208585.php. Accessed December 29, 2010.

40. Gnant M, Mlineritsch B, Schippinger W, et al.

Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009; 360:679-691.

41. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003. Update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:4042-4057.

42. Lipton A, Jun S. RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care.

2008;2:197-203.

43. Amgen presents new XGEVA (denosumab) breast cancer skeletal-related event prevention data at SABCS. December 11, 2010. Medical News Today. http://www.medicalnewstoday.com/articles/211175.php.

Accessed December 14, 2010.

Improving Care for Patients With Metastatic Breast Cancer Continued from page 37 ed as first-line therapy,2 as they provide efficacy with minimal toxicity. A vigorous response may be important for patients with symptomatic disease, but those without symptoms typically benefit from a less aggressive approach.

Chemotherapy is generally used as initial therapy for HR-negative patients or those with hormone-refractory disease or breast cancer that is characterized by symptomatic visceral metastases or rapidly proliferating disease.2,3 The most common chemotherapeutic agents used for the frontline treatment of MBC are anthracyclines and taxanes, which in multidrug schedules produce response rates in the range of 50% to 70%.4 Although effective in this setting, MBC often progresses when patients become resistant to these agents.3 Resistance to anthracyclines and taxanes may be defined clinically as disease recurrence within 6 months of completion of adjuvant or neoadjuvant treatment with these agents or tumor progression that occurs during treatment or within 3 months of the last dose of treatment.5 Several cytotoxic and targeted therapies have now been identified as having clinical activity in patients with Table MBC: Factors That Influence Choice of Treatment Disease-specific factors ER/PR status HER2 status Tumor burden Patient-specific factors Age Disease-associated symptoms Performance status Comorbidities Prior treatment Response to prior treatment Patient preference Availability and access to treatment ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PR, progesterone receptor.

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human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have become resistant to anthracyclines and/or taxanes. These agents include capecitabine, gemcitabine, vinorelbine, liposomal doxorubicin, albumin-bound paclitaxel, ixabepilone, and eribulin.6 A combination of capecitabine plus lapatinib is an option for patients with HER2-positive MBC who have progressed after treatment with an anthracycline, taxane, and trastuzumab.7 As with most chemotherapy and targeted treatments, benefits are accompanied by the potential for adverse events that must be managed effectively to maintain quality of life. Oncology nurses can be instrumental in minimizing toxicities and promoting better adherence to therapy by understanding the mechanism of action of specific agents and their related toxicities.

Three of the adverse events commonly seen with MBC treatments are cardiotoxicity, hypersensitivity reactions, and peripheral neuropathy (PN).

Cardiotoxicity The cardiovascular toxicities associated with breast cancer treatments can range from asymptomatic abnormalities, such as temporary left ventricular ejection fraction decline, to life-threatening events, including congestive heart failure and acute coronary events.8 An thracyclines are well known for causing cardiotoxicity in patients with MBC, and studies have shown that this toxicity increases in relation to the total dose of the drug.9,10 In contrast, trastuzumabrelated cardiotoxicity does not appear to be dose-related and usually responds to standard medical treatment or the discontinuation of the drug.11 Close monitoring of cardiac function is necessary when administering any agents that have the potential to cause cardiac toxicities. As oncology nurses, it is vitally important to be aware of the cardiovascular risks related to various agents and educate patients about the symptoms of

cardiac dysfunction so that they may alert their oncology team for appropriate treatment.

Hypersensitivity Hypersensitivity reactions occur when the patient’s immune system reacts to the agent being infused or the accompanying diluent. These reactions are characterized by nausea, vomiting, flushing, bronchospasm, shortness of breath, rashes, urticaria, angioedema, pain, alterations in blood pressure and heart rate.12 To minimize the risks of this adverse event, patients should be premedicated with both a histamine-1 and histamine-2 blocker 1 hour prior to infusion. Vital signs should be checked before, during, and after the infusion.12 If a patient begins to experience signs and symptoms of a reaction despite precautions, the infusion should be stopped immediately and basic life-supporting steps should be initiated to maintain airway, breathing, and circulation. Supportive care measures include oxygen, corticosteroids, epinephrine, histamine-2 blockers, and intravenous fluids. The decision to retreat should be made on a case-by-case basis after weighing all of the relevant clinical factors.12 Peripheral Neuropathy Neuropathy is a common complication of paclitaxel, vinorelbine, and ixabepilone.13 All patients receiving these therapies should have a baseline assessment of their neurologic function and undergo routine assessment prior to each dose. It is important to document neurotoxicity with a consistent tool, such as the National Cancer InstituteCommon Toxicity Criteria.14 For patients who experience PN, supportive measures should be instituted, as there are no proven agents to prevent or correct this toxicity.

Conclusion The decision-making process for choosing the optimal treatment for metastat-

ic disease is multidimensional and involves subjective as well as objective goals. Tailoring therapy for individual patients involves choosing agents and combination regimens based on factors that can help determine prognosis and predict response to specific treatments.

A better understanding of the biology of breast cancer has led to the development of several novel treatment approaches that are improving responses and prolonging survival in patients with MBC. The challenge for the next decade will be to integrate these promising therapies into the management of the disease. ● References 1. Chung C, Carlson R. Goals and objectives in the management of metastatic breast cancer. Oncologist.

2005;8:512-520.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Breast Cancer, V.2.2011. December 16, 2010. http:/www.nccn. org/professionals/physician_gls/PDF/breast.pdf.

Accessed January 20, 2011.

3. Colozza M, Azambuja E, Personeni N, et al.

Achievements in systemic therapies in the pregenomic era in metastatic breast cancer. Oncologist. 2007;10:253270.

4. Estevez LG, Tusquets I, Muñoz M, et al. Advanced breast cancer: chemotherapy phase III trials that change a standard. Anticancer Drugs. 2007;18:843-859.

5. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25:5210-5217.

6. Moreno-Aspitia A, Perez EA. Treatment options for breast cancer resistant to anthracycline and taxane.

Mayo Clin Proc. 2009;84:533-545.

7. Geyer CE, Forester J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive breast cancer. N Engl J Med. 2006;355:2733-2743.

8. Curigliano G, Mayer E, Burstein H, et al. Cardiac toxicity from system cancer therapy: a comprehensive review. Prog Cardiovascular Disease. 2010;52:94-104.

9. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710-717.

10. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869-2879.

11. Perez EA. Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin Breast Cancer. 2008;8(suppl 3):S114-S120.

12. Ream MA, Tunison D, Yasko JM, ed. Nursing Management of Symptoms Associated with Chemotherapy.

Hypersensitivity reactions. Bala Cynwyd, PA: Meniscus Health Care; 2001:213-224.

13. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006; 24:1633-1642.

14. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. (CTCAE) Publish date May 29, 2009. http://ctep.cancer.gov/forms/ CTCAEv4.pdf. Accessed January 10, 2011.

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:27 AM Page 39

Need a reason to choose Evercare™ Hospice and Palliative Care?

How about seven?

Within our power, we are committed to providing the best hospice and palliative care experience available. That commitment is expressed in our Seven Point Pledge.

4. Respond to all patient-related calls within 15 minutes, 24 hours a day, 7 days a week. A patient’s condition doesn’t take a day off, and neither do we.

Evercare Hospice & Palliative Care pledges to:

5. Provide a hospice staff presence at the time of death. We’ll be there at this important time, as we have throughout the process, to provide comfort and support.

1. Admit all hospice-eligible referrals the same day, unless requested otherwise. Patients deserve timely care and action, especially as they approach end-of-life.

2. Provide direct, extensive physician involvement in the care of each patient. Experts highly trained in hospice and palliative care are involved and available to make personal visits.

3. Achieve acceptable pain control on all patients.

No patient should live in pain. That’s why we place such an emphasis on delivering pain management in a timely and caring manner.

6. Maintain an Unrestricted Options Philosophy regarding patient admissions. We believe in making hospice care available to all those who are eligible.

7. Offer palliative care consults and advanced care planning services. These continuing health care services are important, so we offer expertise in both areas.

Questions?

For questions or referrals, call Evercare Hospice and Palliative Care at:

1-877-273-5534 www.EvercareHospice.com Services are provided regardless of patient’s ability to pay.

Evercare™ Hospice and Palliative Care is committed to the policy that all persons shall have equal access to its programs, facilities, and employment without regards to race, sex, religion, color, age, national origin, disability, sexual orientation or other protected factor. Evercare Hospice and Palliative Care is offered by Evercare Hospice, Inc. © 2011 Evercare

TON_December 2011_v3_TON 12/21/11 11:27 AM Page 40

Answered!

Your FAQs...

Q:

A:

What are the different types of amyloidosis and what treatment options are available?

out multiple myeloma.1 Congo red staining performed on the biopsy will be The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progrespositive for amyloid in <60% of patients.1 Congo red staining of tissue from an 1 involved organ or surrogate site (fat pad, gingiva, or rectum) may also lead to sive organ damage. The incidence of immunoglobulin light chain (AL) amyloidosis (also referred to as primary amyloidosis) diagnosis.3 Deciphering the type of amyloidosis is essential in establishing the 1 appropriate intervention and treatment.3 is approximately one-tenth that of multiple myeloma, a more common cancer of the bone marrow plasma Treatment cells. In approximately 10% of patients, both AL amyloidosis Treatment for AL amyloidosis is highly individualized and is and multiple myeloma are present at the time of diagnosis.2 The process of amyloid formation results in cellular based on age, organ dysfunction, and regimen toxicities.1 The prognosis for The goals of therapy are prompt elimination of the misfoldinjury, tissue damage, and organ dysfunction through patients with ed amyloidogenic light chains, minimization of treatment mechanisms that are not completely understood.1 Patients with amyloidosis usually present with a small plasma cell toxicity, and support of the function of target organs.1 For amyloidosis many years, melphalan plus prednisone was considered the clone with evidence of dysfunction in 1 or more involved varies standard therapy for patients with AL amyloidosis who are organs.1 Most commonly, this includes renal involvement in approximately 70% of amyloidosis patients, with not candidates for autologous stem cell transplantation.2 considerably More recently, dexamethasone has been substituted for nephrotic range proteinuria or renal failure; cardiomyopadepending on the prednisone in association with melphalan, resulting in thy in approximately 60%; and peripheral neuropathy in nature, number, much higher hematologic responses.1 A reduction in proapproximately 20%.1 Among newly diagnosed patients, 3 30% have 3 or more major organ systems involved. teinuria has been noted in up to 50% of patients treated and extent of The prognosis for patients with amyloidosis varies conwith these regimens, though they are not without risk.2 organ involvement.

Melphalan-induced cytogenetic abnormalities can lead to siderably depending on the nature, number, and extent of pancytopenia and/or secondary myelodysplastic syndromes, organ involvement.2 Median survival may be as short as 4 Median survival to 6 months, with cardiac failure, hepatic failure, and/or with an incidence of these complications of up to 6.5%.2 may be as short as 2 However, the actual risk may exceed 20% in those who infection being the major causes of death. However, those 4 to 6 months. patients with limited organ involvement can expect a appear to have a good amyloid response and survive for median survival in excess of 5 years.2 more than 3.5 years.2 Thalidomide as a single agent has limited efficacy and is Types of Amyloid Diseases poorly tolerated, with fatigue and sedation being the major To date, at least 28 different proteins have been identified as causative agents dose-limiting toxicities, followed by fluid retention, constipation, orthostasis, of amyloid diseases.4 AL amyloidosis is the most common form of amyloid peripheral neuropathy, and worsening renal function.1 Somewhat better results disease and is due to deposition of protein derived from immunoglobulin have been obtained when thalidomide was combined with dexamethasone.2 4 Thalidomide/dexamethasone can be considered an option alone or in combilight chain fragments. It is considered a plasma cell dyscrasia in which a monoclonal protein is detectable in the serum or urine in approximately 80% nation with cyclophosphamide for the treatment of patients who relapse after of cases.4 AA (or secondary) amyloidosis is characterized by extracellular tismelphalan/dexamethasone or stem cell transplantation.2 Lenalidomide in combination with dexamethasone may also be reasonable sue deposition of fibrils composed of fragments of serum amyloid A (SAA) for patients who relapse after melphalan/dexamethasone or stem cell transprotein, an acute-phase reactant. AA amyloidosis is related to a chronic disease in which there is ongoing or recurring inflammation, such as rheumatoid arthritis or inflammatory bowel disease.4 Dialysis-related amyloidosis is due to deposition of fibrils derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease on long-term dialysis therapy.4 Amyloid deposition may also be isolated to a single organ, such as the skin, eye, heart, etc, and has been shown to be biochemically identical to systemic forms of amyloid.4

This Monthâ&#x20AC;&#x2122;s FAQ

Answered by:

Carli Greenfield, ACNP

Diagnosis Early diagnosis is the key to effective therapy, allowing reversal of the organ damage and better tolerability of adverse effects of therapy.1 Approximately 40% of patients have light chainâ&#x20AC;&#x201C;only disease, and therefore diagnosis is often missed if only serum protein electrophoresis is performed.1 However, the combination of serum and urine immunofixation electrophoresis with serum free light chain assay approaches 100% sensitivity for diagnosis.1 If a serum monoclonal protein is present, a bone marrow biopsy should be performed to rule

40

December 2011 I VOL 4, NO 8

Ohio State University Medical Center Columbus, Ohio Do you have a question youâ&#x20AC;&#x2122;d like answered?

E-mail us at editorial@greenhillhc.com

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:27 AM Page 41

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_December 2011_v3_TON 12/21/11 11:27 AM Page 42

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_December 2011_v3_TON 12/21/11 11:27 AM Page 43

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_December 2011_FINAL_TON 12/22/11 7:20 AM Page 44

Your FAQs... plantation.2 The most common adverse effects of this combination are cytopenia, fatigue, and rash.1 Hematologic responses have ranged from 41% to 47%.1 In addition, bor-

Answered!

tezomib has significant activity in AL amyloidosis, with the most common nonhematologic toxicities including peripheral sensory neuropathy with or without neuropathic pain, exacer-

bation of orthostatic hypotension, peripheral edema, and constipation or diarrhea.2 A phase 3 study comparing bortezomib/melphalan/dexa methasone with melphalan/dexa-

The Amyloidosis Clinical Trials Network should also be explored for those patients considering clinical trial participation, as novel agents and regimens are showing great promise in the treatment of amyloidosis.

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.

methasone is currently in progress.2 A significant advance in myeloma chemotherapy has been the addition of stem cell transplantation, and this approach has since been adapted for patients with AL amyloidosis.1 The fragility of the amyloidosis patient population was soon evident, however, when some transplant centers reported treatment-related mortality exceeding 40% or more in those with

cardiac involvement.1 In an attempt to reduce treatment-related toxicity, attenuated melphalan dosing has been used in high-risk and older patients, resulting in reduced toxicity but generally lower response rates.1 Both cardiac and renal transplantation have been successfully carried out in AL amyloidosis patients with associated organ involvement.1 The Amyloidosis Clinical Trials Network should also be explored for those patients considering clinical trial participation, as novel agents and regimens are showing great promise in the treatment of amyloidosis. ●

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.

References

AONNKsize_81911

www.AONNonline.org 44

December 2011 I VOL 4, NO 8

1. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011;29:1924-1933.

2. Rajkumar SV. Prognosis and treatment of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases. UpToDate 19.2. http://www.uptodate.com/contents/prognosis-andtreatment-of-immunoglobulin-light-chain-al-amyloido sis-and-light-and-heavy-chain-deposition-diseases.

Updated June 3, 2011. Accessed November 7, 2011.

3. Comenzo RL. How I treat amyloidosis. Blood.

2009;114:3147-3157.

4. Gorevic PD. An overview of amyloidosis.

UpToDate 19.2. http://www.uptodate.com/contents/ an-overview-ofamyloidosis?source=search_result &search=An+overview+of+amyloidosis.&selectedTitl e=1~150. Updated November 2, 2010. Accessed November 7, 2011.

www.TheOncologyNurse.com

TON_December 2011_FINAL_TON 12/22/11 10:27 AM Page 45

Pharmacoeconomics

Thromboembolism After Chemotherapy Raises Healthcare Costs About 30%

By Caroline Helwick

T

he development of venous thromboembolism (VTE) in patients with cancer has a significant impact in terms of morbidity and mortality and healthcare costs, according to a “real-world analysis” reported at the 2011 European Multidisciplinary Cancer Congress.

Gary H. Lyman, MD, MPH, an oncologist at Duke University School of Medicine, Durham, North Carolina, was principal investigator.

Lyman is a frequent contributor in the area of health economics and comparative effectiveness research. “VTE development was associated with a significant economic burden in terms of healthcare expenditure,” he noted.

Lyman and colleagues assessed the economic impact of VTE occurrence using the US-based InVision Data Mart Multiplan/Integrated Health Care Information Solutions database. They retrospectively identified 30,552 patients with cancer who initiated chemotherapy in the 4-year period ending in 2008. Healthcare costs such as inpatient, pharmacy, emergency department, and outpatient expenses were assessed 1 year preindex and postindex treatment (first day of chemotherapy after cancer diagnosis).

The incidence of VTE 3.5 months after the initiation of chemotherapy ranged from 4.8% to 11.9%, depending on tumor site. The highest risk was observed in patients with pancreatic, stomach, and lung cancers. The incidence continued to increase over time postindex treatment, peaking at 9.9% to 21.5% at 12 months, Lyman reported.

High Healthcare Costs Patients who developed VTE within 3.5 months postindex treatment had healthcare costs at baseline that were comparable with persons not developing VTE. During the first year postindex, costs in patients with VTE were significantly higher than in those without VTE, primarily driven by higher inpatient and outpatient costs.

The overall healthcare costs 1 year before receiving chemotherapy were $37,542 for patients developing VTE and $35,342 for those without VTE. By 1 year postindex treatment, costs had risen to $110,362 and $77,984, respectively, Lyman reported.

Costs were higher for patients with VTE in each category of expenditure: inpatient, outpatient, emergency department, and pharmacy.

“Similar results were seen for pa -

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tients who developed VTE within 12 months postindex,” he said.

“The decision for the use of thromboprophylaxis in cancer patients

undergoing chemotherapy should be based on the balance between the potential benefits and harms, including any bleeding risk associated with a

therapy,” Lyman pointed out.

There is a need to assess cost-effectiveness of prevention in this setting, he added. ●

REGISTER TODAY & SAVE $100

April 20-22, 2012 • Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

CORE PRINCIPLE SOLUTIONS, LLC

Teresa Petrella, BSc, MD, MSc, FRCPC Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours.

Early registration of $425 ends January 13, 2012!

REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit.

The universal activity number for this activity is 0468-9999-089-L01-P.

December 2011 I VOL 4, NO 8

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Breast Cancer

CLEOPATRA Affirms Principle of Dual HER2 Blockade in HER2-Positive Metastatic Breast Cancer

By Alice Goodman

D

ual HER2 blockade with trastuzumab plus pertuzumab combined with docetaxel chemotherapy significantly extended progression-free survival (PFS) by about 6

AY OD T 0 TER $10 S I E G RE SAV

months compared to trastuzumab plus docetaxel plus placebo in patients with metastatic HER2-positive breast cancer, according to results from the CLEOPATRA trial presented at the

CTRC-AACR San Antonio Breast Cancer Symposium.

“These findings represent a significant advance in the treatment of advanced breast cancer. The results may be prac-

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 • JW Marriott • Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • Analyze the patient issues around cost, quality, and access to care

Gary Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS

DESIGNATION OF CREDIT STATEMENTS

President, CEO OncoMed

Physician Accreditation – Joint Sponsor The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

46

December 2011 I VOL 4, NO 8

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

tice changing,” said senior author Jose Baselga, MD, PhD, Professor at Harvard Medical School and Associate Director of Massachusetts General Hospital in Boston.

These results affirm the concept of dual HER2 blockade in HER2-positive metastatic breast cancer. Pertuzumab and trastuzumab have distinct mechanisms of action and bind at different sites. “The 2 antibodies are extremely complementary and synergistic in preliminary studies,” he said.

CLEOPATRA was a randomized registration phase 3 study for pertuzumab. The study randomized 808 patients in a 1:1 ratio to trastuzumab/ docetaxel chemotherapy with pertuzumab or placebo. Docetaxel was given every 3 weeks for 6 cycles in both arms, and investigators could decide whether to continue it on an individual basis. Both monoclonal antibodies were given every 3 weeks until evidence of disease progression.

Patients had no prior therapy for metastatic disease, except 1 line of prior hormone therapy was allowed.

Prior chemotherapy was allowed if 1 year had passed. More than threequarters of patients had visceral metastases; the remainder had metastases confined to the bone.

By independent review, median PFS was 12.4 months in the control arm versus 18.5 months in the experimental arm, which was highly statistically significant (P <.0001).

All prespecified subgroups benefitted from dual HER2 blockade, with the exception of patients with nonvisceral metastasis. A strong trend toward improved overall survival was observed for the experimental arm, but this was an interim analysis, and the data need to be more mature for meaningful survival results, Baselga said.

Treatment was safe and tolerable, with no cardiac toxicity observed.

Only minimal side effects were seen with the addition of pertuzumab, including grades 1 and 2 diarrhea and neutropenia.

“This represents an advance in treatment of HER2-positive breast cancer,” said Lisa Carey, MD, University of North Carolina at Chapel Hill, North Carolina, who moderated the press conference where CLEOPATRA was discussed. “The challenge now is to find biomarkers to identify which patients will derive benefit from dual HER2 blockade,” she said. ●

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TON_December 2011_FINAL_TON 12/22/11 10:28 AM Page 47

The Whole Patient

Sexual Issues and Nurse’s Role: Just Ask!

By Alice Goodman

C

ancer and its treatments can cause sexual side effects, and oncology nurses are often in the best position to bring up the topic and provide useful information as well as emotional support. The most important thing a nurse can do to help patients is to initiate the discussion.

“Just ask at some point in your interactions with patients. This opens the door for sexual questions and concerns, and most concerns are easily addressed by the nurse,” stated Anne Katz, RN, PhD, clinical nurse and sexuality counselor at CancerCare Manitoba, Winnipeg, Canada. Katz spoke about sexuality at the 12th Annual Oncology Nursing Society Institutes of Learning in Salt Lake City, Utah.

Although specific cancers may be associated with specific sexual issues, in general, the major sexual issues facing male cancer patients include erectile dysfunction, loss of libido, and changes in orgasm; and the major problems facing females include loss of libido, vaginal dryness and painful intercourse, body image issues, and orgasmic changes.

All oncology nurses should be aware

General principles include bringing up sexuality and making the patient comfortable in discussing sexuality, which is an important part of quality of life. of 2 models that are helpful in assessing patients’ sexuality, Katz said: PLISSIT (permission, limited information, specific suggestions, and intensive therapy) and BETTER (bring up the topic; explain you are concerned with qualityof-life issues, including sexuality; tell patients you will find appropriate resources to address their concerns; timing may not be appropriate now, but tell patients they can ask for help at any time; educate patients about the side effects of their cancer treatment; and record your assessment and intervention in the patient chart).

In her practice as a sexuality counselor, Katz prefers to use the PLISSIT model because it speaks more directly to her training, but she said that the BETTER model is more applicable to nurses.

“Whatever model they use, the most important thing to do is to ask about sexuality,” she said.

She presented 4 common sexual problems that cancer patients can face.

Case 1 is a patient with breast cancer who is unhappy with her breast reconstruction and finds that this interferes with her sexual response. She has thought about leaving her husband so that he can find someone to fulfill his sexual needs. Patient 2 is a man with prostate cancer who had nerve-sparing surgery and cannot have a sufficient erection for sexual intercourse. He does not want to include his wife in the discussion. Patient 3 is a woman with cervical cancer who had a total hysterectomy 3 months ago. She attempted to have sexual intercourse after 6 weeks

and she had no feeling, although prior to surgery she was multiorgasmic and really enjoyed sex. Patient 4 is a man who had a stem cell transplant 1 year ago and now has loss of libido.

The nurse can help by asking patients additional questions, identifying the major issues, and making suggestions.

General principles include bringing up sexuality and making the patient comfortable in discussing sexuality, which is an important part of quality of life (ie, normalizing the sexual concern). Let the patient know that you will help him/her find adequate resources for treating the problem, and if it is beyond your scope, you will refer the patient to an expert. Another important issue is timing of the intervention. Patients may not be ready now to deal with the sexual issues, but let them know they can call on you any time in the future.

It is important to educate patients about possible side effects of treatments, making sure to tell them that not everyone gets these side effects. Also, it is important to record brief details about the discussion of sexuality and side effects in the patient’s chart. ●

Sensitivity and Knowledge About Different Cultures Helps Communication With Patients

By Alice Goodman

T

here has been increasing recognition of the importance of cultural competence in caring for patients and in improving patient outcomes. This subject was explored by Wael Al Zayyer, PhD, Executive Consultant at the King Fahad Specialist Hospital, Damman, Saudi Arabia, during the 12th Annual Oncology Nursing Society Institutes of Learning.

There are various definitions of culture, but for the purposes of his discussion, he defined culture as a shared set of beliefs, values, and expectations of a group according to ethnicity or religion.

Al Zayyer made an important distinction between cultural sensitivity and cultural competence. Culturally competent care entails knowledge about that particular culture, a nonjudgmental attitude free of stereotyping, and skills that facilitate communication. Also, the practitioner has to have experience with the different communities and ethnic groups and the desire to work with people from different cultures, he said.

Training in cultural competence has gained favor around the world; in the

www.TheOncologyNurse.com

United States, some states mandate that physicians be trained in cultural competence, while other states recommend such training. Several models for cultural competence exist, among them BATHE, BELIEF, ESFT, KLEINMAN’S, and LEARN. Whatever model is used, the practitioner has to learn normative cultural values, be aware of language issues when communicating, know about folk illnesses related to that culture, and be aware of patient and family beliefs. Domains to be considered include access to healthcare, social stressors and support network, changes of environment, feeling in control of one’s life, and literacy.

Barriers to achieving cultural competence include underrepresentation of different cultures in the healthcare workforce, complexity of healthcare organizations, lack of human and financial resources, and barriers to communication.

Al Zayyer described specific healthcare issues that are affected by culture.

For pregnancy and birth, cultural issues include circumcision, placenta, breast-

feeding, care of the new mother, visitors after childbirth, and the role of the father. Cultures have different practices related to food preference and intolerance: preparation, types of foods, herbal treatments, use of alcohol and drugs, kosher food for Jewish people, and type of water. End-of-life practices also differ depending on culture and religion, including sharing information about terminal illness, advance directives, care of the body, and organ donation. Cultural expectations and types of support also affect palliative care. Other issues impacted by culture include gender concerns, perceptions of mental illness, and treatment beliefs.

The healthcare practitioner should show respect when communicating with people of different cultures by following expectations regarding eye contact, physical contact, and conversation limits for different groups.

The following are some examples of specific religious issues about death and dying. Hinduism holds that illness is caused by “Karma,” and patients are more likely to accept death. They pre-

fer to be at home facing east with a lamp when dying, he said. Buddhists prefer a quiet place for death and allow organ transplant and autopsy. White is the mourning color for Buddhists.

Judaism does not specify a preferred place for death, but euthanasia and assisted suicide are forbidden, and a rabbi is usually there for spiritual support. Christianity prohibits the use of human tissue obtained by direct abortion. Islamic patients pray 5 times a day, and Friday is the most important day of worship.

During Ramadan, Islamic patients fast for 30 days from sunrise to sunset. Islamic patients prefer a same-sex healthcare provider, and organ donation may be allowed. The Quran is recited during illness and throughout dying, and patients face Mecca during death.

Cultural competence can reduce healthcare disparities, improve communication between the healthcare team and the patient and family, and improve outcomes. “Cultural competence promotes providing care through a holistic approach for the whole patient,” Al Zayyer stated. ●

December 2011 I VOL 4, NO 8

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TON_December 2011_v3_TON 12/21/11 11:29 AM Page 48

New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

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

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

il

f

i dd

TON_December 2011_v3_TON 12/21/11 11:29 AM Page 49

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

80

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

10

MP (n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

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Prostate Cancer

New Bone-Targeting Compound Improves Survival in Metastatic Prostate Cancer

By Caroline Helwick

A

n investigational alpha-pharmaceutical not only prevented skeletal-related events (SREs) in patients with prostate cancer with

bone metastases in a phase 3 study presented at the 2011 European Multidisciplinary Cancer Congress, but it also improved overall survival.

“This is the first drug targeted to bone metastases in prostate cancer to improve survival,” said lead investigator Chris Parker, MD, Royal Marsden

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

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.

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.

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. 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.

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: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.

Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) m may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

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 VELCADE.com.

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.

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.

Use in Pregnancy: 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.

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. All rights reserved.

Printed in USA

V-11-0264

12/11

Hospital, London. “There are other bone drugs used in prostate cancer, but they help to minimize symptoms; they don’t improve survival. In my opinion, radium-223 is likely to become a new standard of treatment for advanced prostate cancer,” Parker told journalists at a press briefing.

Jean-Charles Soria, MD, Institut Gustave Roussy, Villejuif, France, who cochaired the meeting’s scientific program, agreed. “This is really practice changing, and after regulatory approval, I think this is going to be a major player in advanced prostate cancer.”

A US coinvestigator of the trial, Oliver Sartor, MD, Tulane University, New Orleans, Louisiana, said the radiopharmaceutical is far superior to prior compounds of the sort, and the study results were highly impressive.

Radium-223 chloride (Alpharadin; Algeta/Bayer) was recently granted a fast-track designation by the US Food and Drug Administration. The company plans to file a New Drug Application in mid-2012.

The Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial was a phase 3, randomized, double-blind, placebo-controlled, international study that compared radium-223 chloride plus current standard of care with placebo plus current standard of care in 922 men with symptomatic castration-resistant prostate cancer that had spread to the bone. Patients had multiple skeletal metastases on bone scan and were taking regular analgesics for bone pain.

At a planned interim analysis, patients who received radium-223 had the following positive outcomes: • Median overall survival: 14 months compared with 11.2 months for the placebo group, a 30% reduction in mortality (P = .00185) • Time to first SREs: 13.6 months versus 8.4 months, a 64% improvement (P = .00046) • Total alkaline phosphatase (bone marker) normalization: 33% versus 1% (P <.001) • Time to prostate-specific antigen progression: 49% improvement (P = .00015).

Nonhematologic adverse events were not significantly worse with radium-223 versus placebo; the most common grade 3/4 adverse events were bone pain (18% vs 23%, respectively). Other serious toxicities were uncommon.

Based on the interim analysis, the data monitoring committee recommended the study be stopped and patients in the placebo arm be offered radium-223. ●

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TON_December 2011_v3_TON 12/21/11 11:29 AM Page 51

The Oncology Nurse-APN/PA is pleased to announce the Second Annual Oncology Nurse Excellence award sponsored by TREANDA.

Who Will Be the

ONE?

The Oncology Nurse Excellence Award Winner The Oncology Nurse-APN/PA Nurse Excellence award will recognize an oncology nurse nominated by his/her peers for an outstanding contribution to oncology nursing practice, patient care, research, or education in 2011.

The four leading nominees will be profiled in the February issue of The Oncology Nurse-APN/PA. Readers will have an opportunity to vote for the winner online at www.TheOncologyNurse.com/award or by visiting The Oncology Nurse-APN/PA booth at the 2012 ONS Congress. The winner will be announced in the June issue of The Oncology Nurse-APN/PA.

TREANDA is manufactured by Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.

Nomination forms are available at

www.TheOncologyNurse.com/award

TON_December 2011_FINAL_TON 12/22/11 6:54 AM Page 52

Palliative Care

Nurses May Help Drive Integration of Palliative Care for Radiation Therapy Patients

By John Schieszer

D

ue to the tremendous physical, psychological, and economic burdens of end-stage diseases, there now is an increasing need for palliative care as an integral part of the treatment plan in the management of radiation oncology patients, according to Marilyn Haas, PhD, nurse practitioner at CarePartners Supportive and Palliative Services, Asheville, North Carolina. In addition, she said that integrating palliative care earlier rather than later may be especially important in those patients with metastatic disease.

Haas presented a comprehensive model on integrating palliative care for radiation therapy patients at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO). She noted that we are now in a new era for palliative care, and it is the oncology nurses who can help set up palliative care programs at their individual facilities.

“The nurses are the ones who are going to drive this to get this into their practice. The physicians are a little bit skeptical because they relate palliative care to hospice care,” said Haas in an interview with The Oncology NurseAPN/PA. She said this is a common misconception among many healthcare workers who do not realize that palliative care is very different from hospice care.

Palliative care patients receive treatment (radiation, chemotherapy, etc) to control their disease even though it may not be responsive to care. “It is not hospice care nor is it just end-of-life care,” said Haas.

However, palliative care can be part of hospice care.

Palliative medicine was first defined as a specialty in the United Kingdom in 1988. Within 2 years, the concept was brought to Montreal, Canada, by Balfour Mount, MD, a Canadian surgeon, and introduced in the hospital setting, where the term “palliative care unit” was estab-

lished. Today Mount is considered the father of palliative care in North America. The World Health Organization defines palliative care as “the active total care of patients whose disease is not responsive to curative treatment.

Control of pain, of other symptoms, and of psychological, social and spiritual problems is paramount. The goal of palliative care is the achievement of the best possible quality of life for patients and their families.”

Haas said that palliative care affirms life and regards dying as a normal process. It intends to neither hasten nor postpone death and integrates the psychological and spiritual aspects of patient care. Palliative care also offers a support system to help patients live as actively as possible until death.

Using a team approach, palliative care occurs in multiple settings, including in-patient, community, nursing home, and a patient’s home.

Palliative care can significantly

improve quality of life of patients and their families. However, Haas noted there are barriers to referral for palliative care “due to misconceptions and confusion.” She said other barriers to referral for palliative care are discomfort communicating the prognosis and fear of losing control of the patient.

However, she said these barriers can be overcome, and nurses can play a key role in establishing a palliative care clinic within radiation oncology departments. “These are very timeconsuming patients,” said Haas.

“Nurses are going to be leaders in integrating palliative care.”

She said a palliative care team consists of a physician and/or nurse practitioner or physician assistant, registered nurses, medical social workers, and clergy. Haas said palliative care programs also must define the immediate and long-term goals of care and promote advanced planning. In addition, palliative care programs can help educate patients and their families to help them better understand the underlying disease process. Haas said palliative care programs help establish an environment that is comforting and healing and are a natural complement to traditional medical care. ●

Projected Oncologist Shortage

Sharing the Workload With NPs and PAs May Be a Solution for Projected Shortage of Oncology Providers

By Alice Goodman

I

ncorporating nurse practitioners and physician assistants into oncology practices appears to be an effective strategy for dealing with an impending shortage of oncologists and at the same time improving productivity and achieving both patient satisfaction and provider satisfaction, according to a recent study.1 “Patients were aware when the care was provided by a non-physician practitioner (NPP) and were very satisfied with all aspects of the collaborative care they received. The integration of NPP into oncology practice offers a reliable means to address increased demand for oncology services without adding physicians,” wrote the authors.

Practices where the NPP worked with all practice physicians demonstrated significantly higher productivity than practices where the NPP worked exclusively with a specific physician or group of physicians. Interestingly, the practices that had a higher than average number of patient encounters per FTE (full-time equivalent) provider felt they could be

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December 2011 I VOL 4, NO 8

even busier, while being less busy was associated with the subjective perception of being able to see fewer patients.

“There is little observed correlation between the subjective perception of workload and the objective measure of work production,” the authors wrote.

Practices where the NPP worked with all practice physicians demonstrated significantly higher productivity.

In 2007, a study by the American Society of Clinical Oncology (ASCO) projected a shortage of about 4000 oncologists by the year 2020. The demand for oncologists is expected to increase by 48% by 2020, while at the same time the number of oncologists is expected to increase by 14%. Part of what will drive the need for more oncologists is an aging population (the num-

ber of people aged 65 and older is expected to double by 2030) and an 81% expected increase in the number of cancer survivors.

In 2009, ASCO initiated the first phase of the ASCO Study of Collaborative Practices to identify practices that used NPPs. That study identified 226 community hospitals and hospitalbased practices from 43 states. The second phase of that study included 33 diverse practices with more in-depth assessment of experiences of physicians, NPPs, and patients in those practices, including levels of satisfaction.

Approximately 40% of practices were from the Midwest, 30% from the East Coast, 20% from the West, and 10% from the South. The majority were physician owned (84%); 16% were hospital owned. The practices included in the in-depth surveys were mainly those where NPPs see patients independent of the physician, although the physician is usually present in the office.

Ninety-eight percent of patients were aware that an NPP was providing clini-

cal services. Satisfaction measures showed that 92.5% of patients were extremely satisfied with the services they received at every study site. Although physician and NPP satisfaction varied at different sites, overall physician satisfaction score was 79.8% and overall NPP satisfaction score was 78.2%. There was no correlation between physician and NPP satisfaction scores.

Commenting on this study in a press release, ASCO President Michael P. Link, MD, stated: “In anticipation of the projected shortage, ASCO continues to seek solutions that will not only transform oncology care, but translate to a high level of excellence. This study shows that practices are extending oncology services by promoting a collaborative practice with nurse practitioners and physicians’ assistants. In pediatric oncology, nurse practitioners are already an integral part of our practice and are indispensable.” ● Reference 1. Towle EL, et al. J Oncol Pract. 2011;7:278-282.

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:29 AM Page 53

BD Welcomes BD PhaSeal®

BD is pleased to announce the addition of BD PhaSeal, a unique evidence-based closed-system drug transfer device (CSTD) for safe handling of hazardous drugs, to its family of BD Medical products.

At BD, healthcare worker safety has always been an important focus. The addition of BD PhaSeal will help provide an enhanced suite of safety products to its customers.

For more information about BD PhaSeal, call 1-866-487-9250 or visit www.phaseal.com.

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BD, BD Logo and BD PhaSeal are registered trademarks of Becton, Dickinson and Company. © 2011 BD.

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TON_December 2011_v3_TON 12/21/11 12:51 PM Page 54

Cancer Center Profile Breastlink Medical Center Breastlink has a philosophy of providing “Optimal Care” to women.

Can you describe this philosophy and how it impacts your ability to provide personalized care to your patients?

Lori Kells-Rezabek (LKR): In addition to providers specializing in breast cancer who are at the top of their field, we have a whole array of services to ensure that we are providing optimal care.

We have a weekly Radpath conference in which the radiologists, surgeons, and medical oncologists participate. Cases of all new patients diagnosed with breast cancer are presented, treatment options discussed, and recommendations made for optimal treatment, including surgery, neoadjuvant versus adjuvant chemotherapy, and plastic surgery options.

We have a monthly Metastatic Tumor Board that meets and discusses complicated cases of metastatic breast cancer that includes a review of the history, radiology studies, and molecular profile. We then make further recommendations for treatment.

We have a monthly Metastatic Breast Cancer Support Group that meets with both the patients and their husbands to provide psychotherapeutic support. We have a Young Women’s Support Group for women with children that meets monthly.

We send 2 patients to the San Antonio Breast Cancer Symposium every year and then offer our findings and their impressions of the conference in an educational presentation every January.

But most importantly, we have a great team of professionals, including a breast medical oncologist, a breast

Continued from cover

“We consider all issues, and take into account the age of the woman, and recommend treatment based not on age but on quality-of-life issues.”

—Lori Kells-Rezabek, NP, PhD

oncology nurse practitioner, an oncology nurse, and an on-site oncology therapist, who evaluate and treat patients on a daily basis.

What are you excited about right now in the breast cancer field?

LKR: The breast cancer vaccine. We have a collaborative relationship with the University of Washington, which has developed a vaccine for women with HER2/neu–positive breast cancer. We have treated 20 patients to date with the vaccine, with overwhelmingly favorable results. A new clinical trial is planned that we will be participating in for women at high risk for relapse.

Caris molecular profiling. We have been working with a company called Caris that provides us with molecular profiles of our patients with breast cancer. These profiles provide us with potential targets of therapy that are based on the individual patient’s tumor and tell us what the best options of treatment are. Because breast cancer tends to change over time, we routinely repeat biopsies to monitor potential changes in estrogen and progesterone receptors, as well as in HER2/neu status,

and obtain updated molecular profiling if necessary.

Research. We have clinical trials, and we select out trials looking for the newest drugs, diagnostic tools, and molecular tests available for women with breast cancer. We also provide research in the areas of quality of life and survivorship.

What are the most important lifestyle changes women can make for breast cancer prevention?

LKR: Maintaining a BMI (body mass index) under 25. It is important to maintain an ideal body weight, as obesity is the biggest risk factor for the development of breast cancer.

Exercise. Brisk walking for 30 minutes a day has been shown to decrease the risk of breast cancer by 15%. Four hours of strenuous exercise a week has been shown to decrease the risk of breast cancer by 25%.

Optimizing vitamin D. We check vitamin D levels every 6 months and recommend a vitamin D level of 50 or greater. We recommend supplemental vitamin D of approximately 4000 IU daily to keep levels where they need to be to help decrease risk of breast cancer.

Limiting alcohol intake. We recommend limiting wine or beer intake to less than 3 ounces a day, or an average of 21 ounces a week, as this has been shown to decrease risk of breast cancer.

Daily low-dose aspirin. We recommend taking 81 mg aspirin daily to decrease not only the risk of breast cancer, but also colon cancer, lung cancer, and esophageal cancer.

Any advice for nurses just entering the oncology field?

The Manhattan Beach, California, center of Breastlink.

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December 2011 I VOL 4, NO 8

LKR: Working with women who have breast cancer is extremely rewarding. To be able to help and witness these wonderful women fight their courageous battle with this disease is an honor, and the most rewarding job one can imagine! From their diagnosis, to their staging studies and treatment recommendations, often including chemotherapy, I am there with them every step of the

way, encouraging them, supporting them with education and experience, and helping them survive breast cancer.

We have a significant number of women who have been dealing with metastatic disease for 5, 10, and even 20 years, and done so with such courage and grace. I am privileged to be included on their journey. That is the best part of my job, to be able to witness how women deal with their diagnosis and their treatment every day, all the while juggling their work, their relationships, and their families. It is the most rewarding job you can have, to make a difference in someone’s life, and ease their struggles with this disease.

What is a Survivorship Program?

LKR: We have developed a Survivorship Program here at Breastlink that starts the minute the patient calls for an initial consultation. From our expert breast cancer intake advisor (a breast cancer survivor herself), who collects all the necessary information to provide optimal care, to the breast cancer team, we are considering survivorship issues.

From deciding the best referral, whether it be to the surgeon or the medical oncologist first, we are paving the way for the breast cancer patient to be a survivor in the best possible way.

We consider all issues, and take into account the age of the woman, and recommend treatment based not on age but on quality-of-life issues. We also take into account fertility issues in women of childbearing age.

Once women have completed their treatment, they return to their lives with the tools they need to survive breast cancer.

What does it mean to be a community-based medical group conducting research?

LKR: We are the first nonhospital and nonacademic medical group conducting breast cancer research. We are also helping to develop the tools and treatment options for targeted breast cancer therapy while looking at the molecular composition of tumors and their biomarker expression patterns. ●

Did You Know?

The National Cancer Institute currently des ignates 66 research institutions as Cancer Centers. These centers are engaged in transdisciplinary research to reduce cancer incidence, morbidity, and mortality.

—National Cancer Institute Office of Cancer Centers

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:30 AM Page 55

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4

PREWASHED VIALS reduce cytotoxic residue.

G E M C I TA B I N E I N J E C T I O N (38 mg/mL)

2 g/52.6 mL single-dose vial 1 g/26.3 mL single-dose vial 200 mg/5.26 mL single-dose vial

For more information, contact your

Hospira representative or call 1-877-946-7747.

Or visit us at products.hospira.com.

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

TOPOTECAN INJECTION (1 mg/mL)

4 mg/4 mL single-dose vial See Black Box Warning

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

8877 O

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

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.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

For intravenous infusion only.

Initial U.S. Approval: 1996

For Intravenous Infusion Only.

Must Be Diluted Before Use. Initial U.S. Approval: 1996

Must be diluted before intravenous infusion Initial U.S. Approval: 1996

•

•

• •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3.

Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only.

• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) 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)

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning.

Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1) CONTRAINDICATIONS • History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4) • Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS • Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) • Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) • Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) ADVERSE REACTIONS Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%).

(6.1) • The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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.

See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

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

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Made in India

TON_December 2011_FINAL_TON 12/22/11 12:14 PM Page 58

Survivorship

A Call for Improved Guidelines for Adult Cancer Survivors

By John Schieszer

T

here is a lack of guidelines when it comes to standard of care for adult cancer survivors, and it is time to start thinking about establishing such guidelines, according to nurse practitioner Richard Boyajian, who is Clinical Director of Adult Survivorship at Dana-Farber Cancer Institute, Boston, Massachusetts. He said establishing appropriate guidelines could potentially reduce morbidity and mortality.

“Posttreatment standards of care are something that I am a big believer in,” said Boyajian. “We know that on-treatment is a very well-tuned machine, especially in radiation oncology where things are really run very well and very systematically. The problem is when the patient finishes treatment, and that is when the wheels basically fall off the cart.”

He said most cancer patients are just told to come back in a few months to see if their disease has returned after completing treatment. Instead, he said, better treatment plans are needed.

Boyajian said that there is no standard approach to posttreatment care today.

Oncology nurses need guidelines or a blueprint to follow so they know what they can and should be doing for cancer survivors after treatment.

Boyajian presented an educational session on adult cancer survivors entitled “Adult Cancer Survivors: One Size Does Not Fit All” at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO). He said establishing posttreatment management guidelines for cancer survivors can help empower patients and their families. In addition, such guidelines could be designed to improve coordination of care and communication. He said that ultimately this entire issue is about improving quality of life and potentially reducing morbidity and mortality.

“The nurses as usual need to do a lot of the work to get this done. Survivorship is not something that a lot of physicians are

that interested in. There are select handfuls of physicians who have an interest, but the nurses seem to be the passionate ones about survivorship, and what I am trying to do is give them a framework to create these standard guidelines within their own practice,” explained Boyajian.

Currently, Boyajian does not expect that there will be national guidelines developed. He said there are not enough evidence and research studies on which to base recommendations. However, Boyajian said cancer patients cannot wait until research studies are completed.

“So, I am a big believer in consensus guidelines at your institute. It doesn’t matter if you are at a private practice or a major cancer center,” said Boyajian in an

interview with The Oncology NurseAPN/PA. “Basically, you need to set up guidelines for your practice on how you will follow an individual patient.”

He said that in 1971 there were about 3 million cancer survivors in the US, but today there are more than 12 million. Boyajian said a patient diagnosed with cancer at age 35 may have a cumulative risk of a solid cancer of 36% by the age of 75. Boyajian said oncology nurses need guidelines or a blueprint to follow so they know what they can and should be doing for cancer survivors after treatment. He said patients need to be properly assessed for their individual risks and then managed appropriately by a team of healthcare providers.

Boyajian said this issue is only starting to come to the forefront, and he hopes that there will be a grassroots effort that comes from oncology nurses to establish guidelines at their individual healthcare centers. “With the aging of the baby boomers, there are going to be more cancer patients and there is not going to be enough providers,” said Boyajian. “So, as the number of survivors grows, they are taking up more and more of the providers’ time. There needs to be a way to transition these patients off the physicians’ schedule.”

He said that is where oncology nurses can play a central role and help improve survivorship care. ●

Nuts and Bolts of Survivorship Care Plan Explored

By Alice Goodman

G

lobally, there are 20 million cancer survivors, and the number of survivors is expected to grow because people are living longer as a result of newer and better therapies.

Many survivors have little or no understanding of the physical, psychosocial, and economic issues that face them for the rest of their lives. Nurses can play a major role in planning survivorship care to help survivors negotiate the next stages of their lives and enjoy a good quality of life.

At the recent Oncology Nursing Society Institutes of Learning meeting, Stacie Corcoran, RN, MS, AOCNS, Nurse Leader of the Survivorship Program at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, discussed the definition of survivorship, the components of a treatment summary and care plan, and how to set up a survivorship program.

To give some idea of the scope of survivorship issues, a 2005 poll by the Lance Armstrong Foundation (LIVESTRONG POLL) found that 53% of about 1000 cancer survivors reported

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December 2011 I VOL 4, NO 8

secondary health problems (including pain, sexual dysfunction, relationship problems, fertility issues, fear of recurrence, depression, and financial concerns), and 49% reported that their nonmedical cancer needs were not being met. Seventy percent reported that oncologists failed to offer support for

Many survivors have little or no understanding of the physical, psychosocial, and economic issues that face them for the rest of their lives.

health problems secondary to cancer, and only 30% reported that oncologists were willing to discuss these problems.

To bridge this gap, support has been growing among different agencies (including the American Cancer Society, Centers for Disease Control and Pre-

vention, and Institute of Medicine) for planning survivorship care.

“We know that cancer and its treatments have a potential wide range of effects, and there is limited information and lack of guidelines for assessment, prevention, and management,” Corcoran said. “The survivorship period offers many opportunities to improve health and quality of life in the domains of physical, social, psychological, and spiritual well-being.”

Survivors can experience long-term psychological and physical sequelae that include late and long-term effects such as fatigue, pain, weight gain, early menopause, anxiety, and depression. Specific issues are associated with different cancer types and treatments; for example, prostate cancer survivors may experience sexual dysfunction, urinary incontinence, and radiation proctitis. Lung cancer survivors may deal with reduced lung function, renal impairment, pain, neuropathy, and cognitive loss.

Essential components of a survivorship care program include screening for

new cancers, surveillance for recurrence, identification and interventions for consequences of cancer and treatment, health promotion strategies, and last but not least, coordination of care between specialists and primary care providers.

There are several models for survivorship care, but having a nurse practitioner as provider for the posttreatment follow-up offers some advantages. This facilitates shared care and coordinates transition from acute curative therapy to short- and long-term follow-up. A nurse practitioner can coordinate care and ensure continuity by communicating a plan of care to the patient’s primary care provider.

Centers such as MSKCC are in a better position to offer survivors expanded patient services that may not be available at smaller and/or more rural centers.

But other resources in communities may offer support, such as local chapters of the American Cancer Society and CancerCare, support groups for specific cancers, and even the local health club.

There is no “one prescription fits all” for survivorship care, and different cen-

www.TheOncologyNurse.com

TON_December 2011_v3_TON 12/21/11 11:30 AM Page 59

CANCER DRUG REIMBURSEMENT IS COMPLEX. FINANCIAL BARRIERS EXIST FOR YOUR PATIENTS.

IS THE SOLUTION. The OncoADVOCATE Program FOR HEALTH. FOR HELP. FOR YOU. The OncoAdvocate Program is dedicated to helping patients who need financial assistance and support achieve comprehensive access to their oncology drug treatments. In the process, OncoMed relieves your practice of the burden of finding reimbursement solutions and lets you focus on your patientâ&#x20AC;&#x2122;s health.

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TON_December 2011_FINAL_TON 12/22/11 6:59 AM Page 60

Survivorship ters handle it differently. But in general, after primary cancer treatment, patients should be provided with a comprehensive summary and follow-up care plan that is made clear to them. The survivorship care plan should be written by the principal providers of oncology treatment and be reimbursable by third-party payers of healthcare.

The particulars of the plan should

include tumor type and characteristics, treatments received, and contact information for the care provider and institution. Guidelines for surveillance can be found on several American Society of Clinical Oncology (ASCO) Web sites for specific tumor types. ASCO provides templates for survivorship care in practice, and other organizations have similar templates/models (ie, LIVESTRONG

care plan; http://livestrongcareplan.org).

MSKCC offers a range of video presentations by experts that address physical, social, practical, and personal concerns of cancer survivors, Corcoran said.

These videos are available free of charge on MSKCC’s Living Beyond Cancer Web site, the MSKCC Survivorship YouTube Channel, and the iTunes MSKCC Survivorship Podcast station. ●

Did You Know?

Diabetes is associated with an increased risk of colon and rectal cancers, even in studies that controlled for the common risk factors of smoking, obesity, and exercise.

—Am J Gastroenterol. 2011;106: 1911-1921

Reader Survey

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 ©iStockphoto.com/Sean Locke

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

Have patients asked you about the situation with bevacizumab and the FDA?

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

I

n the October issue, we published an article about the FDA review of bevacizumab for use in metastatic breast cancer. We asked our online reading community if this is something they have discussed with patients.

• 56% indicated patients have asked them about the situation

• 41% said patients have not asked about it

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

• 3% only discuss it if the patient brings it up

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.

Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 57 for details.

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.

COEAsize40611MM

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December 2011 I VOL 4, NO 8

www.TheOncology Nurse.com. www.TheOncologyNurse.com

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Lung Cancer

Positive Data Continue to Accrue for Crizotinib in ALK-Positive NSCLC

By Caroline Helwick

I

n patients with advanced non–small cell lung cancer (NSCLC) with ALK gene rearrangements, treatment with crizotinib provided clinically meaningful antitumor activity, producing responses in 51% of patients, in a multicenter phase 2 study reported at the 2011 European Multidisciplinary Cancer Congress.

Rearrangements in ALK are seen in up to 5% of patients, and crizotinib—a first-in-class, oral, potent, and selective small molecular entity—competitively inhibits ALK. The report was based on data from the first 133 evaluable patients who received crizotinib 250 mg twice daily on a continuous basis until progression in an ongoing open-label phase 2 study.

Objective responses were observed in 50.4% of patients, one being a complete response. Stable disease was observed in another 33.8%, reported Dong-Wan Kim, MD, Clinical Researcher at Seoul National University Hospital in South Korea.

Among the responders, 79.4% demonstrated a response within the first 8 weeks of treatment and maintained the response for an average of 42 weeks.

Although 32% of patients discontinued the study, only 4.4% did so as a result of adverse events. Treatment-related grade 3/4 adverse events, mainly elevated liver enzymes and neutropenia, were reported in 26% of patients.

About half the patients completed patient-reported outcomes for key symptoms and global quality of life. Clinically meaningful improvements (≥10-point change) were reported for pain, dyspnea, and cough from as early as cycle 2, and for fatigue, cycle 5; these positive changes were maintained through subsequent cycles. Global quality of life was also maintained over treatment, with clinically meaningful improvement seen by cycle 7, Kim reported.

One of the most commonly reported side effects of treatment with crizotinib is visual events. These are described as image carryover, flashing/trailing lights and floaters, and/or blurry vision, often occurring during light adaptation. A patient-reported questionnaire (Visual Symptom Assessment Questionnaire [VSAQ]) was developed to further characterize these symptoms and their effect on activities of daily living.

At the meeting, Ben Solomon, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia, reported a preliminary analysis of VSAQ findings in 57 patients, showing that the visual effects associated with crizotinib had no or only minimal impact on patients’

www.TheOncologyNurse.com

activities of daily living in the ongoing PROFILE 1005 study of the drug.

“The majority of patients reported that each visual effects event was transient, lasting either 30 seconds or less or between 30 and 60 seconds,” Solomon noted.

Approximately 56% of patients at cycle 2 and 50% at cycle 3 and cycle 4 reported visual effects, but these did not require dose alterations, he said.

The frequency of visual effects varied during cycles 2 to 4. In cycle 2, most patients reported visual effects on mul-

tiple days per week, whereas during cycles 3 and 4 most patients reported visual effects no more than once a week. Most patients experienced these events in the morning or evening, rather than midday.

Most patients said they were not bothered by the visual effects events or found them “only a little bothersome,” Solomon said. Patients did not have regular difficulty seeing at night or adapting to changes in lighting. No clinically meaningful changes were noted on ophthalmic examinations. ●

"

#

!

#

PROGRAM OVERVIEW This is the first global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

CO-CHAIRS

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice.

• Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

TARGET AUDIENCE This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and 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.

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

Rüdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.0 contact hours (0.12 CEUs) of continuing education credit.

The universal activity number for this activity is 0468-9999-11-088-L01-P.

Early registration of $425 ends January 13, 2012!

COMMERCIAL SUPPORT ACKNOWLEDGMENT This activity is supported by educational grants from Genentech, Inc. and Millennium Pharmaceuticals, Inc.

December 2011 I VOL 4, NO 8

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Nutri ion

Karen

with

Bountiful Beets

ŠiStockphoto.com/kryczka

By Karen Connelly, RD, CSO he red, golden, and candy cane beets are the per- ucts. The beet root is not the only source of antioxidant fect addition to any winter menu. Beets are the phytonutrients found in beets, as the leafy greens offer ideal vegetable to incorporate into your winter a wealth of nutrient-packed compounds as well. Beet meals to add immune-boosting, phytonutrient-rich com- greens are an excellent source of flavonoids and the pounds into your diet. With the cold and flu season upon carotenoids beta-carotene, lutein, and zeaxanthin. us, it is time to look to the foods we eat as a weapon and These antioxidant carotenoids may have a positive take advantage of their potential to keep us healthy. impact on improving overall eye health and in the preBeets are packed with phytonutrients that have vention of chronic age-related eye conditions.2 Betaine unique antioxidant and anti-inflammatory properties. is yet another phytonutrient inherent in beets that in a Phytonutrients, as defined by the US Department of recent epidemiologic study exhibited the ability to Agriculture (USDA), are organic components found in reduce inflammatory markers such as homocysteine, C-reactive protein, interfruits, vegetables, legumes, leukin-6, and tumor necrosis grains, nuts, and tea shown to The antioxidant factor-Îą.3 These inflammatory promote human health.1 Beets content of the beet root contain flavonoids (or polyphemarkers are risk factors for the nols) and carotenoids, 2 comdevelopment of cardiovascuand greens have made mon classes of phytonutrients. lar and other chronic condithem the focus of Phytonutrients protect our tions. Additional research is health through a variety of needed on this topic, however, numerous research mechanisms. Based on current the preliminary findings make studies focusing on and ongoing research, the a compelling argument to their anticancer benefits. include betaine-rich beets in USDA proposes that phytonutrients protect our health by your daily diet to promote serving as antioxidants, enoptimal health.3 The antioxidant content of the beet root and greens hancing immune response and cell-to-cell communication, altering estrogen metabolism, converting beta- have made them the focus of numerous research studies carotene to vitamin A, causing apoptosis in cancer focusing on their anticancer benefits. A recent study cells, repairing DNA damage caused by smoking and compared the cytotoxic effect of red beetroot extract to other toxic exposures, and detoxifying carcinogens doxorubicin in human prostate and breast cancer cell lines. Interestingly, the beetroot extract and doxoruthrough the activation of specific enzyme systems.1 The botanical name of the beet is Beta vulgaris, and it bicin both exhibited a dose-dependent cytotoxic effect belongs to the chenopod plant family that also includes in both the prostate and breast cancer cell lines tested.

Swiss chard and spinach. Beets are unique in that their Doxorubicin completely inhibited the growth of the vibrant red-purple and yellow pigments do not primari- prostate cancer cells, while at the same concentration ly come from the more commonly known phytonutri- the beetroot extract was able to decrease the growth ents called anthocyanins but rather from betalains. The rate of those cancer cells. Conventional treatment 2 main types of betalains are betacyanins and betaxan- remains most effective, but these results show the thins. The deep red-purple hued beets obtain their potential power of the beetroot extractâ&#x20AC;&#x2122;s anticancer color from betacyanins. The most studied form of beta- benefit. Betanin, most likely the major betacyanin comcyanins is betanin. The yellow beet owes its golden ponent in beetroot extract, may be responsible for these color to betaxanthins. Most research studies have cytotoxic effects.4 This is an exciting result, as it presfocused on the betaxanthin called vulgaxanthin. Both ents the possibility of using foods in conjunction with of these pigments are water-soluble and often added as conventional treatments to augment their effect or pera natural food coloring to many commercial food prod- haps even lessen the toxicities of these treatments.

Another study showed that betanin pigments have the ability to inhibit tumor growth in cancer cells of the breast, colon, stomach, central nervous system, and Ms Connelly is a Registered lung.5 In this study, betanin also inhibited the action of Dietitian and Certified Specialist in Oncology Nutrition at the proinflammatory enzymes.5 Esophageal cancer was also Steeplechase Cancer Center in thwarted by the chemopreventive properties of beetSomerville, New Jersey. As root.6 This animal study found that red beetroot food part of her responsibilities, she color that contains betanins was able to reduce provides nutrition counseling, esophageal cancer cell proliferation, angiogenesis, and group classes, and monthly inflammation as well as stimulate apoptosis. These findcooking classes to patients ings also raised the question of whether there could be and families. other active components within the beetroot that work

T

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synergistically with the betanins to provide protection against cancer initiation and growth.6 Many of the studies have been epidemiologic or laboratory studies; however, the results have been very promising and hopefully will proceed to larger, randomized controlled studies that use human subjects to validate the health potential of beets. These preliminary studies can provide patients with an opportunity to incorporate specific foods into their diet that have the potential to augment their treatment as well as empower them as being active participants in their own cancer treatment plan.

In addition to the variety of phytonutrients abundant in beets, the root and long, leafy green stems provide numerous vitamins and minerals essential to the proper functioning of our bodies. Beets are an excellent source of folate and a good source of manganese, iron, vitamin C, vitamin A, vitamin K, potassium, and niacin.

Dietary fiber is another added benefit to consuming the beet root and greens. Fiber has the distinct ability of eliminating unwanted toxins from the body, thereby reducing the risk of colon cancer. In an animal study, beet fiber was shown to reduce the incidence of precancerous colonic lesions.7 Dietary fiber can also help to manage cholesterol levels, prevent certain gastrointestinal ailments such as constipation, and improve glycemic control in diabetics. If patients are at risk for developing constipation due to treatment modalities or the use of pain medications, adequate fiber, such as the beet root and greens, as well as adequate fluid intake can be the key to prevention and management of this nagging condition that can impact their overall quality of life. Beets can also be a useful addition to the dietary habits of colon cancer survivors or to people with an increased risk of colon cancer due to family history or lifestyle factors.

Beets are in peak season from June through October.

Purchase beets that are small, round, and firm without any blemishes or cuts and leaves that are bright and green. To prepare beets for storage, trim the green leaves about 2 inches from the root, as the leaves will pull moisture away from the root. The beet greens can be placed in a plastic bag, unwashed, and stored in the refrigerator for 2 to 4 days. The beet root can be stored in the refrigerator in a plastic bag, unwashed, for 10 to 14 days. The long tail attached to the root should not be trimmed, but purchasing roots with an excess amount of hair should be avoided as this may be an indication of toughness and age. Although beets appear firm and hearty, they are actually very delicate and temperature sensitive. The betalain content in beets decreases as the cooking time increases. To retain most of the beet nutrients, bake, steam, or boil them unpeeled, limiting roasting time to less than an hour and steaming time to less than 15 minutes. Canned beets remain a good source of folate and moderate amounts of vitamin C, manganese, iron, copper, and

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Karen

with magnesium. One cup of cooked beets contains about 2 g of protein, 2 to 3 g of fiber, less than 1 g of fat, and 14 to 16 g of carbohydrate, and approximately 74 calories.8 Beet greens are also low in calories, as a half-cup serving has about 19 calories and provides an excellent source of carotenoids, flavonoids, vitamin A, and vitamin K. They can be prepared like Swiss chard—sautéed or boiled. This nutrient profile makes beets an easy addition to most diets. Consumption of beets can cause urine and bowel movements to become red or pink in color. This condition is usually harmless; however, if patients are at risk for bleeding or have certain urinary, gastrointestinal, or surgical issues, avoiding beets at that time may be an appropriate course of action. It can be unsettling for some patients to see this change in urine or bowel movement, and any potential positive impact beets may have on their overall health may not be as important as alleviating their anxiety.

Patients with a history of oxalate urinary tract stones should avoid consuming a large amount of beet greens as they are high in oxalic acid and may exacerbate this condition.

The wide variety of phytonutrients, vitamins, minerals, and fiber that the beet root and greens have to offer make this vegetable an extraordinary addition to any healthy meal plan. Try to incorporate beets into the diet at least once or twice per week in order to obtain their maximum benefit. Canned beets can be used to fulfill this quota, but there are many ways to add raw and fresh-cooked beets into the diet. Add shredded raw beets to your favorite coleslaw recipe or

turn roasted beets into a smooth dressing to top off your salad or side of sautéed beet greens. Be creative and think outside the can—freshly prepared beets are a bounty of goodness. ● References 1. US Department of Agriculture. Agricultural Research Service: Phytonutrients. http://www.usarice.com/doclib/ 124/3844.pdf.

2. American Optometric Association. Lutein and

Zeaxanthin – Eye-Friendly Nutrients. http://www.aoa. org/x4732.xml.

3. Detopoulou P, Panagiotakos DB, Antonopoulou S, et al. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008;87:424-430.

4. Kapadia GJ, Azuine MA, Rao GS, et al. Cytotoxic effect of the red beetroot (Beta vulgaris L.) extract compared to doxorubicin (Adriamycin) in human prostate (PC-3) and breast (MCF-7) cancer cell lines. Anticancer Agents Med Chem. 2011;11:280-284.

5. Reddy MK, Alexander-Lindo RL, Nair MG. Relative inhibition of lipid peroxidation, cyclooxygenase enzymes,

®

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.

©iStockphoto.comHalina Yakushevich

and human tumor cell proliferation by natural food colors. J Agric Food Chem. 2005;53:9268-9273.

6. Lechner JF, Wang LS, Rocha CM, et al. Drinking water with red beetroot food color antagonizes esophageal carcinogenesis in N-nitrosomethylbenzylamine-treated rats.

J Med Food. 2010;13:733-739.

7. Bobek P, Galbavý S, Mariássyová M. The effect of red beet (Beta vulgaris var. rubra) fiber on alimentary hypercholesterolemia and chemically induced colon carcinogenesis in rats. Nahrung. 2000;44:184-187.

8. US Department of Agriculture. National Nutrient Database for Standard Reference: Beets. http://www.nal. usda.gov/fnic/foodcomp/Data/SR20/nutrlist/sr20w306.pdf.

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

Recipe ■ Balsamic Beet Vinaigrette Ingredients 4 beets (roasted, peeled, cooled, and sliced) ½ cup balsamic vinegar ½ cup olive oil

1. Place beets and balsamic vinegar in a blender and puree.

2. Slowly whisk in the olive oil.

3. Toss with your favorite salad.

Nutritional Information Serving size: 2 tablespoons Yield: 24 servings 45 calories, 4.5 g total fat, 0.5 g saturated fat, 0 mg cholesterol, 10 mg sodium, 1 g total carbohydrate, 0 g fiber, 1 g sugar, 0 g protein Visit www.TheOncologyNurse.com for more beet recipes.

www.TheOncologyNurse.com

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.

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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