december 2012 vol 5, no 11

As healthcare professionals whowork with people living withcancer, we often see patients

when they are most vulnerable. For manypatients, their moments of greatest vul-nerability are at the time of diagnosis andwhile discussing treatment. During suchmoments, patients typically feel over-

whelmed and inundated with a largeamount of information to process andassimilate, while at the same time dealingwith the emotional impact of a cancerdiagnosis. Much of that information con-sists of basics on their type of cancer andthe recommended course of therapy,

Genetics as it pertains to cancerrisk tends to be a hot topic in thenews lately. Patients may see a

story that states, for example, “Researchershave found that the risk of developingcancer in women with a mutation in geneQ is 500% higher,” but what does that riskactually mean? One important compo-nent of genetic counseling is the ability toconvey risk to patients.

What Is Risk?Simply stated, risk is a probability. It isthe chance that a particular event mayoccur. In the case of inherited cancerrisk, it is the chance that a person with amutation in a particular gene will devel-op cancer. For the purpose of this article,the hypothetical gene “Q” will be used.There are 2 main categories of risk:

Breast CanCer . . . . . . . . . . . . . . . . 16Bisphosphonates Should Not BeRoutine in Early Breast Cancer

Leukemia . . . . . . . . . . . . . . . . . . . . . . . . 20Relapsed/Refractory ALL VexingProblem

CompLimentary Ce . . . . . . . . . . . . 30Considerations in Multiple Myeloma—

Ask the Experts: Bone Health

supportive Care . . . . . . . . . . . . . . . 38Catheter-Related Thrombosis Can BePrevented

DeCeMbeR 2012 www.TheOncologyNurse.com VOl 5, NO 11

©2012 Green Hill Healthcare Communications, LLC

SUPPORTIVE CARE

Helping Your Patients ManageChemotherapy-Induced Nauseaand VomitingBy Rosalie Canosa, LCSW-RProgram Division Director, CancerCare

Sharon Gentry, RN, MSN, AOCN, CBCNBreast Nurse Navigator, Derrick L. Davis Forsyth Regional Cancer Center,

Winston-Salem, North Carolina

Continued on page 7

I N S I D E

Continued on page 28

The Johns Hopkins Kimmel Cancer Center, located on the cam-pus of Sibley Memorial Hospital, provides medical oncologyservices to cancer patients in the Washington, DC, community.

The joint venture of Johns Hopkins Kimmel Cancer Center and SibleyInfusion Center offers patients access to expert, disease-specificoncologists from Hopkins. Patients are seen by a multidisciplinaryteam, which may include surgeons, radiation oncologists, socialworkers, nutritionists, physical therapists, and pastoral care coun-selors. In addition, patient cases are frequently presented at tumorboard reviews at the main Hopkins campus located in Baltimore,Maryland. Also, patients have access to the diverse portfolio of clin-ical trials available at Hopkins.

CANCER CENTER PROFILE


The medical oncology team at the Johns Hopkins Kimmel Cancer Center and Sibley Infusionincludes Patricia DiZebba, RN; Ariel Ford; Elizabeth Meier; Channing Paller, MD; NatashaSchultz, RN; Jila Ahmadi, RPh; Carol Abrams, RN; Catherine Bishop, NP; and Joyce Scott, CA (left to right).

Photo from Sibley Memorial Hospital.

The Johns Hopkins KimmelCancer Center and SibleyInfusion Center

GENETIC COUNSELING

Inherited Cancer Risk Statistics:Absolute Risk Versus Relative RiskBy Cristi Radford, MS, CGC

CONFERENCE NEWS

Highlights From ASTROBy Alice Goodman

The American Society forRadiation Oncology (ASTRO)54th Annual Meeting, held in

Boston, Massachusetts, coincided withSuperstorm Sandy. Despite the havocwreaked by the storm, Boston was large-ly spared, although ASTRO canceled

Monday afternoon’s Plenary Sessionwhen public transportation was shutdown. Below are some highlights fromthe meeting, including some news storiesfrom the Plenary Session, which wasavailable online.


Reader PollWhat inspired you to

enter the oncology field?Page 6

INDICATIONXGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATIONHypocalcemia• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ)• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

•

W

T

XGEVA® acts precisely to inhibit RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival.1

FOR APPROPRIATE PATIENTS WITH BONE METASTASES FROM SOLID TUMORS

XGEVA® acts precisely to inhibit RANK Ligand, a key mediator of bone

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen.2. Data on fi le, Amgen.

11:20 AM

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Pregnancy• Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions• The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identifi ed.

Please see brief summary of Prescribing Information on the following page.

X

The integrated analysis included three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of SREs in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to fi rst SRE (noninferiority), and the secondary endpoints were time to fi rst SRE (superiority) and time to fi rst and subsequent SREs (superiority). SREs are defi ned as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression. Select exclusion criteria: patients receiving current or prior IV bisphosphonate therapy were excluded from the studies. Patients receiving oral bisphosphonates for the treatment of osteoporosis were not excluded. Daily supplementation of calcium ≥ 500 mg and vitamin D ≥ 400 IU was recommended.1,2

*P value for superiority.†Median time to fi rst SRE: not yet reached for XGEVA®; 26.4 months for zoledronic acid. ‡Excluding breast and prostate cancer.

ACCESS FOR PATIENTSApproximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2§

XGEVA® patients who need help may be eligible for fi nancial assistance2

PERMANENT

J-CODE: J0897

§Based on XGEVA® payor mix and coverage for similar products.

OTHER SOLID TUMORS‡

OR MULTIPLE MYELOMAPROSTATECANCER

BREASTCANCER

INTEGRATEDANALYSIS

DELAY IN MEDIAN TIME TO FIRST SRE

N/A1†

(HR = 0.82,P = 0.010*)

3.6 month delay1

(HR = 0.82,P = 0.008*)

4.2 month delay1

(HR = 0.84, P < 0.001, noninferiority; P = 0.060,

NS for superiority)

8.2 month delay2

(HR = 0.83,P < 0.0001*)

©2012 Amgen Inc. All rights reserved. 07/12 68020-R1-V2 G68979-R1-V2 www.XGEVA.com

SUPERIOR EFFICACY XGEVA® delivered 8.2 more months without a skeletal-related event (SRE) in a prespecifi ed integrated analysis of 3 head-to-head studies vs zoledronic acid2

1-2 11:20 AM

Brief Summary: Consult package insert for complete Prescribing Information

INDICATIONS AND USAGE:Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).

DOSAGE AND ADMINISTRATION:Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations) . There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling:

)The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received

Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria:

5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid)

b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus]

Severe Mineral/Electrolyte Abnormalities

than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations).

0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the JawIn the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an extended treatment phase of approximately 4 months in each trial are included, the incidence of confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ was 14 months (range: 4 – 25).

Postmarketing Experience. Because postmarketing 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.The following adverse reactions have been identified during post approval use of Xgeva:

Severe symptomatic hypocalcemia, including fatal cases.

Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).

USE IN SPECIFIC POPULATIONS:Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva.

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information).

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary

monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information).

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Pregnancy).

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION:Advise patients to contact a healthcare professional for any of the following:

twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions)

jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions)

(see Warnings and Precautions)(see Warnings and Precautions and Use in Specific

Populations)Advise patients of the need for:

Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

68257-R1-V3

Body SystemXgeva

n = 2841 %

Zoledronic Acid n = 2836

%

GA STROINTESTINAL Nausea Diarrhea

31 20

32 19

GE NERAL Fatigue/ Asthenia

45

46

IN VESTIGATIONS b

b

18 32

9 20

NE UROLOGICAL 13

14

RE SPIRATORY Dyspnea Cough

21 15

18 15

Amgen Manufacturing Limited, a subsidiary of Amgen Inc.One Amgen Center Drive

Thousand Oaks, California 91320-1799©2012 Amgen Inc.

All rights reserved. Printed in USA.

Editorial Board

EDITOR-IN-CHIEFBeth Faiman,PhD(c), MSN, APRN-BC, AOCNCleveland Clinic TaussigCancer InstituteCleveland, OH

Elizabeth Bilotti,RN, MSN, APRN,BC, OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Catherine Bishop,DNP, NP, AOCNPJohns Hopkins KimmelCancer Center/SibleyInfusionWashington, DC

Deena DamskyDell, MSN, RN-BC,AOCN, LNCFox Chase Cancer CenterPhiladelphia, PA

Wendy DiSalvo,DNP, APRN, AOCNGenentechNew London, NH

DeniceEconomou, RN,MN, CNS, AOCNCity of Hope NationalMedical CenterDuarte, CA

ConstanceEngelking, RN,MS, CNS, OCNThe CHE ConsultingGroup, Inc.Mt. Kisco, NY

Amy Ford, RN,BSN, OCNQuintilesDallas, TX

Sharon S. Gentry,RN, MSN, AOCNDerrick L. Davis ForsythRegional Cancer CenterWinston-Salem, NC

Cassandra J.Hammond, RN,MSN, CRNPAvid Education Partners,LLCSharpsburg, MD

Shannon Hazen,RN, BSN, OCNNovant HealthPresbyterian CancerCenterCharlotte, NC

Patricia IrouerHughes, RN, MSN,BSN, OCNPiedmont HealthcareRex, GA

Taline Khoukaz,NP, MSN, ACNP-CUniversity of SouthernCaliforniaNorris Cancer Center &HospitalLos Angeles, CA

Sandra E. Kurtin,RN, MS, AOCN,ANP-CArizona Cancer CenterTucson, AZ

Ann McNeill,MSN, RN, NP-C,OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Kena C. Miller,RN, MSN, FNPRoswell Park CancerInstituteBuffalo, NY

Patricia Molinelli,MS, RN, APN-C,AOCNSSomerset Medical CenterSomerville, NJ

Ellen A. Neylon,MSN, FNP-BC,CCRP, OCNColumbia UniversityMedical CenterCenter for LymphoidMalignanciesNew York, NY

Dolores “Jeff”Nordquist, RN, MS,CS, FNPMayo ClinicRochester, MN

MelindaOberleitner, RN,DNS, APRN, CNSCollege of Nursing andAllied Health ProfessionsUniversity of LouisianaLafayette, LA

Jayshree Shah, NPJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Gary Shelton,MSN, NP, ANP-BC,AOCNPNYU Clinical CancerCenterNew York, NY

Lori Stover, RN,BSNWestern PennsylvaniaCancer Institute Pittsburgh, PA

Joseph D.Tariman, PhD,APRN, BCNorthwestern UniversityMyeloma ProgramChicago, IL

Jacqueline MarieToia, RN, MS, DNPNorthwestern UniversityMyeloma ProgramChicago, IL

Pamela HallquistViale, RN, MS,CS, ANP, AOCNSaratoga, CA

Connie Visovsky,RN, PhD, APRNUniversity of South Florida College of Nursing Tampa, FL

Rita Wickham,PhD, RN, AOCNNorthern MichiganUniversity Independent Oncology &Palliative Care ConsultantMarquette, MI

Karla Wilson, RN,MSN, FNP-C, CPONCity of Hope NationalMedical CenterDuarte, CA

PharmacyJohn F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

NutritionKaren Connelly,RD, CSOSomerset Medical CenterSomerville, NJ

Patient AdvocatePeg FordOvarian Cancer AdvocacyAllianceCoronado, CA

Social WorkCarolyn Messner,DSW, MSW, LCSW-R, BCDCancerCareNew York, NY

Managed Care andPharmaceuticalManagementBurt Zweigenhaft,BSOnceMed Onco360Great Neck, NY

Isabell Castellano, RNBristol-Myers Squibb Children’s HospitalRobert Wood Johnson University HospitalNew Brunswick, NJ

Jeanne Westphal, RNMeeker County Memorial HospitalLitchfield, MN

www.TheOncologyNurse.com VOL 5, NO 11 5

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Managing EditorKristen Olafson

[email protected]

Quality Control DirectorBarbara Marino

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Editorial Contact:Telephone: 732.656.7935 Fax: 732.656.7938

The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print);ISSN 1944-9801 (online) is published 11 times a year byGreen Hill Healthcare Communications, LLC, 1249South River Road, Suite 202A, Cranbury, NJ 08512.Telephone: 732.656.7935. Fax: 732.656.7938. Copyright©2012 by Green Hill Health care Com munications,LLC. All rights reserved. The Oncology Nurse-APN/PA®

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do not necessarily reflect those of the Editorial Board, theEditorial Director, or the Publisher. Publication of anadvertisement or other product mention in The OncologyNurse-APN/PA® should not be construed as an endorse-ment of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damageto persons or property arising out of or related to any useof the material contained in this periodical. The reader isadvised to check the appropriate medical literature andthe product information currently provided by the manu-facturer of each drug to be administered to verify thedosage, the method and duration of administration, orcontraindications. It is the responsibility of the treatingphysician or other healthcare professional, relying onindependent experience and knowledge of the patient, todetermine drug dosages and the best treatment for thepatient. Every effort has been made to check generic andtrade names, and to verify dosages. The ultimate respon-sibility, however, lies with the prescribing physician.Please convey any errors to the Editorial Director.

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6 VOL 5, NO 11 www.TheOncologyNurse.com

From the Editor

This issue of The OncologyNurse-APN/PA (TON)brings you highlights of the

news from the 2012 AmericanSociety for Radiation Oncology(ASTRO) annual meeting. Part ofour ASTRO coverage includes theresults of a study that show thatmany patients with incurable lungcancer misunderstood the goals ofpalliative radiation therapy. Thedata from this study illustrate theimportance of clear communica-tion between patients and health-

care professionals. The study presenter noted that health-care professionals may worry that “plain speaking” takesaway hope, but patients who truly understand their situa-tion are empowered to make decisions that are right fortheir situation.In addition to keeping you up-to-date about what is

happening in the world of oncology research, we at TONstrive to provide you with information you can use in your

day-to-day practice. In this issue, Rosalie Canosa andSharon Gentry describe the scope of the problem ofchemotherapy-induced nausea and vomiting and howwe can help patients deal with this debilitating sideeffect. They emphasize the importance of proactivecommunication with patients, pointing out that “weneed to tell patients not to be afraid to speak up” if theydo not understand something or if they need moreinformation. Cristi Radford addresses the issue of absolute risk versus

relative risk when evaluating inherited cancer risk statistics.She clearly describes the different types of risk and clarifieswhat the implications are for individuals. Understandingthe meaning of risk helps us provide perspective to ourpatients when they ask these types of questions—all part ofcommunicating clearly.Please be sure to visit our website, www.The Oncology

Nurse.com, to answer our reader question about whatinspired you to enter the field of oncology. We want to know how you decided to become an oncology professional.All of us at TON wish you the best for 2013. l

Beth Faiman, PhD(c),MSN, APRN-BC, AOCN

Editor-in-Chief

It takes a very special personto become an oncologynurse, advanced practitioner,

or physician assistant. All of us atThe Oncology Nurse-APN/PA areinspired by the dedication andcompassion we routinely observefrom our reading community. Aspart of our reader polls, and inrecognition of the important workyou do, we’d like to invite you toshare your inspiration for workingin this field. Please include yourfirst name and the city where youare located in your response.

Please log on to www.TheOncologyNurse.com to share your story.

What inspired you to enter the oncology field?

Reader Poll

VOL 5, NO 11 7www.TheOncologyNurse.com

Supportive Care

including instructions on adhering to thetherapeutic regimen. Not surprisingly,information and instructions from doc-tors and nurses may not be fully integrat-ed, or may easily get “scrambled,” duringsuch a tender time. Patients may there-fore lack a full understanding of theimportance of following those instruc-tions, or may even forget them. Whileforgetting or not fully understanding disease-related information may havetremendous ramifications for manyaspects of cancer care, it can be particu-larly impactful when dealing with thenausea and vomiting that is often causedby chemotherapy.

Chemotherapy-Induced Nauseaand Vomiting: The Scope of theProblemThe benefits of cytotoxic chemotherapyare undisputed. It is a type of therapy thathas extended the lives of millions of can-cer patients. Yet chemotherapy is oftenassociated with unpleasant side effectsthat negatively affect patients’ quality oflife. One of the more debilitating sideeffects is chemotherapy-induced nauseaand vomiting (CINV), a term thatdescribes the symptoms of nausea andvomiting that occur in reaction tochemotherapeutic agents.1 For cancerpatients receiving chemotherapy or radi-ation therapy, CINV can compromise ornegate the benefits of treatment by mak-ing it very difficult for the patient toadhere to the therapeutic regimen, or bytriggering an interruption or delay oftreatment.While all patients undergoing chemo -

therapy are at risk of CINV, there arenumerous factors that can heighten apatient’s risk of this dreaded complica-tion. Such risk factors include2,3: • Age less than 50 years• Being female• Low alcohol intake (one or fewerdrinks per day)

• History of motion sickness, or ofmorning sickness with pregnancy

• Fear of nausea from chemotherapyor a history of CINV

• Anxiety or nausea associated withpast stress

• Current use of antidepressants orantianxiety medication

There are also numerous treatment-related factors that can affect the inci-dence and severity of CINV. Theseinclude the dosage, schedule, and routeof administration of the chemotherapy

regimen; the level of emetogenicity(likelihood of causing vomiting) of theregimen; the use of multiple agents inthe regimen; and multiple cycles ofchemotherapy.2,4 Chemotherapeuticagents can be categorized according toemetogenicity. Highly emetogenicchemotherapy (HEC) denotes a regi-men that induces emesis (vomiting) in

more than 90% of patients in theabsence of effective prophylacticantiemetic therapy,4 although onlyabout 30% of these patients will vomit ifthey receive antiemetic prophylaxisbefore administration of HEC.3,5,6 Amoderately emetogenic chemotherapy(MEC) regimen is one that carries a

One of the moredebilitating side effects ischemotherapy-inducednausea and vomiting, aterm that describes thesymptoms of nausea and vomiting that occur

in reaction tochemotherapeutic agents.

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Helping Your Patients Manage CINV Continued from cover


TREANDA® (bendamustine HCI) for Injection is his chemo. This is his therapy.

© TRE-2510 August 2012

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©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510 August 2012

LEARN MORE AT WWW.TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

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

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

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0.60.70.80.91.0

Months

HR†=0.27 (95% CI‡: 0.17, 0.43) P<.0001

6 monthsmedian PFS

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).†HR=hazard ratio.‡CI=confi dence interval.

2

≥≥

Important Safety Information

should be monitored closely for these reactions and treated promptly if any occur

Discover the elements of ef� cacy and safety

Single-agent TREANDA tripled median PFS*

2 1 11:16 AM

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 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. 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 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 patientsTREANDA Chlorambucil(N=153) (N=143)

System organ classPreferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with atleast 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0Diarrhea 14 (9) 2 (1) 5 (3)General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0InvestigationsWeight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disordersHyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disordersCough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disordersRash 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

TREANDA Chlorambucil(N=150) (N=141)

Laboratory AbnormalityAll Grades Grade 3/4 All Grades Grade 3/4

n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 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. Post-Marketing 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 phlebitis, 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 LD50 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.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: 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. Reconstitution/Preparation for Intravenous Administration. Aseptically

Sterile Water for Injection, USP 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

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

reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride

drug products should be inspected visually for particulate matter and 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.

Distributed by:Cephalon, Inc.Frazer, PA 19355TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved.©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 April 2012(Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

TRE-2511 August 2012

This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

11:19 AM

30% to 90% risk of emesis.4 Regimenscarrying a low risk of emesis are thosethat induce emesis in only 10% to 30%of patients, and treatments with mini-mal emetogenic risk cause emesis in lessthan 10% of patients.4While CINV is quite common, its

incidence can vary greatly and is diffi-cult to determine. In a 1996 clinicaltrial, CINV was reported in 47 of 48(98%) patients receiving HEC withoutantiemetic therapy.7 In a 2004 trial inwhich 298 patients were treated withantiemetics while receiving MEC orHEC, one-third of the participantsexperienced acute nausea (ie, thatwhich occurs within a few minutes toseveral hours after a chemotherapydose), and the incidence of delayed nau-sea (ie, more than 24 hours afterchemotherapy administration) was60%.8 In a 2005 study of 857 womenwith breast cancer who receivedantiemetic prophylaxis while on MEC,half of the patients experienced CINV.9Although the incidence of CINV hasdeclined over the last decade, CINVremains a threat to patients with cancer. CINV can have a profound impact on

patients’ quality of life, potentially lead-ing to metabolic imbalances, a declinein patients’ self-care and functional abil-ity, worsening of patients’ performancestatus and mental status, nutrient deple-tion, anorexia, surgical wound dehis-cence (bursting open or splitting),esophageal tears, and patients’ refusal,delaying, or prevention of additionaltherapy.10-13 CINV can also impose a significant socioeconomic burden byreducing employee productivity andboosting overall healthcare costs due toprolonged hospitalization and increasednursing expenses.14 A recent retrospec-tive study calculated the mean cost of aCINV-related hospital visit at $5299,with a mean per-patient cost of $731.15

The Value of AntiemesisIn our experience, CINV is easier to pre-vent than to treat. Many patients expe-rience cancer as a chronic disease, andcan benefit from the use of antiemeticmedications during all phases of treat-ment. A variety of antiemetic agents areavailable, including those that can be

administered by the oral, rectal, intra-venous (IV), intramuscular, or transder-mal route. IV agents may be appropriatefor patients who are unable to swallowor digest tablets due to emesis, whileothers may benefit from havingantiemetic medication delivered via atransdermal patch, which may helpreduce the pill burden and simplify treat-ment for these patients. The patch mayalso be appropriate in cases of impairedswallowing ability or limited gut motili-ty, as can occur with certain gastroin-testinal cancers. The National Com -p rehensive Cancer Network, in its latestantiemesis treatment guidelines,4 cau-tions that while some studies suggestthat certain agents are equally effectiveon a population basis, individualpatients may respond differently, and apatient’s individual experience maydrive the selection of antiemesis therapy.Serotonin (5-HT3) antagonists, a

class of agents that includes dolasetronmesylate, granisetron, ondansetron, andpalonosetron, are commonlyused for the prevention andtreatment of CINV. The oraland IV forms of these agentshave been shown to haveequivalent efficacy when ad -min istered at the appropriatedoses,16,17 and granisetron isalso available as a transdermalpatch with demonstrated ef -fect iveness for up to 5 daysfrom first application. Anothercommon preventive regimen

is a “cocktail” containing theneurokinin-1 receptor antag-onist aprepitant (or its IVversion fosaprepitant), thecorticosteroid dexametha-sone, and a benzodiazepineagent such as olanzapine.4Other types of agents, such asphenothiazines, benzamides,antihistamines, butyrophe-nones, and cannabinoids,have also been used forantiemesis, although thesehave largely been replaced bythe 5-HT3 antagonists.4

Challenges in Adhering toAntiemetic Medication RegimensOnce a patient has started chemothera-py, anxiety and emotional stress maycomplicate any efforts to adhere toantiemetic therapy. This is especiallytrue of patients having their first experi-ence with chemotherapy, although itmay still be a lingering issue through

subsequent rounds. All toooften, when a patient istaught what to expectfrom chemotherapy, shenods and appears to under-stand the educationalinformation and is senthome after round one.Three days later she feelssick and anxious. She maybe experiencing a “drop-off ” effect from the anti -emetic regimen, or may

not have taken the drugs as instructed.Even if she followed instructions, thedrugs may not have worked as expect-ed. “I don’t know what to do,” she says,adding that she feels so bad that theemergency room seems a reasonableoption.Two key nursing actions can help the

patient through this vulnerable time.The first action is the “teach-back”method (also known as the “show-me”method or “closing the loop”), whichmust be undertaken before the patientleaves her first chemotherapy treatmentsession.18 Once the patient has beenbriefed on strategies to manage CINV,the “teach-back” method largely con-sists of asking the patient questions such

as, “Tell me what you aregoing to do if you feel nau-seous or have uncontrolledvomiting.” The patient’sanswers may reveal that shedid not fully understand theinformation you have pro-vided and that more infor-mation is required. In suchsituations, chances are thatthe patient’s anxiety andinsecurity made her afraidto speak up during the brief-ing, or that she does not feel

comfortable enough to ask questionsabout the anti emetic medication and itsaccompanying instructions. Wheneverpossible, it is important that the briefingincludes family members or whoeverwill be with the patient after treatment. The second key action is to have a

nurse navigator or clinical nurse call thepatient at home after treatment. Areview of the educational content, aswell as an assessment of the efficacy ofthe antiemetic medications, can confera measure of control to the patient atthis critical time. Documentation of“real-time” symptoms can lead to need-ed medication changes prior to the nextcycle of treatment. In a 2010 article,Sprandio documented how a communi-ty oncology practice achieved a drop inemergency department visits as well as adecrease in unscheduled office visitswhen this quality check was implement-ed.19 The resulting cost savings from

Table Helping Patients Manage CINV: CancerCare Educational Resources

• Connect education workshops and podcasts– Advances in Treating Chemotherapy-Related Nausea and Vomiting– Understanding and Managing Chemotherapy Side Effects

• Publications– Coping With Nausea and Vomiting From Chemotherapy – Tips for Managing Nausea and Increasing Appetite During CancerTreatment

– Understanding and Managing Chemotherapy Side Effects– “Doctor, Can We Talk?” Tips for Communicating With Your Health Care Team

• Online forums– Ask CancerCare: experts answer questions about coping with cancer

Helping Your Patients Manage CINV Continued from page 7

Sharon Gentry, RN,MSN, AOCN, CBCN

Rosalie Canosa,LCSW-R

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Pushing Your Limits

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Supportive Care


www.TheOncologyNurse.com12 VOL 5, NO 11

Supportive Care

avoiding CINV-related hospital visitscan thus be an important metric fornurse navigators to support their role. Sometimes, financial difficulties can

interfere with patients’ efforts to adhereto antiemetic therapy. For somepatients, the cost of treatment is simplytoo high. Others may struggle to pay thecopay, even if their insurance covers the

rest of the cost. As a result, patients mayskip or delay an antiemetic dose, anomission that can have a ruinous effecton their quality of life, not to mentiontheir chemotherapy experience as awhole. Some patients may have limitedaccess to antiemetic treatment. A lackof reliable transportation may make itdifficult, if not impossible, to get to the

doctor’s office, clinic, or pharmacy.Needless to say, a patient will have trou-ble adhering to a medication regimen ifshe lacks the means to obtain it. Therole of the social worker or nurse navi-gator is critical in identifying suchpatients so financial issues can beaddressed before they become a concern.Oftentimes, adherence to antiemetic

therapy is compromised by patients’ mis-perceptions of treatment. Fear of addic-tion (the risk of which is minimal withantiemetic medications) is a powerfulforce in our society, and some patientsmay opt to forgo antiemetic medicationrather than en dure the perceived stigmaof being “on drugs.”

enhancing CommunicationThe challenges of managing CINVmake it crucial for the oncology nurse,nurse navigator, and oncology socialworker to encourage patients to com-municate proactively with the healthprofessionals who are coordinatingtheir care. We need to tell patients notto be afraid to speak up if the antiemet-ic medication is not working, or if theydo not fully understand the instruc-tions for taking it. We need to make itclear that it’s OK to ask questions, andthat a patient should not wait until thenext appointment or next round ofchemotherapy to raise her concerns.

In our experience, treatment-relatedinformation needs to be reinforcedrepeatedly. Not only is it important toask patients if they truly understand whatis expected of them, but it is also impor-tant to follow up and ask if they havebeen taking the medication as directed.Before they leave the clinic, it is helpfulto have patients repeat the instructionsback to you to make sure they under-stand them.The importance of adhering to

antiemetic medication cannot beoveremphasized. We need to helppatients overcome whatever fears orbeliefs may be preventing them fromadhering to antiemetic therapy. None ofthese fears or beliefs is a reason for anycancer patient to have to endure CINV,or to refuse or delay antiemetic therapy.Above all, patients need to feel

empowered and equipped with theinformation they need to help themmanage their disease. Organizationssuch as CancerCare (www.cancercare.org) offer a variety of educationalresources specifically focusing onCINV (see Table). It is our obligationto share that information; we cannotassume that people will get it from

Helping Your Patients Manage CINV Continued from page 11

We need to help patientsovercome whatever

fears or beliefs may bepreventing them from adhering toantiemetic therapy.

“Quality care iseveryone’s business.”

Value-Based Care in Myeloma !&%0!,-�!2�&/-%0!�%(.!,0%!1-��( �*!,-*!�.%0!-�,!&�.! �.)��)-.��+/�&%.3��( ��!--�%--/!-��*!�%�&�-!�.%)(-�"),��-! ��&%(%�%�(-�� 0�(�! �*,��.%�!�(/,-!-��( �*$�,'��%-.-�1%&&��&-)�")�/-�)(�.$!�/(%+/!��$�&&!(#!-�%(�.$!�'�(�#!'!(.�)"�'/&.%*&!�'3!&)'��

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some other source. At the same time,we need to work to ensure patientshave the financial, logistical, and emo-tional support they need to access theirmedications and supportive careresources. In some cases, that supportmay consist of connecting patients withcopay assistance programs, compassion-ate-use initiatives, or clinical trials. Inother cases, we can help arrange trans-portation, or facilitate the involvementof family members, friends, or other care-givers to ease the burden on the cancerpatient. If we are to give patients permis-sion to be proactive in managing theirdisease, we must be proactive ourselvesin helping them.

ConclusionFrom the time of diagnosis, the patientwith cancer embarks upon a life-changing journey marked by multiplerounds of treatment and follow-up.The journey may include treatmentresponse and cancer remission. On theother hand, the itinerary for the jour-ney may change to account for diseaseprogression and downstream treatmentoptions. In most cases, the patient hasnot planned for this journey and mayfeel vulnerable, alone, and unpreparedfor the inevitable bumps in the road. Ifmanaged correctly and appropriately,CINV is a bump that can be avoided,or at least made less disruptive to thepatient’s life. As oncology nurses,nurse navigators, and patient advo-cates, we are in an important positionto help patients negotiate those chal-lenges by providing and reinforcingtreatment- and supportive care–relatedinformation, facilitating communica-tion with doctors and other health pro-fessionals, and encouraging patients tobe proactive in managing the variousaspects of their care. In so doing, wecan demonstrate to our patients thatthey are not alone. By serving as trust-ed guides, we may be able to make thecancer journey a bit less harrowing. l

References1.Chemotherapy-induced nausea and vomiting. Mosby’sMedical Dictionary, 8th ed. Elsevier, Inc; 2009.TheFreeDictionary Web site. http://medical-dictionary.thefreedictionary.com/chemotherapy-induced+nausea+and+vomiting. Accessed June 25, 2012.2. Stricker CT, Eaby-Sandy B. Chemotherapy-inducednausea and vomiting. In: Brown CG, ed. A Guide toOncology Symptom Management. Pittsburgh, PA:Oncology Nursing Society; 2010:91-122.3. Hesketh PJ, Grunberg SM, Herrstedt J, et al.Combined data from two phase III trials of the NK1antagonist aprepitant plus a 5HT3 antagonist and a cor-ticosteroid for prevention of chemotherapy-induced nau-sea and vomiting: effect of gender on treatment response.Support Care Cancer. 2006;14(4):354-360.4. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: Antiemesis.Version 1.2012. http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed November 7, 2011.5.Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal forclassifying the acute emetogenicity of cancer chemother-apy. J Clin Oncol. 1997;15(1):103-109.6. Roila F, Herrstedt J, Aapro M, et al. Guideline updatefor MASCC and ESMO in the prevention of chemother-apy- and radiotherapy-induced nausea and vomiting:results of the Perugia consensus conference. Ann Oncol.2010;21(suppl 5):v232-v243.

7. Kris MG, Cubeddu LX, Gralla RJ, et al. Are moreantiemetic trials with a placebo necessary? Report ofpatient data from randomized trials of placebo antiemet-ics with cisplatin. Cancer. 1996;78(10):2193-2198.8. Grunberg SM, Deuson RR, Mavros P, et al. Incidenceof chemotherapy-induced nausea and emesis after mod-ern antiemetics: perception versus reality. Cancer.2004;100(10):2261-2268.9. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy andtolerability of aprepitant for the prevention ofchemotherapy-induced nausea and vomiting in patientswith breast cancer after moderately emetogenicchemotherapy. J Clin Oncol. 2005;23(12):2822-2830.10. Laszlo J. Emesis as limiting toxicity in cancerchemotherapy. In: Laszlo J, ed. Antiemetics and CancerChemotherapy. Baltimore, MD: Williams & Wilkins,1983:1-5.

11. Ingle RJ, Burish TG, Wallston KA. Conditionabilityof cancer chemotherapy patients. Oncol Nurs Forum.1984;11(4):97-102.12.Mitchell EP. Gastrointestinal toxicity of chemother-apeutic agents. Semin Oncol. 1992;19(5):566-579.13. Richardson JL, Marks G, Levine A. The influence ofsymptoms of disease and side effects of treatment on com-pliance with cancer therapy. J Clin Oncol. 1988;6(11):1746-1752.14. O’Brien BJ, Rusthoven J, Rocchi A, et al. Impact ofchemotherapy-associated nausea and vomiting onpatients’ functional status and on costs: survey of fiveCanadian centres. CMAJ. 1993;149(3):296-302.15. Burke TA, Wisniewski T, Ernst FR. Resource utiliza-tion and costs associated with chemotherapy-inducednausea and vomiting (CINV) following highly or moder-ately emetogenic chemotherapy administered in the US

outpatient hospital setting. Support Care Cancer. 2011;19(1):131-140.16. Kris MG, Gralla RJ, Clark RA, et al. Incidence,course, and severity of delayed nausea and vomiting fol-lowing the administration of high-dose cisplatin. J ClinOncol. 1985;3(10):1379-1384.17. Kris MG, Hesketh PJ, Somerfield MR, et al.American Society of Clinical Oncology guideline forantiemetics in oncology: update 2006. J Clin Oncol.2006;24(18):2932-2947.18.North Carolina Program on Health Literacy. HealthLiteracy Toolkit. Tool 5. http://www.nchealthliteracy.org/toolkit/tool5.pdf. Accessed September 7, 2012.19. Sprandio JD. Oncology patient-centered medicalhome and accountable cancer care. CommunityOncology. 2010;7(12):565-572.


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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Living Proof

INDICATION

CONTRAINDICATIONS

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS▼ Peripheral neuropathy:

▼ Hypotension:

▼ Cardiac toxicity:

▼ Pulmonary toxicity

▼ Posterior reversible encephalopathy syndrome:

▼ Gastrointestinal toxicity:

▼ Thrombocytopenia or Neutropenia:

▼ Tumor lysis syndrome:

▼ Hepatic toxicity:▼ Embryo-fetal risk:

▼

CYP3A4 inhibitors CYP3A4 inducers

ADVERSE REACTIONS

Survival never gets old

VELCADE® (bortezomib) Indication and Important Safety Information

Approved for subcutaneous and IV administration‡

VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months [HR=0.695; 95% CI, 0.57-0.85; p<0.05]; 60.1-month median follow-up†)

7

Approved for subcutaneous and IV administration




‡Approved for subcutaneous and IV administration

Living Proof

Living Proof

For preventing bone metastases inwomen with early breast cancer,the current body of evidence does

not support the use of osteoclast-tar-

geting agents, ie, bisphosphonates,according to Julie Gralow, MD, direc-tor of Breast Medical Oncology at theFred Hutchinson Cancer Research

Center in Seattle, Washington.Gralow presented her thoughts on

this controversial topic at the AmericanSociety of Clinical Oncology 2012

Breast Cancer Symposium, held in SanFrancisco, California.1“There is no question that breast can-

cer treatment can cause accelerated boneloss, most commonly among patientsreceiving aromatase inhibitors,” sheacknowledged. But studies have failed toshow significant differences in the occur-rence of the more clinically relevant endpoint of fracture, and the prevention ofrecurrences and deaths from breast can-cer, she noted. To the point, Gralow reviewed key

data from several important trials eval-uating the benefit of adjuvant bisphos-phonates.

No Real benefit for FracturePreventionThe Z-FAST trial compared upfrontuse of zoledronic acid with its delayeduse in postmenopausal women receiv-ing adjuvant letrozole. Whereas bonemineral density (BMD) was betterwith the immediate use of zoledronicacid—with gain observed with upfrontuse and decline observed without it—fracture rates were similar between thearms: approximately 6% at 36 monthsand 9% to 11% at 61 months, therecent update showed.2“Zoledronic acid preserved BMD but

did not impact fractures,” she said.

Why Not Treat All EarlyBreast Cancer Patients?

bisphosphonates Should Not be Routinein early breast CancerBy Caroline Helwick


Breast Cancer

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 © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: 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. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%. 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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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 of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms.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 of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive 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.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, 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) 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, VELCADE 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 bortezomib 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 VELCADEHCP.com.

V-12-0273 12/12

While it might be tempting to sim-ply prescribe bisphosphonates to allearly breast cancer patients, Gralowwould not recommend this for thefollowing reasons:

• Not all women are at risk for ther-apy-induced bone loss; even thosewith bone loss have a low fractureincidence and can rebound whenstopping drugs.

• The majority of women will not have their cancer recur afteradjuvant endocrine therapy orchemotherapy.

• The subgroup that will benefit hasnot been defined; biologicalmechanisms of action need fur-ther study.

• Osteoclast-targeted agents haveside effects, including osteonecro-sis of the jaw, gastrointestinalupset, renal toxicity, acute phasereactions, and hypocalcemia, andmay have a negative effect onbone quality.

• These drugs can be expensive.


AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012.© 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12XTANDI is a registered trademark of Astellas Pharma Inc.Astellas and the fl ying star logo are trademarks of Astellas Pharma US, Inc.

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety InformationContraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot fl ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

NOW APPROVED for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

Learn more at XtandiHCP.com

• 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1

• Patients were allowed, but not required, to take glucocorticoids1

— In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1

• The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

AND...

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

y


Breast Cancer

BRIEF SUMMARY OF PRESCRIBING INFORMATIONThe following is a brief summary: please see the package insert for full prescribing information.------------------------------ INDICATIONS AND USAGE -----------------------------XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.--------------------------------- CONTRAINDICATIONS -------------------------------PregnancyXTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss . -------------------------- WARNINGS AND PRECAUTIONS -------------------------SeizureIn the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS -------------------------------Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared

in practice.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain,

upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse

placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the

the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in the Randomized Trial

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)

General DisordersAsthenic Conditionsa 9.0 44.4 9.3Peripheral Edema 1.0 13.3 0.8

Musculoskeletal And Connective Tissue DisordersBack Pain 26.4 24.3 4.0Arthralgia 17.3 1.8Musculoskeletal Pain 1.3 0.3Muscular Weakness 9.8 6.8 1.8Musculoskeletal Stiffness

2.6 0.3 0.3 0.0

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)

Gastrointestinal DisordersDiarrhea 21.8 1.1 0.3

Vascular DisordersHot Flush 20.3 0.0 10.3 0.0Hypertension 6.4 2.1 2.8 1.3

Nervous System DisordersHeadache 12.1 0.9 0.0Dizzinessb

Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 3.8

Paresthesia 6.6 0.0 0.0Mental Impairment Disordersc

4.3 0.3 1.8 0.0

Hypoesthesia 4.0 0.3 1.8 0.0Infections And Infestations

Upper Respiratory Tract Infectiond

10.9 0.0 0.3

Lower Respiratory Tract And Lung Infectione

2.4 4.8 1.3

Psychiatric DisordersInsomnia 8.8 0.0 6.0Anxiety 0.3 4.0 0.0

Renal And Urinary DisordersHematuria 6.9 1.8 1.0Pollakiuria 4.8 0.0 0.0

Injury, Poisoning And Procedural ComplicationsFall 4.6 0.3 1.3 0.0Non-pathologic Fractures

4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue DisordersPruritus 3.8 0.0 1.3 0.0Dry Skin 0.0 1.3 0.0

Respiratory DisordersEpistaxis 3.3 0.1 1.3 0.3

a Includes asthenia and fatigue.b Includes dizziness and vertigo.c Includes amnesia, memory impairment, cognitive disorder, and disturbance

in attention.d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis,

pharyngitis, and laryngitis.e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung

infection.

Laboratory Abnormalities

patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both

thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. InfectionsIn the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related InjuriesIn the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.HallucinationsIn the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual,

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012

(continued) Table 1. Adverse Reactions in the Randomized Trial

“There is also a rebound effect inBMD that is important,” Gralownoted. In the ABCSG-12 trial, pre-menopausal patients received ovariansuppression for 3 years plus adjuvanthormonal therapy, with or withoutzoledronic acid.3 The bisphosphonatewas protective against BMD loss.However, a natural rebound in BMD

occurred once the ovarian suppressionwas stopped, she said. “Just because we are suppressing the

ovaries, especially temporarily, or start-ing an aromatase inhibitor, we don’tneed to impact on BMD immediately,”she explained. “There’s a significantrebound of BMD once you take awaythe pressures from these treatments.”

Although zoledronic acid did reducerecurrences by 28% and deaths by36%, the death rate at 84 months wasalready very low (6%) among patientsnot receiving chemotherapy or zole-dronic acid (and in spite of allowing upto 10 positive nodes).A task force of the National Com -

p rehensive Cancer Network, led by

Gralow, defined patients who may be atincreased risk for fracture and who there-fore might be candidates for bisphospho-nates. The algorithm suggests that drugtherapy be considered for patients with aT-score between -1.5 and -2.0, and that itbe initiated in those with a T-score ≤-2.0or who have a 10-year risk >20% for amajor fracture or >3% for a hip fractureby FRAX analysis (WHO Fracture RiskAssessment Tool).

bisphosphonates Should Not be Routine... Continued from page 16

“The task force clearly did not say thatall patients should start drug therapy upfront,” she emphasized.

No Real Protection FromRecurrenceStudies investigating whether bisphos-phonates can prevent bone metastasesand improve survival have producedconflicting results. Two randomized tri-als of oral clodronate showed a reduc-

tion in bone metastases, while a thirddemonstrated an equivalent rate ofbone metastases between the arms. Ameta-analysis using the 5-year datafrom these 3 adjuvant clodronate trialsfailed to show a statistically significantdifference in overall survival or bonemetastasis-free survival,4 although het-erogeneity among the trial was noted,she said. “The largest and most recently report-

ed trial of clodronate, NSABP B-34,5(the 2011 San Antonio Breast CancerSymposium), was flat-out negative forthe primary end point, disease-free sur-vival,” she added.The German GAIN trial of iban-

dronate6 also was completely negativefor a benefit in terms of recurrence orsurvival, she added.Trials of the more potent aminobis-

phosphonate, zoledronic acid, also have

produced conflicting results. Whereasthe ABCSG-12 trial3 and the ZO-FAST trial7 both showed improvementsin disease-free survival in patientsreceiving zoledronic acid, the Z-FASTtrial, with the same design as ZO-FAST, did not.2 The AZURE trial,which evaluated an “intensive” adju-vant zoledronic acid regimen, also failedto show a disease-free or overall survivalbenefit.8“The largest trial in the highest risk

patients using the most intensive dosing(AZURE) was flat-out negative,”Gralow emphasized.There was a suggestion of an overall

survival benefit among women whowere 5 years past menopause prior torandomization—a statistically signifi-cant 25% risk reduction—suggestingthat an estrogen-deficient environmentmight be more susceptible to the effectof zoledronic acid, but these results mustbe interpreted with caution, she said.Gralow added, “If there is a direct

antitumor effect, I don’t know why wehave not seen a hint of this in metastatic studies.” A number of ongoing trials are fur-

ther evaluating clodronate, iban-dronate, zoledronic acid, and thenewest osteoclast inhibitor denosumab.“The results of these trials will be criti-cal in better defining the efficacy ofbone-modifying agents for preventingrecurrence and may provide dataregarding which patients and tumors aremost likely to benefit from treatment,”Gralow said. l

References1.Gralow J. Debate: bone health/role of bisphosphonatesin early-stage breast cancer—con. Presented at:American Society of Clinical Oncology 2012 BreastCancer Symposium; September 13-15, 2012; SanFrancisco, CA. 2. Brufsky AM, Harker WG, Beck JT, et al. Final 5-yearresults of Z-FAST trial: adjuvant zoledronic acid main-tains bone mass in postmenopausal breast cancer patientsreceiving letrozole. Cancer. 2012;118(5):1192-1201.3. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al.Long-term follow-up in ABCSG-12: significantlyimproved overall survival with adjuvant zoledronic acidin premenopausal patients with endocrine-receptor-posi-tive early breast cancer. Presented at: 34th Annual SanAntonio Breast Cancer Congress; December 6-11, 2011;San Antonio, TX. Abstract S1-2.4. Ha TC, Li H. Meta-analysis of clodronate and breastcancer survival. Br J Cancer. 2007;96(12):1796-1801.5. Paterson AHG, Anderson SJ, Lembersky BC, et al.NSABP protocol B-34: a clinical trial comparing adju-vant clodronate vs. placebo in early stage breast cancerpatients receiving systemic chemotherapy and/or tamox-ifen or no therapy—final analysis. Presented at: 34thAnnual San Antonio Breast Cancer Congress; December6-11, 2011; San Antonio, TX. Abstract S2-3.6. Möbus V, Diel IJ, Harbeck N, et al. GAIN (GermanAdjuvant Intergroup Node Positive) study: a phase-IIImulticenter trial to compare dose dense, dose intenseETC (iddETC) vs. EC-TX and ibandronate vs. observa-tion in patients with node-positive primary breast can-cer—1st interim EFFICACY analysis. Presented at: 34thAnnual San Antonio Breast Cancer Congress; December6-11, 2011; San Antonio, TX. Abstract S2-4.7. de Boer R, Bundred N, Eidtmann H, et al. Long-termsurvival outcomes among postmenopausal women withhormone receptor-positive early breast cancer receivingadjuvant letrozole and zoledronic acid: 5-year follow-upof ZO-FAST. Presented at: 34th Annual San AntonioBreast Cancer Congress; December 6-11, 2011; SanAntonio, TX. Abstract S1-3.8. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl JMed. 2011;365(15):1396-1405.


Breast Cancer

----------------------------------DRUG INTERACTIONS -------------------------------Drugs that Inhibit or Induce CYP2C8

the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated . Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended

Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated . Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g.,

reduce the plasma exposure of XTANDI and should be avoided if possible .

Effect of XTANDI on Drug Metabolizing EnzymesEnzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring . -------------------------- USE IN SPECIFIC POPULATIONS ------------------------Pregnancy- Pregnancy Category X XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Nursing MothersXTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric UseSafety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent

in safety or effectiveness were observed between these patients and younger

responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal ImpairmentA dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy

adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed . Patients with Hepatic ImpairmentA dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed

-------------------------------------- OVERDOSAGE --------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general

escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the mouse lymphoma thymidine kinase (Tk) gene mutation assay or the mouse micronucleus assay.

consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy

to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed

PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (PATIENT INFORMATION).

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.

treatment during the course of treatment with XTANDI.

risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

paresthesia, hypoesthesia, and falls.

if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062

Issued: August 2012

Rx Only© 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

The management of relapsed/refractory acute lymphoblasticleukemia (ALL) is a vexing prob-

lem and requires extensive, aggressivesupportive care throughout the course oftherapy, explained Joseph C. Alvarnas,

MD, City of Hope Comp rehensiveCancer Center, Duarte, Cali fornia, in apresentation at the National Com -prehensive Cancer Network (NCCN)7th Annual Congress on HematologicMalignancies.1

The NCCN guidelines for ALL reveala dichotomy between Philadelphia-posi-tive (PH+) and Philadelphia-negative(PH-) relapsed/refractory ALL. In PH+ ALL, gene mutation testing is

important. Patients with PH+ disease

who relapse following cessation of tyro-sine kinase inhibitors (TKIs) can restartTKI-based therapy. For those who arerefractory or relapse on TKI-based thera-py, perform mutational analysis. If theT315I mutation is present, considerhematopoietic cell transplant (HCT) orclinical trial; for V299L, T315A,F317L/V/CI/C, consider nilotinib ratherthan dasatinib. For Y253H, E255K/V, orF359 V/C/I, consider dasatinib ratherthan nilotinib. For any other mutation,consider high-dose imatinib, dasatinib,or nilotinib. PH- ALL is far more difficult to

treat. Most regimens are front-loadedwith the best therapeutic agents, leav-ing few options for second-line treat-ment at relapse. Patients with PH-ALL should be considered for clinicaltrial or allogeneic hematopoietic stemcell transplant if in remission or onchemotherapy.

Several challenges exist for salvagetherapy for adults with relapsed/refrac-tory ALL, Alvarnas continued. It maybe difficult to identify a non–cross-resistant regimen for reinduction. L-asparaginase –containing regimens maybe difficult to administer to olderpatients. Even very intensive regimensmay achieve response rates <30%.Comorbidities may limit therapeuticchoices. Allogeneic HCT representsthe only potentially curative option foradolescents/young adults (AYAs) andadults with ALL. Patients with signifi-cant residual disease are not candidatesfor allogeneic HCT. “The lessons from our experience

with relapsed/refractory ALL aretwofold. First, we would like to avoidrelapse, and we recommend strong riskstratification at the time of diagnosis.Second, move to transplant after firstcomplete response is achieved,” he stat-ed. Five-year overall survival was 62%at City of Hope when adults with ALLwere transplanted in first remission.

Relapsed/Refractory All Vexing ProblemBy Alice Goodman


Leukemia

AGENDA*

FRIDAY, JULY 26, 20133:00 pm – 7:00 pm Registration5:30 pm – 7:30 pm Welcome Reception/Exhibits

SATURDAY, JULY 27, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Welcome to the Second Annual World Cutaneous Malignancies

Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies• Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway

• Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 4:30 pm General Session II: Current Treatment Guidelines in Cutaneous

Malignancies• Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients

• Panel Discussion Management Controversies and AcceptedGuidelines for the Personalized Management of Cutaneous Malignancies

• Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm Meet the Experts/Networking/Exhibits

SUNDAY, JULY 28, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Review of Saturday’s Presentations and Preview of Today’s Sessions8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for

Cutaneous MalignanciesGeneral Session IV: Challenges for the Cutaneous Malignancies Clinician• Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 2:45 pm General Session V: “Hot Data” — What I Learned at Recent Meetings:

Focus on Cutaneous Malignancies2:45 pm – 3:00 pm Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

A 2-day congress dedicated to informing, educating, and fostering the exchangeof clinically relevant information in the field of cutaneous malignancies on topics inmelanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carci-noma, and Merkel cell carcinoma, including:

• Epidemiology and genetic/environmental factors

• Molecular biology and cytogenetics related to the pathogenesis of cutaneousmalignancies

• Risk stratification based on patient and tumor characteristics

• Principles of cancer prevention of melanoma and basal cell carcinoma

• Current treatment guidelines

• Emerging treatment options for personalized therapy

• Future strategies in management based on translational data from current clinicaltrials and basic research

PROGRAM OVERVIEW

This activity was developed for medical and surgical oncologists, dermatologists,radiation oncologists, and pathologists actively involved in the treatment of cu-taneous malignancies. Advanced practice oncology or dermatololgy nurses,oncology pharmacists, and researchers interested in the molecular biology andmanagement of cutaneous malignancies are also encouraged to participate.

TARGET AUDIENCE

Upon completion of this activity, the participant will be able to:

• Review the molecular biology and pathogenesis of cutaneous malignancies asthey relate to the treatment of cutaneous T-cell lymphoma, basal cell carci-noma, Merkel cell tumors, and malignant melanoma

• Compare risk stratification of patients with cutaneous malignancies, and how totailor treatment based on patient and tumor characteristics

• Summarize a personalized treatment strategy that incorporates current stan-dards of care and emerging treatment options for therapy of patients with cu-taneous malignancies

LEARNING OBJECTIVES

��

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DESIGNATION OF CREDIT STATEMENTS

PHYSICIAN CREDIT DESIGNATION

SPONSORS

REGISTERED NURSE DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 12.0AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

This activity is jointly sponsored by Medical Learning Institute Inc, Center of ExcellenceMedia, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

Medical Learning Institute IncProvider approved by the California Board of Registered Nursing, Provider Number15106, for 12.0 contact hours.

Sanjiv S. Agarwala, MDProfessor of Medicine Temple University School ofMedicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

Steven J. O’Day, MDHematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer CenterClinical Associate Professor of MedicineUSC Keck School of MedicineLos Angeles, California

Professor Dr. Med. AxelHauschildProfessor, Department of DermatologyUniversity of KielKiel, Germany

CONFERENCE CO-CHAIRS

July 26-28, 2013Hyatt Regency La Jolla • San Diego, California

• Melanoma

• Basal Cell Carcinoma

• Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma

• Merkel Cell Carcinoma

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN!$175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharmacyeducation. Completion of this knowledge-based activity provides for 12.0contact hours (1.2 CEUs) of continuing pharmacy education credit. The

Universal Activity Number for this activity is (To be determined).

For complete agenda please visit www.CutaneousMalignancies.com

� � ��


The NCCN guidelines for acute lymphoblasticleukemia (ALL) reveal a dichotomy between

Philadelphia-positive andPhiladelphia-negative

relapsed/refractory ALL.

Cancer Center Profile

In 2016, a new hospital with an inte-grated, comprehensive cancer centerwill be completed. This new facility willprovide even greater access to servicesfor many cancer patients in theWashington, DC, area. Catherine Bishop, DNP, NP,

AOCNP, answered some questions fromThe Oncology Nurse-APN/PA about theprograms and services of the JohnsHopkins Kimmel Cancer Center andSibley Infusion Center.

What are you excited about rightnow in the cancer field?Catherine Bishop (CB): My enthusi-asm in the field of oncology comes fromthe many clinical and pharmaceuticaladvances available to patients today.The new drug combinations, moleculartargeted therapies, and markers allow-ing for the identification of treatmentsensitivities move forward the goal ofcure for some, longer disease-free inter-vals and overall survival for others.Understanding the drugs that providethe least response for specific tumorsminimizes toxicities and undue costs fortreatments. The plethora of clinical tri-als ongoing here at Johns Hopkinsallows us to understand what treatmentsyield the most benefit, and which treat-ments don’t work. With the advent of many oral

chemotherapeutic and targeted agents,patients have more freedom to stay athome to receive their therapy. I thinkthis may result in patients feeling theyhave more control over their treat-ment course and thus their personaland professional lives. It also may alle-viate the burden on caregivers to makefrequent trips to the clinic.

What approach does your institution take to treating peoplewith cancer?CB: The Johns Hopkins Kimmel CancerCenter and Sibley Infusion at SibleyMemorial Hospital are truly the finest ofboth institutions. Local Washington,DC, metropolitan patients have access toJohns Hopkins experts in their own com-munity. This translates into conveniencefor patients who gain the disease-specificexpertise from the physicians associatedwith Johns Hopkins without having tomake the trip to Baltimore for every visit.Our clinical approach is team based.

Teams are comprised of the oncologist,the oncology nurse practitioner, and theprimary oncology nurse. Every patient isat the center of this team.

How does that translate to betteroutcomes for your patients?CB: Patients feel well cared for, know-ing that a group of individuals are cur-rent on their plan of care. Here at Johns

Hopkins Kimmel Cancer Center/Sibley Infusion there is never a timewhen one of the providers is not in theclinic. Whether a patient calls orcomes into the clinic in an unsched-uled appointment, one of the teammembers is present and available toaddress his or her needs. This availabil-ity will often preclude an emergencyroom visit.This team approach translates into

comprehensive, quality care, as patientshave access to each discipline. The teamworks together to create a cohesive,patient-centered environment.

What is your role?CB: I am the oncology nurse practi-tioner (NP) within the practice, caringfor a variety of cancer patients with var-ied types of cancer diagnoses. Beforejoining the medical oncology grouphere at Johns Hopkins Kimmel CancerCenter/Sibley Hospital, I was part of acommunity oncology practice andtherefore had the opportunity to gainexperience with many types of cancerdiagnoses. This has proved to be benefi-cial, because while the physicians inthis practice are specialists and diseasespecific, I have the ability and experi-ence to cross over to many cancer diag-noses and to care for these patientsalongside my physician partners.

How has the role of the oncologynurse changed over the past 5 years?CB: Oncology staff nurses have moreautonomy than in the past. I thinkthe hierarchy way of managingpatients is in the past. Staff members

in each discipline have their area ofexpertise and are recognized andrespected for their knowledge.Oncology nurses have professionalcommitments to furthering theirunderstanding of the disease processand treatment protocols. They have aclear understanding of, and embrace, evi-dence-based practice. Oncology RNs aredirect care providers working withpatients on a daily basis who understandhow to manage the sideeffects of chemotherapy.Medicine and nursing withinoncology have led the way increating and maintaining theexemplar of the intradiscipli-nary team. It truly takes ateam to care for one patient. Oncology NPs are inte-

gral members of both themedical and nursing teamwithin oncology. OncologyNPs work collaborativelywith oncologists. Theyoften see patients at their initial visit,and many see follow-up visits as a rou-tine in their daily schedules. OncologyNPs frequently are performing proce-dures such as bone marrow biopsies/aspirations and intrathecal chemo ther-apy and are practicing at advanced lev-els within community, academic, andhospital cancer centers.

What inspired you to enter the fieldof oncology nursing? CB: My mother died of a brain tumor in1992. This personal experience drew meto oncology. When the opportunity pre-sented itself in 1994, I jumped at thechance to rotate from internal medi-

cine to the outpatient cancer center ata large academic institution. I felt Icould relate to the cancer patients andtheir families in a special way becauseof my recent experience with mymother. Oncology nursing is such arewarding specialty. It allows closenesswith patients (and their families) at afragile time in their lives. There are somany opportunities to provide helpand understanding—after all, this isone reason people choose the health-care profession. I hear from others out-side of oncology, “Your job must be sodifficult.” To which I respond, “Thework of oncology is one of the mostrewarding jobs—I cannot think ofdoing anything else.” Our patients giveus so much. Their courage, strength,and resilience inspire us to continuethe work we have been called to do. Itis truly an honor to do this work.

Any advice for nurses just enteringthe field?CB: Oncology nursing is an incrediblyrewarding area of practice. The opportu-nity to understand the science behindthe quickly advancing subspecialty isboth challenging and exhilarating. Itdemands consistently reading the litera-ture to keep abreast of new drugs, newadvances in local control of disease,and predictive and prognostic tools.The qualitative data we gather fromour patients in terms of preferencesrelated to psychosocial aspects and pal-liative and end-of-life care enable us to

understand the type of carethey want during this timein their lives.If a nurse is thinking about

entering or changing to thefield of oncology, my sugges-tion would be to spend sometime with an oncology nurse.Almost every oncology nurseI know welcomes a newnurse, or an experiencednurse entering oncology, intohis or her environment tomentor or speak with about

what it is like to work with the oncologypatient population. Most, if not all,oncology nurses feel they get more thanthey give.

If you weren't working in this field,what would you be doing?CB: I would be involved in the designfield. I have always had a passion forspace design, which spilled over toesthetic design. They go hand in handfor me. I like my personal and profession-al environments to be organized andfunctionally friendly. This translates intomore efficient production—whetherthat is in the kitchen at home or in theoncology clinic. l

The Johns Hopkins Kimmel Cancer Center.... Continued from cover

The patient is at the center of the team-based approach to care. The teamfor this patient (seated) includes an oncologist, Channing Paller; anoncology nurse practitioner, Catherine Bishop; and a primary oncologynurse, Carol Abrams (left to right).Photo from Sibley Memorial Hospital.

Catherine Bishop,DNP, NP, AOCNP


“Unrelated donor transplant pro-duces similar outcomes as relateddonor transplant. Don’t let the lack ofsibling donor keep you from moving onto transplant,” he told listeners.Alvarnas commented that trans-

plant outcomes have not improved

appreciably over the past 3 decades.“We have a long way to go,” he said.“At the same time, intensification ofthe transplant regimen is not feasible.”Experience with transplant raises

the importance of timely transplanta-tion and the need for better drugs

that might improve outcomes, he said. Alvarnas discussed several new

agents that may be useful inrelapsed/refractory ALL. Two agentsthat have shown promising results insmall phase 2 trials are nelarabine, aprodrug of ara-G, and clofarabine, a

second-generation purine nucleosideanalog. Both drugs have distinct side-effect profiles, with different toxicities.Neurologic toxicity is the key dose-limiting toxicity with nelarabine.Other significant toxicities includecytopenia, gastrointestinal effects, andpyrexia. Toxicities of clofarabineinclude elevations of liver enzymes,febrile neutropenia, skin rash, andcytomegalovirus reactivation.

“The use of novel therapeutics inrelapsed/refractory ALL is exciting tome. We would like to identify a paral-lel drug to rituximab in lymphoma. Weare still early on in this process. Twodrugs might be interesting in thisregard [blinatumomab and inotuzumabozogamicin]. These antibodies areimpressively tolerable in heavily pre-treated patients, compared withchemotherapy,” Alvarnas said. l

Reference1. Alvarnas JC. New approaches to the management ofrelapsed/refractory acute lymphoblastic leukemia.Presented at: National Comprehensive CancerNetwork (NCCN) 7th Annual Congress onHematologic Malignancies; September 14, 2012; NewYork, NY.

Supportive Care for All

Patients being treated for ALLrequire aggressive coordinated sup-portive care throughout the entirecourse of therapy. Alvarnas highlighted several sup-

portive care needs:• Preemptive management oftumor lysis syndrome

• Disseminated intravascular co -agulation and L-asparaginasecoagulopathies

• Management of therapy-relat-ed cytopenia

• Management of febrile neu-tropenia/opportunistic infection

• Antiemetic therapy

Relapsed/Refractory All Vexing Problem Continued from page 20


Leukemia

��

TO VIEW THE SERIES ONLINEPLEASE LOG ON TO:

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� � � �

CONQUERING THECANCER CARECONT I NUUM™

� � �

2ND ANNUAL View the

series online at

TheOncologyNurse.com

A 6-part series

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Cancer is an illness associated with substantialphysical, emotional, social, and financial ram-ifications for affected individuals and their

families. In a significant number of cases, the diagnosisof cancer is either preceded by a periodof gradual, nonspecific symptoms ordiscovered by routine screening, andindividuals are then thrust into awhirlwind of diagnostic testing, in-vasive procedures, and complicatedtreatments with very little warning oropportunity to assimilate their circum-stances. Frequently, a multidisciplinaryapproach to treatment is necessary, re-quiring patients to engage with numer-ous medical teams comprising severaldifferent specialties, often in differentlocations. Many patients have beenrelatively healthy prior to the cancer event and there-fore are not sophisticated consumers of medical ser-vices. Consequently, it is incumbent on healthcareprofessionals to be able to facilitate patients’ transitioninto care in order to minimize their distress and maxi-mize their clinical outcomes.Challenges exist beyond the initial diagnosis and

treatment period as well. According to the NationalCancer Institute (NCI), more than 12 million individ-uals in the United States are living with a history of

cancer.1 More than half are living well beyond 5 yearsafter diagnosis. Women comprise a majority of long-term survivors due to the favorable outcomes withbreast, cervical, and uterine cancers.2 The number of

people living with a history of canceris projected to grow considerably overthe next 20 years for 2 major reasons.First, the number of Americans overage 65 is predicted to double betweenthe years 2000 and 2030.3 Conse-quently, as a disease primarily of olderadults, cancer will also increase. Sec-ond, as the effectiveness of cancertreatments improves, the number ofpatients cured of the disease will in-crease, and an even larger percentagewill be living longer with the diseasewhile receiving multiple “lines” of

therapy (first-line, second-line, etc) over time. Theoverall demand for oncology services is expected to in-crease by 48% by 2020, while the supply of oncologistswill increase by only 14% based on current patterns.4

These statistics underscore the need for a wide varietyof health professionals and other support personnel toplay a part in enabling each and every patient to re-ceive quality care that addresses all of their needsthroughout the continuum of the illness. Patients de-fine quality of care based on their ability to5:

Challenges Patients Face in Cancer Care:Implications for the Healthcare TeamLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen,PharmD, BCOP


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The past decade has seen a dramatic upsurge inthe utilization of specialty pharmacies for alltypes of therapeutic modalities, including

those for cancer. The cost of cancer care may rise from

about $125 billion in 2010 to $207 bil-lion by the end of the decade. By thattime, specialty drugs are predicted toaccount for 2 of every 5 pharmacy dol-lars spent.1 The purpose of this articleis to explain the evolution of the spe-cialty pharmacy and the functions itcan serve in the treatment of cancerand to discuss the potential benefitsand challenges of the system from thepoint of view of the patient.

The Evolution of SpecialtyDrugs and SpecialtyPharmacyThere is a lack of consensus on the definition of a

specialty drug. The Food and Drug Administration has

not defined the term. Initially, the label was virtually

synonymous with biotechnology products, either pro-

teins produced by recombinant DNA techniques or

monoclonal antibodies produced with cellular hy-

bridomas, but this is no longer the case. The 2007

Medicare Modernization Act defined a specialty drug

as “a part D drug with plan-negotiated prices that ex-

ceed $400 per month.”2 Other health plans may de-

fine specialty drugs differently. In general, they arehigh cost, administered by injectionor infusion, require special handling,or are used for complex diseases thatrequire special monitoring. In on-cology, however, the most commonagents dispensed by a specialty phar-macy provider (SPP) are the newertargeted agents that are adminis-tered orally. After a systematic re-view of the literature, one academicgroup of authors proposed the mostcritical descriptors of a specialtydrug to be3:• High cost (prescriptions cost more than $600 per month)

• Difficult medication delivery, such as— Special handling requiring strict temperature

control— Restricted location for medication preparation

or distribution site— Restricted location for medication adminis-tration

Convenience, Challenges, and Cost Containment:

The Impact of Specialty Pharmacies on

Patient CareLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University



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The predominant

scenario for systemic treatment

of cancer has traditionally involv

ed administra-

tion of intravenous chemother

apy by highly

trained personnel who closely m

onitored the patient.

When these procedures took place i

n an

oncologist’s office or in a hospit

al infu-

sion center, extensive education

of the

patient and family was possible

. More

recently, however, an increasing

ly com-

mon situation involves the use of

one or

more oral medications and self-a

dmin-

istered subcutaneous therapies

in the

home environment. The direct r

espon-

sibility for drug acquisition and

admin-

istration is shifting to the patie

nts and

their social support network, i

f avail-

able. At the present time, more t

han 20

oral medications are FDA appro

ved for

the first-line treatment of cance

r (Table 1). In addition,

a number of other oral agents ar

e used for tumors that

have relapsed or are refractory to

initial treatment. Ac-

cording to the National Compre

hensive Cancer Net-

work, approximately 25% of a

ll compounds in the

oncology research and developm

ent pipeline are admin-

istered orally, so the trend is like

ly to continue.1

With this shift in responsibility co

mes the increased

possibility that anticancer medic

ations may not be ad-

ministered correctly, especially fo

r regimens that require

repeated dosing. Overall estimat

es of adherence to long-

term oral medication regimens r

ange from 17% to 80%,

with an average around 50%.

2-4 A common assumption

that adherence to oral antica

ncer agents would be

higher, due to the severity of

the disease, has been

proven untrue. Studies indica

te the

adherence rates for cancer therap

y are

15% to 97%.5 Nonadherence

has

been associated with worse out

comes

in a number of disease states and

with

increased physician visits, higher

hos-

pitalization rates, longer hospital

stays,

disease worsening, and increased

mor-

tality.6 Approximately one-th

ird to

two-thirds of all medication-r

elated

hospitalizations are due to medic

ation

nonadherence—at a cost of $100

bil-

lion annually.7 The purpose of t

his ar-

ticle is to describe general con

cepts

regarding patient adherence and

the research related to

adherence to cancer treatment.

The incidence, risk fac-

tors, and consequences of this pr

oblem will be reviewed.

The last article in this series wil

l subsequently examine

the best practices for maximizing

adherence and clinical

outcomes.

��

� ��

Adherence was defined by the W

orld Health Organ-

ization in 2003 as the “extent t

o which a person’s be-

havior, taking medication, fol

lowing a diet, and/or

Impact of Nonadherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOP

Associate Professor, Virginia Commonwealth University

Lea Ann Hansen,

PharmD, BCOP

CONQUERINGTHE

CANCER CARE

CONT I NUUM™

�$%* �%'��+!*%!+


The previous installment in this cancer care se-ries examined the growing importance of oraltherapies for the treatment of cancer and the

implications of patient adherence on its success. At thepresent time, more than 20 oral med-ications are approved by the Food andDrug Administration (FDA) for first-line treatment of cancer. A number ofother oral agents are used for tumorsthat have relapsed or are refractory toinitial treatment, and about 25% of theoncology research pipeline consists oforal compounds.1 This is in addition toself-administered subcutaneous thera-pies for the home environment thatare under FDA review. When cancer medications are ad-ministered orally in the home envi-ronment rather than in the clinic or hospital, the rates

of adherence range from 15% to 97%.2 For example,at the end of the first year of treatment with adjuvanthormonal treatment (AHT) for early-stage breast can-cer, only 79% of patients remained on therapy withouta gap exceeding 60 days and 85% without a gap ex-ceeding 180 days. By year 5, only 27% and 29% re-mained without 60- and 180-day gaps, respectively.3In another study of AHT, patients with a medica-

tion possession ratio (MPR) >80% had a statisticallysignificantly higher 10-year survival rate than those

with a lesser MPR (82% vs 78%).4 (MPR is a metricderived from electronic prescription records based onrefill patterns over time, and 80% is an arbitrary cutpoint for adherence used by many investigators.) Thesame study found survival at 10 yearsto be 81% for those who continuedtherapy versus 74% for those whohad discontinued it. Nonadherencehas also been shown to produce sub-stantial detriment in clinical out-comes in chronic myeloid leukemiaand childhood acute lymphoblasticleukemia.5-8 For each of these disor-ders, prolonged oral therapy hasbeen the standard of care for adecade or more. It is likely that neg-ative consequences of nonadherencewith other oral cancer medications

will be documented in the future as their role in ther-apy matures. The purpose of this article is to discussthe results of available research on maximizing adherence and suggest best practices to improve clin-ical outcomes.

� �� Direct communication with all patients about their

personal barriers to taking daily therapy for a prolongedperiod is an important aspect to maximizing adher-

Best Practices in Maximizing Adherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University



�).+-%�&(��,"+&",

The publishers of The OncologyNurse-APN/PA, The OncologyPharmacist, and PersonalizedMedicine in Oncology are proud to present our 2nd annualConquering the Cancer CareContinuum series. Upcoming topics include:

• Palliation• Pain management• Hospice care • Treatment planning• Survivorship care• Biosimilars in supportive care

� ��

Experience withtransplant raises theimportance of timely

transplantation and theneed for better drugsthat might improve

outcomes.

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139

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*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

Sildenafil is often used by men treatedwith radiation or radical prostatectomyfor prostate cancer to achieve an erec-tion sufficient for sexual intercourse,and it is effective to varying degreeswhen used on an as-needed basis. Arandomized controlled trial has foundthat prophylactic daily use of sildenafilimproved overall sexual function, aswell as domains of sexual function, inprostate cancer patients undergoingradiation therapy.1 This is the first timea phase 3 study has demonstrated theeffectiveness of prophylactic sildenafilin the setting of radiation.“Prostate cancer patients treated

with sildenafil and adjuvant radiationtreatment had improved overall erec-tile function and overall satisfaction oftheir sexual activity and function. The

most significant improvements wereseen at 6 and 12 months after treat-ment, with a slight dip at the 24-monthmark, suggesting that future trials needto be conducted to demonstrate iflonger treatment duration can furtherimprove outcomes,” said lead authorMichael Zelefsky, MD, of MemorialSloan-Kettering Cancer Center in NewYork City. No benefit for sildenafil wasseen among a small group of 31 patientswho were also treated with androgendeprivation therapy.The prospective, randomized, dou-

ble-blind, placebo-controlled trialincluded 295 patients with clinicallylocalized prostate cancer who weretreated with external beam radiationtherapy and/or brachytherapy (perma-nent interstitial implantation of radio -

active “seeds”). Patients were random-ized in a 1:1 ratio to receive either dailysildenafil 50 mg or placebo. Treatmentwas initiated 3 days before radiationtreatment and was continued daily for6 months, when the drug was stopped.After that, sildenafil could be used asneeded. Sexual function was assessed at3-month intervals for the first year andthereafter at 18 and 24 months withthe international index of erectilefunction (IIEF) and the internationalprostate symptom score (IPSS) ques-tionnaires. At baseline, all patients hadexcellent erectile function, as assessedby IIEF.Among 144 patients treated with radi-

ation only who completed IIEF and IPSSquestionnaires, overall sexual functionwas improved with daily sildenafil versus

placebo at all time points. IIEF scoreswere 58.6 for sildenafil versus 49.4 forplacebo at 6 months (P = .006); 56.3versus 48.2, respectively, at 12 months(P = .02); and 54.9 versus 47.6, respec-tively, at 24 months (P = .04). Sig -nificant im provement in overall func-tion, orgasmic function, sexual desire,intercourse satisfaction, and overall sat-isfaction were reported with sildenafilversus placebo. Overall IPSS was alsosignificantly improved with sildenafilversus placebo (P <.001).

Reference1. Zelefsky MJ, Shasha D, Kollmeier M, et al. Results of aprospective randomized double-blind placebo-controlledtrial evaluating the use of prophylactic sildenafil citrateduring radiation therapy in the treatment of prostate can-cer. Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract 3.


Conference News: ASTRO

Memantine delayed cognitive decline inpatients treated with whole-brain radia-tion therapy (WBRT) for brain metas-tases, according to results of a randomizedphase 3 trial.1Cognitive decline is common with

WBRT, occurring in about 50% to 60%of patients by 4 months after radiation.Because the mechanism of radiation-induced cognitive decline appears to besimilar to that of vascular or Alzheimer’sdementia, the researchers postulated thatmemantine, a drug used to treatAlzheimer’s disease, would be of benefitin patients treated with WBRT. “We are excited to see that adding

memantine to the treatment plan forbrain tumor patients helps preserve theircognitive function after whole-brainradiotherapy even 6 months after treat-ment. Our findings suggest that meman-tine may prevent the changes that occurin the brain following radiation therapy,impacting future treatment practices forthese patients, and suggest a role for fur-ther study in patients receiving radiationto the brain,” said presenter Nadia N.Laack, MD, radiation oncologist at theMayo Clinic in Rochester, Minnesota.

Formal discussant of this trial, VinaiGondi, MD, associate director of theCentral Dupage Hospital’s Proton Centerin Warrenville, Illinois, called this study“a good first step” in understanding thecognitive changes resulting from brainradiation and the role of memantine inpreventing or delaying them. He said

that the effect of memantine was modestin this trial and that other strategies toimprove cognitive effects of radiation arebeing pursued by researchers. The study included 508 patients with

brain metastases who received WBRTbetween March 2008 and June 2010.WBRT was delivered as 37.5 Gy in 15daily fractions. Patients were randomizedto memantine 20 mg/day or placebowithin 3 days of the start of radiationtherapy. Six domains of cognitive func-

tion (memory, processing speed, execu-tive function, global function, self-report-ed cognitive function, and quality of life)were assessed by different instruments atbaseline and weeks 8, 16, 24, and 52. Theprimary end point was memory asassessed by the Hopkins Verbal LearningTest-Revised (HVLT-R).

Compliance with the cognitive testingprotocol was suboptimal, with 32% of thepatients completing drug therapy andcognitive assessments. The reasons fornoncompliance appeared to be death,disease progression, and difficulty in get-ting patients to stay longer during a clin-ic visit or in physicians scheduling theextra 20 minutes to 1 hour required forcognitive testing. Of the 508 patientsrandomized to the 2 arms, only 149patients were analyzable at 24 weeks.

For the primary end point of memorydecline as assessed by the HVLT-R,memantine reduced the decline in HVLT-R delayed recall, with a median decline of0 versus –2 for placebo at 24 weeks, witha statistical significance of P = .059. Thisresult was “teetering on the edge of signif-icance,” according to Laack, due to thesmall numbers of patients. At 24 weeks, memantine reduced

the relative risk of cognitive decline by17% versus placebo (P = .01), and itreduced the rate of decline in cogni-tive, executive, and global function aswell as processing speed (P <.01).Patients in both groups experiencedsimilar rates of grade 3 and 4 toxicities,including alopecia, fatigue, headache,and nausea.The investigators plan to evaluate

the effect of memantine on overall sur-vival and progression-free survival inthese patients. Also, tissue specimenswill be studied to identify biomarkers ofcognitive decline as well as of responseto memantine.

Reference1. Brown PD, Shook S, Laack N, et al. Memantine for theprevention of cognitive dysfunction in patients receivingwhole-brain radiation therapy (WBRT): first report ofRTOG 0614, a placebo-controlled, double-blind, ran-domized trial. Presented at: American Society forRadiation Oncology 54th Annual Meeting; October 29,2012; Boston, MA. Abstract 1.

Continued from cover

Memantine Delays Cognitive Decline in Patients With brainMetastases Treated With Whole-brain Radiation

Influencing the Patient-Impact Factor TM

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Prophylactic Sildenafil Improves Sexual Function in Prostate Cancer PatientsUndergoing Radiation

“Our findings suggest that memantine may prevent

the changes that occur in the brain following

radiation therapy.”

—Nadia N. Laack, MD



Doxepin, a tricyclic antidepres-sant approved for the treatmentof depression and anxiety, as

well as moderate pruritus, significantlyimproved oral mucositis pain in patientstreated with radiation therapy for headand neck cancer in a phase 3 trial.1 Inthe study, doxepin was combined withwater and used as an oral rinse. Oral mucositis pain is a significant

problem in patients with head and neckcancer treated with radiation, and treat-ments such as narcotics and mouth rinsesare not particularly effective in alleviat-ing this pain. Smaller studies have sug-gested that doxepin is safe and effectivein reducing oral mucositis pain, and thepresent study establishes its effectivenessin a randomized controlled trial. “Our study validates doxepin rinse as

an effective way to alleviate oral painand sets a new standard of care,” said thelead author of the study, Robert C.Miller, MD, of the Mayo Clinic inRochester, Minnesota.For the N09C6 study, pain was

assessed on a visual analog scale andscored from 0 to 10, with a score of 10signifying severe pain. N09C6 was adouble-blind, randomized, placebo-con-trolled trial of 140 patients with headand neck cancer who had an oralmucositis pain score above 4 on thevisual analog scale. Patients wereenrolled between December 2010 andMay 2012 and were treated with radia-tion at doses above 50 Gy involvingmore than one-third of the oral cavityfor head and neck cancer. The dosage ofthe oral doxepin rinse was 25 mg dis-solved in 5 mL of water and used for 1 minute. Patients were treated on day 1 with either the doxepin rinse or place-bo; on day 2, patients crossed over to theother treatment arm. Patients couldelect to continue treatment with thedoxepin rinse on an as-needed basis.On day 1, doxepin-treated patients

reported area under the curve (AUC)pain score reduction to –9.1 versus –4.7for placebo patients (P = .0003).Crossover data from day 2 showed simi-lar findings, with an AUC pain score of–7.9 in the doxepin group versus –5.6 inthe placebo group (P = .009).Doxepin was well tolerated, but it was

associated with more stinging and burn-ing (mean pain score of 3.7 for doxepinvs 1.1 for placebo) as well as an unpleas-ant taste (mean unpleasant taste at 5minutes 2.9 for doxepin vs 1.6 for place-bo), and it caused greater drowsiness(mean drowsiness score of 3.9 for dox-epin vs 2.8 for placebo). During theoptional continuation phase, the major-ity (64%) of patients elected to contin-ue doxepin.

Reference1. Miller RC, Leenstra J, Qun R, et al. N09C6(Alliance) - a phase III, randomized double-blind

study of doxepin rinse versus placebo in the treatmentof acute oral mucositis pain in patients receiving headand neck radiotherapy with or without chemotherapy.

Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract LBA1.

Doxepin Rinse Improves Oral Mucositis in Patients Treated With Radiation for Head and Neck Cancer

*Other treatment options may also be considered.References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Radiation therapy extends life inolder women with early breastcancer, according to 2 different

studies presented at the ASTRO 54thAnnual Meeting.The first study showed that the addi-

tion of radiation to lumpectomy im -

proved overall survival (OS) as well asbreast cancer–specific survival (CSS) inwomen aged 70 or older.1“Age alone should not impact

whether or not radiation treatment ispresented as a viable treatment optionfor elderly women with early breast can-

cer,” stated Randi Cohen, MD, from theUniversity of Maryland School ofMedicine, Baltimore.The study population included

29,949 women identified in a SEER[Surveillance, Epidemiology and EndResults] Medicare database who were

diagnosed with stage I, estrogenreceptor–positive (ER+) breast can-cer. All women underwent lumpecto-my with or without adjuvant radiationand survived at least 1 year after ini-tial diagnosis. Seventy-six percent(22,781) received adjuvant radiationtherapy.Median survival was 13.1 years for

women treated with surgery plus radi-ation and 11.1 years for those treatedwith surgery alone. Five-year CSS was98.3% for the adjuvant radiationgroup versus 97.6% for the surgery-alone group, a statistically significantdifference (P <.0001). Ten-year CSSwas 95.4% versus 93.3%, respectively(P <.0001); 15-year CSS was 91.4%versus 89.5%, respectively.At all time points, the use of adjuvant

radiation improved OS. At 5 years, OSwas 88.6% for those who received radia-tion versus 73.1% for the surgery-alonearm (P <.0001); at 10 years, OS was 65%versus 41.7%, respectively (P <.0001); at15 years, OS was 39.6% versus 20%,respectively. A related study based on 27,559

patients from a SEER Medicare databasefound that older women with early-stage, low-risk breast cancer treated withradiation after breast-conserving surgery(BCS) had superior CSS and OS rates,compared with women who did notundergo radiation after BCS.2 The studyshowed a 6% decline in the use of radia-tion after 2004, coinciding with revisedNational Comprehensive Cancer Net -work guidelines allowing omission ofradiation therapy as a reasonable optionfor women over age 70 with small ER+tumors treated with adjuvant tamoxifen. The study was presented by Mariam

P. Korah, MD, a radiation oncologist atthe University of Southern CaliforniaKeck School of Medicine in LosAngeles. Breast cancer–specific survival favored

radiotherapy. At 5 years, CSS was 97%for radiotherapy versus 95%, anabsolute difference of 2%; by 8 years,the absolute difference was doubled to4%, favoring radiation: 95% and 91%,respectively.OS also favored the addition of

radiotherapy to surgery. Five-year OSwas 87% versus 69%, respectively, withan absolute difference of 18% favoringradiation, and 8-year OS was 73% ver-sus 49%, respectively, for an absolutedifference of 24% favoring radiation. l

References1. Cohen RJ, Li L, Citron W, et al. Improved survivalwith adjuvant radiation in elderly women with early-stage breast cancer. Presented at: American Societyfor Radiation Oncology 54th Annual Meeting;October 29, 2012; Boston, MA. Abstract 82.2. Korah MP, Sener SF, Tripathy D. Implications ofomitting radiation after breast conserving surgery inelderly women with low risk invasive breast cancer.Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract 84.



TARGET AUDIENCEThis initiative will target medical oncologists, hematologists, breast surgeons, radiationoncologists, oncology nurses, advanced practice nurses, nurse practitioners, physicianassistants, oncology pharmacists, managed care professionals, and others with clinicalresearch and management interest in treatment of ductal carcinoma in situ (DCIS) andearly-stage breast cancer.

STATEMENT OF NEEDAbility to detect DCIS has dramatically improved in recent decades, and the current inci-dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increaseduse of mammography screening.1,2 However, attempts to identify subsets of DCIS womenwho may be spared radiotherapy and perhaps treated with surgery alone have heretoforebeen unsuccessful. This inability to predict which patients will develop recurrent DCIS orinvasive disease has complicated DCIS management. Many clinicians and other health-care professionals dealing with patients diagnosed with DCIS are unaware or incomplete-ly knowledgeable about the most recent results from a clinical trial examining the abilityof the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, andthe implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVESAfter completion of this activity, participants will be better able to:

• Identify approaches currently available or in development to predict recurrence riskin DCIS patients

• Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer

• Describe the design and findings of the ECOG 5194 validation study• Apply the 12-gene assay for DCIS into clinical decision-making• Explain relevant information about the 12-gene DCIS assay and DCIS score topatients

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches

www.coexm.com/ace09LOG ON TODAY TO PARTICIPATE

Release Date: May 8, 2012Expiration Date: May 7, 2013

FACULTYChair:Lawrence J. Solin, MD, FACR,FASTROChairman Department of Radiation OncologyAlbert Einstein Medical CenterPhiladelphia, PA

E. Shelley Hwang, MD, MPHProfessor and Chief, Breast SurgeryDuke University Medical CenterDurham, NC

Kathy D. Miller, MDAssociate Professor Department of MedicineIU School of MedicineIndianapolis, IN

ACCREDITATIONPhysicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activityfor a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.Nurses:CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC)Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status doesnot imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case ManagerCertification. Case Managers number 790005057.

This activity is supported by an educational grant from Genomic Health, Inc.

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Two Studies Show That Radiation extends Survival in elderlyWomen With early breast Cancer


Many patients with incurable lung cancermistakenly believe that radiation therapyadministered for palliative treatment ofpain and other cancer symptoms repre-sents a potential cure, according to a study presented at the ASTRO 54thAnnual Meeting.1 “Our study found that, though most

lung cancer patients are optimistic aboutthe effectiveness of radiation therapy inrelieving symptoms and prolonging life,many have inaccurate beliefs about theability of palliative radiotherapy to curetheir cancer,” said lead author Aileen B.Chen, MD, a radiation oncologist atDana-Farber Cancer Institute in Boston,Mass achusetts. “To help patients makeinformed decisions about radiation treat-ments near the end of life, healthcareproviders need to improve communica-tion with patients and understandingabout the goals and limitations of pallia-tive radiotherapy. While palliative radio-therapy can be very effective at relievingsymptoms from cancer, overly intensivecare can reduce patients’ quality of lifeand lead to significant time and financialburdens for patients and their families.”

The Cancer Care Outcomes Researchand Surveillance (CanCORS) Con so r -tium study was a population-based andhealth system–based prospective cohortstudy. It enrolled 5013 patients withnewly diagnosed lung cancer in 5 geo-graphic regions, 10 Veterans Admin -istration sites, and 5 large health mainte-nance organizations from 2003 to 2005.Patients older than age 21 with stage IIIBor IV lung cancer scheduled to have radi-ation therapy completed a baseline inter-view about 4 months after diagnosis.Responses to the following question wereanalyzed: “After talking with your doctorsabout radiation therapy, how likely didyou think it was that radiation would….”Surveys were completed by 384

patients about their beliefs. Median sur-vival was 11.5 months. More than three-quarters (78%) of patients believed thatradiation was very likely or somewhatlikely to help them live longer; 43%believed that radiation was very likely orsomewhat likely to cure their cancer.About two-thirds (67%) believed thatradiation was very likely to somewhatlikely to help them with problems fromlung cancer, and 66% believed that radi-ation therapy was very likely or some-what likely to have side effects or compli-

cations. Only 36% correctly believed thatradiation therapy was not at all likely tocure their disease.These results suggest that physicians

need to take the lead in educating end-

stage lung cancer patients about the risksversus benefits of radiation therapy.Physicians may be concerned that plainspeaking will take away hope, but datasuggest that honest discussions empower

patients to make decisions that are rightfor them, Chen noted. l

Reference1. Chen AB, Cronin A, Weeks J, et al. Patient beliefsabout palliative radiation therapy (RT) in incurable lungcancer. Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract 4.


Patients Misunderstand Goals of Palliative Radiation Therapy

Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Androgen levels may impact antiandrogen therapy.1-3


3:29 PM

Only 36% correctly

believed that radiation

therapy was not at all likely

to cure their disease.

absolute risk and relative risk. Each cat-egory can produce very different-look-ing numbers.

Absolute RiskAbsolute risk is the chance of develop-ing cancer over a specified time period.This type of risk is not compared with

anything. It is simply the probability ofan event, such as cancer, occurring.One commonly referenced absolute riskis lifetime risk. For example, the lifetimerisk of developing ovarian cancer isapproximately 1 in 70. It can also bestated as a percentage, 1.4%, or as a dec-imal, 0.014. The lifetime risk of devel-

oping ovarian cancer with a BRCAmutation is 10% to 60%. Absolute riskalso may be expressed using any timeinterval, such as a 1-year risk, a 5-yearrisk, and so on. The lifetime risk of ovar-ian cancer is obviously much higherthan a 1-year risk or a 5-year risk,because the lifetime risk adds up all the

absolute risk over a woman’s lifetime. In addition, incidence and preva-

lence are absolute risks. Incidence is thenumber of new cancer cases in a partic-ular population over a specified periodof time. Prevalence is the proportion ofindividuals in a population who have aspecific characteristic (such as a muta-tion in gene Q) or cancer at a specificpoint in time.

Relative RiskRelative risk is a “risk ratio.” It is theratio of the probabilities of 2 absoluterisks. Two groups are compared to showthe relationship between a particularfactor, exposure, or the like. A relativerisk of 1 means that there is no differ-ence between the 2 groups. A relativerisk of 2 means that one group has twiceas great a chance of developing a diseaseas the other group. It allows increase ordecrease in risk due to a particular fac-tor to be portrayed. In the case of inher-ited cancer risk, the number of cancersin a group of people with a mutation ingene Q is compared with the number ofcancers in people without a mutation ingene Q. Sometimes this type of risk isreferred to as “fold” or as a percentage.Risk often seems much higher whenexplained in terms of relative risk. For example, women with a mutation

in gene Q have a relative risk of devel-oping cancer of 5, compared withwomen without a mutation. This alsomeans that women with a mutation in gene Q have 5 times the risk ofwomen without a mutation in gene Q.Sometimes this is stated as a 5-fold risk.Yet another way of stating this statisticis to say that the risk of developing can-cer in women with a mutation in geneQ is 500% higher than the risk in


Genetic Counseling

�� Editor in ChiefSagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Lymphoma ProgramRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Settings• Transplant-Eligible and -Ineligible Patients• Retreatment Settings• Bone Health

Newsletter Series

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Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

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AccreditationThese activities will be accredited for physicians, nurses, and pharmacists.

For complete accreditation information, please refer to each activity.

This activity is jointly sponsored by Medical Learning Institute, Inc.and Center of Excellence Media, LLC.

ALL NEW CONTENT FOR 2012

YOUR QUESTIONS ANSWERED

COEAsize71912AskExperts

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Celgene Corporation.

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Inherited Cancer Risk Statistics... Continued from cover

“Absolute risk is the

chance of developing

cancer over a specified

time period.”

—Cristi Radford, MS, CGC


women without a mutation in gene Q.As relative risk is a comparisonbetween 2 groups, there is no upperlimit to percentage of risk. Therefore, although at first glance a

500% risk may seem huge, it is impor-tant to put risk into perspective. Whatis the underlying absolute risk of can-cer? How common are mutations ingene Q? Also, keep in mind that rela-tive risk does not give one any infor-mation about a person’s actual risk. If a particular cancer is rare, a high

relative risk may lead to only a fewadditional cancer cases. On the otherhand, if a cancer is more common, asmall relative risk may lead to quite afew additional cases of cancer. Thesame is true for a gene mutation. Forexample, let us apply a radio broadcast-er’s statement “A mutation in gene Qraises the risk of cancer in women by 5-fold” to 2 different absolute risks offemale cancer: 0.005 (.5%) and 0.125(12.5%). If you multiply both by 5, younow have 0.025 (2.5%) and 0.625(62.5%). If you had a population of10,000 women, this would be anincrease from 50 to 250 (200 morewomen affected) and 1250 to 6250(5000 more women affected). Manywomen might be comfortable with a2.5% risk of female cancer; however,few would probably be comfortablewith a 62.5% risk of cancer. Another way to think of this is to

use pennies. If you have 1 penny (it israre) and multiply it by 5, you nowhave 5 pennies. You cannot do muchwith 5 pennies. However, if you startwith 50 pennies (now they are com-mon) and multiply them by 5, youhave 250 pennies. Now you can buysomething.

Take-Home Points• Relative risk statistics may be con-veyed several ways, including thefollowing:– Women with a mutation ingene Q have a relative risk ofdeveloping cancer of 5, com-pared with women without amutation.

– Women with a mutation ingene Q have a 5-fold increasein risk, compared with womenwithout a mutation.

– Women with a mutation ingene Q have a 500% higher

risk, compared with womenwithout a mutation.

• Relative risk is a comparisonbetween 2 groups. Therefore, riskoften seems much higher.

• Relative risk provides us very lit-

tle information on an individ-ual’s actual risk of developingcancer. It is important to evalu-ate relative risk in the context ofthe study from which it wasderived. l

Genetic Counseling

If a particular cancer is rare, a high relative riskmay lead to only a fewadditional cancer cases.

If a cancer is morecommon, a small relativerisk may lead to quite a few additional cases

of cancer.


Learn more at inhibitandrogen.com/sequence*Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel.mCRPC=metastatic castration-resistant prostate cancer.References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

CONTINUING EDUCATION

CONSIDERATIONS in

Multiple Myeloma™

5th Annual

ASK THE EXPERTS: Bone Health

G. David Roodman, MD, PhDDirector of Hematology/OncologyDepartment of MedicineIndiana UniversityIndianapolis, IN

Raj Duggal, PharmD, BCOPOncology Clinical PharmacistIU Simon Cancer CenterIndianapolis, IN

Lori Case, RN, BSN, OCNNurse CoordinatorIU Simon Cancer CenterIndianapolis, IN

Supported by educational grants from Celgene Corporation andMillennium: The Takeda Oncology Company.

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LETTER FROM THE EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). Thisis due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinicalinvestigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria fordiagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management ofcomorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regardingthe application and interpretation of recent clinical advances.In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked

questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this fifth issue, experts from Indiana University,Indianapolis, answer questions pertaining to the management of patients with myeloma-related bone disease.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

FACULTY

DECEMBER 2012 • VOLUME 5 • NUMBER 5

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CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionAt the time of diagnosis, two-thirds of patients with multiple mye -

loma (MM) experience bone pain and are very likely to sustain

pathologic fractures. Therefore, an important goal of therapy when

treating the disease is the prevention of fractures and other skele-

tal-related events (SREs). In this article, G. David Roodman, MD,

PhD, discusses recent advances in the management of myeloma-

related bone disease, and novel agents that are being investigated

for their potential to improve patient outcomes.

How should bisphosphonates be used to improve outcomes inpatients with myeloma-related bone disease?

Guidelines from the American Society of Clinical Oncology1 and theEuropean Myeloma Network2 recommend bisphosphonate therapy for MMpatients with either radiographic evidence of lytic bone lesions or severeosteopenia attributable to their disease. New evidence is beginning toemerge, however, to suggest that earlier use of bisphosphonates may be war-ranted. For example, in the Medical Research Council’s Myeloma IX trial,3,4

Morgan and colleagues showed that even patients who did not present with

an SRE at the time of enrollment still obtained clinical benefit from bisphos -phonate therapy. In this trial, a 5.5-month overall survival advantage wasreported among patients who received the intravenous (IV) bisphosphonatezoledronic acid compared with those who received the oral bisphosphonateclodronic acid.3 A subsequent analysis, however, revealed that only patientswith evidence of bone disease achieved the survival benefit.5 Therefore, thesurvival advantage with bisphosphonate use among MM patients who havenot exhibited lytic lesions or osteopenia at diagnosis remains unclear.

D’Arena and colleagues evaluated patients with smoldering myelomawho received IV pamidronate (60-90 mg once a month for 1 year).6 At thetime of progression to symptomatic MM, SREs were reported in 72.7% ofpatients who were observed versus 39.2% of patients treated withpamidronate (P=.009). These results also suggest that bisphosphonates canbe beneficial early in the course of myeloma. However, we cannot be 100%certain that the patients without documented bone disease really did nothave bone disease. In the Myeloma IX trial, the investigators utilized skele-tal survey rather than the more sensitive magnetic resonance imaging(MRI) to detect myeloma-related bone disease, because that was the modal-ity available at the time.3 We now use MRI in clinical practice to obtain a

Advances in the Treatment of Myeloma-Related Bone Disease

G. David Roodman, MD, PhDDirector of Hematology/Oncology, Department of MedicineIndiana University, Indianapolis, IN

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Celgene Corporationand Millennium: The Takeda Oncology Company.

Target AudienceThe activity was developed for physicians, nurses, and pharmacists in -volved in the treatment of patients with multiple myeloma (MM).

Purpose StatementThe purpose of this activity is to enhance competence of physicians, nurs-es, and pharmacists concerning the treatment of MM.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material for a max-imum of 1.0AMA PRA Category 1 Credits™. Physicians should claim only thecredit commensurate with the extent of their participation in the activity. Thisactivity has been planned and implemented in accordance with the EssentialAreas and policies of the Accreditation Council for Continuing MedicalEducation through the joint sponsorship of the Medical Learning Institute Incand the Center of Excellence Media, LLC. The Medical Learning Institute Incis accredited by the Accreditation Council for Continuing Medical Educationto provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro viderNumber 15106, for 1.0 contact hour.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharma-

cy education. Completion of this knowledge-based activity provides for 1.0contact hour (0.1 CEU) of continuing pharmacy education credit. TheUniversal Activity Number for this activity is 0468-9999-12-033-H01-P.

Learning ObjectivesUpon completion of this activity, the participant will be able to:• Describe the impact and consequences of bone destruction in patientswith multiple myeloma (MM)

• Summarize recent evidence-based guidelines for the management ofmyeloma-related bone disease

• Review safety and efficacy data on current and investigational therapiesfor preventing bone loss and skeletal-related events in patients with MM

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses,grants, consulting roles, speakers’ bureau membership, stock ownership, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

The associates of Medical Learning Institute Inc, the accredited providerfor this activity, and Center of Excellence Media, LLC, do not have anyfinancial relationships or relationships to products or devices with anycommercial interest related to the content of this CME/CPE/CE activityfor any amount during the past 12 months.

Planners’ and Managers’ DisclosuresDana Delibovi,Medical Writer, has nothing to disclose.She does intend to discuss either non–FDA-approved or investigationaluse for the following products/devices: pomalidomide and carfilzomib.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosedthat her spouse is investigator on a study for Agenix, ImClone, and Lilly;on the Data Monitoring Committee for Infinity and Pfizer; on theAdvisory Committee for Boehringer Ingelheim; and principal investigoron a study for Pfizer and Sinta.

Faculty DisclosuresSagar Lonial, MD, is a consultant to Bristol-Myers Squibb, CelgeneCorporation, Merck, Millennium: The Takeda Oncology Company,Novartis, and Onyx. He does intend to discuss either non–FDA-approvedor investigational use for the following products/devices: carfilzomib,pomalidomide, MLN9708, vorinostat, panobinostat, and elotuzumab. G. David Roodman, MD, PhD, is a consultant to Amgen Inc and

Celgene Corporation. He does not intend to discuss any non–FDA-approved or investigational uses of any products or devices.Raj Duggal, PharmD, BCOP, has nothing to disclose. He does not intendto discuss any non–FDA-approved or investigational uses of any productsor devices.Lori Case, RN, BSN, OCN, has nothing to disclose. She does not intendto discuss any non–FDA-approved or investigational uses of any productsor devices.

Disclaimer The information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the indepen -dent medical judgment of a healthcare provider relative to diagnostic andtreatment options of a specific patient’s medical condition. Recommenda -tions for the use of particular therapeutic agents are based on the best availablescientific evidence and current clinical guidelines. No bias towards or promotionfor any agent discussed in this program should be inferred.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest,posttest, and evaluation. The pretest, posttest, and evaluation can be com-pleted online at www.mlicme.org/P12029.html. Upon completion of theevaluation and scoring 70% or better on the posttest, you will immediatelyreceive your certificate online. If you do not achieve a score of 70% or bet-ter on the posttest, you will be asked to take it again. Please retain a copyof the certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 or [email protected].

Estimated time to complete activity: 1.0 hourDate of initial release: December 12, 2012Valid for CME/CPE/CE credit through: December 12, 2013

SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app:• Text “scan” to 43588• Go to www.getscanlife.com on your smartphone’s

Web browser, and select “Download”• Visit the app store for your smartphone

New evidence is beginning to emerge, however, to suggest that earlier use of bisphosphonates may be warranted.

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more accurate assessment of a patient’s condition. If individuals have anysymptoms, but have a negative skeletal survey, we conduct an MRI exami-nation, per current recommendations.7 In patients who have a solitary plas-macytoma or a single lytic lesion, we perform an MRI of the spine and pelvisto ensure that they do not have additional lytic disease. There is evidencethat the presence of focal lesions on MRI may indicate a patient with MM—even one who is otherwise asymptomatic—is at risk for rapid progressionand poor prognosis.8,9 Such patients probably should receive therapy.Fluorodeoxyglucose positron-emission tomography scanning combined withcomputed tomography (CT) is an excellent method for examining bone10;however, it can be very expensive and therefore cannot be used routinely. InEurope, clinicians are utilizing total-body CT scans with lower doses of radi-ation. This may eventually become a more standard practice here in theUnited States.

What is your approach to treating bone disease in patients withsevere renal dysfunction?

In patients with very severe renal failure at diagnosis, we use antimyelomatherapy to improve renal function prior to initiating a bisphosphonate.Bortezomib-based therapy has been used successfully to reverse renal failurein patients with MM; 59% of patients will exhibit an improvement in renalfunction within a median of 11 days (range, 8-41 days), with 2 of 9 dialysis-dependent individuals becoming dialysis-independent.11 The InternationalMyeloma Working Group recommends bortezomib plus high-dose dexam-ethasone to accelerate the reversal of renal impairment.12 Bortezomib mayimprove renal impairment by reducing inflammation through the inhibitionof nuclear factor kappa B (NF-�B), a transcription factor with proinflamma-tory effects in the compromised kidney.13

Unfortunately, some patients remain permanently on dialysis despite theuse of effective novel agents. Although pamidronate and zoledronic acidare not recommended for patients with creatinine clearance (CrCl) <30mL/min, I think whenever possible, these individuals should receive bisphos -phonate therapy to alleviate the pain associated with bone disease and tominimize the risk of pathologic fractures. In rare cases, in which patientshave very poor performance status and rapidly progressing disease afterfrontline therapy, we may be unable to administer bisphosphonates for thepurpose of preventing SREs. However, these agents may still be helpful innormalizing calcium levels in patients who are hypercalcemic.

What is the latest evidence regarding the potential of novel agentsto enhance bone health in patients with MM?

Several antimyeloma agents may have secondary pro-bone effects, partic-ularly proteasome inhibitors and immunomodulatory drugs (Figure).14

Mounting evidence suggests that the proteasome inhibitors bortezomib andcarfilzomib have bone anabolic effects. In other words, they are able to buildbone.15-18 These effects have been observed preclinically; clinically, the roleof proteasome inhibition in bone formation requires further study. Proteasome inhibitors stimulate bone formation by their enhancement

of osteoblast differentiation. In a clinical study, Giuliani and colleaguesdemonstrated that in human osteoblast progenitor cells, bortezomib stimu-lated bone nodule formation.16 These researchers, who administered bor -tezomib as monotherapy to 21 relapsed or previously treated patients withMM, reported that individuals who responded to bortezomib in terms oftheir myeloma also showed an increase in the number of osteoblasts permm2 of bone tissue. Patients who responded to bortezomib also exhibitedan increase in the number of Runx2/Cbfa1-positive osteoblastic cells;Runx2/Cbfa1 is an osteoblast transcription factor regulated by BMP-2.These signs of enhanced osteoblast activity were not observed in nonrespond -ers to bortezomib.

Terpos and colleagues reported that bortezomib use reduced patients’serum levels of dickkopf-1 (DKK-1), thus countering the ability of DKK-1to inhibit the Wnt signaling pathway to suppress osteoblast differentiation.18

Their study results also demonstrated a decrease in receptor activator of NF-�B ligand (RANKL) with bortezomib, indicating a reduction in osteoclastactivity. Together, reduction in DKK-1 and RANKL indicates a normaliza-tion of bone remodeling with bortezomib in patients with relapsed MM. Thecaveat with current data is that, for the most part, patients who demonstrat-ed an increase in bone formation markers also showed an antitumorresponse to bortezomib. This makes it unclear if bone formation is the resultof an effect on osteoblast differentiation or is simply an added benefit ofantimyeloma activity. Only one study to date has demonstrated enhancedbone formation markers regardless of whether a patient’s myeloma respond-ed to bortezomib.19

The immunomodulatory agents lenalidomide, thalidomide, and poma-lidomide also appear to have beneficial effects on bone. These drugs havebeen shown to inhibit osteoclast formation and bone remodeling markers inpatients with MM.20-22 Breitkreutz and colleagues examined the osteoclast

Figure. Bortezomib and lenalidomide in the treatment ofmyeloma-related bone disease.14

Reprinted with permission.

Bzb indicates bortezomib; BMP-2, bone morphogenetic protein-2; MSCs, mesenchymal stromalcells; OAFs, osteoclast-activating factors; OCL, osteoclast; Runx2; runt-related transcription factor 2.

In patients with very severe renal failure at diagnosis,we use antimyeloma therapy to improve renal function prior to initiating a bisphosphonate.

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effects of lenalidomide compared with bortezomib, reporting that lenalido-mide reduced levels of RANKL in the serum and bone marrow stromal cellsof patients with MM.20 Anderson and colleagues reported that immunomod-ulators inhibit osteoclastogenesis by diverting osteoclast precursors awayfrom their osteoclast cell lineage toward a granulocytic lineage—a uniquemechanism of action mediated by downregulation of the PU.1 transcriptionfactor.22 Osteoclast inhibition appears to be a class effect of immunomodu-lators. This seems to be more evident with lenalidomide and pomalidomidethan with thalidomide.20-22

Denosumab, a fully humanized monoclonal antibody, is currently ap -proved only for the prevention of SREs in patients with bone metastasesfrom solid tumors.23 However, this novel agent is currently being evaluatedfor potential benefits in patients with MM in a phase 3 trial. RANKLis overexpressed in MM and triggers increased osteoclast activity.15 Deno -sumab inhibits RANKL, and therefore has potent inhibitory effects on thedifferentiation, activity, and survival of osteoclasts,24 although it has notbeen shown to augment bone formation. In clinical trials,25 markers of bothbone resorption and bone formation are reduced with denosumab treatmentin patients with metastatic bone disease, just as they are in trials of bisphos -phonates.26 This is consistent with the suppression of bone remodeling—asless bone is resorbed during treatment, less bone needs to be made.26

ConclusionBone disease is a major morbidity factor in patients with MM, and the asso-

ciated skeletal complications can result in significant morbidity. Bisphos -phonates remain the standard of care for the treatment of myeloma-relatedbone disease, and have been shown to consistently reduce the incidence ofSREs. However, new molecular targets of cell cross-talk in myeloma bone mar-row are currently under investigation, and new drugs are being explored inpreclinical and clinical trials. It is hoped that results from these studies willexpand our armamentarium of treatment options for patients with MM. �

References1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

2. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recom-mendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20:1303-1317.

3. Morgan GJ, Davies FE, Gregory WM, et al; National Cancer Research Institute HaematologicalOncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clo-dronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet.2010;376:1989-1999.

4. Morgan GJ, Child JA, Gregory WM, et al; National Cancer Research Institute HaematologicalOncology Clinical Studies Group. Effects of zoledronic acid versus clodronic acid on skeletalmorbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondaryoutcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-752.

5. Morgan GJ, Davies F, Gregory W, et al. Defining the biological subgroup of multiple myelomapatients which benefits maximally from the overall survival (OS) benefit associated with treat-ment with zoledronic acid (ZOL). J Clin Oncol. 2011;29(suppl). Abstract 8083.

6. D’Arena G, Gobbi PG, Broglia C, et al; Multiple Myeloma Working Group; Gisl (GruppoItaliano Studio Linfomi) Cooperative Group. Pamidronate versus observation in asymptomaticmyeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma. 2011;52:771-775.

7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines™).Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 17,2012.

8. Hillengass J, Fechtner K, Weber M-A, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J ClinOncol. 2010;28:1606-1610.

9. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diag-nostic and clinical implications. J Clin Oncol. 2007;25:1121-1128.

10. Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R. Value of FDG PET in the assess-ment of patients with multiple myeloma. AJR Am J Roentgenol. 2005;184:1199-1204.

11. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Reversibility of renal impairment inpatients with multiple myeloma treated with bortezomib-based regimens: identification of pre-dictive factors. Clin Lymphoma Myeloma. 2009;9:302-306.

12. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiplemyeloma: a consensus statement on behalf of the International Myeloma Working Group. J ClinOncol. 2010;28:4976-4984.

13. Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica. 2007;92:1411-1414.

14. Roodman GD. Bone building with bortezomib. J Clin Invest. 2008;118:462-464.15. Roodman GD. Skeletal imaging and management of bone disease. Hematology. 2008:313-319.16. Giuliani N, Morandi F, Tagliaferri S, et al. The proteasome inhibitor bortezomib affects osteo -blast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110:334-338.

17. Hurchla MA, Garcia-Gomez A, Hornick MC, et al. The epoxyketone-based proteasomeinhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolicactivity in addition to anti-myeloma effects. Leukemia. 2012 Jul 5. doi: 10.1038/leu.2012.183.

18. Terpos E, Heath DJ, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptoractivator of nuclear factor-�B ligand concentrations and normalizes indices of bone remodelingin patients with relapsed multiple myeloma. Br J Haematol. 2006;135:688-692.

19. Delforge M, Terpos E, Richardson PG, et al. Fewer bone disease events, improvement in boneremodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. mel-phalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 2011;86:372-384.

20. Breitkreutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factorsand bone-remodeling markers in multiple myeloma. Leukemia. 2008;22:1925-1932.

21. Bolzoni M, Abeltino M, Storti P, et al. The immunomodulatory drugs lenalidomide and poma-lidomide inhibit multiple myeloma-induced osteoclast formation and RANKL/OPG ratio inmyeloma microenvironment targeting the expression or adhesion molecules. Blood (ASHAnnual Meeting Abstracts). 2010;116. Abstract 448.

22. Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclastformation by down-regulation of PU.1. Blood. 2006;107:3098-3105.

23. Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc; 2010.24. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausalosteoporosis. Biologics. 2008;2:645-653.

25. Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers inpostmenopausal osteoporosis. J Bone Miner Res. 2011;26:530-537.

26. Berenson JR, Lichtenstein A, Porter L, et al; Myeloma Aredia Study Group. Efficacy ofpamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl JMed. 1996;334:488-493.

This is consistent with the suppression of bone remodeling—as less bone is resorbed during treatment, less bone needs to be made.

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Pharmacologic Issues in the Managementof Myeloma-Related Bone Disease

IntroductionBisphosphonate therapy has become an essential component of

treatment for patients with multiple myeloma (MM). Although zole-

dronic acid and pamidronate are highly effective for preventing and

reducing skeletal-related events (SREs), these intravenously adminis-

tered agents may cause adverse events (AEs) that require careful

monitoring throughout the course of therapy. Consideration of pa -

tient comorbidities, such as renal dysfunction, prior to the initiation of

bisphosphonate therapy is critical, as this influences the choice of

agent, as well as the dose and schedule of administration. In this arti-

cle, Raj Duggal, PharmD, BCOP, discusses these key pharmacologic

issues related to the management of myeloma-related bone disease.

Which factors influence the choice of intravenous (IV) bisphospho-nate therapy for patients with myeloma-related bone disease?

Bisphosphonate therapy has an established role in the treatment of patientswith active MM and identified lytic lesions or compression fractures of thespine due to osteopenia.1,2 In the United States, both zoledronic acid andpamidronate are approved by the US Food and Drug Administration (FDA) todecrease bone destruction from osteolytic lesions and minimize SREs in thesepatients.1-4 In clinical practice, zoledronic acid and pamidronate, which are typ-ically administered every 3 to 4 weeks, are considered basically equivalent interms of skeletal protection and pain control.1,2 Therefore, drug selection is dic-tated by patient-specific factors and the healthcare team’s preference.1,5

Infusion time and baseline renal function are 2 major considerations in theselection of bisphosphonate therapy for patients with MM.1 Zoledronic acidis often recommended for patients with a creatinine clearance (CrCl) >30mL/min, as this drug can safely be infused over �15 minutes compared withthe prolonged 2-hour infusion of pamidronate.1,3,4 For patients with an esti-mated CrCl <30 mL/min or serum creatinine (SCr) >3 mg/dL, shorter infu-sion times with zoledronic acid are not recommended, and the infusion timeof pamidronate should be extended to 4 to 6 hours to minimize drug toxicity.1

There is no level of renal dysfunction resulting in absolute contraindicationfor pamidronate therapy.4

In a recent Cochrane review meta-analysis, no statistical difference wasfound regarding the incidence of AEs (including hypocalcemia and renaldysfunction) when comparing bisphosphonates.2 Both pamidronate and zole-dronic acid are associated with osteonecrosis of the jaw (ONJ); the incidenceof this AE rises with increased drug exposure (dose and duration).1-4

Guidelines published by the American Society of Clinical Oncology(ASCO)1 and the National Comprehensive Cancer Network6 cite a signifi-cantly higher incidence of ONJ with zoledronic acid compared with

pamidronate found in a single, prospective study, but this is not supported inthe recent Cochrane review.2

Clinicians at our institution tend to select zoledronic acid as the preferredbisphosphonate, given the advantage of shorter infusion times for patientswith adequate renal function. Pamidronate is typically reserved for patientswith poor renal function at baseline.

What bisphosphonate dosing adjustments are necessary forcomorbidities such as renal impairment?

The primary dose adjustment for bisphosphonate therapy is based on renalfunction.1,3,4 Patients with MM are at risk for renal dysfunction at baselineand during treatment, due to kidney damage from monoclonal light chains,hypercalcemia, hyperuricemia, dehydration, and nephrotoxic pharmacologicagents (including bisphosphonates).2,3,7 Careful consideration of baselinerenal function must occur prior to initiating bisphosphonate therapy in thesepatients (see Tables 1 and 2 for initial dosing recommendations).1,3,4 Once apatient is started on bisphosphonate therapy, ASCO guidelines recommendrechecking SCr levels prior to each subsequent dose.1 Treatment should bewithheld for deterioration in renal function, which is defined as an increasein SCr by �0.5 mg/dL if normal at baseline, or �1 mg/dL if abnormal at base-line. Therapy may be restarted at the previously prescribed dose once the SCrhas returned to within 10% of baseline.1,3,4

Another method of monitoring patients for renal dysfunction involvesperiodic assessments (every 3-6 months) for unexplained albumin spilling

Raj Duggal, PharmD, BCOPOncology Clinical PharmacistIU Simon Cancer CenterIndianapolis, IN

Table 1. Suggested Initial Dosing of Zoledronic Acid Based onRenal Function1,3

Zoledronic DoseCreatinine Clearance (infused over 15 minutes)

>60 mL/min 4 mg

50-60 mL/min 3.5 mg

40-49 mL/min 3.3 mg

30-39 mL/min 3 mg

<30 mL/min Avoid use

Table 2. Suggested Initial Dosing of Pamidronate Based onRenal Function1,4

Serum Creatinine Creatinine Clearance Pamidronate Dose

<3 mg/dL >30 mL/min 90 mg over 2 hours

>3 mg/dL <30 mL/min 90 mg over 4-6 hoursa

Albuminurea

>500 mg/24 hours (unexplained) Hold dose until returns to baselineRestart at 90 mg over �4 hours

aConsider reducing initial dose of pamidronate for baseline renal impairment.

��



into the urine. If there is >500 mg of albumin in the urine measured over 24hours, IV bisphosphonate therapy should be withheld until the level of pro-teinuria returns to baseline. Pamidronate therapy may be reinstituted with aprolonged infusion time (over �4 hours).1,4

ASCO guidelines also recommend periodic monitoring of serum calcium,electrolytes, phosphate, magnesium, and hematocrit/hemoglobin, althoughno specific frequency is given, due to a lack of supportive evidence.1

Commonly, clinicians draw serum calcium levels prior to each dose of bis-phosphonate therapy to monitor for additional drug toxicity and potentially,disease progression.2,3,6 Doses can be delayed for hypocalcemia at the discre-tion of the healthcare team. As long as hypercalcemia is not present, calciumand vitamin D supplementation can be instituted safely to minimize the riskof hypocalcemia.3,4

ONJ is a major concern for patients receiving bisphosphonate therapy, asit can cause significant morbidity.8 Prior to initiating therapy, a routine clin-ical dental exam is recommended, and dental procedures, including extrac-tions, should ideally be completed prior to initiation of therapy. Once thera-py has begun, regular dental exams should be scheduled depending ontreatment- and patient-specific risk factors, such as oral health, bisphospho-nate dose, and duration of therapy. Some clinicians may consider delayingthe dose of bisphosphonate if a dental procedure is scheduled, but no clearrecommendations have been established.1,3,4

How do you decide how long to keep patients on bisphosphonatetherapy?

The optimal duration for bisphosphonate therapy is currently unknown.ASCO guidelines currently recommend monthly bisphosphonate therapy for2 years for patients with active lytic lesions or spinal compression related toosteopenia.1,3,4 After the initial course of therapy, the healthcare team mustdecide whether therapy should be continued on an individualized basis. Iftherapy is stopped, it should be restarted upon relapse with development ofadditional SREs.1

Guidelines published by the European Myeloma Network similarly rec-ommend monthly bisphosphonate therapy for 2 years.8 After this initial

therapy, in those patients who have achieved remission and have stable dis-ease, bisphosphonates can be discontinued. For some individuals, it may bebeneficial to continue bisphosphonate therapy beyond 2 years, at a reduceddose and frequency. However, the panel noted that there is no hard data tosupport this approach.Recently, the Medical Research Council Myeloma IX trial provided evi-

dence that suggests maintenance bisphosphonate therapy might have a moresignificant clinical benefit.9 In this study, subjects were randomized to IVzoledronic acid (4 mg every 3-4 weeks during induction chemotherapy, thenevery 4 weeks thereafter) or oral clodronate (1600 mg/day). In this popula-tion of newly diagnosed MM patients, an overall survival advantage wasnoted with zoledronic acid compared with clodronate. Many study partici-pants received bisphosphonate therapy longer than the 2-year recommenda-tion, so it is possible that this prolonged therapy may have contributed to thedecreased SREs and increased survival times. Due to the study’s small samplesize, additional trials need to be completed to confirm this advantage.9

ConclusionBisphosphonate use has been shown to prevent, reduce, and delay SREs in

MM. Although these agents have an established role in the management ofthe disease, additional evaluations are needed to clarify the optimal durationof therapy, identify candidates for maintenance therapy longer than 2 years,and observe and report on toxicities noted with this extended treatment reg-imen.1,2,9 The successful use of bisphosphonates requires careful assessment ofpatients prior to and during therapy, diligent monitoring for AEs, and a thor-ough understanding of dosing and administration guidelines that will pro-mote optimal clinical outcomes. �

References1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

2. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a networkmeta-analysis. Coch Database Syst Rev. 2012;5:CD003188.

3. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 20124. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; May 2012.5. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid com-pared with pamidronate disodium in the treatment of skeletal complications in patients withadvanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter,comparative trial. Cancer. 2003;98:1735-1744.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines™). Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 31, 2012.

7. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiplemyeloma: a consensus statement on behalf of the International Myeloma Working Group.J Clin Oncol. 2010;28:4976-4984.

8. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: rec-ommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol.2009;20:1303-1317.

9. Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the MedicalResearch Council Myeloma IX trial. Blood. 2012;119:5374-5383.

If there is >500 mg of albumin in the urine measured over 24 hours, IV bisphosphonate therapy should be withheld until the level of proteinuria returns to baseline.

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Nursing Considerations in MyelomaPatients with Skeletal Complications

IntroductionSustaining skeletal integrity and preventing disability are essential

goals of long-term multiple myeloma (MM) care. Achieving these

goals requires pharmacologic therapy with intravenous (IV) bisphos-

phonates, along with strategies to protect mobility and decrease

pain. In this article, Lori Case, RN, BSN, OCN, discusses important con-

siderations in the administration and monitoring of bisphosphonate

therapy, including the prevention and management of osteonecro-

sis of the jaw (ONJ) and other adverse events (AEs). She also summa-

rizes best practices in surgical, physical, and educational interven-

tions that can be used to support bone health in patients with

myeloma.

How do you monitor and manage the renal AEs associated with IVbisphosphonate therapy?

For patients with MM, we have 2 choices for IV bisphosphonate therapy:zoledronic acid and pamidronate. Although generally well tolerated, theseagents can cause kidney function to deteriorate.1,2 Therefore, one concern isthe safe administration of bisphosphonate therapy in patients with renalinsufficiency. In the case of zoledronic acid, dosage must be reduced from thestandard dose of 4 mg for patients whose baseline creatinine clearance(CrCl) is <60 mL/min; use of this drug in patients with severe renal impair-ment is not recommended.1 In addition, zoledronic acid should always beadministered over 15 minutes or longer, to prevent any renal issues that mayarise during the infusion process.1

With pamidronate, caution is advised in patients with marked renalimpairment (serum creatinine [SCr] >3.0 mg/dL).2 Treatment should bewithheld in the event of renal deterioration, which can be defined as anincrease in SCr of �0.5 mg/dL in patients with normal baseline creatinine or�1 mg/dL in patients with an abnormal baseline.2 Doses can generally beresumed when SCr levels return to within 10% of baseline value.Pamidronate dose can be reduced from the standard 90 mg when the SCrlevel is >3.0 mg/dL or the estimated CrCl is <30 mL/min.3 This drug is usu-ally administered over 4 hours, but the infusion time can be increased to 6hours or longer to minimize renal risk.3

A best practice before and during bisphosphonate therapy is frequent mon-itoring of renal function. Prior to each infusion, we check SCr in order to prop-erly dose the bisphosphonate. We also conduct a panel of serum chemistries atleast once every 3 to 4 months. This assessment evaluates potential metaboliceffects of bisphosphonates—hypophosphatemia, hypokalemia, and hypomag-nesemia. If we do discover any abnormalities, we can replace the levels withoral supplementation.

How do you manage the flu-like symptoms that may occur follow-ing a bisphosphonate infusion?

Some patients experience fever, chills, flushing, and body aches resultingfrom a bisphosphonate infusion.1,2 For instance, with zoledronic acid andpamidronate at standard doses, approximately 44% and 33% of patients,respectively, report fever.1,2 We inform our patients that they may experiencethese flu-like symptoms during therapy, so that they are not caught off-guard.We also encourage them to call the clinic if any of these AEs occur. Typically,we recommend acetaminophen to manage mild-to-moderate flu-like symp-toms; use of this medication was reported effective for this indication in a2012 study.4 We do not recommend nonsteroidal anti-inflammatory drugs forMM patients because of the potential for renal toxicity.

For patients with severe flu-like symptoms, we have also utilized dexa -methasone at very low doses. Since many patients are receiving a steroid aspart of antimyeloma therapy, we will try to have them coordinate their week-ly dose on the same day that they are scheduled for their bisphosphonatetreatment, which may prevent or minimize flu-like symptoms.

What strategies do you use to reduce the risk of ONJ related to IVbisphosphonate therapy?

At baseline and at every visit, we look inside the mouth for ulcers, bumps,or protrusions. If individuals wear dentures, we ask them to remove theseappliances so we can closely examine the gums; we also try to ascertainwhether dentures are fitting well. Poorly fitting dentures are a risk factor forONJ, as are invasive dental procedures such as extractions.5 Evidence alsosuggests that periodontal disease may increase the risk of ONJ.6 Thesepotential risk factors can be addressed by ensuring that all patients receive athorough dental checkup and cleaning, and take care of any extractions,dental implants, or other invasive procedures before they start bisphospho-nate therapy.3,7

We educate our patients to continue twice-yearly checkups and cleanings,and to inform their dentists of any and all treatments they are receiving. Ifan invasive dental procedure is recommended during bisphosphonate thera-py, we ask that the dentist call our office before scheduling the procedure, todiscuss risks and benefits. We encourage our patients to call us every timethey are planning to go to the dentist, to reiterate the importance of avoidingspecific procedures.

Prevention of ONJ is critical, because once it occurs, healing—if it hap-pens at all—is a slow process.8,9 We send some patients with ONJ to our oralsurgeon for assessment. The surgeon may be able to smooth jagged boneedges and make the area more comfortable. We prescribe chlorhexidine

Lori Case, RN, BSN, OCNNurse CoordinatorIU Simon Cancer CenterIndianapolis, IN

Poorly fitting dentures are a risk factor for ONJ, as are invasive dental procedures such as extractions.

� ��



mouthwash to keep the area clean, and we use antibiotics for infection.7 Datasuggest that combining antibiotic therapy with oral surgery (eg, curettage,sequestrectomy) may be the most effective approach to ONJ, especially ifaugmented with a novel treatment called O2 hyperbaric/ozonotherapy, whichlocally increases the oxygen content of blood (Figure 1a and 1b). However,even the best available interventions fail to resolve ONJ fully in a significantproportion of patients.9

In addition to bisphosphonate therapy, what strategies can beused to prevent or minimize skeletal-related events (SREs)?

Nonpharmacologic management to prevent SREs and to minimize theirpain and impact on function must be highly individualized. The first thingfor nurses to do is to speak with the physicians about limitations and inter-ventions appropriate to the patient. Taking into consideration the individ-ual’s health status, level of pain, location of osteolytic lesions, and psycho -social profile, we can devise a plan that may include some or all of thefollowing: weight-bearing exercises; strength training; kyphoplasty10,11; phys-ical therapy; localized, palliative radiation therapy; nutritional counselingand calcium/vitamin D supplementation; reduction of alcohol and caffeine(which interfere with calcium and vitamin D absorption); elimination ofcontact sports; and a home-health intervention to minimize the risk of falls. We conduct yearly skeletal surveys in our patients, and will often adjust our

nonpharmacologic recommendations based on the results. Patients need to beeducated about their bone health. An annual skeletal survey can help illus-trate any skeletal changes that have occurred. If there are no changes, it canhelp them to see that therapy is working to prevent further bone damage.

ConclusionWhole-patient care in MM requires a commitment to bone health. Nurses

play a pivotal role in supportive therapy, including careful administration ofbisphosphonates, prevention and control of treatment-related AEs, and indi-vidualized nonpharmacologic regimens to protect against SREs, reduce pain,and maintain function. All of these work together to provide the best possi-ble quality of life for patients. �

References1. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; February 2011.2. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; April 2011.3. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

4. Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibupro-fen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.Osteoporos Int. 2012;23:503-512.

5. Kyrgidis A, Arora A, Lyroudia K, Antoniades K. Root canal therapy for the prevention ofosteonecrosis of the jaws: an evidence-based clinical update. Aust Endod J. 2010;36:130-136.

6. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons;2006. http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf. Accessed December 4, 2012.

7. Shannon J, Shannon J, Modelevsky S, Grippo AA. Bisphosphonates and osteonecrosis of thejaw. J Am Geriatr Soc. 2011;59:2350-2355.

8. Badros A, Terpos E, Katodritou E, et al. Natural history of osteonecrosis of the jaw in patientswith multiple myeloma. J Clin Oncol. 2008;26:5904-5909.

9. Andriani A, Petrucci MT, Caravita T, et al; on behalf of GIMEMA. Evolution of bisphospho-nate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom’smacroglobulinema: a retrospective multicentric study [published online ahead of print March23, 2012]. Blood Cancer J. doi:10.1038/bcj.2012.9.

10. Berenson J, Pflugmacher R, Jarzem P, et al; for the Cancer Patient Fracture Evaluation (CAFE)Investigators. Balloon kyphoplasty versus non-surgical fracture management for treatment ofpainful vertebral body compression fractures in patients with cancer: a multicentre, randomisedcontrolled trial. Lancet Oncol. 2011;12:225-235.

11. Kristinsson SY, Minter AR, Korde N, Tan E, Landgren O. Bone disease in multiple myelomaand precursor disease: novel diagnostic approaches and implications on clinical management.Expert Rev Mol Diagn. 2011;11:593-603.

Figure 1a and b. Efficacy of treatments for ONJ (N=53).9

Patients (%)

80

70

60

50

40

30

20

10

0

*Concomitant O2 hyperbaric/ozonotherapy was used in 16 patients who also received antibiotics and curettage and in 12 patients who also received antibiotics and sequestrectomy. This group of patients isincluded in the data in Figure 1a.

ONJ indicates osteonecrosis of the jaw.

Antibiotics Alone Antibiotics + Antibiotics +(n=19) Curettage (n=22) Sequestrectomy

(n=12)

Resolution of ONJ

Improvement in ONJ

No change/progression in ONJ

10.5%

52.6%

36.9%

45.5%40.9%

13.6%

66.6%

16.7% 16.7%

Patients (%)

80

70

60

50

40

30

20

10

0With O2 Therapy Without O2 Therapy

(n=27) (n=26)

Resolution of ONJ

Improvement in ONJ

No change/progression in ONJ

44.4%48.2%

7.4%

30.8% 30.8%

38.4%

a. Antiobiotics vs antibiotics + oral surgery b. Concomitant O2 hyperbaric/ozonotherapy* vs no concomitant O2 hyperbaric/ozonotherapy

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Supportive Care

Anticoagulation prophylaxis iseffective in preventing bothsymptomatic and asymptom -

atic catheter-related deep vein throm-bosis in ambulatory cancer patientswith locally advanced or metastaticsolid tumors, French investigatorsreported at the European Society forMedical Oncology (ESMO) 2012Congress, held in Vienna, Austria.1Among cancer patients who have

catheters in place for chemotherapy,catheter-related deep vein thrombosiscauses morbidity and mortality. Theincidence of symptomatic events rangesfrom 0.3% to 28.3%, and the incidencerises to 27% to 66% when asymptom -atic episodes are included. Current guidelines from American

and European societies do not recom-mend prophylactic anticoagulation forcancer outpatients, but symptomaticcatheter-related deep vein thrombosis isstill a subject of active research, and thevalue of prophylaxis in this populationis controversial, said Sandrine Lavau-Denes, MD, of the University Hospitalat Limoges in France.Lavau-Denes reported the results of a

phase 3 single-center prospective, ran-domized, open-label trial, conductedover a 10-year period (1999-2010), thatcompared a prophylactic strategy to no

prophylaxis over 3 months of chemo -therapy among 420 patients withadvanced solid tumors.“We found that prophylaxis with

either warfarin or low-molecular-weightheparin was effective in preventingthrombotic events, and there was noincrease in bleeding with prophylaxis,”said Lavau-Denes.

The study was initiated prior to thepublication of the current guidelines.The primary end point was the rate of symptomatic and asymptomaticcatheter-related deep vein thromboses ofthe ipsilateral upper limbs and cervicalveins of patients who received, versusthose who did not receive, thrombopro-phylaxis. It excluded intra luminalthrombosis.Investigators randomized 142 pa -

tients starting a first line of treatmentto low-molecular-weight heparin (atthe recommended dose), 138 to war-farin (1 mg/day), and 140 to a controlarm. Patients were evaluated at base-line and on day 90 (sooner, in the caseof symptoms), using Doppler ultra-sound of the upper limbs and cervicalveins, and venography.

effectiveness of ProphylaxisIn 407 evaluable patients, 42 catheter-related deep vein thromboses occurred(10.3%), 30 (15.1%) of which wereasymptomatic. This included 20 of 135(14.8%) patients in the control arm and22 of 272 (8.1%) patients receivingeither warfarin or low-molecular-weightheparin.The effect of prophylaxis amounted

to a 45% reduction in risk that was sta-

tistically significant (P = .0357).Warfarin and low-molecular-weightheparin were equally effective, Lavau-Denes noted. Rates of symptomatic events were

6.7% in controls, versus 1.1% afterprophylaxis; asymptomatic eventsoccurred in 8.1% and 7.0%, respective-ly. Unrelated deep vein thrombosesalso were prevented. Adverse events were not significant-

ly increased with thromboprophylaxis.Bleeding occurred in 0.7% of controls,2.2% of the low-molecular-weightheparin arm, and 4.5% of the warfarinarm (P = .1361). However, there wasan increase in thrombopenia inpatients receiving thromboprophylaxis(P <.0001), particularly with low-mo -lecular-weight heparin. However, thiswas grade 3/4 in only 12 (8.8%), 4(3.0%), and 7 (5.0%) patients, respec-tively, with no difference among thearms (P = .1039), she said. Prophylaxis was discontinued by

25% in the control arm, 27% in thewarfarin arm, and 33% in the low-mo -lecular-weight heparin arm. For 12.5%of patients in the control arm the rea-son was the occurrence of a thrombot-ic event, compared with 2.2% in thewarfarin arm and 2.2% in the low-mo -lecular-weight heparin arm.

Who Should Receive Prophylaxis?Fausto Roila, MD, of Terni, Italy, whochairs ESMO’s Supportive Care Track,reiterated that routine prophylaxis forambulatory patients with solid tumorsis not recommended by any society,except when patients are considered at high risk. However, he noted,“Thrombosis is a potentially deadlycomplication, and it is not rare.” Therefore, Roila suggested that pri-

mary prophylaxis be considered underthe following circumstances: • The incidence within one’s insti-tution is 8% to 10%

• The tip of the central venouscatheter is not positioned at thejunction between the atrium andthe vena cava

• The patient has factor V Leidenmutation or a previous venousthromboembolism

• The patient has mediastinal syndrome l

Reference1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al.Prophylaxis of catheter-related deep vein thrombosis incancer patients with low-dose warfarin, low molecularweight heparin, or control: a randomized, controlled,phase III study. Presented at: European Society forMedical Oncology 2012 Congress; October 1, 2012;Vienna, Austria. Abstract 1546O PR.

Catheter-Related Thrombosis Can be PreventedBy Caroline Helwick

��

July 26-28, 2013

Hyatt Regency La Jolla • at Aventine3777 La Jolla Village Drive • San Diego, California

��

• Melanoma• Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma • Merkel Cell Carcinoma

SECOND ANNUAL CONFERENCE

“We found that prophylaxis with either warfarin or

low-molecular-weight heparin was effective in

preventing thrombotic events, and there was no

increase in bleeding with prophylaxis.”

—Sandrine Lavau-Denes, MD

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

Docetaxel Injection, USPFor intravenous infusion only. 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, USP 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 despitedexamethasone (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, USP (5.10, 8.1)

ADVERSE REACTIONSMost 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


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

Gemcitabine InjectionFor Intravenous Infusion Only.Must Be Diluted Before Use.Initial U.S. Approval: 1996

INDICATIONS AND USAGEGemcitabine 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 ADMINISTRATIONGemcitabine 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)

CONTRAINDICATIONSPatients with a known hypersensitivity to gemcitabine (4)

WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with

infusion time >60 minutes or dosing more frequently than once weekly. (5.1)

• Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7)

• Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3)

• Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4)

• Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)

• Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

• Radiation toxicity. May cause severe and life-threateningtoxicity. (5.8)

ADVERSE REACTIONSThe 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 [email protected], or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2011


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Oxaliplatin safely and effectively. See full prescribing information for Oxaliplatin.

Oxaliplatin for Injection,powder for solution for intravenous use

Oxaliplatin Injection,solution for intravenous use

Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed warning.

Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1)

INDICATIONS AND USAGEOxaliplatin is a platinum-based drug used in combination with infusional 5-fluorouracil /leucovorin, which is indicated for:• adjuvant treatment of stage III colon cancer in patients who

have undergone complete resection of the primary tumor. • treatment of advanced colorectal cancer. (1)

CONTRAINDICATIONS• Known allergy to Oxaliplatin or other platinum compounds.

(4, 5.1)

WARNINGS AND PRECAUTIONS• Allergic Reactions: Monitor for development of rash, urticaria,

erythema, pruritis, bronchospasm, and hypotension. (5.1)• Neuropathy: Reduce the dose or discontinue Oxaliplatin if

necessary. (5.2)• Pulmonary Toxicity: May need to discontinue Oxaliplatin until

interstitial lung disease or pulmonary fibrosis are excluded. (5.3)

• Hepatotoxicity: Monitor liver function tests. (5.4)• Pregnancy. Fetal harm can occur when administered to

a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.5, 8.1)

ADVERSE REACTIONSMost common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (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.

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

Revised: 04/2011

Manufactured by:Zydus Hospira Oncology Private Ltd.Ahmedabad 382-213, Gujarat, India.for Hospira, Inc.Lake Forest, IL 60045 USA

Product of India

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, AustraliaManufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, IndiaDistributed by: Hospira, Inc., Lake Forest, IL 60045 USA

GUJ DRUGS/G/28/1267

Manufactured by:Hospira Australia LtdMulgrave VIC 3170Australia

Manufactured for:Hospira, Inc.Lake Forest, IL 60045 USA

Reference: 1. Data on fi le. Hospira, Inc.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P12-3707-10.875x13.875-Jul., 12

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com.

As the complexity of healthcare evolves,

we’re doing our part to improve cost savings,

optimize workfl ow and enhance patient care.

With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR CLINICIANS—UNIQUE ONCO-TAIN™ VIALS REINFORCE SAFETY1

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST

AVAILABLE FROMHOSPIRA

160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

See Black Box Warning Below

DOCETAXEL INJECTION (10 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

GEMCITABINE INJECTION(38 mg/mL)



OXALIPLATIN INJECTION(5 mg/mL)

See Black Box Warning Below

OXALIPLATIN INJECTIONOXALIPLATIN INJECTIONOXALIPLATIN INJECTION

1 PVC BOTTOM offers shatter resistance.

2 SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3 GLASS CLARITY allows for easy inspection of the vial as a fi nal safety check before administration.

4 PREWASHED VIALS reduce cytotoxic residue.

UNIQUE ONCO-TAIN SAFETY FEATURES

Docetaxel:WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONOxaliplatin:WARNING: ANAPHYLACTIC REACTIONS

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

december 2012 vol 5, no 11

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