DECEMBER 2012 VOL 5, NO 11

DeCeMbeR 2012

www.TheOncologyNurse.com

VOl 5, NO 11

GENETIC COUNSELING

CANCER CENTER PROFILE

The Johns Hopkins Kimmel Cancer Center and Sibley Infusion Center

Inherited Cancer Risk Statistics: Absolute Risk Versus Relative Risk

By Cristi Radford, MS, CGC

G

enetics as it pertains to cancer risk tends to be a hot topic in the news lately. Patients may see a story that states, for example, “Researchers have found that the risk of developing cancer in women with a mutation in gene Q is 500% higher,” but what does that risk actually mean? One important component of genetic counseling is the ability to convey risk to patients.

What Is Risk?

Simply stated, risk is a probability. It is the chance that a particular event may occur. In the case of inherited cancer risk, it is the chance that a person with a mutation in a particular gene will develop cancer. For the purpose of this article, the hypothetical gene “Q” will be used.

There are 2 main categories of risk: Continued on page 28

SUPPORTIVE CARE

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

Photo from Sibley Memorial Hospital.

he Johns Hopkins Kimmel Cancer Center, located on the campus of Sibley Memorial Hospital, provides medical oncology services to cancer patients in the Washington, DC, community.

The joint venture of Johns Hopkins Kimmel Cancer Center and Sibley Infusion Center offers patients access to expert, disease-specific oncologists from Hopkins. Patients are seen by a multidisciplinary team, which may include surgeons, radiation oncologists, social workers, nutritionists, physical therapists, and pastoral care counselors. In addition, patient cases are frequently presented at tumor board reviews at the main Hopkins campus located in Baltimore, Maryland. Also, patients have access to the diverse portfolio of clinical trials available at Hopkins.

T

Helping Your Patients Manage Chemotherapy-Induced Nausea and Vomiting

By Rosalie Canosa, LCSW-R Program Division Director, CancerCare Sharon Gentry, RN, MSN, AOCN, CBCN Breast Nurse Navigator, Derrick L. Davis Forsyth Regional Cancer Center, Winston-Salem, North Carolina

A

s healthcare professionals who work with people living with cancer, we often see patients when they are most vulnerable. For many patients, their moments of greatest vulnerability are at the time of diagnosis and while discussing treatment. During such moments, patients typically feel over-

CONFERENCE NEWS

Breast CanCer

Highlights From ASTRO

Bisphosphonates Should Not Be Routine in Early Breast Cancer

By Alice Goodman

Leukemia

T

Monday afternoon’s Plenary Session when public transportation was shut down. Below are some highlights from the meeting, including some news stories from the Plenary Session, which was available online.

Continued on page 7

INSIDE

Continued on page 21

he American Society for Radiation Oncology (ASTRO) 54th Annual Meeting, held in Boston, Massachusetts, coincided with Superstorm Sandy. Despite the havoc wreaked by the storm, Boston was largely spared, although ASTRO canceled

whelmed and inundated with a large amount of information to process and assimilate, while at the same time dealing with the emotional impact of a cancer diagnosis. Much of that information consists of basics on their type of cancer and the recommended course of therapy,

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16 20 30

Considerations in Multiple Myeloma— Ask the Experts: Bone Health

Continued on page 24 ©2012 Green Hill Healthcare Communications, LLC

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38

Catheter-Related Thrombosis Can Be Prevented

Relapsed/Refractory ALL Vexing Problem CompLimentary Ce . . . . . . . . . . . .

supportive Care

Reader Poll What inspired you to enter the oncology field?

Page 6

FOR APPROPRIATE PATIENTS WITH BONE METASTASES FROM SOLID TUMORS

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

INDICATION XGEVA 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 skeletalrelated events in patients with multiple myeloma.

IMPORTANT SAFETY 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. 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.

Hypocalcemia ® • XGEVA can cause severe hypocalcemia. Correct pre- Osteonecrosis of the Jaw (ONJ) existing hypocalcemia prior to XGEVA® treatment. Monitor • Osteonecrosis of the jaw (ONJ) can occur in patients calcium levels and administer calcium, magnesium, receiving XGEVA®, manifesting as jaw pain, osteomyelitis, and vitamin D as necessary. Monitor levels more osteitis, bone erosion, tooth or periodontal infection, frequently when XGEVA® is administered with other drugs toothache, gingival ulceration, or gingival erosion. that can also lower calcium levels. In the postmarketing Persistent pain or slow healing of the mouth or jaw after setting, severe symptomatic hypocalcemia has been dental surgery may also be manifestations of ONJ. reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. ® REFERENCES: 1. XGEVA 2. Data on file, Amgen.

(denosumab) prescribing information, Amgen.

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

DELAY IN MEDIAN TIME TO FIRST SRE

INTEGRATED ANALYSIS

BREAST CANCER

8.2 month delay2 (HR = 0.83, P < 0.0001*)

N/A1† (HR = 0.82, P = 0.010*)

PROSTATE CANCER

OTHER SOLID TUMORS‡ OR MULTIPLE MYELOMA

4.2 month delay1 3.6 month delay1 (HR = 0.84, P < 0.001, (HR = 0.82, noninferiority; P = 0.060, P = 0.008*) NS for superiority)

The integrated analysis included three international, phase 3, randomized, double-blind, double-dummy, activecontrolled 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 first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined 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 first SRE: not yet reached for XGEVA®; 26.4 months for zoledronic acid. ‡ Excluding breast and prostate cancer.

ACCESS FOR PATIENTS

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

XGEVA® patients who need help may be eligible for financial assistance2 Based on XGEVA payor mix and coverage for similar products.

§

PERMANENT

J-CODE:

J0897

®

• Perform

an oral examination and appropriate preventive Adverse Reactions dentistry prior to the initiation of XGEVA® and periodically • The most common adverse reactions in patients receiving during XGEVA® therapy. Advise patients regarding oral XGEVA® were fatigue/asthenia, hypophosphatemia, and hygiene practices. Avoid invasive dental procedures nausea. The most common serious adverse reaction was during treatment with XGEVA®. dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

• Patients who are suspected of having or who develop ® ONJ while on XGEVA should receive care by a dentist During post approval use, severe symptomatic or an oral surgeon. In these patients, extensive dental hypocalcemia, including fatal cases has been identified. surgery to treat ONJ may exacerbate the condition.

Pregnancy Please see brief summary of Prescribing Information • Women should be advised not to become pregnant on the following page. 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.

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

www.XGEVA.com

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.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?).

Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 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 GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal )ZQPQIPTQIBUFNJBb 32 20 harm prior to labor; adverse maternal effects occurred infrequently during labor.

NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 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 RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information).

Use in Specific Populations).

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

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 immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in Specific Populations) . There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading.

ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with 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 evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

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 beneďŹ ts in continuing or discontinuing treatment with Xgeva.

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: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 Š2012 Amgen Inc. All rights reserved. Printed in USA.

68257-R1-V3

Editorial Board EDITOR-IN-CHIEF

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

MSN, CRNP

CS, FNP

Avid Education Partners, LLC Sharpsburg, MD

Mayo Clinic Rochester, MN

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

Elizabeth Bilotti,

Shannon Hazen,

RN, MSN, APRN, BC, OCN

RN, BSN, OCN

Melinda Oberleitner, RN,

Karla Wilson, RN, MSN, FNP-C, CPON

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Beth Faiman, PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP

Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

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

Jayshree Shah, NP

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

NP, MSN, ACNP-C

AOCN, LNC

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

MSN, NP, ANP-BC, AOCNP

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

Fox Chase Cancer Center Philadelphia, PA

BSN, OCN

PhD, RN, AOCN

Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Wendy DiSalvo,

Sandra E. Kurtin,

Lori Stover, RN,

DNP, APRN, AOCN

RN, MS, AOCN, ANP-C

BSN

Patient Advocate Peg Ford

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance Coronado, CA

Joseph D. Tariman, PhD,

Social Work Carolyn Messner,

APRN, BC

DSW, MSW, LCSW-R, BCD

Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

Arizona Cancer Center Tucson, AZ

Ann McNeill, MSN, RN, NP-C, OCN

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Northwestern University Myeloma Program Chicago, IL

Constance Engelking, RN,

Kena C. Miller, RN, MSN, FNP

Jacqueline Marie Toia, RN, MS, DNP

MS, CNS, OCN

Roswell Park Cancer Institute Buffalo, NY

Northwestern University Myeloma Program Chicago, IL

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

CancerCare New York, NY

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS OnceMed Onco360 Great Neck, NY

Amy Ford, RN,

Patricia Molinelli,

BSN, OCN

MS, RN, APN-C, AOCNS

Quintiles Dallas, TX

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

Isabell Castellano, RN

Somerset Medical Center Somerville, NJ

Saratoga, CA

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

Sharon S. Gentry,

Ellen A. Neylon,

Connie Visovsky,

Jeanne Westphal, RN

RN, MSN, AOCN

MSN, FNP-BC, CCRP, OCN

RN, PhD, APRN

Meeker County Memorial Hospital Litchfield, MN

Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

www.TheOncologyNurse.com

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

University of South Florida College of Nursing Tampa, FL

VOL 5, NO 11

5

From the Editor

T

his issue of The Oncology Nurse-APN/PA (TON) brings you highlights of the news from the 2012 American Society for Radiation Oncology (ASTRO) annual meeting. Part of our ASTRO coverage includes the results of a study that show that many patients with incurable lung cancer misunderstood the goals of palliative radiation therapy. The Beth Faiman, PhD(c), MSN, APRN-BC, AOCN data from this study illustrate the Editor-in-Chief importance of clear communication between patients and healthcare professionals. The study presenter noted that healthcare professionals may worry that “plain speaking” takes away hope, but patients who truly understand their situation are empowered to make decisions that are right for their situation.

In addition to keeping you up-to-date about what is happening in the world of oncology research, we at TON strive to provide you with information you can use in your

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Eric Iannaccone eric@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Jackie Luma

day-to-day practice. In this issue, Rosalie Canosa and Sharon Gentry describe the scope of the problem of chemotherapy-induced nausea and vomiting and how we can help patients deal with this debilitating side effect. They emphasize the importance of proactive communication with patients, pointing out that “we need to tell patients not to be afraid to speak up” if they do not understand something or if they need more information.

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 clarifies what the implications are for individuals. Understanding the meaning of risk helps us provide perspective to our patients when they ask these types of questions—all part of communicating clearly.

Please be sure to visit our website, www.The Oncology Nurse.com, to answer our reader question about what inspired 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

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

Please convey any errors to the Editorial Director.

BPA Worldwide membership applied for November 2012.

6

VOL 5, NO 11

Reader Poll What inspired you to enter the oncology field? t takes a very special person to become an oncology nurse, advanced practitioner, or physician assistant. All of us at The Oncology Nurse-APN/PA are inspired by the dedication and compassion we routinely observe from our reading community. As part of our reader polls, and in recognition of the important work you do, we’d like to invite you to share your inspiration for working in this field. Please include your first name and the city where you are located in your response.

I

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

Supportive Care Helping Your Patients Manage CINV Continued from cover including instructions on adhering to the therapeutic regimen. Not surprisingly, information and instructions from doctors and nurses may not be fully integrated, or may easily get “scrambled,” during such a tender time. Patients may therefore lack a full understanding of the importance of following those instructions, or may even forget them. While forgetting or not fully understanding disease-related information may have tremendous ramifications for many aspects of cancer care, it can be particularly impactful when dealing with the nausea and vomiting that is often caused by chemotherapy.

• Anxiety or nausea associated with past stress • Current use of antidepressants or antianxiety medication There are also numerous treatmentrelated factors that can affect the incidence and severity of CINV. These include the dosage, schedule, and route of administration of the chemotherapy

One of the more debilitating side effects is chemotherapy-induced nausea and vomiting, a term that describes the symptoms of nausea and vomiting that occur in reaction to chemotherapeutic agents.

Chemotherapy-Induced Nausea and Vomiting: The Scope of the Problem The benefits of cytotoxic chemotherapy are undisputed. It is a type of therapy that has extended the lives of millions of cancer patients. Yet chemotherapy is often associated with unpleasant side effects that negatively affect patients’ quality of life. One of the more debilitating side effects is chemotherapy-induced nausea and vomiting (CINV), a term that describes the symptoms of nausea and vomiting that occur in reaction to chemotherapeutic agents.1 For cancer patients receiving chemotherapy or radiation therapy, CINV can compromise or negate the benefits of treatment by making it very difficult for the patient to adhere to the therapeutic regimen, or by triggering an interruption or delay of treatment.

While all patients undergoing chemotherapy are at risk of CINV, there are numerous factors that can heighten a patient’s risk of this dreaded complication. Such risk factors include2,3: • Age less than 50 years • Being female • Low alcohol intake (one or fewer drinks per day) • History of motion sickness, or of morning sickness with pregnancy • Fear of nausea from chemotherapy or a history of CINV

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regimen; the level of emetogenicity (likelihood of causing vomiting) of the regimen; the use of multiple agents in the regimen; and multiple cycles of chemotherapy.2,4 Chemotherapeutic agents can be categorized according to emetogenicity. Highly emetogenic chemotherapy (HEC) denotes a regimen that induces emesis (vomiting) in

more than 90% of patients in the absence of effective prophylactic antiemetic therapy,4 although only about 30% of these patients will vomit if they receive antiemetic prophylaxis before administration of HEC.3,5,6 A moderately emetogenic chemotherapy (MEC) regimen is one that carries a Continued on page 11

Pushing Your Limits Current activities at www.COEXM.com include:

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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

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VOL 5, NO 11

7

TREANDA速 (bendamustine HCI) for Injection is his chemo.

This is his therapy.

Single-agent TREANDA tripled median PFS* 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.

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

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;¡: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

45

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC; HR=hazard ratio. â&#x20AC;¡ CI=confidence interval.

t 53&"/%" XBT DPNQBSFE XJUI DIMPSBNCVDJM JO B SBOEPNJ[FE PQFO MBCFM QIBTF USJBM JO USFBUNFOU OBÃ&#x2022;WF QBUJFOUT XJUI #JOFU TUBHF # PS $ 3BJ TUBHFT * *7 $-- XIP SFRVJSFE USFBUNFOU /

t 53&"/%" JT BENJOJTUFSFE XJUI B DPOWFOJFOU EPTJOH TDIFEVMF o 5IF SFDPNNFOEFE EPTF GPS 53&"/%" JT NH N2 BENJOJTUFSFE JOUSBWFOPVTMZ PWFS NJOVUFT PO %BZT BOE PG B EBZ USFBUNFOU DZDMF VQ UP DZDMFT o *O UIF QIBTF USJBM QBUJFOUT SFDFJWFE DIMPSBNCVDJM BU B EPTF PG NH LH PSBMMZ PO %BZT BOE O PG B EBZ USFBUNFOU DZDMF VQ UP DZDMFT t *O UIF QJWPUBM QIBTF USJBM UIF NPTU DPNNPO OPO IFNBUPMPHJD BEWFSTF SFBDUJPOT GSFRVFODZ â&#x2030;¥ XFSF QZSFYJB OBVTFB BOE WPNJUJOH O 5IF NPTU DPNNPO IFNBUPMPHJD BCOPSNBMJUJFT GSFRVFODZ â&#x2030;¥ XFSF BOFNJB UISPNCPDZUPQFOJB

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Important Safety Information t 4FSJPVT BEWFSTF SFBDUJPOT JODMVEJOH NZFMPTVQQSFTTJPO JOGFDUJPOT JOGVTJPO SFBDUJPOT BOE BOBQIZMBYJT UVNPS MZTJT TZOESPNF TLJO SFBDUJPOT JODMVEJOH 4+4 5&/ PUIFS NBMJHOBODJFT BOE FYUSBWBTBUJPO IBWF CFFO BTTPDJBUFE XJUI 53&"/%" 4PNF SFBDUJPOT TVDI BT NZFMPTVQQSFTTJPO JOGFDUJPOT BOE 4+4 5&/ XIFO 53&"/%" XBT BENJOJTUFSFE DPODPNJUBOUMZ XJUI BMMPQVSJOPM BOE PUIFS NFEJDBUJPOT LOPXO UP DBVTF 4+4 5&/ IBWF CFFO GBUBM 1BUJFOUT should be monitored closely for these reactions and treated promptly if any occur t "EWFSTF SFBDUJPOT NBZ SFRVJSF JOUFSWFOUJPOT TVDI BT EFDSFBTJOH UIF EPTF PG 53&"/%" PS XJUIIPMEJOH PS EFMBZJOH USFBUNFOU t 53&"/%" JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI B LOPXO IZQFSTFOTJUJWJUZ UP CFOEBNVTUJOF PS NBOOJUPM 8PNFO TIPVME CF BEWJTFE UP BWPJE CFDPNJOH QSFHOBOU XIJMF VTJOH 53&"/%" t 5IF NPTU DPNNPO OPO IFNBUPMPHJD BEWFSTF SFBDUJPOT GPS $-- GSFRVFODZ ö BSF QZSFYJB OBVTFB BOE WPNJUJOH 5IF NPTU DPNNPO IFNBUPMPHJD BCOPSNBMJUJFT GSFRVFODZ ö BSF BOFNJB UISPNCPDZUPQFOJB OFVUSPQFOJB MZNQIPQFOJB BOE MFVLPQFOJB

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.

All rights reserved. TRE-2510 August 2012

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.

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 â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 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 naĂŻve 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 â&#x2030;Ľ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study Chlorambucil TREANDA (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) 116 (77) 16 (11) 110 (78) 14 (10) Platelets Decreased Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) 102 (68) 70 (47) 27 (19) 6 (4) Lymphocytes Decreased 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 LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 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 â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 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. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ 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 VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE 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 0.2â&#x20AC;&#x201C;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 BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM 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 singleuse 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.

50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. Š2008-2012 Cephalon, Inc., or its affiliates.

TRE-2500 TRE-2511 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation.

Information.

TRE-006 TREANDA

April 2012 August

Supportive Care Helping Your Patients Manage CINV Continued from page 7 30% to 90% risk of emesis.4 Regimens carrying a low risk of emesis are those that induce emesis in only 10% to 30% of patients, and treatments with minimal emetogenic risk cause emesis in less than 10% of patients.4 While CINV is quite common, its incidence can vary greatly and is difficult to determine. In a 1996 clinical trial, CINV was reported in 47 of 48 (98%) patients receiving HEC without antiemetic therapy.7 In a 2004 trial in which 298 patients were treated with antiemetics while receiving MEC or HEC, one-third of the participants experienced acute nausea (ie, that which occurs within a few minutes to several hours after a chemotherapy dose), and the incidence of delayed nausea (ie, more than 24 hours after chemotherapy administration) was 60%.8 In a 2005 study of 857 women with breast cancer who received antiemetic prophylaxis while on MEC, half of the patients experienced CINV.9 Although the incidence of CINV has declined over the last decade, CINV remains a threat to patients with cancer.

CINV can have a profound impact on patients’ quality of life, potentially leading to metabolic imbalances, a decline in patients’ self-care and functional ability, worsening of patients’ performance status and mental status, nutrient depletion, anorexia, surgical wound dehiscence (bursting open or splitting), esophageal tears, and patients’ refusal, delaying, or prevention of additional therapy.10-13 CINV can also impose a significant socioeconomic burden by reducing employee productivity and boosting overall healthcare costs due to prolonged hospitalization and increased nursing expenses.14 A recent retrospective study calculated the mean cost of a CINV-related hospital visit at $5299, with a mean per-patient cost of $731.15 The Value of Antiemesis In our experience, CINV is easier to prevent than to treat. Many patients experience cancer as a chronic disease, and can benefit from the use of antiemetic medications during all phases of treatment. A variety of antiemetic agents are available, including those that can be

not have taken the drugs as instructed.

Even if she followed instructions, the drugs may not have worked as expect• Connect education workshops and podcasts ed.

“I don’t know what to do,” she says, – Advances in Treating Chemotherapy-Related Nausea and Vomiting adding that she feels so bad that the – Understanding and Managing Chemotherapy Side Effects emergency room seems a reasonable option.

• Publications Two key nursing actions can help the – Coping With Nausea and Vomiting From Chemotherapy patient through this vulnerable time.

– Tips for Managing Nausea and Increasing Appetite During Cancer The first action is the “teach-back” Treatment method (also known as the “show-me” – Understanding and Managing Chemotherapy Side Effects method or “closing the loop”), which – “Doctor, Can We Talk?” Tips for Communicating With Your Health must be undertaken before the patient Care Team leaves her first chemotherapy treatment session.18 Once the patient has been • Online forums briefed on strategies to manage CINV, – Ask CancerCare: experts answer questions about coping with cancer the “teach-back” method largely consists of asking the patient questions such as, “Tell me what you are administered by the oral, rectal, intra- is a “cocktail” containing the going to do if you feel nauvenous (IV), intramuscular, or transder- neurokinin-1 receptor antagseous or have uncontrolled mal route. IV agents may be appropriate onist aprepitant (or its IV vomiting.” The patient’s for patients who are unable to swallow version fosaprepitant), the answers may reveal that she or digest tablets due to emesis, while corticosteroid dexamethadid not fully understand the others may benefit from having sone, and a benzodiazepine information you have proantiemetic medication delivered via a agent such as olanzapine.4 vided and that more infortransdermal patch, which may help Other types of agents, such as mation is required. In such reduce the pill burden and simplify treat- phenothiazines, benzamides, situations, chances are that ment for these patients. The patch may antihistamines, butyrophethe patient’s anxiety and also be appropriate in cases of impaired nones, and cannabinoids, swallowing ability or limited gut motili- have also been used for Sharon Gentry, RN, insecurity made her afraid ty, as can occur with certain gastroin- antiemesis, although these MSN, AOCN, CBCN to speak up during the briefing, or that she does not feel testinal cancers. The National Com- have largely been replaced by comfortable enough to ask questions prehensive Cancer Network, in its latest the 5-HT3 antagonists.4 about the antiemetic medication and its antiemesis treatment guidelines,4 cautions that while some studies suggest Challenges in Adhering to accompanying instructions. Whenever that certain agents are equally effective Antiemetic Medication Regimens possible, it is important that the briefing on a population basis, individual Once a patient has started chemothera- includes family members or whoever patients may respond differently, and a py, anxiety and emotional stress may will be with the patient after treatment. patient’s individual experience may complicate any efforts to adhere to The second key action is to have a drive the selection of antiemesis therapy. antiemetic therapy. This is especially nurse navigator or clinical nurse call the Serotonin (5-HT3) antagonists, a true of patients having their first experi- patient at home after treatment. A class of agents that includes dolasetron ence with chemotherapy, although it review of the educational content, as mesylate, granisetron, ondansetron, and may still be a lingering issue through well as an assessment of the efficacy of subsequent rounds. All too the antiemetic medications, can confer palonosetron, are commonly often, when a patient is a measure of control to the patient at used for the prevention and taught what to expect this critical time. Documentation of treatment of CINV. The oral from chemotherapy, she “real-time” symptoms can lead to needand IV forms of these agents nods and appears to under- ed medication changes prior to the next have been shown to have stand the educational cycle of treatment. In a 2010 article, equivalent efficacy when adinformation and is sent Sprandio documented how a communiministered at the appropriate home after round one. ty oncology practice achieved a drop in doses,16,17 and granisetron is also available as a transdermal Three days later she feels emergency department visits as well as a patch with demonstrated efsick and anxious. She may decrease in unscheduled office visits fectiveness for up to 5 days be experiencing a “drop- when this quality check was implementRosalie Canosa, off ” effect from the anti- ed.19 The resulting cost savings from from first application. Another LCSW-R Continued on page 12 emetic regimen, or may common preventive regimen Table Helping Patients Manage CINV: CancerCare Educational Resources

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Supportive Care

Helping Your Patients Manage CINV Continued from page 11 avoiding CINV-related hospital visits can thus be an important metric for nurse navigators to support their role.

Sometimes, financial difficulties can interfere with patients’ efforts to adhere to antiemetic therapy. For some patients, the cost of treatment is simply too high. Others may struggle to pay the copay, even if their insurance covers the

rest of the cost. As a result, patients may skip or delay an antiemetic dose, an omission that can have a ruinous effect on their quality of life, not to mention their chemotherapy experience as a whole. Some patients may have limited access to antiemetic treatment. A lack of reliable transportation may make it difficult, if not impossible, to get to the

doctor’s office, clinic, or pharmacy.

Needless to say, a patient will have trouble adhering to a medication regimen if she lacks the means to obtain it. The role of the social worker or nurse navigator is critical in identifying such patients so financial issues can be addressed before they become a concern.

Oftentimes, adherence to antiemetic

enhancing Communication The challenges of managing CINV make it crucial for the oncology nurse, nurse navigator, and oncology social worker to encourage patients to communicate proactively with the health professionals who are coordinating their care. We need to tell patients not to be afraid to speak up if the antiemetic medication is not working, or if they do not fully understand the instructions for taking it. We need to make it clear that it’s OK to ask questions, and that a patient should not wait until the next appointment or next round of chemotherapy to raise her concerns.

“Quality care is everyone’s business.”

We need to help patients overcome whatever fears or beliefs may be preventing them from adhering to antiemetic therapy.

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

6

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VOL 5, NO 11

therapy is compromised by patients’ misperceptions of treatment. Fear of addiction (the risk of which is minimal with antiemetic medications) is a powerful force in our society, and some patients may opt to forgo antiemetic medication rather than endure the perceived stigma of being “on drugs.”

In our experience, treatment-related information needs to be reinforced repeatedly. Not only is it important to ask patients if they truly understand what is expected of them, but it is also important to follow up and ask if they have been taking the medication as directed.

Before they leave the clinic, it is helpful to have patients repeat the instructions back to you to make sure they understand them.

The importance of adhering to antiemetic medication cannot be overemphasized. We need to help patients overcome whatever fears or beliefs may be preventing them from adhering to antiemetic therapy. None of these fears or beliefs is a reason for any cancer patient to have to endure CINV, or to refuse or delay antiemetic therapy.

Above all, patients need to feel empowered and equipped with the information they need to help them manage their disease. Organizations such as CancerCare (www.cancer care.org) offer a variety of educational resources specifically focusing on CINV (see Table). It is our obligation to share that information; we cannot assume that people will get it from

www.TheOncologyNurse.com

Supportive Care some other source. At the same time, we need to work to ensure patients have the financial, logistical, and emotional support they need to access their medications and supportive care resources. In some cases, that support may consist of connecting patients with copay assistance programs, compassionate-use initiatives, or clinical trials. In other cases, we can help arrange transportation, or facilitate the involvement of family members, friends, or other caregivers to ease the burden on the cancer patient. If we are to give patients permission to be proactive in managing their disease, we must be proactive ourselves in helping them.

Conclusion From the time of diagnosis, the patient with cancer embarks upon a lifechanging journey marked by multiple rounds of treatment and follow-up.

The journey may include treatment response and cancer remission. On the other hand, the itinerary for the journey may change to account for disease progression and downstream treatment options. In most cases, the patient has not planned for this journey and may feel vulnerable, alone, and unprepared for the inevitable bumps in the road. If managed correctly and appropriately, CINV is a bump that can be avoided, or at least made less disruptive to the patient’s life. As oncology nurses, nurse navigators, and patient advocates, we are in an important position to help patients negotiate those challenges by providing and reinforcing treatment- and supportive care–related information, facilitating communication with doctors and other health professionals, and encouraging patients to be proactive in managing the various aspects of their care. In so doing, we can demonstrate to our patients that they are not alone. By serving as trusted guides, we may be able to make the cancer journey a bit less harrowing. l References 1. Chemotherapy-induced nausea and vomiting. Mosby’s Medical 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-induced nausea and vomiting. In: Brown CG, ed. A Guide to Oncology 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 NK1 antagonist aprepitant plus a 5HT3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response.

Support Care Cancer. 2006;14(4):354-360.

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis.

Version 1.2012. http://www.nccn.org/professionals/physi cian_gls/pdf/antiemesis.pdf. Accessed November 7, 2011.

5. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15(1):103-109.

6. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol.

2010;21(suppl 5):v232-v243.

www.TheOncologyNurse.com

7. Kris MG, Cubeddu LX, Gralla RJ, et al. Are more antiemetic trials with a placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin. Cancer. 1996;78(10):2193-2198.

8. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics: perception versus reality. Cancer.

2004;100(10):2261-2268.

9. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23(12):2822-2830.

10. Laszlo J. Emesis as limiting toxicity in cancer chemotherapy. In: Laszlo J, ed. Antiemetics and Cancer Chemotherapy. Baltimore, MD: Williams & Wilkins, 1983:1-5.

11. Ingle RJ, Burish TG, Wallston KA. Conditionability of cancer chemotherapy patients. Oncol Nurs Forum.

1984;11(4):97-102.

12. Mitchell EP. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol. 1992;19(5):566-579.

13. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol. 1988; 6(11):1746-1752.

14. O’Brien BJ, Rusthoven J, Rocchi A, et al. Impact of chemotherapy-associated nausea and vomiting on patients’ functional status and on costs: survey of five Canadian centres. CMAJ. 1993;149(3):296-302.

15. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately 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 following the administration of high-dose cisplatin. J Clin Oncol. 1985;3(10):1379-1384.

17. Kris MG, Hesketh PJ, Somerfield MR, et al.

American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol.

2006;24(18):2932-2947.

18. North Carolina Program on Health Literacy. Health Literacy Toolkit. Tool 5. http://www.nchealthliteracy. org/toolkit/tool5.pdf. Accessed September 7, 2012.

19. Sprandio JD. Oncology patient-centered medical home and accountable cancer care. Community Oncology. 2010;7(12):565-572.

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The median age of patients in the VISTAâ&#x20AC; trial was 71 years (range: 48-91).

Survival never gets old 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†)

Approved for subcutaneous and IV administration‡ VELCADE® (bortezomib) Indication and Important Safety Information INDICATION ▼

CONTRAINDICATIONS

Tumor lysis syndrome:

Hepatic toxicity: ▼ Embryo-fetal risk: ▼

▼

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼

Peripheral neuropathy:

▼

Hypotension:

▼

Cardiac toxicity:

▼

Pulmonary toxicity

▼

Posterior reversible encephalopathy syndrome:

▼

Gastrointestinal toxicity:

▼

Thrombocytopenia or Neutropenia:

CYP3A4 inhibitors CYP3A4 inducers

ADVERSE REACTIONS

Living Proof

Breast Cancer

bisphosphonates Should Not be Routine in early breast Cancer

By Caroline Helwick

F

or preventing bone metastases in women 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, director of Breast Medical Oncology at the Fred Hutchinson Cancer Research

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.

Center in Seattle, Washington.

Gralow presented her thoughts on this controversial topic at the American Society of Clinical Oncology 2012

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.

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

V-12-0273

Breast Cancer Symposium, held in San Francisco, California.1 “There is no question that breast cancer treatment can cause accelerated bone loss, most commonly among patients receiving aromatase inhibitors,” she acknowledged. But studies have failed to show significant differences in the occurrence of the more clinically relevant end point of fracture, and the prevention of recurrences and deaths from breast cancer, she noted.

To the point, Gralow reviewed key data from several important trials evaluating the benefit of adjuvant bisphosphonates.

No Real benefit for Fracture Prevention The Z-FAST trial compared upfront use of zoledronic acid with its delayed use in postmenopausal women receiving adjuvant letrozole. Whereas bone mineral density (BMD) was better with the immediate use of zoledronic acid—with gain observed with upfront use and decline observed without it— fracture rates were similar between the arms: approximately 6% at 36 months and 9% to 11% at 61 months, the recent update showed.2 “Zoledronic acid preserved BMD but did not impact fractures,” she said.

Why Not Treat All Early Breast Cancer Patients?

While it might be tempting to simply prescribe bisphosphonates to all early breast cancer patients, Gralow would not recommend this for the following reasons: • Not all women are at risk for therapy-induced bone loss; even those with bone loss have a low fracture incidence and can rebound when stopping drugs.

• The majority of women will not have their cancer recur after adjuvant endocrine therapy or chemotherapy.

• The subgroup that will benefit has not been defined; biological mechanisms of action need further study.

• Osteoclast-targeted agents have side effects, including osteonecrosis of the jaw, gastrointestinal upset, renal toxicity, acute phase reactions, and hypocalcemia, and may have a negative effect on bone quality.

• These drugs can be expensive.

12/12

Continued on page 18

16

VOL 5, NO 11

www.TheOncologyNurse.com

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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

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

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

Important Safety Information Contraindications 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

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, 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.

Learn more at XtandiHCP.com

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 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

Breast Cancer

bisphosphonates Should Not be Routine... â&#x20AC;&#x153;There is also a rebound effect in BMD that is important,â&#x20AC;? Gralow noted. In the ABCSG-12 trial, premenopausal patients received ovarian suppression for 3 years plus adjuvant hormonal therapy, with or without zoledronic acid.3 The bisphosphonate was protective against BMD loss.

However, a natural rebound in BMD

occurred once the ovarian suppression was stopped, she said. â&#x20AC;&#x153;Just because we are suppressing the ovaries, especially temporarily, or starting an aromatase inhibitor, we donâ&#x20AC;&#x2122;t need to impact on BMD immediately,â&#x20AC;? she explained. â&#x20AC;&#x153;Thereâ&#x20AC;&#x2122;s a significant rebound of BMD once you take away the pressures from these treatments.â&#x20AC;?

Continued from page 16

Although zoledronic acid did reduce recurrences by 28% and deaths by 36%, the death rate at 84 months was already very low (6%) among patients not receiving chemotherapy or zoledronic acid (and in spite of allowing up to 10 positive nodes).

A task force of the National Comprehensive Cancer Network, led by

Gralow, defined patients who may be at increased risk for fracture and who therefore might be candidates for bisphosphonates. The algorithm suggests that drug therapy be considered for patients with a T-score between -1.5 and -2.0, and that it be initiated in those with a T-score â&#x2030;¤-2.0 or who have a 10-year risk >20% for a major fracture or >3% for a hip fracture

by FRAX analysis (WHO Fracture Risk Assessment Tool).

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The 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 castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy 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. 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 >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In 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 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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG 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.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH 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 UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI 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 UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa

9.0 44.4 9.3 Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

18

VOL 5, NO 11

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 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 ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI 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 DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In 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 Injuries In 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.

Hallucinations In 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 opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

www.TheOncologyNurse.com

Breast Cancer â&#x20AC;&#x153;The task force clearly did not say that all patients should start drug therapy up front,â&#x20AC;? she emphasized.

No Real Protection From Recurrence Studies investigating whether bisphosphonates can prevent bone metastases and improve survival have produced conflicting results. Two randomized trials of oral clodronate showed a reduc-

tion in bone metastases, while a third demonstrated an equivalent rate of bone metastases between the arms. A meta-analysis using the 5-year data from these 3 adjuvant clodronate trials failed to show a statistically significant difference in overall survival or bone metastasis-free survival,4 although heterogeneity among the trial was noted, she said. â&#x20AC;&#x153;The largest and most recently report-

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG 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 >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. 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 >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. 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., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide 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 >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ 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 Mothers XTANDI 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 Use Safety 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 ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A 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 YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH 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 >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A 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 >VHH &OLQLFDO 3KDUPDFRORJ\@

www.TheOncologyNurse.com

ed trial of clodronate, NSABP B-34,5 (the 2011 San Antonio Breast Cancer Symposium), was flat-out negative for the primary end point, disease-free survival,â&#x20AC;? she added.

The German GAIN trial of ibandronate6 also was completely negative for a benefit in terms of recurrence or survival, she added.

Trials of the more potent aminobisphosphonate, zoledronic acid, also have

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH 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 Fertility Long-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 LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO 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 DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; , QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV Â&#x2021; treatment during the course of treatment with XTANDI. ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG Â&#x2021; 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. ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW Â&#x2021; paresthesia, hypoesthesia, and falls. Â&#x2021; , QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW 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. Â&#x2021; $ SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO 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. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV 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 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

produced conflicting results. Whereas the ABCSG-12 trial3 and the ZOFAST trial7 both showed improvements in disease-free survival in patients receiving zoledronic acid, the Z-FAST trial, with the same design as ZOFAST, did not.2 The AZURE trial, which evaluated an â&#x20AC;&#x153;intensiveâ&#x20AC;? adjuvant zoledronic acid regimen, also failed to show a disease-free or overall survival benefit.8 â&#x20AC;&#x153;The largest trial in the highest risk patients using the most intensive dosing (AZURE) was flat-out negative,â&#x20AC;?

Gralow emphasized.

There was a suggestion of an overall survival benefit among women who were 5 years past menopause prior to randomizationâ&#x20AC;&#x201D;a statistically significant 25% risk reductionâ&#x20AC;&#x201D;suggesting that an estrogen-deficient environment might be more susceptible to the effect of zoledronic acid, but these results must be interpreted with caution, she said.

Gralow added, â&#x20AC;&#x153;If there is a direct antitumor effect, I donâ&#x20AC;&#x2122;t know why we have not seen a hint of this in metastatic studies.â&#x20AC;?

A number of ongoing trials are further evaluating clodronate, ibandronate, zoledronic acid, and the newest osteoclast inhibitor denosumab. â&#x20AC;&#x153;The results of these trials will be critical in better defining the efficacy of bone-modifying agents for preventing recurrence and may provide data regarding which patients and tumors are most likely to benefit from treatment,â&#x20AC;?

Gralow said. l References 1. Gralow J. Debate: bone health/role of bisphosphonates in early-stage breast cancerâ&#x20AC;&#x201D;con. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. 2. Brufsky AM, Harker WG, Beck JT, et al. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer. 2012;118(5):1192-1201.

3. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al.

Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. Presented at: 34th Annual San Antonio Breast Cancer Congress; December 6-11, 2011; San Antonio, TX. Abstract S1-2.

4. Ha TC, Li H. Meta-analysis of clodronate and breast cancer 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 adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapyâ&#x20AC;&#x201D;final analysis. Presented at: 34th Annual San Antonio Breast Cancer Congress; December 6-11, 2011; San Antonio, TX. Abstract S2-3.

6. MĂśbus V, Diel IJ, Harbeck N, et al. GAIN (German Adjuvant Intergroup Node Positive) study: a phase-III multicenter trial to compare dose dense, dose intense ETC (iddETC) vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancerâ&#x20AC;&#x201D;1st interim EFFICACY analysis. Presented at: 34th Annual San Antonio Breast Cancer Congress; December 6-11, 2011; San Antonio, TX. Abstract S2-4.

7. de Boer R, Bundred N, Eidtmann H, et al. Long-term survival outcomes among postmenopausal women with hormone receptor-positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5-year follow-up of ZO-FAST. Presented at: 34th Annual San Antonio Breast Cancer Congress; December 6-11, 2011; San Antonio, TX. Abstract S1-3.

8. Coleman RE, Marshall H, Cameron D, et al. Breastcancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365(15):1396-1405.

VOL 5, NO 11

19

Leukemia

Relapsed/Refractory All Vexing Problem

By Alice Goodman

T

he management of relapsed/ refractory acute lymphoblastic leukemia (ALL) is a vexing problem and requires extensive, aggressive supportive care throughout the course of therapy, explained Joseph C. Alvarnas,

The NCCN guidelines for ALL reveal a dichotomy between Philadelphia-positive (PH+) and Philadelphia-negative (PH-) relapsed/refractory ALL. In PH+ ALL, gene mutation testing is important. Patients with PH+ disease

MD, City of Hope Comprehensive Cancer Center, Duarte, California, in a presentation at the National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies.1

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

July 26-28, 2013

• Merkel Cell Carcinoma

Hyatt Regency La Jolla • San Diego, California

PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors

who relapse following cessation of tyrosine kinase inhibitors (TKIs) can restart TKI-based therapy. For those who are refractory or relapse on TKI-based therapy, perform mutational analysis. If the T315I mutation is present, consider hematopoietic cell transplant (HCT) or clinical trial; for V299L, T315A, F317L/V/CI/C, consider nilotinib rather than dasatinib. For Y253H, E255K/V, or F359 V/C/I, consider dasatinib rather than nilotinib. For any other mutation, consider high-dose imatinib, dasatinib, or nilotinib.

PH- ALL is far more difficult to treat. Most regimens are front-loaded with the best therapeutic agents, leaving few options for second-line treatment at relapse. Patients with PHALL should be considered for clinical trial or allogeneic hematopoietic stem cell transplant if in remission or on chemotherapy.

• Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • 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 clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

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

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

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

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

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 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/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 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 Accepted Guidelines 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

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

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General 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/Exhibits

CONFERENCE REGISTRATION

1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

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

www.CutaneousMalignancies.com

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

The NCCN guidelines for acute lymphoblastic leukemia (ALL) reveal a dichotomy between Philadelphia-positive and Philadelphia-negative relapsed/refractory ALL.

Several challenges exist for salvage therapy for adults with relapsed/refractory ALL, Alvarnas continued. It may be difficult to identify a non–crossresistant regimen for reinduction. Lasparaginase–containing regimens may be difficult to administer to older patients. Even very intensive regimens may achieve response rates <30%.

Comorbidities may limit therapeutic choices. Allogeneic HCT represents the only potentially curative option for adolescents/young adults (AYAs) and adults with ALL. Patients with significant residual disease are not candidates for allogeneic HCT. “The lessons from our experience with relapsed/refractory ALL are twofold. First, we would like to avoid relapse, and we recommend strong risk stratification at the time of diagnosis.

Second, move to transplant after first complete response is achieved,” he stated. Five-year overall survival was 62% at City of Hope when adults with ALL were transplanted in first remission.

Continued on page 22

20

VOL 5, NO 11

www.TheOncologyNurse.com

Cancer Center Profile

The Johns Hopkins Kimmel Cancer Center....

Continued from cover

In 2016, a new hospital with an integrated, comprehensive cancer center will be completed. This new facility will provide even greater access to services for many cancer patients in the Washington, DC, area.

Catherine Bishop, DNP, NP, AOCNP, answered some questions from The Oncology Nurse-APN/PA about the programs and services of the Johns Hopkins Kimmel Cancer Center and Sibley Infusion Center.

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

Catherine Bishop (CB): My enthusiasm in the field of oncology comes from the many clinical and pharmaceutical advances available to patients today.

The new drug combinations, molecular targeted therapies, and markers allowing for the identification of treatment sensitivities move forward the goal of cure for some, longer disease-free intervals and overall survival for others.

Understanding the drugs that provide the least response for specific tumors minimizes toxicities and undue costs for treatments. The plethora of clinical trials ongoing here at Johns Hopkins allows us to understand what treatments yield the most benefit, and which treatments don’t work.

With the advent of many oral chemotherapeutic and targeted agents, patients have more freedom to stay at home to receive their therapy. I think this may result in patients feeling they have more control over their treatment course and thus their personal and professional lives. It also may alleviate the burden on caregivers to make frequent trips to the clinic.

What approach does your institution take to treating people with cancer?

CB: The Johns Hopkins Kimmel Cancer Center and Sibley Infusion at Sibley Memorial Hospital are truly the finest of both institutions. Local Washington, DC, metropolitan patients have access to Johns Hopkins experts in their own community. This translates into convenience for patients who gain the disease-specific expertise from the physicians associated with Johns Hopkins without having to make the trip to Baltimore for every visit.

Our clinical approach is team based.

Teams are comprised of the oncologist, the oncology nurse practitioner, and the primary oncology nurse. Every patient is at the center of this team.

How does that translate to better outcomes for your patients?

CB: Patients feel well cared for, knowing that a group of individuals are current on their plan of care. Here at Johns

www.TheOncologyNurse.com

The patient is at the center of the team-based approach to care. The team for this patient (seated) includes an oncologist, Channing Paller; an oncology nurse practitioner, Catherine Bishop; and a primary oncology nurse, Carol Abrams (left to right).

Photo from Sibley Memorial Hospital.

Hopkins Kimmel Cancer Center/ Sibley Infusion there is never a time when one of the providers is not in the clinic. Whether a patient calls or comes into the clinic in an unscheduled appointment, one of the team members is present and available to address his or her needs. This availability will often preclude an emergency room visit.

This team approach translates into comprehensive, quality care, as patients have access to each discipline. The team works together to create a cohesive, patient-centered environment.

What is your role?

CB: I am the oncology nurse practitioner (NP) within the practice, caring for a variety of cancer patients with varied types of cancer diagnoses. Before joining the medical oncology group here at Johns Hopkins Kimmel Cancer Center/Sibley Hospital, I was part of a community oncology practice and therefore had the opportunity to gain experience with many types of cancer diagnoses. This has proved to be beneficial, because while the physicians in this practice are specialists and disease specific, I have the ability and experience to cross over to many cancer diagnoses and to care for these patients alongside my physician partners.

How has the role of the oncology nurse changed over the past 5 years?

CB: Oncology staff nurses have more autonomy than in the past. I think the hierarchy way of managing patients is in the past. Staff members

cine to the outpatient cancer center at a large academic institution. I felt I could relate to the cancer patients and their families in a special way because of my recent experience with my mother. Oncology nursing is such a rewarding specialty. It allows closeness with patients (and their families) at a fragile time in their lives. There are so many opportunities to provide help and understanding—after all, this is one reason people choose the healthcare profession. I hear from others outside of oncology, “Your job must be so difficult.” To which I respond, “The work of oncology is one of the most rewarding jobs—I cannot think of doing anything else.” Our patients give us so much. Their courage, strength, and resilience inspire us to continue the work we have been called to do. It is truly an honor to do this work.

Any advice for nurses just entering the field?

CB: Oncology nursing is an incredibly rewarding area of practice. The opportuin each discipline have their area of nity to understand the science behind expertise and are recognized and the quickly advancing subspecialty is respected for their knowledge. both challenging and exhilarating. It Oncology nurses have professional demands consistently reading the literacommitments to furthering their ture to keep abreast of new drugs, new understanding of the disease process advances in local control of disease, and treatment protocols. They have a and predictive and prognostic tools. clear understanding of, and embrace, evi- The qualitative data we gather from dence-based practice. Oncology RNs are our patients in terms of preferences direct care providers working with related to psychosocial aspects and palpatients on a daily basis who understand liative and end-of-life care enable us to understand the type of care how to manage the side they want during this time effects of chemotherapy. in their lives.

Medicine and nursing within If a nurse is thinking about oncology have led the way in entering or changing to the creating and maintaining the field of oncology, my suggesexemplar of the intradisciplition would be to spend some nary team. It truly takes a time with an oncology nurse. team to care for one patient.

Almost every oncology nurse Oncology NPs are inteI know welcomes a new gral members of both the nurse, or an experienced medical and nursing team nurse entering oncology, into within oncology. Oncology Catherine Bishop, DNP, NP, AOCNP his or her environment to NPs work collaboratively mentor or speak with about with oncologists. They often see patients at their initial visit, what it is like to work with the oncology and many see follow-up visits as a rou- patient population. Most, if not all, tine in their daily schedules. Oncology oncology nurses feel they get more than NPs frequently are performing proce- they give. dures such as bone marrow biopsies/ aspirations and intrathecal chemother- If you weren't working in this field, apy and are practicing at advanced lev- what would you be doing? els within community, academic, and CB: I would be involved in the design field. I have always had a passion for hospital cancer centers. space design, which spilled over to What inspired you to enter the field esthetic design. They go hand in hand of oncology nursing? for me. I like my personal and professionCB: My mother died of a brain tumor in al environments to be organized and 1992. This personal experience drew me functionally friendly. This translates into to oncology. When the opportunity pre- more efficient production—whether sented itself in 1994, I jumped at the that is in the kitchen at home or in the chance to rotate from internal medi- oncology clinic. l

VOL 5, NO 11

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Leukemia

Relapsed/Refractory All Vexing Problem “Unrelated donor transplant produces similar outcomes as related donor transplant. Don’t let the lack of sibling donor keep you from moving on to transplant,” he told listeners.

Alvarnas commented that transplant outcomes have not improved

appreciably over the past 3 decades.

“We have a long way to go,” he said.

“At the same time, intensification of the transplant regimen is not feasible.”

Experience with transplant raises the importance of timely transplantation and the need for better drugs

Continued from page 20

that might improve outcomes, he said.

Alvarnas discussed several new agents that may be useful in relapsed/refractory ALL. Two agents that have shown promising results in small phase 2 trials are nelarabine, a prodrug of ara-G, and clofarabine, a

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cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer +!*%!+ of gradual, nonspecific symptoms or is projected to grow considerably over discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Pha Associat rmD, BCO adults, cancer will also increase. Sece Professo opportunity to assimilate their circumP r, Virginia Commo stances. Frequently, a multidisciplinary ond, the effectiveness of cancer nweas ersity the number of ™alth Univ approach to treatment is necessary, retreatments improves, he past dec ade has seen quiring patients to engage with numerpatients the utilizat a dramatic cured of the disease will in).+-% &( ion of spec upsu in ,"+&",several ous medical teams comprising crease, andrge an even larger percentage ialty pha types of Medica rmacies for re Modern Lea Annthe Hansen, rapeutic all different specialties, often in different those for can will be living longer with mod as “athe disease ization Act defi alities, incl cer. The BCOP PharmD, ned a spec D dru cost of can uding multiple part locations. Many patients have been about $125 billi receiving “lines” of g with plan ialty drug cer carewhile ceed $40 -negotiated on in 201 may rise from 0 0 to (first-line, prices tha relatively healthy prior to the cancer lion eventbyand second-line, etc) fine over time. per Themonth.” 2 Oth thethere7 bilend of the therapy$20 t exspec er health ialt drugs dec ade. demand plans may fore are not sophisticated consumerstim ofe,medical overall specialtserBy that for oncology services is expected toyindifferently. y drugs are deIn general acco predby unthealthcare icte48% on vices. Consequently, it is incumbent crease , they are for 2 of eve d toby 2020, while the supply of oncologists high cost, adm ry inis 5 tered by pha increase lars spentransition professionals to be able to facilitate patients’ cy dol-by only 14% based on current patterns.4or infusion, t.1 The purp willrma require spec injection ose is of to expand this article underscore the need for a wide varietyor are used ial handlin rsity carePin order to minimize their distress intoBCO lain maxithe evoluti These statistics g, en, PharmD, Commonwealth Unive for complex to 80%, 17% ia cial on Lea Ann Hans ssor, Virgin from of ty diseases tha range the pharmacy mize their clinical outcomes. health professionals and other support personnel torequire spec of ens speProfe regim t ption catio andnthe ial monitor Associate on assumeach oral mediand can functio 2-4 term serv colo ing. In onAnscomm Challenges existic beyond the initial diagnosis play a part e in the around 50%. ent itin enabling beand every patient to re- gy, however, the getreatment system treatm an avera agents would most com of can to the agents disp ance nt scenario forperiod as well.

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Patients dellen y y has efit r pro pha ges highl s sever vider (SP rof cance thesyst ate the otherapy by dueoftothe r,history P) are the poinwith ies indic em 5: usinchem thighe targeted from of view e. Stud veno uals the United States are living a of fine quality of care based on their ability to untru nt. the intra new n of patie of age er prove the pati the tion py are nts that ent. ly monitored are adminis for cancer thera tered oral nnel who close ly. After adherence rates5 nce has trained perso in an The Evo a systema NonadhereHealthcare view dures took place luti tic re15% to 97%. Green Hill outco mes Communications, LLC of the literature, When these proce infuDrugs an on of Spe cialty iated with worse one academ group of or in a hospital d authors pro ic been assoc and with oncologist’s office of the Pharmac Specialty posed the critical desc disease states Lea Ann sive education most y in a number of Hansen hosript r ors highe sion center, exten , More , of a spec There is drug to be 3 cian visitsPharmD, BCO y was possible. a lack of ialty : increased physi stays, P consen patient and famil specialty ly comsus on therates, longer hospital • High cost drug. The ver, an increasing definition (prescription Food andpitalization recently, howe not defined of a ased morof one or Drug Adm s cost mor than $600 ning, and incre worseinis the term. involves the use • e disease per month) tration has Initially mon situation one-third toDifficult medicat synonym dmin, the6 Approximately ous with ion delivery cations and self-a l was virt biotechnolotality. labe n-related— Special han , such as more oral medi teins pro in the uallcatio pies medi y gy all Lea thera dlin of pro duc us g Ann duc ed by reco requiring taneo two-thirds ts, either pro-to medication control istered subcu mbinan strict tem respon-Hansenmon Asstoci oclo t DNA tech rmD perature nal, ant tions are due ate Profess, Pha nt. The direc BCO — Restrict ibod bilP ies pro hospitaliza niquesa or nor,oma home environme brid Virg ed location duced with nce— at cost of $100 s,inia sition and admi Co but acqui dhere mm for this drug nona arcell medication is noonw ular hysibility for ealth Uni nts and longer 7 purpose of this or distribution site preparation theannu ver ally. ng to the patie sityThe case — en, lion . The epts istration is shifti 200gene availLea Ann Hans P 7 ral conc Restricted location ibe rt network, if he previous inst for medicat mD, BCO ticle is to descr Phar allm their social suppo rch related totration than 20 ent in this ion adminis and the resea nt time, more ries examin rence cannt ceradhe Gree care ed the gro regarding patie able. At the prese ence, risk facn Hill ved for se-ent. incid TheHea wing importa r treatm lthc wit ns are FDA appro therap addition, h are Com Infor wed. a 1). cance less e mun to ies revie oral medicatio nce be er (Tabl icati r rence will MP of the adhe oral problem Rons, of cance LLC treatme (82 % vs 78% 4 rs that treatmentimp licationused derquen nt of can quences of this ivedtlyfrom examine conse the first-line ). (MPR s are s of for pattumo cer tors, and ient adh and the elec is a metric series will subse other oral preagent sen clinical tronic prescriptio l treatment. Ac-erenceThe refillence t tim on its article in this and a number of last to initia e, pat suc tory adher mo n g tern cess refrac records bas re tha Nets over tim . Atmaxi or are icat themizin poi ed on nsive Cancern 20 ora the best practices for have relapsed e, and 80% ions are prehe nt for adh approved s in the l med National Com is an arbitra erence use by the Foo outcomes. cording to the all compound Drug Adofmin ry cut d by many d and tely 25% admininvestigato inenare atio pipel work, approxima linedevelopmentistr (FD same study rs.) The rch and treatment continue.1 A) for firstfound surv th Organoncology resea ival at 10 yea is likely toof cancer. Aased to the World Heal trend by be oth the num ed so 81% , er incre defin rs beber orally ora the was n’s for those wh ofAdherence l age istered ity comes to which a perso ther o continu in responsibil nts are use adtha as the “extent t have relacations may notdbefor ed tumors With this shift a diet, and/o rapy versus 74% ization in 2003 n, following for those anticancer medi psed or thatrefr require had discont possibility that initial treaially for regimensare who actory tohavior, taking medicatio inued it. No ctly, espec tment, and abo to longence nad adher has ministered corre of her ut onc ates also 25% of the ence oloall been shown gyestim research pip g. Over to produce repeated dosinora eline consist hcare Communications, LLC stantial det subl compounds 1 s of riment in . Thi Green Hill Healt

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“The use of novel therapeutics in relapsed/refractory ALL is exciting to me. We would like to identify a parallel drug to rituximab in lymphoma. We are still early on in this process. Two drugs might be interesting in this regard [blinatumomab and inotuzumab ozogamicin]. These antibodies are impressively tolerable in heavily pretreated patients, compared with chemotherapy,” Alvarnas said. l

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second-generation purine nucleoside analog. Both drugs have distinct sideeffect profiles, with different toxicities.

Neurologic toxicity is the key doselimiting toxicity with nelarabine.

Other significant toxicities include cytopenia, gastrointestinal effects, and pyrexia. Toxicities of clofarabine include elevations of liver enzymes, febrile neutropenia, skin rash, and cytomegalovirus reactivation.

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clinical out s is in additio comes in chr self-admin n to onic myeloi istered sub cutaneous d leukemia and childh pies for the theraood acute home env lymphobla leukemia. 5-8 ironment are under stic that For each of FDA review these diso . ders, prolon When can rged oral cer medic therapy has been the ations are ministered standard adLea Ann orally in the of care for Hansen, decade or home env ronment rath a PharmD more. It is ier than in , BCOP likely that ative conseq the clinic of adheren negor hospital, uences of non ce range from the rates adherence wit 15% to 97% 2 h at the end oth er oral can will be doc of the first . For examp cer medic umented in year of trea le, atio hormonal the ns tment wit apy mature future as the treatment h adjuvan s. The pur ir role in the (AHT) for t cer, only 79% pose of this rearly-stage the results article is to of patients breast can of availab remained on discuss a gap exceed le researc adherence therapy wit ing 60 day h on ma and suggest hout s and 85% ximizing ceeding 180 best practic ical outcom without a days. By yea es to es. imp gap rove clinexr 5, only 27% mained wit hout 60- and and 29% re180-day gap In anothe s, respecti r study of vely. 3 AHT, pat tion possess ients with ion ratio (M a medicaPR) >80% significant Direct com had a statistic ly higher municatio 10-year surv ally n with all personal bar ival rate tha patients abo riers to tak n those ut their ing daily the period is an rapy for a pro important longed aspect to maximizin Green Hill g adherHealthcare Communicat ions, LLC

Reference 1. Alvarnas JC. New approaches to the management of relapsed/refractory acute lymphoblastic leukemia.

Presented at: National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies; September 14, 2012; New York, NY.

Supportive Care for All Patients being treated for ALL require aggressive coordinated supportive care throughout the entire course of therapy.

Alvarnas highlighted several supportive care needs: • Preemptive management of tumor lysis syndrome • Disseminated intravascular coagulation and L-asparaginase coagulopathies • Management of therapy-related cytopenia • Management of febrile neutropenia/opportunistic infection • Antiemetic therapy

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Memantine Delays Cognitive Decline in Patients With brain Metastases Treated With Whole-brain Radiation Memantine delayed cognitive decline in patients treated with whole-brain radiation therapy (WBRT) for brain metastases, according to results of a randomized phase 3 trial.1 Cognitive decline is common with WBRT, occurring in about 50% to 60% of patients by 4 months after radiation.

Because the mechanism of radiationinduced cognitive decline appears to be similar to that of vascular or Alzheimer’s dementia, the researchers postulated that memantine, a drug used to treat Alzheimer’s disease, would be of benefit in patients treated with WBRT. “We are excited to see that adding memantine to the treatment plan for brain tumor patients helps preserve their cognitive function after whole-brain radiotherapy even 6 months after treatment. Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy, impacting future treatment practices for these patients, and suggest a role for further study in patients receiving radiation to the brain,” said presenter Nadia N. Laack, MD, radiation oncologist at the Mayo Clinic in Rochester, Minnesota.

Formal discussant of this trial, Vinai Gondi, MD, associate director of the Central Dupage Hospital’s Proton Center in Warrenville, Illinois, called this study “a good first step” in understanding the cognitive changes resulting from brain radiation and the role of memantine in preventing or delaying them. He said

tion (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life) were assessed by different instruments at baseline and weeks 8, 16, 24, and 52. The primary end point was memory as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R).

“Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy.”

—Nadia N. Laack, MD

that the effect of memantine was modest in this trial and that other strategies to improve cognitive effects of radiation are being pursued by researchers.

The study included 508 patients with brain metastases who received WBRT between March 2008 and June 2010.

WBRT was delivered as 37.5 Gy in 15 daily fractions. Patients were randomized to memantine 20 mg/day or placebo within 3 days of the start of radiation therapy. Six domains of cognitive func-

Compliance with the cognitive testing protocol was suboptimal, with 32% of the patients completing drug therapy and cognitive assessments. The reasons for noncompliance appeared to be death, disease progression, and difficulty in getting patients to stay longer during a clinic visit or in physicians scheduling the extra 20 minutes to 1 hour required for cognitive testing. Of the 508 patients randomized to the 2 arms, only 149 patients were analyzable at 24 weeks.

For the primary end point of memory decline as assessed by the HVLT-R, memantine reduced the decline in HVLTR delayed recall, with a median decline of 0 versus –2 for placebo at 24 weeks, with a statistical significance of P = .059. This result was “teetering on the edge of significance,” according to Laack, due to the small numbers of patients.

At 24 weeks, memantine reduced the relative risk of cognitive decline by 17% versus placebo (P = .01), and it reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P <.01).

Patients in both groups experienced similar rates of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea.

The investigators plan to evaluate the effect of memantine on overall survival and progression-free survival in these patients. Also, tissue specimens will be studied to identify biomarkers of cognitive decline as well as of response to memantine.

Reference 1. Brown PD, Shook S, Laack N, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiation therapy (WBRT): first report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 1.

Prophylactic Sildenafil Improves Sexual Function in Prostate Cancer Patients Undergoing Radiation Sildenafil is often used by men treated with radiation or radical prostatectomy for prostate cancer to achieve an erection sufficient for sexual intercourse, and it is effective to varying degrees when used on an as-needed basis. A randomized controlled trial has found that prophylactic daily use of sildenafil improved overall sexual function, as well as domains of sexual function, in prostate cancer patients undergoing radiation therapy.1 This is the first time a phase 3 study has demonstrated the effectiveness of prophylactic sildenafil in the setting of radiation.

“Prostate cancer patients treated with sildenafil and adjuvant radiation treatment had improved overall erectile function and overall satisfaction of their sexual activity and function. The

most significant improvements were seen at 6 and 12 months after treatment, with a slight dip at the 24-month mark, suggesting that future trials need to be conducted to demonstrate if longer treatment duration can further improve outcomes,” said lead author Michael Zelefsky, MD, of Memorial Sloan-Kettering Cancer Center in New York City. No benefit for sildenafil was seen among a small group of 31 patients who were also treated with androgen deprivation therapy.

The prospective, randomized, double-blind, placebo-controlled trial included 295 patients with clinically localized prostate cancer who were treated with external beam radiation therapy and/or brachytherapy (permanent interstitial implantation of radio-

active “seeds”). Patients were randomized in a 1:1 ratio to receive either daily sildenafil 50 mg or placebo. Treatment was initiated 3 days before radiation treatment and was continued daily for 6 months, when the drug was stopped.

After that, sildenafil could be used as needed. Sexual function was assessed at 3-month intervals for the first year and thereafter at 18 and 24 months with the international index of erectile function (IIEF) and the international prostate symptom score (IPSS) questionnaires. At baseline, all patients had excellent erectile function, as assessed

by IIEF. Among 144 patients treated with radiation only who completed IIEF and IPSS questionnaires, overall sexual function was improved with daily sildenafil versus

placebo at all time points. IIEF scores were 58.6 for sildenafil versus 49.4 for placebo at 6 months (P = .006); 56.3 versus 48.2, respectively, at 12 months (P = .02); and 54.9 versus 47.6, respectively, at 24 months (P = .04). Significant improvement in overall function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction were reported with sildenafil versus placebo. Overall IPSS was also significantly improved with sildenafil versus placebo (P <.001).

Reference 1. Zelefsky MJ, Shasha D, Kollmeier M, et al. Results of a prospective randomized double-blind placebo-controlled trial evaluating the use of prophylactic sildenafil citrate during radiation therapy in the treatment of prostate cancer. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 3.

THIRD ANNUAL CONFERENCE Influencing the Patient-Impact Factor

TM

May 2-5, 2013 Westin Diplomat Hollywood, Florida

REGISTER TODAY AT www.AVBCConline.org 24

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Conference News: ASTRO Doxepin Rinse Improves Oral Mucositis in Patients Treated With Radiation for Head and Neck Cancer

D

oxepin, a tricyclic antidepressant approved for the treatment of depression and anxiety, as well as moderate pruritus, significantly improved oral mucositis pain in patients treated with radiation therapy for head and neck cancer in a phase 3 trial.1 In the study, doxepin was combined with water and used as an oral rinse.

Oral mucositis pain is a significant problem in patients with head and neck cancer treated with radiation, and treatments such as narcotics and mouth rinses are not particularly effective in alleviating this pain. Smaller studies have suggested that doxepin is safe and effective in reducing oral mucositis pain, and the present study establishes its effectiveness in a randomized controlled trial.

“Our study validates doxepin rinse as an effective way to alleviate oral pain and sets a new standard of care,” said the lead author of the study, Robert C. Miller, MD, of the Mayo Clinic in Rochester, Minnesota.

For the N09C6 study, pain was assessed on a visual analog scale and scored from 0 to 10, with a score of 10 signifying severe pain. N09C6 was a double-blind, randomized, placebo-controlled trial of 140 patients with head and neck cancer who had an oral mucositis pain score above 4 on the visual analog scale. Patients were enrolled between December 2010 and May 2012 and were treated with radiation at doses above 50 Gy involving more than one-third of the oral cavity for head and neck cancer. The dosage of the oral doxepin rinse was 25 mg dissolved in 5 mL of water and used for 1 minute. Patients were treated on day 1 with either the doxepin rinse or placebo; on day 2, patients crossed over to the other treatment arm. Patients could elect to continue treatment with the doxepin 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 –4.7 for placebo patients (P = .0003).

Crossover data from day 2 showed similar findings, with an AUC pain score of –7.9 in the doxepin group versus –5.6 in the placebo group (P = .009).

Doxepin was well tolerated, but it was associated with more stinging and burning (mean pain score of 3.7 for doxepin vs 1.1 for placebo) as well as an unpleasant taste (mean unpleasant taste at 5 minutes 2.9 for doxepin vs 1.6 for placebo), and it caused greater drowsiness (mean drowsiness score of 3.9 for doxepin vs 2.8 for placebo). During the optional continuation phase, the majority (64%) of patients elected to continue doxepin.

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Reference 1. Miller RC, Leenstra J, Qun R, et al. N09C6 (Alliance) - a phase III, randomized double-blind

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

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

INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12191

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Conference News: ASTRO Two Studies Show That Radiation extends Survival in elderly Women With early breast Cancer

R

adiation therapy extends life in older women with early breast cancer, according to 2 different studies presented at the ASTRO 54th Annual Meeting.

The first study showed that the addition of radiation to lumpectomy im-

proved overall survival (OS) as well as breast cancer–specific survival (CSS) in women aged 70 or older.1 “Age alone should not impact whether or not radiation treatment is presented as a viable treatment option for elderly women with early breast can-

cer,” stated Randi Cohen, MD, from the University of Maryland School of Medicine, Baltimore.

The study population included 29,949 women identified in a SEER [Surveillance, Epidemiology and End Results] Medicare database who were

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the 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 OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in 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 to patients

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

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Kathy D. Miller, MD Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

ACCREDITATION Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation 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 does not 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 Manager Certification. Case Managers number 790005057.

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diagnosed with stage I, estrogen receptor–positive (ER+) breast cancer. All women underwent lumpectomy with or without adjuvant radiation and survived at least 1 year after initial diagnosis. Seventy-six percent (22,781) received adjuvant radiation therapy.

Median survival was 13.1 years for women treated with surgery plus radiation and 11.1 years for those treated with surgery alone. Five-year CSS was 98.3% for the adjuvant radiation group versus 97.6% for the surgeryalone group, a statistically significant difference (P <.0001). Ten-year CSS was 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, OS was 88.6% for those who received radiation versus 73.1% for the surgery-alone arm (P <.0001); at 10 years, OS was 65% versus 41.7%, respectively (P <.0001); at 15 years, OS was 39.6% versus 20%, respectively.

A related study based on 27,559 patients from a SEER Medicare database found that older women with earlystage, low-risk breast cancer treated with radiation after breast-conserving surgery (BCS) had superior CSS and OS rates, compared with women who did not undergo radiation after BCS.2 The study showed a 6% decline in the use of radiation after 2004, coinciding with revised National Comprehensive Cancer Network guidelines allowing omission of radiation therapy as a reasonable option for women over age 70 with small ER+ tumors treated with adjuvant tamoxifen.

The study was presented by Mariam P. Korah, MD, a radiation oncologist at the University of Southern California Keck School of Medicine in Los Angeles.

Breast cancer–specific survival favored radiotherapy. At 5 years, CSS was 97% for radiotherapy versus 95%, an absolute difference of 2%; by 8 years, the absolute difference was doubled to 4%, favoring radiation: 95% and 91%, respectively.

OS also favored the addition of radiotherapy to surgery. Five-year OS was 87% versus 69%, respectively, with an absolute difference of 18% favoring radiation, and 8-year OS was 73% versus 49%, respectively, for an absolute difference of 24% favoring radiation. l References 1. Cohen RJ, Li L, Citron W, et al. Improved survival with adjuvant radiation in elderly women with earlystage breast cancer. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 82.

2. Korah MP, Sener SF, Tripathy D. Implications of omitting radiation after breast conserving surgery in elderly women with low risk invasive breast cancer.

Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 84.

www.TheOncologyNurse.com

Conference News: ASTRO Patients Misunderstand Goals of Palliative Radiation Therapy

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

Many patients with incurable lung cancer mistakenly believe that radiation therapy administered for palliative treatment of pain and other cancer symptoms represents a potential cure, according to a study presented at the ASTRO 54th Annual Meeting.1 “Our study found that, though most lung cancer patients are optimistic about the effectiveness of radiation therapy in relieving symptoms and prolonging life, many have inaccurate beliefs about the ability of palliative radiotherapy to cure their cancer,” said lead author Aileen B. Chen, MD, a radiation oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts. “To help patients make informed decisions about radiation treatments near the end of life, healthcare providers need to improve communication with patients and understanding about the goals and limitations of palliative radiotherapy. While palliative radiotherapy can be very effective at relieving symptoms from cancer, overly intensive care can reduce patients’ quality of life and lead to significant time and financial burdens for patients and their families.”

Reference

cations. Only 36% correctly believed that radiation therapy was not at all likely to cure their disease.

These results suggest that physicians need to take the lead in educating end-

stage lung cancer patients about the risks versus benefits of radiation therapy.

Physicians may be concerned that plain speaking will take away hope, but data suggest that honest discussions empower

1. Chen AB, Cronin A, Weeks J, et al. Patient beliefs about palliative radiation therapy (RT) in incurable lung cancer. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 4.

Only 36% correctly believed that radiation therapy was not at all likely to cure their disease.

The Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium study was a population-based and health system–based prospective cohort study. It enrolled 5013 patients with newly diagnosed lung cancer in 5 geographic regions, 10 Veterans Administration sites, and 5 large health maintenance organizations from 2003 to 2005.

Patients older than age 21 with stage IIIB or IV lung cancer scheduled to have radiation therapy completed a baseline interview about 4 months after diagnosis.

Responses to the following question were analyzed: “After talking with your doctors about radiation therapy, how likely did you think it was that radiation would….”

Surveys were completed by 384 patients about their beliefs. Median survival was 11.5 months. More than threequarters (78%) of patients believed that radiation was very likely or somewhat likely to help them live longer; 43% believed that radiation was very likely or somewhat likely to cure their cancer.

About two-thirds (67%) believed that radiation was very likely to somewhat likely to help them with problems from lung cancer, and 66% believed that radiation therapy was very likely or somewhat likely to have side effects or compli-

www.TheOncologyNurse.com

Androgen levels may impact antiandrogen therapy.1-3 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.

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Genetic Counseling

Inherited Cancer Risk Statistics... absolute risk and relative risk. Each category can produce very different-looking numbers.

Absolute Risk Absolute risk is the chance of developing cancer over a specified time period.

This type of risk is not compared with

Continued from cover

anything. It is simply the probability of an event, such as cancer, occurring.

One commonly referenced absolute risk is lifetime risk. For example, the lifetime risk of developing ovarian cancer is approximately 1 in 70. It can also be stated as a percentage, 1.4%, or as a decimal, 0.014. The lifetime risk of devel-

oping ovarian cancer with a BRCA mutation is 10% to 60%. Absolute risk also may be expressed using any time interval, such as a 1-year risk, a 5-year risk, and so on. The lifetime risk of ovarian cancer is obviously much higher than 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 prevalence are absolute risks. Incidence is the number of new cancer cases in a particular population over a specified period of time. Prevalence is the proportion of individuals in a population who have a specific characteristic (such as a mutation in gene Q) or cancer at a specific point in time.

Newsletter Series

YOUR QUESTIONS ANSWERED

™

™

Editor in Chief

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

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

“Absolute risk is the chance of developing cancer over a specified time period.”

—Cristi Radford, MS, CGC

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

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

ALL NEW CONTENT FOR 2012 Accreditation These 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.

COEAsize71912AskExperts

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Relative Risk Relative risk is a “risk ratio.” It is the ratio of the probabilities of 2 absolute risks. Two groups are compared to show the relationship between a particular factor, exposure, or the like. A relative risk of 1 means that there is no difference between the 2 groups. A relative risk of 2 means that one group has twice as great a chance of developing a disease as the other group. It allows increase or decrease in risk due to a particular factor to be portrayed. In the case of inherited cancer risk, the number of cancers in a group of people with a mutation in gene Q is compared with the number of cancers in people without a mutation in gene Q. Sometimes this type of risk is referred to as “fold” or as a percentage.

Risk often seems much higher when explained in terms of relative risk.

For example, women with a mutation in gene Q have a relative risk of developing cancer of 5, compared with women without a mutation. This also means that women with a mutation in gene Q have 5 times the risk of women without a mutation in gene Q. Sometimes this is stated as a 5-fold risk.

Yet another way of stating this statistic is to say that the risk of developing cancer in women with a mutation in gene Q is 500% higher than the risk in

www.TheOncologyNurse.com

Genetic Counseling women without a mutation in gene Q. As relative risk is a comparison between 2 groups, there is no upper limit to percentage of risk.

Therefore, although at first glance a 500% risk may seem huge, it is important to put risk into perspective. What is the underlying absolute risk of cancer? How common are mutations in gene Q? Also, keep in mind that relative risk does not give one any information about a person’s actual risk.

If a particular cancer is rare, a high relative risk may lead to only a few additional cancer cases. On the other hand, if a cancer is more common, a small relative risk may lead to quite a few additional cases of cancer. The same is true for a gene mutation. For example, let us apply a radio broadcaster’s statement “A mutation in gene Q raises the risk of cancer in women by 5fold” to 2 different absolute risks of female cancer: 0.005 (.5%) and 0.125 (12.5%). If you multiply both by 5, you now have 0.025 (2.5%) and 0.625 (62.5%). If you had a population of 10,000 women, this would be an increase from 50 to 250 (200 more women affected) and 1250 to 6250 (5000 more women affected). Many women might be comfortable with a 2.5% risk of female cancer; however, few would probably be comfortable with a 62.5% risk of cancer.

Another way to think of this is to use pennies. If you have 1 penny (it is rare) and multiply it by 5, you now have 5 pennies. You cannot do much with 5 pennies. However, if you start with 50 pennies (now they are common) and multiply them by 5, you have 250 pennies. Now you can buy something.

If a particular cancer is rare, a high relative risk may lead to only a few additional cancer cases.

If a cancer is more common, a small relative risk may lead to quite a few additional cases of cancer.

Take-Home Points • Relative risk statistics may be conveyed several ways, including the following: – Women with a mutation in gene Q have a relative risk of developing cancer of 5, compared with women without a mutation.

www.TheOncologyNurse.com

– Women with a mutation in gene Q have a 5-fold increase in risk, compared with women without a mutation.

– Women with a mutation in gene Q have a 500% higher

risk, compared with women without a mutation.

• Relative risk is a comparison between 2 groups. Therefore, risk often seems much higher.

• Relative risk provides us very lit-

tle information on an individual’s actual risk of developing cancer. It is important to evaluate relative risk in the context of the study from which it was derived. l

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.

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CONTINUING EDUCATION DECEMBER 2012 • VOLUME 5 • NUMBER 5

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Bone Health LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the 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, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, 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, Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

G. David Roodman, MD, PhD Director of Hematology/Oncology Department of Medicine Indiana University Indianapolis, IN

Raj Duggal, PharmD, BCOP Oncology Clinical Pharmacist IU Simon Cancer Center Indianapolis, IN

Lori Case, RN, BSN, OCN Nurse Coordinator IU Simon Cancer Center Indianapolis, IN

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

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

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 1249 South River Road Suite 202B Cranbury, NJ 08512

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

www.TheOncologyNurse.com

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-033-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the impact and consequences of bone destruction in patients with multiple myeloma (MM)

• Summarize recent evidence-based guidelines for the management of myeloma-related bone disease • Review safety and efficacy data on current and investigational therapies for preventing bone loss and skeletal-related events in patients with MM Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might 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, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted

by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

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

Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose.

She does intend to discuss either non–FDA-approved or investigational use 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 disclosed that her spouse is investigator on a study for Agenix, ImClone, and Lilly; on the Data Monitoring Committee for Infinity and Pfizer; on the Advisory Committee for Boehringer Ingelheim; and principal investigor on a study for Pfizer and Sinta.

Faculty Disclosures Sagar Lonial, MD, is a consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. He does intend to discuss either non–FDA-approved or 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–FDAapproved or investigational uses of any products or devices.

Raj Duggal, PharmD, BCOP, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational uses of any products or devices.

Lori Case, RN, BSN, OCN, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational uses of any products or devices.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for 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 completed online at www.mlicme.org/P12029.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

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Estimated time to complete activity: 1.0 hour Date of initial release: December 12, 2012 Valid for CME/CPE/CE credit through: December 12, 2013 SCAN HERE to Download the PDF or Apply for Credit.

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Advances in the Treatment of MyelomaRelated Bone Disease G. David Roodman, MD, PhD Director of Hematology/Oncology, Department of Medicine Indiana University, Indianapolis, IN

Introduction At the time of diagnosis, two-thirds of patients with multiple myeloma (MM) experience bone pain and are very likely to sustain

an SRE at the time of enrollment still obtained clinical benefit from bisphosphonate therapy. In this trial, a 5.5-month overall survival advantage was reported among patients who received the intravenous (IV) bisphosphonate zoledronic acid compared with those who received the oral bisphosphonate clodronic acid.3 A subsequent analysis, however, revealed that only patients with evidence of bone disease achieved the survival benefit.5 Therefore, the survival advantage with bisphosphonate use among MM patients who have not exhibited lytic lesions or osteopenia at diagnosis remains unclear.

pathologic fractures. Therefore, an important goal of therapy when treating the disease is the prevention of fractures and other skeletal-related events (SREs). In this article, G. David Roodman, MD, PhD, discusses recent advances in the management of myelomarelated bone disease, and novel agents that are being investigated

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

for their potential to improve patient outcomes.

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

Guidelines from the American Society of Clinical Oncology1 and the European Myeloma Network2 recommend bisphosphonate therapy for MM patients with either radiographic evidence of lytic bone lesions or severe osteopenia attributable to their disease. New evidence is beginning to emerge, however, to suggest that earlier use of bisphosphonates may be warranted. 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

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

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

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

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

Reprinted with permission.

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

more accurate assessment of a patient’s condition. If individuals have any symptoms, but have a negative skeletal survey, we conduct an MRI examination, per current recommendations.7 In patients who have a solitary plasmacytoma or a single lytic lesion, we perform an MRI of the spine and pelvis to ensure that they do not have additional lytic disease. There is evidence that the presence of focal lesions on MRI may indicate a patient with MM— even one who is otherwise asymptomatic—is at risk for rapid progression and poor prognosis.8,9 Such patients probably should receive therapy.

Fluorodeoxyglucose positron-emission tomography scanning combined with computed tomography (CT) is an excellent method for examining bone10; however, it can be very expensive and therefore cannot be used routinely. In Europe, clinicians are utilizing total-body CT scans with lower doses of radiation. This may eventually become a more standard practice here in the United States.

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

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

Bortezomib-based therapy has been used successfully to reverse renal failure in patients with MM; 59% of patients will exhibit an improvement in renal function within a median of 11 days (range, 8-41 days), with 2 of 9 dialysisdependent individuals becoming dialysis-independent.11 The International Myeloma Working Group recommends bortezomib plus high-dose dexamethasone to accelerate the reversal of renal impairment.12 Bortezomib may improve renal impairment by reducing inflammation through the inhibition of nuclear factor kappa B (NF- B), a transcription factor with proinflammatory effects in the compromised kidney.13

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Several antimyeloma agents may have secondary pro-bone effects, particularly proteasome inhibitors and immunomodulatory drugs (Figure).14 Mounting evidence suggests that the proteasome inhibitors bortezomib and carfilzomib have bone anabolic effects. In other words, they are able to build bone.15-18 These effects have been observed preclinically; clinically, the role of 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 colleagues demonstrated that in human osteoblast progenitor cells, bortezomib stimulated bone nodule formation.16 These researchers, who administered bortezomib as monotherapy to 21 relapsed or previously treated patients with MM, reported that individuals who responded to bortezomib in terms of their myeloma also showed an increase in the number of osteoblasts per mm2 of bone tissue. Patients who responded to bortezomib also exhibited an 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 nonresponders to bortezomib.

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

Terpos and colleagues reported that bortezomib use reduced patients’ serum levels of dickkopf-1 (DKK-1), thus countering the ability of DKK-1 to inhibit the Wnt signaling pathway to suppress osteoblast differentiation.18 Their study results also demonstrated a decrease in receptor activator of NFB ligand (RANKL) with bortezomib, indicating a reduction in osteoclast activity. Together, reduction in DKK-1 and RANKL indicates a normalization of bone remodeling with bortezomib in patients with relapsed MM. The caveat with current data is that, for the most part, patients who demonstrated an increase in bone formation markers also showed an antitumor response to bortezomib. This makes it unclear if bone formation is the result of an effect on osteoblast differentiation or is simply an added benefit of antimyeloma activity. Only one study to date has demonstrated enhanced bone formation markers regardless of whether a patient’s myeloma responded to bortezomib.19 The immunomodulatory agents lenalidomide, thalidomide, and pomalidomide also appear to have beneficial effects on bone. These drugs have been shown to inhibit osteoclast formation and bone remodeling markers in patients with MM.20-22 Breitkreutz and colleagues examined the osteoclast

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CONSIDERATIONS IN MULTIPLE MYELOMA

effects of lenalidomide compared with bortezomib, reporting that lenalidomide reduced levels of RANKL in the serum and bone marrow stromal cells of patients with MM.20 Anderson and colleagues reported that immunomodulators inhibit osteoclastogenesis by diverting osteoclast precursors away from their osteoclast cell lineage toward a granulocytic lineage—a unique mechanism of action mediated by downregulation of the PU.1 transcription factor.22 Osteoclast inhibition appears to be a class effect of immunomodulators. This seems to be more evident with lenalidomide and pomalidomide than with thalidomide.20-22

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

Denosumab, a fully humanized monoclonal antibody, is currently approved only for the prevention of SREs in patients with bone metastases from solid tumors.23 However, this novel agent is currently being evaluated for potential benefits in patients with MM in a phase 3 trial. RANKL is overexpressed in MM and triggers increased osteoclast activity.15 Denosumab inhibits RANKL, and therefore has potent inhibitory effects on the differentiation, activity, and survival of osteoclasts,24 although it has not been shown to augment bone formation. In clinical trials,25 markers of both bone resorption and bone formation are reduced with denosumab treatment in patients with metastatic bone disease, just as they are in trials of bisphosphonates.26 This is consistent with the suppression of bone remodeling—as less bone is resorbed during treatment, less bone needs to be made.26 Conclusion

Bone disease is a major morbidity factor in patients with MM, and the associated skeletal complications can result in significant morbidity. Bisphosphonates remain the standard of care for the treatment of myeloma-related bone disease, and have been shown to consistently reduce the incidence of SREs. However, new molecular targets of cell cross-talk in myeloma bone marrow are currently under investigation, and new drugs are being explored in preclinical and clinical trials. It is hoped that results from these studies will expand our armamentarium of treatment options for patients with MM. References 1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.

2007;25:2464-2472.

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2. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations 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 Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic 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 Haematological Oncology Clinical Studies Group. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes 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 myeloma patients which benefits maximally from the overall survival (OS) benefit associated with treatment 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 (Gruppo Italiano Studio Linfomi) Cooperative Group. Pamidronate versus observation in asymptomatic myeloma: 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 wholebody magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.

9. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic 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 assessment 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 in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors. Clin Lymphoma Myeloma. 2009;9:302-306.

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

13. Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomibbased 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 osteoblast 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 proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity 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 receptor activator of nuclear factor- B ligand concentrations and normalizes indices of bone remodeling in 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 bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-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 factors and 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 pomalidomide inhibit multiple myeloma-induced osteoclast formation and RANKL/OPG ratio in myeloma microenvironment targeting the expression or adhesion molecules. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 448.

22. Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation 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 postmenopausal osteoporosis. Biologics. 2008;2:645-653.

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

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

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Pharmacologic Issues in the Management of Myeloma-Related Bone Disease Raj Duggal, PharmD, BCOP Oncology Clinical Pharmacist IU Simon Cancer Center Indianapolis, IN

pamidronate found in a single, prospective study, but this is not supported in the recent Cochrane review.2 Clinicians at our institution tend to select zoledronic acid as the preferred bisphosphonate, given the advantage of shorter infusion times for patients with adequate renal function. Pamidronate is typically reserved for patients with poor renal function at baseline.

Introduction Bisphosphonate therapy has become an essential component of treatment for patients with multiple myeloma (MM). Although zole-

What bisphosphonate dosing adjustments are necessary for comorbidities such as renal impairment?

dronic acid and pamidronate are highly effective for preventing and reducing skeletal-related events (SREs), these intravenously administered agents may cause adverse events (AEs) that require careful monitoring throughout the course of therapy. Consideration of patient 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 article, 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) bisphosphonate therapy for patients with myeloma-related bone disease?

Bisphosphonate therapy has an established role in the treatment of patients with active MM and identified lytic lesions or compression fractures of the spine due to osteopenia.1,2 In the United States, both zoledronic acid and pamidronate are approved by the US Food and Drug Administration (FDA) to decrease bone destruction from osteolytic lesions and minimize SREs in these patients.1-4 In clinical practice, zoledronic acid and pamidronate, which are typically administered every 3 to 4 weeks, are considered basically equivalent in terms of skeletal protection and pain control.1,2 Therefore, drug selection is dictated by patient-specific factors and the healthcare teamâ&#x20AC;&#x2122;s preference.1,5 Infusion time and baseline renal function are 2 major considerations in the selection of bisphosphonate therapy for patients with MM.1 Zoledronic acid is often recommended for patients with a creatinine clearance (CrCl) >30 mL/min, as this drug can safely be infused over 15 minutes compared with the prolonged 2-hour infusion of pamidronate.1,3,4 For patients with an estimated CrCl <30 mL/min or serum creatinine (SCr) >3 mg/dL, shorter infusion times with zoledronic acid are not recommended, and the infusion time of pamidronate should be extended to 4 to 6 hours to minimize drug toxicity.1 There is no level of renal dysfunction resulting in absolute contraindication for pamidronate therapy.4 In a recent Cochrane review meta-analysis, no statistical difference was found regarding the incidence of AEs (including hypocalcemia and renal dysfunction) when comparing bisphosphonates.2 Both pamidronate and zoledronic acid are associated with osteonecrosis of the jaw (ONJ); the incidence of 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 significantly higher incidence of ONJ with zoledronic acid compared with

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The primary dose adjustment for bisphosphonate therapy is based on renal function.1,3,4 Patients with MM are at risk for renal dysfunction at baseline and during treatment, due to kidney damage from monoclonal light chains, hypercalcemia, hyperuricemia, dehydration, and nephrotoxic pharmacologic agents (including bisphosphonates).2,3,7 Careful consideration of baseline renal function must occur prior to initiating bisphosphonate therapy in these patients (see Tables 1 and 2 for initial dosing recommendations).1,3,4 Once a patient is started on bisphosphonate therapy, ASCO guidelines recommend rechecking SCr levels prior to each subsequent dose.1 Treatment should be withheld for deterioration in renal function, which is defined as an increase in SCr by 0.5 mg/dL if normal at baseline, or 1 mg/dL if abnormal at baseline. Therapy may be restarted at the previously prescribed dose once the SCr has returned to within 10% of baseline.1,3,4 Another method of monitoring patients for renal dysfunction involves periodic assessments (every 3-6 months) for unexplained albumin spilling

Table 1. Suggested Initial Dosing of Zoledronic Acid Based on Renal Function1,3 Zoledronic Dose (infused over 15 minutes)

Creatinine Clearance >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 on Renal 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 baseline Restart at 90 mg over 4 hours

a

Consider reducing initial dose of pamidronate for baseline renal impairment.

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CONSIDERATIONS IN MULTIPLE MYELOMA

into the urine. 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. Pamidronate therapy may be reinstituted with a prolonged infusion time (over 4 hours).1,4 ASCO guidelines also recommend periodic monitoring of serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin, although no specific frequency is given, due to a lack of supportive evidence.1 Commonly, clinicians draw serum calcium levels prior to each dose of bisphosphonate therapy to monitor for additional drug toxicity and potentially, disease progression.2,3,6 Doses can be delayed for hypocalcemia at the discretion of the healthcare team. As long as hypercalcemia is not present, calcium and vitamin D supplementation can be instituted safely to minimize the risk of hypocalcemia.3,4

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.

ONJ is a major concern for patients receiving bisphosphonate therapy, as it can cause significant morbidity.8 Prior to initiating therapy, a routine clinical dental exam is recommended, and dental procedures, including extractions, should ideally be completed prior to initiation of therapy. Once therapy has begun, regular dental exams should be scheduled depending on treatment- and patient-specific risk factors, such as oral health, bisphosphonate dose, and duration of therapy. Some clinicians may consider delaying the dose of bisphosphonate if a dental procedure is scheduled, but no clear recommendations have been established.1,3,4 How do you decide how long to keep patients on bisphosphonate therapy?

The optimal duration for bisphosphonate therapy is currently unknown.

ASCO guidelines currently recommend monthly bisphosphonate therapy for 2 years for patients with active lytic lesions or spinal compression related to osteopenia.1,3,4 After the initial course of therapy, the healthcare team must decide whether therapy should be continued on an individualized basis. If therapy is stopped, it should be restarted upon relapse with development of additional SREs.1 Guidelines published by the European Myeloma Network similarly recommend monthly bisphosphonate therapy for 2 years.8 After this initial

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therapy, in those patients who have achieved remission and have stable disease, bisphosphonates can be discontinued. For some individuals, it may be beneficial to continue bisphosphonate therapy beyond 2 years, at a reduced dose and frequency. However, the panel noted that there is no hard data to support this approach.

Recently, the Medical Research Council Myeloma IX trial provided evidence that suggests maintenance bisphosphonate therapy might have a more significant clinical benefit.9 In this study, subjects were randomized to IV zoledronic acid (4 mg every 3-4 weeks during induction chemotherapy, then every 4 weeks thereafter) or oral clodronate (1600 mg/day). In this population of newly diagnosed MM patients, an overall survival advantage was noted with zoledronic acid compared with clodronate. Many study participants received bisphosphonate therapy longer than the 2-year recommendation, so it is possible that this prolonged therapy may have contributed to the decreased SREs and increased survival times. Due to the studyâ&#x20AC;&#x2122;s small sample size, additional trials need to be completed to confirm this advantage.9 Conclusion

Bisphosphonate use has been shown to prevent, reduce, and delay SREs in MM. Although these agents have an established role in the management of the disease, additional evaluations are needed to clarify the optimal duration of therapy, identify candidates for maintenance therapy longer than 2 years, and observe and report on toxicities noted with this extended treatment regimen.1,2,9 The successful use of bisphosphonates requires careful assessment of patients prior to and during therapy, diligent monitoring for AEs, and a thorough understanding of dosing and administration guidelines that will promote optimal clinical outcomes.

References 1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice 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 network meta-analysis. Coch Database Syst Rev. 2012;5:CD003188.

3. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 2012 4. 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 compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced 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 (NCCN Guidelinesâ&#x201E;˘). 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 multiple myeloma: 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: recommendations 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 longterm bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX trial. Blood. 2012;119:5374-5383.

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Nursing Considerations in Myeloma Patients with Skeletal Complications Lori Case, RN, BSN, OCN Nurse Coordinator IU Simon Cancer Center Indianapolis, IN

Introduction Sustaining skeletal integrity and preventing disability are essential goals of long-term multiple myeloma (MM) care. Achieving these goals requires pharmacologic therapy with intravenous (IV) bisphosphonates, along with strategies to protect mobility and decrease pain. In this article, Lori Case, RN, BSN, OCN, discusses important considerations in the administration and monitoring of bisphosphonate therapy, including the prevention and management of osteonecrosis of the jaw (ONJ) and other adverse events (AEs). She also summarizes best practices in surgical, physical, and educational interventions that can be used to support bone health in patients with myeloma.

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

For patients with MM, we have 2 choices for IV bisphosphonate therapy: zoledronic acid and pamidronate. Although generally well tolerated, these agents can cause kidney function to deteriorate.1,2 Therefore, one concern is the safe administration of bisphosphonate therapy in patients with renal insufficiency. In the case of zoledronic acid, dosage must be reduced from the standard dose of 4 mg for patients whose baseline creatinine clearance (CrCl) is <60 mL/min; use of this drug in patients with severe renal impairment is not recommended.1 In addition, zoledronic acid should always be administered over 15 minutes or longer, to prevent any renal issues that may arise during the infusion process.1 With pamidronate, caution is advised in patients with marked renal impairment (serum creatinine [SCr] >3.0 mg/dL).2 Treatment should be withheld in the event of renal deterioration, which can be defined as an increase 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 be resumed when SCr levels return to within 10% of baseline value.

Pamidronate dose can be reduced from the standard 90 mg when the SCr level is >3.0 mg/dL or the estimated CrCl is <30 mL/min.3 This drug is usually administered over 4 hours, but the infusion time can be increased to 6 hours or longer to minimize renal risk.3 A best practice before and during bisphosphonate therapy is frequent monitoring of renal function. Prior to each infusion, we check SCr in order to properly dose the bisphosphonate. We also conduct a panel of serum chemistries at least once every 3 to 4 months. This assessment evaluates potential metabolic effects of bisphosphonatesâ&#x20AC;&#x201D;hypophosphatemia, hypokalemia, and hypomagnesemia. If we do discover any abnormalities, we can replace the levels with oral supplementation.

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

Some patients experience fever, chills, flushing, and body aches resulting from a bisphosphonate infusion.1,2 For instance, with zoledronic acid and pamidronate at standard doses, approximately 44% and 33% of patients, respectively, report fever.1,2 We inform our patients that they may experience these 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 symptoms; use of this medication was reported effective for this indication in a 2012 study.4 We do not recommend nonsteroidal anti-inflammatory drugs for MM patients because of the potential for renal toxicity.

For patients with severe flu-like symptoms, we have also utilized dexamethasone at very low doses. Since many patients are receiving a steroid as part of antimyeloma therapy, we will try to have them coordinate their weekly dose on the same day that they are scheduled for their bisphosphonate treatment, which may prevent or minimize flu-like symptoms.

What strategies do you use to reduce the risk of ONJ related to IV bisphosphonate 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 these appliances so we can closely examine the gums; we also try to ascertain whether dentures are fitting well. Poorly fitting dentures are a risk factor for ONJ, as are invasive dental procedures such as extractions.5 Evidence also suggests that periodontal disease may increase the risk of ONJ.6 These potential risk factors can be addressed by ensuring that all patients receive a thorough dental checkup and cleaning, and take care of any extractions, dental implants, or other invasive procedures before they start bisphosphonate therapy.3,7

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

We educate our patients to continue twice-yearly checkups and cleanings, and to inform their dentists of any and all treatments they are receiving. If an invasive dental procedure is recommended during bisphosphonate therapy, we ask that the dentist call our office before scheduling the procedure, to discuss risks and benefits. We encourage our patients to call us every time they are planning to go to the dentist, to reiterate the importance of avoiding specific procedures.

Prevention of ONJ is critical, because once it occurs, healingâ&#x20AC;&#x201D;if it happens at allâ&#x20AC;&#x201D;is a slow process.8,9 We send some patients with ONJ to our oral surgeon for assessment. The surgeon may be able to smooth jagged bone edges and make the area more comfortable. We prescribe chlorhexidine

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CONSIDERATIONS IN MULTIPLE MYELOMA

Figure 1a and b. Efficacy of treatments for ONJ (N=53).9 a. Antiobiotics vs antibiotics + oral surgery

80

b. Concomitant O2 hyperbaric/ozonotherapy* vs no concomitant O2 hyperbaric/ozonotherapy 80

Resolution of ONJ Improvement in ONJ

70

Resolution of ONJ Improvement in ONJ

70

66.6%

No change/progression in ONJ

No change/progression in ONJ

60

60

50

Patients (%)

Patients (%)

52.6% 45.5% 40.9% 36.9%

40 30 20

13.6%

50

48.2% 44.4% 38.4%

40 30.8% 30.8% 30 20

16.7% 16.7%

10.5% 10

10

0

7.4%

0 Antibiotics Alone (n=19)

Antibiotics + Curettage (n=22)

Antibiotics + Sequestrectomy (n=12)

With O2 Therapy (n=27)

Without O2 Therapy (n=26)

*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 is included in the data in Figure 1a.

ONJ indicates osteonecrosis of the jaw.

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

Conclusion

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

References

Nonpharmacologic management to prevent SREs and to minimize their pain and impact on function must be highly individualized. The first thing for nurses to do is to speak with the physicians about limitations and interventions appropriate to the patient. Taking into consideration the individualâ&#x20AC;&#x2122;s health status, level of pain, location of osteolytic lesions, and psychosocial profile, we can devise a plan that may include some or all of the following: weight-bearing exercises; strength training; kyphoplasty10,11; physical therapy; localized, palliative radiation therapy; nutritional counseling and calcium/vitamin D supplementation; reduction of alcohol and caffeine (which interfere with calcium and vitamin D absorption); elimination of contact 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 be educated about their bone health. An annual skeletal survey can help illustrate any skeletal changes that have occurred. If there are no changes, it can help them to see that therapy is working to prevent further bone damage.

www.TheOncologyNurse.com

Whole-patient care in MM requires a commitment to bone health. Nurses play a pivotal role in supportive therapy, including careful administration of bisphosphonates, prevention and control of treatment-related AEs, and individualized nonpharmacologic regimens to protect against SREs, reduce pain, and maintain function. All of these work together to provide the best possible quality of life for patients.

1. 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 clinical practice 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 ibuprofen 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 of osteonecrosis 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 BisphosphonateRelated 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 the jaw. 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 patients with multiple myeloma. J Clin Oncol. 2008;26:5904-5909.

9. Andriani A, Petrucci MT, Caravita T, et al; on behalf of GIMEMA. Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstromâ&#x20AC;&#x2122;s macroglobulinema: a retrospective multicentric study [published online ahead of print March 23, 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 of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235.

11. Kristinsson SY, Minter AR, Korde N, Tan E, Landgren O. Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management.

Expert Rev Mol Diagn. 2011;11:593-603.

VOL 5, NO 11

37

Supportive Care

Catheter-Related Thrombosis Can be Prevented

By Caroline Helwick

A

nticoagulation prophylaxis is effective in preventing both symptomatic and asymptomatic catheter-related deep vein thrombosis in ambulatory cancer patients with locally advanced or metastatic solid tumors, French investigators reported at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1 Among cancer patients who have catheters in place for chemotherapy, catheter-related deep vein thrombosis causes morbidity and mortality. The incidence of symptomatic events ranges from 0.3% to 28.3%, and the incidence rises to 27% to 66% when asymptomatic episodes are included.

Current guidelines from American and European societies do not recommend prophylactic anticoagulation for cancer outpatients, but symptomatic catheter-related deep vein thrombosis is still a subject of active research, and the value of prophylaxis in this population is controversial, said Sandrine LavauDenes, MD, of the University Hospital at Limoges in France.

Lavau-Denes reported the results of a phase 3 single-center prospective, randomized, open-label trial, conducted over a 10-year period (1999-2010), that compared a prophylactic strategy to no

prophylaxis over 3 months of chemotherapy among 420 patients with advanced solid tumors.

“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,” said Lavau-Denes.

tients starting a first line of treatment to low-molecular-weight heparin (at the recommended dose), 138 to warfarin (1 mg/day), and 140 to a control arm. Patients were evaluated at baseline and on day 90 (sooner, in the case of symptoms), using Doppler ultrasound of the upper limbs and cervical veins, and venography.

“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

The study was initiated prior to the publication of the current guidelines.

The primary end point was the rate of symptomatic and asymptomatic catheter-related deep vein thromboses of the ipsilateral upper limbs and cervical veins of patients who received, versus those who did not receive, thromboprophylaxis. It excluded intraluminal thrombosis.

Investigators randomized 142 pa-

effectiveness of Prophylaxis In 407 evaluable patients, 42 catheterrelated deep vein thromboses occurred (10.3%), 30 (15.1%) of which were asymptomatic. This included 20 of 135 (14.8%) patients in the control arm and 22 of 272 (8.1%) patients receiving either warfarin or low-molecular-weight heparin.

The effect of prophylaxis amounted to a 45% reduction in risk that was sta-

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tistically significant (P = .0357).

Warfarin and low-molecular-weight heparin were equally effective, LavauDenes noted.

Rates of symptomatic events were 6.7% in controls, versus 1.1% after prophylaxis; asymptomatic events occurred in 8.1% and 7.0%, respectively. Unrelated deep vein thromboses also were prevented.

Adverse events were not significantly increased with thromboprophylaxis.

Bleeding occurred in 0.7% of controls, 2.2% of the low-molecular-weight heparin arm, and 4.5% of the warfarin arm (P = .1361). However, there was an increase in thrombopenia in patients receiving thromboprophylaxis (P <.0001), particularly with low-molecular-weight heparin. However, this was grade 3/4 in only 12 (8.8%), 4 (3.0%), and 7 (5.0%) patients, respectively, with no difference among the arms (P = .1039), she said.

Prophylaxis was discontinued by 25% in the control arm, 27% in the warfarin arm, and 33% in the low-molecular-weight heparin arm. For 12.5% of patients in the control arm the reason was the occurrence of a thrombotic event, compared with 2.2% in the warfarin arm and 2.2% in the low-molecular-weight heparin arm.

Who Should Receive Prophylaxis?

Fausto Roila, MD, of Terni, Italy, who chairs ESMO’s Supportive Care Track, reiterated that routine prophylaxis for ambulatory patients with solid tumors is not recommended by any society, except when patients are considered at high risk. However, he noted, “Thrombosis is a potentially deadly complication, and it is not rare.”

Therefore, Roila suggested that primary prophylaxis be considered under the following circumstances: • The incidence within one’s institution is 8% to 10% • The tip of the central venous catheter is not positioned at the junction between the atrium and the vena cava • The patient has factor V Leiden mutation or a previous venous thromboembolism • The patient has mediastinal syndrome l Reference

Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California

38

VOL 5, NO 11

1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al.

Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract 1546O PR.

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

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

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

Docetaxel Injection, USP

Gemcitabine Injection

Oxaliplatin for Injection,

For intravenous infusion only.

Initial U.S. Approval: 1996

For Intravenous Infusion Only.

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

powder for solution for intravenous use

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 despite dexamethasone (5.5) CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) •

•

•

• •

WARNINGS AND PRECAUTIONS Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur.

Severe skin toxicity may require dose adjustment (5.7) Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection, USP (5.10, 8.1)

ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda. gov/medwatch

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

• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

Oxaliplatin Injection, solution for intravenous use Initial U.S. Approval: 2002 WARNING: ANAPHYLACTIC REACTIONS See 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 USAGE Oxaliplatin 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 REACTIONS Most 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

ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2011

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

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

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1 g/26.3 mL single-dose vial P12-3707-10.875x13.875-Jul., 12

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