OCTOBER 2012 - VOL 5, NO 9 - The Oncology Nurse

OCTOBER 2012

www.TheOncologyNurse.com

VOL 5, NO 9

Breast Cancer Awareness Month GENETIC COUNSELING

Breast Cancer Service

Inherited Breast Cancer Risk: Consider the Possibilities

By Alice Goodman

By Cristi Radford, MS, CGC

CANCER CENTER PROFILE

Fox Chase Cancer Center

A

s with most cancers, the genetic contribution to breast cancer is often classified as sporadic, familial, and hereditary. The majority of breast cancer cases, approximately 70%, are considered sporadic; these cases do not run in families and are not believed to have an underlying genetic predisposition. The remaining 30% of cases are thought to have some type of genetic influence.

Traditionally, it has been estimated that 20% to 25% of cases have a “clustering” in the family, but the contribution of environment and/or genetics is unclear; these

cases are considered familial. The other 5% to 10% of cases are considered hereditary and caused by mutations in highly penetrant breast cancer susceptibility genes. Thus, up to 30% of breast cancer cases may have an underlying inherited risk; however, the risk conveyed by the underlying gene mutation(s) may vary greatly. In 2012, this equates to approximately 68,061 newly diagnosed women1—women who also have family members, both male and female, at an elevated risk of developing cancer.

Continued on page 18

BREAST CANCER Left to right: Jessie Schol, breast navigator; Tracey Newhall, breast navigator, Caryn Vadseth, thoracic navigator; Joanne Stein, head and neck navigator; Rebecca Loss, infusion room navigator; Catherine McFarland, gastrointestinal navigator; and Carol Cherry, gynecologic navigator, nurse navigators at the Fox Chase Cancer Center.

Photo courtesy of Fox Chase Cancer Center.

ox Chase Cancer Center (FCCC) is 1 of 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers (ie, “centers of excellence” in the United States. FCCC was one of the first institutions to be awarded the elite NCI designation, which it received in 1974. In July 2012, FCCC joined the Temple Health System.

F

Continued on page 15

NEWS BRIEFS

Continued Benefit for Everolimus in Updated Results of BOLERO-2 New Data Show Positive Effect on Bone

By Caroline Helwick

U

pdated results from the pivotal phase 3 BOLERO-2 trial uphold, and even add to, the previous benefits reported for the addition of everolimus to exemestane in advanced breast cancer, including a positive effect on bone markers.1,2

The 18-month data from BOLERO-2 were reported at the American Society of Clinical Oncology 2012 Breast Cancer Symposium, held in San Francisco, California.

BOLERO-2 is a phase 3, double-blind, Continued on page 12

By Alice Goodman

INSIDE

High-Density Mammograms in Breast Cancer Patients Do Not Increase Risk of Death

A

lthough mammographic density is associated with increased risk of developing breast cancer, a new National Cancer Institute– sponsored study suggests that dense breasts do not increase the risk of death in women who are already diagnosed with breast cancer (Gierach GL, et al.

J Natl Cancer Inst. 2012;104:12181227). In a large population of women

The PaTienT’s Voice

...........

14

Death Be Not Proud

with breast cancer, high density on mammogram was not associated with increased risk of breast cancer–specific death or all-cause mortality.

Breasts with a greater proportion of fibroglandular tissue block the passage of x-rays to a greater extent than fatty tissue. These breasts are said to be mammographically dense. Typically,

BreasT cancer

Zoledronic Acid: Less Frequent Dosing May Be Just as Good . . . . . 20 No Association Between TaxaneInduced Neuropathy and Clinical Outcomes in Early Breast Cancer . .21 Chemotherapy-Related Adverse Events Add to Economic Burden in Metastatic Breast Cancer . . . . . . .25

Continued on page 7 ©2012 Green Hill Healthcare Communications, LLC

comPlimenTary ce . . . . . . . . . . . .

26

Considerations in Multiple Myeloma— Ask the Experts: Transplant-Eligible and -Ineligible Patients BesT PracTices . . . . . . . . . . . . . . . . .

34

Group Visit Proves Highly Satisfying to Breast Cancer Survivors conference news

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

Highlights From ASCO 2012 Breast Cancer Symposium

36

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 BioPharma Partners LLC New York, NY

Amy Ford, RN,

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MS, RN, APN-C, AOCNS

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

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Somerset Medical Center Somerville, NJ

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

University of South Florida College of Nursing Tampa, FL

OCTOBER 2012 I VOL 5, NO 9

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From the Editor

O

ctober is National Breast Cancer Awareness Month.

The October 1, 2012, presidential proclamation acknowledging this points out that “Breast cancer touches the lives of Americans from every background and in every community across our Nation.” The proclamation states that during this month “we honor those we have lost, lend our strength to those who Beth Faiman, PhD(c), MSN, APRN-BC, AOCN carry on the fight, and pledge to eduEditor-in-Chief cate ourselves and our loved ones about this tragic disease.”

We at The Oncology Nurse-APN/PA (TON) recognize all that you do to educate and treat those who have breast cancer or who are at risk of developing breast cancer. This month, we’re highlighting news about breast cancer and its treatment as we strive to bring you information that you can use.

With all the news coming from the American Society of Clinical Oncology 2012 Breast Cancer Symposium, we

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

present our summary of highlights of interest to TON readers. These studies help us keep current about the status of some of the latest research. We also give you an update about the BOLERO-2 trial, with results reporting continued benefit of everolimus in the treatment of advanced breast cancer.

We tell you about a breast cancer survivorship clinic at the Duke Cancer Center. Two oncology nurse researchers, Kathy J. Trotter, DNP, CNM, FNP-C, and Susan M. Schneider, PhD, RN, AOCN, FAAN, described how this program works in a presentation at the Breast Cancer Symposium.

Cristi Radford, in her genetic counseling column, provides information about the genetic contribution to breast cancer, which, like other cancers, is often classified as sporadic, familial, and hereditary. She points out that up to 30% of breast cancer cases may have an underlying inherited risk and explains what is currently known about the risks conveyed by the underlying gene mutation(s).

As always, we hope the information in this issue benefits your practice. Let us know what you think. Please contact us at editorial@greenhillhc.com. l

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OCTOBER 2012 I VOL 5, NO 9

Regorafenib Approved to Treat Metastatic Colorectal Cancer The US Food and Drug Administration (FDA) approved regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib approval was granted on September 27, 2012.

The FDA approval was based on the results of Study 14387, an international, randomized, double-blind, placebo-controlled trial that enrolled 760 patients who had been previously treated for mCRC. All the patients in the trial had received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with bevacizumab.

Of the patients with KRAS wild-type tumors, all but 1 received panitumumab or cetuximab.

Patients randomized to the regorafenib arm received regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle plus best supportive care. Patients in the control group received matching placebo with best supportive care.

Patients in the regorafenib arm had a statistically significant prolongation in overall survival (hazard ratio [HR] 0.77; 95% confidence interval [CI]: 0.64, 0.94; P= .0102).

The median survival time was 6.4 months (95% CI: 5.8, 7.3) in the regorafenib arm and 5.0 months (95% CI: 4.4, 5.8) in the placebo arm.

There was also a statistically significant improvement in progression-free survival (HR 0.49; 95% CI: 0.42, 0.58; P <.0001). In the regorafenib arm, the median progressionfree survival was 2.0 months (95% CI: 1.9, 2.3). Median progression-free survival was 1.7 months (95% CI: 1.7, 1.8) in the placebo arm. No difference in overall response rate was observed. Partial responses were experienced by 5 patients (1%) in the regorafenib arm and by 1 patient (0.4%) in the placebo arm.

Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia were the most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib. The most serious adverse drug reactions in patients receiving regorafenib were hepatotoxicity, hemorrhage, and gastrointestinal perforation. Regorafenib

was approved with a boxed warning describing the risk of hepatotoxicity.

Regorafenib was reviewed under the FDA’s priority review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. Regorafenib was approved 1 month ahead of the product’s prescription drug user fee goal date of October 27, 2012, the date the FDA was scheduled to complete review of the drug application.

Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, noted that regorafenib “is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past two months.”

Potentially Contaminated Medication From NECC On October 4, 2012, the FDA and the US Centers for Disease Control and Prevention (CDC) recommended that all healthcare professionals cease use and remove from pharmaceutical inventory any product produced by the New England Compounding Center (NECC). The FDA and CDC issued the health advisory after a multistate outbreak of Aspergillus meningitis among patients who received an epidural steroid injection of preservative-free methylprednisolone acetate suspension prepared by NECC. On October 6, NECC announced a voluntary recall of all products currently in circulation that were compounded at and distributed from its facility in Framingham, Massachusetts, stating that it was taking this action “out of an abundance of caution due to the potential risk of contamination, and in cooperation with an investigation being conducted by the U.S. Food and Drug Administration, the Centers for Disease Control and Prevention and the Massachusetts Board of Registration in Pharmacy.”

The situation with NECC has focused attention on the regulation of pharmaceutical compounding companies.

Currently, the FDA has limited authority over the operations of compounding pharmacies, which are mainly regulated at the state level. According to the International Academy of Compounding Pharmacists, there are approximately 7500 pharmacies in the United States that specialize in advanced compounding services, with approximately 3000 providing sterile compounding. l

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News Briefs High-Density Mammograms... Continued from cover mammographic breast density decreases with age, which is thought to be due to a gradual replacement of fibroglandular tissue with fatty tissue as part of normal aging.

The study included more than 9000 women aged 30 years or older who received a confirmed diagnosis of breast cancer between January 1996 and December 2005. Patients were followed for a mean of 6.6 years; at follow-up, 1795 deaths were reported, 889 from breast cancer and 810 due to other causes.

For the analysis of breast density, the Breast Imaging, Reporting & Data System score was used by radiologists who reviewed individual mammograms.

The investigators also analyzed data on tumor characteristics and personal and health factors.

Patients with high-density breasts were not at higher risk of breast cancer death, compared with those with lowdensity breasts in an analysis adjusted for health-related and tumor-related characteristics. This finding is consis-

tent with that of a previous smaller study that analyzed the association between breast density and mortality risk. The risk of death due to breast cancer was increased among women with lower breast density who were obese. The authors suggested that a tumor microenvironment with a high percentage of fat may precipitate cancer growth and proliferation.

Lead author Gretchen L. Gierach, PhD, National Cancer Institute, stated in a press release, “Overall, it was reas-

suring to find that high mammographic breast density, one of the strongest risk factors for breast cancer, was not related to risk of death from breast cancer or death from any cause among breast cancer patients. Given that we identified subsets of women with breast cancer for whom low density was associated with poor prognoses, our findings underscore the need for an improved understanding of the biological components that are responsible for breast density.”

Study Tracks Risk of Heart Failure With Trastuzumab The incidence of heart failure and cardiomyopathy were significantly increased in women with breast cancer treated with trastuzumab either alone or in combination with anthracyclinebased chemotherapy, according to the results of a recent large, populationbased, retrospective cohort study (Bowles EJ, et al. J Natl Cancer Inst. 2012;104: 1293-1305). An adjusted analysis found that the risk of heart failure and/or cardiomyopathy was 4 times greater among women treated with trastuzumab alone and 7 times greater in women treated with trastuzumab plus anthracycline versus women who did not receive any chemotherapy.

The study was based on data from 8 integrated Cancer Research Network health maintenance systems. Overall, the risk of anthracycline-associated heart failure/cardiomyopathy in women under the age of 65 years was similar in this study as in previously reported randomized clinical trials, but the risk associated with trastuzumab alone or when combined with an anthracycline was higher than in previous reports.

Lead author Erin J. Aiello Bowles noted that this study shows that findings of clinical trials may not be generalizable to individual patients treated in realworld settings.

The study included 12,500 women, with a mean age of 60 years, diagnosed with invasive breast cancer from January 1, 1999, through December 31, 2007.

Women with preexisting heart failure/ cardiomyopathy were excluded.

At a median follow-up of 4.4 years, 46.5% had not been treated with chemotherapy, about 30% had received anthracycline-based chemotherapy alone, 0.9% had received trastuzumab with no anthracycline, 3.5% had received anthracycline plus trastuzumab, and about 20% had received other chemotherapy.

Baseline characteristics were different among the groups. Women who received anthracycline alone or in combination with trastuzumab were younger, had been diagnosed at later stages, had fewer comorbidities, and were slightly more likely to be treated with radiation therawww.TheOncologyNurse.com

py, compared with women who did not receive any chemotherapy or who received other chemotherapy.

With increasing follow-up, the incidence of heart failure/cardiomyopathy increased in all groups, but the greatest increase was seen in the trastuzumabtreated patients. In the group treated with anthracyclines, the cumulative incidence of heart failure/cardiomyopathy increased from 1.2% at year 1 to 4.3% at year 5; this increase was similar to that for patients treated with other chemotherapies (from 1.3% to 4.5%).

Patients who did not receive any chemotherapy had a cumulative incidence of heart failure/cardiomyopathy of 0.9% at year 1 and 3.1% at year 5. The greatest increase was observed in patients treated with anthracycline plus trastuzumab: from 6.2% at year 1 to 20.1% by year 5.

At 5 years, the cumulative incidence of heart failure/cardiomyopathy was greater in older women for all treatment

groups, but as women aged, the hazard ratio for heart failure/cardiomyopathy decreased.

The investigators noted that the study demonstrates the importance of observational comparative safety and effectiveness studies to complement data from clinical trials. These observational studies provide an estimate of risks and benefits in community practices that treat patients who often are not eligible for clinical trials but who still receive treatments based on clinical trial data.

en with HER2-positive breast cancer, but she stated that there are still safety concerns related to risks of heart failure/cardiomyopathy. These risks, shown in the current study as well as in other studies, justify long-term surveillance for congestive heart failure in women treated with trastuzumab and for women enrolled in trials.

Also, Geiger expressed concern that about 25% of women in this study had received trastuzumab as adjuvant therapy before it was proven to be of benefit

The risk associated with trastuzumab alone or when combined with an anthracycline was higher than in previous reports.

In an accompanying editorial (Geiger AM. J Natl Cancer Inst. 2012;104: 1269-1270), Ann Geiger, PhD, Wake Forest University, Winston-Salem, North Carolina, acknowledged the important survival benefits of trastuzumab in wom-

in randomized clinical trials in the adjuvant setting. This was probably based on data from the metastatic setting. She advocated longer follow-up on the risks of new treatments to justify their continued use.

Missing Gene May Account for 25% or More Breast Cancers Although preliminary, a recent experimental study published in the journal Genetics (Wallace MD, et al. Genetics. 2012;192: 385-396) found that lack of the neurofibromin 1 (NF1) gene was observed in more than 1 of every 4 experimentally induced breast cancers. The study findings also suggest that tamoxifen will not be effective in cancers that lack the NF1 gene.

This research—if borne out in humans—will have huge implications for the estimated 60,000 new cases of breast cancer that will be diagnosed in the United States and the 383,000 cases that will be diagnosed worldwide in 2012.

In the study, the NF1 gene was missing in about 28% of breast cancers. Previous studies have shown that NF1 depletion causes tamoxifen resistance, and patients with tumors that have low NF1 levels had worse outcomes on tamoxifen.

The NF1 gene has negative effects on the RAS oncogene, which is involved in intracellular signaling that controls cell growth. When NF1 is lacking, RAS becomes hyperactivated and can lead to tumor proliferation.

The study employed a mouse model with elevated mutation rates that led to breast cancers in 80% of the animals.

When the researchers looked at the genomes of mice that developed mammary tumors, nearly all were missing the NF1 gene, explained senior author of the paper, John Schimenti, PhD, professor of genetics at the College of Veterinary Medicine, Cornell University, Ithaca, New York.

Human breast cancers have many causes, and each patient’s tumor has a unique set of gene variants as well as new mutations, making it extremely difficult to identify individual genes that drive the cancer, explained Schimenti in a press release from Cornell. The mouse model used in the study is inbred, and the mice get exactly the same type of tumor every time, eliminating “noise” and allowing the researchers to identify NF1 as a driver of these mutations, according to the press release.

RAS is hyperactivated in the mouse model for breast cancer. Chemotherapy agents that interrupt the RAS pathway are available for the treatment of breast cancer, and it is possible that these drugs will be effective in breast cancers that have low levels of NF1 or cancers with a missing NF1 gene.

The Cornell researchers plan to study whether insertion of a replacement NF1 gene can reverse tumor growth in mice lacking the gene. They are also studying whether RAS inhibitors can slow the growth of breast cancer in the mouse model. In the paper, the researchers stated that RAS inhibitors could slow tumor cell growth in vitro.

Marsha Wallace, a graduate student at Cornell, was lead author of the paper. The authors note that the loss of NF1 may trigger activation of other pathways in addition to RAS, and it will be important to understand these effects as well.

Continued on page 12

OCTOBER 2012 I VOL 5, NO 9

7

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

VISIT US AT THE 2012 ADVANCED CONTENT CONFERENCE TO LEARN MORE

Survivall nnever ever ggets ets oold ld VELCADE® (bortezomib) delivered ered >13-month overall survival advantage in combination with MP* vs MP alone for previously viou untreated multiple myeloma (median 56.4 vs 43.1 months†; 60.1-month median follow-upp‡)

Approved for subcutaneous and IV administration§ VELCADE (bortezomib) Indication Ind and Important Safety Information INDICATION reatment of patients

CONTRAINDICATIONS tients withh hype hypersensitivity to VELCADE is cont contraindicated for

WARNINGS, PRECAUTIONS, AND D DRUG INTERACTIONS luding severe cases, may occur – tion or discontinua ntinuation. Patients thy should uld be treated with VELCADE only after careful risk-benefit assessment Use caution whenn treating patients ▼ those with a history of syncope, ▼

▼ ▼ ▼

s for, or existing se ha y disease has been reported iting have occurred and vomiting and may require use of antiemetic and antidia antidiarrheal

ytopenia or neutropenia can occur; ccur; complete blood counts should be regularly monitored throughout rough treatment ▼ erior Acute cute Hepatic Failure ▼

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. *Melphalan+prednisone. † HR=0.695 (95% CI, 0.57-0.85); p<0.05. ‡ STTA: a randomized, open-label, international phase 3 trial (N=682) evaluating VIST the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTPP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. § The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL).

Living Proof

Noteworthy Numbers October is Breast Cancer Awareness Month—a time to educate people about early cancer detection, novel breast cancer treatments, and ways to support survivors. Today’s educational efforts will aid generations to come and positively influence the following breast cancer statistics.

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

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

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

VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. 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 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% 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 benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

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

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia.

The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Nearly 1 in 3 cancers diagnosed in women in the United States is breast cancer.

The median age at the time of breast cancer diagnosis was 61 years between 2004 and 2008.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 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, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).

Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study 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 events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

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 events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) 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. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) 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.

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An estimated 230,480 cases of invasive breast cancer were diagnosed among women in 2011, as well as approximately 57,650 additional cases of in situ breast cancer.

Between 1995 and 2007, 95% of new diagnoses and 97% of breast cancer deaths occurred in women 40 years of age and older.

A woman’s risk of breast cancer approximately doubles once a firstdegree relative (mother, sister, daughter) is diagnosed with breast cancer.

In 2011, about 2140 cases of breast cancer occurred among men, accounting for about 1% of all breast cancers.

Although mortality rates differ by ethnicity and geography, overall breast cancer death rates decreased by 2.2% per year between 1990 and 2007.

Many factors, including age, race, and cancer stage, influence the following relative survival rates: • 85.9% 5 years after diagnosis • 82% 10 years after diagnosis • 77% 15 years after diagnosis Up from 2.5 million in 2010, there were more than 2.6 million breast cancer survivors in the US in 2011.

Sources http://www.breastcancer.org/symptoms/ understand_bc/statistics http://www.cancer.org/Research/Cancer FactsFigures/BreastCancerFactsFigures/ breast-cancer-facts-and-figures-2011-2012

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

Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card and ongoing charitable donations to various co-pay assistance foundations.

A commitment to care — Since 1985, when our first product was approved, we have donated $2.85* billion in free medicine through the Genentech® Access to Care Foundation (GATCF) and other product donation programs.

Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care. *GATCF donation value is based on the most current forecast.

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Breast Cancer Continued Benefit for Everolimus... Continued from cover randomized, international trial comparing treatment with the aromatase inhibitor exemestane (25 mg once daily) plus the mammalian target of rapamycin (mTOR) inhibitor everolimus (10 mg once daily) or placebo in 724 postmenopausal women with advanced estrogen receptor-positive breast cancer who progressed or recurred after treatment with letrozole or anastrozole.

groups.” The study’s lead author was Francis P. Arena, MD.1 By local assessment, PFS was 7.8 months with everolimus/exemestane versus 3.2 months with exemestane alone, for a 55% reduction in risk. By central review, PFS was 11.0 months with the combination and 4.1 months with exemestane, for a 62% reduction in risk. The differences in each analysis

Photo © ASCO/Todd Buchanan 2012.

“Patients who took everolimus not only had less bone loss but actually seemed to improve from baseline.

This is an unusual finding.”

—Hope S. Rugo, MD

In the previous 12-month analysis, the combination was associated with more than a doubling in disease-free survival, which led to the recent US Food and Drug Administration approval of the regimen after treatment with letrozole or anastrozole. The incorporation of an mTOR inhibitor into an endocrine-based regimen is a novel approach and represents a milestone in treating this disease, said Gabriel Hortobagyi, MD, chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston, and the principal investigator of the pivotal trial.

“Everolimus is the first and only treatment that boosts the effectiveness of endocrine therapy,” he said. “This approval redefines the treatment and management of advanced hormone receptor-positive breast cancer.”

The incorporation of an mTOR inhibitor into an endocrine-based regimen is a novel approach and represents a milestone in treating this disease.

18-Month Update Shows 55% Reduction in Risk At the Breast Cancer Symposium, Hope S. Rugo, MD, of the University of California San Francisco, reported, “The progression-free survival [PFS] at the 18-month follow-up confirms the benefits observed at the 6.5-month and 12.5-month follow-ups, and the PFS benefits were consistent in all sub-

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OCTOBER 2012 I VOL 5, NO 9

were highly significant (P <.0001).

Overall survival differences, however, have yet to emerge, although the difference between the arms is widening, she said. Mortality rates are 25.4% with the combination and 32.2% in the control arm, for an absolute difference of 6.8% favoring the everolimus arm.

A post hoc analysis showed that, in addition to significantly improving PFS, everolimus plus exemestane does not compromise health-related quality of life (Abstract 125).3 Whereas the combination resulted in higher rates of grade 3/4 toxicity, especially stomatitis and fatigue, and more patients discontinued treatment in the experimental arm, the analysis consistently showed that time to deterioration according to the 30-item EORTC QLQ-C30 score was actually longer, not shorter, with the combination, Rugo reported.

Positive Effects on Bone Markers and Progression in Bone In addition to delaying progression, an exploratory analysis of BOLERO-2 suggested that everolimus reduces bone turnover and reverses the increase in bone resorption associated with endocrine therapy, reported Lowell L. Hart, MD, of Florida Cancer Specialists in Fort Myers.2 Bone turnover markers analyzed at 6 and 12 weeks after treatment initiation included bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal crosslinking telopeptide of type 1 collagen.

Progressive disease in bone was defined as worsening of a preexisting bone lesion or a new bone lesion.

In the placebo arm, bone-marker

levels increased over baseline by more than 30%, but in the everolimus arm they actually decreased by more than 30%, for an absolute difference of 66%, Hart reported.

At day 60, progressive disease in the bone was observed in 3.03% of the combination arm versus 6.16% of the control arm (P = .0263), and this trend was sustained beyond 6 months. Hart reported that the delay in bone progression was seen in patients with and without bone metastases at baseline, and regardless of the use of bisphosphonates.

Fractures were observed in 2.3% of patients receiving the combination versus 3.8% on single-agent exemestane.

The positive bone effects occurred in addition to the reported increase in PFS, and “data suggest favorable bone health clinical benefits,” Hart said. “The boneprotective effect with everolimus suggests the potential for using everolimus in the adjuvant breast cancer setting for this purpose.” This hypothesis, in fact, will be tested in a trial by SWOG (Southwest Oncology Group).

Rugo elaborated on these findings.

“Patients who took everolimus not only had less bone loss but actually seemed to improve from baseline. This is an unusual finding,” she said, noting that it is in keeping with preclinical models that suggest that mTOR inhibitors alter the effect of exemestane on bone.

“You are actually getting some buildup of the bone,” she pointed out, “which

suggests that there is a site-specific effect with this targeted agent. This is exciting.

It is not something we have seen much with other targeted agents.”

Future Trials of Everolimus BOLERO-4, an open-label, international, single-arm phase 2 study, will evaluate everolimus plus letrozole in 200 patients, who will also receive everolimus plus exemestane upon progression. The phase 2 BOLERO-6 trial will evaluate everolimus, with and without exemestane, versus capecitabine in 300 patients. The phase 2 PrECOG trial will evaluate fulvestrant plus everolimus in 132 patients. SWOG 2107 will move everolimus into the adjuvant setting, evaluating 5 years of endocrine therapy with and without everolimus in high-risk early breast cancer patients. l References 1. Arena FP, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.

Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 99.

2. Hart LL, Baselga J, Rugo HS, et al. Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets). Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 102.

3. Rugo HS, Beck JT, Baselga J, et al. BOLERO-2: Health-related quality-of-life (HRQoL) in metastatic breast cancer patients treated with everolimus and exemestane versus exemestane. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 125.

News Briefs Lymphadenectomy in Low-Risk Endometrial Cancer Continued from page 7

A prospective study at the Mayo Clinic found that lymphadenectomy did not improve survival in women with low-risk endometrial cancer and was associated with increased morbidity and cost (Dowdy SC, et al. Gynecol Oncol. 2012;127:5-10). The study included 385 women who underwent surgery for low-risk endometrial cancer; 80 patients had lymphadenopathy and 305 did not. In the first 30 days, the rate of complications was significantly higher in the cohort that had undergone lymphadenectomy: 37.5% versus 19.3% (P <.001). Lymph node metastasis was found in 1 case (0.3%).

At a median follow-up of 5.4 years, only 5 of 31 deaths were due to endometrial cancer. Cause-specific survival was 97.3% in the nonlymphadenectomy group versus 99% in those who did

not have lymphadenectomy. Furthermore, none of the 11 recurrences that were detected occurred in the nodal areas that would have been removed by lymphadenectomy.

At a median follow-up of 5.4 years, only 5 of 31 deaths were due to endometrial cancer.

The median 30-day cost of care was $15,678 for the patients with lymphadenectomy, compared with $11,028 for the patients who did not undergo lymphadenectomy. If all 305 nonlymphadenectomy patients had undergone lymphadenectomy, the additional cost would have been almost $1,500,000, the authors wrote.

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News Briefs Routine Ovarian Cancer Screening Nixed The US Preventive Services Task Force (USPSTF) recommended that tests used to screen for ovarian cancer should not be routinely used in otherwise healthy women. These tests include ultrasound imaging and assessing blood levels of CA-125. The recommendation was based on evidence that the risks of these tests outweigh the benefits. The panel agreed that the tests do not lower the death rate from ovarian cancer, and the false-positive yield leads to unnecessary procedures with high rates of complications. The full recommendation appears in the September 11 issue of Annals of Internal Medicine.

Ovarian cancer accounts for about 3% of all cancers in women. It is difficult to detect at early stages, so most women who present with the disease are at relatively advanced stages, when it is often fatal.

The task force is an independent body of medical experts, and the current recommendation comes on the heels of rejection of routine PSA screening for prostate cancer in otherwise healthy men and against routine use of mammography in women under age 50 years. The decision was not based on the cost of screening, but rather on risks and benefits.

Some experts… acknowledge that many doctors will continue to perform screening despite the data, because patients may demand it.

Some experts involved in the ovarian cancer screening recommendation acknowledge that many doctors will continue to perform screening despite the data, because patients may demand it. A recent study published in February in Annals of Internal Medicine found that one-third of 1088 physicians surveyed believed that screening was effective, and many routinely offered it to patients (Baldwin LM, et al. Ann Intern Med. 2012;156:182-194).

The chair of the USPSTF stated that no existing screening method reduces death from ovarian cancer. “In fact, a high percentage of women who undergo screening experience false-positive test results and consequently may be subjected to unnecessary harms, such as major surgery,” said Virginia A. Moyer, MD. “Otherwise healthy women” refers to women who have no signs or symptoms of ovarian cancer and do not harbor the BRCA1 and BRCA2 mutations, which

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increase the risk of developing the disease.

Evidence for the recommendation includes 3 major randomized clinical trials: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, the UK Collaborative Trial of Ovarian Cancer Screening, and the Shizuoka Cohort Study of Ovarian Cancer Screening.

The PLCO trial, the results of which were published in the Journal of the American Medical Association in 2011 (Buys SS, et al. JAMA. 2011;305:22952303), included 78,216 women aged 55 to 74 years; half the women underwent screening and half did not. After 13 years of follow-up, the death rate from ovarian cancer was similar in both

groups. However, in the screened group, 3285 women (10%) had falsepositive results. Surgery to remove the ovaries was performed in 1080 women, with a 15% rate of serious complications. The investigators found that the number needed to treat with surgery to find 1 case of ovarian cancer was 20 women. l

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

Scan Here to Register.

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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The Patient’s Voice

Death Be Not Proud

By MMA

J

ohn Donne, a 16th century poet, wrote a work called “Death, be not proud” (also known as “Holy Sonnet 10”) about death. One line in particular always catches my attention: “….And soonest our best men with thee do go.” Donne stated the obvious: everyone dies, and for many, death comes too soon.

Benjamin Franklin also addressed the inevitability of death (adding a little to it) when he famously wrote in a letter to Jean-Baptiste Le Roy in the late 1700s, that “In this world nothing can be said to be certain, except death and taxes.”

In our modern culture, often hailed for its lack of profundity, death also lives.

The Band Perry, an American country group, sings of premature death in their hit song “If I Die Young.” In the hit movie saga “Twilight,” death makes up one of the principal themes, albeit ironically, through a story of the undead.

Mass media headlines throughout the world herald the death of thousands, every day, of every ethnicity, and of every cause, leaving unreported the demise of thousands more. The point is, death is everywhere.

Well, everywhere except on the cancer ward. Nope. On the cancer ward, no one ever speaks of death. Certainly, patients are encouraged to have advance directives should they become incapacitated. Oh, and there are memorials twice a year (more for children) in the nondenominational chapel for those who succumb to cancer, which I discovered by looking at my hospital’s webpage (it is the last item on a long list of

other services for patients). But bulletin boards in the ward’s hallways announce birthdays, exercise groups, and inspirational quotes. Doctors and nurses talk about progress forward, what is next, and how to cope with the side effects of treatment. Cleaning personnel mop the floors and talk about how they hope the day goes well. The blood folks sneak in very early in the morning, draw the blood, clean up, and go on to the next patient. All the hospital personnel on my floor go about their business as if death did not exist.

Why all the silence about death?

And, really, what does happen to the people who die on this floor, and why will no one admit that people actually die in this hospital?

But this is a cancer ward, chock full of horrendously ill people, and some of us are going to die very prematurely, some of us maybe even today.

“What happens to the people who die on this floor?” I asked my CNA when she came in to check my blood pressure last night.

An awkward silence followed. I felt the blood pressure cup tightening around my arm. Clearly disturbed by my question (and, perhaps, under instructions not to talk about death with patients), she gave me her answer. “I

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OCTOBER 2012 I VOL 5, NO 9

really do not know,” she told me. “I have been here for 3 months, and I have never heard of anyone dying on this floor.”

“Incredible,” I felt like replying in a biting, sarcastic tone. “Here we are on a floor of pure cancer patients, many who are preparing for or have undergone a stem cell transplant, others who I hear gagging for breath, and yet others who cry out in the night for pain medication that always seems to arrive only after at least a few minutes of excruciating suffering. Yet, none of them die of this

often terminal illness. What an amazing hospital this must truly be—full of cancer patients, none of whom die.

Alleluia. Praise be that I am here!”

“Oh,” I actually replied, kindly, as she wrote down my blood pressure reading on her folded piece of paper. “I imagine that they do die, but we just do not see them. Maybe they get left in their room and are snuck out, covered in a sheet, when no one is around. Or maybe they just get transferred to the ICU when it is clear they will die.”

“Maybe,” she said with an uncomfortable chuckle. “You have a good day!”

She gathered up all the blood pressure paraphernalia, turned, and left my room.

Why all the silence about death?

And, really, what does happen to the people who die on this floor, and why will no one admit that people actually die in this hospital?

When you keep your silence and do not tell me, I am forced to come up with my own theories. I, for example, firmly believe that patients on the verge of death get sent to the ICU (my other theory—dead folks lying cold in their beds until they can be snuck out under a white sheet—seems too Hollywood-ish to me). I have heard hushed comments and seen sideways glances in the hallways among nurses as they share the information that, “Oh, so and so got sent to ICU.” It is as if those patients should not be talked about in a normal tone. They no longer have the privilege of being on this floor with all of us, the survivors. Instead, as death approaches, they are banished to the mysterious I-C-U, a wasteland of the

almost dead. Hospital personnel, nurses included, certainly do not want the death of the few to impede the recuperation of the many! Those on the verge of death somehow failed—they did not try hard enough, or they did not follow their medication schedule to the word, or they did not have the innate inner strength to survive. They need to get off this floor!

Admittedly, this is a cynical and probably unproductive accommodation of fragmented facts, or rather my interpretation of what seem to be the facts.

However, if I am not told the facts, if I do not get even a general idea of what would happen to me should my death be imminent, what do you want me to think?

My life would be a lot easier if my nurse, upon my admission to the hospital, would tell me something like: “Of course we do not expect that you will pass away during your stay here. Most patients go home. However, should we perceive that you are at an imminent risk of death, you will be transferred to the ICU to get the intensive care you need (note: you can substitute here whatever the real process is). When you are better, you will come back up here to this floor.”

I don’t want it to seem that because the disease beat me that I somehow lacked inner strength.

That is all. You do not have to go on and on about death. We do not have to fall into a depression. I just want to know what will happen if the outcome of all this is not what I, my family, and friends would have hoped for. I want to be treated with dignity even should I not make it. I don’t want it to seem that because the disease beat me that I somehow lacked inner strength, or was an embarrassment to the cancer patient team, or did not love my children—and my life in general—enough to survive. I do not want to ever feel I have been banished from the living.

Death should not be proud. Yet, cancer patients and oncology nurses should be. Part of maintaining that honor is addressing even the most difficult issues.

Death, obviously, is one of those. l MMA is undergoing treatment for cancer. She wishes to use her initials.

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Cancer Center Profile

Fox Chase Cancer Center FCCC is known for its nursing excellence, and this 100-bed hospital in Philadelphia consistently wins top ratings for treating all types of adult cancers. Its website states that FCCC offers “the best technology and the best people,” and 2 of its scientists have won the Nobel Prize.

FCCC is fertile ground for cancer research, with basic scientists and staff physicians working together to move important laboratory discoveries to patient care. In fact, new treatments and technologies are often available at FCCC before filtering down as standard care in community oncology practices.

At any given time, FCCC has about 170 ongoing clinical trials, and FCCC offers excellent postdoctoral research opportunities.

More recently, FCCC has incorporated nurse navigators into management of several types of adult cancers. The Oncology Nurse-APN/PA spoke with FCCC’s breast cancer nurse navigator Jessie Schol, RN, BSN, OCN, about her role and the changing landscape of treatment for breast cancer.

What is the approach to treating people with cancer at Fox Chase Cancer Center?

JS: We now have a “service line” approach for each type of cancer, with all of the doctors, nurses, nurse navigators, and schedulers collaborating to treat specific cancers. That way, the patient sees the same practitioners at each visit and has a comfort level in having the same people treat her/him week in and week out. In addition to the comfort level for patients, there is also a comfort level for the whole team.

The new-patient office and the nurse navigator are the first points of contact in the service line. The nurse navigator schedules all appropriate appointments and refers the patient to appropriate services.

How is this different from the previous model?

JS: Under the old system, the newpatient schedulers had the patient fax her report to the new-patient office, which would then send those reports to breast cancer nurses, and then appointments would be scheduled. This could take a week.

For the past 2 years, we have had 2 full-time breast cancer nurse navigators who serve as a contact/liaison before patients walk through the doors for the first time. Under the new system, a patient with breast cancer can call the nurse navigator directly, and then I or the other breast cancer nurse navigator, Tracey Newhall, can make a recommendation based on our conversation with the patient. This moves the patient through the system more quickly and alleviates anxiety.

Jessie Schol, RN, BSN, OCN, breast cancer nurse navigator at Fox Chase Cancer Center, talks to a patient.

Photo courtesy of Fox Chase Cancer Center.

gator either through the new-patient office, a direct phone call to the phone number on our website, a friend’s referral, or a physician’s referral.

“One of the best pieces of Photo courtesy of Fox Chase Cancer Center.

What are you excited about right now in the field of oncology?

Jessie Schol (JS): Oncology has become more patient focused, and now we have more-specific therapies targeted to tumor biology instead of a “carte blanche” approach to cancer treatment.

The emphasis is now on customer service, aiming to be responsive to the patient’s needs. The role of nurse navigator is a key component of that approach.

Continued from cover

advice I ever got from my mentor was to set tangible goals: look for one small change you can make every day, for example, to help a patient with her nausea.”

—Jessie Schol, RN, BSN, OCN

We now have 7 different nurse navigators at Fox Chase: 2 for breast cancer, 1 for gynecologic cancers, 1 for gastrointestinal cancers, 1 for thoracic cancers, 1 for head and neck cancers, and 1 in the infusion room.

How does a patient with breast cancer enter the system at Fox Chase?

JS: Patients come to the nurse navi-

What inspired you to become an oncology nurse?

JS: During nursing school, I met a nurse recruiter from Fox Chase whose enthusiasm about the oncology program was inspiring. I worked in FCCC’s nurse extern program while in nursing school and found it was a wonderful environment with loving and caring nurses. I felt that I could make a difference in

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patients’ lives by being an oncology nurse. The faculty at Fox Chase were very supportive. I love the changes in the practice of oncology. The field has evolved so that now we offer more outpatient services that allow patients to live their lives.

What advice do you have for nurses just entering the field?

JS: First, seek a strong, compassionate mentor. If the current mentor is not a good fit for you, don’t be afraid to speak out and request a change. One of the best pieces of advice I ever got from my mentor was to set tangible goals: look for one small change you can make every day, for example, to help a patient with her nausea. This sustains you. Look to your patients to get your satisfaction.

What would you be doing if you were not an oncology nurse?

JS: Honestly, I can’t see myself doing anything else that could give me the spiritual, emotional, and professional satisfaction that I get from my job. It is a great fit, and I feel that it is my calling. l

October 4-6, 2013 The Seaport Boston Hotel 1 Seaport Lane Boston, MA 02210

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15

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

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

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.

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.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (* 5%) reported in patients receiving

Important Safety Information

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. Š 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6397 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

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

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

XTANDI in the randomized clinical trial 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

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (* 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot flush, headache, and upper respiratory tract infection1

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

Genetic Counseling

Inherited Breast Cancer Risk: Consider the Possibilities Continued from cover

Cristi Radford, MS, CGC

Of the cases with an inherited risk, those with germline mutations in the BRCA1/2 genes are still estimated to account for the majority of known cases (25% to 40%), while other cancer susceptibility genes account for approximately 20%, and the associated gene(s) in the remaining cases remain unknown.2,3 It is no longer believed that the

majority of high-risk cases are accounted for by a â&#x20AC;&#x153;BRCA3â&#x20AC;? gene, but rather by moderate-risk breast cancer genes in a polygenic setting. Although genes other than BRCA1/2 may be individually rare, collectively they represent at least onefifth of inherited breast cancer cases and warrant identification. Identifying individuals with an inherited risk not only

allows healthcare providers to provide high-risk surveillance and risk-reducing options, it also spares individuals in a family without the familial mutation from undergoing unnecessary procedures.

DNA Repair Pathways In simplistic terms, cancer is the uncontrolled growth of abnormal cells in

(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

OCTOBER 2012 I VOL 5, NO 9

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 e Infection 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

Genetic Counseling the body. Humans have mechanisms to prevent this from occurring, but when the DNA of a cell changes and is not repaired by these mechanisms, cell growth and division are affected. As a result, cells may not die but instead form tumors. Therefore, when a person is born with a mutation in a gene that helps repair DNA, he or she may have an increased risk of developing cancer.

Thus, when searching for genes that pre-

dispose an individual to an increased cancer risk, many researchers have focused on genes involved in DNA repair pathways. One of these pathways is the Fanconi anemia (FA) pathway.

Fanconi anemia is a genetic syndrome characterized by bone marrow failure, physical anomalies, and increased risk for malignancy. Mutations in at least 13 genes cause Fanconi anemia.4 It is primarily an autosomal recessive condition. The

----------------------------------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\@

gene products associated with the FA pathway regulate DNA repair by homologous recombination. Additionally, the members of the pathway interact with other proteins involved in cellular checkpoints and DNA repair. When there is DNA damage, the FA pathway sends proteins to the damaged area, triggering DNA repair. This pathway became of particular interest in breast cancer risk when it was discovered that homozygous muta-

-------------------------------------- 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. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG 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. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW 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

tions in BRCA2, a breast cancer susceptibility gene, were found to be one genetic cause of Fanconi anemia.5 Similarly, studying the Nijmegen breakage syndrome pathway led to the discovery of other genes associated with a moderate risk of breast cancer. Nijmegen breakage syndrome, also an autosomal recessive condition, is characterized by short stature, microcephaly, distinctive facial features, intellectual disability, and a variety of health problems. It is associated with homozygous or compound heterozygous mutations in the NBS1 gene, which is part of the MRE11-RAD50NBN/NBS1 (MRN) pathway. The MRN pathway is also involved in DNA damage response.3 Studying both the FA and MRN pathways has identified several genes that place individuals at a moderately increased risk of developing breast cancer. Although researchers have postulated an association between genes in these pathways and the risk of breast cancer for a while, this association could not be proven without large case-control studies. Advances in genetic technology have allowed these types of studies to take place, with the result that many of the genes can now be analyzed in either a clinical or research setting through the use of â&#x20AC;&#x153;cancer panels,â&#x20AC;? a sequencing technology that can simultaneously detect mutations in multiple genes that contribute to hereditary cancers, including breast cancer.

Breast Cancer Susceptibility Genes Genes that are known to be associated with a high risk of breast cancer include BRCA1, BRCA2, TP53, PTEN, STK11, and CDH1. These genes convey between a 10- and 20-fold increased risk for developing breast cancer.3,6,7 RAD51C and RAD51D, genes recently discovered to be linked to hereditary breast and ovarian cancer families, may also fall into this category.8 However, more studies are needed to determine if their penetrance is truly in the highest risk category. For the time being, they should be considered moderate-risk genes. Such genes place individuals at a 3- to 5-fold increase. Other genes in this category include NF1, CHEK2, PALB2, RAD50, BRIP1, BARD1, and MRE11.9 Additionally, ATM, NBN(NBS1), and MUTYH heterozygotes are also associated with an increased risk for breast cancer.10,11 These 3 genes are unique from the other moderate-risk genes listed in that they are most recognized for the autosomal recessive genetic syndromes with which they are associated: ATM = ataxia telangiectasia, NBN(NBS1) = Nijmegen breakage syndrome, and MUTYH = MUTYH-associated polyposis (MAP). When a female is heterozygous for a mutation, she also has an increased risk for breast cancer.

For women of child-bearing age, being a Continued on page 20

www.TheOncologyNurse.com

OCTOBER 2012 I VOL 5, NO 9

19

Genetic Counseling

Inherited Breast Cancer Risk: Consider the Possibilities Continued from page 19 carrier of an NBN and/or ATM mutation also has implications for preconception and prenatal genetic counseling, as the offspring may be at risk for Nijmegen breakage syndrome and/or ataxia telangiectasia. Additionally, a recent study suggests that females with Lynch syndrome may also have up to a 4-fold risk of breast cancer.12 However, at this point, it is not clear if this is a true association and if it is true for each gene associated with Lynch syndrome. It is likely that our ideas about the specific penetrance of various genes will continue to change as more is learned about them through continued research.

females at an increased risk of breast cancer is important as it allows mammogram and breast MRI to begin at a younger age, as well as the option of riskreducing mastectomy. Additionally, the genes that place individuals at an increased risk for breast cancer also place them at an increased risk for other cancers—cancers that may be preventable.

For example, consider the case of Leslie, a 38-year-old female recently diagnosed with invasive breast cancer.

Because she was adopted, her family history is almost entirely unknown. The only information she knows is that her biological mother was diagnosed with a

The extent of the risk depends on the family history.

The Importance of Genetic Diagnosis Females with a family history of breast cancer are considered to be at an increased risk of the disease. However, the extent of the risk depends on the family history—the risk may vary from 1.8-fold to more than 5-fold. However, if an underlying germline mutation is identified, such as in BRCA1/2, the risk may increase to 20-fold. Identifying

“female cancer” at age 40 and died at age 42. Leslie’s personal and family history could be associated with a variety of mutations. If she were found to have a mutation in BRCA1, Leslie’s medical management would change to most likely include risk-reducing salpingo-oophorectomy, while if she were found to have a PTEN mutation she would undergo a hysterectomy and annual thy-

roid examinations. However, if she were found to have an alteration in STK11, her management would change to include surveillance and risk-reducing options for several cancers, including colon, stomach, pancreas, small intestine, and ovarian. At the same time, if she were found to have a mutation in PALB2, her management may only include research studies for early detection of pancreatic cancer. Thus, genetic diagnosis would impact her medical management options. Additionally, it would allow at-risk family members to be tested and screened appropriately.

Take-Home Messages • Many genes (at least 16) place a female at increased risk for breast cancer, as well as other cancers; consider all possibilities when assessing a survivor and at-risk family members.

• Genetic technology and testing options continue to evolve; remember to assess individuals for genetic testing options on an annual basis.

• Although “panel testing” appears optimistic, its use in clinical care will continue to evolve as more is learned about the cancer risks conveyed by moderately penetrant genes. l

References 1. Howlader N, Noone AM, Krapcho M, et al, eds.

SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER website, April 2012.

2. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006; 295(12):1379-1388.

3. Hollestelle A, Wasielewski M, Martens JW, et al.

Discovering moderate-risk breast cancer susceptibility genes. Curr Opin Genet Dev. 2010;20(3):268-276.

4. D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010;362 (20):1909-1919.

5. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science.

2002;297(5581):606-609.

6. Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7(1):73-82.

7. Chun N, Ford JM. Genetic testing by cancer site: stomach. Cancer J. 2012;18(4):355-363.

8. Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.

Nat Genet. 2010;42(5):410-414.

9. Ripperger T, Gadzicki D, Meindl A, et al. Breast cancer susceptibility: current knowledge and implications for genetic counseling. Eur J Hum Genet. 2009;17:722731.

10. Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol.

2012;124(2):347-353.

11. Win AK, Cleary SP, Dowty JG, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011;129 (9):2256-2262.

12. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958-964.

Breast Cancer

Zoledronic Acid: Less Frequent Dosing May Be Just as Good

By Caroline Helwick

I

n women with metastatic breast cancer, less frequent dosing of zoledronic acid (ZA) may be as protective as the standard monthly infusion, according to 2 studies presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The Italian ZOOM trial was a phase 3 prospective randomized study of 425 women with stage IV breast cancer and bone metastases. After 1 year of standard ZA treatment (4 mg every 4 weeks), patients were randomized to continue with monthly infusions or to receive ZA every 3 months (4 mg every 12 weeks).

The study concluded that an every12-week infusion was not inferior to the standard monthly infusion. The mean skeletal morbidity rate (number of skeletal-related events per patient per year) was 0.26 and 0.22, respectively, which indicated statistical noninferiority of the less frequent dosing schedule.

Toxicities were also similar between the arms, reported Dino Amadori, MD, of

20

OCTOBER 2012 I VOL 5, NO 9

the Istituto Scientifico Romagnolo in Meldola, Italy.

Bone Turnover A Canadian study looked at 1 turnover following a single dose of ZA and found that after a single 4-mg dose, bone turnover remained suppressed at 12 weeks in 73% of patients.

The study involved 26 patients with metastatic breast cancer to the bone and no prior ZA treatment. Patients received a single dose of ZA, and biomarkers of bone turnover (serum carboxy-terminal collagen crosslinks [CTX]) were collected every 2 weeks subsequently.

Patients remained on study if their biomarkers remained suppressed but came off study as soon as they escaped from suppression (rise >50% of baseline).

At 12 weeks, 73% of patients had continued suppression of bone turnover by serum CTX. The patients who escaped suppression did so at a median of 8 weeks after the first infusion.

“Biomarkers of bone turnover have been found to correlate with the risk of developing a skeletal-related event, and with response to bisphosphonate therapy,” noted Christine E. Simmons, MD, of the University of Toronto.

The magnitude of suppression of serum CTX at week 4 was significantly greater in those who had continued suppression compared with those who escaped suppression before 12 weeks (75% vs 58%; P = .02). The absolute baseline value of CTX was significantly lower in patients who maintained suppression (507 ng/L vs 745 ng/L; P = .04). Quality-of-life scores and pain medication use did not change appreciably during this period.

“Our study suggests that ZA does not need to be given at conventional dosing frequency in the majority of patients, and can be withheld without increased morbidity or effect on quality of life,” Simmons said. “We think that baseline serum CTX (<600 ng/L) and magnitude of suppression of CTX (>70%) may predict for those who can wait 12 weeks between doses.”

Studies Address an Important Issue Teresa Gilewski, MD, of Memorial Sloan-Kettering Cancer Center, New York, who discussed the findings at the Best of ASCO meeting in Boston, Massachusetts, said the studies address

an important issue that has implications for patient convenience and cost of care.

While confirmation is needed, she said, it is possible that some patients may fare as well with less frequent infusions.

ASCO guidelines state that bonemodifying agents should be continued until the patient’s performance status substantially declines; however, the optimal schedule and duration of ZA have not been widely established.

Gilewski questioned whether some patients may be doing well enough— having significant reductions in the volume of bone destruction—that longterm ZA treatment may be unnecessary.

“The biggest strength of the Italian study is that it raises an incredibly important clinical question, in terms of patient compliance and economic issues,” she said. While the study did not assess the extent of bone destruction, she believes that such data might help guide the dosing interval. “In patients with a lot of destruction, we may be less likely to change the infusion schedule, compared to patients with just 1 or 2 sites. But if patients are doing well, we may be more willing to consider the change,” Gilewski said.

Currently, however, she said the data are preliminary and should not yet be clinically applied. Studies are under way that may validate the findings. l

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Breast Cancer

No Association Between Taxane-Induced Neuropathy and Clinical Outcomes in Early Breast Cancer

By Alice Goodman

The association between hyperglycemia and neuropathy was significant.

“This finding provides reassurance that biomarkers predictive for neuropathy will likely not enrich for patients who are more likely to benefit from taxane therapy and may also be useful for the identification of patients who are most likely to benefit from adjunctive therapies to mitigate neuropathy,” wrote the authors.

The study population included 4554 women with operable breast cancer— either axillary node-positive or high-risk node-negative breast cancer. They were treated with up to 4 cycles of doxorubicin/cyclophosphamide every 3 weeks and then randomized to 1 of 4 treatment arms: 4 cycles of paclitaxel 175 mg/m2 every 3 weeks (arm P3), 12 cycles of paclitaxel 80 mg/m2 every week (arm P1), 4 cycles of docetaxel 100 mg/m2 every 3 weeks (arm D3), or 12 cycles of docetaxel 35 mg/m2 every week (arm D1). Grade 2 to 4 peripheral neuropathy was evaluated using the National Cancer Institute Common Toxicity Criteria (version 2.0) grading scale. End points were overall survival, disease-free

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survival, and recurrence-free survival.

Grade 2 to 4 neuropathy developed in 18%, 22%, 15%, and 13% of patients in the P3, P1, D3, and D1 treatment arms, respectively. In a model adjusted for age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, neuropathy, and hyperglycemia, no significant relationship was observed between neuropathy and the 3 end points.

The risk of neuropathy was decreased

in premenopausal patients compared with postmenopausal patients, and the risk of neuropathy was higher in blacks than in other races and in obese patients versus nonobese patients. The association between hyperglycemia and neuropathy was significant and remained significant after adjusting for age, race, obesity, and menopausal status. Hyperglycemia was also associated with inferior outcomes, but only in the P3 arm.

“These findings must…be interpreted with caution because treatmentassociated hyperglycemia may be multifactorial and not reflect patients with a formal diagnosis of diabetes,” the authors wrote. l Reference 1. Schneider BP, Zhao F, Wang M, et al. Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer. J Clin Oncol. 2012;30:3051-3057.

www.avbcconline.org

THIRD ANNUAL CONFERENCE MAY 2-5, 2013

A

ccording to an analysis of the Eastern Cooperative Oncology Group trial ECOG-E1199 by Schneider and colleagues, the development of grade 2 to 4 peripheral neuropathy in patients with operable breast cancer who received taxanes does not appear to affect clinical outcome.1 “We found that, although neuropathy was a common complication that was associated with necessary dose reductions [of taxanes], it was not associated with a higher risk of recurrence or inferior survival,” wrote Bryan P. Schneider, MD, and colleagues. Schneider is affiliated with ECOG at the Indiana University School of Medicine, Indianapolis.

The investigators of this study previously identified several single nucleotide polymorphisms that were significantly associated with an increased risk for developing grade 2 to 4 peripheral neuropathy in patients with breast cancer treated with taxane-containing chemotherapy. The present study suggests that this biomarker will not be useful for identifying patients who will derive preferential benefit from taxane therapy.

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

!

For more information please visit

www.AVBCConline.org OCTOBER 2012 I VOL 5, NO 9

21

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). EfďŹ cacy relative to ďŹ rst-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;Ą: 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;Ą CI=confidence interval.

s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A RANDOMIZED OPEN LABEL PHASE TRIAL IN TREATMENT NAĂ&#x2022;VE PATIENTS WITH "INET STAGE " OR # 2AI STAGES ) )6 #,, WHO REQUIRED TREATMENT . s 42%!.$! IS ADMINISTERED WITH A CONVENIENT DOSING SCHEDULE n 4HE RECOMMENDED DOSE FOR 42%!.$! IS MG M2 ADMINISTERED INTRAVENOUSLY OVER MINUTES ON $AYS AND OF A DAY TREATMENT CYCLE UP TO CYCLES n )N THE PHASE TRIAL PATIENTS RECEIVED CHLORAMBUCIL AT A DOSE OF MG KG ORALLY ON $AYS AND N OF A DAY TREATMENT CYCLE UP TO CYCLES s )N THE PIVOTAL PHASE TRIAL THE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FREQUENCY â&#x2030;Ľ WERE PYREXIA NAUSEA AND VOMITING N 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ WERE ANEMIA THROMBOCYTOPENIA

NEUTROPENIA LYMPHOPENIA AND LEUKOPENIA N Important Safety Information s 3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS TUMOR LYSIS SYNDROME SKIN REACTIONS INCLUDING 3*3 4%.

OTHER MALIGNANCIES

AND EXTRAVASATION HAVE BEEN ASSOCIATED WITH 42%!.$! 3OME REACTIONS SUCH AS MYELOSUPPRESSION INFECTIONS AND 3*3 4%. WHEN 42%!.$! WAS ADMINISTERED CONCOMITANTLY WITH ALLOPURINOL AND OTHER MEDICATIONS KNOWN TO CAUSE 3*3 4%.

HAVE BEEN FATAL 0ATIENTS SHOULD BE MONITORED CLOSELY FOR THESE REACTIONS AND TREATED PROMPTLY IF ANY OCCUR s !DVERSE REACTIONS MAY REQUIRE INTERVENTIONS SUCH AS DECREASING THE DOSE OF 42%!.$!

OR WITHHOLDING OR DELAYING TREATMENT s 42%!.$! IS CONTRAINDICATED IN PATIENTS WITH A KNOWN HYPERSENSITIVITY TO BENDAMUSTINE OR MANNITOL 7OMEN SHOULD BE ADVISED TO AVOID BECOMING PREGNANT WHILE USING 42%!.$! s 4HE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FOR #,, FREQUENCY â&#x2030;Ľ ARE PYREXIA

NAUSEA AND VOMITING 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ ARE ANEMIA THROMBOCYTOPENIA NEUTROPENIA LYMPHOPENIA AND LEUKOPENIA

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

Š2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a 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 TREANDA Chlorambucil (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) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous 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-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation.

Information.

TRE-006 TREANDA

April 2012 August

Breast Cancer

Chemotherapy-Related Adverse Events Add to Economic Burden in Metastatic Breast Cancer

By Caroline Helwick

A

dverse events (AEs) related to chemotherapy for metastatic breast cancer (MBC) create a substantial economic burden that is primarily explained by increased inpatient, outpatient, and pharmacy costs, said Sara A. Hurvitz, MD, of the University of California Los Angeles, who presented an economic analysis at the 2012 Annual Meeting of the American Society of Clinical Oncology.

“In addition, an analysis of healthcare costs stratified by the number of AEs reported by patients showed a clear trend: the economic burden of AEs increases with the number of AEs reported,” she added.

The study is the first to assess costs associated with AEs that occur during treatment for MBC, she said.

Hurvitz led a study sponsored by Genentech that aimed to quantify the economic impact of AEs reported in patients with MBC receiving first- or second-line therapy with taxanes or capecitabine for at least 30 days per treatment episode. Patients were selected from the PharMetrics Integrated Database. The data elements included pharmacy and medical claims from more than 100 healthcare plans in the United States, covering more than 70 million lives between 2000 and 2010.

The eligible cohort included 3222 patients who used a taxane (docetaxel, paclitaxel) first-line (n = 1866), capecitabine first-line (n = 812), taxane second-line (n = 715), or capecitabine second-line (n = 369). Patients treated with both classes during the same episode were excluded. The AE list included almost 2 dozen possible AEs. AEs were commonly seen in each of the 4 study cohorts. With taxanes, 94.6% of first-line patients and 94.4% of second-line patients experienced at least 1 event during treatment. With capecitabine, 83.7% and 84.0%, respectively, experienced at least 1 AE. Nausea/vomiting was the most common complication with either agent, Hurvitz reported.

In general, patients who experienced no AEs in the study were relatively younger and had fewer comorbidities at baseline.

Incremental Monthly Costs Associated With AEs The incremental costs associated with chemotherapy-related complications were estimated by comparing the average costs between the cohorts with AEs and without AEs for the 4 treatment groups. The analysis revealed the following:

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• Taxanes first-line: AEs were associated with a 38.7% increase in monthly costs, over patients without AEs ($3547). These incremental costs were mainly driven by increased inpatient costs and other drug costs (other than chemotherapy).

• Taxanes second-line: AEs were associated with a 69.5% increase in monthly costs ($5320). Incremental costs were mainly driven by incremental pharmacy costs for chemotherapy and other drugs.

• Capecitabine first-line: AEs were associated with a 9% increase in monthly costs ($4933). Incremental costs were mainly driven by inpatient and outpatient costs.

• Capecitabine second-line: AEs were associated with an 82.9% increase in monthly costs ($4933).

Incremental costs were mainly driven by inpatient and outpatient costs.

Increasing AEs per Episode Led to Higher Costs The more AEs per episode, the greater the cost of care, the analysis further found. For example, for taxane first-line therapy, the mean cost for a treatment without an AE episode was approximately $10,000, which rose to approximately $11,000 in the setting of 1 or 2 AEs and to almost $15,000 in the setting of more than 4 AEs.

symptoms with capecitabine, both approaching $16,000 on average.

Hurvitz cautioned that the study has limitations: cause-and-effect associations cannot be confirmed and the reported rates are restricted to duration of an episode of treatment and did not take into account complications occurring after treatment ended. It is also a retrospective observational study based on claims data, though this also has the

The more AEs per episode, the greater the cost of care, the analysis further found.

For second-line capecitabine, treatment without an AE episode cost approximately $6000, but rose to approximately $14,000 in the setting of more than 4 AEs. The average monthly costs per type of AE were highest for skin toxicity with taxanes and for constitutional

advantage of being a valid, large sample-source of clinical practice data, she pointed out.

“Further research evaluating the clinical and economic consequences of chemotherapy-related AEs in a prospective manner can further characterize the effects seen here,” she said. l

SAVE THE DATE SECOND ANNUAL CONFERENCE

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

OCTOBER 2012 I VOL 5, NO 9

25

CONTINUING EDUCATION OCTOBER 2012 • VOLUME 5 • NUMBER 3

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Transplant-Eligible and -Ineligible Patients 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 third issue, experts from Washington University answer questions pertaining to the management of transplant-eligible and -ineligible patients.

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

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

Ravi Vij, MD Associate Professor of Medicine Washington University School of Medicine Section of Stem Cell Transplant and Leukemia Division of Medical Oncology St. Louis, MO

Maggie Kavanaugh, ANP-BC Adult Nurse Practitioner Bone Marrow Transplant, Leukemia and Lymphoma Barnes-Jewish Hospital Washington University School of Medicine St. Louis, MO

Lindsay Hladnik, PharmD, BCOP Clinical Pharmacist, Hematologic Malignancies/SCT Barnes-Jewish Hospital/Washington University Department of Pharmacy St. Louis, MO

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

26

OCTOBER 2012 I VOL 5, NO 9

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 1.25 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 1.25 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 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-026-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the impact of novel regimens for MM as they relate to

improved patient outcomes prior to and following transplantation • Evaluate the efficacy and safety of newer therapies for patients with MM who are ineligible for transplant • Review evidence-based strategies for preventing and managing adverse events commonly seen with novel agents used in the transplant and nontransplant settings for 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.

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

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; on the Advisory Committee for Boehringer Ingelheim; and on the data monitoring committee and principal investigator on a study for Pfizer.

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. *Ravi Vij, MD, is a consultant for Celgene Corporation and Onyx Pharmaceuticals, has received grant support from Celgene, and is on the speakers’ bureau for Celgene Corporation and Millennium: The Takeda Oncology Company.

Maggie Kavanaugh, ANP-BC, is on the speakers’ bureau for Celgene Corporation.

Lindsay Hladnik, PharmD, BCOP, has nothing to disclose. *Content will include non–FDA-approved uses.

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.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the indepen dent 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/P12027.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.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Estimated time to complete activity: 1.25 hours Date of initial release: October 12, 2012 Valid for CME/CPE/CE credit through: October 12, 2013

SCAN HERE to Download the PDF or Apply for Credit.

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Frontline Therapy for Transplant-Eligible and -Ineligible Patients Ravi Vij, MD Associate Professor of Medicine, Washington University School of Medicine Section of Stem Cell Transplant and Leukemia Division of Medical Oncology, St. Louis, MO

Introduction The use of novel targeted therapies has significantly improved outcomes in multiple myeloma (MM). The impact of these agents has been especially impressive in the frontline setting, both for pretransplant induction regimens, as well as for the initial treatment of patients not eligible for transplant. In this article, Ravi Vij, MD, discusses recent data from key clinical trials of newer combination regimens for myeloma and provides insights regarding the selection of therapeutic approaches in the era of novel agents.

How has the use of novel frontline therapies improved outcomes in transplant-eligible patients with MM?

There is no doubt that the incorporation of thalidomide, bortezomib, and lenalidomide into frontline combinations has greatly improved complete response (CR) rates, especially when these therapies are used in triplet regimens. Follow-up data from phase 3 clinical trials extending 1 to 2 years or longer are showing a progression-free survival (PFS) advantage with many newer combinatioms. Our hope is that with extended followup, this will translate into an overall survival (OS) advantage, as CR has been shown to be a surrogate for this end point in numerous clinical trials.

www.TheOncologyNurse.com

In the Total Therapy 2 trial, incorporation of thalidomide not only improved CR and very good partial response (VGPR) rates following autologous stem cell transplant (ASCT), but it also translated into better PFS and OS in specific subsets of patients with MM.1-3 Prolonged 5-year OS was reported in younger patients (<65 years of age), with longer 5-year eventfree survival (EFS) and OS reported in complete responders to therapy.1 Trials that compared thalidomide-based combinations with vincristine, doxorubicin, and dexamethasone have reported improvements in response and PFS in patients treated with thalidomide as part of induction therapy.4,5 In a 2012 meta-analysis,6 which included 2 randomized trials of thalidomide,2,5 the use of this agent was shown to improve CR and PFS (but not OS) compared with chemotherapy.

In a seminal group of clinical trials, bortezomib-based therapies improved response rates and PFS versus comparator regimens in the transplant setting (Table 1).7-10 The 2012 meta-analysis mentioned above,6 which included 3 randomized trials of bortezomib,7,8,11 reported improved CR and PFS with regimens using this agent. Though not yet studied in a randomized clinical trial, the 3-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is also a commonly used pretransplant induction regimen.

There are no randomized studies of lenalidomide specifically in the pretransplant setting. The best data on this agent as induction come from the ECOG E4A03 trial of lenalidomide plus dexamethasone in a patient population that could choose between transplant or continuing with the initial regimen.12 In this trial, lenalidomide plus low-dose dexamethasone (Rd) was associated with better OS at 1 year versus lenalidomide plus high-dose dexa-

OCTOBER 2012 I VOL 5, NO 9

27

CONTINUING EDUCATION

Table 1. Bortezomib-Based Induction Prior to Transplant7-10

Trial

Regimen

N

CR + VGPR Postinduction (%)

CR + VGPR Post-ASCT (%)

PFS

VTD vs TD

236

62a

82a

68% at 3 yr

238

28

64

56% at 3 yr

VD vs VAD

223

37.7a

67.7a

Median 36 mo

218

15.1

46.7

Median 29.7 mo

PAD vs VAD

308

42a

76b

Median 36 mo

305

15

55

Median 27 mo

VD vs vTD

99

36

58

Median 30 mo

100

49c

74d

Median 26 mo

Cavo et al7

Harousseau et al IFM 2005-018

Sonneveld et al HOVON-659

Moreau et al IFM 2007/0210

P Value

.0057

.063

.005

.22

a P<.001; bP=.001; cP=.05; dP=.02.

ASCT indicates autologous stem cell transplant; CR, complete response; PAD, bortezomib, doxorubicin, and dexamethasone; PFS, progression-free survival; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone; VGPR, very good partial response; vTD, reduced-dose bortezomib, thalidomide, and dexamethasone; VTD, bortezomib, thalidomide, and dexamethasone.

Table 2. RD Plus ASCT versus Rd: Results from the ECOG E4A03 Trial12,13

N

1-Year Survival Probability

3-Year Survival Probability

All patients

141

.94

.78

RD patients

65

.89

.79

Rd patients

76

.97

.78

All patients

68

1.0

.94

RD patients

38

1.0

.95

Rd patients

30

1.0

.93

Treatment No Early Transplant

bination.14 In patients with renal insufficiency, which requires lenalidomide dose reduction,15 I often substitute cyclophosphamide for lenalidomide and treat patients with CyBorD.16 In this population, bortezomib-based regimens may offer the best chance of reversing renal dysfunction.17 In addition, there is evidence from several trials that including bortezomib as part of the initial treatment regimen overcomes certain high-risk cytogenetics in MM.7,9,14 Over the past 18 months, we have been administering bortezomib as a subcutaneous injection, based on data showing that subcutaneous dosing offers equivalent response to treatment and reduced peripheral neuropathy compared with intravenous dosing.18

Early Transplant

ASCT indicates autologous stem cell transplant; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone.

methasone (RD) (96% vs 87%, respectively; P=.0002), which was attributed to a greater incidence of toxicity-related deaths during the first 4 cycles in the high-dose dexamethasone group. Subsequent analysis of patients who survived the first 4 cycles in this trial showed that those patients treated with either regimen who had undergone early ASCT had superior survival at 1 and 3 years posttransplant compared with those who did not undergo early ASCT (Table 2). This advantage for postinduction ASCT was observed in both younger and older age groups.12,13 In a recent phase 1/2 trial of newly diagnosed patients, treatment with lenalidomide, bortezomib, and dexamethasone (RVD) led to favorable results, with 100% of patients in the phase 2 population achieving a partial response or better and 74% achieving VGPR, with good tolerability.14 Three-drug regimens such as this, which combine 2 novel agents plus 1 conventional drug, may be an optimal choice for induction as long as there are no contraindications.

What is your approach to selecting induction therapy for transplanteligible patients?

In my practice, I tend to favor triplet regimens over doublet regimens. We commonly use RVD, given the impressive response data seen with this com-

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OCTOBER 2012 I VOL 5, NO 9

Do you think that the improved efficacy seen with newer induction regimens will allow patients to delay transplant?

Expert opinions vary widely regarding this topic. Certainly, the Group Myelome-Autogreffe trial showed that ASCT produced a median OS exceeding 5 years in younger patients with symptomatic MM, whether performed early (as frontline therapy) or late (as rescue treatment). However, median EFS, average time without symptoms, treatment, and treatment-related toxicity (TWiSTT) analysis favored early transplant.19 Patients in this trial received 3 or 4 treatments with vincristine, doxorubicin, and methylprednisone pretransplant.19 Unfortunately, there are no prospective studies designed to replicate this trial in the age of thalidomide, bortezomib, and lenalidomide. However, a retrospective analysis did show that, among patients who received immunomodulatory drugs (ie, lenalidomide or thalidomide) in frontline therapy, followed by early stem-cell mobilization, delaying ASCT resulted in an OS similar to that observed with early ASCT.20 In my practice, I do continue to advocate taking patients to transplant early in the course of the disease. I may delay ASCT in specific situations, such as for a patient with a poor performance status after induction or an individual who is extremely reluctant to undergo transplant. However, I do strongly urge these patients to undergo ASCT at first progression, if they are able. There are no data to suggest that delaying transplant beyond first progression provides the same benefits and survival as early transplant. Some oncologists suggest delaying ASCT in patients who achieve CR during induction with novel therapies. This is a rational argument, but not an

www.TheOncologyNurse.com

CONSIDERATIONS IN MULTIPLE MYELOMA

approach I have personally adopted, as ASCT is likely to provide more durability to the response even in these patients.

Figure. Median Progression-Free Survival in a Comparative Trial of MPR-R, MPR, and MP27

Which newer frontline therapies are effective for transplant-ineligible patients?

Conclusion

Today, there are numerous effective frontline regimens available for transplant-eligible and -ineligible patients. Choosing an appropriate therapy requires a thorough evaluation of patient-related factors, including performance

www.TheOncologyNurse.com

MPR-R

* 30

MPR

31

MP

25

Months

In the nontransplant setting, most randomized trials have evaluated the safety and efficacy of adding a novel agent to melphalan plus prednisone (MP). Five such trials were conducted using thalidomide plus MP (MPT); all showed superior PFS. However, only 2 trials showed an OS advantage.21 The VISTA trial compared bortezomib plus MP (VMP) with MP alone in newly diagnosed, transplant-ineligible patients.22-24 Results of this trial, after 5 years of follow-up, showed a sustained OS advantage with the 3-drug regimen.24 Mateos and colleagues recently compared VMP with bortezomib, thalidomide, and prednisone (VTP) in patients who were 65 years of age. Results showed essentially equivalent overall response rates after induction with these 2 therapies (80% with VMP vs 81% with VTP), and similar 1-year OS rates (92% and 89%, respectively).25 However, it is important to note that investigators in this trial incorporated 2 different maintenance strategies after initial therapy: bortezomib plus prednisone and bortezomib plus thalidomide.

The use of these maintenance regimens made it more difficult to analyze the effect of frontline therapy on outcomes.

In the community-based, open-label UPFRONT study, older transplantineligible patients received 24 weeks of induction therapy with 1 of 3 regimens: bortezomib plus dexamethasone (VD), bortezomib, thalidomide, and dexamethasone (VTD), or VMP.26 Regardless of the frontline regimen assigned, all patients were treated with bortezomib maintenance therapy for 25 weeks. Overall, the investigators concluded that the 3 regimens were relatively similar in efficacy and yielded encouraging results for this population.

Lenalidomide-based therapy for transplant-ineligible patients was recently investigated in the randomized MM-015 trial, which compared melphalan, prednisone, and lenalidomide (MPR) versus MPR followed by lenalidomide maintenance (MPR-R) versus MP alone.27 In this trial, there was a significant PFS advantage seen with MPR-R (Figure), but the benefit was limited to patients who were between 65 and 75 years of age. None of the arms showed an OS advantage.

In all of these trials, MP was used as both the comparator and a component of the study regimen, which was necessary for drug approval by the US Food and Drug Administration. However, few would accept MP as a clinical standard. Melphalan is a slow-acting drug with potential to cause substantial myelosuppression and is being used less frequently in the frontline setting.

Certainly, early follow-up from the UPFRONT study suggests that nonâ&#x20AC;&#x201C;melphalan-containing bortezomib combinations provide similar CR and OS rates.26 Currently, we are eagerly awaiting results from the multicenter, phase 3 MM-020 study (also known as the FIRST trial), which is evaluating the safety and efficacy of Rd given until disease progression versus Rd for 18 4-week cycles versus MPT for 12 6-week cycles.28 Another important fact to keep in mind is that the definition of transplantineligible continues to evolve. Today we are performing more and more transplants in patients who are 65 years of age. In my view, the truly transplantineligible population is older than 75 years of age. For this elderly population, we do not have sufficient data on the tolerability of regimens such as VMP, MPT, or MPR, and more studies are needed.21-23

35

20 15 10

14

13

5 0 All Patients

*Median progression-free survival significantly longer in MPR-R group than in MP or MPR groups ( <.001).

MP indicates melphalan plus prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, lenalidomide, followed by continuous lenalidomide maintenance.

status, comorbidities, and disease-related features. It is also important to consider the efficacy and toxicity profiles of specific agents and combination regimens so that therapy can be tailored to the individual needs of each patient.

Patient preference, based on factors such as route of administration and affordability, may play a role in determining the choice of therapy. Deciding when to initiate ASCT in eligible candidates is also a complex decision that involves careful consideration of risks, benefits, and patient preferences.

References 1. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030.

2. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112:3115-3121.

3. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol.

2010;28:1209-1214.

4. Macro M, Divine M, Uzunhan Y, et al. Dexamethasone + thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma (MM): a randomized trial. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 57.

5. Lockhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120.

6. Wang L, Ran X, Wang B, Sheng Z, Liu L. Novel agents-based regimens as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: a metaanalysis of randomized controlled clinical trials. Hematol Oncol. 2012;30:57-61.

7. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.

8. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629.

9. Sonneveld P, Schmidt-Wolf I, ven der Holt B, et al. HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 40.

10. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:5752-5758.

11. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. First analysis of HOVON-65/GMMGHD4 randomized phase III trial comparing bortezomib, adriamycin, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 653.

12. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group.

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.

13. Siegel DS, Jacobus S, Rajkumar SV, et al; on behalf of the Eastern Cooperative Oncology Group.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell trans-

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CONTINUING EDUCATION

plantation in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts).

2010;116:Abstract 38.

14. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.

15. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012.

16. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341.

17. Dimopoulos MA, Terpos E, Chanan-Kahn 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.

18. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

19. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-3136.

20. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118:1585-1592.

21. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696.

22. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone or ini-

tial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.

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

24. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts).

2011;118:Abstract 476.

25. Mateos M-V, Oriol A, Teruel A-I, et al. Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) in elderly myeloma patients included in the GEM 2005MAS65 Spanish randomized trial. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 477.

26. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011; 118:Abstract 478.

27. Palumbo A, Hajek R, Delforge M, et al; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.

28. Study to determine efficacy and safety of lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide in patients with previously untreated multiple myeloma (FIRST) (NCT00689936). http://www.clinicaltrials.gov/ct2/show/NCT00689936?term=nct00689936& rank=1. Accessed September 26, 2012.

Nursing Considerations in the Frontline Treatment Setting Maggie Kavanaugh, ANP-BC Adult Nurse Practitioner Bone Marrow Transplant, Leukemia and Lymphoma Barnes-Jewish Hospital Washington University School of Medicine, St. Louis, MO

Introduction In the frontline setting for multiple myeloma (MM), multidrug regimens based on novel agents can generate a range of adverse events (AEs) that require nursing intervention. Transplant-eligible patients must cope with the effects of induction followed by the impact of autologous stem cell transplant (ASCT). Patients ineligible for transplant—typically, the elderly or those compromised by comorbidities—face elevated drug toxicity risks. In this article, Maggie Kavanaugh, ANP-BC, discusses the nurse’s role in navigating such risks,

receive adequate hydration, and we offer nutritional counseling. The advent of subcutaneous dosing of bortezomib also has reduced the GI toxicity associated with use of this agent.5 We monitor hepatic function in patients scheduled to receive bortezomib, since dosing must be adjusted when a patient experiences hepatic impairment.2 With lenalidomide administration, doses need to be reduced in patients with renal dysfunction, so monitoring of serum creatinine and creatinine clearance must be performed routinely (Table 1).3 The use of bortezomib has been shown to affect blood glucose control in patients with comorbid diabetes.2 When bortezomib is combined with dexamethasone—a corticosteroid that can induce hyperglycemia6—blood glucose levels must be watched closely.

All 3 of these novel agents can cause peripheral neuropathy (PN), although our experience is that both the risk and the severity of PN may be greater with bortezomib and thalidomide than with lenalidomide. Now that we have the ability to administer bortezomib subcutaneously, we are able to reduce the risk and severity of PN associated with this agent.5 Baseline assess-

so as to balance treatment efficacy with patient comfort.

How do you manage common AEs associated with frontline regimens in the transplant-eligible patient?

Many drugs used in frontline regimens for MM are associated with hematologic toxicities—neutropenia, anemia, thrombocytopenia. Compounding the problem is the anemia associated with the myeloma disease process itself.1 For these reasons, weekly monitoring of blood counts is an essential part of patient care. Monitoring enables us to make adjustments to dosing and to determine whether the initiation of treatment is improving an individual’s myeloma-related anemia.

We also need to monitor metabolic, hepatic, renal, and gastrointestinal (GI) function on a regular basis. Bortezomib, lenalidomide, and thalidomide are associated with diarrhea, nausea, and constipation,2-4 all of which can, in turn, impact quality of life and nutritional status. We ensure that patients

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OCTOBER 2012 I VOL 5, NO 9

Table 1. Suggested Lenalidomide Dose Reductions for Renal Impairment3 Degree of Renal Dysfunction

Renal Function (Cockcroft-Gault CrCl)

Moderate

30-60 mL/min

10 mg orally every 24 hours

Severe (not on dialysis)

<30 mL/min

15 mg orally every 48 hours

End-stage renal disease (on dialysis)

<30 mL/min

5 mg orally every 24 hoursa

Dose for MM

CrCl indicates creatinine clearance; MM, multiple myeloma. a Doses that fall on dialysis days should be given after dialysis.

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CONSIDERATIONS IN MULTIPLE MYELOMA

ment of neuropathy, with follow-up evaluation at every visit, is the best way to ensure that we detect developing PN early. We are then able to modify or discontinue a patient’s dose before symptoms erode his or her functional status. An important part of the neurologic assessment is a review of all medications the patient takes for comorbid conditions, since some of these drugs may also cause or exacerbate PN. These would include certain antihypertensives and anticonvulsants, as well as drugs used to treat rheumatoid arthritis and gout.

Some prophylactic treatment is required with novel therapies. Since herpes zoster virus reactivation is a risk associated with bortezomib use,2 we administer antiviral prophylaxis. When a patient is also treated with dexamethasone, we sometimes provide chemoprophylaxis for fungal and Pneumocystis jirovecii pneumonia infections.7

Table 2. Risk Assessment for VTE Prophylaxis in Patients Treated with Immunomodulatory Agents10-13 Individual Risk Factors

Treatment-Related Risk Factors High-dose dexamethasone ( 480 mg/month or 120 mg/week)

2

Obesity (BMI 30 kg/m ) Previous VTE Central venous catheter or pacemaker Chronic renal disease (CrCl <40 mL/min)

Doxorubicin Combination chemotherapy

Diabetes Medications (erythropoietin, estrogen) Immobility General surgery Trauma (major or lower extremity)

How do you counsel patients and their families before and after ASCT?

In the pretransplant phase, patients need to undergo testing of major organ systems to verify transplant eligibility. It is the nurse’s responsibility to explain the need for these tests. We also discuss the process by which stem cells will be collected and educate patients on the goal of ASCT: to deliver very high doses of chemotherapy, safely, by collecting blood cells ahead of time and then reinfusing them later. Considerable confusion surrounds the word “transplant,” so it is imperative that we explain the ASCT process very carefully to both patients and their families.

Prior to transplantation, a social worker from our team will conduct a psychosocial evaluation of the patient. This assessment is designed to identify patient needs for emotional support, caregiving, housing, financial assistance, and any other matter that could affect recovery. At this time, we may discover that a patient is experiencing anxiety or depression, and we will refer that person for the necessary psycho/oncology services. We may also ascertain that the caregiver needs some support to navigate through these services.

Because we are now performing more transplants in patients aged 65 to 70 years, we must remember to focus on needs related to elderly patients, including psychosocial issues associated with aging, Medicare reimbursement, or the lack of a spouse/caregiver.

Once the transplantation process has begun, nurses must continue counseling and educating patients appropriately. A major issue posttransplant is securing insurance coverage for supportive medications, such as prophylactic antibiotics, antiemetics, or proton pump inhibitors. We work with families to help them manage reimbursement and costs. We also follow patients to ensure that they start the recommended reimmunization process 6 months posttransplant.8 In patients who are ineligible for transplant because of age or comorbidities, what strategies do you use to balance the need for efficacy with the need to prevent AEs?

The nontransplant population today consists mainly of patients who are quite elderly, with poor performance status and marked comorbidities such as cardiac problems, poorly controlled hypertension or diabetes, pulmonary issues, and renal impairment with dialysis. Obviously, any pharmacologic treatment in these patients can be risky. We try to tailor the regimen to the patient’s specific comorbidity in order to manage risk. For example, when renal impairment is present, we will consider a bortezomib-based regimen, because strong evidence suggests that this agent can reverse renal dysfunction in patients with MM.9 In patients receiving immunomodulatory drugs in combination with steroids, it is imperative to provide effective venous thromboembolism prophylaxis when recommended (Table 2).10-13 In the elderly population, an all-oral regimen, such as lenalidomide plus

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Blood-clotting disorders Number of Risk Factors

Prophylaxis

0-1

Aspirin 81-325 mg daily

2+

LMWH (enoxaparin 40 mg SC daily, or equivalent) Warfarin (INR 2-3)

BMI indicates body mass index; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; VTE, venous thromboembolism.

dexamethasone, may be advantageous. Oral therapy means less travel to and from the center for treatments, which is helpful in older patients who may be dependent on family members for transportation. With the use of oral regimens, however, we need to ensure that no factors are present that will predispose a patient to nonadherence, such as dementia or lack of a live-in caregiver.

We always provide medication diaries for patients to help support compliance.

Conclusion

Although current frontline therapies for MM have improved patient outcomes, they require close monitoring and timely action to minimize AEs. Active, prompt nursing intervention is needed to manage the toxicities associated with the use of multidrug regimens, reduce the impact of ASCT, and minimize risks among elderly or vulnerable patients.

References 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-23.

2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012.

3. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012.

4. Thalomid [package insert]. Summit, NJ: Celgene Corporation; August 2010.

5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

6. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15:469-474.

7. Worth LJ, Dooley MJ, Seymour JF, Mileshkin L, Slavin MA, Thursky KA. An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital. Br J Cancer. 2005;92:867-872.

8. Centers for Disease Control and Prevention; Infectious Diseases Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation.

MMWR Recomm Rep. 2000;49(RR10):1-128.

9. Dimopoulos MS, Terpos E, Chanan-Kahn 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.

10. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomideassociated thrombosis in myeloma. Leukemia. 2008;22:414-423.

11. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71.

12. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest.

2008;133(6 suppl):381S-453S. 13. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin prophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:983-993.

OCTOBER 2012 I VOL 5, NO 9

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CONTINUING EDUCATION

Pharmacologic Considerations in the Frontline Treatment Setting Lindsay Hladnik, PharmD, BCOP Clinical Pharmacist, Hematologic Malignancies/SCT Barnes-Jewish Hospital/Washington University Department of Pharmacy St. Louis, MO

Introduction The management of multiple myeloma (MM) is rapidly changing, with novel agents and combination regimens providing improved rates of response and survival. However, to provide optimal benefits for patients, it is imperative to consider factors such as medical comorbidities, treatment-related toxicities, and the inherent, myelomarelated risks of bone disease and thromboembolism. In this article, Lindsay Hladnik, PharmD, BCOP, describes the role of the pharmacist in identifying and addressing the needs of each patient, to individualize drug selection and dosing strategies.

What is the impact of newer dosing forms or schedules on frontline MM treatment?

61% after 4 cycles of treatment.3 In this study, oral cyclophosphamide 300 mg/m2 was given weekly on days 1, 8, 15, and 22; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11; and oral dexamethasone 40 mg on days 1 to 4, 9 to 12, and 17 to 20, in a 28-day cycle. A second cohort of patients were administered a modified regimen in hopes of reducing toxicity while maintaining dose delivery.4 This cohort received the same weekly cyclophosphamide schedule; weekly bortezomib 1.5 mg/m2 IV on days 1, 8, 15, and 22; and the same dexamethasone schedule for cycles 1 and 2, then 40 mg once weekly for cycles 3 and 4. The modified schedule of once-weekly bortezomib demonstrated comparable efficacy, with an ORR of 93%, and a VGPR rate of 60% after 4 cycles of therapy. The once-weekly bortezomib cohort experienced less grade 3/4 toxicities compared with the twice-weekly bortezomib cohort (37%/3% vs 48%/12%). There were also fewer dose reductions of bortezomib (13% vs 21%) and dexamethasone (20% vs 30%). Neuropathy rates were similar (57% once-weekly vs 64% twice-weekly) although the total bortezomib dose per cycle was higher in the once-weekly cohort (6 mg/m2) versus the twice-weekly cohort (5.2 mg/m2). This modified dosing schedule of CyBorD was reported in a small cohort of patients (N=30), but seems to maintain efficacy while offering a more convenient option for patients, possibly increasing therapy compliance, and with less adverse events.

Low-dose dexamethasone plus lenalidomide

Subcutaneous bortezomib

In January 2012, the US Food and Drug Administration approved subcutaneous (SC) administration of bortezomib for the treatment of MM. One of the studies leading to the approval was the MMY-3021 trial, which compared the safety and efficacy of SC versus intravenous (IV) administration of the drug.1 This was an international, multicenter, phase 3, open-label trial that randomized patients with relapsed MM to receive up to 8 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, administered by SC injection or IV push. SC administration was noninferior to IV when assessed for the primary efficacy endpointâ&#x20AC;&#x201D;overall response rate (ORR) after 4 cycles of single-agent treatment (42% in each arm). Rates of complete response (CR), near-complete response, and very good partial response (VGPR) after 4 cycles; ORR after 8 cycles (with or without the addition of dexamethasone); time to response; duration of response; time to progression (TTP); progression-free survival (PFS); and 1-year overall survival (OS) were similar between treatment arms. However, the SC route demonstrated improved tolerability compared with the IV route, especially in terms of peripheral neuropathy (PN) (Table).1 Guidelines for the treatment of MM set forth by the National Comprehensive Cancer Network recognize SC bortezomib as an option for patients with preexisting or high-risk PN.2 This route of administration may also offer a more convenient means of drug delivery for certain patients who have poor venous access, or it may decrease the need for repeated access of a central venous catheter.

32

Lenalidomide combined with low-dose dexamethasone is an acceptable induction option in newly diagnosed MM. The phase 3 open-label, noninferiority ECOG E4A03 trial randomized patients to receive either lenalidomide plus high-dose dexamethasone (RD; oral lenalidomide 25 mg/day on days 1-21 plus oral dexamethasone 40 mg/day on days 1-4, 9-12, and 17-20 of each 28-day cycle) or lenalidomide plus low-dose dexamethasone (Rd; same schedule of lenalidomide plus oral dexamethasone 40 mg/day on days 1, 8, 15, and 22 of each 28-day cycle).5 Despite the fact that the ORR rate (CR + partial response) after 4 cycles was higher with RD versus Rd (79% vs 68%; P=.008), this did not translate into an improvement in TTP, PFS, or OS in the RD arm. The trial was stopped early, and patients were allowed to cross over from the high-dose to low-dose dexamethasone arm because OS was significantly higher with Rd than with RD (1-year OS: 96% vs 87%; P=.0002). This difference was thought to be related to increased toxicities seen with RD versus Rd, including deep vein thrombosis/pulmonary embolism (26% vs 12%; P=.0003) and infections (16% vs 9%; P=.04). The

Table. Incidence of Peripheral Neuropathy in the Phase 3 MMY-3021 Trial1 SC Bortezomib (N=147), N (%)

IV Bortezomib (N=74), N (%)

P Value

Any peripheral neuropathy

56 (38%)

39 (53%)

.044

Once-weekly bortezomib

Grade 2

35 (24%)

30 (41%)

.012

One of the induction regimens we use at our institution is the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), based on results from a phase 2 study showing an ORR of 88%, with a VGPR rate of

Grade 3

9 (6%)

12 (16%)

.026

OCTOBER 2012 I VOL 5, NO 9

IV indicates intravenous; SC, subcutaneous.

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CONSIDERATIONS IN MULTIPLE MYELOMA

incidence of early mortality within the first 4 months was 5% with RD and 0.5% with Rd (P=.003). Rd may be preferred over RD for induction in patients 65 years of age, given the fact that the inferior survival outcome with high-dose dexamethasone was greater in this age group.

What are your strategies for initiating bisphosphonate support for patients with MM?

Bone involvement is common in myeloma, and it is extremely important to prevent skeletal-related events in this patient population, in hopes of maintaining quality of life and performance status. Bisphosphonate therapy is recommended for all MM patients with lytic destruction of bone or compression fracture of the spine from osteopenia detected on plain radiographs or imaging studies.6 It is reasonable to initiate therapy in patients with osteopenia but without evidence of documented lytic bone involvement.6 Acceptable options for therapy include pamidronate 90 mg IV over at least 2 hours or zoledronic acid 4 mg IV over at least 15 minutes, every 3 to 4 weeks. Therapy may be continued for a 2-year duration. Further use should be at the physician’s discretion and on an individualized basis.6 The initiation of bisphosphonate therapy is not recommended in patients with a solitary plasmacytoma, smoldering/indolent myeloma, or with monoclonal gammopathy of undetermined significance.6 Patients must have their renal function monitored during bisphosphonate therapy, including a serum creatinine prior to each dose, as zoledronic acid and pamidronate have both been associated with renal deterioration.6 The dose of zoledronic acid should be adjusted in patients with mild-to-moderate renal impairment (creatinine clearance [CrCl]) 30-60 mL/min) per the manufacturer’s package insert.7 With pamidronate, no dosing guidelines are available for patients with preexisting renal impairment.8 Guidelines published by the American Society of Clinical Oncology (ASCO) recommend that healthcare professionals consider a dose reduction of the initial pamidronate dose in this setting.6 Neither the package labeling for zoledronic acid nor pamidronate recommend the use of these agents in patients with severe renal impairment.7,8 Patients with a serum creatinine >3 mg/dL were excluded in studies and limited pharmacokinetic data exist in patients with a CrCl <30 mL/min.7,8 However, in this population, ASCO guidelines state that pamidronate 90 mg IV over 4 to 6 hours may be administered to patients with extensive bone disease in the setting of existing severe renal impairment.6 In the setting of renal deterioration, bisphosphonate therapy should be withheld and further work-up initiated.

Other considerations during bisphosphonate therapy include the risk of developing osteonecrosis of the jaw. Prior to initiating bisphosphonate therapy, it is recommended that patients undergo a comprehensive dental examination and preventive dentistry.6 Active oral infections should be appropriately treated and areas at high risk for infection should be eliminated.6 During therapy, patients should maintain good oral hygiene and invasive dental procedures should be avoided, if possible.

What is the pharmacist’s role within the interdisciplinary team in ensuring the safety and efficacy of treatment?

The oncology pharmacist has an integral role among the interdisciplinary team to ensure therapies are being administered in the most safe and efficacious manner possible. The treatment of MM is complex, and therapies continue to evolve as new data become available. It is important for us to help prevent and manage complications and toxicities that are associated with

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treatment. Supportive care issues such as bone health, as previously discussed, along with others such as venous thromboembolism (VTE) prophylaxis and medication dose adjustments for renal dysfunction, are just a few of the issues that need to be addressed by our team.

There are several risk factors, both patient and therapy related, that must be considered when evaluating VTE risk in MM. The International Myeloma Working Group (IMWG) has published guidelines on risk assessment and prophylaxis of VTE in this population.9 These recommendations take into account certain antimyeloma therapies, such as the combination of immunomodulators (thalidomide and lenalidomide) with high-dose steroids, which increase the risk of VTE and warrant prophylaxis, provided contraindications do not exist.

Renal impairment (serum creatinine 2 mg/dL) is common in MM, occurring in approximately 20% of newly diagnosed patients, and in more than 50% of patients some time during the course of their disease.10 Several management strategies have been recommended for MM patients with renal impairment, including hydration; management of hypercalcemia and/or hyperuricemia; avoidance of nonsteroidal anti-inflammatory drugs, loop diuretics, IV contrast, and other potentially nephrotoxic medications.10 When systemic therapy for MM is initiated, however, it is important to evaluate the need for dose adjustment based upon renal dysfunction. Dose adjustments for renal impairment are necessary for agents such as lenalidomide and melphalan. The IMWG has published guidelines for the management of MM patients with renal impairment11 and addresses these issues. Of course, it is also important to evaluate the patient’s entire medication profile and adjust accordingly for the degree of renal impairment.

Conclusion

Advances in frontline therapies for MM have led to improved response rates and survival. Working with the interdisciplinary team to ensure safe and efficacious administration of these therapies is vital to optimize outcomes.

Additionally, the management of supportive care issues are crucial to maintain the best quality of life for our patients.

References 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed October 1, 2012.

3. Reeder C, Reece D, Kukreti V, et al. Cyclophosphamide, bortezomib, and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial.

Leukemia. 2009;23:1337-1341.

4. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417.

5. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group.

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.

6. 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.

7. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. March 2012.

8. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008.

9. Palumbo A, Rajkumar SV, Dimopolous MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

10. Gaballa MR, Laubach JP, Schlossman RL, et al. Management of myeloma-associated renal dysfunction in the era of novel therapies. Expert Rev Hematol. 2012;5:51-68.

11. 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.

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33

Best Practices

Group Visit Proves Highly Satisfying to Breast Cancer Survivors

By Caroline Helwick

Follow-up Clinic Begins 3 Years Postdiagnosis The group medical appointment for breast cancer survivors was initiated at Duke Cancer Center in 2008, adapted from the Centering Healthcare Institute model. Patients who are at least 3 years postdiagnosis attend the clinic together in groups of 6 or 7.

titioner and have access as well to a dietitian, social worker, or physical therapist.

“It is important to make this visit multidisciplinary,” she said. “They are most interested, at this point, in talking with a dietitian,” she added.

Very Satisfied Patients The researchers evaluated the level of patient satisfaction with the model and also determined if there might be a cost benefit to the group visit model.

A 22-item Likert-type questionnaire sought opinions from 122 patients regarding logistics and the style and function of care delivered. Second, a retrospective analysis of clinical financial data on 300 patients was performed. For this, revenues from the group medical visit by the nurse practitioner were compared with those obtained from traditional physician visits.

A review of time to the third available appointment for each clinician was also recorded.

Overall, 98% of the 122 respondents felt the program provided quality care, and 97% were likely to recommend the clinic to other breast cancer survivors.

More than 80% of respondents added comments, with the vast majority being positive. From these comments, several qualitative themes emerged, most strikingly that patients appreciat-

An interdisciplinary group visit format in the front-end of the appointment provides education and support.

An interdisciplinary group visit format in the front-end of the appointment provides education and support.

The first hour includes a review of the patients’ personal care plans and a 45minute facilitated group discussion.

After this, half the patients leave for mammography and laboratory testing, while half remain with the nurse prac-

ed the opportunity to share with other survivors and to receive nursing care with such a high level of attention and professionalism.

“At first I was wary about this program, but only one visit converted me,” one patient wrote. “It felt warm and friendly, versus clinical, which is exactly what I needed.”

Photo from Duke Photography.

A

“group visit” model, led by nurse practitioners, is a feasible and highly satisfactory means of following breast cancer survivors, according to 2 oncology nurse researchers from the Duke Cancer Center’s program.

Kathy J. Trotter, DNP, CNM, FNP-C, and Susan M. Schneider, PhD, RN, AOCN, FAAN, described their breast cancer survivorship clinic at the American Society of Clinical Oncology 2012 Breast Cancer Symposium held in San Francisco, California, in September.1 “The group visit replaces the followup medical appointment. The idea was to offload the medical oncologists so they could see more newly diagnosed and sicker patients,” said Trotter. “This is a billable service that I as a nurse practitioner provide, though oncologists could do this as well.”

“We love it, the patients like it, it works,” she said.

A group meeting for breast cancer survivors, part of the breast cancer survivorship clinic at Duke Cancer Center.

Program Is Cost-Effective The cost-benefit analysis revealed that revenues and direct costs were nearly equal between the 2 delivery models.

A review of time to the third available appointment for the primary referring oncologist dropped from 29.4 days to 26.7 days, while the nurse practitioner’s time remained stable at 8.7 days.

“Our financial manager told me that for each new patient that the oncologist is free to see, that is $8400 [revenue] for our budget,” Trotter said.

“But what is immeasurable is the community value of a center that takes care of its patients. Even though we are not actually making money from this, patients are spreading the word that we are a center that will take care of you.”

William Sikov, MD, of University Medicine in Providence, Rhode Island, led a “poster discussion walk” at the meeting, where he commented on the potential value of this format. He said the patient volume at large medical centers “threatens to swamp the ability of

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OCTOBER 2012 I VOL 5, NO 9

physicians to see patients for follow-up, to the detriment of seeing new patients.

This is an interesting approach.”

Sikov suggested one of the greatest benefits is the group sharing experience in which patients feel the commonality of their condition. “I may have a difficult time convincing the stage I patient with a twinge in her knee that she doesn’t need a bone scan. It is meaningful for patients to hear from around the room that other patients have these symptoms too. They see that certain things really are common.”

Trotter responded that such peer support is part of what the group visit offers. “But my job is to see that we get the correct information out,” she said, “and that patients understand when they don’t need to worry, and when they need to see us right away.” l Reference 1. Trotter KJ, Schneider SM. Evaluation of a breast cancer survivorship clinic that uses a group medical appointment model: patient program evaluation and financial analysis. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 90.

October 4-6, 2013 The Seaport Boston Hotel 1 Seaport Lane Boston, MA 02210

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VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. *The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright Š 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

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Conference News

Highlights From ASCO 2012 Breast Cancer Symposium

By Caroline Helwick

T

he American Society of Clinical Oncology 2012 Breast Cancer Symposium, held September 13-15 in San Francisco, California, offered all members of the cancer team

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

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.

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.

OCTOBER 2012 I VOL 5, NO 9

Barriers to Mammography Screening Among the Underserved Despite the provision of free services, fear of cost, fear of procedural pain, and fear of abnormal findings remain barriers to mammography screening among medically underserved women, according to research from Washington University School of Medicine, St. Louis, Missouri. Investigators evaluated barriers to mammography screening as part of an outreach registry of Breast Health Center patients to determine the effectiveness of mobile mammography among the medically underserved (Abstract 13).1

Fear of cost, fear of procedural pain, and fear of abnormal findings remain barriers to screening.

E. Shelley Hwang, MD, MPH

ACCREDITATION

36

an upfront view of new data and an opportunity for one-on-one interaction with experts in the field. The following are a few research items of interest to oncology nurses.

They surveyed 8739 women, the majority of whom were black (54%), were uninsured (74%), and had an annual income <$20,000 (87%). Three major barriers to mammography screening among this underserved population were identified: fear of cost (40%), fear of mammogram-related pain (13%), and fear of receiving bad news (13%).

Compared with white patients, nonHispanic African Americans were 2 times as likely and Hispanics were 3 times as likely to report being afraid of receiving bad news.

Mammography was most rare among patients living in the Missouri Bootheel geographic area, those without insurance, those from ethnic and racial minority backgrounds, and those who use only mobile mammography services. More breast health education is needed in these populations, the study concluded.

Sexual Dysfunction in Breast Cancer Survivors Patient-perceived sexual dysfunction is a documented consequence of breast cancer treatment that patients feel is not being addressed effectively

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Conference News during routine care, according to the results of a 30-item survey of 75 postsurgical breast cancer patients conducted by Michigan State University researchers (Abstract 67).2 Sixty-four percent of women felt that their cancer treatment had a negative impact on sexual function, and 47% experienced emotional distress because of it. Although 60% expressed a desire to discuss the problem with a physician, only 23% did so. Nearly half of the respondents would like an appointment with a “counselor.”

Treatment was discontinued due to vascular toxicity 3 times more often with tamoxifen (11%) than with an aromatase inhibitor (3%).

Factors that interfered with sexual function were fatigue (76%), dyspareunia (65%), scars (57%), hot flashes (75%), and breast tenderness (75%).

Whereas 42% of lumpectomy patients felt that their surgery had a negative impact on intimate relationships, this figure rose to 70% among mastectomy patients. Interestingly, no significant difference was observed between women who had reconstruction versus those who did not. Sexual dysfunction was independent of age, postoperative interval, and interfering factors.

The authors encouraged providers to address issues of sexual dysfunction during follow-up and to intervene when appropriate.

Vascular Toxicities Do Not Lead to Endocrine Therapy Discontinuations A large retrospective cohort study of 629 postmenopausal women treated with endocrine therapy found a high incidence of vascular toxicities, but a low rate of treatment discontinuations because of this (Abstract 68).3 The vascular toxicities were consistent with those described in published reports: with aromatase inhibitors, an increase in cardiovascular events and hypercholesterolemia; and with tamoxifen, a higher incidence of thrombosis.

Vascular toxicities were observed in 37% of patients receiving tamoxifen and 25% to 35% of patients on aromatase inhibitors. The most common toxicities seen with tamoxifen were peripheral edema (23.2%) and thromboembolic events (7.1%). Patients on

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aromatase inhibitors were also likely to have peripheral edema (19%), as well as hypercholesterolemia (5.4%), arrhythmia (5.2%), and cardiovascular events (4.8%). Preexisting vascular comorbidities significantly increased the risk of developing a new vascular toxicity if the patients were taking letrozole or tamoxifen.

Treatment was discontinued due to

vascular toxicity 3 times more often with tamoxifen (11%) than with an aromatase inhibitor (3%), mostly due to thromboembolic events (7.1% vs 2.9%).

“These results are encouraging and suggest that the risk of vascular toxicities should not preclude selection of the optimal endocrine strategy,” said Susan F. Dent, MD, of the Ottawa Hospital Cancer Centre in Canada.

Metformin May Reduce Risk of Developing Breast Cancer A meta-analysis of published studies found that metformin use in women with diabetes is associated with a 17% lower risk of developing invasive breast cancer (Abstract 25).4 The analysis identified 443 studies, of which 7 (all observational) met study criteria. Diabetic women taking metContinued on page 38

“Quality care is everyone’s business.”

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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Conference News

Highlights From ASCO 2012 Breast Cancer Symposium formin experienced an overall 17% reduction in the risk of breast cancer.

The risk reduction was 25% for those taking the drug for more than 3 years, and 6% when exposure was 3 years or less. Older studies (prior to 1997) also found a greater association.

“Because this finding is based upon

observational studies, it may reflect bias or confounding,” acknowledged Rowan T. Chlebowski, MD, PhD, of the David Geffen School of Medicine at the University of California Los Angeles. “But the finding of a stronger effect size associated with studies of longer duration of met-

formin use and those that had longer observation periods suggest that the finding may be real. If the result is confirmed in prospective studies with a large number of breast cancer events, clinical trials should assess whether metformin can reduce breast cancer risk.”

Statin Use Ameliorates Risk of Bone Metastasis The use of statins was associated with a reduced risk of bone metastases in breast cancer and improved diseasefree survival (Abstract 40).5 The study, by investigators from Albert Einstein Medical Center in Philadelphia, Pennsylvania, was a retrospective review of 841 stage I to III breast cancer patients, stratified according to the use of statins for 3 months or longer. Patients who used statins had a 51% reduction in metastasis to the bone, but not to other sites. Their median disease-free survival was 63.6 months versus 53.9 months among nonusers.

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YOUR QUESTIONS ANSWERED

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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

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

Continued from page 37

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

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.

The use of statins was associated with a reduced risk of bone metastases in breast cancer and improved disease-free survival.

Gentry T. King, MD, explained that the mevalonic acid pathway has been implicated in the promotion of a microenvironment for bony metastasis from breast cancer. The statins, which act on this pathway, have in vitro antineoplastic and antiosteoclast activity against breast cancer through interference with this pathway.

“I would not yet prescribe a statin for the purpose of reducing bone metastasis risk,” he said, “but if patients are already on them, because of the possible protective effect, I would certainly not take the patient off the statin.” l References

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.

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OCTOBER 2012 I VOL 5, NO 9

1. Fayanju OM, Kraenzle S, Drake BF, et al. Barriers to mammography among underserved women in a breast health center outreach program. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 13.

2. Block EA, Zomerlei TA, Keto J, et al. Perceived sexual dysfunction in breast cancer survivors. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 67.

3. Dent SF, Crawley FL, Graham NA, et al. Vascular toxicities of endocrine therapy in early-stage breast cancer: encouraging observations in a nontribal setting.

Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 68.

4. Col N, Ochs L, Springmann V, et al. Metformin and breast cancer risk: a meta-analysis and critical literature review. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 25.

5. King GT, Yun JH, Chae YK, et al. Statin use and the development of bone metastasis in breast cancer patients. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 40.

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

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