journal of hematology oncology pharmacy | december 2012 vol 2, no 4

Journal oF

hematologyoncologyPharmacy™

The Peer-reviewed Forum For oncology Pharmacy PracTiceTm

DECEMBER 2012Vol 2 I No 4

©2012 Green Hill Healthcare Communications, LLC

orIgInal reSearchEarly Access to Investigational Agents through the National Cancer Institute’s Treatment Referral CenterTali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

Evaluation of Pharmacists’ Interventions in Altering Prescribing Patterns for the Treatment of VTE in Patients with CancerVikki M. Steward, PharmD; Hind Hamid, PharmD;Kimberly Hooker, PharmD

revIew artIcleChemotherapy-Induced Diarrhea: Options for Treatment and PreventionElizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

From the LiteratureConcise Reviews of Studies Relevant to Hematology Oncology PharmacyBy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

WWW.JHoPoNlINE.CoM

superiority

reduction in risk of first sre in 3 individual studies• Breast cancer: 18% vs zoledronic

acid (P = 0.010, superiority)3

• Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3

• Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3

– Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2

– XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma

*Excluding breast and prostate cancer. †P value for superiority.

Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events 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.3

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3

PER

CEN

TAG

E O

F P

ATI

ENTS

WIT

HO

UT

SRE

0 6 12 18 24 303 9 15 21 27

STUDY MONTH

50

30

20

10

70

90

80

100

60

40

0

Median time: 19.4 months

Median time:

8.2 month delay in time to first SRE

27.7 months

XGeVA® delayed the median time to first sre in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1

XGEVA® 120 mg Q4W (n = 2,862)zoledronic acid 4 mg Q4W (n = 2,861)

Hr = 0.83 (95% Ci: 0.76–0.90) P < 0.0001†

Time to first SRE, evaluated in more than 5,600 patients1,2

17%RISK

REDUCTION

preCise ACtionno Dose ADjustments subCutAneous injeCtion

XGeVA® acts precisely to bind to rAnK Ligand, a key mediator of bone resorption, to inhibit osteoclast activity3

XGeVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGeVA® is administered once every 4 weeks as a single, 120 mg subcutaneous injection3

©2012 Amgen inc. All rights reserved. 07/12 64002-r5-V1 G69091-r1-V1 www.XGeVA.com

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 skeletal-related events in patients with multiple myeloma.

importAnt sAfety informAtion

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 hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

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

osteonecrosis of the jaw (onj)• Osteonecrosis of the jaw (ONJ) can occur in

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

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

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

pregnancy• Women should be advised not to become pregnant when

taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

inDiCAtion

Adverse reactions• The most common adverse reactions

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

please see brief summary of prescribing information on the following page.

referenCes: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on file, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

XGEVa®, tHe first AnD onLy rAnK LiGAnD inHibitor to preVent sres

Brief Summary: Consult package insert for complete Prescribing Information

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

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).DOSAGE AND ADMINISTRATION:Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: None.

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

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

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

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling:• Hypocalcemia (see Warnings and Precautions)• Osteonecrosis of the Jaw (see Warnings and Precautions)The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

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

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

• At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more

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

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

Severe Mineral/Electrolyte Abnormalities• Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less

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

• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

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

Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.The following adverse reactions have been identified during post approval use of Xgeva:• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.

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

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).USE IN SPECIFIC POPULATIONS:Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

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

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information).Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information).Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Pregnancy).Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva.PATIENT COUNSELING INFORMATION:Advise patients to contact a healthcare professional for any of the following:• Symptoms of hypocalcemia, including paresthesias or muscle

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

• Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions)

• Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions)

• Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations)

Advise patients of the need for:• Proper oral hygiene and routine dental care• Informing their dentist that they are receiving Xgeva• Avoiding invasive dental procedures during treatment with XgevaAdvise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

Body SystemXgeva

n = 2841 %

Zoledronic Acid n = 2836

%

GA STROINTESTINAL Nausea Diarrhea

31 20

32 19

GE NERAL Fatigue/ Asthenia

45

46

IN VESTIGATIONS Hypocalcemiab

Hypophosphatemiab

18 32

9

20

NE UROLOGICAL Headache

13

14

RE SPIRATORY Dyspnea Cough

21 15

18 15

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

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

All rights reserved. Printed in USA.

68257-R1-V1

S:6.875”S:9.875”

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117 www.JHOPonline.com l Journal of Hematology Oncology Pharmacy Vol 2, No 4 l December 2012

Editorial Board

CliniCal Controversies

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy ServicesIndiana University Simon Cancer CenterIndianapolis, IN

PraCtiCal issues in PharmaCy management Timothy G. Tyler, PharmD, FCSHP Director of PharmacyComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

original researCh R. Donald Harvey, PharmD, FCCP, BCPS, BCOPAssistant Professor, Hematology/Medical Oncology Department of Hematology/Medical OncologyDirector, Phase 1 UnitWinship Cancer InstituteEmory University, Atlanta, GA

review artiClesScott Soefje, PharmD, BCOPAssociate Director, Oncology PharmacySmilow Cancer Hospital at Yale New HavenYale New Haven HospitalNew Haven, CT

From the literatureRobert J. Ignoffo, PharmD, FASHP, FCSHPProfessor of Pharmacy, College of PharmacyTouro University–California Mare Island Vallejo, CA

Patrick J. Medina, PharmD, BCOPAssociate ProfessorDepartment of PharmacyUniversity of Oklahoma College of PharmacyOklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCPAssociate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

seCtion editors

Co-editors-in-ChieF

Joseph Bubalo, PharmD, BCPS, BCOPAssistant Professor of MedicineOncology Clinical Specialist and Oncology LeadOHSU Hospital and ClinicsPortland, OR

Sandra Cuellar, PharmD, BCOPDirector Oncology Specialty ResidencyUniversity of Illinois at Chicago Medical CenterChicago, IL

Sachin Shah, PharmD, BCOP Associate ProfessorTexas Tech University Health Sciences CenterDallas, TX

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy PracticeSamford University McWhorter School of PharmacyBirmingham, AL

John M. Valgus, PharmD, BCOP, CPPHematology/Oncology Senior Clinical Pharmacy SpecialistUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Daisy Yang, PharmD, BCOP Clinical Pharmacy SpecialistUniversity of Texas M. D. Anderson Cancer CenterHouston, TX

editors-at-large

Nominate a pharmacist at TheOncologyPharmacist.com/award

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Nominate a pharmacist before December 31, 2012. The 6 leading nominees will be profiled online and in the February issue of The Oncology Pharmacist. Vote for the winner at TheOncologyPharmacist.com/award. The winner will be announced at the 2013 Hematology/Oncology Pharmacy Association (HOPA) meeting, March 20–23, 2013 in Los Angeles, CA, and profiled in the April 2013 issue of The Oncology Pharmacist.

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Table of ConTenTs

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Com munications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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ORIGINAL RESEARCH120 Early Access to Investigational Agents through the National Cancer Institute’s Treatment Referral Center Tali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

132 Evaluation of Pharmacists’ Interventions in Altering Prescribing Patterns for the Treatment of VTE in Patients with Cancer Vikki M. Steward, PharmD; Hind Hamid, PharmD; Kimberly Hooker, PharmD

REvIEw ARtICLE143 Chemotherapy-Induced Diarrhea: Options for Treatment and Prevention Elizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

From the Literature153 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

Publishing sTaff

Mission sTaTeMenTThe Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed jour-nal founded in 2011 to provide hematolo-gy and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal oF

HEmAtOLOGyONCOLOGyPHARmACy™

The Peer-reviewed Forum For oncology Pharmacy PracTiceTm

DECEMBER 2012 VoluME 2, nuMBER 4

ORIGINAL RESEARCH

120 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2012 l Vol 2, No 4

Although medical oncology has furthered effec-tive cancer treatment for many decades, finding effective treatment for patients with advanced

cancer is challenging. Millions of dollars support public-ly funded cancer research every year, and patients expect that the latest cancer research will bring us one step closer to discovering a cure.

Instances often exist when patients have exhausted all standard therapies, and they are ineligible for any active research studies. The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD) has a long history of providing early access to investiga-tional agents for patients with cancer for treatment or for

nonresearch use. DCTD, as an investigational new drug (IND) sponsor for dozens of agents, may approve early access to investigational agents that (1) show evidence of therapeutic activity in a specific cancer diagnosis and (2) have reasonably acceptable risks of toxicity. Treatment use is frequently referred to as “compassionate use,” “expanded access,” “treatment IND,” or “single-pa-tient IND,” and is regulated under 21 Code of Federal Regulations Part 312, subpart I.1,2

The NCI’s Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program DCTD, distributes investigational agents through multi-ple protocol mechanisms. Although the following mech-anisms differ somewhat, all of them require adverse event reporting as a basic requirement of IND sponsorship.

One such mechanism was the Group C designation

Dr Johnson is Senior Clinical Research Pharmacist and Mr Boron is Senior Clinical Research Pharmacist at the National Cancer Institute, National Institutes of Health, Rockville, MD.

Early Access to Investigational Agents through the National Cancer Institute’s Treatment Referral CenterTali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

Background: The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD), as an investigational new drug sponsor, may provide early access to investigational agents for treatment use. Until recently, the NCI had 3 protocol mechanisms for distributing investigational agents through the Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program of the NCI’s DCTD. The first mechanism is the Group C protocol, the second mechanism is the TRC protocol, and the third, and most common, mechanism is the Special Exception protocol. Objectives: The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011. Methods: Capital Technology Information Services performed PMB data mining for all treat-ment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception.Results: More than 60% of requests were either referred or approved between 2000 and 2011. The peak number of requests was 1664 between 2000 and 2011 and occurred in 2003. The peak was mostly a result of Special Exception requests; however, more than 400 TRC requests and 20 Group C requests were approved that year. The total number of requests dropped precipitously after 2003, and since 2008 have totaled fewer than 50 annually. All Group C and TRC protocols were completed by March 2006. The lowest number of treatment use requests occurred in 2011. Conclusion: Providing agents through the Special Exception mechanism is one way that prom-ising investigational new drug agents can get to patients with life-threatening illnesses. In general, the PMB’s TRC is a useful drug information resource for sites conducting clinical research in oncology, and it provides a valuable service to the oncology community.

J Hematol Oncol Pharm. 2012;2(4):120-127.www.JHOPonline.comDisclosures are at end of text

Early Access to Investigational Agents through the NCI

121 www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 2, No 4 l December 2012

Table 1 Special Exception Procedures Checklist

****SPECIAL EXCEPTION PROTOCOL CHECKLIST****

Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require the fol-lowing steps to be completed as indicated:

****Statement of Investigator (FDA 1572), Supplemental Investigator Data Form (IDF), and Financial Disclo-sure Form (FDF): A physician must be registered with the National Cancer Institute as an investigator by having completed a “Statement of Investigator” (FDA Form 1572), IDF, and FDF. A copy of the most recent Curriculum Vitae is also needed. If the physician’s NCI investigator registration is not current and the Form 1572, IDF, and FDF have been faxed to the NCI, then they must be followed by the signed originals within 10 working days.****

Protocol: A brief protocol must be submitted, for each patient, which describes the treatment plan, expected adverse events, efficacy, and monitoring procedures. For your convenience we have devised a standard protocol form, which is included. After completion, the original must be returned to the address below within 10 working days of receipt of the investigational agent.

Institutional Review Board (IRB) Approval: You must obtain Institutional Review Board Approval before treating your patient and retain documentation of this approval in the patient’s medical records.

Informed Consent: You must obtain a written informed consent, which must be signed by the patient or their guardian prior to treatment. The informed consent does not need to be forwarded to NCI, but should be retained in the patient’s medical records. For certain agents we also provide a Model Informed Consent to be used as a guideline to writing your own.

Final Patient Report: Upon completion of therapy you must provide NCI a report of the treatment experience, which describes any adverse events and efficacy. We have enclosed The Report of the Independent Investigator form OR other Data Collection Forms, to be used. These forms can be returned to the NCI by fax at 301-402-4870 or mail.

NCI must also be notified, in writing, if the patient is NOT treated under the Special Exception Protocol, with a brief explanation.

Adverse Events: Adverse events should be graded by the Common Terminology Criteria for Adverse Events, and then reported to the NCI via Adverse Event Expedited Reporting System (AdEERS). The procedure for reporting the adverse event is dependent on the grading, the attribution, and if the event is expected or unexpected. All life-threatening and fatal (grade 4 and 5) adverse events should be reported via AdEERS. If this grade 4 and 5 adverse event is not listed on the agent-specific toxicity list (ie, unexpected), then the investigator should also call the Investigational Drug Branch at 301-230-2330. Grade 2 and 3 unexpected events and any serious event leading to hospitalization should also be reported via AdEERS. Computer-based training and detailed instructions on reporting of adverse events can be found at http://ctep.cancer.gov, and then click on Reporting Guidelines. A summary is also included in this packet. Special Exception Protocol adverse event reporting guidelines should follow those developed for phase 2 clinical trials. Please call the AdEERS Help Line at 301-897-7497 for any problems while submitting adverse event reports.

When reporting in AdEERS use the Special Exception Protocol number as the patient ID in the patient information section.

All Serious Adverse Events must be reported within 10 days of occurrence If the protocol does not appear in the AdEERS application contact the Treatment Referral Center at 301-496-5725 or AdEERSMD at 301-897-7497 or [email protected].

Investigational Drug Accountability: Investigational drug accountability records (enclosed) must be maintained and retained in your records. An authorized representative of the FDA, NCI, or drug manufacturer may inspect these records upon request.

Agent Reorders: Additional agent may be requested by completing the enclosed Clinical Drug Request Form and faxing it to 301-480-4612. You may only order more agent for the patient specifically named on this protocol. The patient’s first name and initial of last name should be indicated on the Clinical Drug Request. Telephone orders will not be accepted.Failure to comply with any of the above procedures may result in suspension of an investigator’s status thus pre-venting or delaying future shipments of all investigational agents.

If there are any questions concerning this packet of information, contact the Special Exceptions Coordinator by phone at 301-496-5725, or by fax at 301-402-4870. If the Coordinator is unavailable, then contact the Special Exceptions Pharmacist at the same numbers.

ORIGINAL RESEARCH


established in 1976 by the NCI, with US Food and Drug Administration (FDA) approval. The agents that were considered worthy of altering the standard of care, but were not yet available commercially, were handled through this program.1,3 Since 1975, the NCI has ap-proved or distributed 21 agents under the Group C pro-tocol mechanism.3,4 The Group C protocol mechanism is no longer active, and the last protocol was closed to ac-crual in 2005. Historically, Group C–designated agents:• Had reproducible efficacy in specific tumor types• Were considered likely to change standard of care

practice• Could safely be administered by a properly trained

healthcare provider• Did not require a specialized supportive care facility

for treatment• Were likely to have a New Drug Application (NDA)

or a Biologics License Application (BLA) approval in the near future.A second mechanism is the TRC protocol. These pro-

tocols are written for medications that show efficacy in a certain disease and can be used in a large population with relative ease of use. Eligibility criteria and study objectives are written simply so as to capture patients who are not eligible for available clinical trials.3,4 TRC agents:• Have highly promising activity in high-priority tumor

types• Have limited availability that necessitates an equitable

distribution system• Have participation generally limited to NCI-designated

cancer centers• May have an NDA or a BLA submitted, but time to

approval and marketing may be delayed.The most common treatment protocol, the Special

Exception protocol, is approved on a case-by-case basis and is written for individual patients.3,4 Special Exception agents:• Vary from patient to patient• Have therapeutic activity in a specific cancer diagnosis • Must have a justification provided by the requesting

investigator• Must have a well-established and acceptable safety profile.

The Cancer Therapy Evaluation Program has received thousands of treatment use requests from mostly domestic investigators, but also some from international investiga-tors. The submitted requests are reviewed and are assigned a disposition within the Cancer Therapy Evaluation Program. Since 1994, 1 or more pharmacists within the PMB served as the point of contact for treatment use re-quests and as a general resource for the oncology research community. The pharmacist reviews the request and asks for additional information if needed. The pharmacist evaluates active studies that may be suitable based on the

patient’s history. If the patient is eligible for 1 or more on-going studies, the investigator is referred to the appropriate studies. If the patient is not eligible for any active studies and the request is justified, then the pharmacist collabo-rates with Cancer Therapy Evaluation Program senior in-vestigators to assess eligibility for one of the treatment use mechanisms. If suitable, the Cancer Therapy Evaluation Program requests approval from the pharmaceutical col-laborator. Once all parties have approved the request, the documentation is authorized, and arrangements are made to send the agent to the investigator so the patient can start treatment as soon as possible.

The Special Exception Checklist (Table 1) outlines the regulatory requirements that the investigator must meet to access a Special Exception protocol. Requests that do not meet the appropriate conditions that are described above are denied.

The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011. It is an update to an article published in 2000 by 4 pharmacists at the Cancer Therapy Evaluation Program.3 Our database query begins in January 2000. The Shalabi and colleagues report ended with a total of 1015 requests for 1999.3

MethodsCapital Technology Information Services performed

the PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception; requests that were not categorized as such were not counted for the analysis, but counted instead as “other.” Request disposi-tion was only prospectively recorded in the PMB database after 2002, when the database became fully functional. Gaps in data from requests before 2002 were completed from internal annual reports that were manually collated at the end of each respective year. All discrepancies were reconciled between paper reports and the PMB database.

ResultsThe results of the database query by request disposi-

tion from January 1, 2000, to December 31, 2011, are displayed by year in Figure 1. The total numbers of an-nual requests by type are displayed in Figure 2. The peak request total for this time period occurred in 2003, with 1664 requests. The peak was mostly a result of Special Exception requests; however, more than 400 TRC and 20 Group C requests were approved that year—more than any other single year in the analysis.

The total number of requests dropped precipitously after 2003, and since 2008 they have totaled fewer than



50 annually. Both bevacizumab and 5-azacitidine were FDA approved in 2004, accounting for 350 TRC protocol requests and 708 Special Exception protocol requests in 2003, respectively. All other Group C and TRC protocols were completed by March 2006 (Table 2). The lowest number of requests through the TRC occurred in 2011.

With the exception of 2011, the PMB either referred or approved more than two thirds of the requests annu-ally between 2000 and 2011. Requests that were counted as “other” came from either the public or healthcare professionals outside of the NCI. Most inquiries involved agent availability and available clinical trials for specific diseases at the NCI. Table 3 provides examples of these inquiries from 2000 to 2011.

DiscussionThe PMB’s TRC has seen a significant change in the

total number of treatment use requests over the past decade. With a peak of 1664 requests in 2003, the PMB currently only receives a few dozen requests for a variety of agents in clinical development. The days of enrolling hundreds of patients into an NCI-sponsored treatment use protocol are in the past, because the requests through

the TRC to provide early access to cancer therapies has diminished.

Of note, the number of FDA-approved oncology agents increased annually, and there is certainly no shortage in the number of practice-changing therapies that emerge from clinical research. Why then the de-crease in requests? Two phenomena are likely respon-sible for this change—a reduced NDA approval time and a smaller number of investigational agents that are either manufactured by the NCI or for which the NCI is the sole source.

Before the Prescription Drug User Fee Act (PDUFA) of 1992, the median time from first NDA submission to FDA approval for new molecular entities and significant bio-

Total Treatment Use Requests, by DispositionFigure 1

1800

1600

1400

1200

1000

800

600

400

200

0

Trea

tmen

t use

requ

ests

, N

Year

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Approvals

Denials

Referrals

Total

725

819

1080

814

395

271

1664

10548 38 41 28

The days of enrolling hundreds of patients into an NCI-sponsored treatment use protocol are in the past, because the requests through the TRC to provide early access to cancer therapies has diminished.

ORIGINAL RESEARCH


logic agents was 2.7 years between 1985 and 1989.5 Since 1992, the approval times gradually decreased, and the most recent 5-year increment (2005-2009) demonstrated a median approval time of 1.2 years.5 Antineoplastic agents in particular have a median approval time of 0.5 years for the same period, and have generally seen reduced times in overall drug development (IND filing to FDA approval) since 1980. This is despite more than a 4-fold increase in the number of antineoplastic agents that have been ap-proved since 1980—11 from 1980 to 1989, 38 from 1990 to 1999, and 47 from 2000 to 2009.5

Based on the timing of the TRC and Group C pro-tocols as shown in Table 2, all of these protocols were closed to accrual approximately the same time as the NDAs were approved. The TRC and Group C protocols successfully bridged the gap between positive clinical trial results and NDA approval, without interfering with marketing approval. Many patients benefited from practice-changing therapies that would not have been otherwise accessible to them.

Early drug development was the mainstay of the NCI’s Cancer Chemotherapy National Service Center, a con-gressionally mandated initiative that was started in 1955.

Its mission was to screen and evaluate novel compounds for the treatment of cancer. By 1976, it was consolidated within the Developmental Therapeutics Program (DTP).6 Over the years, the DTP collected hundreds of thousands of compounds, some of which reached clinical development.6

The NCI was responsible for developing a number of agents with unique mechanisms of action, often with min-imal industry collaboration.7 The NCI’s Frederick facility manufactured agents, and, in a few instances, the NCI was the only source of drug available for clinical research. Although most of the agents that were developed at the NCI were not responsible for the bulk of the treatment requests, 5-azacitidine, developed at the NCI was provid-ed to thousands of patients via the Group C and Special Exception protocols. Table 4 lists agents developed by the NCI that the PMB received Special Exception requests between 2000 and 2011. One of the agents listed in Table 4, chimeric 14.18, has been requested for treatment use from the PMB in the past year for pediatric patients with neuroblastoma. These requests accounted for more than 20% of requests in 2011.

In the past 25 years, pharmaceutical companies have stepped up investment in anticancer drug development,

Treatment Use Requests, by TypeFigure 2

1200

1000

800

600

400

200

0

Trea

tmen

t use

requ

ests

, N

Year

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

SPEX

TRC

Group C

SPEX indicates Special Exception; TRC, Treatment Referral Center.

698

798

1061

1195

729

371

271

10548 38 40 28



resulting in more industry-directed development.8 It is not unheard of for the pharmaceutical company to have a pending NDA approval for the agent of interest, while simultaneously developing it with the NCI, in less preva-lent malignancies. As a result of increased industry focus on cancer drug development, the DCTD holds fewer active INDs. For example, the DCTD held INDs for 200

agents in 1997 compared with approximately 90 agents today.7 As pharmaceutical industry drug development plans become more comprehensive, companies evaluate the need for their own early access programs, and this, along with the ability to prescribe commercially available agents off label, have led to a diminished need for NCI treatment use protocols.

Table 2 TRC and Group C Protocols from 2000 to 2011

Protocol number IND agent Protocol title

Closed to accrual date

Number of accrued patients

NDA approval date

TRC-9701 Nelarabine (506U78)

CPD 506U78 (686673) in patients with relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma

3/10/2006 36 2005

TRC-0201 Oxaliplatin Oxaliplatin (NSC 266046) in combination with 5-FU and leucovorin (FOLFOX4) for patients who have not received prior chemotherapy for advanced CRC

8/5/2004 37 2002

TRC-0301 Bevacizumab A multicenter study of the anti-VEGF mono-clonal antibody bevacizumab plus 5-FU/leuco-vorin in patients with metastatic CRC that has progressed after standard chemotherapy

2/27/2004 350 2004

I91-6 (Group C)

5-azacitidine Guidelines for the clinical use of 5-azacitidine (NSC 102816) in AML

6/29/2005 170 2004

5-FU indicates 5-fluorouracil; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CPD, compound; CRC, colorectal cancer; IND, investigational new drug; NDA, New Drug Application; NSC, National Service Code; TRC, Treatment Referral Center; VEGF, vascular endothelial growth factor.

Table 3 Types of “Other” Inquiries Received at the Pharmaceutical Management Branch

From healthcare professionalsFrom patients through Cancer Information Service Miscellaneous

Availability of investigational agents in the United States and other countries

Available disease-specific clinical trials

IRB requesting guidance for treatment use protocol review

Availability of commercial agents that were formerly investigational at the NCI

List of available agents in NCI development

IRB requesting package insert for former investigational agent

Availability of ancillary commercial agents for active studies

Patient financial assistance for commercial drugs

Private physician’s office requesting name of suitable IRB for cooperative group studies

Nonhuman use request of agents for animal or in vitro studies

Expediting clinical trial screening at NIH Clinical Center

Investigator requesting permission to publish case report using SPEX drug

Temperature excursion data for former investigational agents

Filling prescriptions in the United States from other countries where drug is not available

Local physician request for cooperative group study

Other formulations of active investigational agents

IRB indicates Institutional Review Board; NCI, National Cancer Institute; NIH, National Institutes of Health; SPEX, Special Exception.

ORIGINAL RESEARCH


The PMB TRC pharmacist serves as a drug infor-mation resource for the cancer community inside and outside of the NCI. Not only is this pharmacist the point of contact for PMB-directed drug information questions, but also for relevant inquiries that come through the Cancer Information Service, the NCI’s

community hotline. The types of questions have varied over the years, but they mostly pertain to agent or clin-ical trial availability.

ConclusionsAlthough the activities of the TRC at the PMB have

Table 4 National Cancer Institute Manufactured Drugs

Drug name Pharmaceutical collaborators Outcome and year

17-AAG Pharmacia IND withdrawn 2012

5-azacitidine Pharmion/Celgene FDA approved 2004 (Vidaza-Pharmion/Celgene)

9-Aminocamptothecin (9-AC) Pharmacia IND withdrawn 2005

BL22 IND withdrawn 2008

CAI IND withdrawn 2010

Carboxypeptidase Microbiological Research Establishment (CAMR)/Protherics

FDA approved 2012 (Voraxaze-Protherics/BTG)

Chimeric 14.18 NCI development ongoing (United Therapeutics, Inc)

COL-3 Collagenex Pharmaceuticals, Inc IND withdrawn 2010

Depsipeptide (romidepsin) Celgene FDA approved 2009 (Istodax-Celgene)

Fenretinide R.W. Johnson Pharmaceuticals NCI development ongoing

Flavopiridol (Alvocidib) NCI development ongoing

gp100:209-217(210M) peptide NCI development ongoing

Halichondrin B analog (eribulin) Eisai, Inc FDA approved 2010 (Halaven-Eisai, Inc)

Homoharringtonine IND withdrawn 2008

LMB-2 NCI development ongoing

MART-1:26-35(27L) peptide IND withdrawn 2008

Nelarabine (506U78) GlaxoSmithKline FDA approved 2005 (Arranon- GlaxoSmithKline)

O6-BG NCI development ongoing

PANVAC Therion NCI development ongoing

Proteinase 3:PR1 peptide IND withdrawn 2010

PS-341 (bortezomib) Millennium FDA approved 2003 (Velcade-Millennium)

rF-gp100P209 (recombinant fowlpox-gp100P209)

Therion IND withdrawn 2012

Sodium phenylbutyrate Elan Pharmaceutical Research Corporation/Virium Pharmaceuticals

IND withdrawn 2008

Suramin Parke Davis and Company IND withdrawn 2008

Thymidine IND withdrawn 2004

XL119 (becatecarin, rebeccamycin analog)

Exelixis/Bristol Myers Squibb IND withdrawn 2008

FDA indicates US Food and Drug Administration; IND, investigational new drug; NCI, National Cancer Institute.



decreased over the past several years, the infrastructure at the DCTD is available to meet the demand for larger-scale, expanded-use protocols if necessary. The current trends in the pharmaceutical industry obviate a lot of the need at the present time, but future circumstances may change that as early drug development enters new frontiers.

The DCTD is the IND sponsor for more than 90 investigational agents, a number of which have unique mechanisms of action. As an IND sponsor, the DCTD has the privilege and the responsibility to further develop these agents, especially those that demonstrate positive clinical trial results. Providing agents through the Special Exception mechanism is one way that effective agents get to patients with life-threatening illnesses who may benefit from these agents. The PMB reviews requests serves as the liaison with the pharmaceutical collaborator and coor-dinates with other Cancer Therapy Evaluation Program branches and the requesting investigator. In general, the PMB’s TRC is a useful drug information resource for sites that are conducting clinical research in oncology, and it provides a valuable service to the oncology community.

Clinical pharmacists at sites have a role in the Special Exception process. They can help identify patients who are neither suitable for standard care treatment nor eligi-ble for active clinical trials. As drug therapies grow more complex, clinical pharmacists can assist investigators who are navigating the details and determine the best options for a patient. In addition, pharmacists can be instrumental in preparing the Special Exception proto-col for submission, obtaining Institutional Review Board

approval, securing drug supply, monitoring toxicities, and ensuring patient follow-up.

Special Exception requests for DCTD-held IND agents are directed to the PMB at the Cancer Therapy Evaluation Program. See http://ctep.cancer.gov/branches/pmb/referral_ center.htm for current contact information. n

AcknowledgmentThe authors would like to thank Patricia R. Schettino,

RPh, MS, for her writing assistance.

Author Disclosure StatementDr Johnson reported no conflicts of interest. Mr Boron

has a stock benefit at MedImmune/AstraZeneca through his spouse’s employment.

References1. Wittes RE. Noninvestigational uses of investigational drugs: some implications of FDA’s revised regulations. J Natl Cancer Inst. 1988;80:301-304.2. Food and Drug Administration, HHS. Expanded access to investigational drugs for treatment use. Final rule. Fed Regist. 2009;74:40900-40945.3. Shalabi AM, High J, Edwards MS, Montello M. Obtaining investigational agents from the National Cancer Institute: when clinical trials are not an option. Highlights Oncol Pract. 2000;18:8-14.4. Montello MJ, Greenblatt JJ, Fallavollita A, Shoemaker D. Accessing inves-tigational anticancer agents outside of clinical trials. Am J Health Syst Pharm. 1998;55:651-652, 660.5. Kaitin KI, DiMasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009. Clin Pharmacol Ther. 2011;89:183-188. 6. Monga M, Sausville EA. Developmental therapeutics program at the NCI: molecular target and drug discovery process. Leukemia. 2002;16:520-526.7. Christian MC, Pluda JM, Ho PT, et al. Promising new agents under devel-opment by the Division of Cancer Treatment, Diagnosis, and the centers of the National Cancer Institute. Semin Oncol. 1997;24:219-240.8. Collins M. The NCI Developmental Therapeutics Program. Clin Adv Hematol Oncol. 2006;4:271-273.

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

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

LEARN MORE AT WWW.TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

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

20100 30 4025155

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

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

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

6 monthsmedian PFS

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

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301)

• TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30

minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and

15 (n=148) of a 28-day treatment cycle, up to 6 cycles

• In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150)

Important Safety Information

• Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur

• Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment

• TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

• The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia

Discover the elements of ef� cacy and safety

Single-agent TREANDA tripled median PFS*

TRE-2510b_CLL_A_Ad_JHOP.indd 2 9/10/12 12:48 PM

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

Number (%) of patientsTREANDA Chlorambucil(N=153) (N=143)

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

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

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

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

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

n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]OVERDOSAGE: The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

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

TRE-2511b August 2012

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

TRE-2510b_CLL_A_Ad_JHOP.indd 3 9/10/12 12:51 PM

ORIGINAL RESEARCH


Venous thromboembolism (VTE) is a common comorbidity among patients with cancer. It is often one of the initial signs for the presence of

malignancy, and its presence increases the complexity of patient care within this patient population. Studies have shown that 15% to 20% of all acute VTE cases are associated with malignancy, 2% to 5% of cases are diagnosed concurrently with cancer, and 5% to 10% of cases are diagnosed during a cancer follow-up visit.1 Therefore, VTE is a significant complication affecting

quality of life and patient prognosis. In fact, VTE is known to represent one of the leading causes of death in this patient population,2 and it is discovered at au-topsy in at least 50% of patients with cancer.3,4 This percentage is thought to be underestimated; therefore, it is imperative to recognize this medical problem and to appropriately deploy effective treatment to reduce morbidity and mortality.

The management of VTE among patients with cancer can be problematic for medical oncologists because of the complexity of the cancer process, and because of pa-tient-specific and treatment-related risk factors. Patients with cancer who are aged ≥65 years, are of African American ethnicity, are of female sex, and whose med-ical history includes other comorbid conditions, such as

Dr Steward is Pharmacy Practice Resident, Dr Hamid is Oncology Pharmacy Clinician at the Cancer Center, and Dr Hooker is Clinical Pharmacy Manager, all at DCH Regional Medical Center, Tuscaloosa, AL.

Impact of Pharmacists’ Interventions on Prescribing Patterns for the Treatment of VTE in Patients with CancerVikki M. Steward, PharmD; Hind Hamid, PharmD; Kimberly Hooker, PharmD

Background: Venous thromboembolism (VTE) is a common comorbidity and a significant complication among patients with cancer. Its management can be quite problematic for med-ical oncologists. Guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for 6 months as the preferred treatment, and it is important for the prescribing patterns of medical oncologists to align with these recommendations to ensure optimal patient care. Objectives: The main objectives of this study were to assess the medical oncologists’ pre-scribing patterns for VTE treatment among patients with cancer at DCH Regional Medical Center, to make clinical interventions in an effort to comply with the guideline recommenda-tions, and to assess the impact of these clinical interventions. Methods: A retrospective chart review of patients with cancer who were diagnosed with VTE between January 2010 and June 2010 was conducted to assess their prescribed treatment regimens. Pharmacists made clinical interventions consisting of education to healthcare pro-viders, development of VTE treatment preprinted order forms, and direct recommendations to align prescribing patterns with the preferred guidelines’ recommendation. Thereafter, pro-spective data of medical oncologists’ prescribing patterns were collected during three 5-week segments (15 weeks).Results: Thirty-nine of the 54 patients with cancer in the retrospective chart review met the inclusion criteria. Three (8%) patients were prescribed LMWH monotherapy for the treatment of VTE. After pharmacists’ educational interventions and collaboration with medical oncologists, 70% of patients who were assessed were prescribed LMWH monotherapy (P = .001) in accor-dance with the guidelines’ recommendation for VTE treatment. This desired prescribing pattern decreased to 59% in the absence of a pharmacist’s collaboration. Nevertheless, a significant difference (P <.05) was found for the prescribing of LMWH monotherapy by medical oncologists after pharmacists’ interventions compared with the initial review of such prescribing patterns.Conclusion: This study shows that although initially sporadically prescribed, LMWH monotherapy for VTE treatment in patients with cancer significantly increases after interventions by pharmacists.


Impact of Pharmacists’ Interventions on Prescribing Patterns


obesity, pulmonary, renal, and/or cardiac disease, are at increased risk for VTE.5,6 Chemotherapy or hormone therapy and indwelling central venous catheters, which are often used in the medical oncology setting, also present as clinical risk factors for developing VTE.7 Chemotherapy increases the risk of VTE and recurrent VTE by 6-fold and 2-fold, respectively.8 Specifically, the agents thalidomide and lenalidomide, which are frequently used for the treatment of multiple myeloma and myelodysplastic syndrome, are strongly associated with the risk of VTE.9-11 For patients receiving these agents, prophylactic anticoagulation is typically initiated to lower the incidence of VTE.7,12,13

Although the pathophysiology of thrombosis forma-tion and blood coagulation in patients with cancer has been studied for many years, it remains poorly under-stood. Research suggests that the cause of thrombosis is associated with malignant cells that are potentially secreting procoagulants (cysteine protease that directly activates factor X) and are stimulating the immune system to secrete cytokines that increase coagulopathy.14 Endothelial cell injury and inflammation associated with malignancy can result in coagulation activation and el-evated clotting factors.15 This may explain why patients with cancer exhibit a high rate of resistance to the oral anticoagulant warfarin. In addition, solid tumors com-pressing vessels can cause turbulent blood flow, which increases the risk of coagulation.14

The standard regimen for VTE treatment among the general medically ill patient population typically consists of unfractionated heparin, fondaparinux, or low-molecu-lar-weight heparin (LMWH) for the initial 5 to 10 days, overlapping with warfarin to bridge to subsequent extend-ed anticoagulant therapy (≥3 months).1,7,16 This regimen has been shown to be effective for most patients pending appropriate compliance to therapy. Therefore, it is logical to think of this approach as an appropriate option for a pa-tient with cancer who is presenting with VTE. However, in the recently published American College of Chest Physicians (ACCP) Guidelines (9th edition), the ACCP suggests the use of LMWH extended anticoagulant ther-apy over vitamin K antagonist therapy as the preferred treatment of VTE in patients with cancer.17

LMWHs are favored over other treatment options, because they can conveniently be administered in an out-patient setting and are associated with a reduced risk of developing adverse effects, such as heparin-induced throm-bocytopenia.1 Publication of the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anti-coagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial demonstrated evidence for LMWH superiority over war-farin without increasing the risk of bleeding.18

Patients with cancer exhibit a high rate of resistance to warfarin, and there are other significant issues asso-ciated with the use of warfarin to treat patients with cancer. Variability in dietary intake, potential liver dys-function, and chemotherapy-induced nausea and vomit-ing make it difficult to achieve the target international normalized ratio (INR) of 2.0 to 3.0.1,19

Anticoagulation with warfarin can also be hazardous because the chemotherapy regimens, as well as the supportive therapy, are more likely to have drug interac-tions with oral anticoagulants, thereby altering the dose requirement.19 Therefore, warfarin therapy requires more frequent monitoring than the guidelines’ recommended LMWH monotherapy. Invasive surgical procedures, concomitant radiation therapy, and metastases, partic-ularly those to the brain, often lead to interruption in oral anticoagulation to avoid supratherapeutic INRs and potential hemorrhage.19,20 This interruption in oral anticoagulation therapy can, in turn, place the patient at significant risk for recurrent thrombosis.

Despite the known issues regarding VTE manage-ment in patients with cancer, we hypothesized that the prescribing patterns of the medical oncologists at DCH Regional Medical Center (RMC) do not correspond with preferred treatment guidelines for VTE, but instead mimic treatment options for acute VTE among the medically ill patient population. This study evaluated prescribing practices, while allowing the principal inves-tigator the opportunity to make patient-specific recom-mendations and to provide education for all healthcare providers involved in the care of patients with cancer.

MethodsThis research was a single-center study conducted at

DCH RMC, which is located in Tuscaloosa, AL, and is a community owned, not-for-profit hospital licensed for approximately 600 beds. It is the flagship hospital within the DCH Health System and a major referral center, serving 11 western Alabama counties. Oncology is an area of specialty provided at DCH Cancer Center, a hos-pital-based cancer center affiliated with M.D. Anderson Physicians Network. The research was approved by the DCH Health System Institutional Review Committee in December 2010. Throughout all parts of the study, 4 medical oncologists were staffed at the institution. The

Patients with cancer exhibit a high rate of resistance to warfarin, and there are other significant issues associated with the use of warfarin to treat patients with cancer.

ORIGINAL RESEARCH


principal investigator was a postgraduate year 1 pharma-cy practice resident.

Part 1Part 1 of the study was a retrospective chart review.

Diagnosis-related group (DRG) codes were used to iden-tify all patients with cancer between January 2010 and June 2010 who had a primary or secondary documented diagnosis of VTE. The documented VTE could be either a deep-vein thrombosis (DVT; DRG code 453.4) and/or a pulmonary embolism (PE; DRG code 415.19). Patients were excluded if they met any of the following criteria: age >18 years; diagnosis of benign tumors; diagnosis of myeloproliferative disorders, multiple myeloma, or my-elodysplastic syndrome, as well as any other diagnosis for which thalidomide or lenalidomide was included within the chemotherapy regimen; and laboratory work performed at a facility other than DCH RMC. Data collection included patient demographics, cancer type, documented date of VTE event(s), number of VTE events during part 1 of the study, prescribed VTE treat-ment regimen, length of LMWH therapy (if available), and details regarding warfarin therapy if used within the VTE treatment regimen.

The primary objective of part 1 was to assess whether the prescribing patterns of the medical oncologists corre-sponded with the preferred guidelines for the treatment of VTE in patients with cancer. At the time the study was conducted, the preferred guidelines referred to the most current guidelines published by the American Society of Clinical Oncology, the ACCP, and the National Comprehensive Cancer Network, all of which recom-mend the use of LMWH monotherapy for 6 months.3,21,22

Concomitant use of warfarin within the majority of VTE treatment regimens was anticipated. Therefore, the secondary objective was to evaluate the frequency of optimal INRs among the physician-managed oral antico-agulation therapy. INR collection began 5 to 7 days after initiation of warfarin therapy or once the INR was ≥2.0, and all subsequent INRs were collected for 6 months. The INRs were reviewed and classified as therapeutic (target range, 2.0-3.0) or nontherapeutic (<2.0 or >3.0). Patients receiving thalidomide or lenalidomide as a part of their chemotherapy regimen were excluded, because they were likely receiving prophylactic anticoagulation.

Parts 2 and 3In parts 2 and 3 of the study, the principal investigator

made clinical recommendations for LMWH monothera-py in an effort to establish the evidence-based guidelines’ recommendation as the standard of care at the institu-tion. Specifically, in part 2, both inpatient and outpa-tient oncology VTE treatment preprinted order forms

were developed and approved by the medical oncologists and the DCH Forms Committee. Each form included an indication for LMWH use, dosing information (in-cluding dosage adjustments), duration of therapy, mon-itoring parameters, orders for patient self-administration education, orders for case management and/or medica-tion assistance involvement, and scheduled follow-up visits. The primary objective of part 2 was to help make prescribing LMWH monotherapy more convenient for medical oncologists.

Part 3 of the study consisted of the principal investiga-tor providing an educational series of presentations and newsletter articles to all healthcare providers involved in the care of patients with cancer. The medical oncologists were presented with the results of the part 1 retrospec-tive chart review revealing their prescribing patterns and a detailed explanation of the evidence-based literature supporting the preferred recommendation for the treat-ment of VTE in patients with cancer. The pharmacy and nursing staffs were presented with an overview of VTE among patients with cancer, the preferred treatment recommendation and suggestions on how to identify patients at risk and how to intervene to optimize patient care, and, finally, they were introduced to the inpatient and outpatient VTE treatment preprinted order forms.

Pharmacists were instructed to determine whether or-ders and prescriptions for LMWH were for treatment or for prophylaxis therapy, and to make clinical interventions to ensure optimal dosing and use of the preprinted order forms when appropriate. Furthermore, education involved composing an article for Chemo Savvy, the newsletter for DCH Cancer Center Physicians, as well as another article for P&T News, the hospital’s Pharmacy and Therapeutics Committee newsletter. The primary objective of part 3 was to increase the multidisciplinary team’s awareness of the evidence-based guideline recommendation for VTE treatment among patients with cancer.

Part 4The final part of the study, part 4, was a 15-week pro-

spective period divided into three 5-week segments. The initial 5-week segment consisted of an evaluation of the medical oncologists’ prescribing patterns for the post–ed-ucational intervention-only period. During this segment, any patient with cancer and suspected VTE was reported to the principal investigator by the oncology nursing staff. The principal investigator would then follow the patient to confirm the VTE diagnosis and to collect the treatment regimen that was prescribed by the medical oncologist. Pharmacists did not engage in any collaborative efforts with medical oncologists during this segment.

During the second 5-week segment of part 4, the prin-cipal investigator screened and followed patients with



cancer concurrently with the 4 medical oncologists. If an acute VTE was documented, the principal investigator collaborated with the patient’s medical oncologist re-garding the patient and made a direct recommendation for the guidelines’ preferred treatment, LMWH mono-therapy, as appropriate.

After the second 5-week segment, there was a 3-week dormant period during which the principal investigator discontinued concurrent interventions and collabora-tion with the medical oncologists.

Thereafter began the third and final 5-week segment of part 4. This segment was similar to the second 5-week segment; however, the principal investigator did not discuss the patients with the medical oncologists if an acute VTE was documented and did not intervene re-garding their prescribing patterns. In turn, the medical oncologists did not consult the principal investigator for VTE treatment recommendations. Instead, the principal investigator observed and recorded the medical oncolo-gists’ prescribing patterns. The primary objective of part 4 was to evaluate the impact of the previous clinical interventions. Data collected for each patient in part 4 were the same as previously defined for the retrospective chart review in part 1 of the study.

All data were collected and interpreted by the princi-pal investigator. The hospital statistician and the prin-cipal investigator analyzed the data. Statistical analysis using Pearson’s chi-squared test was performed for non-parametric data to evaluate the impact of the clinical interventions. The P value of significance was .05.

ResultsPart 1

A total of 75 patients were identified through the hospital database search for having a diagnosis of cancer, as well as a diagnosis of VTE, between January 2010 and June 2010. Of these, 54 patients met the inclusion crite-

Patient Population in Part 1Figure 1

75 patients identified through database search

54 patient charts were reviewed

15 were excluded because of: • Insufficientdata • VTEdiagnosisoutside the study period

Study population (part 1)N = 39

VTE indicates venous thromboembolism.

Table 1 Characteristics of Patient Population in Parts 1 and 4

Patient characteristics

Part 1, retrospective

(N = 39)

Part 4, prospective(N = 27)

Age, mean, yrs 66.2 62.9

Male sex, N (%) 24 (62) 11 (41)

Cancer type, N (%)

Bladder 0 (0) 2 (7)

Brain 1 (3) 0 (0)

Breast 2 (5) 0 (0)

Cervical 0 (0) 1 (4)

Colon 4 (10) 5 (19)

Esophagus 1 (3) 0 (0)

Kidney 0 (0) 1 (4)

Leukemia 1 (3) 1 (4)

Liver 1 (3) 0 (0)

Lung 12 (31) 7 (26)

Lymphoma 2 (5) 1 (4)

Ovarian 1 (3) 0 (0)

Pancreas 0 (0) 2 (7)

Prostate 10 (26) 0 (0)

Rectal 0 (0) 1 (4)

Skin 1 (3) 0 (0)

Stomach 2 (5) 2 (7)

Uterine 1 (3) 0 (0)

Othera 0 (0) 4 (15)

VTE event, N (%)

DVT 13 (33) 20 (74)

PE 19 (49) 3 (11)

DVT + PE 7 (18) 4 (15)

Recurrent VTE 6 (15) 3 (11)aOther cancer types include adenocarcinoma of unknown primary origin, hepatobiliary cancers, and Kaposi’s sarcoma.DVT indicates deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

21 met exclusion criteria

ORIGINAL RESEARCH


ria for the retrospective chart review. During the retro-spective chart review, it was discovered that 15 of these patients met the exclusion criteria. Therefore, the study population for part 1 consisted of 39 patients (Figure 1).

Patients within the part 1 study population were predominantly male (62%) and aged 22 to 89 years (mean, 66 years). This population consisted of a variety of cancer types. The 2 types representing the majority of patients were lung (31%) and prostate (26%) cancer. PE was the most prevalent (49%) type of VTE event among the part 1 study population; however, 18% of the patients were diagnosed with a DVT and a PE during the study period. Six patients (15%) experienced a recurrent VTE event during the study period, 5 of whom had the same type of VTE event as before. The characteristics of the part 1 study population are shown in Table 1.

A total of 7 treatment regimens were prescribed by the medical oncologists when managing VTE in the ob-served patients with cancer, including: (1) heparin only; (2) heparin plus warfarin; (3) heparin plus LMWH; (4) heparin, LMWH, and warfarin; (5) LMWH only; (6) LMWH plus warfarin; and (7) inferior vena cava filter only. The LMWH-only treatment regimen represents the guidelines’ preferred recommendation of LMWH monotherapy. Of the 39 patients, 3 (8%) were pre-scribed the guidelines’ preferred recommendation of LMWH monotherapy. The majority (41%) of the part 1 study population received LMWH with concomitant warfarin to bridge into long-term anticoagulation ther-apy (Figure 2).

The vast majority (74%) of patients in part 1 were prescribed a VTE treatment regimen that involved war-farin as a component of their anticoagulation therapy.

INRs were collected for the 6 months immediately after the documented VTE event for those patients, to assess whether they were being maintained within the thera-peutic range of 2.0 to 3.0 for appropriate anticoagulation. The number of INRs collected per patient was inconsis-tent; however, more than 50% of the INRs were non-therapeutic for the heparin plus warfarin treatment reg-imen, and more than 65% were nontherapeutic for the remaining regimens (Figure 3). Of the nontherapeutic INRs, 69% of those obtained were subtherapeutic (INR <2.0), and the highest INR level obtained was 14.8.

Parts 2 and 3The VTE inpatient and outpatient oncology treat-

ment preprinted order forms were approved and imple-mented in February 2011. The educational presentation series was conducted by the principal investigator in January and February 2011, and it consisted of 7 total presentations to the medical oncologists, pharmacists, and nursing staff. Of the 4 medical oncologists, 3 at-tended at least 1 of the educational presentations. The inpatient pharmacists, cancer center pharmacists, and nursing staff each had 2 opportunities to attend an ed-ucational presentation. Approximately 20 pharmacists and 30 nurses attended the educational presentation. In addition, the educational newsletter articles were pub-lished in the February 2011 issue of Chemo Savvy and in the February/March 2011 issue of P&T News.

VTE Treatment Regimens for the Patient Population in Part 1 (N = 39)

Figure 2

LMWH indicates low-molecular-weight heparin; VTE, venous thromboembolism.

LMWH only 8%

LMWH plus warfarin

41%

Inferiorvenacava filter

8%

Heparin only8%

Heparin plus warfarin

20%

Heparin plus LMWH

2%

Heparin, LMWH, and warfarin

13%

INR Levels of Patients with VTE Treatment Regimen Involving Warfarin

Figure 3

INR indicates international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.

100

75

50

25

0

Patie

nts,

%

Heparin plus Heparin, LMWH plus warfarin LMWH, plus warfarin warfarin

Treatment regimen

4654

33

67

34

66

INRtherapeuticlevel

INRnontherapeuticlevel



Part 4The impact of the pharmacists’ interventions was

assessed throughout the 15 weeks of part 4 of the study, which was divided into three 5-week segments. The first 5-week segment consisted of the evaluation of the med-ical oncologists’ prescribing patterns for the post–educa-tional intervention-only period. Of the 12 patients with cancer who were reported to the principal investigator by the oncology nursing staff, 7 patients were screened for VTE, all of whom had a documented VTE (Table 2). Of these patients, 5 (71%) were prescribed the LMWH-only treatment regimen. Compared with the retrospec-tive chart review in part 1, a significant difference (P = .001) was found among medical oncologists’ prescribing of LMWH monotherapy.

Data collected from the second 5-week segment involved direct collaboration with the medical oncol-ogists regarding patient care. A total of 214 patients were screened on the inpatient and the outpatient medical oncology services. Among these 214 patients, 54 patients had a cancer diagnosis, 11 of whom were identified as having had a VTE event (Table 2). Of 11 documented VTE events, 8 (73%) were treated with the LMWH-only regimen, which again was significant (P = .001) compared with part 1 of the study. Only 1 patient

from the initial 5-week segment and 1 patient from the second 5-week segment (14% and 9%, respectively) received therapy with LMWH plus warfarin, which was the most prevalent treatment regimen in part 1.

A 3-week dormant period was allowed before the beginning of the third 5-week segment of part 4 to tran-sition to independent prescribing of VTE treatment by the medical oncologists. In the final 5-week segment, 217 patients were screened on the oncology service and 68 of them were actual patients with cancer. Of

Table 2 Part 4 Patient Population for Each 5-Week Segment

First 5-week segment

Second 5-week segment

Third 5-week segment

Total patients identified, N 12 214 217

Excluded patients, N 2 109 101

Total patients with cancer, N 10 105 116

Total patients with cancer screened for VTE, N

7 54 68

Total documented VTEs, N 7 11 14

VTE indicates venous thromboembolism.

Table 3 Summary of Prescribing Patterns for VTE in Patients with Cancer

Treatment regimens

Part 1 results, retrospective Part 4 results, prospective

Before pharmacist’s intervention

(N = 39)

First 5-week segment,

posteducation onlya

(N = 7)

Second 5-week segment,

pharmacist’s concurrent

interventions (N = 11)

Third 5-week segment, after pharmacist’s concurrent

interventions (N = 14)

Heparin only, N (%) 3 (8) 1 (14) — —

Heparin plus warfarin, N (%)

8 (20) — 1 (9) —

Heparin plus LMWH, N (%)

1 (2) — — 3 (21)

Heparin, LMWH, plus warfarin, N (%)

5 (13) — — 1 (7)

LMWH onlyb, N (%) 3 (8) 5 (71)P = .001

8 (73)P = .001

6 (43)P = .068

LMWH plus warfarin, N (%)

16 (41) 1 (14) 1 (9) 2 (14)

IVC filter only, N (%) 3 (8) — 1 (9) 2 (14)

P <.05.aPeriod between educational presentations to medical oncologist’s and pharmacist’s concurrent intervention.bSignificant difference between prescribing LMWH only in part 1 and in all components of part 4.IVC indicates inferior vena cava; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.

ORIGINAL RESEARCH


the patients with cancer, 14 were found to have had a documented VTE event (Table 2), 6 (43%) of whom had VTE events that were treated with LMWH only. Although still significant, this percentage of LMWH monotherapy treatment regimens prescribed is slightly decreased from when there was a pharmacist’s collabo-ration. A summary of the results of parts 1 and 4 of the study are outlined in Table 3.

DiscussionThis study demonstrates that the medical oncologists

at DCH RMC are receptive to pharmacists’ interven-tions to comply with evidence-based guidelines in the form of education and patient-specific recommenda-tions. This statement is supported by the statistical significance found in the increased prescribing of the guidelines’ preferred recommendation, LMWH mono-therapy, after pharmacists’ interventions compared with previous prescribing patterns (from 8% to 73%). This is important, because patients with cancer are at an increased risk for developing VTE and recurrent VTE. Therefore, medical oncologists should be aware of this evidence to optimize patient care.

There are several strengths to our study. First, the study has used evidence-based recommendations to op-timize patient care. Studies have already demonstrated the effectiveness of 6-month LMWH monotherapy in patients with cancer18,23,24; this is the rationale support-ing the acceptance of this recommendation, which is in accordance with current guidelines.

Second, the assessment of INRs in part 1 for patients who had received warfarin within their VTE treatment regimen is also a strength. Although warfarin has already been shown to present significant problems when used in patients with cancer, collecting these data within our institution demonstrated to our medical oncologists the need to improve anticoagulation therapy in the majority of their patients with cancer. The medical oncologists were the same throughout all parts of the study; however, the methods for monitoring and adjusting warfarin ther-apy varied among medical oncologists. Therefore, the INR data collection was important, because it showed

the results of this nonstandardized physician-managed oral anticoagulation therapy.

Finally, the multidisciplinary education and preprint-ed order forms were vital for this study, because they reinforced the evidence-based guidelines’ recommenda-tion and helped improve adherence to the guidelines in an effort to make this recommendation the standard of care at DCH RMC. In addition, the LMWH on the for-mulary changed during this study, and the education and preprinted order forms helped eliminate confusion about which LMWH to prescribe to the patients with cancer.

LimitationsThe limitations of our study include the possibility of

VTE events not accounted for during the initial 5-week post–educational intervention-only segment of part 4. This is believed to be true, because the identification and the reporting of potential patients were exclusively voluntary for the nursing staff.

Furthermore, because of the multiple tasks involved in caring for patients with cancer, as well as the distrac-tions, it is quite possible that some patients were missed, especially because reporting patients with suspected VTE to the principal investigator was not part of the nurses’ daily routine.

Some VTE events could have been attributed to the presence of central venous catheters, which was also viewed as a limitation to the study, because the primary cause of the VTE event was not investigated.

In addition, the indication for warfarin was not inves-tigated; therefore, warfarin therapy could have been for anticoagulation related to conditions such as atrial fibril-lation or artificial heart valves. However, these patients were not excluded from our study. Finally, given the limitation of being a hypothesis-generated pilot study with a small sample size, a larger confirmatory study to be conducted over a longer duration of time is warranted.

ConclusionsOur future directions include continued pharmacists’

inventions within the area of VTE in patients with can-cer to increase adherence to evidence-based guidelines. This may consist of follow-up educational series for new staff members and reminders for the current staff. Clinical updates should be presented, as appropriate, to keep the staff abreast of the most recent guideline recom-mendations. This study did not evaluate the impact of changing prescribing patterns on the long-term out comes of our patients. Therefore, outcome studies evaluating the 6-month duration of LMWH monotherapy is a future direction. These outcome studies should address the clin-ical validity of adherence to the guidelines’ recommen-dation and determine whether patients at our institution

This study demonstrates that the medical oncologists at DCH RMC are receptive to pharmacists’ interventions to comply with evidence-based guidelines in the form of education and patient-specific recommendations.



experience less bleeding and fewer recurrent VTEs as a result of these educational/intervention efforts.

As pharmacists continue to become more prevalent in the clinical setting, it is imperative that we are aware of this high-risk population and of the appropriate treat-ment. In addition to continued education and interven-tions to the medical staff, patient education can certainly be performed by pharmacists, because the feasibility of long-term self-injections of LMWH remains a practical issue. This study offers a positive contribution to the practice of pharmacy and supplements the existing litera-ture that demonstrates the impact of clinical pharmacists on patient care. n

AcknowledgmentsThe authors would like to express their gratitude to

Timothy Martin, PharmD, Director of Pharmacy; Ariel Anguiano, Jr, MD, Medical Oncologist; Sandy Barger, Oncology Nurse Manager; Robin Tidmore, Medication Assistance Coordinator; Tom Wyatt, Research Statistician; and members of the DCH Residency Advisory Group for their help in the successful completion of this study.

Author Disclosure StatementDr Steward, Dr Hamid, and Dr Hooker have reported no

conflicts of interest.

References1. Er O, Zacharski L. Management of cancer-associated venous thrombosis. Vasc Health Risk Manag. 2006;2:351-356.2. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-634.3. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophy-

laxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505.4. Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the prob-lem and approaches to management. Ann Oncol. 2005;16:696-701.5. Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110: 2339-2346.6. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol. 2009;27:4839-4847.7. Mandalà M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism in cancer patients: ESMO clinical recommendations. Ann Oncol. 2009;20(suppl4):182-184.8. Karimi M, Cohan N. Cancer-associated thrombosis. Open Cardiovasc Med J. 2010;4:78-82.9. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed mul-tiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436.10. Zangari M, Barlogie B, Thertulien R, et al. Thalidomide and deep vein throm-bosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma. 2003;4:32-35.11. Zonder JA, Barlogie B, Durie BG, et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexameth-asone: benefit of aspirin prophylaxis. Blood. 2006;108:403; author reply 404.12. ten Cate-Hoek AJ, Prins MH. Low molecular weight heparins in cancer. Management and prevention of venous thromboembolism in patients with malig-nancies. Thromb Res. 2008;122:584-598.13. Goldsmith M, Whitelaw G, Jewell K, et al. The role of community oncologists in the prevention and treatment of VTE: clinical guidelines and CMS payment policy. Commun Oncol. 2009;6:563-568.14. Zacharski LR. Malignancy as a solid-phase coagulopathy: implications for the etiology, pathogenesis, and treatment of cancer. Semin Thromb Hemost. 2003;29:239-246.15. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treat-ment challenges, and management strategies. Semin Thromb Hemost. 2003;29:247-258.16. McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism. Circulation. 2004;110(9 suppl 1):I3-I9.17. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE dis-ease: Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S-e494S.18. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153.19. Rhodes S, Bond S. A review of the practical advantages of low molecular weight heparin in the treatment of cancer-related venous thromboembolism. Eur J Oncol Nurs. 2008;12:425-429.20. Zacharski LR, Prandoni P, Monreal M. Warfarin versus low-molecular-weight heparin therapy in cancer patients. Oncologist. 2005;10:72-79.21. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S.22. National Comprehensive Cancer Network. Clinical Practice Guidelines in Onco-logy. Venous thromboembolic disease. Version 1.2010. www.nccn.org/professionals/ physician_gls/PDF/vte.pdf. Accessed September 28, 2012. 23. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembo-lism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162:1729-1735.24. Deitcher SR, Kessler CM, Merli G, et al. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12:389-396.

As pharmacists continue to become more prevalent in the clinical setting, it is imperative that we are aware of this high-risk population and of the appropriate treatment.

APPROVED FO

R

SUBCUTANEO

US AND IV

ADMINISTRAT

ION If you defi ne value as an overall survival advantage:VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE

At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)†

At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you defi ne value as defi ned length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you defi ne value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modifi cation or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefi t assessment

Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

Closely monitor patients with risk factors for, or existing heart disease

Acute diffuse infi ltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fl uid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. 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 REACTIONSMost 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 the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233).

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the effi cacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specifi ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signifi cantly 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.

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

VELCADEHCP.COM

3832_milpro_fa3_val_ahdb.indd 1 6/14/12 2:18 PM

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.

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. Printed in USA V-12-0095 6/12

3832_milpro_fa3_val_ahdb.indd 2 6/14/12 2:18 PM


REVIEW ARTICLE

Diarrhea is a well-recognized side effect that is associated with various phases of a patient with cancer’s treatment cycle. Radiotherapy, chemo-

therapy, infection, and graft-versus-host disease can all potentially augment this dose-limiting toxicity. Some regimens, especially those targeting colorectal cancer (CRC) and other malignancies of the gastrointestinal (GI) tract, are associated with an increased incidence of severe or refractory chemotherapy-induced diarrhea (CID). In some studies, CID has been reported as a side effect in up to 82% of patients with cancer, with up to 33% experiencing grades 3 and 4 diarrhea.1 GI toxicity has also been linked to many cases of death and is often an underrecognized and undertreated complication of chemotherapy.2

Severe diarrhea resulting in dehydration, neutro-penia, fever, malnutrition, renal insufficiency, infectious complications, or severe electrolyte imbalances can lead to hospitalization.2 The presence of CID can influence providers to change chemotherapy agents, reduce treat-ment doses, delay therapy, or even to discontinue ther-

apy, leading to potentially worsened clinical outcomes.2 A study by Arbuckle and colleagues demonstrated that grades 1 and 2 diarrhea may lead to an alteration in che-motherapy for 11% of patients, whereas approximately 45% of patients experiencing any-grade CID required dose reduction in chemotherapy.3,4 Although it is well known that CID can result in significant morbidity and mortality, no comprehensive treatment guidelines exist for historically used and newly evaluated medications for the treatment of CID.

Mechanism of Chemotherapy-Induced DiarrheaThe exact mechanism of CID is not completely

understood; however, various theories point to a multi-factorial process resulting in an imbalance between the absorption and the secretion of fluid in the GI tract.5 Other contributing factors, such as diet, concomitant medications, and infectious complications, can en-hance diarrhea in patients with cancer.4 The frequency of CID varies based on the chemotherapy regimen and on the administration schedule.

Mechanism of Fluorouracil-Induced DiarrheaUp to 50% of patients treated with weekly 5-fluoro-

uracil in combination with leucovorin experience CID.6

Fluorouracil therapy results in mitotic arrest and apop-

Dr Koselke is Hematology/Oncology Pharmacy Resident, and Dr Kraft is Hematology/Oncology Clinical Pharmacist and Clinical Assistant Professor, University of Michigan Hospitals and Health Centers, Pharmacy Services, Ann Arbor, MI.

Chemotherapy-Induced Diarrhea: Options for Treatment and PreventionElizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

Background: Chemotherapy-induced diarrhea (CID) is a predictable yet undertreated side effect of several frequently used chemotherapy agents and can lead to delays in treatment and poor quality of life. Although the exact cause of CID is not completely understood, various theories point to a multifactorial process resulting in an imbalance between the absorption and the secretion of fluid in the gastrointestinal tract. Medications such as loperamide and diphenoxylate plus atropine are frequently used along with nonpharmacologic measures to treat mild CID. Objectives: To discuss the currently recommended treatment for CID, as well as other potential medications for the treatment and the prevention of CID. With the emergence of new therapeutic alternatives for severe CID, an update of the current treatment options is warranted.Discussion: Although guidelines exist for the treatment of CID, patient needs often exceed these recommendations. Through different mechanisms of action, medications such as corti-costeroids, antibiotics, glutamine, palifermin, and activated charcoal have been studied for the prevention of CID. For patients with treatment-resistant CID, small clinical trials suggest that probiotics or octreotide long-acting release may be an effective alternative.Conclusion: Further investigations should be conducted with promising therapies for validation before being recommended for guideline inclusion for the treatment of CID.


REVIEW ARTICLE


tosis of the crypt cells in the GI tract.5 Necrosis of this tissue enhances the imbalance of the ratio of immature secretory crypt cells to mature villus enterocytes.7 It also causes bowel wall inflammation, thereby stimulating additional secretion of fluid and electrolytes into the intestinal lumen5 and significantly altering the osmotic gradient in the GI tract, which contributes to the in-creased secretion of fluid into the stool.8

Mechanism of Irinotecan-Induced DiarrheaIrinotecan, a cornerstone in the management of CRC,

with a 2-pronged effect, can induce acute (within 24 hours) and delayed (2-14 days postadministration) diar-rhea.6 Irinotecan is a prodrug converted into its active form, SN-38, both of which are released into the feces by hepatobiliary and intestinal secretions.4 SN-38 is inacti-vated in the liver to SN-38G. As it eventually reaches the intestinal lumen, SN-38G is transformed back into its active form by beta-glucuronidase, an enzyme secret-ed by intestinal microflora, causing direct mucosal dam-age and toxicity.4 Irinotecan also induces the production of prostaglandin E2 and thromboxane A2, inflammatory cytokines, and tumor necrosis factor alpha, all causing additional mucosal damage.4

Additional Drugs Causing Chemotherapy- Induced Diarrhea

Other chemotherapeutic regimens have been associ-ated with diarrhea, although at a considerably lower rate than either fluorouracil or irinotecan. Epidermal growth factor receptor (EGFR)-targeted therapies result in grade 3 or greater diarrhea in <10% of cases.6 Patients treated with EGFR tyrosine kinase inhibitors (eg, erlotinib, gefi-tinib, or lapatinib) experience diarrhea in up to 60% of cases, with grades 3 and 4 diarrhea occurring much less often.6 Unlike irinotecan- and fluorouracil-based regi-mens, EGFR therapies rarely need to be dose-reduced as a result of severe diarrhea.6 The mechanism of CID for these therapies has not been adequately investigated.6

Therapy with ipilimumab, a human monoclonal anti–cytotoxic T-lymphocyte antigen (CTLA)-4 antibody used for the treatment of metastatic melanoma, often results in GI and skin toxicities.9 Weber and colleagues estimated the incidence of grade 2 or greater diarrhea between 32% and 35%.10 Blockade of CTLA-4 in the GI tract causes dysregulation of the mucosal immune sys-tem, resulting in colitis and diarrhea.9 This mechanism of diarrhea is significantly different from fluorouracil or irinotecan and is often not adequately treated with con-ventional therapies.

Assessment of Chemotherapy-Induced DiarrheaCurrently, there is a lack of comprehensive standard-

ized assessment methods for CID.5 The most frequently used criteria for categorizing CID is the Common Terminology Criteria for Adverse Events, which assesses patient symptoms on a scale of 1 to 5 (Table 1).8,11 CID is classified into 2 categories, complicated and uncom-plicated. Uncomplicated diarrhea is defined as patients with grade 1 or 2 diarrhea and no additional signs or symptoms. Complicated CID is classified by patients with grade 3 or 4 diarrhea or patients with grade 1 or 2 diarrhea and 1 additional risk factor, such as moderate- to-severe cramping, grade 2 or greater nausea and vom-iting, decreased performance status, fever, sepsis, neutro-penia, frank bleeding, or dehydration.

Guideline-Recommended Therapy for Uncomplicated Chemotherapy-Induced Diarrhea

The last consensus conference for the management of CID was published in 1998,7 and the resulting guide-lines were last updated in 2004.2 Loperamide, tincture of opium, and octreotide remain the only agents currently recommended by treatment guidelines, because of the lack of data supporting other therapies for CID (Figure).2

These guidelines recommend dietary modification, along with loperamide (4 mg initially, followed by 2 mg every 4 hours or after every unformed stool), as the

Table 1 Common Terminology Criteria for Adverse Events for Diarrhea

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline

Increase of 4-6 stools per day over baseline; moderate increase in ostomy output com-pared with baseline

Increase of ≥7 stools per day over baseline; incontinence; hospi-talization indicated; severe increase in ostomy output com-pared with baseline; limiting self-care activities of daily life

Life-threatening consequences; urgent intervention indicated

Death

Source: Reference 11.

Chemotherapy-Induced Diarrhea


standard first-line therapy for the treatment of uncom-plicated CID (Table 2).2,4,12-21 Patients can discontinue loperamide therapy when they have been free of diar-rhea for at least 12 hours.2

If diarrhea persists for more than 24 hours, high-dose loperamide (2 mg every 2 hours) is recognized as an appro-priate therapeutic option in addition to initiating oral an-tibiotics for the prevention of infectious complications.2

If diarrhea persists for more than 48 hours with high-dose loperamide therapy, loperamide should be stopped and a second-line treatment should be considered when the patient is evaluated by a physician; options include subcutaneous (SC) octreotide, tincture of opium, or oral budesonide.2

LoperamideLoperamide, a synthetic opiate derivative, is the ini-

tial drug of choice for CID; it has reduced the incidence of irinotecan-induced diarrhea from 80% to 9% in sev-eral studies.5,8 Loperamide acts as an antidiarrheal agent by exerting agonistic effects on opioid receptors in the GI tract, resulting in decreased peristalsis and increased fluid reabsorption.5 Loperamide is minimally absorbed and produces a limited side-effect profile.6 Although rare, loperamide can cause a paralytic ileus, and patients should be routinely monitored while using high-dose loperamide.5 Other side effects include abdominal pain, dry mouth, drowsiness, and dizziness.4 Although loper-amide has been proved to be extremely effective in uncomplicated diarrhea, its utility as monotherapy for severe diarrhea is limited.8,22

Tincture of OpiumTincture of opium, like loperamide, works by slowing

GI peristalsis and increasing intestinal transit time.4 No studies have specifically evaluated tincture of opium in the treatment of CID; however, it is frequently used as an antidiarrheal agent and can safely be used as a second-line therapy for refractory diarrhea.4 Common side effects are usually mild and include nausea and vomiting.4

AtropineIn the treatment of irinotecan-induced, acute-onset

diarrhea, atropine monotherapy works as a competitive antagonist at anticholinergic receptors, typically dosed as 0.25 to 1 mg intravenous (IV) or SC.4 Grades 1 to 4 and grades 3 to 4 acute-onset diarrhea are typically seen in 51% and 8% of patients receiving irinotecan infu-sions, respectively.12 In a study by Yumuk and colleagues, 66 patients with metastatic CRC who received irinotec-an were premedicated with 0.5 mg of SC atropine before their infusion. In a total of 444 infusions, acute-onset diarrhea was not seen in any of these patients.12

Diphenoxylate plus AtropineThere are little efficacy data supporting the use of

diphenoxylate plus atropine compared with loperamide for the treatment of CID8; however, one double-blind study comparing these agents suggests that loperamide is the more effective agent.7 In one study of 614 patients who experienced acute diarrhea, the efficacy of lopera-

Proposed Algorithm: Primary Treatment Options for Uncomplicated Chemotherapy-Induced Diarrhea

Figure

Uncomplicated CIDa

aFor grade 3 or 4 (complicated CID), or for grades 1 and 2 CID with additional symptoms, the patient should be medically evaluated.CID indicates chemotherapy-induced diarrhea.Note: This proposed algorithm is based, in part, on Reference 2.

Patient received irinotecan? Atropine

Standard-dose loperamide

Reassess 12-24 hours later; CID unresolved (grades 1-2)

Yes

Ipilimumab-induced CID?

High-dose loperamideand/or

diphenoxylate/atropine combination

Consider steroids; CID unresolved

No


Change to or add on:diphenoxylate/atropine (if not done

before, or tincture of opium)


Consider changing to, or adding, nonguideline-based therapies

Yes

No

REVIEW ARTICLE


mide was compared with diphenoxylate plus atropine.23 Patients were initially treated with loperamide 2 mg or with diphenoxylate 2.5 mg plus atropine 0.025 mg and were instructed to take an additional tablet after each unformed stool. Of patients in the loperamide group, 42% required 2 to 3 tablets to control diarrhea, whereas 2 to 3 tablets of diphenoxylate plus atropine controlled diarrhea in only 23% of patients. Diarrhea was controlled within 24 hours in 47% of patients in the loperamide group compared with 37% of patients in the diphenoxylate plus atropine group. In addition, within the 72-hour study period, fewer tablets of loperamide were required versus in the diphenoxylate plus atropine group (4.37 vs 5.75 tablets; P = .01).23

Diphenoxylate plus atropine can be used in combina-tion with loperamide for the treatment of grade 1 or 2 diarrhea at a dosage of 1 to 2 tablets every 6 to 8 hours.4 Side effects include dry mouth, blurred vision, insomnia, and dyspepsia.4

Guideline-Recommended Therapy for Aggressive Chemotherapy-Induced Diarrhea

Standard- or high-dose loperamide therapy is often unsuccessful in the treatment of aggressive (complicat-ed) CID in 9% to 30% of cases.7,22 Patients experiencing refractory grade 1 or 2 CID, as well as grade 3 or 4 CID can be treated more aggressively with SC octreotide

acetate (100-150 mcg 3 times daily).2 The octreotide dose can be titrated until the symptoms of diarrhea are under control.2 In addition, patients should receive flu-ids and antibiotic therapy according to the guidelines.2 Hospitalization is often required for patients who are unable to be adequately rehydrated orally or those who have other complicating symptoms.1 Antidiarrheal treat-ment should be continued until the patient is symptom free for at least 24 hours.2 Patients experiencing grade 2 or greater diarrhea before a scheduled chemotherapy session should have treatment suspended until complete symptom resolution for at least 24 hours.4

OctreotideOctreotide is a synthetic somatostatin analogue that

regulates intestinal fluid and electrolyte transport.24 Octreotide inhibits the secretion of hormones in the gut, including serotonin, gastrin, insulin, and secretin.24 Through these mechanisms, octreotide increases GI tran-sit time and reduces intestinal secretions.8 Numerous studies have displayed the effectiveness of short-acting SC octreotide for the treatment of CID.25 In a study by Gebbia and colleagues, patients were treated with 500 mcg of SC octreotide 3 times daily compared with oral loperamide 4 mg 3 times daily in patients with grade 3 or 4 diarrhea.26 Complete resolution of diarrhea was seen in 80% of patients receiving octreotide compared with only

Table 2 Dosing Guidelines for Selected Medications

Medication Suggested dosing guidelines

Loperamide 4 mg orally initially, then 2 mg every 4 hrs or after every unformed stool; can increase to 2 mg every 2 hrs if needed2

Deodorized tincture of opium (10 mg/mL) 10-15 drops in water orally every 3-4 hrs3

Atropine 0.25-1 mg IV or SC3

Diphenoxylate/atropine 1-2 tablets by mouth every 6-8 hrs3

Octreotide 100-150 mcg SC 3 times daily, or 25-50 mcg/hr by continuous infusion4

Budesonide 9 mg by mouth daily, or 3 mg by mouth 3 times daily13,14

Glutamine 0.3 mg/kg IV daily, or 20 g by mouth daily15,16

Celecoxib 400 mg by mouth twice daily12

Octreotide LAR 30-40 mg SC every 28 days17

Probiotics (Lactobacillus rhamnosus GG) 1-2 × 1010 by mouth twice daily18

Activated charcoal 250 mg by mouth every 8 hrs19

Kampo medicine 7.5 mg by mouth 3 times daily20

Palifermin 40 mcg/kg IV daily21

IV indicates intravenous; LAR, Long-acting release; SC, subcutaneous.Sources: References 2-4, 12-21.



30% of patients treated with loperamide (P <.001).26 A dosage of SC octreotide 100 to 150 mcg 3 times

daily has been shown in clinical trials to reduce grades 3 and 4 CID by 60% to 95%.1 As of the last revision (in 2004), the guidelines recommend a dose of 100 to 150 mcg of SC octreotide 3 times daily or 25 to 50 mcg hour-ly by continuous infusion.2 This dose can be increased up to 0.5 mg 3 times daily until diarrhea is under control.2

A study by Goumas and colleagues evaluated 100 mcg versus 500 mcg of SC octreotide in patients with grades 3 or 4 diarrhea after loperamide failure.27 Patients treated with 500 mcg had significantly more symptom control than those treated with the 100-mcg dose (approxi-mately 90% vs 61%, respectively; P <.05), with a similar side-effect profile.2 Drawbacks for the use of octreotide include the administration of SC injection and a high cost profile.8 Side effects of SC octreotide include GI symptoms and, rarely, injection-site reactions.4

AntibioticsWidespread inflammation and necrosis in the bowel

predisposes patients to infections from opportunistic pathogens, especially if they are immunocompromised or neutropenic.5 Increased epithelial permeability, as well as a reduced immune system, enable microflora to translocate out of the GI tract, predisposing patients to potential life-threatening gram-negative sepsis.4 The guidelines suggest the initiation of antibiotics for pa-tients who are experiencing diarrhea for more than 24 hours for the prevention of septic complications.2 An oral fluoroquinolone, such as ciprofloxacin, for 7 days, has been recommended by the Independent Panel for Management of Chemotherapy-Induced Diarrhea.2,4

Nonguideline-Based TherapiesBudesonide

Budesonide, an oral, topically active synthetic gluco-corticoid, provides anti-inflammatory activity within the intestines.4,13 Historically, budesonide has been used as an anti-inflammatory agent in the treatment of inflam-matory bowel disease (IBD). Of note, when patients with irinotecan-induced diarrhea underwent colonoscopy, findings were similar to those seen in patients with IBD.13 Budesonide decreases inflammation through the inhi-bition of mucosal prostaglandins within the intestines, restoring mucosal function and leading to intestinal fluid absorption.4 With a 90% first-pass effect in the liver, budesonide presents an improved safety profile compared with traditional oral glucocorticoids.14

In a study of 21 patients with loperamide-refractory diarrhea, budesonide decreased the severity of grade 3-4 diarrhea by at least 2 grades in 86% of patients treated with irinotecan.13 The dosage studied in this trial was 9

mg, given once daily for 3 to 5 days, starting the day of chemotherapy. Most patients saw a reduction in diarrhea within 24 to 48 hours.13 A second study evaluated the effects of budesonide (3 mg 3 times daily) in patients with advanced CRC.14 Patients in the budesonide arm expe-rienced a shorter duration (1.8 vs 4.2 days, respectively) and fewer episodes (0.7 vs 2.2, respectively) of diarrhea than patients receiving placebo. Patients treated with budesonide also required fewer doses of loperamide (24.9 vs 36.2 capsules, respectively). Although findings were not statistically significant, a trend toward clinical im-provement with budesonide therapy was demonstrated.14

Budesonide prophylaxis has been studied in the pre-vention of severe colitis, a common adverse effect of therapy with ipilimumab. However, Weber and col-leagues found no difference between the treatment arms of ipilimumab plus budesonide or ipilimumab plus placebo in patients with grade 2 or higher diarrhea (33% vs 35%, respectively).10 Likewise, Berman and colleagues demonstrated that prophylactic oral budesonide did not prevent GI toxicity in patients undergoing treatment with ipilimumab.9 The authors theorized that the lack of effect was a result of insufficient amounts of budesonide reaching the distal colon.9

Corticosteroids in Ipilimumab-Induced ColitisAlthough ipilimumab-associated colitis did not show

response to prophylaxis with oral budesonide, response has been demonstrated with drug withdrawal and with systemic steroid administration.9,28 In 676 patients who were treated with ipilimumab for metastatic melanoma, the most common immune-related adverse event was diarrhea, with up to 32% of patients experiencing any grade of CID.29,30 Thirty-four patients experienced grade 3 to 5 enterocolitis.30 Of these patients, 29 (85%) were treated with high-dose corticosteroids (≥40-mg predni-sone equivalent daily), with a median dose of 80 mg daily of prednisone or an equivalent.29,30 Complete resolution was seen in 74% of patients treated with steroids, 3% of patients improved to grade 2 severity, and 24% did not improve their Common Toxicity Criteria (CTC) score.30 Ipilimumab’s package insert recommends the dis-continuation of therapy in patients experiencing severe enterocolitis and the initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg daily of prednisone or an equiv-alent.30 When CID improves to grade 1 or less, steroids can be tapered over a duration of at least 1 month. Trials have shown that rapid steroid tapering can result in the recurrence or the worsening of CID in some patients.30

GlutamineGlutamine, the most abundant amino acid in the

body, serves as oxidative fuel for enterocytes.22 It is es-

REVIEW ARTICLE


sential for normal intestinal structure, and it enhances nutrient transport in the GI tract.4 Over time, marked glutamine depletion develops in patients with cancer, enhancing the incidence and the severity of diarrhea. It has been proposed that glutamine supplementation may aid in protecting the gut mucosa from toxic chemother-apeutic agents.

In a randomized, double-blind, crossover study, Li and colleagues evaluated the prophylactic effect of glutamine in 54 patients with GI cancer.31 Patients were admin-istered 20 g of IV alanyl-glutamine dipeptide (0.3 g/kg daily) on day 1 of chemotherapy and continued therapy for 5 days. Nausea and vomiting, as well as diarrhea, decreased significantly in patients treated with gluta-mine (P <.05). A 2001 study by Daniele and colleagues demonstrated that 18 g of oral glutamine daily increased intestinal absorption (P = .02) and decreased intestinal permeability (P = .04) to a greater extent than placebo in patients with CRC.16 Although the exact mechanism and extent with regard to decreasing CID remain uncer-tain, these studies have shown promise for patients with CID who are undergoing treatment for GI cancer.16,31

COX-2 InhibitorsClinical trials suggest that diarrhea may be induced

by the overproduction of thromboxane A and prosta-glandins in the GI tract.32 The body uses cyclooxygenase (COX), an enzyme found in normal tissue, to convert arachidonic acid into prostaglandins.32 The prostaglan-din PGE2 stimulates mucous and chloride secretion from the epithelial cells in the colon, leading to significant diarrhea.22 In preclinical data, both COX-2 and PGE2 levels increased in a direct relationship to diarrhea inci-dence in rats given irinotecan.22 In this trial, celecoxib, a COX-2 selective inhibitor, at doses of ≥10 mg/kg daily was shown to reduce PGE2 levels, ameliorate diarrhea, and reduce weight loss while enhancing the anticancer effect of irinotecan.22

However, in a study by Maiello and colleagues, 81 patients with advanced CRC were randomized to receive

FOLFIRI or FOLFIRI plus celecoxib.33 Celecoxib was given continuously as a 400-mg twice-daily dose starting on the first day of chemotherapy.33 No significant toxicity differences were seen between groups. Although preclini-cal trials suggest that celecoxib may be beneficial in alle-viating CID, human studies have yet to show significant benefit of adding celecoxib to traditional chemotherapy.

Long-Acting OctreotideIn the GI tract, octreotide suppresses gastric emptying

and inhibits active chloride secretion in the small intes-tine, allowing for water and electrolyte reabsorption.25 Octreotide long-acting release (LAR) is the intramus-cular form of octreotide, which is slowly released over a period of 4 to 6 weeks.25 A case series by Rosenoff and colleagues evaluated 3 patients with severe refractory diarrhea who were treated with 30 mg of octreotide LAR every 28 days.34 All 3 patients experienced prompt resolution of diarrhea, improved quality of life, and com-pletion of full-dose chemotherapy.34

In regard to the dosing of octreotide LAR, data sup-porting the use of 30-mg versus 40-mg dosing every 28 days has not been convincing.17 In the STOP trial, an open-label, randomized multicenter study by Rosenoff and colleagues, 147 patients with active or previous CID were randomized to receive 30 mg or 40 mg of octreotide LAR every 28 days.17 The primary end point was the pro-portion of patients with grade 3 or 4 diarrhea during the study period; secondary end points included the number of patients requiring IV fluids or changes in chemother-apy dosage, as well as a quality-of-life survey.17 Although fewer patients in the 40-mg treatment group experienced CID (48.4% vs 61.7% in the 30-mg group), differences did not reach significance (P = .14); however, with both dosages, the amount of CID was reduced significantly, because all patients experienced CID with previous cycles. The authors concluded that although octreotide LAR can be used safely and effectively for CID, no spe-cific prophylactic dosing recommendations (30 mg vs 40 mg) can be made at this time.17 Octreotide is generally reserved as a second-line treatment of CID after patients fail treatment with loperamide, based on the increased drug cost of octreotide.6 Octreotide LAR could be con-sidered for patients with refractory CID as a part of their CID management when other alternatives fail.17

ProbioticsProbiotics, nonpathogenic microorganisms such as

Lactobacillus rhamnosus, Lactobacillus acidophilus, and bifidobacterium, have been extensively studied in the pre-vention of diarrhea associated with irritable bowel syn-drome and Crohn’s disease.4,6 The possible mechanisms of action include providing a protective physical barrier

Octreotide is generally reserved as a second-line treatment of CID after patients fail treatment with loperamide, based on the increased drug cost of octreotide. Octreotide LAR could be considered for patients with refractory CID as a part of their CID management when other alternatives fail.



from infectious bacteria, degrading carcinogens, and pro-ducing anti-inflammatory effects on the bowel mucosa.35 One clinical trial assessed the efficacy of Lactobacillus rhamnosus GG in reducing fluorouracil-induced CID in patients with CRC.18 L rhamnosus GG was administered orally twice daily at a dosage of 1 to 2 × 1010 daily for 24 weeks. A significant reduction in grade 3 to 4 diar-rhea (22% vs 37% in the control group, respectively; P = .027) was seen with probiotic therapy.18 In addition, decreased abdominal discomfort and fewer dosage reduc-tions in chemotherapy were seen with the use of probi-otics.18 Immunocompromised patients should, however, be cautious of severe infections, such as sepsis, resulting from the use of probiotics.4 In that trial, no blood cul-tures from any of the patients grew Lactobacillus during the study period18; however, case reports have identified probiotics as a source of clinical bloodstream infections, especially in immunocompromised patients.36

Activated CharcoalActivated charcoal, an adsorbent, has been used in

the acute treatment of drug overdoses and poisonings.4 Its use as a prophylactic CID agent presents mechanistic potential, because it decreases enterohepatic cycling and increases SN-38 (irinotecan’s toxic form) clearance from the gut.6 A 2008 study by Sergio and colleagues evaluated the use of activated charcoal prophylaxis in children who were receiving a chemotherapy regimen of irinotecan plus either cisplatin plus doxorubicin (N = 20) or carboplatin (N = 2).19 Activated charcoal was given as a 250-mg capsule starting the evening before chemotherapy and every 8 hours thereafter until the end of the cycle.19 Loperamide was given at the onset of diarrhea (2 mg every 2 hours). Twenty-eight events of diarrhea were recorded, with a frequency of 28.88% in the activated charcoal group and 71.42% in the control group (P = .002).19 Grade 3 diarrhea was significantly more frequent in the control group (42.85% vs 2.22%, respectively). Children in the activated charcoal group completed their chemotherapy cycles more often, and compliance was nearly doubled. No significant adverse events to activated charcoal were reported in this trial.19

Michael and colleagues completed a similar study of activated charcoal in adults.37 Patients received 5 mL of aqueous Charcodote (1000 mg activated charcoal) plus 25 mL of water the evening before and subsequently every 8 hours for 48 hours postirinotecan chemotherapy during their first cycle.37 The patients then served as their own control, and they received no activated charcoal during their second cycle. Grade 3 to 4 diarrhea was present in 7.1% versus 25% of patients in cycles 1 and 2, respec-tively. The use of loperamide increased to more than 10 tablets in 25% of patients and in 54% of patients in cycles

1 and 2, respectively. The patients received 98% of their planned chemotherapy in the first cycle as opposed to only 70% in the second cycle. Again, activated charcoal was well tolerated and had excellent patient compliance.37 In these 2 trials, prophylactic use of activated charcoal has shown decreased grades 3 and 4 diarrhea and loperamide use, while optimizing the amount of irinotecan that could be administered.19,37 A phase 3, randomized controlled trial should be considered to validate these results.

NeomycinIrinotecan-induced diarrhea is enhanced by the in-

testinal bacterial production of beta-glucuronidases, causing the transformation of SN38-G into its active form, SN-38.38 Several trials have evaluated the use of neomycin, a poorly absorbed aminoglycoside antibiot-ic, in its effect in treating CID through the reduction of intestinal microflora.39 In patients with CRC who are experiencing delayed-type diarrhea after their first irinotecan cycle, 1000-mg neomycin 3 times daily was administered for 2 days before and for 5 days after their second cycle.39 Of the 7 patients in the trial, 5 expe-rienced no diarrhea after the second treatment course with neomycin (P = .03).39 Fecal cultures did not reveal any neomycin-resistant or pathogenic microorganisms. In addition, neomycin did not alter the plasma kinetics of SN-38 or irinotecan, and thus did not alter the effica-cy of chemotherapy.39

Another study evaluated the combination of neomy-cin 25,000 IU plus bacitracin 2500 IU dosed 1000 mg 3 times daily for days 2 to 5 and days 16 to 19 of each cycle.40 All 15 patients with diarrhea in the first cycle had complete resolution of diarrhea for cycles 2 to 4.40 Neomycin was also studied as a prophylactic regimen at a dose of 660 mg 3 times daily for 3 days, starting 2 days before receiving irinotecan (350 mg/m2 once every 3 weeks).41 The overall incidence, severity, and duration of diarrhea were not statistically significant between the neomycin arm and placebo (P = .33); however, neomycin did show a 45% lower incidence of grade 3 delayed-onset diarrhea and a reduced duration of di-arrhea by 0.9 days.41 The variation seen among trials could result from a difference in the treatment dose and duration of neomycin.

CefpodoximeDespite the potential risk for antibiotic-induced di-

arrhea, a number of antibiotics have shown promise in decreasing the incidence and the severity of CID.4 The third-generation cephalosporin, cefpodoxime, possess-es the benefit of eliminating Escherichia coli, a known beta-glucuronidase producer, while not eradicating the anaerobes that are important for intestinal coloniza-

REVIEW ARTICLE


tion. A phase 1, prospective, pediatric study performed by McGregor and colleagues investigated if this oral cephalosporin would allow for the dose escalation of irinotecan.42 In this study, 17 patients were treated with escalating levels of irinotecan starting at 20 mg/m2 per dose, the previously established maximum tolerated dose, for days 1 to 5 and days 8 to 12 of a 21-day course. Cefpodoxime (10 mg/kg daily, divided twice daily) was given to patients starting 2 days before chemotherapy and was continued as long as the patient was participat-ing in the study.42

This study demonstrated that with the addition of cefpodoxime, the maximum tolerated dose of irinote-can could be increased to 30 mg/m2 per dose; however, diarrhea and diarrhea-associated dehydration remained the major dose-limiting toxicities when doses exceeded 30 mg/m2. Although prolonged administration of antibi-otics may have the ability to increase the incidence of infections, none were demonstrated in this trial.42 Based on these results, further trials with cefpodoxime in chil-dren and adults are warranted and are under way.

Levofloxacin plus CholestyramineFlieger and colleagues hypothesized that the combina-

tion of cholestyramine, a bile acid chelator that reduces enterohepatic recirculation, plus levofloxacin to inhibit beta-glucuronidase production would be beneficial in patients with CID.43 Of patients with colorectal adeno-carcinoma, 51 were treated with levofloxacin 500 mg daily and cholestyramine 4 g 3 times daily beginning the day before irinotecan administration and continu-ing for 3 days thereafter. The treatment of acute-onset diarrhea and delayed-onset diarrhea with standard doses of atropine and loperamide, respectively, was offered if necessary. Of the total patients in this trial, 78% report-ed no diarrhea. Only 22% of patients developed grade 1 to 2 diarrhea, 2% developed grade 3 diarrhea, and no patients developed grade 4 diarrhea.43 This prospective study illustrated that intestinal microflora suppression in combination with the reduction of enterohepatic recir-culation of active chemotherapy provides suppression of diarrhea to well below the normal incidence of 40%.43 In addition, the short duration of antibiotic therapy supports a prompt recovery time of intestinal microflora, thereby decreasing potential adverse effects.

Kampo Medicine (Hangeshashin-To)Hangeshashin-to (TJ-14) is a Chinese herbal product

that is used in the treatment of acute gastroenteritis and that contains baicalin, a beta-glucuronidase inhibitor.44,45 Based on same mechanistic theory proposed for the use of oral antibiotics, TJ-14 may reduce active SN-38 concen-trations in the intestine.44 A randomized, single-center

trial by Mori and colleagues was conducted to investigate if the administration of TJ-14 would prevent and control CID.20 The trial included 41 patients with advanced non–small-cell lung cancer who were treated with irino-tecan and cisplatin.20 The patients in the treatment arm were given TJ-14 at a dose of 7.5 g 3 times daily begin-ning more than 3 days before chemotherapy.20 Treatment with TJ-14 continued for a minimum of 21 days after the start of treatment with irinotecan plus cisplatin.20 Loperamide was administered to patients with severe di-arrhea (grade ≥2). All but 2 patients (95%) in the TJ-14 group experienced some grade of diarrhea; however, the treatment arm did show an improved overall grade of diarrhea (P = .044) and a significantly lower incidence of grades 3 and 4 diarrhea (P = .018).20 The frequency and duration of diarrhea between the groups showed no difference. The major side effect of TJ-14, constipation, occurred in 11% of patients.20

PaliferminPalifermin, a recombinant form of human keratino-

cyte growth factor (KGF), has been approved to reduce the incidence and the duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy that requires hemato-poietic stem-cell support.46 The binding of KGF to its receptor results in the proliferation and differentiation of epithelial cells in multiple tissues, including the buc-cal mucosa, esophagus, stomach, and small intestine.46 Gibson and colleagues tested the efficacy of palifermin as an antidiarrheal agent in rats that were treated with irinotecan chemotherapy.47 One large dose (10 mg/kg) of palifermin was compared with multiple small doses (3 mg/kg daily for 3 days) or with placebo before adminis-tration of chemotherapy. The animals receiving palifer-min prophylaxis had less severe diarrhea (single dose, 5%; multiple dose, 11%; and placebo, 28%; P <.05) in addition to maintaining their body weight.47

In a study by Rosen and colleagues, 64 patients with metastatic CRC being treated with fluorouracil plus leucovorin were receiving palifermin (40 mcg/kg) for 3 consecutive days before 2 chemotherapy cycles.21 Although the incidence of severe mucositis in patients treated with palifermin was half that of the placebo control group (P = .016) and reduced the need for che-motherapy dose reductions, the incidence of diarrhea did not differ between the groups.21 Grade 2 or higher CTC was observed in 20% of patients receiving placebo and in 18% of patients receiving palifermin during cycle 1.21 The most common adverse reactions to palifermin include skin toxicities (ie, rash, erythema) and oral toxicities (ie, reversible tongue thickening and tongue discoloration and alteration in taste).46



Other Treatments for Chemotherapy-Induced DiarrheaAlthough not included in this review because of lim-

ited human data and the severity of side-effect profiles, thalidomide, cyclosporine, and racecadotril have been considered and have been used in limited studies as treatment options for CID.

ConclusionAlthough guidelines exist for the treatment of CID,

patient needs often exceed these recommendations. The majority of the clinical trials discussed in this article were limited by their small population size and their short-term follow-up. Further investigation should be conducted with promising therapies for validation before recommendation for guideline inclusion. Furthermore, with the emergence of new therapeutic alternatives in patients with severe CID, an update to the current treat-ment guidelines is warranted. n

Author Disclosure StatementDr Koselke and Dr Kraft reported no conflicts of interest.

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rhea: results of the STOP trial. J Support Oncol. 2006;4:289-294.18. Österlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97:1028-1034.19. Sergio GC, Felix GM, Luis JV. Activated charcoal to prevent irinotecan- induced diarrhea in children. Pediatr Blood Cancer. 2008;51:49-52.20. Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of kampo medicine (hangeshashin-to) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2003;51:403-406.21. Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral muco-sitis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006;24:5194-5200.22. Yang X, Hu Z, Chan SY, et al. Novel agents that potentially inhibit irinotecan- induced diarrhea. Curr Med Chem. 2005;12:1343-1358.23. Dom J, Leyman R, Schuermans V, Brugmans J. Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 8: clinical investigation. Use of a flexible dosage schedule in a double-blind comparison of loperamide with diphenoxylate in 614 patients suffering from acute diarrhea. Arzneimittelforschung. 1974;24:1660-1665.24. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100(9 suppl):2026-2046.25. Prommer EE. Established and potential therapeutic applications of octreotide in palliative care. Support Care Cancer. 2008;16:1117-1123.26. Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loper-amide in the treatment of diarrhea following chemotherapy. Anticancer Drugs. 1993;4:443-445.27. Goumas P, Naxakis S, Christopoulou A, et al. Octreotide acetate in the treat-ment of fluorouracil-induced diarrhea. Oncologist. 1998;3:50-53. 28. Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277-286.29. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.30. Yervoy (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.31. Li Y, Ping X, Yu B, et al. Clinical trial: prophylactic intravenous alanyl-gluta-mine reduces the severity of gastrointestinal toxicity induced by chemotherapy— a randomized crossover study. Aliment Pharmacol Ther. 2009;30:452-458. 32. Fakih MG, Rustum YM. Does celecoxib have a role in the treatment of patients with colorectal cancer? Clin Colorectal Cancer. 2009;8:11-14.33. Maiello E, Giuliani F, Gebbia V, et al. FOLFIRI with or without celecoxib in advanced colorectal cancer: a randomized phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM). Ann Oncol. 2006;17 (suppl 7):vii55-vii59. 34. Rosenoff SH. Octreotide LAR resolves severe chemotherapy-induced diarrhoea (CID) and allows continuation of full-dose therapy. Eur J Cancer Care (Engl). 2004;13:380-383.35. Miller AC, Elamin EM. Use of probiotics for treatment of chemotherapy- induced diarrhea: is it a myth? JPEN J Parenter Enteral Nutr. 2009;33:573-574.36. Salminen MK, Tynkkynen S, Rautelin H, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of lactobacillus rhamnosus GG in Finland. Clin Infect Dis. 2002;35:1155-1160.37. Michael M, Brittain M, Nagai J, et al. Phase II study of activated charcoal to prevent irinotecan-induced diarrhea. J Clin Oncol. 2004;22:4410-4417.38. Schmittel A, Jahnke K, Thiel E, Keilholz U. Neomycin as secondary prophylaxis for irinotecan-induced diarrhea. Ann Oncol. 2004;15:1296.39. Kehrer DF, Sparreboom A, Verweij J, et al. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res. 2001;7:1136-1141.40. Alimonti A, Satta F, Pavese I, et al. Prevention of irinotecan plus 5-fluorouracil/leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol. 2003;14:805-806.41. de Jong FA, Kehrer DF, Mathijssen RH, et al. Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. Oncologist. 2006;11:944-954.42. McGregor LM, Stewart CF, Crews KR, et al. Dose escalation of intravenous irinotecan using oral cefpodoxime: a phase I study in pediatric patients with refrac-tory solid tumors. Pediatr Blood Cancer. 2012;58:372-379.43. Flieger D, Klassert C, Hainke S, et al. Phase II clinical trial for prevention of delayed diarrhea with cholestyramine/levofloxacin in the second-line treatment with irinotecan biweekly in patients with metastatic colorectal carcinoma. Oncology. 2007;72:10-16.44. Sharma R, Tobin P, Clarke SJ. Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol. 2005;6:93-102.45. Kase Y, Hayakawa T, Takeda S, et al. Pharmacological studies on antidiarrheal effects of hange-shashin-to. Biol Pharm Bull. 1996;19:1367-1370.46. Kepivance (palifermin injection) [package insert]. Thousand Oaks, CA: Amgen; 2012.47. Gibson RJ, Bowen JM, Keefe DM. Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats. Int J Cancer. 2005;116:464-470.


FROM THE LITERATURE

n Enzalutamide Prolongs Overall Survival in Prostate Cancer after Chemotherapy Background: The once-daily oral androgen receptor signaling inhibitor enzalutamide differs from current antiandrogen therapies by its ability to inhibit nuclear translocation of the androgen receptor and its coactiva-tor recruitment, in addition to other benefits in prostate cancer. This novel agent is administered without the need for concomitant prednisone, which has been pos-tulated to activate androgen-receptor signaling.

Design: In this phase 3, double-blind, placebo-con-trolled clinical trial, enzalutamide significantly prolonged survival in patients with castration-resistant prostate cancer (CRPC) after standard chemotherapy. A total of 1199 men with CRPC who had received chemotherapy were randomized in a 2:1 ratio to oral enzalutamide 160 mg daily or to placebo. The primary end point was overall survival (OS).

Results: Based on the study design, the trial was stopped when 520 deaths occurred, and an interim analy-sis was conducted. At that point, the OS was not reached with enzalutamide. The median OS was 18.4 months in the group receiving enzalutamide (confidence interval [CI], 18.3-not reached) compared with 13.6 months with placebo (CI, 11.3-15.8). Enzalutamide was significantly (P <.001) superior to placebo in all the secondary end points. These secondary measures showed that 54% of patients who received enzalutamide had reduced pros-tate-specific antigen (PSA) levels by more than 50% versus by 2% in the placebo group; the quality-of-life re-sponse rate was 43% with enzalutamide versus 18% with placebo; time to PSA progression was 8.3 months versus 3.0 months, respectively; radiographic progression-free survival was 8.3 months versus 2.9 months (hazard ratio, 0.40), respectively; and time to first skeletal-related event was 16.7 months versus 13.3 months (hazard ratio, 0.69), respectively.

The rates of adverse events (AEs) were similar in the 2 groups, with the exception of higher rates of fatigue, diarrhea, and hot flashes reported with enzalutamide than with placebo. In addition, 5 patients (0.6%) had seizures while taking enzalutamide. Of note, AEs of

grade ≥3 occurred 8.4 months earlier with placebo than with enzalutamide—the median time to such events was 4.2 months with placebo and 12.6 months with enzalu-tamide. Enzalutamide is currently being investigated in clinical trials of men with earlier-stage prostate cancer.

Takeaway: The results are impressive and show that enzalutamide is as effective as other second-line therapies for advanced CRPC. Of note, prednisone, a known stim-ulator of androgen receptor and receptor signaling, is not required with this drug, thereby avoiding its AEs. Another valuable result was that the clinical benefits occurred in the presence of castrate levels of testosterone and that androgen-receptor signaling and overexpression play an important role in CRPC. It may be rational to combine enzalutamide and antiandrogens in CRPC, but follow-up studies are needed. Enzalutamide may be added to the other drugs that prolong survival in CRPC. It is clear that enzalutamide has a safer toxicity profile than the cytotoxic drugs mitoxantrone and docetaxel, but it should be used with caution in patients with a history of seizures or those receiving drugs that lower the seizure threshold. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.

n Anastrozole-Fulvestrant Combination Improves Overall Survival in Metastatic Breast Cancer Background: Fulvestrant downgrades the estrogen re-ceptor and may therefore improve survival in postmeno-pausal women with hormone-receptor (HR)-positive metastatic breast cancer.

Design: The Southwest Oncology Group (SWOG) study randomized 707 postmenopausal patients with pre-viously untreated HR-positive metastatic breast cancer to anastrozole alone or to a combination of anastrozole plus fulvestrant. All patients received 1 mg of anastro-zole; those in the combination group also received a 500-mg loading dose of fulvestrant on day 1, followed by 250 mg on days 14, 28, and every 28 days thereafter. Patients in the anastrozole-alone group whose disease progressed were strongly encouraged to cross over to re-ceive fulvestrant alone. Early in 2011, when the 500 mg of fulvestrant was approved by the US Food and Drug

Concise Reviews of Studies Relevant to Hematology Oncology PharmacyBy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section EditorClinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University-California, Mare Island, Vallejo, CA

FROM THE LITERATURE


Administration, all patients were allowed to receive the 500-mg dose.

Results: In the SWOG study, the median progres-sion-free survival (PFS) was 15.0 months with the combi-nation therapy and 13.5 months with anastrozole alone, representing a significant difference (P = .007); the over-all survival (OS) was 41.3 months with anastrozole alone and 47.7 months with the combination therapy, also a significant difference (P = .049), although 41% of these patients crossed over to fulvestrant after progression. This is the first study of first-line hormone therapy used for HR-positive metastatic breast cancer that shows an improve-ment in OS. It is also the first study to show the superi-ority of concurrent therapy with 2 hormonal modulators over monotherapy, especially an improvement in OS. Toxic effects were mild and similar between the 2 groups. However, more patients who received the combination therapy discontinued treatment because of toxicity.

Takeaway: Although this study shows a significant difference in PFS for the combination of anastrozole and fulvestrant, the difference was only 1.5 months. The anastrozole group was allowed to cross over to low-dose fulvestrant, which did not improve OS versus the combination group. Three other studies have shown that high-dose fulvestrant after an aromatase inhibitor improved OS. In an unplanned subset analysis in the current study, the greatest benefit was seen in patients previously untreated with tamoxifen. This study con-trasts with another recent study that showed no benefit from the combination of low-dose fulvestrant plus anas-trozole (Bergh J, et al. J Clin Oncol. 2012;30:1919-1925). Mehta and colleagues suggest that further studies should be performed, combining an aromatase inhibitor and high-dose fulvestrant in comparison to an aromatase inhibitor or high-dose fulvestrant alone. Therefore, this study has too many confounding variables, and it is un-clear whether the combination of low-dose fulvestrant plus anastrozole cannot be recommended at this time. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435-444.

n Adding Cetuximab to Chemotherapy Improves Outcomes in Patients with KRAS G13D MutationBackground: Although epidermal growth factor re-ceptor (EGFR) monoclonal antibodies were initially indicated for the treatment of EGFR-expressing meta-static colorectal cancer (mCRC), studies conducted in patients with mCRC have failed to show benefits of the EGFR monoclonal antibodies cetuximab and panitu-mumab for patients with KRAS mutations. About 40% of patients have a KRAS mutation; most frequent muta-tions are G12D (13%), G12V (9%), and G13D (8%).

Design: This new analysis of pooled data from previ-

ously published studies evaluated progression-free sur-vival (PFS), overall survival (OS), and response to therapy using published results from 1378 patients in the 2 randomized clinical trials, CRYSTAL and OPUS. Among the 533 patients (39%) with KRAS mutations, 83 (16%) had the G13D mutation, 125 (23%) had the G12V mutation, and 325 (61%) had other mutations.

Results: Previous comparisons between patients with KRAS wild-type tumors and patients with KRAS muta-tions have not differentiated between subtypes of KRAS mutations, but this analysis shows significant variations in treatment effects in terms of the response rate and duration of PFS in patients with the KRAS G13D mu-tation compared with all the other mutations (including KRAS G12V). There was no significant OS difference between the groups; median OS was 15.4 months with the combination versus 14.7 months with chemotherapy alone (hazard ratio, 0.89; P = .68) in patients with the G13D mutation. Patients with G12V and other muta-tions did not benefit from the combination. However, in the subgroups of patients with the KRAS G13D mu-tation, PFS improved significantly by adding cetuximab to standard chemotherapy, leading to a median PFS of 7.4 months with the combination compared with 6.0 months with placebo (hazard ratio, 0.47; P = .039); similarly, tumor response rate was 40.5% versus 22.0%, respectively (odds ratio [OR], 3.38; P = .042). Of note, patients with the KRAS G13D mutation who received chemotherapy alone had worse outcomes than those with other mutations receiving chemotherapy alone (response rate, 22.0% vs 43.2%; OR, 0.40; P = .032).

Takeaway: This study confirms the results from a previous report by the same authors, indicating that the type of KRAS mutation plays a role in the response of the EGFR inhibitors cetuximab and pantimumab. The results show that tumor response and PFS were significantly bet-ter with cetuximab plus FOLFOX or FOLFIRI in patients with mCRC and KRAS G13D mutation compared with chemotherapy alone. These outcomes were comparable to those of patients with the KRAS wild-type. Of note, patients with KRAS G13D treated with chemotherapy alone had a worse response rate and PFS than patients with other KRAS mutations. However, patients with the G12V mutation treated with the combination had worse OS compared with the wild-type mutation group. Further research is ongoing to determine the mechanism associated with these differences. The lesson is that KRAS mutation subtypes affect the tumor biology of CRC and should be considered in treatment planning. This study suggests that KRAS screening should be broadened to include KRAS subtypes. Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13D tumor muta-tions with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 2012;30:3570-3577.

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BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

Docetaxel Injection, USPFor intravenous infusion only. Initial U.S. Approval: 1996

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID

RETENTION

See full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1)

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6)

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4)

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4)

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4)

• Severe fluid retention may occur 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 REACTIONSMost common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


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

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

INDICATIONS AND USAGEGemcitabine is a nucleoside metabolic inhibitor indicated for:• Ovarian cancer in combination with carboplatin (1.1)• Breast cancer in combination with paclitaxel (1.2)• Non-small cell lung cancer in combination with cisplatin (1.3)• Pancreatic cancer as a single-agent (1.4)

DOSAGE AND ADMINISTRATIONGemcitabine Injection is for intravenous use only.• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8

of each 21-day cycle (2.1)• Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8

of each 21-day cycle (2.2)• Non-small cell lung cancer: 4-week schedule, 1000 mg/m2

over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3)

• Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4)

• Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4)

DOSAGE FORMS AND STRENGTHS• 200 mg/5.26 mL injection vial (3)• 1 g/26.3 mL injection vial (3)• 2 g/52.6 mL injection vial (3)

CONTRAINDICATIONSPatients with a known hypersensitivity to gemcitabine (4)

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

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

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

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

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

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

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

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

ADVERSE REACTIONSThe most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at [email protected], or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2011


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

Oxaliplatin for Injection,powder for solution for intravenous use

Oxaliplatin Injection,solution for intravenous use

Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed

warning.

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

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

who have undergone complete resection of the primary tumor.

• treatment of advanced colorectal cancer. (1)

CONTRAINDICATIONS• Known allergy to Oxaliplatin or other platinum

compounds. (4, 5.1)

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

urticaria, erythema, pruritis, bronchospasm, and hypotension. (5.1)

• Neuropathy: Reduce the dose or discontinue Oxaliplatin if necessary. (5.2)

• Pulmonary Toxicity: May need to discontinue Oxaliplatin until interstitial lung disease or pulmonary fibrosis are excluded. (5.3)

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

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

ADVERSE REACTIONSMost common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

Revised: 04/2011

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

Product of India

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

GUJ DRUGS/G/28/1267

Manufactured by:Hospira Australia LtdMulgrave VIC 3170Australia

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

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

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P12-3707-8.125x10.875-Jul., 12

AVAILABLE FROMHOSPIRA

160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

See Black Box Warning Below

DOCETAXEL INJECTION (10 mg/mL)

2 g/52.6 mL single-dose vial

1 g/26.3 mL single-dose vial

200 mg/5.26 mL single-dose vial

GEMCITABINE INJECTION(38 mg/mL)

For more information, contact your

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

As the complexity of healthcare evolves, we’re doing our part to improve cost savings, optimize workfl ow and enhance patient care.

With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR CLINICIANS—UNIQUE ONCO-TAIN™ VIALS REINFORCE SAFETY1

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

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

1 PVC BOTTOM offers shatter resistance.

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

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

4 PREWASHED VIALS reduce cytotoxic residue.

UNIQUE ONCO-TAIN SAFETY FEATURES



OXALIPLATIN INJECTION(5 mg/mL)

See Black Box Warning Below

OXALIPLATIN INJECTION

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

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

journal of hematology oncology pharmacy | december 2012 vol 2, no 4

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