JHOP December 2014 by The Oncology Pharmacist

December 2014 Vol 4 I No 4

Journal OF

hematology Oncology ™ Pharmacy The Peer-Reviewed Forum for Oncology Pharmacy Practice

Editorial

Pharmacy Practice Opportunities: Is This the Time for Change? Joseph Bubalo, PharmD, BCPS, BCOP Original Research

Prescribing of Low-Molecular-Weight Heparin and Warfarin in Patients with Acute Venous Thromboembolism and Active Cancer David W. Stewart, PharmD, BCPS; Somi Rikhye, MD, MPH; Brian Odle, PharmD; John Bossaer, PharmD, BCPS; Emily Flores, PharmD, BCACP

Assessment of Patients’ Knowledge and Management of Chemotherapy-Related Adverse Effects Thao K. Huynh, PharmD; James A. Trovato, PharmD, MBA, BCOP, FASHP Symptom management overview

Hiccups By Joseph Bubalo, PharmD, BCPS, BCOP From the Literature

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

WWW.JHOPONLINE.COM

For appropriate patients receiving highly emetogenic chemotherapy,

Up to 5 Days of Prevention Begins With a Regimen Including EMEND® (fosaprepitant dimeglumine) for Injection Prescribe EMEND for Injection, a 5-HT3 antagonist, and a corticosteroid for the proven prevention of chemotherapy-induced nausea and vomiting.

EMEND for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information • EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. • Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. • EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Selected Important Safety Information (continued) • Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. • Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. • There have been isolated reports of immediate hypersensitivity reactions, including flushing, erythema, dyspnea, and anaphylaxis, during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. • Coadministration of EMEND for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle.

emendforinjection.com

Major oncology professional society guidelines recommend use of a regimen including EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid starting on Cycle 1, Day 1.1–3,a Selected Important Safety Information (continued)

Selected Important Safety Information (continued)

• The efficacy of hormonal contraceptives (including birth control pills, skin patches, implants, and certain IUDs) may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. • Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. • In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater, were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). • In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

• In clinical trials, EMEND for Injection increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND for Injection should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND for Injection. EMEND increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND for Injection 115 mg followed by aprepitant.

Please see the adjacent Brief Summary of the Prescribing Information. a

Based on the Category 2A level of evidence and consensus. Category 2A: Based upon lower-level evidence, there is uniform National Comprehensive Cancer Network ® consensus that the intervention is appropriate. 2

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed November 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

References: 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189– 4198. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Version 2.2014. Antiemesis. www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Published April 18, 2014. Accessed November 18, 2014. 3. Irwin MM, Lee J, Rodgers C, et al. Putting Evidence Into Practice: Improving Oncology Patient Outcomes. ChemotherapyInduced Nausea and Vomiting Resource. Pittsburgh, PA: Oncology Nursing Society; 2012.

Brief Summary of the Prescribing Information for INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin-1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80 or any other components of the product. Known hypersensitivity reactions include: flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use with Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration with Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration with Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1100 individuals and the overall safety of aprepitant was evaluated in approximately 6500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence ≥1% and greater than standard therapy (n=550) are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 In an additional active-controlled clinical study in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant. A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection.

EMEND® (fosaprepitant dimeglumine) for Injection

Less Common Adverse Reactions: Adverse reactions reported in either HEC or MEC studies in patients treated with the aprepitant regimen with an incidence <1% and greater than standard therapy are listed below: Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, faeces hard, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND ® (aprepitant). The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during post approval use of fosaprepitant and aprepitant. 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. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis. Immune system disorders: hypersensitivity reactions including anaphylactic reactions. DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not induce CYP3A4. Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, two studies conducted with fosaprepitant and oral midazolam, and one study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents CYP3A4 substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT 3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150-mg intravenous on Day 1. An oral aprepitant regimen of 125 mg on Day 1, and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.

EMEND® (fosaprepitant dimeglumine) for Injection

Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. Other Chemotherapeutic Agents: EMEND for Injection should be used with caution in patients receiving other chemotherapeutic agents that are primarily metabolized through CYP3A4 [see Warnings and Precautions]. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide coadministration. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as ↑, decrease as ↓, no change as ↔). Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC ↑ 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8, and AUC ↓ 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC ↑ 1.5-fold A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant. CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure [mean (SD) of 24.3 (± 10.2) mm Hg with fosaprepitant versus 15.6 (± 4.1) mm Hg without fosaprepitant] and resulted in a small further maximum decrease in systolic blood pressure [mean (SD) of 29.5 (± 7.9) mm Hg with fosaprepitant versus 23.8 (± 4.8) mm Hg without fosaprepitant], which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval, beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant up to 1000 mg/kg twice daily (plasma AUC 0-24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to

25 mg/kg/day (plasma AUC 0-24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients with Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC 0-24hr) of 0.7 to 1.6 times the human exposure (AUC 0-24hr = 19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant. Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling (Patient Information)]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the EMEND for Injection regimen. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND ® (aprepitant) and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For more detailed information, please read the Prescribing Information. uspi-mk0517-iv-1408r011 Revised: 08/2014 Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1119216-0002 11/14

Publishing Staff

Senior Vice President, Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Frederique Evans fevans@the-lynx-group.com Associate Editor Lara J. Lorton Copyeditor Hina Khaliq Editorial Assistant Cara Guglielmon Senior Production Manager Lynn Hamilton

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Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

December 2014

Volume 4, number 4

Journal OF

hematology Oncology Pharmacy™ The Peer-Reviewed Forum for Oncology Pharmacy Practice

Table of Contents Editorial 108 Pharmacy Practice Opportunities: Is This the Time for Change?

Joseph Bubalo, PharmD, BCPS, BCOP Original Research 110 Prescribing of Low-Molecular-Weight Heparin and Warfarin in Patients

with Acute Venous Thromboembolism and Active Cancer David W. Stewart, PharmD, BCPS; Somi Rikhye, MD, MPH; Brian Odle, PharmD; John Bossaer, PharmD, BCPS; Emily Flores, PharmD, BCACP

122 Assessment of Patients’ Knowledge and Management of Chemotherapy-

Related Adverse Effects Thao K. Huynh, PharmD; James A. Trovato, PharmD, MBA, BCOP, FASHP departments

Symptom Management Overview 117 Hiccups By Joseph Bubalo, PharmD, BCPS, BCOP From the Literature 128 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Michael Kodada IT Manager Kashif Javaid Administrative Services Team Leader Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications 1249 South River Road – Ste 202A Cranbury, NJ 08512 Phone: 732-656-7935 • Fax: 732-656-7938

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MISSION STATEMENT The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology 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 Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (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 © 2014 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, 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. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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Editorial Board

Co-Editors-In-Chief Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

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

Section Editors Clinical Controversies

Original Research

Practical Issues in Pharmacy Management

Review Articles

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Associate Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University Atlanta, GA Scott Soefje, PharmD, MBA, BCOP Director of Pharmacy University Medical Center Brackenridge Austin, TX

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

From the Literature

Symptom management overview

Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Division of Hematology and Medical Oncology Oncology Clinical Pharmacy Specialist OHSU Hospital and Clinics Portland, OR

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro Universityâ&#x20AC;&#x201C;California Mare Island, Vallejo, CA

editors-At-Large Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Robert Mancini, PharmD, BCOP Oncology Pharmacist PGY2 Oncology Residency Director St. Lukeâ&#x20AC;&#x2122;s Mountain States Tumor Institute Boise, ID

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist The University of Texas M. D. Anderson Cancer Center Houston, TX

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EDITORIAL

Pharmacy Practice Opportunities: Is This the Time for Change? Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine, Division of Hematology and Medical Oncology, Oncology Clinical Pharmacy Specialist, Oregon Health and Science University Hospital, OHSU Hospital and Clinics, Portland

ew guidelines and position statements are being published with increasing regularity from a variety of sources, which impact both clinical and practice issues in oncology patient care. Recent publications affect the management of human epidermal growth factor receptor 2–positive and –negative breast cancer, recognize the effects of obesity on cancer, and standards of practice for clinical pharmacy.1-4 Standardization of care is a prominent goal of guidelines in support of optimal patient outcomes, and although these publications offer useful guidance, it is not infrequent that questions arise regarding our performance with the guidelines currently in place. As the American Society of Clinical Oncology and other organizations put quality initiatives into place, there is concern about how practices will be alerted and operationalize them in a timely manner to support patient care.5 Most practices will be measured against published guidelines, and there are continuous efforts to create specific, measurable goals in the provision of care for patients with cancer illustrating that guideline-level care is being delivered. Two articles in this issue offer important insights into aspects of patient care and associated opportunities for pharmacists. In the article by Stewart and colleagues, we find that evidence-based

Most practices will be measured against published guidelines, and there are continuous efforts to create specific, measurable goals in the provision of care for patients with cancer illustrating that guideline-level care is being delivered. care of venous thromboembolic disease recommendations, which have been well publicized through multiple venues, is still not applied consistently in some practices (see “Prescribing of Low-Molecular-Weight Heparin

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and Warfarin in Patients with Acute Venous Thromboembolism and Active Cancer” on page 110). This article provides baseline numbers, which could be used to support a pharmacy service expansion and assist our busy medical providers in updating venous thromboembolism care. In the article by Huynh and Trovato, we see a timely assessment and discussion of patient education as they follow directions for self-care with the use of targeted antineoplastics (see “Assessment of Patients’ Knowledge and Management of Chemotherapy-Related Adverse Effects” on page 122). In both instances, there is an opportunity for pharmacists to impact patient care and a clear need for additional support for patients. Investigators also are documenting the readiness of pharmacists to take on more responsible roles as part of improving pharmacists’ clinical practice and emphasizing the need to better define clinical practice.6,7 The changing face of healthcare is likely to create many new opportunities, making this a great time to grow your practices. If pharmacists do nothing, it is very likely that other groups of practitioners will step in and fill practice gaps as they appear. The organizations that employ pharmacists have a need for practitioners who can show quality outcomes and the ability to improve patient care. I applaud the efforts of Drs Stewart, Huynh, Trovato, and colleagues, and would encourage other practitioners to step forward and take the opportunity to improve patient care and continue to validate the care currently provided. As you are assessing opportunities, be sure to take advantage of proven processes in the work that has been previously published by your predecessors in pharmacy. Design your systems so they can be measured and are easily reportable. As you review or develop a service, does it encompass the current consensus statements? Do you have baseline outcomes that you can compare your future results against? Think about these and the other individualized components of your projects as you take these steps forward.

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EDITORIAL

Pharmacists are trained in the performance of quality projects, have increased levels of education and practice skills through residency, and sufficient opportunities in daily practice to make a difference,8 as shown by the

Look carefully at your budget and your practice site(s) to see where you can start today. aforementioned articles. Look carefully at your budget and your practice site(s) to see where you can start today. By building quality into every new project, making data and outcomes reportable within increasingly computerized health records, and documenting outcomes, pharmacists can move their practices forward.

Good luck as you move into the New Year. n

References

1. Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2â&#x20AC;&#x201C;negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32:3307-3329. 2. Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014;32:3568-3574. 3. Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2100-2108. 4. American College of Clinical Pharmacy. Standards of practice for clinical pharmacists. Pharmacotherapy. 2014;34:794-797. 5. Coory M, White VM, Johnson KS, et al. Systematic review of quality improvement interventions directed at cancer specialists. J Clin Oncol. 2013;31:1583-1591. 6. Rouse MJ, Vlasses PH, Webb CE; Council on Credentialing in Pharmacy. Credentialing and privileging of pharmacists: a resource paper from the Council on Credentialing in Pharmacy. Am J Health Syst Pharm. 2014;71:1891-1900. 7. Harris IM, Phillips B, Boyce E, et al. Clinical pharmacy should adopt a consistent process of direct patient care. Pharmacotherapy. 2014;34:e133-e148. 8. Flannery AH, Adams VR, Burgess DS. Optimizing postgraduate year 3 training. Am J Health Syst Pharm. 2014;71:1924-1925.

THE WESTIN SEATTLE â&#x20AC;˘ SEATTLE, WASHINGTON

http://pmo-live.com

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Original Research Original Research

J Hematol Oncol Pharm. 2014;4(4):110-114 www.JHOPonline.com Disclosures are at end of text

Background: Malignancy is a significant risk factor for venous thromboembolism (VTE), conferring a 4- to 7-fold increased risk in patients with cancer. Because of its effect on certain tumors, low-molecular-weight heparin (LMWH) has been evaluated as a treatment option for cancer and as an alternative to traditional warfarin therapy in patients with active cancer. LMWH is associated with a reduced recurrence of VTE, fewer adverse bleeding events, and, in some instances, decreased mortality. The American College of Chest Physicians/American Society of Clinical Oncology has recommended LMWH for at least the initial 3 to 6 months when treating VTE in patients with cancer, based on the positive outcomes associated with LMWH. Objective: The purpose of this study was to evaluate physician prescribing patterns for LMWH or warfarin in patients with acute VTE and active cancer. Methods: We conducted a retrospective chart review of hospitalized patients at a community teaching hospital with an affiliated regional cancer center located in a rural area of the United States. Patients included in the analysis had an International Classification of Diseases, Ninth Revision code indicative of any cancer type and a concomitant code for any VTE. The primary outcome was the drug prescribed at discharge for the treatment of VTE. Secondary outcomes included specialty of the prescribing physician, adverse bleeding events, and the need for transfusion. VTE treatment regimen was evaluated using the binomial test, and logistic regression analysis was used to determine correlation of the prescriber’s specialty with the patient’s prescribed regimen. Results: Of 129 patients included in the analysis, 107 (82.9%) were prescribed warfarin compared with 9 (7%) who were prescribed LMWH. Hematologists and oncologists were more likely to prescribe LMWH than general practitioners (odds ratio, 7.8; 95% hazard ratio, 1.5-42). Seven patients had a documented adverse bleeding event and 2 patients required a transfusion. Four of the 7 adverse bleeding events and 1 of the 2 transfusions occurred in the group receiving vitamin K antagonist therapy. Conclusion: Physicians in our system were significantly more likely to prescribe warfarin for acute treatment of VTE in patients with active cancer—despite consistent evidence and multiple evidence -based guidelines recommending treatment with LMWH in this patient population. This was lower than other observations in Canadian populations but may more accurately represent nonteaching centers in the United States, particularly those in rural areas. Specialists in oncology were significantly more likely to prescribe LMWH than generalists.

alignancy has long been recognized as a risk factor for venous thromboembolism (VTE), dating back to the 19th century, when Armand Trousseau diagnosed the syndrome on himself.1 Although the risk for thromboembolism varies based on patients’ cancer type overall, it has been estimated that Drs Stewart, Odle, and Flores are Associate Professors of Pharmacy Practice, and Dr Bossaer is Assistant Professor of Pharmacy Practice, Bill Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN; Dr Rikhye is an Emergency Medicine Physician, Professional Emergency Physician Services, Oakland, MD.

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patients with cancer have a 4- to 7-fold higher risk for thromboembolism than the general population.1-3 Tumor production of hypercoagulable substances (eg, tissue factor and tumor compression of blood vessels) may explain part of the increased risk for VTE associated with malignancy.4 In addition, patients with cancer often have indwelling catheters and receive medications (eg, tamoxifen, bevacizumab, cisplatin, lenalidomide) that increase the risk for thrombosis.5,6 Low-molecular-weight heparin (LMWH) and sulfated non–anticoagulant LMWH have been shown to suppress tumor growth with and without traditional chemotherapeutic agents.7 In addition, intracellular processes

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affecting cancer cell adhesion and migration have been shown to be inhibited with LMWH products.8-12 Enoxaparin has also been shown to suppress cell proliferation in adenocarcinomic epithelial cell lines.13 Because of these targeted effects on specific cancer cells, LMWH derivatives are being evaluated not only for their therapeutic effects, but also as drug delivery vehicles for chemotherapy.14,15 Clinically, LMWH has consistently been shown to decrease rates of recurrent VTE with similar or lower rates of major bleeding compared with traditional vitamin K antagonist (VKA) therapy.16-20 LMWH may also positively impact survival, particularly for patients with less advanced disease progression, presenting a more favorable prognosis.10,21-25 Based on these findings, contemporary guidelines have reached a consensus that patients with cancer should be treated with LMWH long term when diagnosed with VTE.26-28 Despite a large body of evidence, there is still reluctance by physicians to follow guidelines because of subjective fears regarding exposing patients to LMWH for a prolonged period.29,30 Two large studies of patients with cancer and VTE, which were based on 2 large databasesâ&#x20AC;&#x201D;the Multicenter Advanced Study for a Thromboembolism Registry (MASTER) and the Computerized Registry of Patients with Venous Thromboembolism (RIETE)â&#x20AC;&#x201D;featuring a substantial subgroup of patients with cancer (approximately 20% in each registry), noted that significantly more patients with cancer were treated with LMWH than patients without cancer. Those rates, however, were only 30% and 50%, respectively, compared with patients receiving VKA therapy.31,32 To evaluate the dissemination of evidence-based, clinical recommendations in a community teaching setting, we designed a study to evaluate the prescribing rates of LMWH for the long-term management of VTE in patients with active cancer.

Methods This study was conducted in the United States at a single, regional, referral community teaching hospital with an affiliated regional cancer center located in a rural area. After receiving local institutional review board approval, medical records from January 1, 2005, to December 31, 2009, that were listed with an International Classification of Diseases, Ninth Revision (ICD-9) code for any cancer type and a concomitant ICD-9 code for any VTE, were identified and reviewed. Patients were excluded if they received warfarin prior to admission, were given an inferior vena cava filter, were pregnant, had a documented contraindication to anticoagulation at the time of admission, or died during hospitalization. Patients with duplicate events were only included for their initial event.

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Table 1 Reasons for Patient Exclusion Exclusion criteria Patients, N Warfarin prior to admission

Inferior vena cava filter

Death

Contraindication to anticoagulation

Additional data collected included patient demographics; cancer type; VTE type; length of time since cancer diagnosis; serum creatinine measurements; international normalized ratio; platelet count at discharge; history of thrombocytopenia or heparin-induced thrombocytopenia (HIT); specialty of the prescriber; and bleeding events prior to or during admission. The principal outcome of this study was the primary maintenance of anticoagulant prescribed at the time of discharge. LMWH prescribed as a short-term bridge for chronic warfarin therapy was classified as warfarin (VKA group), and LMWH therapy prescribed as the primary maintenance regimen was classified as LMWH (LMWH group). Secondary outcomes included specialty of the prescriber, adverse bleeding events during hospitalization, and whether a contraindication to anticoagulant therapy existed at the time of discharge. Patients were considered to have an adverse bleeding event if their hemoglobin decreased by more than 2 g/dL in any one 24-hour period during admission, if they required a transfusion of packed red blood cells, or if an adverse bleeding event requiring increased physician monitoring was documented. Patients were considered to have a contraindication to anticoagulant therapy if the provider stated so at the time of discharge, regardless of clinical reasoning. The binomial test was used to evaluate anticoagulant prescribed at the time of discharge expecting a conservative 70% prescribing rate for warfarin (30% for LMWH). Logistic regression analysis was used to evaluate the correlation of the type of discharging physician with the prescribing of LMWH or warfarin at the time of discharge. Chi-square, Fisher exact test, and the studentâ&#x20AC;&#x2122;s t-test were used when appropriate to evaluate baseline patient demographics. Data analyses were completed using IBM SPSS Statistics, version 21 (IBM Corporation, Armonk, NY).

Results Of the 244 patients identified based on the inclusion criteria, 115 were excluded (Table 1); 129 patients were included in the study analysis. One hundred seven patients were prescribed warfarin, or warfarin plus LMWH at discharge. Nine patients were prescribed LMWH as the

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Original Research

Table 2 Patient Demographics Characteristics

Low-molecularweight heparin

Vitamin K antagonist

(N = 9)

(N = 107)

33.3

40.2

White, %

66.7

72.0

Black/African American, %

11.1

0.9

Unknown, %

22.2

27.1

DVT, %

62.5

58.9

PE, %

12.5

34.6

DVT + PE, %

25.0

6.5

Breast, %

11.1

3.7

Colon/rectal, %

11.1

9.3

Esophageal gastrointestinal, %

11.1

0.9

—

10.3

Lung, %

11.1

33.6

Other, %

66.7

42.2

Age (mean), yrs Sex, male, % Race

Type of VTE

Type of cancer

Hematologic, %

DVT indicates deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

econdary Outcome: Prescribed Agent by Specialty Table 3 S of Prescriber Low-molecular- Vitamin K Specialty of weight heparin antagonist prescriber (N = 9) (N = 107) Odds ratio Generalist

—a

Hematologist/ oncologist

7.8 (95% CI, 1.5-41.8)

CI indicates confidence interval. a Comparator group.

primary treatment for their VTE at time of discharge, and 13 patients were not prescribed any anticoagulants. The mean age of patients was 62 and 63 years in the LMWH and VKA groups, respectively (Table 2). There were no statistical differences with any variables between the 2 study groups. Two patients prescribed warfarin had either HIT or a positive HIT antibody test during the time of admission. Of the 9 patients who received LMWH, 1 patient was documented to have “refused warfarin” at the time of

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their discharge. One patient who received neither LMWH nor warfarin was documented as “intolerant to warfarin”; however, no other contraindications to LMWH or any other anticoagulants were noted. Significantly fewer patients (n = 9; 7.40%) were prescribed LMWH as their primary anticoagulant at the time of discharge compared with warfarin (n = 107 [82.9%]; P <.0001). Of the patients prescribed LMWH at discharge, 4 (44.4%) were prescribed LMWH by a hematologist/oncologist, and 3 by general practitioners. Only 7 of the 107 patients (6.5%) who were prescribed warfarin were under the care of a hematologist/oncologist. Hematologists/oncologists were therefore 7.8 times more likely (P = .016) to prescribe LMWH than warfarin compared with any general practitioner based on logistic regression analysis of practice specialty in regard to prescribing of LMWH versus VKA (Table 3). Seven patients had documented bleeding during admission with only 2 patients requiring transfusion. Four patients were prescribed warfarin and 1 patient was prescribed LMWH for the treatment of VTE at the time of discharge.

Discussion A frequently hypothesized reason for the discrepancies between prescribing more efficacious LMWH in patients with cancer and VTE is the increase in cost.33 For patients without prescription coverage, generic warfarin can be obtained for merely a few dollars each month, whereas LMWH would cost patients thousands of dollars for a 6-month treatment period. For patients without prescription coverage, cost would be an inhibitive deterrent to obtaining the more effective LMWH treatment. Conversely for those with prescription coverage, patient cost may be less of an issue. A cost-effectiveness analysis published in 2005 found that LMWH provided a quality-adjusted life expectancy of 1.097 quality-adjusted life-years with a cost of $15,329.33 The vast majority of the cost were attributed to pharmacy costs for LMWH. Although the LMWH enoxaparin is now available as a generic, its costs are still high compared with warfarin therapy. With the early mortality benefit associated with LMWH, it is likely prudent to still preferentially consider it in accordance with current guidelines, when the patient has prescription coverage to offset the drug acquisition cost. It is well known by clinicians that there is substantial lag time between the publication of new research findings and their incorporation into everyday clinical practice. A literature search using PubMed and the Internet, yielded little to no information regarding the typical lag time from publication, guideline incorporation or bedside use. Several researchers have attempted to measure

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the time from translational research to bedside implementation, but there is no consensus on how to define and measure this process.34 Even measuring the uptake of clinical trial results leads researchers down the road of counting publications and citations,35 which has little to no meaning for those trying to answer the question of true dissemination to bedside clinical practice. We present data on a treatment approach that is clearly known to be beneficial. The Chest antithrombotic guidelines incorporated a recommendation to use LMWH for the initial 3 to 6 months after the diagnosis of acute VTE in patients with cancer in the 2004 iteration of their guidelines.36 Contemporary papers have been written on this issue with directives on how to improve adherence to guidelines29,37; however, there is still a disconnect between adherence to long-standing evidence-based recommendations and actual clinical practice. Previous studies have demonstrated that a large proportion, and in some instances the majority of prescribers, do not adhere to the recommendation to use LMWH for the initial acute treatment of VTE in patients with active cancer. LMWH prescribing rates increased from 32% to 60%, approximately, during the 3 to 5 year period following the 2004 CHEST guidelines in a Canadian patient population.38-40 Similar to our study, Rahme and colleagues observed a higher rate of LMWH prescribing among oncologists compared with general practitioners; however, their logistic regression model did not show a significant difference40 as did our study. This is likely due to the higher rate (59%) of prescribing in their study by general internists/practitioners compared with no LMWH prescribed by generalists in our study. The complexity of this issue drove Johnson and colleagues to evaluate the reasons physicians may not adhere to the recommendation to prescribe LMWH for these patients.30 Key findings were that physicians struggled with the appropriateness of this recommendation with concerns ranging from increased patient burden to individual patient prognosis. Although physicians may not adhere to this recommendation for a variety of reasons, the result is the same: the patient often receives warfarin instead of LMWH despite the evidence favoring the latter. Despite these known barriers, we expected to see higher rates of LMWH prescriptions in our cohort in a community teaching hospital, but the rates of LMWH prescribing for acute VTE in patients with active cancer were abysmally low. This study indicates that specialists (oncologists) who should be more familiar with evidence-based recommendations in patients with cancer did indeed prescribe LMWH almost 8-fold more often than their general practitioner colleagues. A qualitative study looking at the way physicians make decisions in

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this patient population also identified a similar trait among oncologists compared with general practitioners.30 This could also be explained by specialists being more likely to exhibit traits of an “innovator” or “early adopter” as defined by Berwick,41 suggesting that they are more likely to be early utilizers of novel therapies. Although previous registry data have estimated substantially higher LMWH prescribing rates in this population,31,32 our data may more accurately represent “realworld” prescribing rates in a typical, community American healthcare setting, particularly in rural areas. There are real barriers to prescribing LMWH that include access and medication acquisition cost that are difficult to identify, even in qualitative “think aloud” studies. These types of health disparities, such as access to specialists and prescription drug coverage, are observed more often in rural areas.42 Likewise, these data are consistent with the observation by Rahme and colleagues that showed a correlation between residing in a rural area and being prescribed VKAs instead of LMWH.40

Limitations The limitations of our current study include the retrospective nature of the observations that were recorded. In addition, our LMWH group was small and comprised only 7% of our total patient population. Taking the primary outcome we evaluated into consideration, this demonstrated a significant difference in prescribing choice for our patient population. The cancer type was more widely distributed, which prevented any meaningful interpretations between the malignancy type and prescribing patterns of physicians. Although this is a limitation, given that some malignancies have a much higher rate of thrombosis than others, it is unlikely this weighs on the decision of prescribers because clinicians may disregard evidence-based guideline recommendations. Conclusion We evaluated prescribing patterns of physicians in regard to evidence-based treatment recommendations for patients with active cancer and acute deep vein thrombosis and/or pulmonary embolism. Similar to previous studies, we observed a very low rate of adherence to guideline recommendations, which was more pronounced in our rural geographic area than in previous Canadian studies. To our knowledge, contemporary data in a US patient population are not available, which suggests the possibility that this large discrepancy may not be limited to only our rural area. Evidence demonstrates that patients with cancer and acute VTE treated with LMWH have a lower recurrence of VTE, lower mortality rates, and decreased adverse bleeding when compared with traditional warfarin

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Original Research

therapy. Hematologists and oncologists are more likely than their generalist colleagues to follow evidence-based treatment guidelines when prescribing LMWH in this patient population. n Acknowledgments The authors thank Jarrett Wyatt, PharmD (student pharmacist at time of data collection), for his assistance in data collection and entry. The abstract was presented in poster format at the ACCP Virtual Poster Forum May 2013. Author Disclosure Statement Dr Stewart serves on the Speaker’s Bureau for Janssen Pharmaceuticals. Dr Rikhye, Dr Odle, Dr Bossaer, and Dr Flores reported no conflicts of interest.

References

1. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110:1723-1729. 2. Dammacco F, Vacca A, Procaccio P, et al. Cancer-related coagulopathy (Trousseau’s syndrome): review of the literature and experience of a single center of internal medicine. Clin Exp Med. 2013;13:85-97. 3. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815. 4. Davila M, Amirkhosravi A, Coll E, et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost. 2008; 6:1517-1524. 5. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab. JAMA. 2008;300:2277-2285. 6. Starling N, Rao S, Cunningham D, et al. Thromboembolism in patients with advanced gastroesophageal cancer treated with anthracycline, platinum, and fluoropyrimidine combination chemotherapy: a report from the UK National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group. J Clin Oncol. 2009; 27:3786-3793. 7. Phillips PG, Yalcin M, Cui H, et al. Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin. Anticancer Res. 2011;31:411-420. 8. Carmazzi Y, Iorio M, Armani C, et al. The mechanisms of nadroparin-mediated inhibition of proliferation of two human lung cancer cell lines. Cell Prolif. 2012;45: 545-556. 9. Chalkiadaki G, Nikitovic D, Katonis P, et al. Low molecular weight heparin inhibits melanoma cell adhesion and migration through a PKCa/JNK signaling pathway inducing actin cytoskeleton changes. Cancer Lett. 2011;312:235-244. 10. Lee AYY. The effects of low molecular weight heparins on venous thrombo embolism and survival in patients with cancer. Thromb Res. 2007;120(suppl 2): S121-S127. 11. Castelli R, Porro F, Tarsia P. The heparins and cancer: review of clinical trials and biological properties. Vasc Med. 2004;9:205-213. 12. Maraveyas A, Ettelaie C, Echrish H, et al. Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion. Blood Coag Fibrinol. 2010;21:452-458. 13. Arab WA, Kotb R, Sirois M, et al. Concentration- and time-dependent effects of enoxaparin on human adenocarcinomic epithelial cell line A549 proliferation in vitro. Can J Physiol Pharmacol. 2011;89:705-711. 14. Hou L, Yao J, Zhou J, et al. Pharmacokinetics of a paclitaxel-loaded low molecular weight heparin-all-trans-retinoid acid conjugate ternary nanoparticulate drug delivery system. Biomaterials. 2012;33:5431-5440. 15. Hou L, Fan Y, Yao J, et al. Low molecular weight heparin-all-trans-retinoid acid conjugate as a drug carrier for combination cancer chemotherapy of paclitaxel and all-trans-retinoid acid. Carbohydr Polym. 2011;86:1157-1166.

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16. 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. 17. Lee AYY. Treatment of established thrombotic events in patients with cancer. Thromb Res. 2012;129(suppl 1):S146-S153. 18. Romera A, Cairols MA, Vila-Coll R, et al. A randomised open-label trial comparing long-term sub-cutaneous low-molecular-weight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg. 2009;37:349-356. 19. Hull RD, Townshend G. Long-term treatment of deep-vein thrombosis with low-molecular-weight heparin: an update of the evidence. Thromb Haemost. 2013; 110:14-22. 20. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med. 2002;162:1729-1735. 21. Noble S. Low-molecular-weight heparin and survival in lung cancer. Thromb Res. 2012;129(suppl):S114-S118. 22. Saraiya B, Goodin S. Management of venous thromboembolism and the potential to impact overall survival in patients with cancer. Pharmacother. 2009;29:1344-1356. 23. Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129. 24. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004;22:1944-1948. 25. Klerk CPW, Smorenburg SM, Otten H-M, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005; 23:2130-2135. 26. Mandalà M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22 (suppl 6):vi85-vi92. 27. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-2204. 28. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2): e419S-e494S. 29. Debourdeau P, Beckers M, Gerome P, et al. How to improve the implementation of guidelines on cancer-related thrombosis. Expert Rev Anticancer Ther. 2011;11:473-483. 30. Johnson MJ, Sheard L, Maraveyas A, et al. Diagnosis and management of people with venous thromboembolism and advanced cancer: how do doctors decide? A qualitative study. BMC Med Inform Decis Mak. 2012;12:75. 31. Imberti D, Agnelli G, Ageno W, et al. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry. Haematologica. 2008;93:273-278. 32. Monreal M, Falgá C, Valdés M, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2006;4:1950-1956. 33. Aujesky D, Smith KJ, Cornuz J, et al. Cost-effectiveness of low-molecular-weight heparin for secondary prophylaxis of cancer-related venous thromboembolism. Thromb Haemost. 2005;93:592-599. 34. Morris ZS, Wooding S, Grant J. The answer is 17 years, what is the question: understanding time lags in translational research. J R Soc Med. 2011;104:510-520. 35. Rosas SR, Schouten JT, Cope MT, et al. Modeling the dissemination and uptake of clinical trials results. Res Eval. 2013;22:179-186. 36. Büller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl 3):401s-428s. 37. Kaatz S, Qureshi W, Lavender RC. Venous thromboembolism: what to do after anticoagulation is started. Cleve Clin J Med. 2011;78:609-618. 38. Cook LM, Kahn SR, Goodwin J, et al. Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice. J Thromb Haemost. 2007;5:937-941. 39. Kahn SR, Springmann V, Schulman S, et al. Management and adherence to VTE treatment guidelines in a national prospective cohort study in the Canadian outpatient setting. Thromb Haemost. 2012;108:493-498. 40. Rahme E, Feugère G, Sirois C, et al. Anticoagulant use in patients with cancer associated venous thromboembolism: a retrospective cohort study. Thromb Res. 2013;131:210-217. 41. Berwick DM. Disseminating innovations in health care. JAMA. 2003;289:1969-1975. 42. Ricketts TC. The changing nature of rural health care. Annu Rev Public Health. 2000;21:639-657.

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Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Symptom Management Overview

Symptom Management Overview Section Editor: Joseph Bubalo, PharmD, BCPS, BCOP

Submit Your

Symptom Management Update Readers are invited to submit brief updates with practice insights on the care of a specific symptom or a cluster of symptoms associated with a condition that is often seen in patients with cancer—to be presented in the form of a “How I Treat” type of article. The goal of this new section is to provide a quick background to enhance providers’ understanding of the symptoms associated with a specific condition and their characteristic presentation(s) and etiology. The emphasis should be on a concise description of available treatments and current course of therapy.

What is Symptom Management Overview? Each review should provide a brief description of the symptom(s) associated with a common condition in oncology and its evidence-based management Article Format • Length of article: 800-1200 words • Tables: 1-3 • Describe the symptom(s) • Etiology • Treatment options: dose(s), frequency, titration parameters • Course of therapy: time to effect/symptom resolution, expected effects, special or target populations for specific therapies, side effects and their management, as appropriate • References: minimum 5; maximum 15

How to submit

Submit a Word file of your article at

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This section provides a quick update of symptomatic conditions in oncology and their management. Readers are invited to submit brief updates following the guidelines provided on page 117.

Hiccups By Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine, Division of Hematology and Medical Oncology, Oncology Clinical Pharmacy Specialist, Oregon Health and Science University Hospital, OHSU Hospital and Clinics, Portland, OR

Symptom Overview Hiccups are an underreported respiratory complication that can significantly impair an individual’s quality of life. Responsible for at least 4000 hospital admissions

annually, they often are not considered significant in the need to care for a patient’s other pressing comorbidities such as malignancy.1

Etiology Hiccups occur secondary to an involuntary spasm of the diaphragm and intercostal muscles, which is followed by the sudden closure of the glottis generating the “hic” sound. These involuntary spasms occur at a rate of 4 to 60 per minute and predominantly involve the left hemidiaphragm.1 The pathogenesis of hiccups is complex with a variety of etiologies, resulting in the neurophysiologic effect of the condition (Table 1).1-4 The hiccup reflex arc is composed of efferent and afferent limbs, as well as a central hiccup center. The nerves that are involved in this reflex include the vagus, phrenic, and elements of the sympathetic nervous chain—primarily in the thoracic region.1,5 This chain of nerves can be activated at multiple points, making the true cause of an individual’s hiccups hard to discern and treat. In addition, there is a male predominance of those with hiccups in most reports.1 Most hiccups are benign and self-limiting with cessation in minutes; however, some can last longer and become persistent or intractable hiccups, which are defined as lasting longer than 48 hours and 1 month, respectively.1,5 When diagnosing intractable hiccups, a careful physical and laboratory review should be performed to evaluate the myriad of possible causes. Intractable hiccups can result in anxiety, increased depression, sleep loss, impaired nutrition and fluid intake, aspiration, and induction of cardiac arrhythmias via activation of underlying

cardiac pathology.1,5 This may result in significant impairment, and more rarely, death of the patient. Table 1 Causes of Hiccups1-4 Cancer

Multiple tumor types, especially those that may involve the abdomen, thoracic, or central nervous system

Metabolic derangements

Electrolyte disorders (especially hyponatremia), uncontrolled diabetes, uremia, or hypoadrenalism

Central nervous system disorders

Meningitis, encephalitis, stroke, hemorrhage

Pulmonary and cardiothoracic disorders

Myocardial infarction, pericardial disease, pneumonia, pleural inflammation/effusion, mechanical ventilation

Gastric disease

Esophagitis, gastric distension, ascites, subdiaphragmatic processes, obstruction, pancreatitis

Surgical

Anesthesia, epidural injections, thoracic procedures

Medications

Antibiotics, barbiturates, corticosteroids, anabolic steroids, antineoplastics (platinums, cyclophosphamide, taxanes, vinca alkaloids, topoisomerase inhibitors, gemcitabine), opioids, benzodiazepines, perphenazine, aripiprazole, clozapine, risperidone, and inhaled anesthetics

TREATMENT OPTIONS Self-limited hiccups do not require intervention as they will generally resolve without causing significant distress. Although there is little scientific evidence to

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support their use, it is common for people to try a variety of nonpharmacologic interventions to resolve their hiccups. Common interventions include the pressure or

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Symptom Management Overview

Treatment Options stimulation of different body areas, sudden frightening experiences, ingestion of sugar or a glass of liquid, black pepper–induced sneezes, or breathing into a paper bag.1 Patients with persistent or intractable hiccups often require pharmacologic intervention to alleviate the condition or complications. The only US Food and Drug Administration–approved hiccup remedy is chlorpromazine, which may not be useful in many patients because of its associated side effects listed in Table 2.2,4-20 There are no randomized, adequately powered clinical trials to determine the efficacy of pharmaceuticals for the treatment of hiccups. Many agents have been tried, with anecdotal success, and are hypothesized to work via a

variety of neural mechanisms to decrease the activity of irritated nerves via sodium, calcium, or gamma-aminobutyric acid (GABA)-enervated pathways (Table 2). Each agent has a different risk-to-benefit ratio, and when assessing which agent to use, it is important to consider the patient’s level of organ function, tolerance to side effects, and risk for drug interactions. Older anticonvulsants such as phenytoin, valproic acid, and carbamazepine were previously used, but have largely been replaced with dopamine antagonists (eg, chlorpromazine, haloperidol, metoclopramide), GABA enhancers (baclofen, gabapentin), or calcium channel blockers (nifedipine, nimodipine). In severe cases, intra-

Table 2 Treatments of Hiccups Agent Evidence

Dose

Amantadine

Case reports

100 mg orally, twice daily

Amitriptyline2,11

Case reports

25-90 mg daily

Sedation, dry mouth, orthostatic hypotension

Use with caution in the elderly

Baclofen2,12,13,20

Case reports and series, 1 double-blind placebo-controlled trial (4 patients)

5 mg (twice daily) to 10 mg (4 times daily) 15-30 mg daily usual range, maximum 60 mg

Sedation, confusion, EPS, hypotension

May be used in combination with other agents May take 2-3 days for full effect

Carvedilol14

Case report

6.25 mg (4 times daily)

Hypotension, bradycardia

Also managed tardive effects of chronic chlorpromazine and metoclopramide

Chlorpromazine2,5,6,12,15

FDA-approved, 50patient uncontrolled report

12.5-50 mg every 4-6 hours as needed

Sedation, EPS, postural hypotension

Increased risk for systemic or tardive effects in patients aged >55 years Effective 80% in 1 series

Gabapentin2,7,10,16

Case series and reports

900-1200 mg daily, dosed 3 times daily

Sedation

Haloperidol2,15

Multiple case reports

2-10 mg daily

Sedation, hallucinations, EPS

Methylphenidate9

Case report

5-20 mg daily, 5 mg twice daily

Dose early in the day to avoid sleep disturbances

Metoclopramide4,12,15,17

Multiple case reports

10 mg every 4-6 hours, up to 80 mg daily

Generally well tolerated. Increased sedation and EPS above 60 mg daily

Midazolam2,8,15

Case reports

15 mg daily subcutaneously

Sedation

Sedating doses used initially followed by continuous infusion

Nifedipine18

Case report

10-20 mg 3 times daily

Hypotension

May need continuous use

Nimodipine

Case report

30 mg (orally, 3 times daily) or 10 mg intravenous continuous infusion

Olanzapine17,20

Multiple case reports

2.5-10 mg daily, as 1 or 2 doses

Sedation, EPS

Successfully combined with baclofen

Side effects

Comments Has shown benefits in patients with Parkinson disease

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venous lidocaine, which blocks sodium channels, has been used to resolve postoperative hiccups, although this practice is limited because of the risk for cardiac side effects.1 Nebulized lidocaine has also been used in the palliative care setting to manage refractory hiccups.1 Although diazepam is a well-documented cause of hiccups, midazolam has been used to terminate hiccups and may be useful in the setting of terminal sedation or delirium.8 Methylphenidate may be useful to try in the sedated patient.6 Acupuncture has been an effective nonpharmacologic intervention in some patients, and the use of phrenic nerve blocks has been helpful in intractable hiccups.21 Multiple agents have been combined in attempts to manage hiccups with variable effects; however, the limiting factor is generally the additive side effects, especially sedation.20 Currently, there is little guidance on which agent should be used initially for hiccups of different etiologies. Because of the larger body of literature, most practitioners use chlorpromazine, metoclopramide, or baclofen as the initial treatment modality; a trial of multiple single agents or combinations of agents is also common. Some practitioners believe that baclofen may be the most effective agent, although it is slower to take effect than other agents.2 Most agents are continued for several days after cessation of hiccups, then weaned off as tolerated. Some patients’ hiccups will recur, requiring the medication to be restarted. The goal is then to wean to the lowest effective dose. In conclusion, although there are many reports of agents that help with the management of intractable hiccups, little current evidence exists regarding which agent, at what dose, and for which etiology should be

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used initially in patients. Agent and dose selection should be based on individual patient risks and comorbidities to achieve the best effect with minimal adverse consequences. n

References

1. Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol. 2009;7:122-127, 130. 2. Walker P, Watanabe S, Bruera E. Baclofen, a treatment for chronic hiccup. J Pain Symptom Manage. 1998;16:125-132. 3. Silverman MA, Leung JG, Schak KM. Aripiprazole-associated hiccups: a case and closer look at the association between hiccups and antipsychotics. J Pharm Pract. 2014;27:587-590. 4. Cersosimo RJ, Brophy MT. Hiccups with high dose dexamethasone administration: a case report. Cancer. 1998;82:412-414. 5. Rousseau P. Hiccups. South Med J. 1995;88:175-181. 6. Friedgood CE, Ripstein CB. Chlorpromazine (thorazine) in the treatment of intractable hiccups. J Am Med Assoc. 1955;157:309-310. 7. Moretti R, Torre P, Antonello RM, et al. Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up. Neurologist. 2004;10: 102-106. 8. Wilcock A, Twycross R. Midazolam for intractable hiccup. J Pain Symptom Manage. 1996;12:59-61. 9. Maréchal R, Berghmans T, Sculier P. Successful treatment of intractable hiccup with methylphenidate in a lung cancer patient. Support Care Cancer. 2003;11:126-128. 10. Wilcox SK, Garry A, Johnson MJ. Novel use of amantadine: to treat hiccups. J Pain Symptom Manage. 2009;38:460-465. 11. Stalnikowicz R, Fich A, Troudart T. Amitriptyline for intractable hiccups. N Engl J Med. 1986;315:64-65. 12. Oneschuk D. The use of baclofen for treatment of chronic hiccups. J Pain Symptom Manage. 1999;18:4-5. 13. Ramírez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. Am J Gastroenterol. 1992; 87:1789-1791. 14. Stueber D, Swartz CM. Carvedilol suppresses intractable hiccups. J Am Board Fam Med. 2006;19:418-421. 15. Moro C, Sironi P, Berardi E, et al. Midazolam for long-term treatment of intractable hiccup. J Pain Symptom Manage. 2005;29:221-223. 16. Tegeler ML, Baumrucker SJ. Gabapentin for intractable hiccups in palliative care. Am J Hosp Palliat Care. 2008;25:52-54. 17. Rizzo C, Vitale C, Montagnini M. Management of intractable hiccups: an illustrative case and review. Am J Hosp Palliat Care. 2014;31:220-224. 18. Mukhopadhyay P, Osman MR, Wajima T, et al. Nifedipine for intractable hiccups. N Engl J Med. 1986;314:1256. 19. Hernández JL, Fernández-Miera MF, Sampedro I, et al. Nimodipine treatment for intractable hiccups. Am J Med. 1999;106:600. 20. Thompson AN, Ehret Leal J, Brzezinski WA. Olanzapine and baclofen for the treatment of intractable hiccups. Pharmacotherapy. 2014;34:e4-e8. 21. Schiff E, River Y, Oliven A, et al. Acupuncture therapy for persistent hiccups. Am J Med Sci. 2002;323:166-168.

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Evasion of apoptosis may be a question of balance Increased BCL-2 expression helps cancer cells to survive1

BCL-2

Displacement of pro-apoptotic proteins may trigger apoptosis1

Pro-apoptotic proteins sequestered by BCL-2

Free pro-apoptotic proteins

Increased expression of BCL-2 impairs the pathway to programmed cell death Like normal cells, cancer cells will often induce expression of pro-apoptotic proteins in response to stressors like limited metabolic resources, rapid cell division, or exposure to cytotoxic agents1. Cancer cells may increase expression of the anti-apoptotic protein, BCL-21. Pro-apoptotic proteins are bound and sequestered by BCL-2, helping the cancer cell to avoid programmed cell death2.

Mitochondria

Pro-apoptotic proteins—if displaced from BCL-2—have the potential to trigger apoptosis1.

To learn more about the BCL-2 pathway, visit BOOTH #1343 and #1909 at the ASH annual meeting

References: 1. Letai, A.G., Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer, 2008. 8(2): p. 121-32. 2. Garcia-Saez, A.J., The secrets of the Bcl-2 family. Cell Death Differ, 2012. 19(11): p. 1733-40.

A3469581

Original Research Original Research

Assessment of Patients’ Knowledge and Management of ChemotherapyRelated Adverse Effects Thao K. Huynh, PharmD; James A. Trovato, PharmD, MBA, BCOP, FASHP

J Hematol Oncol Pharm. 2014;4(4):122-127 www.JHOPonline.com Disclosures are at end of text

Background: It is important that patients treated with chemotherapy be educated about what to expect from their regimen and the correct use of supportive care medications at home. In addition to patient education, it is equally important to determine any barriers that may hinder their understanding of the education they are provided. Objectives: To evaluate patients’ knowledge of their chemotherapy’s expected adverse effects and their ability to manage them. Secondary objectives included assessing patients’ satisfaction with the education provided and the preferred method of receiving this education. Methods: This study was a multicenter, prospective, survey-based study at a large teaching hospital and a smaller community hospital. Participation in the study involved patient consent to complete a 14-question survey between December 2013 and May 2014. Descriptive statistics were used to analyze the results of the survey responses. Results: Of the 92 surveys distributed, 67 were returned for analysis. The majority of patients (91%) responded that they had a good understanding of the chemotherapy regimen they were receiving, but only 52.2% of patients were able to list the specific chemotherapy agents. Similar results were seen from patients regarding their understanding of premedications. Patients treated at the community hospital infusion center were more confident in knowing which chemotherapy side effects to expect at home and were able to list chemotherapy-related adverse effects in correlation to a greater extent than patients at the larger teaching hospital infusion center. Conclusion: Patients with cancer at the community hospital had an oncology pharmacist present at least 2 days per week, which increased patient comfort in consulting with a pharmacist for chemotherapy-related adverse effect management. The results of this study will help increase the awareness of the gaps that exist in patients’ knowledge and management of chemotherapy-related adverse effects. The results also highlight opportunities for oncology pharmacists to provide patient education as well as ongoing monitoring and management of adverse effects.

atients undergoing chemotherapy treatment in the outpatient setting often receive information about expected adverse effects related to chemotherapy from a variety of healthcare professionals, including nurses, pharmacists, and physicians. Although the repetition of providing this information may help the patient learn the expected adverse effects of their chemotherapy regimen, our experience has been that patients are apprehensive about self-managing chemotherapy-related adverse effects. It is crucial that patients are educated about their chemotherapy and management of adverse effects prior to and during subsequent cycles of treatment to abate the anxiety and distress that may be associated with a lack Dr Huynh is a PGY-2 Oncology Pharmacy Practice Resident, and Dr Trovato is an Associate Professor, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD.

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of knowledge.1,2 In our experience, when speaking with patients in outpatient chemotherapy infusion centers, patients are not knowledgeable about how to self-monitor for chemotherapy-related adverse effects, including when to expect them and how to manage them effectively at home. In addition, we have observed that patients cannot state the names of the chemotherapy agents they are receiving, including the names of any supportive care premedications and the reason they are being used. Although it is important that patients treated with chemotherapy be educated about what to expect from their chemotherapy regimen and appropriate use of supportive care medications, it is equally important that patients be assessed about their understanding of the counseling points provided to them.3,4 The lack of knowledge about their chemotherapy treatment and how to manage related adverse effects could lead to increased hospital admissions, increased morbidity, and decreased quality of life for the patient.3 A study by

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Weeks and colleagues showed that 69% of patients with advanced lung cancer and 81% of patients with advanced colorectal cancer did not report understanding that chemotherapy will not be a cure to their cancer.5 In related studies, clinical pharmacy services in the ambulatory oncology setting have been analyzed and led investigators to the conclusion that pharmacists are able to provide drug-related and consultative interventions. Drug-related interventions range from medication reconciliation to adverse effect management and prevention. Consultative interventions include patient education and answering drug information questions. In the study by Ruder and colleagues, during the patient education sessions, the pharmacist reviewed the treatment plan, adverse effects, and how to prevent them. Patient satisfaction was also assessed for the time spent with a pharmacist, and 28 patients (68%) strongly agreed that the medications recommended by the pharmacist for side effect management due to chemotherapy were beneficial.6 Iihara and colleagues reported that pharmacists can reduce physicians’ workload in outpatient oncology clinics and improve patient care. Pharmacists accomplished workload reduction by dedicating 75 hours per month to provide patient education. As a crucial team member, pharmacists were able to educate more patients and increase the prescriptions for supportive care medications each month.7 Tuffaha and colleagues evaluated ambulatory pediatric cancer patients and found that 247 (26%) of 939 interventions were related to pharmacist-provided patient counseling. This included education on the chemotherapy treatment plan, number of cycles, infusion time, common adverse effects, and recommendations to mitigate chemotherapy-related adverse effects.8 Similarly, Krzyzanowska and colleagues found that of 583 pharmacist interventions in an adult ambulatory clinic, 143 consisted of patient education.6 McKee and colleagues evaluated patient–pharmacist relationships and found that 86% of patients agreed that it is important to discuss treatment with a pharmacist and 84.3% of patients stated that they learned something new from an encounter with a pharmacist.9 To date, no study has evaluated ambulatory patient understanding of chemotherapy medications and management of supportive care medications. Based on the study by Weeks and colleagues, who found that a majority of oncology patients had poor insight into their treatment plan,5 we designed and implemented this prospective, survey-based study. The purpose of this study was to identify gaps in patients’ knowledge and their understanding of expected adverse effects related to chemotherapy treatment and the supportive care medications used to manage them. At the conclusion of this study, we hope to share further insight into the gaps that still exist

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in the education provided to patients regarding their chemotherapy. The primary objective of this study was to evaluate patients’ knowledge of their chemotherapy regimen and management of expected adverse effects. Secondary objectives included assessing patients’ satisfaction with the education provided to them and the preferred method of receiving this education. The hypothesis of this study was that more than 50% of ambulatory oncology patients will not be confident in understanding their chemotherapy treatment and management of their chemotherapyrelated adverse effects at home.

Methods This was a multicenter, prospective, survey-based study involving 2 different outpatient chemotherapy infusion centers within the same university-based health system. One infusion center was part of a large teaching hospital, and consisted of 32 infusion chairs with 3 clinical staff pharmacists in the oncology satellite pharmacy dispensing chemotherapy to inpatients and outpatients. The other site was based in a smaller community hospital with a total of 22 infusion chairs, including 7 in a physician’s office owned by the community hospital. One clinical staff pharmacist dispensed all intravenous medications, including chemotherapy, to the main outpatient site at the community hospital, and the rest of the chemotherapy dispensed to the physician’s office was prepared by the nursing staff. In addition, an oncology pharmacy specialist was present at the community hospital outpatient infusion centers 2 days per week to provide patient education and other clinical services. All adult ambulatory cancer patients were identified for this study by viewing the outpatient infusion center schedule in order to identify patients currently receiving chemotherapy. All patients consented to participate in the study between December 2013 and May 2014. During the study period, patients were included if they were aged ≥18 years and currently receiving chemotherapy treatment. This study was approved by the Institutional Review Board. All patients were notified that participation in the study was voluntary and that they could stop taking the survey at any time. To ensure the privacy and comfort of patients participating in the study, private rooms and isolated areas were available to complete the survey. Participation in the study required the patient to complete a survey containing 14 questions with an estimated completion time of 20 minutes. The investigators reviewed the survey questionnaire with the patient in great detail and answered any questions about it. Patients were excluded from the study and not asked to complete the survey if they did not speak English, were sleeping, undergoing a nursing procedure,

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Figure Survey Questions 1. Please list all of the chemotherapy medications that you are receiving:

9. W hen I have chemotherapy side effects at home, I usually: (check all that apply) h Contact my physician h Contact my pharmacist h Manage it with medications I have at home

h I am unsure of all the chemotherapy medications that I am

receiving

h Go to the emergency department h Contact the oncology clinic h Do nothing

2. I have a good understanding of how often and for how long I will need to get chemotherapy treatment: (check one)

h I havenâ&#x20AC;&#x2122;t experienced any side effects h Other (Please describe):

h Strongly agree h Agree h Disagree h Strongly disagree

3. Sometimes patients receive medications before their chemotherapy to help prevent certain side effects. I have a good understanding of the medications I will receive before my chemotherapy and what side effects they will help prevent: (check one)

10. I received information about my chemotherapy treatment and side effects from my: (check all that apply) h Oncologist

h Pharmacist

h Family & friends

h Internet

h Nurse

h Other (please describe):

h Strongly agree h Agree h Disagree h Strongly disagree

4. Please list all of the medications you will receive before your chemotherapy:

11. I would feel most comfortable receiving information about my chemotherapy treatment from my: (check all that apply) h Oncologist

h Pharmacist

h Family & friends

h Internet

h Nurse

h Other (please describe): h I am unsure of all the medications I will receive before my

chemotherapy

5. I feel confident that I know which chemotherapy side effects I may experience at home: (check one)

h Pharmacist

h Family & friends

h Internet

h Nurse

h Other (please describe):

6. Please list the chemotherapy side effects that you may experience at home:

13. I feel that my side effects from chemotherapy can be better managed if I could spend more time with my: (check all that apply)

chemotherapy treatment

7. I am confident that I can manage any chemotherapy side effects that I may experience at home: (check one) h Strongly agree h Agree h Disagree h Strongly disagree

8. I know which medications I have at home and how to use them for chemotherapy side effects: (check one) h Strongly agree h Agree h Disagree h Strongly disagree

h Oncologist

h Strongly agree h Agree h Disagree h Strongly disagree

h I do not expect to experience any side effects with my

124

12. I would feel most comfortable receiving information about managing my chemotherapy side effects from my: (check all that apply)

Journal of Hematology Oncology Pharmacy

h Oncologist

h Pharmacist

h Family & friends

h Internet

h Nurse

h Other (please describe):

14. I would prefer to receive information about my chemotherapy treatment and side effects in the following way(s): (check all that apply) h Pamphlet/brochure

h Cancer-related website

h Face-to-face meeting h DVD/Video h E-mail

h Telephone

h I would not like to receive any information h Other (please describe):

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or wanted privacy; they did not have to complete the survey at their first meeting with the investigator. Patients were given the survey in the outpatient infusion center and were allowed to take the survey home to reread and complete. Patients were also encouraged to discuss with family and friends if this would help with their decision to complete the survey. Data collection consisted of patient responses to a nonvalidated survey created by the investigators (Figure). The survey questionnaire included the following 4 categories: patients’ knowledge of chemotherapy and premedications, patients’ understanding of the management of chemotherapy-related adverse effects, methods reported by patients for management of chemotherapy adverse effects at home, and patient satisfaction of chemotherapy education provided to them. The sample size goal was 50 patients. Because the intent of this study was to use descriptive statistics to analyze the results of the survey questions, no sample size calculation was performed. In previously published studies involving surveys targeting oncology patients, the number of surveys analyzed was in the range of 55 to 150.5,6 Because of the time constraints with conducting this study, we aimed to achieve a sample size of 50 patients.

Results A total of 92 patient surveys were distributed; 67 surveys received consent and were returned. All 67 patients were enrolled in the study. Primary end points of the study evaluated patients’ knowledge of their chemotherapy regimen and related adverse effects. Although most patients responded that they had a good understanding of the chemotherapy regimen they were receiving, which was defined as patients answering “strongly agree” or “agree” to that question, few patients were able to list all of the chemotherapy medications they were receiving— 91% and 52.2%, respectively. Patients responded similarly to the question regarding their understanding of premedications and the ability to list their premedications—97% and 29.8%, respectively. Similar inconsistencies were seen from patients completing the survey at both outpatient infusion centers (Table 1). Results from questions relating to patients’ understanding of the management of chemotherapy-related adverse effects are available in Table 2. Patients treated at our smaller community hospital infusion center were more confident in knowing which chemotherapy-related side effects to expect at home and were able to list chemotherapy-related adverse effects in correlation. Patients at the larger teaching hospital infusion center were able to do the same; however, these patients were not able to list chemotherapy-related adverse effects to the same extent as those patients being treated at the com-

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Table 1 P atient Understanding of Chemotherapy and Premedications Teaching Community All sites hospital hospital (N = 67), (N = 46), (N = 21), N (%) N (%) N (%) Ability to list chemotherapy medications

35 (52.2)

23 (50.0)

12 (57.1)

Good understandinga of frequency and duration of chemotherapy treatment

61 (91.0)

41 (89.1)

20 (95.2)

Good understandinga of premedications given prior to chemotherapy

65 (97.0)

45 (97.8)

20 (95.2)

Ability to list premedications

20 (29.8)

14 (30.4)

6 (28.6)

Good understanding is defined as patient responses of “strongly agree” or “agree.”

Table 2 P atient Understanding of Management of Chemotherapy-Related Adverse Effects Teaching Community All sites hospital hospital (N = 67), (N = 46), (N = 21), N (%) N (%) N (%) Confidenta in which chemotherapy-related side effects may be experienced at home

62 (92.5)

42 (91.3)

20 (95.2)

Ability to list chemotherapyrelated adverse effects

55 (82.1)

35 (76.1)

20 (95.2)

Confidenta in managing chemotherapy-related side effects at home

62 (92.5)

42 (91.3)

20 (95.2)

Knowledgea of medications at home and used to manage adverse effects

62 (92.5)

42 (91.3)

20 (95.2)

Confident and knowledge are defined as patient responses of “strongly agree” or “agree.”

munity hospital. The majority of patients at both sites stated that if chemotherapy side effects did occur at home, most would manage it with the medications they had at home (Table 3). Survey questions evaluating patient satisfaction with the chemotherapy education provided showed pharmacists as having a minimal role in educating patients (34.3%); only 41.8% of patients felt most comfortable with pharmacists providing information on management of adverse effects. Patient preference for receiving education and side effect management by other healthcare professionals are also listed in Table 4. The majority

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Original Research

ethods Reported by Patients for Chemotherapy Side Table 3 M Effects at Home Teaching Community All sites hospital hospital (N = 67), (N = 46), (N = 21), Method reported N (%) N (%) N (%) Contact my physician Contact my pharmacist Manage it with medications at home Go to the ED Contact the oncology clinic Do nothing I haven’t experienced any side effects Other

23 (34.3)

14 (30.4)

9 (42.9)

3 (4.5)

3 (6.5)

0 (0.0)

43 (64.2)

25 (54.3)

18 (85.7)

5 (7.5)

3 (6.5)

2 (9.5)

18 (26.9)

10 (21.7)

8 (38.1)

0 (0.0)

13 (19.4)

10 (21.7)

3 (14.5)

3 (4.5)

3 (6.5)

0 (0.0)

ED indicates emergency department.

(88.1%) of patients preferred a face-to-face meeting as a method of receiving chemotherapy education and adverse effect information. A small percentage (41.8%) of patients also preferred to receive a pamphlet or brochure.

Discussion Despite that a majority of patients prefer a face-toface meeting to discuss chemotherapy treatment and adverse effects, our large teaching hospital infusion center does not have a dedicated oncology pharmacist to provide education to patients, whereas our smaller community hospital has an oncology pharmacist on-site approximately 2 days per week. Because of the volume of inpatient and outpatient chemotherapy at the teaching hospital, the role of the clinical staff pharmacist in the oncology satellite is mainly limited to distributive functions. At the moment, an outpatient oncology pharmacy specialist is not part of the pharmacy practice model. The analysis of these 2 centers showed that, in general, patients preferred oncol-

Table 4 P atient Satisfaction of Chemotherapy Education Provided Teaching Community All sites hospital hospital (N = 67), (N = 46), (N = 21), N (%) N (%) N (%)

Outcome

126

Patients received pharmacist-provided education

23 (34.3)

6 (13.0)

17 (81.0)

Patients received oncologist-provided education

60 (89.6)

39 (84.8)

21 (100.0)

Patients received nurse-provided education

46 (68.7)

30 (65.2)

16 (76.2)

Patients’ comfort with pharmacist-provided chemotherapy treatment information

24 (35.8)

11 (23.9)

13 (61.9)

Patients’ comfort with oncologist-provided chemotherapy treatment information

63 (94.0)

42 (91.3)

21 (100.0)

Patients’ comfort with nurse-provided chemotherapy treatment information

46 (68.7)

30 (65.2)

16 (76.2)

Patients’ comfort with pharmacist-provided chemotherapy side effect management

28 (41.8)

11 (23.9)

17 (81.0)

Patients’ comfort with oncologist-provided chemotherapy side effect management

64 (95.5)

43 (93.5)

21 (100.0)

Patients’ comfort with nurse-provided chemotherapy side effect management

51 (76.1)

33 (71.7)

18 (85.7)

Patients feel chemotherapy side effects can be better managed if more time was spent with a pharmacist

13 (19.4)

5 (10.9)

8 (38.1)

Patients feel chemotherapy side effects can be better managed if more time was spent with an oncologist

26 (38.8)

15 (32.6)

11 (52.4)

Patients feel chemotherapy side effects can be better managed if more time were spent with a nurse

22 (32.8)

16 (34.8)

6 (28.6)

Patients prefer a face-to-face meeting as a method of receiving information about chemotherapy treatment and side effects

59 (88.1)

40 (87.0)

19 (90.5)

Patients prefer a pamphlet/brochure as a method of receiving information about chemotherapy treatment and side effects

28 (41.8)

14 (30.4)

14 (66.7)

Patients prefer a cancer-related website as a method of receiving information about chemotherapy treatment and side effects

8 (11.9)

7 (15.2)

1 (4.8)

Patients prefer e-mail as a method of receiving information about chemotherapy treatment and side effects

8 (11.9)

5 (10.9)

3 (14.3)

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Knowledge and Management of Chemotherapy-Related Adverse Events

ogist-provided chemotherapy treatment and adverse effects information. However, more community hospital cancer patients, who were familiar with the role of the oncology pharmacist, preferred pharmacist-provided education and felt more comfortable consulting with a pharmacist for management of their chemotherapy related adverse effects. In previous literature, patients have indicated a high importance but low satisfaction with pharmacist inquiry into the patient’s medication regimen.10 When pharmacists are available and able to follow-up with patients’ adverse effects management, there was a 74% positive response from patients.11 The majority of patients felt that pharmacist-run follow-up services allowed them to become more confident in managing medications on their own.11 The results of the secondary objective in this study as well as previous literature show a great potential for pharmacists to impact and improve patient care.

Limitations Based on the results of the study, the hypothesis was refuted because more than 50% of patients were confident in their understanding of their chemotherapy treatment and management of their chemotherapy-related adverse effects at home. Although, the data did not support our hypothesis, data supporting the primary objective of assessing patients’ knowledge of their chemotherapy regimen and management of expected adverse effects provided a more accurate reflection of patients’ understanding and did not directly correlate with patients’ confidence level. Patients’ overconfidence could be confounded by the fact that this was a pharmacist-administered survey and was a limitation to this study. Since this survey was nonvalidated, there is the possibility that the survey questions did not measure what they were designed to measure. Other limitations included fewer patients at the community infusion center compared with the large teaching hospital, which may skewed the results of the data, because a single patient response may have significantly altered the data. In addition, because of the voluntary nature of the consent and that patients can stop taking the survey at any time, not all questions were answered on all 67 surveys. The results of the lack of responses for a few questions may have altered the data outcomes as well. Furthermore, not asking patients to list names of medications they use at home for chemotherapy-related adverse effect management or their indications in the assessment were other limitations in this study. We encountered a language barrier with some patients. Five patients did not consent to the survey at our teaching hospital infusion center because they did not speak En-

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glish. In addition, 5 patients at our teaching hospital infusion center and 5 patients at our community hospital infusion center asked the study investigators to read the survey questions out loud and fill out the survey for the participants. This may have influenced patients’ responses in answering questions with having the investigator administrating the survey. Another limitation to the study was that the investigators could not verify the accuracy of patient premedications and expected adverse effects of chemotherapy because the investigators did not use patient identifiers after administering the survey to verify the treatment regimen the patient received.

Conclusion The results of this study will help to increase awareness of the gaps that exist in patients’ knowledge and management of chemotherapy-related adverse effects. This knowledge gap outlines opportunities that oncology pharmacists may be able to fill by providing much needed patient education and ongoing monitoring and management of chemotherapy-related adverse effects. Future studies analyzing the impact of pharmacist-provided education to patients with cancer in the ambulatory setting are warranted. To our knowledge, this was the first study to assess patient understanding of chemotherapy and related adverse effects. The results of our study provide further evidence of how oncology pharmacists can provide a valuable patient care service to cancer patients receiving chemotherapy in the outpatient setting. n Author Disclosure Statement Dr Huynh and Dr Trovato reported no conflicts of interest.

References

1. National Comprehensive Cancer Network. NCCN Clinical Guidelines in Oncology. Distress Management Version 2. 2014. July 8, 2014. 2. Traeger L, Greer JA, Fernandez-Robles C, et al. Evidence-based treatment of anxiety in patients with cancer. J Clin Oncol. 2012;30:1197-1205. 3. Krzyzanowska MK, Treacy J, Maloney B, et al. Development of a patient registry to evaluate hospital admissions related to chemotherapy toxicity in a community cancer center. J Oncol Pract. 2005;1:15-19. 4. Neuss MN, Desch CE, McNiff KK, et al. A process for measuring the quality of cancer care: the Quality Oncology Practice Initiative. J Clin Oncol. 2005;23:6233-6239. 5. Weeks JC, Catalano PJ, Cronin A, et al. Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med. 2012;367:1616-1625. 6. Ruder AD, Smith DL, Madsen MT, Kass FH III. Is there a benefit to having a clinical oncology pharmacist on staff at a community oncology clinic? J Oncol Pharm Pract. 2011;17:425-432. 7. Iihara H, Ishihara M, Matsuura K, et al. Pharmacists contribute to the improved efficiency of medical practices in the outpatient cancer chemotherapy clinic. J Eval Clin Pract. 2012;18:753-760. 8. Tuffaha HW, Abdelhadi O, Omar SA. Clinical pharmacy services in the outpatient pediatric oncology clinics at a comprehensive cancer center. Int J Clin Pharm. 2012;34:27-31. 9. McKee M, Frei BL, Garcia A, et al. Impact of clinical pharmacy services on patients in an outpatient chemotherapy academic clinic. J Oncol Pharm Pract. 2011;17:387-394. 10. Gourdji I, McVey L, Loiselle C. Patients’ satisfaction and importance ratings of quality in an outpatient oncology center. J Nurs Care Qual. 2003;18:43-55. 11. Ryan N, Chambers C, Ralph C, et al. Evaluation of clinical pharmacists’ follow-up service in an oncology pain clinic. J Oncol Pharm Pract. 2013;19:151-158.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

nM olecular

Profiling Not Cost-Effective for Adjuvant Chemotherapy Decision-Making in Patients with Node-Negative Breast Cancer

BACKGROUND: Node-negative breast cancer (NNBC) accounts for 70% to 80% of breast cancer diagnoses. Treatment decisions regarding the use of adjuvant chemotherapy are usually based on several factors, including tumor size and histology, expression of estrogen receptor (ER) and/or progesterone receptor, and expression of human epidermal growth factor receptor-2 (HER-2). These factors are important when assessing prognosis and risk of recurrence in patients with cancer. Although the use of adjuvant chemotherapy in patients with NNBC has a negative impact on quality of life, serious side effects, and increased overall costs of therapy, it does improve survival and delays recurrence in certain subsets of patients, mainly triple-negative cases and those with tumor size >0.5 cm. The purpose of this study was to compare the costeffectiveness of the genomic testing (MammaPrint) to a proven risk calculator (Adjuvant! Online) for decisions regarding the use of adjuvant chemotherapy. METHODS: Researchers analyzed the economic impact of using the genomic test MammaPrint, a 70-gene signature, versus 2 other strategies to guide the clinical decision to use adjuvant chemotherapy in patients with NNBC. The study was conducted in France and was supported by the French National Cancer Institute. Data were taken from the TRANSBIG Consortium validation study conducted with the MammaPrint genomic test. A total of 307 patients with NNBC who did not receive any systemic adjuvant therapy were included in the study. Eligibility criteria included age <61 years at diagnosis and a tumor size <5 cm. The majority (69%) of the patients had ER-positive breast cancer; 41% had a grade 2 or 3 tumor. In the base-case analysis, 3 strategies were used to decide whether to use adjuvant chemotherapy, including; (1) the MammaPrint genomic test, (2) the prognostic diagnosis, Adjuvant! Online; and (3) using systematic chemotherapy in all patients. The time horizon for overall survival (OS) was 10 years. In the first 2 strate-

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gies, only women at high risk for recurrence were assumed to receive chemotherapy. In the systematic chemotherapy strategy, all patients were assumed to receive chemotherapy, regardless of risk for recurrence. The costs were based on the French National Health Insurance Scheme, life-years, and quality-adjusted lifeyears (QALYs), and were calculated for each of the 3 strategies for the 10-year time horizon. RESULTS: Without the use of adjuvant chemotherapy, the 10-year OS for patients with NNBC is 77% (95% confidence interval [CI], 71%-81%). The mean differences in life-years and QALYs were similar among the 3 strategies. The MammaPrint genomic test was associated with a higher cost than the other 2 strategies: the mean difference was an additional €2037 (range, €1472€2515) for MammaPrint compared with Adjuvant! Online and €657 (95% CI, –€642 to €3130) compared with systematic chemotherapy. However, when the cost of the genomic test was reduced, the test became a more cost-effective strategy. Based on a €50,000 per QALY willingness-to-pay threshold, the Adjuvant! Online strategy had a 92% (76% in patients with ER-positive NNBC) probability of being the most cost-effective strategy; systematic chemotherapy had a 6% (4% in the patients with ER-positive disease) likelihood of being the most cost-effective strategy; and the MammaPrint genomic test had only a 2% (20% in patients with ER-positive NNBC) probability of being the most cost-effective strategy. DISCUSSION: These results indicate that the use of the MammaPrint test to determine which patients with NNBC are at high risk for disease recurrence and would benefit from adjuvant chemotherapy is not cost-effective. The health outcomes in this study were almost identical among the 3 strategies evaluated. The high cost of the MammaPrint genomic test renders it less cost- effective than the other 2 options for routine use to determine the benefit of adjuvant chemotherapy in patients with NNBC. If the cost of the test were lower, however, it would become more cost-effective. Source: Bonastre J, Marguet S, Lueza B, et al. Cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer. J Clin Oncol. 2014;32:3513-3519.

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December 2014

Vol 4, No 4

FROM THE LITERATURE

COMMENTARY BY ROBERT J. IGNOFFO

This study shows that the MammaPrint genomic test is unlikely to be cost-effective for making decisions regarding the use of adjuvant chemotherapy in patients with NNBC. The US Food and Drug Administration has approved MammaPrint to assist in assigning risk of recurrence in ER-positive and -negative breast cancer, but has not been approved for predicting benefit from adjuvant systemic therapy. This study shows that the use of this genomic test added to the cost of therapy and did not optimize decision-making in patients with NNBC. The authors cautioned that the study was limited by the small sample size and inability to calculate reliable survival predictions. Furthermore, the results may not be generalizable to other patients with breast cancer because the study population was generally younger (47 years) than the usual age for NNBC. nB iomarker-Driven

New Anticancer Drugs Reduce Toxicity and the Associated Costs

BACKGROUND: The new anticancer drugs approved by the US Food and Drug Administration (FDA) for the treatment of patients with cancer often result in prolonged survival and improved quality of life; however, increasing reports have noted rare but serious adverse events linked to new therapies, and managing these events further increases the cost of therapy. A recent study evaluated anticancer drugs approved by the FDA between 2000 and 2011 to identify grade 3 or 4 adverse events and their associated costs. METHODS: In this meta-analysis of 41 studies related to anticancer drugs in development, researchers analyzed the frequency and costs of 12 grade 3 or 4 adverse events. They calculated the estimated incremental drug prices and the incremental costs associated with the management of these common events based on the type of new drug and target specificity. The 41 studies included a total of 27,539 patients. The studies involved 19 experimental anticancer drugs, of which 12 were targeted agents and 7 were chemotherapies. RESULTS: Drugs that target a specific molecular mutation or a specific target on the cancer cells were associated with a lower incidence of grade 3 or 4 adverse events compared with controls (P = .22); by contrast, other drugs, including angiogenesis inhibitors and chemotherapy agents, were associated with increased toxicity compared with controls (P <.001). In the latter, the risk for toxicity increased regardless of whether the control arm contained an active or inactive treatment.

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December 2014

In addition, the median monthly drug cost was higher for the experimental drugs compared with the controls, regardless of the type of drug. The median incremental drug price for the experimental drugs was $6000 (range, –$620 to $32,900) per patient per month (PPPM). The PPPM median cost was lowest, at $4610 (range, –$620 to $9150), for targeted drugs with the greatest specificity; followed by chemotherapy, at $5730 (range, $2780$7790); and highest, at $6690 (range, $2870-$32,900), for the less specific targeted agents. The median cost of managing adverse events was higher for the new drugs than for the controls using chemotherapy or drugs with less specific molecular targets. However, for those drugs with specific molecular targets, the cost of managing toxicity was lower than for the controls. New anticancer drugs are associated with increased toxicity, which may lead to a small increase in treatment cost. Toxicity was not observed in drugs with a specific molecular target on cancer cells, the investigators noted. These results suggest that developing biomarker-driven drugs should be encouraged as a way to reduce toxicity and the associated costs and to improve overall outcomes. Source: Niraula S, Amir E, Vera-Badillo F, et al. Risk of incremental toxicities and associated costs of new anticancer drugs: a meta- analysis. J Clin Oncol. 2014;32:3634-3642. COMMENTARY BY ROBERT J. IGNOFFO

One of the benefits to performing a meta-analysis is that more of the rare or uncommon toxicities may be observed when they would not have been otherwise noted. In this study, the investigators were able to identify with greater frequency the serious adverse effects from experimental anticancer drugs and the costs associated with their management. Most cases of grade 3 or 4 adverse reactions came from new nonspecific targeted anticancer drugs. Gastrointestinal perforation was one of the reported serious adverse effects and likely was due to new antiangiogenesis inhibitors, which are known to cause this problem. With more than half of the new drugs falling into the class of a targeted agent, the incidence of serious adverse effects from new drugs was substantially lower compared with traditional cytotoxic chemotherapy. This is probably due to the lower incidence of chemotherapy-induced myelosuppression leading to hospitalization, which is not a common toxicity of targeted drugs. Thus, it is not surprising that many of the new drugs—especially specific targeted agents—do not substantially increase the overall cost of administering the treatment.

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FROM THE LITERATURE

n Panobinostat

Improves Outcomes in Relapsed/Refractory Myeloma

BACKGROUND: Panobinostat is a potent, oral histone deacetylase (HDAC) inhibitor that has shown synergistic antitumor activity when combined with bortezomib (Velcade) and dexamethasone (Decadron). HDAC inhibitors could help overcome the acquired resistance to proteasome inhibitors, such as bortezomib, by blocking the aggresome pathway (an escape route for myeloma cells as they evade the ubiquitin proteasome pathway). METHODS: The multicenter, randomized, double-足 blind phase 3 clinical trial known as PANORAMA1 compared the use of panobinostat plus bortezomib and dexamethasone with placebo plus bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. RESULTS: PANORAMA1 enrolled 768 patients with relapsed and/or refractory myeloma from 215 centers in 34 countries. Patients with disease refractory to bortezomib were excluded. The patients were randomized to panobinostat or to placebo, both in combination with bortezomib and dexamethasone, for a maximum of 12 cycles. Patients were followed for a median of approximately 6 months. The primary end point was median progression-free survival (PFS), which was significantly longer in the panobinostat group (11.99 months) than in the placebo group (8.08 months), a 27% reduction in the risk for disease progression. The 2-year PFS was 20.6% with panobinostat versus 8.4% with placebo. For patients who achieved a complete response or near-complete response, the median PFS was 19.38 months in the panobinostat group and 15.21 months in the placebo group. The addition of panobinostat to the combination of bortezomib and dexamethasone also led to longer median duration of response and longer time to first disease progression, relapse, or myeloma-related death. These results were consistent across all subgroups, suggesting a clinical benefit with the addition of the HDAC to the treatment regimen, regardless of any previous treatment or baseline patient characteristics. At the time of this analysis, the overall survival data were not yet mature, but the median survival duration was 33.64 months with panobinostat and 30.39 months with placebo. Although this 13% mortality risk reduction was not statistically significant, the panobinostat group had significantly more complete or near-complete responses than the placebo group (27.6% vs 15.7%, respectively; P = .006).

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Serious adverse events occurred in 60% of patients receiving panobinostat versus 42% of patients receiving placebo. Neuropathy was not increased in the experimental group, but that group did have more cases of diarrhea, thrombocytopenia, asthenia, and fatigue. The investigators noted that the results with pano足 binostat are better than those seen with another HDAC inhibitor, vorinostat (Zolinza), which, when added to bortezomib, did not lead to a significant increase in PFS; panobinostat is a more potent pan-HDAC inhibitor, with more potent in vitro inhibitory activity than vorin足 ostat, they noted. PANORAMA1 is the first phase 3 clinical trial to show a benefit for a 3-drug versus a 2-drug combination in patients with relapsed and/or refractory myeloma. Source: San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206. COMMENTARY BY ROBERT J. IGNOFFO

This international, phase 3, randomized clinical study uniformly showed that the addition of panobinostat improved PFS and delayed recurrence in patients with relapsed/refractory myeloma. The improvement in median PFS was 4 months, which on the surface may not appear exceedingly impressive, but in the setting of advanced disease demonstrates that panobinostat is a very active agent. It appeared to be particularly effective in patients with high-risk cytogenetic characteristics. Of note is that approximately 44% of the patients received prior bortezomib and 57% received a stem cell transplant. It is important to point out that the higher tumor response rate in the panobinostat group suggests that this drug may be useful in the first-line setting by allowing more patients to undergo potentially curative stem cell transplants. Although the panobinostat combination produced a higher incidence of grade 3 or 4 toxicities, it is noteworthy that it did not cause additive neurotoxicity. Diarrhea and asthenia were more frequent adverse effects in panobinostat 3-drug combination. This study shows that panobinostat may be an important new second-line agent for treating relapsed/refractory myeloma. Further studies using panobinostat as a firstline agent are warranted.

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December 2014

Vol 4, No 4

Innovations in Oncology Management A newsletter series for oncology practice administrators, administrative staff, advanced practice clinicians, and oncology pharmacists. The series will provide concise, up-to-date information on current issues that are impacting the business of oncology.

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Topics include: Part 1: Patient Support Services Part 2: Oral Parity Legislation Part 3: Emerging Payment and Delivery Models Part 4: Working Collaboratively with Local Payers TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

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References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079. ©2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568