JHOP June 2015 web

June 2015 Vol 5 I No 2

Journal OF

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

TM

Editorial

Improving Patient Outcomes with Standardization Patrick J. Medina, PharmD, BCOP Original Research

Analyzing Trends in Oral Anticancer Agents in an Academic Medical Facility Elizabeth Gustafson, PharmD; Jacob K. Kettle, PharmD, BCOP

Fluorouracil Overdose: Clinical Manifestations and Comprehensive Management During and After Hospitalization Ivyruth W. Andreica, BSN, PharmD; Erin Pfeifer, PharmD, BCPS; Marina Rozov, PharmD, BCPS; Erica Tavares, PharmD, BCPS; Anastasiya Shakurova, PharmD; Taylor Ortiz, MD Symptom management overview

Hyperuricemia Management

By Amber Diaz, PharmD, BCOP; 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

© 2015 Green Hill Healthcare Communications, LLC

NOW APPROVED

LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Visit LENVIMAinfo.com Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2.

Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

Events of renal impairment were reported in 14% of LENVIMAtreated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

Please see Brief Summary of Prescribing Information on the following pages.

LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved.

Printed in USA/February 2015 LENV0014

LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information.

1 INDICATIONS AND USAGE LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food. Continue LENVIMA until disease progression or until unacceptable toxicity occurs.

Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Severe Renal or Hepatic Impairment The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C).

2.2 Dose Modifications Hypertension • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment.

• Withhold LENVIMA for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2.

• Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction or hemorrhage • Discontinue for a Grade 4 event.

• Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of the adverse event.

Arterial thrombotic event • Discontinue LENVIMA following an arterial thrombotic event.

Renal failure and impairment or hepatotoxicity • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of renal impairment or hepatotoxicity.

• Discontinue LENVIMA for hepatic failure.

Proteinuria • Withhold LENVIMA for ≥2 grams of proteinuria/24 hours.

• Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours.

• Discontinue LENVIMA for nephrotic syndrome.

Gastrointestinal perforation or fistula formation • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT prolongation • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation.

• Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline.

Reversible posterior leukoencephalopathy syndrome (RPLS) • Withhold for RPLS until fully resolved.

• Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve.

Table 1

Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa Adverse Reaction

Modification

Adjusted Doseb

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

20 mg (two 10 mg capsules) orally once daily

Second occurrencec

Interrupt until resolved to Grade 0-1 or baseline

14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily

Third occurrencec

Interrupt until resolved to Grade 0-1 or baseline

10 mg (one 10 mg capsule) orally once daily

Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of LENVIMA Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification 4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hypertension In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients.

The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group.

Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension.

5.2 Cardiac Dysfunction In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMAtreated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.

Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

5.3 Arterial Thromboembolic Events In Study 1, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMAtreated patients and 1% in the placebo group.

Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

5.4 Hepatotoxicity In Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.

Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. a b

5.5 Proteinuria In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group.

Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

5.6 Renal Failure and Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting.

Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

5.7 Gastrointestinal Perforation and Fistula Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group.

Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

5.8 QT Interval Prolongation In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics.

Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

5.9 Hypocalcemia In Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction.

Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

5.10 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

5.11 Hemorrhagic Events In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients.

Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

5.12 Impairment of Thyroid Stimulating Hormone Suppression LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.

Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 5.13 Embryofetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions sections in the full prescribing information.

• Hypertension • Cardiac Dysfunction • Arterial Thromboembolic Events • Hepatotoxicity • Proteinuria • Renal Failure and Impairment • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation • Hypocalcemia • Reversible Posterior Leukoencephalopathy Syndrome • Hemorrhagic Events • Impairment of Thyroid Stimulating Hormone Suppression 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 practice.

Safety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions. The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months.

The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinerefractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo.

Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.

In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAtreated patients than patients receiving placebo in the double-blind phase of the DTC study.

Table 2

Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4 LENVIMA 24 mg N=261 All Grades Grades 3-4 (%) (%)

Electrocardiogram QT prolonged

9

44 2

16 2

4 0

9 2 5 2 2 0.4 1 0.4 0.4

17 25 8 15 11 15 2 8 4

0 1 0 0 1 1 0 0 0

11 0.4

35 8

4 0

5

28

3

13 7 2

15 18 2

1 1 1

3 0 0.4

11 3 9

1 0 0

11

3

0

3 0.4 0 0

1 3 5 2

0 0 0 0

1 0 0

5 18 1

0 0 0

0

3

0

1 1

1 5

0 0

2

2

0

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes rash macular, rash maculo-papular, rash generalized, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively). a

Table 3

Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

Laboratory Abnormality

Chemistry Creatinine increased Alanine aminotransferase (ALT) increased Aspartate aminotransferase (AST) increased Hypocalcemia Hypokalemia Lipase increased Hematology Platelet count decreased

LENVIMA 24 mg N=258b Grades 3-4 (%)

Placebo N=131b Grades 3-4 (%)

3 4 5 9 6 4

0 0 0 2 1 1

2

0

With at least 1 grade increase from baseline Subject with at least 1 post baseline laboratory value In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. a b

LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176

S:9.75”

Adverse Reaction Vascular Disorders 73 Hypertensiona Hypotension 9 Gastrointestinal Disorders Diarrhea 67 Nausea 47 41 Stomatitisb Vomiting 36 Abdominal painc 31 Constipation 29 d 25 Oral pain Dry mouth 17 Dyspepsia 13 General Disorders and Administration Site Conditions e Fatigue 67 Edema peripheral 21 Musculoskeletal and Connective Tissue Disorders Arthralgia/Myalgiaf 62 Metabolism and Nutrition Disorders Weight decreased 51 Decreased appetite 54 Dehydration 9 Nervous System Disorders Headache 38 Dysgeusia 18 Dizziness 15 Renal and Urinary Disorders Proteinuria 34 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 32 21 Rashg Alopecia 12 Hyperkeratosis 7 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 Cough 24 Epistaxis 12 Psychiatric Disorders Insomnia 12 Infections and Infestations h Dental and oral infections 10 Urinary tract infection 11 Cardiac Disorders

Placebo N=131 All Grades Grades 3-4 (%) (%)

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Infertility Females LENVIMA may result in reduced fertility in females of reproductive potential.

Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.

8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.

Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

8.5 Geriatric Use Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied.

8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily.

10 OVERDOSAGE There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

Cardiac Dysfunction: Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles.

Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.

Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure.

Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.

Gastrointestinal perforation or fistula formation: Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding.

Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA.

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

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

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

editors-At-Large

30

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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Publishing Staff

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Editorial Director Frederique H. Evans fevans@the-lynx-group.com Copyeditor Hina Khaliq Senior Production Manager Lynn Hamilton

The LYNX Group President/CEO Brian Tyburski

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Content Marketing Director Samantha Weissman Web Content Manager Anthony Trevean

June 2015 Journal OF

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

TM

Table of Contents Editorial 33 Improving Patient Outcomes with Standardization

Patrick J. Medina, PharmD, BCOP Original Research 34 Analyzing Trends in Oral Anticancer Agents in an Academic

Medical Facility Elizabeth Gustafson, PharmD; Jacob K. Kettle, PharmD, BCOP

43 Fluorouracil Overdose: Clinical Manifestations and Comprehensive

Management During and After Hospitalization Ivyruth W. Andreica, BSN, PharmD; Erin Pfeifer, PharmD, BCPS; Marina Rozov, PharmD, BCPS; Erica Tavares, PharmD, BCPS; Anastasiya Shakurova, PharmD; Taylor Ortiz, MD departments

Symptom Management Overview 39 Hyperuricemia Management

By Amber Diaz, PharmD, BCOP; Joseph Bubalo, PharmD, BCPS, BCOP From the Literature 48 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

Content Digital Manager Allison Musante Digital Programmer Michael Amundsen Jr Digital Media Specialist Charles Easton IV Meeting & Events Planner Linda Mezzacappa Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Sales Assistant Aadam Mohamed Administrative Assistant Amanda Hedman 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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Volume 5, number 2

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 © 2015

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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3RD ANNUAL

se V Jh rie iew op s o th On nli e lin ne e. at co m

A 5-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 3rd annual Conquering the Cancer Care Continuum series.

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Good Manufacturing Practice Lillie D. Shockney, RN, BS, MAS

University Distinguished Service Associate Professor of Breast Cancer Johns Hopkins University School of Medicine, Baltimore, MD

am very excited to announce our Conquering the Cancer Care Continuum series. these t publications will continue to address

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uum he t g n i r e Conaqnuceri Care CC o n t i n u uCmonquering th Cancer Care e ™

• Advances in Side Effect Management • Impact of the Affordable Care Act in Cancer Care • Pediatric Patient Care

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EDITORIAL

Improving Patient Outcomes with Standardization Patrick J. Medina, PharmD, BCOP Co-Editor-in-Chief, Journal of Hematology Oncology Pharmacy, Associate Professor, Department of Pharmacy, University of Oklahoma College of Pharmacy, Oklahoma City

T

he continued increase in oral chemotherapy agents receiving US Food and Drug Administration approval, and their expanded use in the first-line setting or in combination with intravenous agents, continues to impact the oncology practice. Approximately 25% of all cancer drugs approved are oral agents, with the trend expected to continue.1 In the past, issues with intravenous chemotherapy such as co-pays and patient compliance were easily ascertained because patients were seen in the clinic, and medications were administered directly to them. Through the increased use of oral chemotherapy agents, several safeguards regarding safety and patient compliance have been removed.2 Several articles have been published on the need to have appropriate policies in place ensuring that patients are receiving optimum care for their cancer when taking oral chemotherapy.

In this issue of the Journal of Hematology Oncology Pharmacy, Elizabeth Gustafson, PharmD, and Jacob K. Kettle, PharmD, BCOP, examine a variety of drug-related problems associated with oral chemotherapy use in an outpatient setting (see â&#x20AC;&#x153;Analyzing Trends in Oral Anticancer Agents in an Academic Medical Facility,â&#x20AC;? on page 34). One of the more striking problems identified in their research was treatment-related toxicity secondary to an oral chemotherapy agent, which was reported by 80% of patients, with 36% classified as severe. In addition, 17% of patients required hospitalization within 90 days of treatment initiation because of toxicity from an oral chemotherapy agent. Finally, a potential drug interaction related to an increase in oral anticancer agent toxicity was identified in 20% of all patients. With these statistics, it is shocking, but not surprising, that pharmacists and other healthcare practitioners have to increase their efforts to provide appropriate patient counseling on these medications that patients are entrusted to take at home.

A recent European cross-sectional study demonstrated the lack of standardization in oral chemotherapy use.

Just over half of 157 oncologists in the study reported

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handing out educational material with the first prescription of oral chemotherapy as a way to limit avoidable side effects, and approximately 23% reported having no systems in place to monitor adherence.3 Only 6% of the 112 centers surveyed in the same study reported that a pharmacist was responsible for developing the educational material, demonstrating a potentially expanded role for the profession. A similar 2007 study of US cancer centers demonstrated an equal lack of consistency regarding oral chemotherapy prescribing practices.4

With these statistics, it is shocking, but not surprising, that pharmacists and other healthcare practitioners have to increase their efforts to provide appropriate patient counseling on these medications that patients are entrusted to take at home.

Despite the many demonstrated clinical benefits of oral chemotherapy agents, inconsistent practice standards regarding their use still exist. Standardization of prescribing procedures and appropriate monitoring of these agents should positively impact patient outcomes. Although a variety of efforts have been made, pharmacists should continue to work with other healthcare practitioners to refine the practice of prescribing oral chemotherapy agents. Continued efforts to maximize their benefit, and, just as importantly, minimize their harm with standard practice procedures are still needed. n

References

1. US Food and Drug Administration. Drug approvals and databases. www.fda.gov/ Drugs/InformationOnDrugs/default.htm. Updated December 16, 2014. Accessed April 28, 2015.

2. Weingart SN, Brown E, Bach PB, et al. NCCN task force report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(Suppl 3):S1-S14.

3. Bourmaud A, Pacaut C, Melis A, et al. Is oral chemotherapy prescription safe for patients? A cross-sectional survey. Ann Oncol. 2014;25:500-504.

4. Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety practices at US cancer centres: questionnaire survey. BMJ. 2007;334:407.

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Original Research

Analyzing Trends in Oral Anticancer Agents in an Academic Medical Facility Elizabeth Gustafson, PharmD; Jacob K. Kettle, PharmD, BCOP É

Audiocast at JHOPonline.com

J Hematol Oncol Pharm.

2015;5(2):34-37 www.JHOPonline.com Disclosures are at end of text

Background: The advent of novel oral anticancer agents is shifting the paradigm in cancer care.

Although this approach offers numerous advantages, including increased patient convenience compared with conventional parenteral therapy, the expanding utilization of oral therapy creates a unique set of challenges to providing optimum patient care.

Objectives: The purpose of this study is to quantify the use of oral anticancer agents and analyze the incidence of various drug-related problems among patients treated with these medications.

Methods: A 1-year review of all prescriptions filled for oral anticancer agents was conducted at an outpatient cancer center pharmacy in an academic medical center. From this population, 100 patients were randomly selected for a detailed retrospective chart review.

Results: In 1 year, 1061 prescriptions were filled for oral anticancer agents. Patients took a mean of 10.9 additional medications with 2.1 major drug interactions identified. Treatment-related toxicity secondary to an oral anticancer agent was reported by 80% of patients, with 36% classified as severe. Seventeen percent of patients were hospitalized because of confirmed or suspected toxicity from the oral anticancer agents within 90 days of initiation.

Conclusion: Patients prescribed oral anticancer agents exhibit significant polypharmacy and drug–drug interactions and frequently experience adverse events leading to dose reductions, discontinuation, and hospitalization. Although further research is necessary, these data suggest that a detailed drug therapy monitoring strategy is an essential component to maximize safety and efficacy during therapy with oral anticancer agents.

A

lthough traditional oncology treatment has predominantly revolved around the parenteral administration of chemotherapy, novel oral treatments are changing the landscape of oncology practice.

The number of oral anticancer agents approved by the US Food and Drug Administration (FDA) has increased substantially in recent years.1 This trend is expected to continue as the National Comprehensive Cancer Network task force estimates that more than a quarter of the approximately 400 oncology drugs in development will be administered orally.1 Although oral anticancer agents offer numerous advantages, including markedly improved patient convenience, the increased use of this treatment modality simultaneously generates numerous treatment challenges compared with conventional chemotherapy. Barriers to optimal utilization of oral therapy include ensuring patient adherence, identifying and resolving drug interactions, and monitoring and managing adverse effects. These challenges are further compounded by the high cost of, and restricted access to, many oral anticancer agents.

Dr Gustafson is a PGY2 Oncology Pharmacy Practice Resident, Providence Alaska Medical Center, Anchorage, AK, and Dr Kettle is an Oncology Clinical Pharmacy Specialist, Department of Pharmacy, University of Missouri Health Care, Columbia, MO.

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The purpose of this descriptive study is to quantify oral anticancer agent use at an academic medical center, and to analyze the frequency of various drug-related problems.

Methods A review of the electronic pharmacy prescription database at the outpatient cancer center pharmacy was conducted to identify the total number of prescriptions filled for oral anticancer agents in 2013 (Figure). For the purposes of this study, an oral anticancer agent was defined as any orally administered medication with an FDA-approved indication for the treatment of malignancy. One hundred patients were then randomly selected from this larger population for further analysis as part of the retrospective chart review. Evaluated outcomes included quantification of the number of medications on the patient profile, the number of major drug–drug interactions, the occurrence and severity of adverse events, and hospital admissions associated with the oral anticancer agent within 90 days of treatment initiation. Patients were subdivided based on age (≥65 or <65 years) to assess the presence of increased complications in elderly patients. Patients had to be ≥18 years of age in order to be included in the analysis.

The number of total medications and drug interactions were assessed at the time of oral anticancer agent initiation. Drug interactions were analyzed and identi-

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Analyzing Trends in Oral Anticancer Agents

Results A total of 1061 oral anticancer agent prescriptions were filled for 268 unique patients during the study period (Figure). The most common medications filled were capecitabine, anastrozole, and tamoxifen. Several drugs were filled only once during the entire year, including pazopanib, vorinostat, dabrafenib, and enzalutamide.

Overall, 65% of the patients included in the retrospective analysis were women, and 60% of the patients were <65 years of age. See Table 1 for a summary of demographic information.

The medication profile review revealed that patients were prescribed a mean of 10.9 medications (standard deviation, 5.5; range, 0-33) in addition to their oral anticancer agents, and had a mean of 2.1 major drug interactions (standard deviation, 2.7; range, 0-17) at the onset of oral anticancer agent therapy. A drug interaction potentially associated with an increase in oral anticancer agent toxicity was identified in 20% of patients,

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Capecit

270 260 250 240 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

abine Anastr ozole Tamox ifen Letrozo le Etopos ide Imatin ib Sunitin ib Hydrox yurea Everoli mus Exeme stane Dasati nib Sorafe nib Vemur afenib Lapatin ib Regora fenib Merca ptopur in Bicaluta e mide Cyclop hospha mide Temoz olomid e Nilotin ib Tretino in Ponati nib Procar bazine

Figure Prescriptions for Oral Anticancer Agents Filled in 2013

Number of total prescriptions

fied according to the online database Micromedex; only interactions classified as major (ie, life-threatening and/or requiring medical intervention to minimize or prevent serious adverse effects) or contraindicated were included.2 Drug interactions affecting the oral anticancer agent were further defined as either increasing toxicity or decreasing efficacy. The adverse event analysis continued for a period of 90 days after initiation of the oral anticancer agent. Documentation in the medical record was not routinely sufficient to apply standardized toxicity grading scales; therefore, adverse reactions were determined as severe if they resulted in dose reduction, treatment discontinuation, hospital admission, or if they were described specifically as “severe” in the medical chart. Toxicities not resulting in one of the aforementioned qualities were classified as mild to moderate. Hospital admissions within 90 days of therapy initiation were considered to be associated with the oral anticancer agent therapy only if specifically stated as such in the medical chart.

During the study period, there was no formalized oral chemotherapy compliance program or other review and monitoring system in place for patients receiving oral anticancer agents.

Analysis of outcomes was primarily completed using descriptive statistics. In the subgroup analysis, the Student t-test was used for the number of medications and drug interactions, and the chisquare test was used to calculate adverse events and admission rates. For all statistical tests, a P value of ≤.05 was noted as statistically significant.

with 8% of patients having >1 such interaction. Concomitant medications, described as reducing efficacy of anticancer therapy, were noted in 8% of patients. Overall, 80% of patients reported treatment-related toxicity within 90 days of initiation; 36% of these inter­actions were classified as severe. Hospitalization was required for oral therapy–induced toxicity in 17% of patients within 90 days of initiation.

Subgroup analysis did not indicate any difference between younger (age <65 years) and elderly (age ≥65 years) patients regarding the number of drug interactions, frequency of toxicity, and hospital admissions (Table 2).

Discussion Although polypharmacy, drug interactions, and adverse reactions were expected in patients treated with an oral anticancer agent, the degree of these findings was greater than anticipated. Perhaps the most unforeseen finding was that approximately 1 in 6 patients

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Original Research

Table 2 Subgroup Analysis Based on Age-Group

Table 1 Patient Demographics Characteristics

Patients

(N = 100)

Age, yrs Median

60.7

Range

30-89

Sex, %

End point

Age <65 Age 竕･65 yrs yrs (N = 60) (N = 40) P value

Total number of medications (mean), N

11.4

10.3

.3

Drug interactions per patient (mean), N

2.3

1.9

.3

Male

35

Toxicity of any severity

85%

72.5%

.2

Female

65

Admission within 90 days

20%

12.5%

.3

Oral anticancer agent, % Capecitabine

25

Sunitinib

10

Tamoxifen

8

Etoposide

8

Sorafenib

7

Imatinib

5

Other

37

Oncology diagnosis, % Breast

30

Colorectal

17

Renal-cell carcinoma

9

Gastrointestinal stromal tumor

7

Hepatocellular carcinoma

6

Chronic myeloid leukemia

5

Small-cell lung cancer

5

Melanoma

5

Other

16

were hospitalized within 90 days of therapy for reasons potentially attributable to the oral anticancer agent.

Hospitalizations were seen following treatment with conventional chemotherapy administered in oral formulations (eg, capecitabine and etoposide), as well as targeted and hormonal therapy. These outcomes must be considered with caution; because of selection bias, the heterogeneity of the study population and retrospective nature of this study could have contributed to this surprising result.

The frequency of drug interactions impacting the oral anticancer agents was also concerning. Although the clinical impact of these interactions is largely uninvestigated, our data suggest that approximately 1 in 10 patients were potentially receiving subtherapeutic dosing.

The acid-suppressing medications (eg, proton pump inhibitors and histamine 2-receptor antagonists), which are well known to alter the bioavailability of numerous

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medications by increasing gastric pH levels, were the most common culprits in this review.3 We observed that interactions capable of leading to increased toxicity were seen in 1 of 5 patients prescribed an oral anticancer agent, which may explain the higher-than-expected frequency of adverse events and hospitalizations; however, too many confounding variables exist to draw a clear association. In addition, because of the limited data available it is not explicitly clear whether patients were truly taking all interacting medications as indicated on the reviewed medication profile. The filling pharmacist certainly may have intervened to resolve various drug-ﾂｭ related problems on many occasions. In addition, factors such as noncompliance or inaccurate medication lists could have interfered with the results. Despite these limitations, these data clearly demonstrate that patients prescribed oral anticancer agents are at a considerable risk for complications relating to drug窶電rug interactions, and that a thorough medication profile review is essential to providing adequate care.

The overwhelming polypharmacy among patients receiving oral anticancer agents was far beyond what was estimated prior to initiating the study. Previous studies have demonstrated abandonment rates with oral anticancer agents exceeding 50% once a patient begins filling 竕･5 prescriptions per month.4 The average patient in our study population had a medication profile more than double this threshold. This finding is particularly alarming given that decreased oral anticancer agent compliance may result in poorer response rates in disease states such as chronic myeloid leukemia.5 These results reinforce the need to closely monitor patients receiving oral anticancer agents, as is recommended in current practice guidelines.6,7 The potential implications of suboptimal oral anticancer agent therapy presents profound challenges, which must be addressed.

Additional studies are warranted to assess single medications and/or disease states, and to describe the true clinical consequences of drug-related problems in patients treated with oral anticancer agents.

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Conclusion Results from this study indicate that patients prescribed oral therapy for cancer experience substantial polypharmacy, drug interactions, and adverse drug events that can negatively affect disease outcomes. Although further research is necessary, these data suggest that a detailed drug therapy monitoring strategy is an essential component to maximizing safety and efficacy during therapy with oral anticancer agents. As the paradigm of oncology shifts from parenteral medications to an increased number of oral therapies, adapting clinical practice and developing new strategies for therapeutic monitoring will be an essential component of providing optimal patient care. n

References

1. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(suppl 3):S1-S14.

2. Micromedex Healthcare Series. DRUGDEX System [database online]. Greenwood Village, CO: Truven Health Analytics, Inc; 2013. www.micromedexsolutions.com.

Accessed June 12, 2014.

3. Segal EM, Flood MR, Mancini RS, et al. Oral chemotherapy food and drug interactions: a comprehensive review of the literature. J Oncol Pract. 2014;10:e255-e268.

4. Streeter SB, Schwartzberg L, Husain N, et al. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011;7(suppl 3):46s-51s.

5. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381-2388.

6. Neuss MN, Polovich M, McNiff K, et al. 2013 updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards including standards for the safe administration and management of oral chemotherapy. J Oncol Pract. 2013;9(suppl 2):5s-13s.

7. Goodin S, Griffin N, Chen B, et al. Safe handling of oral chemotherapy agents in clinical practice: recommendations from an international pharmacy panel. J Oncol Pract. 2011;7:7-12.

Author Disclosure Statement Dr Kettle is an advisor for Genentech and Amgen. Dr Gustafson reported no conflicts of interest.

Audiocast. Interview with Jacob K. Kettle, PharmD, BCOP, author of Analyzing Trends in Oral Anticancer Agents in an Academic Medical Facility.

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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. The updates will be presented in the form of a “How I Treat” type of article.

The goal of this section is to present 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 38.

Hyperuricemia Management

By Amber Diaz, PharmD, BCOP; Joseph Bubalo, PharmD, BCPS, BCOP Dr Diaz is Oncology Clinical Pharmacy Specialist, Oregon Health and Science University Hospital, OHSU Hospital and Clinics, Portland; and Dr Bubalo is 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

Symptom Overview Hyperuricemia is a complication commonly associated with tumor lysis syndrome (TLS) in patients with hematologic cancers. It is characterized by an increased serum uric acid concentration driven by the purine catabolism pathway, which converts purine nucleic acids to hypo­ xanthine, to xanthine, and then to uric acid via the xanthine oxidase enzyme.1 In the context of TLS, hyperuricemia is defined as a uric acid level ≥8 mg/dL, based on Cairo and Bishop’s laboratory criteria.2 Accumulation can result in uric acid crystal precipitation in the renal tubules, leading to renal damage and potential renal failure.

omparison of General and Cancer-Related Risk Table 1 C Factors for Hyperuricemia General

Cancer-related

Renal dysfunction: • Anuria • Oliguria • Uremia • Decreased urine output

Aggressive hematologic malignancies: • NHL • ALL • AML • CML in blast crisis

Dehydration

High tumor burden

Acidic urine

High tumor cell proliferation rate

Diabetes

High sensitivity to cytotoxic treatment

Gout

Etiology Hyperuricemia occurs most commonly in patients with aggressive hematologic malignancies that have ≥1 of the following characteristics: a high tumor burden; a rapid rate of proliferation; or are more sensitive to cytotoxic treatment.1,3 As an important component of TLS, hyperuricemia is most frequently seen in patients with high-grade, non-Hodgkin lymphomas, especially Burkitt lymphoma, and other aggressive hematologic disorders, including acute lymphoblastic leukemia and acute myeloid leukemia. In addition to cancer-related causes, which can result in spontaneous versus treatment-­related

Hypertension Hypotension Nephrotoxins ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; NHL, non-Hodgkin lymphoma.

Sources: References 1-4.

TLS, the associated hyperuricemia can be exacerbated by underlying renal dysfunction, dehydration, or other comorbidities outlined in Table 1.1-4

treatment options Treatment is focused on prophylaxes, and prevention of the hyperuricemic component of TLS. Aggressive fluid hydration is essential to increase urine output and promote uric acid excretion. Intravenous (IV) fluid infusion rates should be sufficient to maintain urine output at >100 mL/hr (or 3 mL/kg/hour in children weighing <10 kg); up to 3 L/m2 is recommended for adult patients with high risk of TLS.3,4 Selection of fluids and initial rates should be guided by the

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cardiovascular status of the patient,3 and clinical assessment of patient-specific factors. Use of sodium bicarbonate for urine alkalinization is no longer recommended in light of studies showing that alkalinization may be ineffective in preventing uric acid nephropathy,3,5 contribute to acute kidney injury,3,6 and increase risk of precipitation of xanthine crystals in renal tubules when used in patients receiving allopurinol.1 Allopurinol is considered a mainstay for preventing

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Symptom Management Overview

Table 2 Comparison of Common Antihyperuricemic Agents Drug

Common doses

Notable adverse events

Notable drug interactions

Allopurinol

Oral: Loading: 600-800 mg/day on day 1 Continuation: 300 mg/day Intravenous: 200-400 mg/m2/day (maximum 600 mg daily) either once daily or in divided doses 2 to 3 times daily

Dermatologic hypersensitivity (1%-3%) Diarrhea (>1%) Nausea (1.3%) Renal insufficiency and/or renal failure (1.2%) Liver function abnormalities (>1%)

Thiazide diuretics Azathioprine and mercaptopurine (dose reductions of 50%-70% required when used with allopurinol) Theophylline derivatives Amoxicillin/ampicillin antibiotics (may increase potential for hypersensitivity reactions) Didanosine

Febuxostat

Oral: 40-60 mg once daily

Rash (0.5%-1.6%) Nausea (1.1%-1.3%) Liver function abnormalities (4.6%-6.6%) Arthralgia (0.7%-1.1%)

Azathioprine Mercaptopurine Theophylline derivatives

Rasburicase

Intravenous: Weight based: 0.1-0.2 mg/kg once daily Fixed dosing: 1.5-7.5 mg intravenously once, with repeated doses given as needed based on uric acid levels

Rash (13%) Headache (26%) Nausea (27%) Vomiting (50%) Fever (46%) Methemoglobinemia (<1%) Hemolysis (<1%)

None known

Sources: References 1, 3, 7-15.

hyperuricemia associated with TLS.3 Allopurinol works as a competitive xanthine oxidase inhibitor, effectively blocking the conversion of hypoxanthine and xanthine to uric acid.1,3 Allopurinol is available both orally and intravenously. Although the efficacy of the IV formulation is equivalent to that of the oral formulation, oral dosing is preferred in most cases for cost considerations.

Use of IV allopurinol should be restricted to patients who are unable to tolerate oral medications.1 In adults, allopurinol is given as a load of 600 to 800 mg orally per day in divided doses starting 12 to 48 hours prior to initiating cytotoxic therapy,3 followed by 300 mg orally once daily throughout active treatment and until uric acid levels and all other TLS laboratory values have normalized.3 IV dosing of allopurinol in adults is 200 to 400 mg/m2 (maximum 600 mg daily) either once daily or in divided doses 2 to 3 times daily. Most of the evidence recommending renal dose adjustments for allopurinol originates from the chronic treatment of gout, where a dose reduction of 50% may be recommended in patients with renal insufficiency.1 However, it is unclear whether renal adjustment is required in the short-term treatment of acute TLS.7 Allopurinol primarily works to prevent further production of uric acid; however, it is unable to break down preexisting uric acid.3 When given concurrently with IV hydration, allopurinol prophylaxis is preferred for at least 1 to 2 days prior to initiation of chemo-

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therapy to allow for excretion of existing uric acid loads.3 This pretherapy treatment may not be possible, depending on tumor kinetics (which may require urgent therapy for other clinical indications).

Febuxostat, a selective xanthine oxidase inhibitor, may be a suitable antihyperuricemic alternative to allopurinol.8 Although it is rare, hypersensitivity reactions are associated with allopurinol, and renally impaired patients may be at an increased risk.7 Febuxostat is associated with fewer hypersensitivity reactions, and does not require renal adjustment,8 so it may provide an alternative for patients who have known hypersensitivity to allopurinol. Febuxostat is currently indicated for the management of gout-associated hyperuricemia; however, recent studies suggest its potential usefulness in the context of TLS.9 Febuxostat doses of 40 to 60 mg daily successfully lowered uric acid levels in a single-institution study of Japanese patients with cancer managed for intermediate-risk TLS. Another single-institution, retrospective study of Japanese patients with cancer at risk for TLS showed no significant difference between 300 mg daily of allopurinol and 40 mg daily of febuxostat in lowering uric acid levels.10 Finally, rasburicase, a recombinant urate oxidase enzyme, promotes the conversion of uric acid to the inactive soluble metabolite allantoin.1 Although it is very effective in reducing uric acid levels, rasburicase is typi-

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cally reserved—because of its high cost—for treatment of patients who have already developed hyperuricemia with TLS, or as prophylaxis for high-risk individuals.1 Rasburicase is considered the therapy of choice for hyperuricemia despite prophylactic allopurinol use. Recommended IV dosing for rasburicase is 0.1 to 0.2 mg/kg once daily with treatment duration ranging from 1 to 7 days1,3; however, there is growing evidence supporting the safe and effective use of single-dose and fixed-dose rasburicase as a potential cost-saving strategy. Most of the data for single-dose rasburicase are retrospective reviews based on single-institution experiences using fixed doses of rasburicase ranging from 1.5 to 7.5 mg,11-13 and 1 prospective study using a historical control group.14 Repeat doses may be given based on continued serum uric acid level monitoring.11,12 Rasburicase is relatively fast-acting, with a decrease in uric acid levels observed within 4 hours of administration.14 Rasburicase is contraindicated in patients with a known glucose-6-phosphate dehydrogenase deficiency because of an increased risk for hemolysis.15 Serious adverse reactions to rasburicase are rare, but include hypersensitivity reactions (eg, anaphylaxis), hemolysis, and methemoglobinemia. Of clinical importance, rasburicase causes continued ex vivo enzymatic degradation of uric acid in blood samples kept at room temperature, leading to falsely low uric acid measurements. Blood samples should be placed in chilled tubes with a heparin anticoagulant, immersed immediately in an ice water bath, and assayed within 4 hours of collection to ensure accurate results.15 Allopurinol and rasburicase may be used concomitantly to optimize treatment of TLS, with allopurinol preventing formation of new uric acid, and rasburicase eliminating the existing uric acid load. For a comparison

of common antihyperuricemic agents, see Table 2.1,3,7-15 In summation, patients with highly aggressive hematologic cancers are at an increased risk for hyperuricemia as part of their clinical course. The best form of treatment remains prevention of hyperuricemia with aggressive fluids and allopurinol. Rasburicase is an option for patients at high risk for hyperuricemia, or for patients with clinically significant hyperuricemia. n

References

1. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26: 2767-2778.

2. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

3. Mughal TI, Ejaz AA, Foringer JR, et al. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev. 2010;36:164-176.

4. Tosi P, Barosi G, Lazzaro C, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93:1877-1885.

5. Conger JD, Falk SA. Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest. 1977;59:786-793.

6. Ten Harkel AD, Kist-Van Holthe JE, Van Weel M, et al. Alkalinization and the tumor lysis syndrome. Med Pediatr Oncol. 1998;31:27-28.

7. Allopurinol tablet [package insert]. Huntsville, AL: Qualitest Pharmaceuticals; 2012.

8. Uloric (febuxostat) tablet [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013.

9. Takai M, Yamauchi T, Ookura M, et al. Febuxostat for management of tumor lysis syndrome including its effects on levels of purine metabolites in patients with hematological malignancies - a single institution’s, pharmacokinetic and pilot prospective study. Anticancer Res. 2014;34:7287-7296.

10. Maie K, Yokoyama Y, Kurita N, et al. Hypouricemic effect and safety of febuxostat used for prevention of tumor lysis syndrome. Springerplus. 2014;3:501.

11. Clemmons AB, Ensley E, Hoge S, et al. Fixed-dose rasburicase in overweight and obese patients versus normal-weight patients. Ann Pharmacother. 2014;48:1152-1158.

12. Herrington JD, Dinh BC. Fixed, low-dose rasburicase for the treatment or prevention of hyperuricemia in adult oncology patients. J Oncol Pharm Pract. 2015;21: 111-117.

13. McBride A, Lathon SC, Boehmer L, et al. Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome. Pharmacotherapy. 2013;33:295-303.

14. Reeves DJ, Bestul DJ. Evaluation of a single fixed dose of rasburicase 7.5 mg for the treatment of hyperuricemia in adults with cancer. Pharmacotherapy. 2008;28: 685-690.

15. Elitek (rasburicase) powder for solution, for intravenous infusion [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2011.

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Immunotherapy in

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Case Report

Fluorouracil Overdose: Clinical Manifestations and Comprehensive Management During and After Hospitalization Ivyruth W. Andreica, BSN, PharmD; Erin Pfeifer, PharmD, BCPS; Marina Rozov, PharmD, BCPS; Erica Tavares, PharmD, BCPS; Anastasiya Shakurova, PharmD; Taylor Ortiz, MD Background: Uridine triacetate, a proposed antidote for fluorouracil overdoses, is available for investigational use in the United States. When used with supportive measures, the survival rate of patients has been shown to drastically improve. To our knowledge, previously published case reports do not discuss the care and outcome of patients beyond 5 days postdischarge, or after reaching neutrophil nadir. This case report follows a patient posthospitalization and through neutrophil count recovery.

Objective: To discuss the overall management of a fluorouracil overdose from initial exposure, through hospitalization and posthospitalization, to recovery.

Case: A 60-year-old man with rectal carcinoma and liver metastases was admitted to the emergency department following a confirmed fluorouracil overdose from an ambulatory infusion pump issue, and received approximately 4.4 g of fluorouracil over 20 minutes. The patient developed neutropenia postdischarge that required intervention.

Discussion: Complications from fluorouracil include profound neutropenia, gastrointestinal toxicity, cardiotoxicity, and infection. When the overdose was identified, an initial assessment of hemodynamic status was performed; laboratory tests including complete blood count, electrolytes, liver function, and serum creatinine were obtained; and an electrocardiogram was reviewed. Intravenous hydration therapy, electrolyte correction, and oral glutamine were administered. Twenty hours after the overdose, uridine triacetate was administered, followed by filgrastim, and later levofloxacin. The patient had increased ostomy output, nausea, vomiting, mucositis, nonsustained electrocardiogram changes, and an episode of hypotension. Because of an elevated white blood cell count, filgrastim was discontinued; however, the patient had severe neutropenia 5 days later, requiring further treatment with filgrastim.

Conclusion: To minimize complications and reduce mortality, prompt recognition of a fluorouracil overdose, administration of uridine triacetate and supportive care, and avoidance of medications that inhibit fluorouracil clearance is vital. Close monitoring throughout the expected neutrophil nadir is equally impor­tant during the posthospitalization period after a fluorouracil overdose.

T

he antineoplastic and antimetabolite fluorouracil has been used extensively to treat colon, breast, and other solid tumor cancers.1 Treatment regimens incorporating fluorouracil vary widely depending on patient and tumor characteristics, and may range from intermittent bolus doses with radiation therapy to multiday, continuous intravenous (IV) infusions as part of combination chemotherapy.

Continuous fluorouracil infusions are commonly administered via an ambulatory infusion pump, which allows the patient to receive therapy at home. According to the National Institutes of Health, approximately 275,000 paDrs Andreica, Rozov, and Tavares are Clinical Pharmacists, Department of Pharmacy, Massachusetts General Hospital, Boston, MA. Dr Pfeifer is Clinical Pharmacist, Childrenâ&#x20AC;&#x2122;s Hospital, Colorado, Aurora. Dr Shakurova is Clinical Informatics Pharmacist, Partners eCare, Boston, MA. Dr Ortiz is Oncologist, Wentworth-Douglass Hospital, Dover, NH.

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2015;5(2):43-47 www.JHOPonline.com Disclosures are at end of text

tients in the United States receive fluorouracil annually as part of their chemotherapy regimen. Approximately 3% of these patients will have some degree of toxic reaction, and >1300 deaths occur in the United States each year because of fluorouracil exposure.2 Continuous infusion pumps can predispose patients to a fluorouracil overdose because of potential errors in programming, calculation errors, and device malfunctions, which have resulted in numerous cases where patients received higher than intended doses or rates of administration.3,4 Other potential causes of overexposure to fluorouracil include intrinsic deficiency in metabolism through dihydropyrimidine dehydrogenase gene mutations,5,6 and accidental administration of the oral prodrug capecitabine.5 Complications from overexposure can manifest during a period of days or weeks. Known side effects such as nausea, vomiting, diarrhea, and mucositis typically have an early onset, manifesting approximately 3 to 8 days after exposure.7 Low blood counts have a delayed onset,

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Case Report

appearing approximately 9 to 14 days after exposure to fluorouracil. Although not common, delay in low white counts appearing up to 20 days later have been reported.1 In the past, patients who received an overdose of fluorouracil were managed solely with supportive care, including colony-stimulating factors and antibiotics.7 Despite these measures, fluorouracil overdose can result in serious toxicities, including death. The oral investigational drug uridine triacetate, which exerts its action by competing with fluorouracil for ribonucleic acid (RNA) integration, is the only antidote available for fluorouracil overdose. To date, approximately 140 cases of overdose have been treated with uridine triacetate, with a reported 96% survival rate. In addition, 50% of the patients treated with uridine triacetate were able to resume their chemotherapy treatment within 30 days of a fluorouracil overdose. Five deaths have been reported to date, but according to the manufacturer, these were not related to the antidote (R. Tremmel, PharmD, Clinical Safety Manager, Wellstat Therapeutics, e-mail communication, May 2014).

In addition to uridine triacetate, the administration of oral glutamine has been proposed to prevent intestinal changes that affect absorption, hence reducing fluorouracil-induced diarrhea.8 If the overdose rate is greater than 10 times the intended rate with a completed delivery of 50% of the intended total fluorouracil dose, supportive therapy with IV hydration, filgrastim, fluoroquinolones, and oral glutamine is recommended.9 To our knowledge, this case report is the first to extensively describe a patient’s clinical course, complications, and response to treatment following a fluorouracil overdose.

Case Report A 60-year-old man with rectal carcinoma and liver metastases was admitted to the emergency department following a confirmed fluorouracil overdose.

The patient, who weighed 84.1 kg on admission, received his tenth cycle of IV chemotherapy earlier that day: bevacizumab 5 mg/kg (422 mg), oxaliplatin 85 mg/ m2 (176 mg), leucovorin 400 mg/m2 (828 mg), and fluorouracil 1920 mg/m2 (3974 mg) infusion administered during the course of 46 hours.

An infusion pump malfunction resulted in the entire dose of fluorouracil and an additional 469 mg, which was contained within the overfill compartment, being administered to the patient in 20 minutes. The patient was immediately referred to his local emergency department and, within 90 minutes, transferred to a tertiary care center.

The patient was asymptomatic at presentation to the tertiary center, with stable vital signs and a benign electrocardiogram (ECG). Review of laboratory results indi-

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cated that the basic metabolic panel and liver function tests were within normal range. Phosphorus was depleted (1.5 mg/dL), and magnesium was on the low end of normal (1.5 mEq/L). The patient received electrolyte repletion, as well as glutamine 15 g orally every 12 hours, with the first dose given 9 hours after the overdose.

Uridine triacetate was obtained in accordance with the investigational protocol provided by Wellstat Therapeutics. The patient’s regimen of uridine triacetate 10 g orally every 6 hours for 20 doses was initiated 20 hours after the overdose. To ensure the absorption of the antidote amid chemotherapy-induced nausea and vomiting, the patient received ondansetron 8 mg intravenously prior to each dose of uridine triacetate. Filgrastim 5 mcg/ kg (420 mcg) intravenously was also administered.

On day 1, the patient was admitted for observation.

He continued to receive uridine triacetate per protocol.

He also continued therapy with glutamine 15 g orally every 12 hours. On day 3, an ECG demonstrated 3 beats of nonsustained ventricular tachycardia (NSVT) and premature ventricular contractions (PVCs). On day 6, the patient had an episode of hypotension and intermittent, asymptomatic tachycardia, which resolved with the administration of IV fluids. On days 1 to 4, the patient had a moderate increase in loose ostomy output, nausea with 1 episode of vomiting, and mucositis with 1 ulceration on the inside of his cheek. He received loperamide 4 mg orally daily, clotrimazole troches 4 times daily, equal parts of antacid (Maalox), lidocaine, and diphenhydramine (magic mouthwash) 10 mL orally 3 times daily, filgrastim 420 mcg intravenously daily (total of 6 doses), and levofloxacin 500 mg orally daily, which was later increased to 750 mg. On day 4, his complete blood count (CBC) revealed that his white blood cells (WBCs) increased from 3.5 × 10³ cells/mm3 at presentation to 25.9 × 10³ cells/mm3, likely secondary to preemptive filgrastim administration.

The patient’s WBC subsequently fell to 6.7 × 10³ cells/mm3 at discharge on day 7, despite continued filgrastim administration (see the patient’s hematologic trends in the Table). The patient’s absolute neutrophil count (ANC) at discharge was 5.56 × 10³ cells/mm³. His platelets declined from 233 × 10³/mm³ at presentation to 79 × 10³/mm³ at discharge. No significant changes were observed in his basic metabolic panel, hemoglobin/­ hematocrit, or liver function tests.

The patient was discharged on day 7 with prescriptions for clotrimazole troches 4 times daily, magic mouthwash 10 mL 3 times daily, and loperamide 2 mg orally every 4 hours as needed for loose stool. He received 6 days of levofloxacin therapy as an inpatient and was to continue levofloxacin upon discharge, to be discontinued at the discretion of the patient’s outpatient oncologist. The pa-

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tient declined further levofloxacin treatment postdischarge upon discussion with his provider.

At outpatient follow-up on day 11, the patient presented with grade 3 mucositis. His CBC revealed a WBC count of 0.9 × 10³ cells/mm3, an ANC of 0.19 × 10³ cells/mm³, and platelets of 88 × 10³/mm³. Filgrastim was reinitiated at 480 mcg subcutaneously daily and continued through day 14, when his WBC count was 14.5 × 10³ cells/mm3 and ANC was 11 × 10³ cells/mm³.

Approximately 1 month following the overdose, chemotherapy was discussed with the patient, but he declined further treatment.

On day 28 he was described by his primary oncologist as having fully recovered, with no mucositis or gastrointestinal problems, and a stable CBC. The patient’s only residual side effect was alopecia.

Discussion Infusion pump malfunctions and programming errors have led to numerous cases of fluorouracil overdose, often resulting in serious harm to the patients.

In one case reported to the Institute for Safe Medication Practices (ISMP) Canada, a 43-year-old woman with advanced nasopharyngeal carcinoma died of an accidental fluorouracil overdose because of a possible infusion pump error.3 Bamat and colleagues described 98 cases in which patients received uridine triacetate following fluorouracil overdose.5 Of these patients, 96 recovered fully after treatment with uridine triacetate.

However, the number of cases related to pump malfunctions and programming errors was not defined, and the supportive measures used during treatment were not discussed. McEvilly and colleagues reported the case of a 55-year-old man whose 46-hour 5-fluorouracil infusion had been incorrectly programmed to be administered over 4 hours. Treatment with uridine triacetate was described with a brief mention of supportive measures, such as pegfilgrastim.10 However, the authors did not expand on the role of supportive treatment measures, which may include fluid and electrolyte repletion, and management of gastrointestinal and hematologic adverse effects.

The ISMP has identified many causal factors for fluorouracil overdoses relating to infusion pump errors, and provides safe practice recommendations for fluorouracil overdose prevention.3 Examples of causative factors include a lack of programming safeguards, miscalculations, faulty pharmacy label designs, failed independent double-­ check systems, lack of familiarity with protocol, and pump design contributions.3 To minimize the risk for error, the ISMP encourages the use of enhanced independent double check during infusion pump programming, using infusion pumps with safeguards, and reviewing the pump-dosing screen with the patient. The

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Table Hematologic Trends Following 5-Fluorouracil Overdosea WBC (×103/mm3)

ANC (×103/mm3)

Platelets (×103/mm3)

Filgrastim dose (mcg)

0

3.5

2.97

233

—

1

7.7

5.73

202

420

2

15.6

13.52

175

420

3

23.3

21.47

166

420

4

25.9

24.57

150

420

5

19.6

17.75

124

420

6

9.7

8.11

101

420

7

6.7

5.56

79

—

8

2.4

1.46

95

—

11

0.9

0.19

88

480

12

—

—

—

480

13

5.0

3.55

109

480

14

14.5

11.02

136

480

Day

The overdose/admission occurred on day 0 and the discharge on day 7.

ANC indicates absolute neutrophil count; WBC, white blood cell.

a

patient in our case report was transferred from an outside facility, which hindered our ability to identify the exact cause of the overdose other than what was reported. We would recommend evaluating the pump for possible malfunctions or other causative factors such as programming errors. Pumps that have malfunctioned should be reported to the manufacturer.

Understanding fluorouracil’s mechanism of action is essential to understanding the treatment of a fluorouracil overdose. Fluorouracil exhibits cytotoxic activity through disruption of the biologic processes of both RNA and deoxyribonucleic acid (DNA) thereby inhibiting normal function. Fluorouracil is metabolized into the active metabolites, fluorouridine triphosphate (FUTP), fluorodeoxyuridine triphosphate (FdUTP), and fluorodeoxyuridine monophosphate (FdUMP). FdUTP and FdUMP target DNA through disincorporation of FdUTP during DNA synthesis and the inhibition of thymidylate synthase. FUTP is responsible for the interruption of RNA transcription and function, resulting in apoptosis. Uridine is a naturally occurring pyrimidine nucleoside and is 1 of the 4 basic nucleosides responsible for the formation of RNA.11 It is part of the same biochemical pathway as FUTP, which makes it an effective antidote, reducing the effects of the active metabolite. Intrinsically, uridine is converted to uridine triphosphate (UTP), which then competitively inhibits the incorporation of FUTP into RNA. UTP inherently reduces the toxic effects of FUTP on the gastrointestinal mucosa and the bone marrow.7

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Case Report

25

20

15

10

5

11

8

5

4

3

2

1

dis Day 6 ch of ar ge 7

Da

y

0

0

ANC indicates absolute neutrophil count; WBC, white blood cell.

Uridine triacetate has been granted orphan drug status by the US Food and Drug Administration for the treatment of fluorouracil overdose. Uridine triacetate is available through an orphan drug program from Wellstat Therapeutics.4,12 When overexposure to fluorouracil is suspected, the patient’s provider can contact Wellstat Therapeutics, who will facilitate procurement of the medication. The recommended adult dose of uridine triacetate is 10 g orally every 6 hours for a total of 20 doses, initiated within 3 to 96 hours following overexposure. The antidote does not require adjustment for weight, compromised renal or hepatic functions, or advanced age (>65 years).

Uridine triacetate is available as orange-flavored packets, which can be mixed in applesauce to improve palatability.

Because of anticipated nausea and vomiting associated with fluorouracil, Wellstat Therapeutics recommends preceding each dose of uridine triacetate with an antiemetic to ensure full absorption. If a patient vomits within 2 hours of uridine triacetate administration, a repeat dose of uridine triacetate 10 g is recommended within 15 minutes. The next dose is then given at the originally scheduled time. Our patient received 8 mg of ondansetron 20 minutes before each dose of uridine triacetate. Throughout his inpatient course, he experienced nausea with 1 episode of vomiting, which did not interfere with his antidote regimen. Because of recent concerns about ondansetron dose-dependent risk of arrhythmia,13 we would encourage using the minimum effective dose. Several

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14

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medications may interfere with the absorption of uridine triacetate, including bismuth, sucralfate, and cholestyramine.

Wellstat Therapeutics provides a list of WBC (×103 /mm3) medications that should be avoided 3 3 ANC (×10 /mm ) during the treatment period.

Filgrastim In addition to uridine triacetate, our patient received glutamine, which is a nonessential amino acid that can be synthesized from glucose.14 Intrinsically, glutamine is part of the regulatory system for cell growth in the gastrointestinal tract.

Oral glutamine is traditionally given as a nutritional supplement for the treatment of short bowel syndrome.15 In recent years, its use has expanded to critically ill patients on mechanical ventilation, burn patients, and patients with major elective surgery, trauma, or head and neck cancer, because of its effects on intestinal epithelium and gut integrity maintenance.16 The recommend oral dose is 30 g daily in divided doses; side effects may include nausea and vomiting.15 The use of glutamine to prevent chemotherapy-related mucositis and gastrointestinal side effects remains controversial. It is theorized that several cancer cells utilize glutamine for accelerated cell growth.14 While receiving oral glutamine 15 g twice daily following his fluorouracil overdose, our patient developed grade 3 mucositis.

In anticipation of neutropenia, the human granulocyte colony-stimulating factor filgrastim was initiated.

With therapy, the patient’s WBC count and ANC initially increased, but began to drop on day 5, despite continued filgrastim administration. Filgrastim was not continued at discharge on day 7, and the patient presented to the outpatient clinic on day 11 with a WBC count of 0.9 × 10³ cells/mm3 and an ANC of 0.19 × 10³ cells/ mm³. Filgrastim was restarted on day 11 and continued through day 14, when neutropenia resolved (Figure). For future cases, we recommend continuing therapy with a human granulocyte colony-stimulating factor as appropriate, through the ANC nadir and to recovery, which may take up to 14 days.

Fluorouracil may cause diarrhea in up to 80% of patients.17 Our patient’s diarrhea resolved with the use of loperamide, an agent recommended by the American Society of Clinical Oncology guidelines. Loperamide doses as high as 4 mg at first onset, then 2 mg every 2 hours until the patient is diarrhea-free for 24 hours, have been recommended. The patient received a daily standing dose of loperamide because ostomy output was consistently loose. He had the option to receive additional 13

Figure WBC and ANC Levels During Treatment with Filgrastim

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Fluorouracil Overdose: Clinical Manifestations and Comprehensive Management

loperamide, as needed, and required 1 additional dose during hospitalization. No adverse effects related to loperamide 4 mg daily were observed in our patient. The addition of antibiotics is recommended for patients with diarrhea for more than 24 hours despite treatment with loperamide.17 Hydration therapy consisting of dextrose 5% water and normal saline administered at a rate of 150 to 300 mL/hr was also administered to match the increase in the patient’s output and maintain total body burden.

Cardiotoxicity is a dose-dependent side effect of fluorouracil, occurring in 1.2% to 18% of cases.18 Cardiotoxic effects may include acute coronary syndrome, cardiomyopathy, vasospastic angina, coronary thrombosis and dissection, malignant arrhythmias, and cardiac death.

Our patient had one instance of hypotension and intermittent tachycardia, which resolved with the administration of IV fluids. In addition, 3 beats of NSVT and PVCs were found on an ECG, but did not recur; hence no further intervention was pursued. Calcium channel blockers and nitrates, due to possible vasodilator effects, have been used to resolve fluorouracil-induced cardiotoxic effects.19,20 However, angiotensin-converting enzyme inhibitors have not been shown to be efficacious.21 We recommend continuous ECG monitoring and intervention with vasodilators if sustained cardiotoxic effects are observed. Close surveillance, repletion of electrolytes, and IV hydration may be helpful.

Additional considerations include avoiding medications that could reduce the clearance of fluorouracil.

These include cimetidine, metronidazole, and thiazide diuretics. Because of fluorouracil’s strong inhibiting effect on cytochrome P450 2C9 (CYP2C9), we also advise using caution if the patient is receiving medications activated or metabolized by this enzyme (eg, phenytoin and clozapine).21

Conclusion Fluorouracil overdose is a potentially life-threatening complication of therapy. Safeguards, as recommended by ISMP, should be used whenever possible to minimize the risks for dosing, programming, and pump delivery errors.

The management of a fluorouracil overdose requires a comprehensive approach that extends beyond the initial hospitalization period. Uridine triacetate plays an important role in mitigating the potentially devastating toxicities of a fluorouracil overdose. Because of its orphan drug status, timely procurement and delivery of uridine triacetate is vital. Although antidote administration has improved rates of recovery, it is important for clinicians to continue to monitor the patient closely because of the prolonged/delayed side effects of fluorouracil. Myelosuppression, which may persist after the

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initial exposure period, may require supportive care with human granulocyte colony-stimulating factors and antibiotics for the prevention of infections. Close monitoring should be exercised during the critical period following a fluorouracil overdose and through the expected neutrophil nadir. Future opportunities include the development and implementation of treatment protocols that would help guide clinicians in providing care quickly, effectively, and consistently from presentation and through recovery. n Author Disclosure Statement The authors reported no conflicts of interest.

Acknowledgments Wellstat Therapeutics Corporation was the source for the investigational medication, uridine triacetate.

References

1. Adrucil (fluorouracil) package insert. Irvine, CA: Gensia Sicor Pharmaceuticals, Inc; 1999.

2. National Institutes of Health. Public teleconference regarding licensing and collaborative research opportunities for: methods and compositions relating to detecting dihydropyrimidine dehydrogenase (DPD). Fed Regist. 2008;73:38233.

3. Institute for Safe Medication Practices. Fluorouracil error ends tragically, but application of lessons learned will save lives. www.ismp.org/newsletters/acutecare/articles/ 20070920.asp. Published September 20, 2007. Accessed February 4, 2015.

4. Bamat MK, Tremmel R, O’Neil JD, et al. Uridine triacetate: an orally administered, life-saving antidote for 5-FU overdose [ASCO abstract 9084]. J Clin Oncol. 2010; 28(suppl 15).

5. Bamat MK, Tremmel R, Helton J, et al. Clinical experience with uridine triacetate for 5-fluorouracil overexposure: an update. Ann Oncol. 2013;24(suppl 4):iv71.

6. Wellstat Therapeutics. Uridine triacetate as antidote for patients at excess risk of 5-FU toxicity due to overdosage or impaired elimination, In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine; 2014. www.clinicaltrials. gov/ct2/show/NCT01432301. NLM Identifier NCT01432301.

7. Fox A, Howland M. Vistonuridine®: a novel antidote for 5-fluorouracil. Toxicology letter. 2010;15. www.upstate.edu/poison/pdf/tox_newsletter/01_10toxnews.pdf.

Accessed June 4, 2014.

8. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut. 2001;48:28-33.

9. Gill S. Management of 5-fluorouracil (5FU) infusion overdose at the BCCA (interim guidance). www.bccancer.bc.ca/NR/rdonlyres/46753FA3-46ED-4AD4-A45040A1371E4BDD/49369/5FUInfusorOverdoseManagementGuideline_1Feb2011.pdf.

Published February 1, 2011. Accessed February 20, 2015.

10. McEvilly M, Popelas C, Tremmel B. Use of uridine triacetate for the management of fluorouracil overdose. Am J Health Syst Pharm. 2011;68:1806-1809.

11. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330-338.

12. Wellstat Therapeutics. Uridine triacetate (formerly known as vistonuridine) and 5-FU overexposure. www.wellstattherapeutics.com/therapeutics/html/randd/compounds/ visto-5fu.html. Accessed February 20, 2014.

13. US Food and Drug Administration. FDA drug safety communication: new information regarding QT prolongation with ondansetron (Zofran). www.fda.gov/Drugs/ DrugSafety/ucm310190.htm. Updated February 15, 2013. Accessed June 9, 2014.

14. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35:427-433.

15. NutreStore (L-glutamine powder for oral solution) package insert. Torrance, CA: Emmaus Medical, Inc; 2008.

16. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33:277-316.

17. Benson AB III, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-2926.

18. Sorrentino MF, Kim J, Foderaro AE, et al. 5-Fluorouracil induced cardiotoxicity: review of the literature. Cardiol J. 2012;19:453-458.

19. Farina A, Malafronte C, Valsecchi M, et al. Capecitabine-induced cardiotoxicity: when to suspect? how to manage? a case report. J Cardiovasc Med. 2009;10:722-726.

20. Sentürk T, Kanat O, Evrensel T, et al. Capecitabine-induced cardiotoxicity mimicking myocardial infarction. Neth Heart J. 2009;17:277-280.

21. Fluorouracil. Lexi-Comp Online [database online]. Hudson, OH: Lexi-Comp, Inc. June 9, 2014.

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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 Universityâ&#x20AC;&#x201C;California, Mare Island, Vallejo, CA nA nti-CD19

CAR T-Cells Show Promise in B-Cell Cancer

BACKGROUND: Patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options and a median survival of <10 months.

Although recent advances have improved the treatment of B-cell malignancies, new treatments for chemotherapy-refractory cases are needed. Previous reports showed that a single infusion of autologous T-cells that express anti-CD19 chimeric antigen receptor (CAR) in patients with indolent B-cell malignancies led to lengthy remissions. In what is believed to be the first study of its kind, researchers evaluated the safety and efficacy of autologous anti-CD19 CAR T-cells in patients with advanced CD19-positive B-cell malignancies.

METHODS: The study included 15 patients with advanced B-cell malignancies. Of these, 9 patients had DLBCL, with 3 different subtypes: 4 patients had primary mediastinal B-cell lymphoma, 4 patients had DLBCL not otherwise specified, and 1 patient had DLBCL transformed from chronic lymphocytic leukemia (CLL). In addition, 2 patients had indolent lymphomas, and 4 had CLL. All patients received an initial conditioning chemotherapy regimen consisting of cyclophosphamide at a total dose of 120 mg/kg to 60 mg/kg followed by 5 daily infusions of fludarabine 25 mg/m2. A day later, patients received a single infusion of anti-CD19 CAR T-cells.

RESULTS: Of the 15 patients, 8 achieved complete remission, 4 achieved partial remission, 1 had stable disease, and 2 were not evaluable for response. In the subgroup of 9 patients with DLBCL, 4 of 7 evaluable patients with chemotherapy-refractory DLBCL had complete remission; 3 of these 4 patients are in ongoing complete remission, with durations ranging from 9 to 22 months.

Of the patients with DLBCL, 2 achieved partial response, and 1 achieved stable disease. In the subgroup of 6 patients with indolent B-cell malignancies, all patients achieved a complete remission or partial remission; 3 of 4 patients with CLL are in ongoing complete remission ranging from 14 to 23 months.

The peak level of CAR-positive blood cells varied among patients from 9 to 777 CAR-positive cells/ÂľL. These levels peaked between 7 and 17 days after infusion. Grade 3 and 4 acute toxicities included fever,

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hypotension, delirium, and other neurologic toxicities; these toxicities were transient and resolved within 3 weeks after cell infusion.

This is the first study to show a successful treatment of DLBCL with anti-CD19 CAR T-cells. The majority of patients with chemotherapy-refractory DLBCL and indolent B-cell malignancies achieved complete remission; these findings demonstrate the feasibility and effectiveness of treating this patient population with anti-CD19 CAR T-cells.

Infusion with anti-CD19 CAR T-cells may offer a powerful new treatment option for patients with chemotherapy-refractory B-cell malignancies. The researchers recommended further development of this approach for advanced B-cell malignancies.

Source: Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540-549.

COMMENTARY BY ROBERT J. IGNOFFO

In this study, Kochenderfer and colleagues report extremely positive results from the use of autologous anti-CD19 chimeric antigen receptor (CAR) T-cells in several patients with chemotherapy-refractory B-cell lymphomas. The investigators modified their previous methods and produced autologous CAR T-cells containing CD28, a costimulatory moiety, that led to successful production of CAR T-cells in all 15 patients on the first try. It is remarkable that partial and complete responses were achieved in 8 and 4 of the 15 patients with advanced B-cell lymphomas, respectively. It is noteworthy that the median duration of these responses was 11 to 12 months (range, 6 to 23+ months). Grade 3 and 4 toxicities from CAR T-cell therapy occurred within 2 weeks of therapy, but were transient, and were related to cytokine release, with the most common being hypotension and fever.

This study confirms that the infusion of CAR T-cells is an effective strategy for treating refractory B-cell lymphomas.

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FROM THE LITERATURE

nL envatinib

Prolongs Progression-Free Survival in Advanced Thyroid Cancer

BACKGROUND: Lenvatinib (Lenvima) is a novel oral multitargeted tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1 to 4; platelet-derived growth factor receptor alpha; RET; and KIT-signaling networks. In a phase 2 study of patients with radioactive iodine therapy–refractory differentiated thyroid cancer, lenvatinib demonstrated clinical benefit. Based on these results, researchers conducted a phase 3 study to assess progression-free survival (PFS) among patients who received lenvatinib compared with placebo.

METHODS: The SELECT study was a randomized, double-blind, placebo-controlled, multicenter, phase 3 study involving 392 patients with progressive differentiated thyroid cancer that was refractory to radioactive iodine therapy. Patients were randomized in a 2:1 ratio to lenvatinib 24 mg daily in 28-day cycles (N = 262) or to placebo (N = 131). Pretreatment with 1 previous TKI regimen was permitted. At disease progression, patients in the placebo group could receive open-label lenvatinib. The median duration of treatment was 13.8 months for the lenvatinib group and 3.9 months for the placebo group. The primary end point was PFS, and the secondary end points were response rate, overall survival, and safety.

RESULTS: The median PFS was 18.3 months among the patients who received lenvatinib compared with 3.6 months with placebo, a 14.7-month PFS extension with active treatment (hazard ratio for disease progression or death, 0.21; 99% confidence interval, 0.14-0.31; P <.001). This is the longest improvement in PFS observed in studies comparing active drug therapy and placebo in patients with differentiated thyroid cancer.

The PFS benefit associated with lenvatinib was observed in all prespecified groups. Lenvatinib was associated also with a significantly greater patient response rate compared with placebo—64.8% versus 1.5%, respectively. Furthermore, more complete and partial responses were observed with lenvatinib than with placebo (4 and 165 vs 0 and 2, respectively). The median overall survival was not reached in either group.

Adverse events of any grade, which occurred in >40% of patients in the lenvatinib group, included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The most frequently reported grade ≥3 adverse events reported in the lenvatinib group included hypertension (41.8%),

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proteinuria (10.0%), decreased weight (9.6%), fatigue (9.2%), and diarrhea (8.0%).

A total of 37 patients in the lenvatinib group and 3 patients in the placebo group discontinued treatment because of adverse events.

The 10-year survival rate for patients with differentiated thyroid cancer refractory to radioactive iodine therapy is 10% from time of metastasis. Lenvatinib was associated with significant improvement in PFS and response rate among patients with progressive, radioactive iodine–refractory, differentiated thyroid cancer, which offers a new treatment option for this patient population.

Although the toxic effects of lenvatinib therapy were considerable, most toxic effects were managed with dose modification and medical therapy. Based on these results, in February 2015, the US Food and Drug Administration approved lenvatinib for the treatment of patients with differentiated thyroid cancer that is refractory to radioactive iodine therapy.

Source: Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630.

COMMENTARY BY ROBERT J. IGNOFFO

This study, which was funded by Eisai Inc, demonstrated that lenvatinib greatly improves progression-free survival (PFS) in patients with refractory thyroid cancer. Compared with placebo, lenvatinib produced a nearly 15-month improvement in PFS. Grade 3 or 4 toxicities were typical for a multitargeted tyrosine kinase inhibitor, with hypertension, fatigue, diarrhea, and proteinuria being the predominant adverse effects. Hand-foot syndrome, nausea, vomiting, stomatitis, and decreased appetite were also common.

These results are better than those reported in the DECISION trial (also funded by pharma), which compared the safety and efficacy of sorafenib with placebo in patients with radioiodine-refractory thyroid cancer.

Until lenvatinib receives US Food and Drug Administration approval, sorafenib will remain one of the most effective treatments for patients with differentiated thyroid cancer that is refractory to radioiodine.

Source: Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet. 2014;384:319-328.

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FROM THE LITERATURE

nR uxolitinib More Effective Than Standard

Therapy in the Treatment of Polycythemia Vera

BACKGROUND: Polycythemia vera, a myeloproliferative neoplasm characterized by elevated red blood cell levels, poses an increased risk for thrombotic and cardiovascular events and a significant clinical burden. If untreated, polycythemia vera can transform to myelofibrosis or to acute myeloid leukemia. Based on earlier results of a phase 2 study, researchers conducted a new phase 3 clinical study to evaluate the clinical benefit of ruxolitinib (Jakafi), a Janus kinase (JAK) 1 and 2 inhibitor, versus standard therapy in patients with polycythemia vera that was resistant to standard therapy with hydroxyurea. Standard therapy was selected by the investigator and could include hydroxyurea, interferon alfa or pegylated interferon, pipobroman, anagrelide, immunomodulators such as lenalidomide or thalidomide, or no medication. The study was funded by Novartis and Incyte companies.

METHODS: The study included 222 patients with polycythemia vera requiring phlebotomy for hematocrit control, a spleen volume of â&#x2030;Ľ450 cm3, and no previous treatment with a JAK inhibitor participating in the RESPONSE trial. The RESPONSE study was an international, randomized, open-label, multicenter, phase 3 clinical trial that randomized phlebotomy-dependent patients with splenomegaly in a 1:1 ratio to a 10-mg twice-daily dose of ruxolitinib (N = 110) or to standard therapy (N = 112) selected by the investigator.

The primary end point was hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) was used to evaluate symptom outcomes.

RESULTS: The median exposure time to therapy was 81 weeks in the ruxolitinib group and 34 weeks in the standard therapy group. Significantly more patients receiving ruxolitinib achieved the primary end point versus the standard therapy group (20.9% vs 0.9%, respectively). Furthermore, ruxolitinib was associated with a higher rate (60%) of hematocrit control through week 32 compared with standard therapy (19.6%) (including hydroxyurea in 58.9% of the patients, interferon in 11.6%, anagrelide in 7.1%, immunomodulators in 4.5%, and pipobroman in 1.8%; no medication was administered in 15.2%). In addition, 38.2% and 0.9% of patients in the 2 groups, respectively, had at least a 35% reduction in spleen volume. Ruxolitinib was also associated with a significantly higher rate of complete hematologic response compared with standard therapy (23.6% vs 8.9%, respectively).

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Overall, 49% of patients in the ruxolitinib group had at least a 50% reduction in the MPN-SAF total symptom score at week 32 versus 5% in the standard therapy group. The ruxolitinib group also maintained their primary response at week 32 through week 48 compared with the standard therapy group (19.1% vs 0.9%, respectively).

Because crossover was allowed, the impact of ruxolitinib on overall survival could not be determined.

In terms of safety, ruxolitinib was associated with a greater incidence of grade 3 or 4 anemia and thrombocytopenia (2% and 5%, respectively) compared with standard therapy (0% and 4%, respectively). Grade 1 and 2 herpes zoster infection occurred in 6% of patients receiving ruxolitinib versus no patients in the standard therapy group. Grade 3 and 4 toxicities were less with ruxolitinib compared with the standard therapy group.

Fewer patients discontinued ruxolitinib therapy compared with standard therapy.

However, through week 32, more patients (N = 6) in the standard therapy group had thromboembolic events compared with the ruxolitinib group (N = 1).

The US Food and Drug Administration approved ruxolitinib for the treatment of patients with polycythemia vera in December 2014.

Source: Vannucchi AM, Kiladjian JJ, Griesshammer M, et al.

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426-435.

COMMENTARY BY ROBERT J. IGNOFFO

In addition to the increased risk of clotting, constitutional symptoms associated with polycythemia vera (eg, itching, sweating, and fatigue) are particularly bothersome. This randomized trial showed that ruxolitinib is well-tolerated and significantly more effective than standard therapies in controlling hematocrit levels, reducing spleen volume, and improving polycythemia veraâ&#x20AC;&#x201C;related symptoms in patients who have had inadequate responses to, or unacceptable side effects from, hydroxyurea.

Although survival benefits could not be demonstrated for ruxolitinib because of the study design, the benefits of effective hematocrit control and improved quality of life were significant.

Ruxolitinib is an important new drug in the treatment of refractory polycythemia vera, especially in patients with spleen-related symptoms who have progressed or experienced severe adverse effects from hydroxyurea.

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SAVE THE DATE JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

The Global Biomarkers Consortium (GBC) and World Cutaneous Malignancies Congress (WCMC) will be holding their fourth annual joint meeting focused on personalized and precision medicine in oncology (PMO) on July 22-25, 2015, in Seattle, Washington.

July 22-24 A Focus on the Application of Molecular Biomarkers in Clinical Practice Across Multiple Tumor Types

SCHEDULE OF EVENTS (subject to change)

July 24-25 Spotlight on Cutaneous Malignancies, Including Melanoma, Cutaneous T-Cell Lymphoma, and Basal Cell Carcinoma

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Famil Cancer Center San Francisco, CA

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PMOLive2015_112114

Hope S. Rugo, MD, is a Professor of Medicine in the Divis

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