Journal of Oncology Pharmacy Practice current issue

Verification of imatinib cost-effectiveness in advanced gastrointestinal stromal tumor in British Columbia (VINCE-BC study)

2008-08-21

Background. This cost-effectiveness analysis of imatinib in British Columbia Cancer Agency (BCCA) patients with advanced gastrointestinal stromal tumors (GIST) was performed to justify funding.

Patients and Methods. A pragmatic, retrospective review identified BCCA patients with advanced GIST who received imatinib or historical treatment during successive, pre-specified time periods. Primary outcome was the cost-effectiveness (CE) of imatinib based on median overall survival (MOS). Secondary outcomes were cost-effectiveness based on median progression-free survival (PFS) and comparison to literature efficacy. This study took the BCCA perspective. Sensitivity analyses varying effectiveness over the 95% confidence interval (CI), cost to its extremes, discounting level at 0, 3, and 5%, and substituting life expectancy for MOS were performed.

Results. Forty-six and 47 patients in the imatinib and historical groups respectively showed MOS with imatinib to be 66.7 months (95%CI 61.7— infinity) compared to 7.7 (95%CI 6.0—12.6) in the historical group. Median-PFS were 45.3 months (95%CI 24.4—infinity) and 5.6 (95%CI 3.5—8.5) respectively. Imatinib effectiveness was similar to literature reports. The annual incremental CE ratio for imatinib was $15,882 CDN per median life year gained and $23,603 CDN per median year of PFS.

Conclusions. Imatinib for advanced GIST seems cost-effective in BC. Results were robust across a range of sensitivity analyses. J Oncol Pharm Practice (2008) 14: 105—112.

Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell transplantation

2008-08-21

Aprepitant (AP) is a known inhibitor of cytochrome P450 3A4 which may affect tacrolimus metabolism. We retrospectively examined the effect of oral AP on intravenous tacrolimus concentrations in 26 patients undergoing reduced intensity transplantation from 09/2005 to 09/2006. Oral AP 125 mg daily was administered on transplant day +1 and 80 mg on days +2 and +3. Intravenous tacrolimus was administered as a 0.03 mg/kg/day continuous infusion on day -6 through day +1 (pre-AP), during-AP (days +2 to +7), and post-AP starting on day +8. Tacrolimus doses were adjusted to achieve concentrations of 5—20 ng/mL. Dose-corrected tacrolimus concentrations (ng/mL/mg per dose) in the pre-AP, during-AP, and post-AP time periods were: 8.12 (95% CI: 7.3—9.1), 11.63 (95% CI: 9.63—13.63), and 11.42 (95% CI: 8.12—14.7), respectively (P<0.01 between pre-AP and during-AP, P<0.01 between during-AP and post-AP, P = 0.01 between pre-AP and post-AP time periods). Although statistically significant, the observed rise was not clinically significant between during-AP and post-AP time periods. Previous work has shown that AP is not expected to exert an inhibitory effect within 48 h of AP discontinuation. Collectively, these data suggest that AP effect on tacrolimus metabolism is of minor clinical significance. A controlled trial is needed to confirm these findings. J Oncol Pharm Practice (2008) 14: 113—121.

Use of prescription and nonprescription medications and supplements by cancer patients during chemotherapy: questionnaire validation

Hanigan, M. H, dela Cruz, B. L, Thompson, D. M, Farmer, K. C, Medina, P. J — 2008-08-21

Background. Cancer patients take medications for coexisting disease and self-medicate with over-the-counter drugs (OTCs). A complete analysis of the use of prescription drugs, OTCs, and supplements during cancer treatment has never been done.

Methods. The study developed and validated a self-administered questionnaire on the use of concomitant medications by patients undergoing treatment with chemotherapy. The questionnaire listed 510 prescription medications, OTCs, and supplements (including vitamins, minerals, and herbs). Fifty-two subjects completed the questionnaire while visiting the infusion clinic to receive chemotherapy. On a subsequent visit the subjects brought their medications to the clinic and a pharmacist reviewed their completed questionnaire.

Results. Ninety-six percent of the subjects reported taking prescription medications within 3 days prior to chemotherapy, 71% reported taking OTCs and 69% reported use of supplements. The subjects took an average of 5.5 (range 0—13) prescription drugs, 2.2 (0—20) OTCs, and 1.9 (0—11) supplements. Twenty-one drugs were each taken by at least 10% of the subjects. Acetaminophen was taken by 59.6% of the subjects. One subject reported taking five acetaminophen-containing drugs. The questionnaire's sensitivity was 92.0%, specificity 99.9%.

Conclusion. Within 3 days prior to chemotherapy, subjects took an average of 9.6 concomitant medications, many of which alter drug metabolism and or disposition. In clinical trials, multivariate analysis of all concomitant medications could add to clinically relevant data to identify drug interactions that negate or potentiate the efficacy of cancer treatment regimens. In some instances, apparent resistance of tumors to chemotherapy may be the result of drug interactions. J Oncol Pharm Practice (2008) 14: 123—130.

The use and effectiveness of granulocyte colony-stimulating factor in primary prophylaxis for febrile neutropenia in the outpatient setting

Tuffaha, H. W, Treish, I. M, Zaru, L. — 2008-08-21

Objectives. To conduct a drug utilization review (DUR) on the use of granulocyte colony-stimulating factor (G-CSF) and to study the effectiveness of this agent in preventing the incidence of febrile neutropenia (FN).

Methods. Outpatients to whom G-CSF was dispensed were identified and their actual medical records were reviewed to verify patients who received G-CSF for primary prophylaxis. Literature was reviewed to determine the expected incidence and risk of FN for chemotherapy regimens used, and the compliance of prescribers with the institutional guidelines was evaluated. After that, the proportion of patients who developed FN was identified and compared to the expected incidence from literature. Data analysis was performed on the outcome of patient-cycle.

Results. Of the 99 patient-cycles, 53 (53%) were compliant with guidelines whereas 46 (47%) were not. FN developed in 12 (12.1%, 95% CI = 5.7, 18.5) while the expected average incidence of FN was 32.7%. Eleven (21%, 95% CI = 10.1, 32.2) of the 53 patient-cycles that were compliant with guidelines developed FN, whereas one patient among the non-compliant group developed FN (2%, 95% CI = 0.0, 6.2). The expected incidence of FN was 42.9 and 21.5%, in the compliant group, and noncompliant group, respectively. Based on expected FN rates, the respective reduction in the incidence of FN was 51, and 90%.

Conclusions. Lack of adherence to institutional guidelines was noticed in G-CSF prescribing. Reasons behind poor compliance with the guidelines must be verified and resolved. Prophylactic G-CSF is effective in reducing the incidence of FN; however, further research in a larger population is warranted to confirm these findings. J Oncol Pharm Practice (2008) 14: 131—138.

Screening and management of osteoporosis in breast cancer patients on aromatase inhibitors

Gibson, K., O'Bryant, C. L — 2008-08-21

Objective. Breast cancer patients are at an increased risk of osteoporosis due to age, cancer, chemotherapy, and aromatase inhibitor therapy. This retrospective review determined if patients treated with aromatase inhibitors received appropriate screening and management for osteoporosis.

Design. University of Colorado Cancer Center breast cancer patients treated with aromatase inhibitor therapy during July 2005 through July 2006 were studied. Data was collected for each patient from the time of breast cancer diagnosis up to April 2007. The study endpoints included (1) appropriate screening for osteoporosis, (2) incidence of osteoporosis diagnosis, and (3) initiation of appropriate drug therapy for bone loss. Appropriate management was defined as adherence to the 2003 American Society of Clinical Oncology guidelines for bone health issues in women with breast cancer.

Results. Of the 54 patients included in this study, 12 (22.2%) had no DEXA scans documented, 22 (40.7%) patients received a baseline DEXA scan and 8 (14.8%) patients received baseline and yearly DEXA scans. During the study timeline, 26 (48%) patients were diagnosed with osteopenia and 4 (7%) patients were diagnosed with osteoporosis. Forty-one (75.9%) patients received calcium and vitamin D therapy. Bisphosphonate therapy was received by less than one-third of the osteopenic patients and three-fourths of the osteoporotic patients.

Conclusions. The majority of patients were not adequately screened which may have falsely lowered the diagnosis of osteoporosis resulting in omission of drug therapy. All high-risk patients should receive calcium and vitamin D therapy and be evaluated for bisphosphonate therapy. Screening and medical management for osteoporosis in breast cancer patients on aromatase inhibitors is an important area for clinical intervention. J Oncol Pharm Practice (2008) 14: 139—145.

Pharmaceutical care in an inpatient pediatric hematopoietic stem cell transplant service

Prot-Labarthe, S., Therrien, R., Demanche, C., Larocque, D., Bussieres, J.-F. — 2008-08-21

Introduction. Hematopoietic stem cell transplant patients represent a population at high risk for drug-related problems. Our objective is to describe pharmacist interventions in a hematopoietic stem cell transplant pediatric unit.

Methods and Patients. The Hematopoietic Stem Cell Transplant Unit of the Centre Hospitalier Universitaire Sainte-Justine performs around 50 hematopoietic stem cell transplants per year. During a pharmaceutical care specialized residency program, a French pharmacist participated in certain clinical activities. Drug-related problems and clinical interventions were compiled over 31 nonconsecutive days using a tool developed by the Société Française de Pharmacie Clinique. Data concerning patients, drugs, intervention, documentation, approval (if needed), and estimated impact were compiled.

Results. During the 31-day period, 525 interventions were collected (16.9 ± 3.7 per day), targeting 29 patients. The main drug-related problems were adverse drug reactions (N = 125, 23.8%), untreated indication (N = 92, 17.5%) and failure to receive drug (N = 89, 17.0%). The pharmacist's interventions concerned mainly dose adjustment (N = 174, 33.1%) and drug monitoring (N = 132, 25.1%). Among the 324 (61.7%) interventions requiring a physician's approval, 302 (93.2%) were accepted without any change.

Conclusion. A pharmacist is able to perform clinically relevant interventions in a hematopoietic stem cell transplant unit, given the complexity of the pharmacotherapy. Our description of drug-related problems and interventions may help other pharmacists already working or developing pharmaceutical care in a hematopoietic stem cell transplant unit to compare their practice and it is one of the few reported in the literature. J Oncol Pharm Practice (2008) 14: 147—152.

Managing reduced methotrexate clearance in a patient with a heterozygous methylenetetrahydrofolate reductase gene polymorphism

Gammon, D. C, Bhatt, M. S, Patel, B., Anderson, M., Van Horn, A., Glantz, M. J — 2008-08-21

High dose methotrexate has become one of the treatments of choice for patients with primary CNS lymphomas due to its ability to penetrate the blood—brain barrier. A potentially serious complication of this therapy is methotrexate-related nephrotoxicity. We report the case of a patient with a common genetic polymorphism that may have predisposed this patient experience clinically significant toxicity from systemic folate depletion. After the first cycle of chemotherapy that included high dose methotrexate, the patient's serum creatinine rose and the patient's methotrexate level remained above the toxic range for six days. On cycle two, the patient was treated with a 25% dose reduction in methotrexate and more aggressive hydration and alkalization. With this alteration in the regimen, the patient was able to receive six more cycles and had a complete radiographic tumor response in the brain and a disappearance of tumor cells in the CSF without any further renal complications. This case report illustrates the feasibility of administering high dose methotrexate with modifications as a treatment of choice in individuals with methylenetetrahydrofolate reductase gene mutations. J Oncol Pharm Practice (2008) 14: 153—156.

Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant

Howell, J. E, Szabatura, A. H, Hatfield Seung, A., Nesbit, S. A — 2008-08-21

Purpose. Ifosfamide is metabolized by the cytochrome P450 system to its active form, ifosforamide mustard. A potential side effect is neurotoxicity, often manifesting as confusion, hallucination, or seizure. Aprepitant, a neurokinin-1 inhibitor, is recommended for highly and moderately emetogenic chemotherapy regimens and may interfere with the metabolism of ifosfamide as it inhibits CYP3A4. The objective of the study is to identify if an increase in the incidence of neurotoxicity may be associated with the use of aprepitant with concomitant ifosfamide.

Methods. A retrospective study of inpatients with sarcoma who received a two or four-day regimen of MAI (mesna, doxorubicin, and ifosfamide) between January 1, 2004 and December 31, 2006 was conducted. Data collection focused on characterizing neurotoxicity of patients receiving ifosfamide with or without aprepitant. Correlation between serum creatinine, albumin, liver function tests, age, gender, and total doses of ifosfamide was examined.

Results. A total of 45 patients received ifosfamide of which 23 (51%) were male and 24 (53%) received aprepitant. All baseline characteristics were similar for those who received aprepitant versus those who did not. No significant differences were noted between patients with or without neurotoxicity for age, gender, or liver enzymes. Eight patients (18%) of 45 developed neurotoxicity of which six (75%) of those patients also received aprepitant. A trend of increased occurrence of neurotoxicity was noted with aprepitant administration (6 vs. 2 patients respectively, p = 0.176), although a statistical difference was not observed. A relative risk of 2.6 (95% CI, 0.47—26.6) was associated with the addition of aprepitant.

Conclusions. An increased risk was identified for ifosfamide-induced neurotoxicity associated with aprepitant use; however, the observed difference was not statistically significant. The necessity of aprepitant given in association with ifosfamide may need to be reconsidered due to this risk. J Oncol Pharm Practice (2008) 14: 157—162.

Letter to the editor

Feng Xu, — 2008-08-21