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HSC transplantation using genetically modified autologous cells is a promising therapeutic strategy for various genetic diseases, cancer, and HIV. However, for many of these conditions, the current efficiency of gene transfer to HSCs is not sufficient for clinical use. The ability to increase the percentage of gene-modified cells following transplantation is critical to overcoming this obstacle. In vivo selection with mutant methylguanine methyltransferase (MGMTP140K) has been proposed to overcome low gene transfer efficiency to HSCs. Previous studies have shown efficient in vivo selection in mice and dogs but only transient selection in primates. Here, we report efficient and stable MGMTP140K-mediated multilineage selection in both macaque and baboon nonhuman primate models. Treatment consisting of both O6-benzylguanine (O6BG) and N,N'-bis(2-chloroethyl)-N-nitroso-urea (BCNU) stably increased the percentage of transgene-expressing cells from a range of initial levels of engrafted genetically modified cells, with the longest follow-up after drug treatment occurring over 2.2 years. Drug treatment was well tolerated, and selection occurred in myeloid, lymphoid, and erythroid cells as well as platelets. Retrovirus integration site analysis before and after drug treatments confirmed the presence of multiple clones. These nonhuman primate studies closely model a clinical setting and should have broad applications for HSC gene therapy targeting human diseases of malignant, genetic, and infectious nature, including HIV.

Background: Blockade of the CD28 costimulatory molecule by recombinant human cytotoxic T lymphocyte (CTL)-associated antigen (CTLA4)-Ig or CD40-CD154 interaction with the monoclonal antibody 5C8 together with donor-specific transfusion led to enhanced engraftment in the canine model of dog leukocyte antigen (DLA)-identical marrow transplantation after 1 Gy total body irradiation. To reduce or eliminate total body irradiation conditioning regimens, we have sought to develop canine specific reagents., Methods: We have created a fusion protein of the extracellular domain of canine (c) CTLA-4 linked to the hinge-CH2-CH3 domains of canine IgG1 in a pcDNA3.1+ vector. Chinese hamster ovarian cells were cotransfected with CTLA4-Ig vector and a dihydrofolate reductase-containing vector. Stable, high producing clones were generated., Results: Cell binding and mixed leukocyte reactions indicated no significant differences in activity between cCTLA4-Ig and human CTLA4-Ig. Mixed leukocyte reaction data indicated that combinations of cCTLA4-Ig and the monoclonal antibody 5C8 were superior in blocking H-thymidine uptake compared to either reagent alone. In dogs, the circulating half-life of cCTLA4-Ig was approximately 7 days with no immune response against the fusion protein. Finally, two injections of cCTLA4-Ig effectively tolerized two dogs against eight consecutive challenges with sheep red blood cells, given over 330 days as indicated by a complete block of IgG antibody production. Tolerance was broken in one of the two dogs when a ninth injection of sheep red blood cell was given subcutaneously in incomplete Freund's adjuvant., Conclusion: cCTLA4-Ig is an effective nonimmunogenic blocking reagent of the CD28 costimulatory pathway in dogs and is a promising reagent for studies of tolerance induction in hematopoietic cell transplantation in the canine model.

Purpose: Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS., Experimental Design: A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily i.v. fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve., Results: A two-compartment model best fits the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean squared error for the area under the concentration-time curve for each simulated individual. The LSS times chosen were 0.583, 1.5, 6.5, and 24 hours after the start of the 30-minute fludarabine infusion., Discussion: The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining four blood samples (using the LSS) and maximum a posteriori Bayesian estimation., Conclusion: These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving i.v. fludarabine in the ambulatory clinic.

This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) busulfan, therapeutic drug monitoring and clinical outcome in hematopoietic stem cell transplant (HCT) patients. Busulfan is commonly used in HCT as it is toxic to the marrow. Busulfan is available as oral or i.v. formulation. The most common significant toxicity of busulfan is sinusoidal obstruction syndrome. Even with the introduction of i.v. busulfan, variability in the systemic concentrations of busulfan after weight-based dosing and the association between busulfan plasma exposure and outcome in HCT patients have led to the continued use of therapeutic drug monitoring of busulfan. New strategies for personalizing busulfan dosing are being studied to maximize the use of busulfan for optimal disease control with the least toxicity to HCT patients. One such strategy currently being evaluated is if busulfan clearance can be accurately predicted by genetic polymorphism of glutathione S-transferase (GST), with the currently available data suggesting that GST polymorphisms cannot be used to personalize busulfan dosing.

Purpose: Fludarabine is a key component of several reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Shortly after reduced-intensity conditioning, the percent of donor natural killer (NK) cells has been associated with progression-free survival. Insufficient suppression of the recipient's NK cells by fludarabine may lead to lower donor chimerism; however, the effect of fludarabine upon NK cells is poorly understood. Thus, in purified human NK cells we evaluated the uptake and activation of fludarabine to its active metabolite, fludarabine triphosphate (F-ara-ATP), and assessed the degree of interindividual variability in F-ara-ATP accumulation., Methods: Intracellular F-ara-ATP was measured in purified NK cells isolated from healthy volunteers (n = 6) after ex vivo exposure to fludarabine. Gene expression levels of the relevant transporters and enzymes involved in fludarabine uptake and activation were also measured in these cells., Results: F-ara-ATP accumulation (mean +/- SD) was 6.00 +/- 3.67 pmol/1 x 10(6) cells/4 h, comparable to average levels previously observed in CD4(+) and CD8(+) T-lymphocytes. We observed considerable variability in F-ara-ATP accumulation and mRNA expression of transporters and enzymes relevant to F-ara-ATP accumulation in NK cells from different healthy volunteers., Conclusions: Human NK cells have the ability to form F-ara-ATP intracellularly and large interindividual variability was observed in healthy volunteers. Further studies are needed to evaluate whether F-ara-ATP accumulation in NK cells are associated with apoptosis and clinical outcomes.

Purpose: Fludarabine is an integral anticancer agent for patients with chronic lymphocytic leukemia (CLL) and those receiving conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT). An individual's response to fludarabine may be influenced by the amount of CD4(+) and CD8(+) T-lymphocyte suppression. Fludarabine undergoes cellular uptake and activation to form the cytotoxic metabolite, fludarabine triphosphate (F-ara-ATP)., Methods: We have previously developed a highly sensitive LC-MS method to quantitate intracellular F-ara-ATP concentrations in a leukemic cell line. However, quantitation of F-ara-ATP concentrations within CD4(+) and CD8(+) T-lymphocytes from pharmacokinetic blood samples obtained from patients receiving fludarabine therapy is not feasible because of the limited number of T-lymphocytes that can be isolated from each blood sample. Thus, we sought to determine F-ara-ATP accumulation after ex vivo exposure of freshly isolated human CD4(+) or CD8(+) T-lymphocytes to fludarabine. The method was optimized in T-lymphocytes obtained from healthy volunteers, and proved to be a feasible method to determine F-ara-ATP accumulation in patients undergoing HCT., Results: Considerable variability was observed in F-ara-ATP accumulation in HCT patients (10.5- and 12.5-fold in CD4(+) and CD8(+) cells, respectively), compared to healthy volunteers (1.6- and 1.9-fold in CD4(+) and CD8(+) cells, respectively). Larger variability was also observed in gene expression of transporters and enzymes involved in F-ara-ATP accumulation in HCT patients; however, F-ara-ATP accumulation was not correlated with gene expression, which is in agreement with previous studies., Conclusions: The quantitation of F-ara-ATP accumulation in T-lymphocytes provides a novel tool to evaluate patient sensitivity to fludarabine. This tool can be used in future studies to evaluate whether intracellular F-ara-ATP accumulation is associated with efficacy and/or toxicity in patients receiving fludarabine.

High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.

Purpose: We investigated the potential drug-drug interaction between imatinib and fludarabine, which may be concomitantly administered in chronic myeloid leukemia (CML) patients receiving fludarabine-based conditioning for allogeneic hematopoietic cell transplantation (HCT). Imatinib is an inhibitor of human equilibrative transporters (hENTs), which are responsible for the intracellular uptake of fludarabine., Methods: Intracellular accumulation of fludarabine triphosphate (F-ara-ATP), the active metabolite of fludarabine, was measured in CD4(+) and CD8(+) T-lymphocytes isolated from healthy volunteers, which were treated in vitro with fludarabine alone, and in the presence of either imatinib or NBMPR, a known hENT inhibitor., Results: Imatinib significantly inhibited F-ara-ATP accumulation in CD4(+) and CD8(+) T-lymphocytes in a concentration-dependent manner. The observed imatinib inhibition was comparable to inhibition observed with NBMPR. The inhibition of F-ara-ATP by imatinib is likely due to inhibition of nucleoside transporters hENT1 and hENT2., Conclusions: There is significant in vitro drug interaction between imatinib and fludarabine. This effect may be of important consideration in patients receiving fludarabine-based conditioning prior to HCT.

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.

In a previous study comparing fluconazole and itraconazole administered as antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients, we found that fluconazole administration concurrent with cyclophosphamide (CY)-based conditioning was associated with fewer early toxicities compared to itraconazole. Fluconazole inhibits cytochrome P450 2C9, which is involved with the activation of CY, and so might provide protection from CY-related toxicities. To investigate this further, we compared CY and CY-metabolite data from patients who received fluconazole (n = 56) concurrent with CY-containing conditioning and in patients who did not (n = 17). The fluconazole group had greater exposure to CY, and lower peak serum concentration of CY-metabolite 4-hydroxycyclophosphamide. In a separate cohort, we examined outcomes in patients randomized to receive either fluconazole (n = 152) or placebo (n = 147) concurrent with CY-containing conditioning in a prior randomized trial. Patients who received fluconazole experienced less hepatic and renal toxicity, and had lower mortality. No difference in relapsed malignancy was apparent. These data support the hypothesis that fluconazole, when coadministered with CY, decreases CY-related toxicities by inhibiting cytochrome P450 2C9 metabolism.

The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with liver toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P < .0001), higher AUC(HCY) (P < .0001), and higher AUC(CEPM) (P = .15) than CY/TBI-conditioned patients. Among patients receiving (T)BU/CY, 17 (23%) developed SOS, and there were no statistically significant associations between the AUC of CY or its metabolites and SOS, nonrelapse mortality, relapse, or survival (all P >.15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.

Purpose: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model., Experimental Design: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide)., Results: The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCY and CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively., Conclusions: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.

To reduce the incidence of graft-versus-host disease (GVHD), we added Thymoglobulin (THY) to dose-adjusted oral busulfan plus cyclophosphamide (targeted BUCY). The starting dose of THY was 4.5 mg/kg given over days -3, -2, and -1, escalated in steps of 1.5 mg/kg in cohorts of 15 evaluable patients. Escalation was dependent on acute GVHD incidence and Epstein-Barr virus reactivation. Fifty-six patients with myelodysplastic syndrome and other myeloid disorders underwent transplantation with peripheral blood progenitor cells from related (n=30) or unrelated (n=26) donors. All but 2 patients achieved engraftment, and 56% survived in remission beyond 1 year. The incidence of acute GVHD was 50%, and that of chronic GVHD was 34%. The highest THY dose was 6.0 mg/kg, a dose at which 1 patient experienced Epstein-Barr virus reactivation. Nine patients did not receive the prescribed THY dose. Results were comparable for related and unrelated transplants and for patients given 4.5 or 6.0 mg/kg THY. Among 27 myelodysplastic syndrome patients (14 with related and 13 with unrelated donors) who underwent transplantation concurrently with targeted BUCY without THY, the incidence of acute and chronic GVHD was 82%. Thus, THY 4.5 to 6.0 mg/kg seemed beneficial for GVHD prevention in BUCY-conditioned patients who underwent transplantation with peripheral blood progenitor cells, although relapse-free survival did not differ significantly from that in comparable historical controls not given THY.

A method is described for the quantification of two metabolites of cyclophosphamide, specifically 4-hydroxycyclophosphamide (HCy), and carboxyethylphosphoramide mustard (CEPM). Plasma HCy is derivatized to the phenylhydrazone which is quantitated by LC-MS monitoring the chloride adduct of the derivative. The LLOQ based on material applied to the system is approximately 20 fmol. Plasma CEPM concentration is determined using LC-MS with a deuterated internal standard. Both assays have 50-fold dynamic range and require less than 4h to complete. The development of this rapid analytical method makes it feasible to adjust the dose of cyclophosphamide based on the pharmacokinetic disposition of HCy and CEPM in hopes of decreasing nonrelapse mortality in cancer patients.

Objective: To review the pharmacology, pharmacokinetics, clinical evidence, and safety, as well as the potential directions for use, of the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab., Data Sources: A MEDLINE search (1966-December 2005) was conducted using the following terms: cetuximab, Erbitux, C225, epidermal growth factor receptor, and EGFR. Additional information was obtained via meeting abstracts, bibliographies from relevant articles, national guidelines, and the manufacturer., Study Selection and Data Extraction: Preclinical and clinical trials utilizing cetuximab in the treatment of solid tumors were selected from the data sources. All published, randomized clinical trials involving cetuximab in treatment of metastatic colorectal cancer and studies providing a description of the pharmacology, pharmacokinetics, safety, or efficacy were included in this review., Data Synthesis: Many solid tumors overexpress EGFR, making it an ideal target for anticancer agents. Cetuximab is the only EGFR monoclonal antibody commercially available and is approved for the treatment of EGFR-expressing, metastatic colorectal cancer in patients refractory or intolerant to irinotecan. Data on patients with other solid tumors are encouraging with cetuximab used as monotherapy or in combination with chemotherapy, radiation, or other targeted agents. Common adverse effects include dermatologic and hypersensitivity reactions., Conclusions: Further clinical data are necessary to clearly define the role of cetuximab in the treatment of patients with solid malignancies, with emphasis on survival and quality-of-life benefits relative to its cost.

Although limited data are available about cyclophosphamide disposition in patients with renal insufficiency, nothing has been reported in anephric patients. We characterized cyclophosphamide pharmacokinetics in an anephric child with bilateral Wilms tumor, both on (day 1) and off (day 2) hemodialysis. The median cyclophosphamide clearance on and off hemodialysis was 5.34 and 3.82 L/hr*m(2), respectively, demonstrating elimination of cyclophosphamide in this anephric child. The off hemodialysis clearance was similar to that in children with normal renal function. Hydroxycyclophosphamide (HCY) AUC was 20.6 and 8.77 microM*hr on and off hemodialysis. Carboxyethylphosphoramide mustard (CEPM) AUC obtained on hemodialysis (i.e., 194 microM*hr) was similar to that in children with normal renal function, although an elevated CEPM AUC was observed when hemodialysis was not received (i.e., 383 microM*hr). With the recent findings that clinical outcomes are related to CEPM AUC, further data are needed regarding the pharmacokinetics of cyclophosphamide and relevant metabolites in anephric children.

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

Unlabelled: Due to advances in the methods used to quantitate vinorelbine, this study was conducted to characterize fully the bioavailability of an oral dosage form of vinorelbine. Twenty-seven eligible patients with solid tumors were enrolled onto this study and were treated in a randomized crossover design to receive either 70 mg/m2 orally or 30 mg/m2 intravenously followed by the alternative treatment one week later. Vinorelbine was administered orally as a soft-gelatin capsule. Pharmacokinetic sampling was carried out for 7 days following each dose. Whole blood vinorelbine concentrations were measured using a sensitive LC/MS/MS method. The data from patients were excluded if they vomited within 3 h after the oral dose., Results: Three subjects were removed from study following the first dose due to safety reasons. Of the remaining 24 subjects, five experienced vomiting within 3 h of oral dosing. Total body clearance calculated from the intravenous dose was 43.65 L/h (+/-10.9) and the terminal half-life was estimated to be 49 h. Using complete data from the remaining 19 subjects, the mean absolute bioavailability of the oral dosage formulation of vinorelbine was calculated to be 33% (+/-18%). In conclusion we have characterized the pharmacokinetics of both orally administered and intravenous vinorelbine over 7 days after administration and have determined the mean oral bioavailability of this oral formulation to be 33%.

Background: In the U.S., the majority of premenopausal patients with early-stage breast carcinoma are treated with adjuvant chemotherapy. However, to the authors' knowledge, there have been few formal analyses of adjuvant chemotherapy cost performed to date, especially in premenopausal women. The objective of the current study was to evaluate the direct medical cost of adjuvant chemotherapy in women with early-stage breast carcinoma., Methods: The attributable cost of adjuvant chemotherapy was evaluated by comparing the total cost of care for patients with breast carcinoma (cases) during the period from diagnosis to 9 months subsequent with the cost for age-matched and gender-matched control patients without breast carcinoma over an equivalent time period. The authors identified cases from a linked database of claims records from a managed care organization, and the Cancer Surveillance System registry. Controls were identified from the managed care organization from which the cases originated. Resource prices were based on reimbursements from the managed care organization., Results: The attributable cost of adjuvant chemotherapy was estimated to be dollar 23,019 (95% confidence interval, dollar 19,596-dollar 26,441), based on 1239 women. The cost appeared to decrease with increasing age at diagnosis, with total costs of dollar 26,834, dollar 19,889, and dollar 17,098 for women < 50, 50-59, and > or = 60 years, respectively. Also, costs were higher for regional versus local disease (dollar 36,076 vs. dollar 12,659), for women who had a mastectomy versus breast-conserving surgery (dollar 31,075 vs. dollar 17,889), and for women who had no comorbidities versus > or = 1 comorbidity (dollar 23,606 vs. dollar 21,340). Contributors to high chemotherapy cost included use of chemotherapy agents not included in clinical guidelines during the study period, use of supportive care agents, and hospitalizations., Conclusions: The attributable cost of adjuvant chemotherapy in patients with early-stage breast carcinoma is significant. The integration of managed care claims data with clinical data from the Cancer Surveillance System registry offered a unique opportunity to derive more informative and accurate disease burden estimates in oncology., (Copyright 2005 American Cancer Society)

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.

Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. At the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved. There was a suggestion of increased toxicity without improved efficacy at the 60 mg/kg/d dosage level. Accordingly, the 45 mg/kg/d dosage was therefore selected for phase II, and another 15 patients were added to this group from the phase I study (n=26). The concentrations at steady state for this dosage at days 0, 6, 13, 20, and 27 were 2.73, 3.02, 3.20, 2.62, and 2.64 microg/mL, respectively. No toxicities were attributed to MMF at this dose. The median time to engraftment after hematopoietic cell transplantation was 15 days (range, 10-20 days). The incidence of acute GVHD was 62%, which was comparable to a group of historical controls receiving CSP and methotrexate (MTX) for GVHD prophylaxis. Although a significant improvement in the prevention of GVHD was not suggested, compared with CSP and MTX, MMF in combination with CSP could be considered in cases in which MTX is contraindicated.

Ifosfamide nephrotoxicity is attributed to the formation of a toxic metabolite, chloroacetaldehyde, via N-dechloroethylation, a reaction that is purportedly catalyzed by CYP3A and CYP2B6. Because allelic variants of CYP3A5 are associated with polymorphic expression of microsomal CYP3A5 in human liver and kidneys, we hypothesized that ifosfamide N-dechloroethylation depends on CYP3A5 genotype. We compared ifosfamide N-dechloroethylation activity in cDNA-expressed CYP3A4 and CYP3A5. Ifosfamide N-dechloroethylation was also assessed in liver (N = 20) and kidney (N = 21) microsomes from human donors with different CYP3A5 genotypes. Ifosfamide N-dechloroethylation was catalyzed by recombinant CYP3A5 at a rate comparable with recombinant CYP3A4. In human liver microsomes matched for CYP3A4 protein content, N-dechloroethylation was more than 2-fold higher in that from donors carrying CYP3A5*1 allele that express CYP3A5 relative to that from donors homozygous for the mutant CYP3A5*3. Correlation analysis revealed that ifosfamide N-dechloroethylation was significantly associated with CYP3A4 and CYP3A5 protein concentration but not with age, sex, or CYP2B6 protein concentration. In hepatic microsomes not expressing CYP3A5 protein, ifosfamide N-dechloroethylation was inhibited 53 to 61% and 0 to 3% by monoclonal antibodies specific for CYP3A4/5 or CYP2B6, respectively. Ifosfamide N-dechloroethylation was not detected in renal microsomes obtained from CYP3A5*3/*3 donors. In contrast, it was readily measurable in microsomes isolated from four kidneys of CYP3A5*1 carriers, which was almost completely inhibited by the CYP3A inhibitor ketoconazole. CYP2B6 protein could not be detected in this panel of human renal microsomes. In conclusion, CYP3A5*1 genotype is associated with higher rates of ifosfamide N-dechloroethylation in human liver and kidneys.

Purpose: Gene expression profiling has been proposed as an alternative to clinical guidelines to identify high-risk patients for adjuvant chemotherapy. However, the outcomes associated with gene expression profiling are not clear, and guidelines for the appropriate use of genomic technologies have not been established., Methods: We developed a decision analytic model to evaluate the incremental cost and quality-adjusted life years of gene expression profiling versus NIH clinical guidelines in a hypothetical cohort of premenopausal early stage breast cancer patients 44 years of age. We conducted empirical analyses and identified literature-based data to inform the model, and performed probabilistic sensitivity analyses to evaluate uncertainty in the results. We interpreted the implications of our findings for treatment guidelines and policies., Results: Use of gene expression profiling resulted in an absolute 5% decrease in the proportion of cases of distant recurrence prevented, 0.21 fewer quality-adjusted life years, and a cost savings of USD 2882. The chosen test cutoff value to identify a tumor as poor prognosis and the cost of adjuvant chemotherapy were the most influential parameters in the analysis, but our findings did not change substantially in sensitivity analyses. Regardless of the test cutoff used to identify a poor prognosis tumor, the gene expression profiling assay studied in our analysis, at its current level of performance, did not attain the threshold sensitivity (95%) necessary to produce equal or greater quality-adjusted life years than NIH guidelines., Conclusion: Although the use of gene expression profiling in breast cancer care holds great promise, our analysis suggests additional refinement and validation are needed before use in clinical practice.

A high-performance liquid chromatography (HPLC)-mass spectrometry (MS) method has been developed for the analysis of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) from biological samples. Quantification is carried out by selected ion monitoring of the parent ion. Baseline separation of the monophosphate (F-ara-AMP) and diphosphate (F-ara-ADP) is achieved using the volatile ion-pairing reagent dimethylhexylamine. This method is selective and sensitive with an on-column detection limit of approximately 50 fmol. It also permits simultaneous monitoring of endogenous adenosine phosphates. The utility of the assay has been demonstrated by the analysis of F-ara-ATP in human leukemic cells after incubation with 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A) at clinically relevant concentrations.

Results of a previous phase I study suggested that a single 3 mg/m2 dose of the humanized non-FcR-binding anti-CD3 monoclonal antibody visilizumab (Nuvion) was well tolerated and had efficacy for the treatment of steroid-refractory acute graft-versus-host disease (GVHD). We now report results of a multicenter phase II study in which visilizumab was given to 44 participants with steroid-refractory acute GVHD. Eighty-two percent of the participants had visceral involvement, and 86% had overall grade III or IV acute GVHD at study entry. The respective complete and overall response rates were 14% and 32% at 42 days. Plasma Epstein-Barr virus DNA increased to more than 1000 copies per milliliter in 19 subjects. Seventeen received rituximab, and no fatal lymphoproliferative disorders were observed. Survival at 180 days was 32% (95% confidence interval, 18%-46%). The administration of visilizumab as used in this study seems to be sufficiently safe and effective to warrant further assessment for treatment or prevention of GVHD.

Unlabelled: Premenopausal women who develop ovarian failure after receiving chemotherapy are at a higher risk of rapid bone loss. Pharmacists have successfully implemented osteoporosis screening programmes in the general population and thus, assessment of breast cancer survivors for ovarian failure and osteopenia could represent a novel focus for oncology pharmacists. Therefore, we conducted a retrospective chart review to determine the adequacy of ovarian failure and osteoporosis assessment and management in premenopausal breast cancer survivors., Methods and Results: The charts of 20 women diagnosed with early stage breast cancer treated with cyclophosphamide over a 4.5-year timespan were included. Their median age was 36.7 years (range 29.8-41). The median cyclophosphamide cumulative dose was 9 g/m(2) (range 2.4-14.45), with a median duration of follow-up being 4.62 years. The assessment of ovarian failure mainly occurred by documenting menstrual periods, which has been questioned as a reliable method for assessing ovarian failure. Menses stopped while or shortly after receiving chemotherapy in 11 women. Prior to and during cyclophosphamide administration, osteoporosis screening or counselling was not documented for any patient. After completion of chemotherapy administration, eight patients were counselled regarding osteoporosis and seven women were screened for osteoporosis with a dual X-ray absorptimetry (DXA) scan. Five women had DXA scans indicative of osteopenia according to World Health Organization guidelines., Conclusions: Improvements are needed in the documentation and potentially also the management of ovarian failure and osteoporosis in premenopausal breast cancer survivors receiving cyclophosphamide-based regimens. This represents a potential opportunity for pharmacists to manage long-term chemotherapy toxicity.

Purpose: Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide., Methods: Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66., Results: The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months., Conclusion: It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.

Although limited data are available about topotecan disposition in patients with renal insufficiency, nothing has been reported in anephric patients. The objective of this report is to characterize topotecan disposition in an anephric child with Wilms tumor, both on and off hemodialysis. The patient received topotecan and cyclophosphamide for four cycles; topotecan was administered daily for 5 days, with hemodialysis on the second and fourth day. Therapy was well tolerated, with grade 3 thrombocytopenia and grade 2 neutropenia noted after cycle four. The median topotecan lactone clearance was 15.5 L/h/m off hemodialysis and 18.7 L/h/m on hemodialysis. Topotecan clearance was minimally affected by hemodialysis and was similar to that observed in children without renal failure.

Goals of Work: The purpose of this study was to examine the specific herbs or vitamins (HV) used by patients receiving chemotherapy. Specifically, the following aspects were investigated: (1) HV use among adult cancer patients receiving chemotherapy, (2) the frequency of potential chemotherapy-HV interactions, (3) communication patterns between oncologists and their cancer patients taking HV, and (4) patients' reactions to two hypothetical scenarios of chemotherapy-HV interactions., Patients and Methods: Adult cancer patients receiving chemotherapy at a university-based outpatient clinic over a 1-month period were sent a validated eight-page questionnaire regarding the use of complementary/alternative medicine, focusing on HV use. A total of 76 patients participated; relevant medical information was obtained from study participants' charts. The chemotherapy received was compared with HV use to assess for potentially detrimental chemotherapy-HV interactions., Results: HV use in patients receiving chemotherapy was common (78%), with 27% of the study participants being at risk of a detrimental chemotherapy-HV interaction. Most patients (>85%) would discontinue their HV or ask their medical oncologist for advice if a detrimental chemotherapy-HV interaction was suspected. Although most patients discussed HV use with their oncologist, the majority also relied on their friends and naturopathic physician for information regarding HV., Conclusions: Considerable potential exists for detrimental chemotherapy-HV interactions. Methods to improve communication of HV use between cancer patients receiving chemotherapy and health-care practitioners are necessary to identify and minimize the risk of these interactions.

Background: Ifosfamide-induced nephrotoxicity is well recognized in children, although it has also been reported in adults. Whether ifosfamide nephrotoxicity is more common in children than in adults is not known., Procedure: Medical records of adults and children diagnosed with sarcoma whom received ifosfamide with a cumulative dose >20 g/m(2) were evaluated. Twenty-five children (20 g/m(2) of ifosfamide have similar susceptibility to ifosfamide-induced nephrotoxicity. Factors other than age and cumulative dose should be considered for understanding the inter-individual variation in nephrotoxicity., (Copyright 2004 Wiley-Liss, Inc.)

Paclitaxel-induced myalgias and arthralgias occur in a significant fraction of patients receiving therapy with this taxane, potentially impairing physical function and quality of life. Paclitaxel-induced myalgias and arthralgias are related to individual doses; associations with the cumulative dose and infusion duration are less clear. Identification of risk factors for myalgias and arthralgias could distinguish a group of patients at greater risk, leading to minimization of myalgias and arthralgias through the use of preventive therapies. Optimal pharmacologic treatment and possibilities for the prevention of myalgias and arthralgias associated with paclitaxel are unclear, partially due to the small number of patients treated with any one medication. The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) is the most frequently documented pharmacologic intervention, although no clear choice exists for patients who fail to respond to NSAIDs. However, the increasing use of weekly paclitaxel could necessitate daily administration of NSAIDs for myalgias and arthralgias and leave patients at risk for adverse effects. This concern may also limit the use of corticosteroids for the prevention and treatment of paclitaxel-induced myalgias and arthralgias. Data from case reports suggest that gabapentin (Neurontin), glutamine, and, potentially, antihistamines (e.g., fexofenadine [Allegra]) could be used to treat and/or prevent myalgias and arthralgias. Given the safety profile of these medications, considerable enthusiasm exists for evaluating their effectiveness in the prevention and treatment of paclitaxel myalgias and arthralgias, particularly in the setting of weekly paclitaxel administration.

The purpose of this study was to characterize the concentration-response effects of cyclophosphamide (CPA) with and without dexamethasone (DEX; 10 microM) on the expression of CYP3A4 and CYP2B6 in cultured human hepatocytes at concentrations representative of standard- and high-dose CPA therapy (25 to 750 microM). CPA produced concentration-dependent increases in CYP3A4 and CYP2B6 activity and immunoreactive protein that peaked at 250 and 125 microM, respectively, and declined thereafter. The inductive effect of CPA alone and in combination with DEX was greater in magnitude for CYP2B6 compared with CYP3A4. To further examine the inductive effect of CPA on CYP3A4, CPA (250 microM) and DEX (10 microM) alone and in combination were examined in 10 hepatocyte preparations. The combination of CPA and DEX yielded higher rates of 6beta-hydroxytestosterone formation than either agent alone. However, the effect was less than additive in human hepatocyte cultures with relatively high baseline CYP3A4 activity and additive or synergistic in human hepatocyte cultures with relatively low baseline CYP3A4 activity. Induction index was highly correlated with CYP3A4 baseline activity for both CPA (r(2) = 0.75) and CPA plus DEX (r(2) = 0.85). To investigate the potential mechanism for CPA-induced increases in CYP3A4 activity, the ability of CPA alone and in combination with DEX to activate pregnane X receptor (PXR) was explored using transient transfection assays. CPA produced a dose-dependent increase in PXR activation that was maximal at the highest CPA concentration studied (500 microM). The addition of DEX to CPA resulted in a minor increase in PXR activation compared with CPA alone. These results indicate that CPA alone and in combination with DEX differentially induces the expression of CYP3A4 and 2B in a concentration-dependent manner, which may be mediated partially through activation of PXR. The impact of these effects on the efficacy and toxicity of CPA therapy warrants further investigation.

Purpose: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection., Methods: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR + 25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR., Results: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P < 0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias -1% and -18%, respectively)., Conclusion: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.

Objective: To describe a systematic evaluation of the outcomes associated with revising institutional guidelines for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) to promote cost-effective use of the serotonin (5-HT3) antagonists., Methods: The 5-HT3 antagonist of choice in the antiemetic guidelines was revised from intravenous ondansetron to oral granisetron in August 1995. Patient assessments were conducted immediately prior to (Period 1) and after (Period 2) guideline revision using validated questionnaires. The effectiveness of the two 5-HT3 antagonists were compared and reported to the prescribing oncologists. Outcomes were assessed one year after guideline revision (Period 3) using identical methods., Results: No difference was found in the rate of total control (no emesis, no nausea) between patients receiving oral granisetron (60%) and intravenous ondansetron (56%) (p = 0.408, Period 1 vs. 2). Nausea severity, the number of emesis episodes, and use of rescue antiemetics were also equivalent. Prescriber compliance with using the 5-HT3 antagonist of choice and dose increased from 48% to 61% following adoption of oral granisetron. By Period 3, compliance increased to 78%, and satisfactory control of acute CINV was again documented. The costs for prevention of acute CINV decreased from $107 in Period 1 (intravenous ondansetron only) to $65 in Period 3 (oral granisetron)., Conclusions: Outcomes associated with use of oral granisetron and intravenous ondansetron were equivalent in this patient population. Guideline revision and outcome documentation by the oncology pharmacists resulted in increased compliance with institution guidelines and a 40% cost savings.

Purpose: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures., Methods: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone., Results: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59)., Conclusions: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

Objective: To conduct a retrospective drug utilization evaluation comparing the use of granulocyte colony-stimulating factor (G-CSF) at a university medical center with the American Society of Clinical Oncology (ASCO) CSFs Practice Guidelines., Methods: Patients who received G-CSF from June 1, 1996, to December 31, 1996, were identified through the pharmacy computer system and the medical records were reviewed for a randomly selected sample of 26% of the 289 patients identified. Outpatient, inpatient, and electronic medical records were reviewed for the indication, dosage, day of initiation, day of discontinuation, and absolute neutrophil count (ANC) monitoring plan for each course of G-CSF; these records were subsequently compared with the ASCO guidelines., Results: The use of G-CSF after chemotherapy was evaluated in 51 patients who received a total of 182 courses of G-CSF. The goal of chemotherapy was curative in 61% of courses. Sixty-five percent of G-CSF courses were prescribed for primary prophylaxis. Of these, 74% followed chemotherapy in patients with an expected incidence of febrile neutropenia > or =40% or followed chemotherapy in patients with compromised marrow reserve secondary to extensive prior therapy or in patients older than 60 years. Most of the G-CSF courses (75%) were rounded to the nearest vial size. The areas of greatest departure from the ASCO guidelines included aspects of initiation and discontinuation of G-CSF courses and inadequate documentation of ANC recovery., Conclusions: These results demonstrate a number of specific opportunities for oncology pharmacists to improve the use of G-CSF in patients receiving chemotherapy. Recommendations were made to the pharmacy and therapeutics committee and medical oncologists to improve compliance with the ASCO guidelines.

It is widely believed that patients' reluctance to report pain and adhere to treatment recommendations are significant barriers to cancer pain control. However, few investigators have examined barriers to cancer pain management from the cancer patient's perspective. Ambulatory patients with cancer who had experienced cancer-related pain in the previous month or were currently taking analgesics for cancer pain control were asked to participate in this study. Information regarding (a) pain assessment, (b) pain medication use, (c) concerns and barriers to compliance, (d) communication patterns regarding pain and pain control, and (e) demographics were collected during a 10-min structured interview. Approximately 20% of patients with a current cancer diagnosis who were approached reported that they had experienced pain or taken analgesic drugs during the preceding month. Eighty-eight percent of these patients ranked their pain as five or greater (scale, 0-10), and 81% reported impaired function due to pain. Major barriers to effective treatment included forgetfulness, the belief that pain should be tolerated, concerns about side effects, and fear and disdain of dependence, addiction, and tolerance. One-third of patients felt that their pain could not be better controlled than it currently was. Patients reported frequent communication regarding pain and pain control with physicians (52%), nurses (41%), and pharmacists (17%). The low pain prevalence, coupled with high pain intensity and associated dysfunction, appears to be a reflection of patient's unwillingness to report pain of mild to moderate intensity. In addition to previously recognized factors, stoicism and fatalism represent significant barriers to cancer pain control.

Thrombotic and hemorrhagic events may result from high circulating concentrations of platelets (> 1,000,000/mm3), and measures to reduce the platelet count are indicated in symptomatic or extreme thrombocytosis. The platelet count can be decreased quickly by plasmapheresis, but the effect is transient. Patients with thrombocytosis secondary to a myeloproliferative disease, such as chronic myelogenous leukemia (CML), frequently require more sustained suppression of the platelet count. Hydroxyurea, busulfan, and interferon are used to maintain a lower platelet count but are occasionally ineffective or intolerable. An alternative to these therapies is anagrelide, a quinazolin derivative that was approved by the Food and Drug Administration in March 1997. Because current dosing guidelines for anagrelide are scarce, the dosing method of the Anagrelide Study Group that published the largest study to date on the drug's efficacy in thrombocytosis was followed. Two unexpected episodes of anagrelide-induced thrombocytopenia occurred despite following these dosing methods. This prompted a critical evaluation of the pharmacodynamic response and the appropriateness of anagrelide dosage recommendations. A case of thrombocytosis treated with anagrelide in a patient with CML is described.