Dataset Information

Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine.

ABSTRACT:

Background

Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients.

Methods

Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ⩾3, hand-foot syndrome ⩾2, or neutropenia ⩾2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan-Meier method.

Results

A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n = 1193). Overall, four regimens were evaluated: capecitabine-radiotherapy (n = 1178), capecitabine-oxaliplatin (n = 519), capecitabine triplet (n = 181) and capecitabine monotherapy (n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group (p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups.

Conclusions

Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing.

SUBMITTER: de Man FM

PROVIDER: S-EPMC6466460 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine.

de Man Femke M FM Veerman G D Marijn GDM Oomen-de Hoop Esther E Deenen Maarten J MJ Meulendijks Didier D Mandigers Caroline M P W CMPW Soesan Marcel M Schellens Jan H M JHM van Meerten Esther E van Gelder Teun T Mathijssen Ron H J RHJ

Therapeutic advances in medical oncology 20190415

<h4>Background</h4>Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients.<h4>Methods</h4>Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed bas ...[more]

PMID: 31019570

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Project description:The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.

Project description:OBJECTIVE:The goal of this study was to explore conceptual benefits of characterizing delineated target volumes based on surface area and to utilize the concept for assessing risk of therapeutic toxicity in radiosurgery. METHODS AND MATERIALS:Four computer-generated targets, a sphere, a cylinder, an ellipsoid and a box, were designed for two distinct scenarios. In the first scenario, all targets had identical volumes, and in the second one, all targets had identical surface areas. High quality stereotactic radiosurgery plans with at least 95% target coverage and selectivity were created for each target in both scenarios. Normal brain volumes V12Gy, V14Gy and V16Gy corresponding to received dose of 12 Gy, 14 Gy and 16 Gy, respectively, were computed and analyzed. Additionally, V12Gy and V14Gy volumes and values for seven prospective toxicity variables were recorded for 100 meningioma patients after Gamma Knife radiosurgery. Multivariable stepwise linear regression and best subset linear regression analyses were performed in two statistical software packages, SAS/STAT and R, respectively. RESULTS:In a phantom study, for the constant volume targets, the volumes of 12 Gy, 14 Gy and 16 Gy isodose clouds were the lowest for the spherical target as an expected corollary of the isoperimetric inequality. For the constant surface area targets, a conventional wisdom is confirmed, as the target volume increases the corresponding volumes V12Gy, V14Gy and V16Gy also increase. In the 100-meningioma patient cohort, the best univariate model featured tumor surface area as the most significantly associated variable with both V12Gy and V14Gy volumes, corresponding to the adjusted R2 values of 0.82 and 0.77, respectively. Two statistical methods converged to matching multivariable models. CONCLUSIONS:In a univariate model, target surface area is a better predictor of spilled dose to normal tissue than target largest dimension or target volume itself. In complex multivariate models, target surface area is an independent variable for modeling radiosurgical normal tissue toxicity risk.

Dataset Information

Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine.

Background

Methods

Results

Conclusions

Publications

Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine.

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