Relationships between body composition parameters and fluorouracil pharmacokinetics

Gusella, Milena; Toso, S.; Ferrazzí, Eros; Ferrari, Mariano; Padrini, Roberto

doi:10.1046/j.1365-2125.2002.01598.x

Cited by 83 publications

(62 citation statements)

References 20 publications

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“…Capecitabine is a prodrug that is metabolized to 5-FU. Consistent with our findings, Gusella et al (6) reported that fat-free mass (LBM plus bone tissue) and total body water were better predictors of 5-FU pharmacokinetics (clearance and volume of distribution) than BSA or total body weight.…”

Section: Discussionsupporting

confidence: 81%

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Prado

Baracos

McCargar

et al. 2009

Clinical Cancer Research

943

709

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Purpose: Body composition has emerged as an important prognostic factor in cancer patients.Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). Experimental Design: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1of treatment, andTTP was determined prospectively.Results: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05). Conclusion: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.

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Section: Discussionsupporting

confidence: 81%

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Prado

Baracos

McCargar

et al. 2009

Clinical Cancer Research

943

709

View full text Add to dashboard Cite

show abstract

“…Gusella et al (9) reported that fat-free mass (LBM without i.m. fat and fat in cell membranes) and total body water (intracellular and extracellular water) were better predictors of 5-FU pharmacokinetics (clearance and volume of distribution) than BSA or total body weight.…”

Section: Discussionmentioning

confidence: 99%

Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy Toxicity

Prado

Baracos

McCargar

et al. 2007

Clinical Cancer Research

540

428

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Purpose: Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Experimental Design: Toxicity after cycle 1was graded according to National Cancer Institute CommonToxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Results: Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Conclusion: Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition. 5-Fluorouracil (5-FU) is a potent anti-metabolite used to treata variety of solid tumors, and it is a well-established form of chemotherapy for colorectal cancer (1). The Mayo regimen of bolus 5-FU and leucovorin is associated with significant myelosuppression, mucositis, and diarrhea. In one study, 35% of patients had significant toxicity with patients experiencing dose reductions, therapy discontinuations, hospitalization, and even death (2). Attempts have been made to identify clinical variables to predict patients at risk for severe toxicity (3), but an approach for individualizing 5-FU dosing remains unclear.Interpatient variation in toxicities can arise from differences in target protein(s) expression, drug metabolism, and excretion. Disparate metabolism and excretion of anticancer drugs in turn can be due to environmental, physiologic, and genetic factors.Our hypothesis is that a physiologic factor, heterogeneous body composition of cancer patients, and, specifically, relative amounts of lean and adipose tissue compartments contribute to interpatient variation in toxicities. We propose that the size of lean and fat compartments relate to the pharmacokinetic properties of a drug, as hydrophilic drugs distribute into the lean compartment, whereas lipophilic drugs distribute into the fat compartment.Currently, for most chemotherapy, dose is determined using body surface area (BSA). The practice originated from observations that basal metabolic rates scaled between species according to weight. Early investigators used BSA to estimate an appropriate starting dose for an anticancer drug for phase I studies based on preclinical animal studies (4). BSA dosing became established in clinical settings in part by dogma and not due to s...

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“…The differences seen in toxicities between patients were attributable to varia- tion in LBM [20]. Lean body mass was a better predictor of 5 FU pharmacokinetics than were standard anthropometric measures [21].…”

Section: Discussionmentioning

confidence: 95%

Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts

Karmali¹,

Maxuitenko²,

Gorman³

2013

JCT

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Background: Paclitaxel (PTX) is approved for the treatment of refractory ovarian cancer and breast cancer, but is problematic due to severe, dose-dependent, potentially irreversible neurotoxicity. Alternative formulations using nanoparticles and liposomes have been developed to avoid solvent-related toxicity. These formulations allow improved delivery; however, toxicity, compensatory signaling, and drug resistance still pose challenges. Conversion of cytotoxic agents to their orotate compounds offers a potentially improved approach by increasing bioavailability and reducing toxicity. Orotate salts are neutral and acquire lipophilic properties, easing diffusion through lipid membranes. The orotate salt of PTX (PTXO) may yield an improved safety profile. Combination therapy with cytotoxic drugs, antiangiogenics and/or signal transduction pathway inhibitors has shown better efficacy than cytotoxic monotherapy. The combination of carboxyamidotriazole orotate (CTO, a calcium signal transduction pathway inhibitor) and PTX may be more effective than PTX alone at non-toxic doses. Materials and Methods: PTXO alone, and combinations of CTO with PTX and PTXO were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combinations. The tolerated combinations, PTX monotherapy, and PTXO monotherapy were then tested to evaluate their antitumor activity in female athymic NCr-nu/nu mice with subcutaneously implanted OVCAR-5 human ovarian tumor. Antitumor activity was measured by median time to doubling, median tumor growth delay, and mean percent body weight loss. Results: CTO, PTX, and PTXO showed significant inhibition of growth of the human OVCAR-5 ovarian tumor xenografts. The combination of low PTX and CTO, or high PTXO monotherapy, had significant efficacy and it was less toxic than high PTX as measured by body weight loss. Conclusions: Low-dose CTO is effective and has low toxicity, suggesting the potential for maintenance therapy for ovarian cancer. PTXO offers efficacy and a strategy for minimizing body weight loss, and may improve outcomes for patients who demonstrate toxicity to PTX.

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Relationships between body composition parameters and fluorouracil pharmacokinetics

Cited by 83 publications

References 20 publications

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy Toxicity

Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts

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