Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients

Abstract

Body surface area (BSA)-based dosing leads to wide inter-individual variations in drug pharmacokinetics and pharmacodynamics, whereas body composition has been shown to be a more robust determinant of efficacy and toxicity of certain chemotherapeutic agents. We correlated various parameters of body composition with doxorubicin pharmacokinetics and hematologic toxicities in Asian patients with locally advanced or metastatic breast cancer. Our analysis included 84 patients from two studies who received pre- or post-operative single-agent doxorubicin; pharmacokinetic parameters were available for 44 patients. Body composition parameters were derived from CT cross-sectional images and population pharmacokinetic analysis was conducted using mixed-effects modeling. Higher intra-abdominal fat volume and fat ratio (intra-abdominal:total abdominal fat volume) correlated with greater incidence of grade 4 leukopenia on cycle 1 day 15 (mean intra-abdominal fat volume: 97.4 ± 46.5 cm(3) vs 63.4 ± 30.9 cm(3), p = 0.014; mean fat ratio: 0.43 ± 0.11 vs 0.33 ± 0.09, p = 0.012, grade 4 vs grade 0-3 leukopenia). On subset analysis, this relationship was maintained even in underweight patients. Concordantly, there were positive correlations between doxorubicin AUC and intra-abdominal fat volume as well as total abdominal fat volume (r (2) = 0.324 and 0.262, respectively, all p < 0.001). BSA and muscle volume did not predict for doxorubicin pharmacokinetics or toxicities. High-intra-abdominal fat volume but not BSA predicted for greater doxorubicin exposure and hematologic toxicities, suggesting that body composition is superior to BSA in determining doxorubicin pharmacokinetics and pharmacodynamics. Body composition has an emerging role in chemotherapy dose determination.

Body mass index as a prognostic factor in Asian patients treated with chemoimmunotherapy for diffuse large B cell lymphoma, not otherwise specified

“…The results of the presented study showing the differences of estimated HR and statistical significances of underweight and severe obese patients between sexual and age groups may also implicate a dissimilar pharmacokinetics between these groups. In fact, a pharmacologic study of breast cancer patients suggested that body composition rather than body surface area predicts the clearance of doxorubicin and chemotherapeutic toxicities [37]. Furthermore, recent reports also demonstrated the prognostic significance of body composition in patients with DLBCL [38,39], suggesting that body composition has implications for the pharmacokinetics and prognosis of DLBCL [40].…”

Clinical implications of low skeletal muscle mass in early-stage breast and colorectal cancer

“…40 Among 84 Asian breast cancer patients with non-metastatic breast cancer, higher levels of visceral fat was associated with a higher risk of grade 4 leukopenia (p=0.014), whereas lower skeletal muscle index was associated with a trend towards a higher rate of grade 3/4 leukopenia and neutropenia (p=0.051). 41 A smaller earlier study of 24 stage II–III breast cancer patients treated with epirubicin based chemotherapy found that lower lean body mass was associated with higher risks of toxicity with differences in pharmacokinetics. 42 In combination, these studies suggest that measures of body composition are better predictors of chemotherapy related toxicity than the widely used body surface area.…”

Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy

“…Pre-existing sarcopenia was associated with toxicity in 50% of patients compared to 20% who were non sarcopenic ( p =0.03); time to tumor progression (TTP) was also shorter for sarcopenic vs non-sarcopenic patients (101 versus 173 days, respectively; p =0.05) and had an independent effect on TTP in multivariate model (HR= 2.6; p =0.01) (7). In an Asian study of early breast cancer patients, which examined the association between body composition and toxicity from doxorubicin, it was shown that higher increased visceral fat was significantly associated with grade 4 leukopenia ( p =0.014)(8). These findings suggest that different body composition measures may be a predictor of chemotherapy toxicity.…”