Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens

Abstract

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing.

Keywords: Body composition; chemotherapy toxicity; colon cancer; irinotecan; lean body mass; neuropathy; oxaliplatin.

Figure 1

Relationship between computed tomography defined lean body mass (LBM) and body surface area (BSA) in 776 colorectal cancer patients referred to a medical oncology service in northern Alberta, Canada. (A) Shows a weak relationship between BSA and LBM, R ² = 0.5341. (B) Potential effect of body composition across quintiles of the ratio of LBM/BSA. Upper panel shows the potential variation in 5‐Fluorouracil (5FU)/kg LBM that would result in this population as a consequence of the variation in body composition, if all patients were to be administered 425 mg/m² of 5FU (lower panel).

Figure 2

Distribution of the estimated oxaliplatin dose/kg lean body mass in French patients, from lowest to highest value. Estimated mg oxaliplatin/kg lean body mass for FRENCH population cohort (n = 58) varied from 2.5 to more than 6.0 mg/kg. A value of 3.09 mg/kg LBM was determined to be the cut point for dose‐limiting toxicity (Area under ROC curve = 0.708). Toxicity rates were 0/17 (0.0%) and 18/41 (44.0%) using this cut point to separate the data into two groups (P = 0.005; Fisher's Exact Test).

Figure 3

Combined characteristics of French and Canadian Populations. (n = 138). Data were stratified into three groups based on the estimate of oxaliplatin dose/kg lean body mass: ≤3.09, between 3.09 and 3.55 and ≥3.55; ^a,b,c means with different superscripts are different, P < 0.04.