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...

clinicaltrials.gov Identifier: NCT00680901.

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Angiogenesis is a critical hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anticancer therapies for solid tumors. VEGF receptor-2 is the premier receptor responsible for many of the cancer-driven VEGF-induced spectrum of biologic changes, including modification of blood vessel structure and function, proliferation and migration. Unlike all clinically approved angiogenesis inhibitors, the fully human monoclonal antibody ramucirumab (IMC-1121B) specifically and potently inhibits VEGF receptor-2. Phase I clinical trials have shown safety across a wide range of ramucirumab doses with impressive, albeit early, evidence of both stable disease and partial responses in a variety of tumor types. In this article, we review the current data on ramucirumab and make comparisons with commercially available antiangiogenic agents.

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