To study whether primary site or advancing stage of disease influenced whole body protein metabolism, [1-14C]leucine was used in five gastric and nine colorectal cancer patients and ten with benign disease. No differences were found by primary site or by comparing cancerous to benign patients. No differences were found between TNM stages 1, 2, or 3. Flux, synthesis and breakdown rates (2.30 +/- 0.29, 1.88 +/- 0.33, and 1.66 +/- 0.26 mmole leucine kg-1 day-1, respectively) were significantly greater in disseminated (stage 4) disease than in localized (stages 1-3) disease (1.71 +/- 0.32, 1.44 +/- 0.23, and 1.09 +/- 0.23 mmole leucine kg-1 day-1). Advanced cancer stage is marked by accelerated leucine metabolism, with flux and synthesis rates influenced primarily by feeding and secondarily by stage of disease. Protein breakdown rates correlated most closely to the stage of cancer. Cancer cachexia is the result of appetite suppression, decreased nutrient intake, and altered metabolism of endogenous substrates. Protein metabolism probably changes as a consequence, not a cause, of altered intake and energy metabolism in the tumor-bearing host.