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Anorexia, with its attendant reduction of food intake and progressive depletion of body stores, is among the major causes of the anorexia-cachexia syndrome occurring in cancer patients (J). Results from a number of studies (2-6) suggest that the enhanced brain availability of the amino acid precursor of serotonin, tryptophan, may play a role in the pathogenesis of cancer anorexia by increasing brain serotoninergic activity. During tumor growth, plasma-free tryptophan concentrations, one of the major determinants of brain tryptophan concentrations and serotonin synthesis, are significantly increased (2-4). Tryptophan entry into the brain is regulated by a specific transport system, which is competitively shared by the other large neutral amino acids (i.e., branchedchain amino acids [BCAAs], tyrosine, phenylalanine, and methionine). Thus, it is conceivable that entry of tryptophan into the brain may be reduced by increasing the plasma levels of competitors of tryptophan (7). We therefore hypothesized that the oral administration of BCAAs to cancer patients with anorexia would lead to decreased brain tryptophan concentrations and reduced serotoninergic activity, eventually resulting in an improvement of food intake. To test this hypothesis, 28 anorexic, not weight-losing patients, who had been admitted to our institutions in Italy with newly diagnosed, resectable cancers and who were undergoing surgical resection of the tumors, were enrolled in the study. None of the patients received radiotherapy and/or chemotherapy during the study or in the previous 4 weeks. The research protocol, double-blinded and placebo-controlled, was approved by the ethics committees at our institutions in Italy. After giving written, informed consent prior to surgery, patients were randomly assigned to receive either 4.8 g three times per day of a BCAA mixture (leucine, 2.36 g; isoleucine 1.28 g, and valine 1.16 g; BCAA group; n = 15 patients) or a placebo (isonitrogenous dose of glycine; placebo group; n = 13 patients), both obtained from Bracco Industria Chimica, Milan, Italy. BCAAs and a placebo, in powder form, were dissolved in tap water, and patients were required to take them orally three times per day, 60 minutes before each meal, for 7 consecutive days. Nutritional status prior to and at the end of the study was investigated by means of biochemical indices (serum levels of C3, prealbumin, transferrin, and ceruloplasmin). Daily caloric intake was evaluated in each patient throughout the study by carefully weighing food before and after each meal. The presence of anorexia was investigated prior to and at the end of the study, using a previously described questionnaire (4). On days 0 (base line), +3, and +7, blood samples were collected from all patients immediately before dinner (i.e., 1 hour after the drug, either BCAAs or a placebo, was taken) for the determination of plasma amino acids, including tryptophan, as previously described (4). Student's / test and chi-squared test were used to statistically analyze the results. A two-sided P value of <.05 was considered to indicate statistical significance. Data are expressed as mean value ± standard error. Only 25 patients completed the study, since three patients (one in the placebo group and two in the BCAA group) underwent surgery earlier than anticipated for reasons not related to the trial. Assessable patients in the placebo (n = 12) and BCAA (n = 13) groups were comparable for sex (male to female ratio = 7:5 and 7:6, respectively), age (64.6 ± 3.1 years [range, 41-81 years] and 65.0 ± 3.1 years [range, 47-83 years], respectively), and tumor origin (lung/gastrointestinal tract/urinary bladder/pancreas/ breast/neck; 4/4/1/1/1/1 and 5/5/1/1/1/0, respectively). In all patients, the biochemical indices of nutritional status were within the normal range prior to and at the end of the study (data not shown). In the placebo group, plasma amino acid patterns did not change throughout the study period (Fig. 1, A and B). In the BCAA group, plasma large neutral amino acids (LNAAs) increased significantly (Fig. 1, A), mainly as a consequence of an increase in BCAA concentrations (104.7 ± 14.4 |imol/dL on day +7; +121% versus base line; P<.0\). Consequently, the free tryptophan/LNAA ratio, which closely predicts brain tryptophan concentrations (5), decreased significantly in patients receiving BCAA (Fig. 1, B). The incidence of anorexia decreased significantly among patients in the BCAA group when compared with the base line (100% prior to and 45% at the end of the study; P<.05), while it did not change among patients in the placebo group (100% versus 84%, respectively). When compared with the base line, caloric intake by the patients increased significantly in the BCAA group but remained unchanged in the placebo group (Fig. 2). Cancer anorexia impinges significantly on quality of life, reduces the benefits of antineoplastic therapy, and ultimately

Effects of Administration of Oral Branched-Chain Amino Acids on Anorexia and Caloric Intake in Cancer Patients