Efficacity of the association of a methionine-free diet with nitrosourea in metastatic cancer treatment: Preliminary results of a phase II clinical trial Free

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The growth of human and animal tumors with in vitro and in vivo models has been shown to be inhibited by dietary methionine (MET) restriction. Furthermore, cytostatic drugs (Fluoropyrimidines, nitrosoureas, platinoïds) in association with MET restriction presented with a substantial improvement of their therapeutic index. On the basis of these data, we initiated a phase I clinical trial of dietary MET restriction with nitrosourea treatment (cystemustine) for metastatic melanomas or recurrent gliomas, aimed to determine the feasability of this association and the optimal MET-free diet duration in 10 patients (AACR 2004, abstract n°3741). With a good tolerance of the association (acceptability of the diet, nutritional status), the optimal plasmatic MET depletion (41%) was obtained at the at 1^st day of diet. We then realized a phase II clinical trial to evaluate the putatively increased therapeutic index of cystemustine with a 1 day dietary MET restriction. Currently, 20 patients have been included in this phase I/II clinical trial, who have received a median of 4 cycles [range, 1-7] of 2 weeks of the association of a MET-free diet and cystemustine (60 mg/m²) on the last day of the MET-free diet period. The 20 patients comprised 18 metastatic melanomas and 2 recurrent glomas. Fifteen have been previously treated by chemotherapy. Toxicity remained mainly hematologic and consisted of WHO grade 3-4 thrombocytopenia in 30% of patients, leucopenia in 30% of patients, neutropenia in 25% of patients. The main non hematological toxicity was only of WHO grade 1-2 :nausea and vomiting in 35% of patient and hepatic toxicity in 25% of patients. Among the 20 patients included, 14 were assessable for response (after 4 cycles). No objective response, 2 stable and 12 disease progressions have been observed after 4 cycles of treatment. The median survival was 4.1 months [0.4-43.3]. The absence of objective response cast doubt on the potentiating effect of the concomitant administration of a MET free diet and nitrosourea and the fact of the plasmatic MET depletion (38.3 ± 33.4%) realised by a synthetic diet is sufficient or not to produce an effect. On an other hand, these result were not surprising since most of the patients have been previously treated for metastatic disease, not only with 1 line (6 patients), but also with 2 ( 3 patients) 3 (1 patient) or 4 lines of chemotherapy (1 patient). Nevertheless, the overall survival and toxicity were comparable with previous trial testing cystemustine alone in second line of melanoma. These preliminary results might be confirmed in a largest cohort.