Megestrol acetate for anorexia in patients with far-advanced cancer: a double-blind controlled clinical trial.

The aim of this study was to evaluate a low-dose regimen of megestrol acetate (MA; 320 mg/day) on appetite in advanced cancer patients. Out-patients with far-advanced non-hormone responsive tumours and loss of appetite were randomised in a phase III trial, with two consecutive phases: a 14-day double-blind placebo controlled phase (phase A) and a 76-day open phase (phase B). During phase A, patients were treated with MA, two 160 mg tablets/day, or placebo. In phase B, the MA dose was titrated to clinical response in both groups. Appetite, food intake, body weight, performance status, mood and quality of life were evaluated with standardised measures; patients' global judgement about treatment efficacy was also requested. Of 42 patients entering the study, 33 (17 MA and 16 placebo) were evaluable for efficacy. The appetite score improved significantly with MA after 7 days (P = 0.0023), and this effect was still significant at 14 days (P = 0.0064). Patients judged the treatment with MA effective in 88.2% of cases (14th day), whilst placebo was considered effective by 25% (P = 0.0003). None of the other measures showed significant changes during treatment. The remarkable effect on appetite evident after 7 days, without serious side-effects, shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease.

Low-dose glutathione administration in the prevention of cisplatin-induced peripheral neuropathy in rats.

So far various drugs have been used in an attempt to prevent or reduce cisplatin (CDDP)-induced peripheral neuropathy. Of those tried reduced glutathione (GSH) is one of the most promising. Its effectiveness has already been demonstrated by means of morphological methods in CDDP-treated rats in which high doses of GSH (up to 1200 mg/kg) were given. In the current study neurophysiological and morphological methods were used to evaluate the effect of low doses (150-300 mg/kg) of GSH i.p. on the peripheral nervous system of the rat. Four groups of 8 female Wistar rats were treated as follows: (A) CDDP 2 mg/kg i.p. weekly for 9 courses; (B) same as (A) plus GSH 150 mg/kg i.p. weekly; (C) same as (A) plus GSH 300 mg/kg i.p. weekly; (D) same as (A) plus GSH 150 mg/kg i.p. on the day of DDP injection followed by 150 mg/kg/day over the next 2 days. Eleven age-matched untreated rats were used as controls. Sensory conduction velocity was recorded in the tail nerve and morphologic and morphometric examinations were performed on the dorsal root ganglia neurons (L4-L6) in each animal. The results demonstrated that the neurophysiological and pathological changes induced by CDDP administration were less severe in rats co-treated with GSH. No significant differences could be related to the 3 different regimens of GSH co-treatments. This experiment confirms that GSH is able to reduce the neurotoxicity of CDDP and that it is effective even at doses as low as those used in the present study.

Neuroprotectant drugs in cisplatin neurotoxicity.

Cisplatin (CDDP) is one among the most effective and widely used anticancer drugs. Its use is, however, often limited by its peripheral neurotoxicity, which may be severely disabling and sometimes not reversible. To prevent or reduce CDDP peripheral neurotoxicity several "neuroprotective" drugs have been proposed. This goal is of extreme importance in the treatment of cancer patients, especially in view of the better results obtained by anticancer chemotherapy in terms of longer disease-free survival which has made even more crucial than in the past the point of the quality of life of the long-surviving patients. The data of pre-clinical and clinical studies with neuroprotectant agents are often conflicting, in some cases because of inadequate methods of evaluation and/or study design used to examine their effectiveness. The aims of this review will be 1) to discuss and describe the most appropriate methods of evaluation of CDDP and neuro-protectant drugs in experimental in vitro and in vivo pre-clinical studies 2) to evaluate critically the results of the clinical trials reported so far with the combined treatment and 3) to explore the possible future strategies to achieve neuroprotection during high-dose CDDP treatment in humans.

Weekly cisplatin +/- glutathione in relapsed ovarian carcinoma.

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450-650 mg m-2 were randomized to receive cisplatin 50 mg m-2 weekly +/- 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.

Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomized trial in patients operated on for endometrial cancer.

A randomized pilot trial was performed to evaluate the feasibility of administration of glutathione (GSH, 1200 mg, i.v.) as a protector in preventing diarrhea in patients operated on for endometrial cancer and submitted to adjuvant radiotherapy of the pelvis. Diarrhea occurred in 52% of patients in the untreated control group and only in 28% of patients in the GSH-treated group. Our preliminary data indicate that GSH administered before radiotherapy reduced the occurrence of diarrhea from oxidative damage to the intestinal mucosa. A large-scale phase III study is required to obtain definitive conclusions on the protective potential of GSH.

A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity.

AIMS AND BACKGROUND: The clinical use of cisplatin (CDDP), one of the most active agents in advanced ovarian cancer, is limited by nephrotoxicity and cumulative neurotoxicity. In preclinical studies, reduced glutathione (GSH) demonstrated a protective action against CDDP nephrotoxicity. We treated 20 patients with advanced ovarian carcinoma, with polychemotherapy containing CDDP + GSH, to assess the protective action of GSH against CDDP nephrotoxicity. METHODS: Between January 1988 and December 1989, 20 patients, with advanced ovarian carcinoma (St. III-IV-FIGO), not pretreated received CDDP: 45 mg/m2 i.v., on day 1-2, + cyclophosphamide (CPA): 900 mg/m2 i.v. on day 2 + GSH 2500 mg i.v. in normal saline 100 ml (in 15 min), before CDDP, every 21-28 days. RESULTS: A pathologic complete response rate (PCR) of 55% (11/20) was observed (7/14 patients with bulky disease). Median survival was 26.5 months and 5 patients were still alive and disease free at 35 months. Toxicity was limited, without any case of nephrotoxicity. CONCLUSIONS: On the basis of our previous experience with the same regimen without GSH, this study suggests that also in the clinical setting, GSH has no negative interference on CDDP activity and that GSH might improve the therapeutic index of CDDP. However, our data need to be confirmed by large randomized clinical studies.

La atención medica de los trabajadores / Workers' medical assistance

The importance of an adequate medical assistanc eto workers in Chile is emphasized in order to improve health levels. Ther is not a formal document of health policy for workers, there only exists a legal backup in the Sanitary Code in force; in its ruling and through Law 16.744 of the Work Code. Following this, there is a detailed presentation of the different areas to be developed for improving the preventive function to be performed in relation to worker's health: close study of the work environment, of occupational health and of labor epidemiology