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The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.

Since tamoxifen is widely used in breast cancer treatment and has been proposed for the prevention of breast cancer, its endometrial iatrogenic effects must be carefully examined. We have investigated the association between endometrial cancer and tamoxifen use or other treatments in women treated for breast cancer in a case‐control study. Cases of endometrial cancer diagnosed after breast cancer (n = 135) and 467 controls matched for age, year of diagnosis of breast cancer and hospital and survival time with an intact uterus were included. Women who had received tamoxifen were significantly more likely to have endometrial cancer diagnosed than those who had not (crude relative risk = 4.9, p = 0.0001). Univariate and adjusted analyses showed that the risk increased with the length of treatment (p = 0.0001) or the cumulative dose of tamoxifen received (p = 0.0001), irrespective of the daily dose. Women who had undergone pelvic radiotherapy also had a higher risk (crude relative risk = 7.8, p = 0.0001). After adjusting for confounding factors, the risk was higher for tamoxifen users (p = 0.0012), treatment for more than 3 years (all p < 0.03) and pelvic radiotherapy (p = 0.012). Women who had endometrial cancer and had received tamoxifen had more advanced disease and poorer prognosis than those with endometrial cancer who had not received this treatment. Our results suggest a causal role of tamoxifen in endometrial cancer, particularly when used as currently proposed for breast cancer prevention. Pelvic radiotherapy may be an additional iatrogenic factor for women with breast cancer. Endometrial cancers diagnosed in women treated with tamoxifen have poorer prognosis. Women who receive tamoxifen for breast cancer should be offered gynaecological surveillance during and after treatment. A long‐term evaluation of the risk–benefit ratio of tamoxifen as a preventive treatment for breast cancer is clearly warranted. Int. J. Cancer 76:325–330, 1998.© 1998 Wiley‐Liss, Inc.

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

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