FEASIBILITY, ENDOCRINE AND ANTITUMOR EFFECTS OF A TRIPLE ENDOCRINE THERAPY WITH TAMOXIFEN, A SOMATOSTATIN ANALOG AND AN ANTIPROLACTIN IN POSTMENOPAUSAL METASTATIC BREAST-CANCER - A RANDOMIZED STUDY WITH LONG-TERM FOLLOW-UP

Suppression of the secretion of prolactin, growth hormone and insulin- like growth factor 1 (IGF-1) might be important in the growth regulati on and treatment of breast cancer. Because oestrogens may counteract t he anti-tumour effects of such treatment, the combination of an anti-o estrogen (tamoxifen), a somatostatin analogue (octreotide) and a poten t anti-prolactin (CV 205-502) might be attractive. In this respect, we performed a first exploratory long-term study on the feasibility of c ombined treatment and possible clear differences in endocrine and anti -tumour effects during such combined treatment vs standard treatment w ith tamoxifen alone. Twenty-two post-menopausal patients with metastat ic breast cancer (ER and/or PR positive or unknown) were randomized to receive either 40 mg of tamoxifen per day or the combination of 40 mg of tamoxifen plus 75 mu g of CV 205-502 orally plus 3 x 0.2 mg of oct reotide s.c. as first-line endocrine therapy. An objective response wa s found in 36% of the patients treated with tamoxifen alone and in 55% of the patients treated with combination therapy. Median time to prog ression was 33 weeks for patients treated with tamoxifen and 84 weeks for patients treated with combination therapy, but the numbers are too small for hard conclusions. There was no difference in overall post-r elapse survival between the two treatment arms. With respect to the en docrine parameters, there was a significant decrease of plasma IGF-1 l evels in both treatment arms, whereas during combined treatment plasma growth hormone tended to decrease and plasma prolactin levels were st rongly suppressed; in some patients insulin and transforming growth fa ctor alpha (TGF-alpha) decreased during the triple therapy. Although t here was no significant difference in mean decrease of plasma IGF-1 le vels between the two treatment arms, combined treatment resulted in a more uniform suppression of IGF-1. Therefore, the addition of a somato statin analogue and an anti-prolactin may potentially enhance the effi cacy of anti-oestrogens in the treatment of breast cancer owing to fav ourable endocrine and possible direct anti-tumour effects. Large phase III trials using depot formulations (to increase the feasibility) of somatostatin analogues are warranted to demonstrate the potential extr a beneficial anti-tumour effects of such combination therapy.