Primary and salvage therapy with LH-RH analogues in ovarian cancer

The efficacy of modern surgical and chemotherapeutic options for the treatment of ovarian cancer is still unsatisfactory. In spite of the availability of new cytotoxic agents, the majority of ovarian cancer patients will finally die of chemoresistant disease. LH-RH agonists in conventional doses have been shown to induce objective responses in approximately 9% of patients with refractory ovarian cancer and disease stabilization in 26% of these women. As toxicity of LH-RH agonists is low or absent, and since their efficacy is not strikingly inferior to that of experimental chemotherapy, they have a vital indication in the salvage situation. A trial is presently being performed among platinum/taxol-refractory patients, comparing the impact of the LH-RH agonist leuprorelin and that of the cytotoxic agent treosulfane on survival and quality of life. The addition of LH-RH agonists in conventional doses to standard first-line surgical and chemotherapy does not improve relapse-free and overall survival. For many years it has been suggested that LH-RH agonists inhibit proliferation of ovarian cancer by suppressing endogenous gonadotropins, which were considered to be mitogenic in this malignancy. Recent experimental and clinical data have made this hypothesis questionable. In contrast, a large body of experimental evidence has emerged during the past few years indicating that LH-RH agonists and antagonists directly inhibit proliferation of ovarian cancer through LH-RH receptors expressed by 80% of these tumors. To exploit these direct antiproliferative effects of LH-RH analogues, higher tissue concentrations are necessary than those achieved with the conventional doses used today. Alternative routes of administration or higher systemic doses of potent LH-RH antagonists, such as Cetrorelix, might improve the efficacy of this approach. Clinical trials addressing this issue are under way. Finally, the LH-RH receptors expressed by ovarian cancers could be employed for targeted chemotherapy using cytotoxic LH-RH analogues. This approach has been shown to be effective in experimental models and might be tested in clinical trials in the near future.