Treatment of patients who have symptomatic or advanced hepatocellular carcinoma (HCC) is still a challenge, because the mean survival is only a few months.1 As curative treatments such as surgery or percutaneous ablation are excluded, arterial chemoembolization is the preferred palliative option; however, improved survival is only observed in a small percentage of patients with good liver function.2 No medical treatment has been proven effective.2
The influence of sex hormones on the growth of HCC has been suspected for a long time.3 On the basis of experimental studies and findings showing estrogen receptors in tumor cells, treatment with tamoxifen, an antiestrogenic drug effective in breast cancer,4 has been tested in patients who have unresectable HCC.5, 6 The positive influence of androgens on HCC growth is also supported by other results. First, HCC mainly occurs in males (with a male/female ratio between 5 and 91), with a poorer outcome in males than in females.7 Second, occurrence of HCC has been reported in patients treated with androgens8 or in bodybuilders.9 Third, serum testosterone has been found to be a predictive factor of HCC occurrence in patients with hepatitis C virus and cirrhosis10 and in hepatitis B virus carriers.11 Fourth, androgen receptors have been found in normal livers and in livers with cirrhosis12 as well as HCC.13 In tumor cells, androgen receptors seem to be present more frequently and in greater concentrations than estrogen receptors.14 Furthermore, experimental studies have suggested a promoter effect of androgens on tumor growth,15 which may be suppressed via antiandrogen treatment16 or castration.17 Some clinical studies have also suggested that the presence of androgen receptors has a negative influence on survival or HCC recurrence after surgery,18 although these results remain controversial.19, 20
Several uncontrolled studies testing the effect of antiandrogens in HCC patients have failed to demonstrate a significant effect on tumor size of either peripheral antiandrogens (e.g., flutamide,21 ketoconazole,22 and cyproterone acetate23) or agonists of the gonadostimulin-releasing hormone (e.g., triptorelin24 and buserelin25). However, these nonrandomized trials show neither a decrease nor a stabilization of tumor growth. The aim of our randomized trial was to assess the effect of antiandrogen treatment on survival in European male patients who have advanced HCC. We chose to only include male patients because the carcinogenetic influence of androgens could be different between males and females.26 To obtain complete androgen blockade as recommended in prostate cancer (a tumor with high concentrations of androgen receptors), we used an association of leuprorelin, a luteinizing hormone–releasing hormone agonist, and flutamide, a nonsteroid peripheral antagonist that is supposed to be more effective than steroid antagonists.27 Because two randomized trials suggested that tamoxifen might be effective at the time our trial began,5, 6 tamoxifen was administered in both groups to specifically test the antiandrogenic effect of leuprorelin, which also depresses estrogen secretion. However, further randomized studies including larger numbers of patients2 showed no favorable (and no deleterious) effect on survival, which supports the use of tamoxifen as a placebo in our trial.