Advantages of the combination therapy in previously untreated and treated patients with advanced prostate cancer.

In order to achieve a more complete blockade of androgens of both testicular and adrenal origin at the start of treatment, we have administered the pure antiandrogen Flutamide in association with orchiectomy (13 patients) or the LHRH agonist [d-Trp6]LHRH ethylamide (118 patients) to previously untreated patients with clinical stage D2 prostate cancer. The mean duration of treatment was 491 days (102–1208 days). The response was assessed according to the criteria of the U.S. National Prostatic Cancer Project. A complete response has been observed in 30 patients (23%) while partial and stable responses have been achieved in 50 (38%) and 45 (34%) patients, respectively. A positive objective response has thus been observed in 125 of 131 patients (95%). Serum PAP became normal before 6 months in all except 8 (6.1%) of patients. Quite remarkably, 23 of 48 patients treated for 2 years (47.9%) have achieved a complete response. Of the 20 deaths, 12 (9%) were due to prostate cancer, while 8 (6%) resulted from other causes. The probability of continuing a positive response after 2 years of treatment (according to Kaplan and Meier) is 60% while the probability of survival at the same time interval is 89%. This survival should be compared to values of approx 50% achieved with previous treatments limited to inhibition of testicular androgen secretion or action. The present data demonstrate that the combined blockade of androgens achieved with Flutamide and castration provides an objective response in approx 95% of patients, and markedly prolongs the period of remission while the death rate within the first 2 years is lower than that obtained with previous treatments. The important prolongation of survival is achieved with an excellent quality of life. Two-hundred and three patients have clinical stage D2 prostate cancer previously treated by orchiectomy, estrogens or LHRH agonists alone received, at the time of relapse, the same combination therapy. Patients already castrated received only Flutamide while, for those previously treated with DES, the estrogen was replaced by the LHRH agonist (d-Trp6]LHRH ethylamide in association with Flutamide. Flutamide was given as additional medication to those already receiving an LHRH agonist alone. Complete, partial and stable objective responses assessed according to the criteria of the U.S. National Prostatic Cancer Project were obtained in 11 (5.4%), 17 (8.4%) and 38 (18.7%) patients, respectively, for a total objective response rate of 32.5%. Progression continued in 137 (67.5%) patients. The present data obtained in a large population of relapsing patients clearly demonstrate that a large number of tumors were left growing under the influence of androgens still present after standard treatment limited to blockade of testicular androgens. By adding the pure antiandrogen Flutamide to block the action of adrenal androgens remaining active after castration, a positive objective response is seen in one third of cases, thus providing those patients with a marked improvement in quality of life and most likely survival. Without this treatment, progression would have continued in all cases. In a large proportion of patients who did not reach an objective response, subjective improvement has been obtained, thus improving their quality of life. Since it is most likely that a proportion of androgen-sensitive tumors remain in all patients, even at the time of relapse, it is important that the combination therapy with Flutamide be continued for life in all cases.