Locally advanced prostate cancer (T3-4N0M0) has a poor prognosis when treated with external irradiation, leading to attempts to combine irradiation with other therapies for a better outcome. Bolla and colleagues report on a large trial of an analog of luteinizing hormone-releasing hormone (LHRH) as adjunctive therapy to external irradiation in locally advanced prostate cancer.

The large international trial recruited men younger than 80 years with histologically proven T1-2 prostatic adenocarcinoma of grade 3 or T3-4 prostatic carcinoma of any histologic grade. All patients underwent laboratory and radiologic investigation to exclude those with evidence of distant metastases or growth in common iliac or para-aortic lymph nodes. Patients with a history of malignant disease (except adequately treated basal-cell carcinoma of the skin) also were excluded.

More than 400 men were randomly assigned to therapy with either external irradiation or external irradiation plus LHRH-analog therapy. Radiation therapy was given on five days per week for seven weeks. LHRH-analog therapy was administered subcutaneously every four weeks for three years. Serum prostate-specific antigen levels were measured two months after completion of radiation therapy, then every three months for three years, and then every six months thereafter. Other outcomes measured included size of the prostate gland, evidence of local or distant spread, and toxic effects of therapy.

The 208 patients assigned to radiotherapy alone were comparable to the 207 assigned to radiotherapy plus LHRH-analog therapy. Approximately one half of the men in each group reported additional chronic conditions. Cardiovascular disease was reported by 29 percent of the group that received only radiother-apy and by 24 percent of the men who received combined therapy. Follow-up data were available for 412 men, with a median follow-up time of 66 months. Eleven men in the combined-therapy group and one in the radiation group discontinued treatment because of adverse events.

Outcomes were significantly improved with combination therapy (see the accompanying table). The five-year survival rate of 78 percent in the combined-therapy group was significantly better than the 62 percent rate in the radiotherapy group. Of the 78 deaths in the radiotherapy group, 54 percent were attributed to prostate cancer. In the combined-therapy group, 24 percent of the 50 deaths were attributed to prostate cancer. Five-year disease-free survival rates also showed a significant advantage for combined therapy, with 74 percent of patients clinically disease-free compared with 40 percent in the radiotherapy group.

The authors conclude that the addition of androgen suppression to external radiation significantly improved total and disease-free survival in locally advanced prostate cancer. The optimal period of androgen-deprivation therapy has not been established.