Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.

Abstract

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.

Southwest oncology group strategies in prostatic carcinoma

“…This study was closed in 1984 before reaching its accrual goal due to slow accrual and interest in other strategies. There was no evidence for a survival advantage due to chemotherapy, but the statistical power was small due to this early closure [5].…”

Does chemotherapy have a role before hormone-resistant disease develops?

“…In NPCTG 1700, Huben and Murphy [14] reported that methotrexate plus DES or orchiectomy was not superior to ADT with either DES or orchiectomy or to buserelin. A Southwest Oncology Group (SWOG) trial reported by Osborne et al [15] randomly assigned 143 men to initial ADT (DES or orchiectomy) plus doxorubicin and cyclophosphamide or ADT with delayed chemotherapy at the time of hormoneresistant prostate cancer (HRPC). Only nonsignifi cant differences were seen in the form of initial response rates (63% vs 48%, P = 0.059), time to treatment failure, overall survival, and median survival.…”

Goserelin

“…The first [56] proposes that prostatic malignancies are heterogeneously composed of clones of both androgen-dependent and androgen-independent cells before hormonal treatment begins, and that clones of androgen-independent cells will develop irrespective of the extent of androgen deprivation. Proponents of this theory support treatment with hormonal manipulation in combination with chemotherapy, but a study by the Southwest Oncology Group [57] reported that there was no advantage for combination therapy with respect to time to treatment failure or duration of survival. In vitro data indicate that goserelin inhibits both androgendependent and androgen-independent clones (section 1.3).…”