Randomized comparison of total androgen blockade alone versus combined with weekly epirubicin in advanced prostate cancer.

Hormone deprivation is the gold standard for the treatment of metastatic prostate cancer. However, prostate cancer being primarily a heterogeneous tumor comprising hormone-dependent, hormone-sensitive, and hormone-insensitive cells, at least the latter remain unaffected by hormonal manipulations, thus making disease progression almost inevitable. In quest of a more comprehensive therapy we therefore studied the concept of early combined chemoendocrine therapy in a prospective randomized multicenter trial. The purpose of this study was to evaluate whether patients with previously untreated advanced prostate cancer benefit from combining total androgen blockade (TAB) with weekly epirubicin chemotherapy (E-TAB). From April 1988 to January 1991, 145 previously untreated patients with either metastatic (n = 117) or locally advanced (n = 28) histologically confirmed prostate cancer were randomly allocated to treatment with TAB by bilateral orchiectomy and flutamide 250 mg t.i.d. or TAB plus weekly epirubicin 25 mg/m2 i.v. for 18 weeks (E-TAB). The study endpoints were progression-free survival and overall survival. In addition the effects of treatment on quality of life were assessed by two methods. At regular intervals patients self-assessed ten qualities of physical, functional and emotional health using 5-point scales. In order to evaluate the time without disease progression and treatment-induced adverse effects, a modified Q-TWiST (quality-adjusted time without symptoms and toxicity) model was applied. At a median follow-up of 81 months, progression-free survival and overall survival in the TAB and E-TAB groups were 12 and 18 months (p < 0.02) and 22 and 30 months (p = 0.12), respectively. In patients with > 5 sites of bone metastasis (D2max), the corresponding periods were 9 and 14 months (p = 0.005) and 17 and 27 months (p = 0.06), respectively. Subjective quality of life assessment showed no impairment of quality of life by epirubicin treatment. Stage D and D2max patients treated with E-TAB had an average gain in Q-TWiST of 5 months (p = 0.098) and 8 months (p = 0.03), respectively, compared to the TAB treatment. Objective toxicities were generally mild with either treatment. In conclusion, the combination of TAB and epirubicin was well tolerated by patients with advanced prostate cancer and resulted in a significant extension of progression-free survival. This effect of E-TAB on objective treatment outcome was accompanied by prolonged time without treatment-induced adverse effects and tumor progression, i.e., time with good quality of life. Therefore, further studies with E-TAB appear warranted in patients with advanced prostate cancer.