Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the Outcomes of a Phase 3, Single Institution Randomized Clinical Trial

Abstract

To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70Gy to 78Gy. Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70Gy in 35 fractions versus 78Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. With a median follow-up of 14.3years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70Gy versus 78Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P=.042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P=.018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P=.045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P=.469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P=.061). Salvage therapy was more common in the 70Gy arm, at 38.7% versus 21.9% in the 78Gy arm (P=.002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. Dose escalation by 8Gy (78Gy vs 70Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.