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

Abstract

Purpose: To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy.

Methods and materials: 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 70 Gy in 35 fractions versus 78 Gy 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.

Results: With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy 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 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy 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.

Conclusions: Dose escalation by 8 Gy (78 Gy vs 70 Gy) 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.

Figure 1:. Cumulative Incidence of Biochemical and/or Clinical Failure for the Entire Patient Cohort Treated to 70 Gy vs. 78 Gy

Biochemical and/or clinical failure at 15 and 20 years was significantly better for patients receiving 78 Gy (Red Line; 12.0% and 12.2%, respectively) compared to 70 Gy (Blue Line; 18.9% and 19.2%, respectively) (Subhazard Ratio [sHR]: 0.61; 95% Confidence Interval [CI]: 0.38 – 0.98; Fine-Gray P=0.042).

Figure 2:. Cumulative Incidence of Biochemical and/or Clinical Failure for Low-, Intermediate-, and High-Risk Patients Treated to 70 Gy vs. 78 Gy

Sub-group analysis demonstrated no difference in the cumulative incidence of biochemical and/or clinical failure in patients with low risk (Fine-Gray P=0.064), intermediate risk (Fine-Gray P=0.344) and high risk (Fine-Gray P=0.223) disease per the National Comprehensive Cancer Network risk stratification criteria.

Figure 3:. Cumulative Incidence of Distant Metastatic Failure for the Entire Patient Cohort Treated to 70 Gy vs. 78 Gy

Distant metastatic failure at 15 and 20 years was significantly better for patients receiving 78 Gy (Red Line; 1.1% and 1.4%, respectively) compared to 70 Gy (Blue Line; 3.4% and 4.2%, respectively) (Subhazard Ratio [sHR]: 0.33; 95% Confidence Interval [CI] 0.13 – 0.82; Fine-Gray P=0.018).

Figure 4:. Cumulative Incidence of Prostate Cancer-Specific Mortality for the Entire Patient Cohort Treated to 70 Gy vs. 78 Gy

Cumulative incidence of prostate cancer-specific mortality at 15 and 20 years was significantly higher in the patients receiving 70 Gy (Blue Line; 6.2% and 10.2%, respectively) compared to 78 Gy (Red Line; 3.2% and 5.4%, respectively) (Subhazard Ratio [sHR] 0.52, 95% Confidence Interval [CI] 0.27 – 0.98; Fine-Gray P=0.045).