Hazards of dose escalation in prostate cancer radiotherapy

Abstract

Purpose: To assess the benefit of escalating the dose in definitive prostate cancer radiotherapy vs. the associated risk of complications.

Materials and methods: Between 1987 and 1999, 1087 patients with clinical Stage T1b-T3 adenocarcinoma of the prostate were definitively irradiated without hormonal therapy and had a pretreatment serum prostate-specific antigen (PSA) and Gleason score recorded. The median follow-up was 65 months. Doses ranged from 64 to 78 Gy, with the treatment techniques corresponding to the year of therapy and the prescribed dose. A total of 301 patients were treated on a randomized protocol to either 70 or 78 Gy. Also, 163 patients were treated with three-dimensional conformal therapy and had dose-volume histograms available for review.

Results: Tumor stage, grade, pretreatment PSA level, and radiation dose were all independent predictors of PSA disease-free survival (PSA-DFS) in multivariate analysis. The hazard rate for biochemical failure peaked at 1.5-3 years after radiotherapy. Although a statistically significant dose effect on PSA-DFS was found in the pretreatment PSA levels of those with both < or =10 ng/mL and >10 ng/mL, in those with a pretreatment PSA < or =10 ng/mL, the improvement in outcome was only seen going from a dose level of 64-66 Gy to 68-70 Gy with a 5-year PSA-DFS rate of 66% vs. 81% (p <0.0001). This was also confirmed by the data from the randomized patients who showed no difference in outcome whether treated to 70 Gy or 78 Gy. In patients with a pretreatment PSA level >10 ng/mL, a statistically significant improvement was found in disease-free outcome among the 64-66-Gy, 68-70-Gy, and 78-Gy levels. PSA-DFS was approximately 50% better at each higher dose level at 5 and 8 years after treatment. The dose had a statistically significant impact in both intermediate- and high-risk groups. Rectal morbidity was both dose and volume related. Although at 5 years after therapy, the Grade 2-3 rectal complication rate was twice as high for patients treated to 78 Gy than to 70 Gy, 26% vs. 12%, this risk could be markedly diminished by adhering to dose-volume constraints.

Conclusions: In intermediate- and high-risk prostate cancer patients, although it appears that radiation-dose escalation may improve PSA-DF outcome, the price paid in treatment morbidity can be high without adequate attention to dose-volume constraints of normal tissue. Care must be taken to consider not only the hazard of tumor recurrence but also that of complications.