Late toxicity rates following definitive radiotherapy for prostate cancer

Abstract

Introduction: Most patients survive many years following external beam radiotherapy (RT) for nonmetastatic prostate cancer and are therefore at risk for late treatment sequelae. The relationships between RT dose, treatment technique, and late toxicity rates are incompletely understood. Here we perform a meta-analysis and systematic review to characterize those effects.

Materials and methods: We performed a review of published series that report late gastrointestinal (GI) and genitourinary (GU) toxicity rates following definitive RT for prostate cancer using the RTOG Late Radiation Morbidity Scoring Schema. Univariate analyses were performed to test RT technique, RT dose, pelvic irradiation, and androgen deprivation therapy (ADT) as predictors of moderate (grade ≥ 2) and severe (grade ≥ 3) GI and GU toxicity. To isolate the effect of radiotherapy dose on late toxicity, we also performed a meta-analysis restricted to randomized trials that tested RT dose escalation. Statistical analyses were repeated using the subset of studies that utilized escalated RT doses.

Results: Twenty published reports detailing the treatment techniques and toxicity outcomes of 35 patient series including a total of 11,835 patients were included in this analysis. Median rates of moderate late toxicity were 15% (GI) and 17% (GU). For severe effects, these values were 2% (GI) and 3% (GU). Meta-analysis of five randomized trials revealed that an 8-10 Gy increase in RT dose increases the rate of both moderate (OR = 1.63, 95% CI: [1.44 to 1.82], p < 0.001) and severe (OR = 2.03, 95% CI: [1.64 to 2.42], p < 0.001) late GI toxicity. Among 17 series where doses of at least 74 Gy were utilized, use of intensity-modulated radiotherapy (IMRT) or proton beam radiotherapy (PBRT) was associated with a significant decrease in the reported rate of severe GI toxicity compared to 3-D RT.

Conclusion: Meta-analysis of randomized dose escalation trials demonstrates that late toxicity rates increase with RT dose. Series where dose escalated RT is delivered using IMRT or PBRT have relatively short follow up but report lower late GI toxicity rates than those employing 3-D RT.

Figure 1

Late toxicity rates. (□ = 2-D RT, ○ = 3-D RT, × = IMRT, △ = PBRT).

Figure 2

Forest plots depicting the effect of dose escalation on late toxicity in five randomized trials (Beckendorf et al, Dearnaley et al, Peeters et al, Pollack et al, and Zeitman et al, from top to bottom). Area of solid squares is proportional to sample size. Extent of diamond represents the 95% confidence interval for the pooled estimate of effect size. OR = odds ratio, GI = gastrointestinal, GU = genitourinary.