Factors Associated with Grade 3-4 Late Toxicity after Hypofractionated Prostate Salvage Radiation.

Abstract

We previously reported disease outcomes on patients treated with moderately hypofractionated salvage RT (65-70 Gy in 26-28 fractions using imaging guided IMRT) with >13 years of follow-up. The rate of all late surgical/radiation/disease related grade 3-5 toxicities was 27%, which were documented at a median of 8.7 years after the end of radiation. Here we performed an analysis to attempt to identify factors associated with these toxicities. A total of 161 patients were analyzed; 44 patients experienced 58 late grade ≥3 toxicities. These were analyzed in several groups which included: all (n = 44), GU (n = 40), GU excluding incontinence (n = 35), stricture/fistula related (n = 28), hematuria related (n = 7), and grade 4 stricture/fistula related (n = 8). We investigated patient factors (age, preRT IPSS), surgical factors (clip volume, approach, margin status), and disease factors (stage, Gleason group, PSA nadir, preRT PSA, surgery to RT time). Surgical clip volume was contoured on CT and recorded in cc. Significance was determined using Mann-Whitney U test for continuous variables and Fisher's Exact test for binary variables. A higher volume of surgical clips in the prostate fossa was found to be significantly related to eventual grade ≥3 stricture/fistula related event (p = 0.05). The mean surgical clip volume was found to be 2.30 cc in those with a documented grade ≥3 stricture/fistula compared to 1.23 cc in those without. Patients with a positive margin had a 30.0% rate of grade ≥3 GU toxicity compared to 16.2% in those with a negative margin (p = 0.03). Surgical clip volume was not found to be significantly related to pathologic stage, nor to eventual biochemical failure (p = 0.799/0.897). A positive margin was associated with a lower rate of biochemical failure after salvage (p = 0.04). Grade 3 events were documented at a median of 7.7 years and grade 4 events at 12.0 years after the end of radiation. Our previous study found a high rate of grade ≥3 toxicities at time points for which there is a paucity of data both in conventional and hypofractionated regimens, particularly in the era of modern surgical and radiation techniques. We also found late toxicities can occur with increasing severity for many years after salvage radiotherapy. This analysis suggests that margin positivity and volume of surgical clips might identify patients at higher risk for late grade ≥3 toxicities, although the etiologies of these toxicities, whether surgery or radiation-related, are uncertain.