Abstract
Purpose or Objective The primary results of our phase 3 multicenter randomized controlled FLAME trial showed that by adding a focal boost up to 95 Gy to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival improved significantly, without significantly increasing cumulative toxicity. The
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aim of the present study was to investigate the association between radiation dose to the bladder and urethra and late genitourinary (GU) toxicity grade ≥2 in the whole study cohort, irrespective of randomization arm. Materials and Methods The dose-effect relations of the urethra and bladder near maximum dose and GU toxicity grade ≥2 up to five years after treatment were assessed. Patients with a previous transurethral resection of the prostate were excluded from the analysis. While for the bladder and other organs at risk, dose constraints were used for treatment planning, a urethra dose constraint was not incorporated. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity endpoints was investigated. Results With a median follow-up of 72 months (interquartile range (IQR) 58-86), acute and late cumulative GU toxicity grade ≥2 up to five years was seen in 45% and 31% of patients, respectively (Table 1). Urethral strictures occurred in 20 patients (4%). The median planned dose to the D2cm3 of the bladder and the D0.1cm3 of the urethra was 75 Gy (IQR 74-76) and 80 Gy (IQR 78-87), respectively. A total of 480 patients were included for further analysis. Dose-effect relations were observed for the bladder and urethra dose, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p<0.0001) and 1.12 (95% CI 1.11-1.14, p<0.0001), respectively. For the subdomains urinary frequency, urinary retention and urinary incontinence, associations between both the dose to the urethra and bladder and the endpoints were observed (Table 1). Dose-effect curves are shown for both dose parameters (Figure 1). Conclusion By using a longitudinal dose-effect model, we found that an increased dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Although cumulative toxicity showed no significant difference between the treatment arms of the FLAME trial, dose-effect relations to the urethra and bladder were observed. We propose that focal boost treatment plans should incorporate a urethra dose- constraint in addition to the pre-existing bladder dose-constraints. We suggest a urethra dose-constraint of D0.1cm3 ≤ 80 Gy to be used for the FLAME fractionation scheme. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment for prostate cancer.
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