Introduction
The only potentially curative treatment option for prostate cancer (PCa) patients with a biochemical recurrence (BCR) after radical prostatectomy is salvage external beam radiotherapy (sEBRT) to the prostate bed. The 5-year biochemical recurrence-free survival (bRFS) after sEBRT is 50-60%. A predisposing factor for BCR after sEBRT may originate at the primary tumour site, indicating insufficient local treatment.
The optimal dose and fractionation for sEBRT is still under debate, due to the knowledge that PCa is a relatively radio-resistant tumour with a strong dose–response relationship. A systematic review of sEBRT reported a 2.0% (95% CI 1.1-3.2) improvement in bRFS for each additional Gy above 64 Gy, independent of other factors. Although higher doses increased bRFS, more side effects were observed. The SAKK 09/10 trial found that dose-intensified sEBRT, from 64 Gy to 70 Gy, only increased the late grade II gastrointestinal toxicity (OR 2.2 CI 1.21-4.0, p=0.009) in the 70 Gy arm without significant improvement in bRFS. However, this dose intensified RT treatment of 70 Gy used in the SAKK 09/10 trial may be too low to induce improvement in bRFS.
Many studies reported a low a/B ratio for PCa cells, indicating a high sensitivity to the dose per fraction rather than the total physical dose. The reported PCa a/B ratio is < 2 Gy, which is far below that of bowel and bladder (4 – 5 Gy), has led to the concept of hypofractionation (i.e., increasing the dose per fraction instead of the total dose). This means that a higher biologically effective dose can be given without increasing the total physical dose to the surrounding tissues. Therefore, hypofractionation may offer the opportunity to increase efficacy in terms of local tumour control, without enhancing radiation-induced late side effects.
Role of hypofractionation in primary PCa
In definitive RT for primary PCa, many RCTs reported the efficacy and non-inferiority of hypofractionated RT for primary PCa. Two studies reported the non-inferiority and safety of the 20 x 3 Gy regimen compared to 37 x 2 Gy and 39 x 2 Gy. Furthermore, a meta-analysis including 5,969 patients in 9 RCTs, comparing moderate hypofractionation with standard fractionation reported an improvement in 5-year bRFS, clinical recurrence free survival (RR = 1.04, p = 0.01) and 5-year disease-free survival (RR = 1.04, p = 0.02) with comparable grade 2-4 acute/late gastrointestinal and genitourinary toxicity. Another meta-analysis reported that hypofractionated RT compared to conventionally fractionated RT was associated with significantly improved disease free survival (HR 0.869; p = 0.047). Both meta-analyses support the anticipated superiority of hypofractionated RT in primary PCa. Therefore, nowadays hypofractionated RT is standard of care in definitive RT for patients with primary PCa.
Hypofractionation in salvage radiotherapy
Yet, in the postoperative salvage setting, data on hypofractionation in sEBRT are sparsely reported. A few non-randomised and retrospective reports on hypofractionated sEBRT are available. Most reports show adequate disease control and acceptable rates of acute and late side effects. However, these studies included relatively small patient numbers and used various fraction dose, total dose, target volumes, inclusion criteria and reported only limited follow-up. A retrospective study including 181 patients observed low grade 3 late GU and GI toxicity rates of 2.7% and 1.6% at 5 years using a moderate hypofractionated RT (65-74 Gy). A phase II study, including 61 patients treated with 15 fractions of 3.4 Gy and a median follow-up of 16 months, reported acceptable grade ≥ 2 late GU and GI toxicity of 8.2% and 11.5%, respectively. Furthermore, a published systematic review reported encouraging results on bRFS and supported the tolerance of hypofractionated sEBRT, but stressed the importance of conducting RCTs comparing hypofractionated with standard fractionated sEBRT. Besides the advantage of hypofractionation in enhancing effective dose without increasing late toxicity, the reduction of treatment time could offer improved tumour control and a more convenient regimen to patients.
In conclusion, high-level evidence for the implementation of hypofractionated sEBRT is currently lacking and the next step is to perform RCTs investigating the role of hypofractionation in sEBRT.
Ongoing phase III RCTs, such as the PERYTON-trial (ClinicalTrials.gov Identifier: NCT04642027), the RG GU003 trial (NCT03274687) and the PAROS-trial (Deutsches Register klinischer Studien: DRKS00015231) will help to define the definitive role of hypofractionation in the salvage setting.