Early or delayed radiotherapy after prostatectomy-who really benefits?

The review by Gandaglia et al. (1) clearly shows that we are in the process of drawing a roadmap towards the use of postprostatectomy radiotherapy. The outline is clear: we know that some patients benefit from the combination of surgery and radiotherapy, and we know that these patients have an increased risk of side effects. However, at this moment, the roadmap also shows a lot of gaps; we don’t have clear evidence which patients will really benefit, and there is no clarity about the optimal treatment delivery. The by Gandaglia et al. (1) drawn roadmap reveals many of these gaps, and provides a good starting point for future studies.

Any cancer treatment should balance oncological and functional outcomes. Early adjuvant radiotherapy in men with increased risk of locally remnant disease was shown to improve clinical progression free survival in 3 and overall survival in 1 RCT even at relatively doses of radiotherapy without additional androgen ablation. Scrutinizing the control groups in these 3 trials is important to understand the clinical value of these findings at today’s standards. As correctly remarked by the authors of the systematic review, not all men in the control group with PSA recurrence did receive salvage radiotherapy and if so, relatively later at higher PSA levels than currently performed. A recent retrospective analysis suggested that compared to early adjuvant radiotherapy, early salvage radiotherapy may be similarly effective to control metastases-free survival at 8 years (2). The role of pelvic radiotherapy in the salvage setting remains undetermined and data from the RTOG05-34 trial on this topic are to be awaited.

Interestingly, several retrospective series have suggested a benefit of pelvic radiotherapy in men with proven nodal metastases after prostatectomy (3-6). The poor description of patient selection and method of radiotherapy used prohibits any conclusions on the use of radiotherapy in men with pN1 disease.

Still some recent clinical findings need to be considered. Although, as correctly noted by the authors, 68Ga-PSMA-PET may perform better at higher PSA values. A recent systematic review found positive 68Ga-PSMA PET scans in 42% of men with a PSA between 0–0.2 (7). This is well below the generally assumed optimal threshold of 0.5 for a favorable outcome of salvage radiotherapy (8). However, a positive 68Ga-PSMA-PET scan will almost certainly alter the decision to perform salvage radiotherapy to the prostatic fossa. Considering the toxicity of any additional local treatment after prostatectomy (increased risk of urinary, sexual, and bowel problems) (9); up to 58% 3-year incontinence after SRT (10), and the paucity of data on an overall survival benefit, a 68Ga-PSMA-PET scan should be strongly considered in all men with a rising PSA after prostatectomy. This is supported by the recent retrospective observation that despite local salvage radiotherapy 43% of men with Gleason 9–10 cancers develop metastases and 54% of men have biochemical recurrence overall (11).

The decision on additional radiotherapy after prostatectomy should be a well balanced one weighing a possible survival benefit versus earlier toxicity, in particular when an early use of radiotherapy is considered. In the near future 68Ga-PSMA-PET scanning will have to prove itself as a good road sign how to continue.