European Urology

Van der Kwast TH, Bolla M, Van Poppel H, Van Cangh P, Vekermans K, Da Pozzo L, Bosset JF, Kurth KH, Schröder FH, Colette L
J Clin Oncol 2007;25:4178–86.
Expert's summary:
In 1992, the European Organization for Research and Treatment of Cancer (EORTC) initiated a multicentre, randomised trial on immediate adjuvant radiotherapy versus wait-and-see after radical prostatectomy on 1005 patients at high risk of recurrence (N0M0, pT3a or b, or positive surgical margins pT2). The 5-yr biochemical and loco regional progression-free survival rates were significantly better for the group receiving immediate radiotherapy (74% vs. 52.6% and 95.4% vs. 85.5%, respectively). The benefit was substantial in all subgroups of risk factors [1]. One experienced uropathologist reviewed 552 of the specimens and correlated surgical margins, extracapsular extension, seminal vesicle invasion, and Gleason score with the 5-yr biochemical-free survival. The presence of positive surgical margins (322 patients) was the only predictive factor of positive effect of radiotherapy to such an extent that there was no benefit in case of negative margins. For every 1000 patients at high risk of recurrence, adjuvant irradiation would prevent biochemical relapse at 5 yr for 291 patients in case of positive margins and only for 88 patients in case of negative margins. The site of the margins had no influence on the results.
Expert's comment:
This critical study stresses four main points.

The quality of surgery in high-risk prostate cancer patients (ie, negative surgical margins) is a significant risk factor for biochemical progression-free survival. The vast majority of scientific publications on radical prostatectomy reports on functional results. However, young urologists should still have in mind the rules of carcinoma surgery for high-risk patients.

This study will certainly clarify the indications for adjuvant radiotherapy. However, despite the fact that immediate radiotherapy increases biochemical progression-free survival, it also significantly increases the rate of severe toxic effects (4.2% vs. 2.6%), but its superiority over early salvage irradiation is still debated [1].

Despite the statistical evidence, the clinical benefit of a biochemical-free survival needs to be established for men with prostate cancer. This illustrates the great heterogeneity in study designs and particularly in the choice of the primary end points, which are not always pertinent to clinical benefit.

The most troubling result is that surgical margins were identified as the only significant prognostic factor only after central pathologic review [2]. The concordances for surgical margin status, as well as for extraprostatic extension, between initial pathology and review were only 69.4% and 57.4%, respectively [3]. No clear explanation can be found for this discrepancy considering that the reviewed cases were recruited from high-volume centres (supposed to provide experienced pathologic analysis) and that the definition of surgical margins is now supposed to be based on a consensus. A close collaboration between urologists and pathologists is clearly mandatory in the interpretation of prostatectomy specimens. Also mandatory for every multicentre trial on prostate cancer is now a centralised pathology review.