Purpose: The randomized controlled European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 studied the effect of radiotherapy after prostatectomy in patients with adverse risk factors. Review pathology data of specimens from participants in this trial were analyzed to identify which factors predict increased benefit from adjuvant radiotherapy.

Patients and Methods: After prostatectomy, 1,005 patients with stage pT3 and/or positive surgical margins were randomly assigned to a wait-and-see (n = 503) and an adjuvant radiotherapy (60 Gy conventional irradiation) arm (n = 502). Pathologic review data were available for 552 patients from 11 participating centers. The interaction between the review pathology characteristics and treatment benefit was assessed by log-rank test for heterogeneity (P < .05).

Results: Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P < .01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization.

Conclusion: Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set.

Our subset analysis of these patients showed that adjuvant radiotherapy reduces the risk of biochemical recurrence specifically in those with positive surgical margins, whereas those with negative margins (irrespective of other risk factors) in general do not seem to benefit. Importantly, our data indicate that about three patients with positive margins need to be treated with adjuvant radiotherapy to prevent one biochemical recurrence. We emphasize here that this conclusion was only reached after a scrutinized central review of the prostatectomy specimens, whereas data from local pathology did not show this marked effect of surgical margin status on radiotherapy outcome. Obviously, this variability in assessment of surgical margin status detracts from the generalized applicability of our findings. It was noted that the level of agreement between local and review pathology varied strongly for the different participating hospitals ( scores between 0.13 and 0.64),which emphasizes the importance of the uniform application of well-established rules regarding the determination of margin status in prostatectomy specimens. The somewhat worse pathologic features, including positive margins and invasion of seminal vesicles, of the nonreviewed patient group as compared with the reviewed patients may have biased our results. However, in the population with available pathology review, the treatment benefit was strongest in the patients with adverse pathologic factors, including positive surgical margins, and therefore it is likely that our conclusions remain valid for the entire population.

Prostate cancer differs from most other malignancies because of its slowly developing nature: nonradical resection of prostate cancer is not always followed by rapid biochemical recurrence; likewise, a local recurrence does not necessarily evolve toward systemic spread and death as a result of the disease. A biochemical recurrence is reported in approximately 30% to 75% of patients with positive surgical margins. The strong variation reported in literature is likely due to additional factors such as Gleason score distribution and stage distribution of the patients under study, as well as interobserver variation for determination of margin status. It has also been noted that the majority of patients with biochemical recurrence will not develop a local recurrence or distant disease, and biochemical progression is by some considered a poor surrogate marker for disease progression. Local growth can lead to anxiety of the patient and to additional treatment.

Some studies claimed that apex positivity is less likely to result in biochemical or local recurrence, but this was not substantiated by other series and also not in our patient group. In addition, we did not show a difference in treatment benefit for patients with only apex positivity as compared with those with positive lateral margins. Those with both apex and lateral margin positivity seemed to benefit more than those with positivity at one of the sites, emphasizing the predictive impact of positive surgical margins. Unfortunately, we were not able to perform subgroup analysis for actual clinical recurrence of disease, given that the number of events was too small. Some controversy exists in the literature with regard to the clinical significance of surgical margin status as the sole adverse risk factor. Although most but not all studies have shown that positive surgical margin status represents an independent risk factor for biochemical recurrence, in addition to Gleason sum, preoperative PSA, and pathologic stage, it is not certain that positive surgical margins add to the risk of actual local recurrence or systemic disease. Those few studies reporting on prognosticators for clinical recurrence so far failed to demonstrate any independent prognostic impact of surgical margin status,but their relative short follow-up periods may have contributed to these negative findings. In a similar vein, it remains uncertain to what extent prostate cancer–specific or metastases-free survival of the various subsets of patients with positive margins will be influenced by adjuvant radiotherapy. These pertinent questions may be solved when longer follow-up data of the participants of our trial EORTC 22911 become available.