EBRT after RP is used in up to 50% of patients with adverse pathology[17, 18]. Despite its benefits on cancer control, the effect of EBRT after RP on OCM is unknown. We addressed this void and tested OCM rates between RP only vs matched RP + EBRT patients. We hypothesized that no OCM rate difference should exist between these two groups, since combination therapy candidates have been selected as surgical candidates initially and therefore it may be postulated that their OCM should be very similar to that of their RP only counterparts. Our analyses yielded several noteworthy observations.
First, the rate of RP + EBRT ranged from 2.7% in the low-risk group, 5.4% in the intermediate-risk group and to 17.0% in the high-risk group. Therefore, non-negligible proportions of intermediate-risk and high-risk patients are exposed to EBRT after RP. Unfortunately, our data did not allow to explain the underlying rationale for EBRT after RP in these individuals, due to insufficiently detailed data regarding RP pathology and/or surgical margins.
Second, important differences in patient-, as well as tumor characteristics between RP and RP + EBRT patients were recorded, across all risk strata. Specifically, RP + EBRT patients exhibited higher median patient age, higher median PSA values, higher cT stages, higher biopsy Gleason score and higher rates of clinically node positive disease. These differences demonstrate the need for strictest adjustment in the form of PSM and additional multivariable adjustment, as well as adjustment for CSM, to ensure that RP and RP + EBRT populations are comparable regarding patient and tumor characteristics.
Third, in matched competing risks analyses, we invariably recorded higher OCM in RP + EBRT than RP only patients. The excess OCM after RP + EBRT ranged from highest in the low-risk group (+ 8.5%), to intermediate in the intermediate-risk group (+ 4.2%) and to lowest in the high-risk group (+ 2.1%). All of the above OCM rate differences achieved independent predictor status despite the strictest PSM, multivariable adjustment and additional adjustment for CSM and respectively yielded multivariable CRR HR of 2.1 (p < 0.001) in low-risk PCa, HR of 1.3 (p < 0.001) in intermediate-risk PCa and HR of 1.2 (p < 0.001) in high-risk PCa. Additionally, we tested for effect modification according to age strata. Here, we identified important effect modifications of OCM that increased with age. The effect was most pronounced in oldest patients (≥ 71 years), across all risk strata (HR 4.2 in low-risk, HR 4.1 in intermediate-risk and HR 4.1 in high-risk, all p < 0.001). Its size was intermediate in the intermediate age category (61–70 years), also across all risk strata (HR of 2.3 in low-risk, HR of 1.9 in intermediate-risk and HR of 1.8 in high-risk, all p < 0.001).
The above findings indicate that the effect of EBRT after RP is most pronounced in elderly patients (≥ 71 years) and intermediate in the intermediate age strata (61–70 years). Interestingly, this effect is of similar relative magnitude in all risk groups. However, its absolute magnitude, expressed in absolute OCM rate differences is strongest in low-risk PCa groups. This observation may partly be explained by competing CSM that mostly affects high-risk patients and is least operational in low-risk patients. Based on the highest absolute rate of excess OCM after RP + EBRT in low-risk patients and lowest absolute rate of excess OCM after RP + EBRT in high-risk patients, it is unlikely that ADT may represent an underlying cause, since the opposite association would be expected, if ADT was directly related to OCM rates. Nonetheless, an interplay between EBRT, ADT and patient characteristics, including age must be suspected. More detailed, ideally prospective studies, will allow to validate our observations and elucidate the true causative factors. Additionally, our observations question the selection criteria for EBRT after RP that predominantly target elderly individuals. Ideally, intensification of therapy should predominantly focus on younger patients.
Taken together, we recorded excess OCM after EBRT delivered to RP patients, relative to their counterparts treated with RP only. The excess OCM was operational across all risk strata and ranged from + 2.1% (high-risk), + 4.2% (intermediate-risk) to + 8.5% (low-risk). Interestingly, within each PCa risk stratum, intermediate age (61–70 years) predisposed to two-fold OCM increase and oldest age (≥ 71 years) predisposed to four-fold OCM increase. Nonetheless, the absolute increase in OCM was highly statistically significant even in the high-risk group and even despite strictest PSM, multivariable adjustment and further adjustment for CSM. In consequence, our observations deserve further investigation in other epidemiological and/or institutional databases to validate our findings and to elucidate the underlying causes.
Our study has limitations and should be interpreted in the context of its retrospective and population-based design. First, no distinction could be made according to adjuvant or salvage EBRT after RP. Second, no information on the type or dose of EBRT, or the type or dose of concomitant ADT was available. Last, but not least, no information was available about cancer control outcomes that preceded OCM or CSM. However, since the study was focused on OCM rates that were adjusted for CSM in competing risks analyses, this limitation does not affect its primary outcome.