Postoperative elective pelvic nodal irradiation compared to prostate bed irradiation in locally advanced prostate cancer – a retrospective analysis of dose-escalated patients

Post-prostatectomy radiotherapy can be given as adjuvant [1‐3] or salvage [4] treatment with or without androgen-deprivation therapy (ADT) [5, 6]. The addition of ADT has just recently been shown to improve biochemical progression-free survival (bPFS) [5] and also overall survival (OS) after longer follow-up [6] when added to moderate-dose radiation therapy (66 and 64.8 Gy, respectively, at the lower end of most recent EU and US guideline recommendations (≥66 and ≥ 64–65 Gy [7, 8])). Although an optimal dose has not been established for salvage or adjuvant radiotherapy, some series indicate that doses > 70 Gy might improve bPFS [7‐12]; however, dose escalation was associated with increased risk of toxicity even in recent series using highly conformal techniques such as intensity-modulated radiotherapy (IMRT) [13‐15].

Aside from dose escalation and addition of ADT, there is ongoing discussion about the effect of elective whole-pelvic radiotherapy (WPRT). Despite negative studies in the primary setting [16, 17] and an absence of evidence in the post-prostatectomy situation at the time when the survey was conducted, WPRT has been considered by 74% of radiation oncologists in the salvage setting [18]. Interim results from the 3-arm randomized NRG-Oncology/RTOG-0534 trial support this approach; the study recently reported a bPFS benefit in the salvage setting by adding ADT or ADT plus WPRT to prostate bed (“fossa-only”; PBRT) irradiation [19].

We primarily conducted this study to analyze outcomes of patients with locally advanced but lymph-node-negative tumors (T3–4/N0) treated with two standardized, dose-escalated (71.43–79.29 Gy equivalent-doses-in-2-Gy-fractions, EQD-2) post-prostatectomy radiotherapy strategies with or without WPRT (44 Gy, EQD-2 with volumes in line with RTOG recommendations [20]). Supplementary analyses were done as a pooled cohort with all node-negative patients (including T1–2/N0) and with node-positive patients (N1); however, both groups were not included in the main model due to extreme imbalances of PBRT and WPRT usage.

With this study, we provide a retrospective analysis on the addition of WPRT to dose-escalated PBRT after prostatectomy for locally advanced node-negative tumors. Most available studies reported on patients treated with prostate bed doses ranging from 61.2–72 Gy [19, 26‐30] with only two European series reporting on toxicity of higher-dose series (EQD-2: 75–77 Gy) [15, 31]. WPRT doses in recent studies ranged from 40 to 54 Gy. WPRT was associated with a bPFS benefit in some studies [26, 29, 30] while others described an association limited to subgroups [28] or found no association at all [27, 32]. The strongest but not yet fully published evidence so far in support of combining PBRT and WPRT comes from an interim analysis of the RTOG-0534/SPPORT trial which showed significantly different 5-year failure-free survival rates between PBRT, PBRT plus ADT and WPRT plus ADT arms of 71.7, 82.7 and 89.1%, respectively. Additionally, a trend towards increased metastases-free survival was reported when WPRT plus ADT was compared to the PBRT arm without ADT (p = 0.014; the 3-arm trial requires a P value of 0.0125 for one-sided significance [19]). The trial protocol allowed for doses between 64.8–70.2 Gy and (dose-)subgroup analyses have not yet been reported. Biochemical failure rates were calculated using the Phoenix definition (PSA 2 ng/ml above nadir or clinical progression); patients who initiated second salvage prior to this definition were censored. In our analysis, we used a definition of two PSA rises and counted patients who initiated second salvage as events, even if salvage was initiated after one increase in PSA levels. Our dose escalation strategy does not allow for a quantification of the benefit associated with 79.29 Gy EQD-2 compared to 71.43 Gy EQD-2 because we cannot separate benefits associated with positive margins [25] from benefits of dose escalation which was almost exclusively used in margin-positive patients plus a minority (6.4%) who received escalation after detection of recurrence in imaging (MRI as published [33] or PET-CT). Additionally, patients who received the higher dose were mostly treated postoperatively (76.9%) while 95.2% of patients with lower-dose treatment had a salvage strategy associated with a more unfavorable risk selection. Therefore, we did not attempt to quantify benefits of the two dose escalation levels but only analyzed benefits of WPRT in combination with PBRT at the high-dose-end of the currently used spectrum, the use of which was more evenly distributed across subgroups with fewer baseline imbalances as detailed in Table 1.

We found a 5-year bPFS benefit of 12.1% (FFBF: 11.6%) after WPRT/PBRT compared to PBRT-only which is higher compared to the 6.4% benefit observed in the RTOG-0534 dataset after WPRT and ADT vs. PBRT and ADT.

However, due to baseline imbalances and the retrospective nature of our analysis, the univariate model has to be interpreted with caution. Nevertheless, multivariate models showed a significant association of WPRT with longer bPFS and FFBF and thus, for the analyzed cohort, confirms the preliminary results of RTOG-0534. This was also true for the pooled patient cohort which includes patients who did not have advanced disease and the full cohort which also included node-positive patients (T1–4/N0–1; all M0); however, as mentioned it is uncertain if the associations of WPRT with outcomes can be extrapolated to any subgroup other than locally advanced, node-negative patients in our cohort because almost all patients with positive nodes were treated with WPRT while only 8 patients with T1–2/N0 tumors had WPRT.

Interestingly, the association of WPRT with longer bPFS in our cohort was consistent in the subgroup of patients who had salvage radiotherapy but not in patients with postoperative/adjuvant strategy. We cannot determine if the benefit of WPRT occurred because of a worse risk selection due to the salvage situation, the negative margin situation or the lower dose approach, as these factors overlapped. Likely, patients with negative margins, negative imaging and rising PSA values will have a higher risk of (undetected) microscopic disease in the lymph nodes compared to patients with an identifiable lesion (including R1) which explains rising or stable PSA values. Based on our dataset, the benefit of larger fields may be smaller in patients with positive margins. This hypothesis is in line with the previously reported improved outcomes for patients with positive margins in the adjuvant settings using PBRT [34, 35] and in the nomogram published by Tendulkar et al. for the salvage [25] situation (83% of patients had PBRT). In patients with rising PSA values and an identifiable lesion, the risk of an occult (second) lesion may be lower compared to the risk in patients without any identified lesion explaining rising PSA values. However, this hypothesis cannot be ascertained with our dataset and we look forward to subgroup analysis of the RTOG-0534 trial which allowed for patients with positive or negative margins.

WPRT and dose escalation in our dataset were associated with a significantly increased risk of toxicity; furthermore, pelvic radiotherapy increased symptom burden and decision regret for radiotherapy (details will be reported separately). A higher risk of side effects has been described for dose-escalated radiotherapy in this setting even if most advanced techniques are applied [13‐15]; furthermore, an increased incidence of toxicity following WPRT in line with our data has been reported previously [15]. For this reason, improved accuracy in the identification of patients who benefit from WPRT is mandatory.

Our study has several weaknesses; first, it is a retrospective analysis and therefore hypothesis-generating; second, it is uncertain if our data can be extrapolated to patients who received radiation doses below 70 Gy; third, ADT-usage was infrequent and duration was heterogeneous. Finally, we did not perform a patterns-of-recurrence analysis and did not systematically analyze imaging prior to inclusion; therefore, we do not know how many recurrences occurred in the pelvis and we cannot provide details on patients with selective dose escalation to lymph nodes after advanced imaging as they were excluded from the dataset. Despite these shortcomings our results indicate that WPRT was associated with longer bPFS and FFBF in patients with locally advanced node-negative prostate carcinoma who received radiotherapy to the prostatic bed after prostatectomy; although the result was significant in the whole patient group, subgroup analyses indicated that the benefit was more pronounced in patients with rising PSA values without detectable disease or positive margins. Our data together with the final results of RTOG-0534 will help to further refine patient selection in the postoperative/salvage setting.

We found a significant benefit in bPFS associated with WPRT in patients with locally advanced prostate carcinoma who underwent dose-escalated radiotherapy at the prostate bed. Incidence of grade 2+ toxicity was higher in patients who had received WPRT or higher doses (79.29 Gy compared to 71.43 Gy). In subset analyses, the association of WPRT with longer bPFS was only observed in patients with rising PSA values but not in patients with non-salvage postoperative radiotherapy for positive margins. Taken together, our data indicate that there is a benefit of WPRT vs. PBRT in patients with rising PSA values.