Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

[1] N. Fossati, N.M. Buffi, A. Haese, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol. 2015;68:132-138 Crossref
[2] J.M. Caster, A.D. Falchook, L.H. Hendrix, R.C. Chen. Risk of pathologic upgrading or locally advanced disease in early prostate cancer patients based on biopsy Gleason score and PSA: a population-based study of modern patients. Int J Radiat Oncol Biol Phys. 2015;92:244-251 Crossref
[3] G.P. Swanson, M. Riggs, M. Hermans. Pathologic findings at radical prostatectomy: risk factors for failure and death. Urol Oncol. 2007;25:110-114 Crossref
[4] A.J. Stephenson, M.W. Kattan, J.A. Eastham, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27:4300-4305 Crossref
[5] A. Heidenreich, P.J. Bastian, J. Bellmunt, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479
[6] J.L. Mohler, A.J. Armstrong, R.R. Bahnson, et al. Prostate cancer, version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30
[7] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref
[8] T. Wiegel, D. Bartkowiak, D. Bottke, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66:243-250 Crossref
[9] I.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-962 Crossref
[10] A. Briganti, T. Wiegel, S. Joniau, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur Urol. 2012;62:472-487 Crossref
[11] A.J. Stephenson, P.T. Scardino, M. Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041 Crossref
[12] A. Briganti, R.J. Karnes, S. Joniau, et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur Urol. 2014;66:191-199
[13] A.J. Stephenson, S.F. Shariat, M.J. Zelefsky, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332 Crossref
[14] N. Fossati, R.J. Karnes, C. Cozzarini, et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur Urol. 2016;69:728-733Crossref
[15] M.R. Abern, M.K. Terris, W.J. Aronson, et al. The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer. Cancer. 2014;120:1656-1662 Crossref
[16] A. Briganti, R.J. Karnes, G. Gandaglia, et al. European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT). Natural history of surgically treated high-risk prostate cancer. Urol Oncol. 2015;33 163.e7-13
[17] B.J. Trock, M. Han, S.J. Freedland, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769Crossref
[18] S.E. Cotter, M.-H. Chen, J.W. Moul, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932 Crossref
[19] T. Wiegel, G. Lohm, D. Bottke, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009-1016 Crossref
[20] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Crossref
[21] N. Ohri, A.P. Dicker, E.J. Trabulsi, T.N. Showalter. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48:837-844 Crossref
[22] O. Yossepowitch, A. Briganti, J.A. Eastham, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65:303-313 Crossref
[23] C.J.D. Wallis, P. Cheung, S. Herschorn, et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br J Cancer. 2015;112:977-982 Crossref
[24] N. Suardi, A. Gallina, G. Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014;65:546-551 Crossref
[25] C. Carrie, A. Hasbini, G. de Laroche, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17:747-756 Crossref

Despite the widespread use of prostate-specific antigen (PSA) screening over the last two decades, approximately 25% of contemporary patients treated with radical prostatectomy (RP) for localised prostate cancer (PCa) show locally advanced disease at final pathology in both European and American series [1] and [2]. These patients often present concomitant adverse pathologic features such as poorly differentiated disease and positive surgical margins, and they are at higher risk of recurrence and cancer-related death [3] and [4].

Two options essentially can be offered currently to pT3 node-negative PCa patients with undetectable postoperative PSA: immediate adjuvant radiation therapy (aRT) to the prostatic fossa or initial biochemical monitoring followed by early salvage radiation therapy (esRT) before PSA level exceeds 0.5 ng/ml [5] and [6].

The postsurgical management of these patients still represents a continuous matter of debate. Two main issues may be identified from the current literature. The first one relates to the lack of level-1 evidence in this field. Three randomised clinical trials compared aRT with initial observation in patients affected by locally advanced PCa [7], [8], and [9]. However, the study design of these historical trials did not systematically include in the observational arm the patients who underwent esRT at a PSA level ≤0.5 ng/ml. Conflicting results emerged from these trials for the outcomes of metastasis-free survival (MFS) and overall survival (OS). The specific reasons for such a discrepancy might be related to the heterogeneity of patient populations and the lack of defined treatment protocols.

Second, the currently available evidence supporting the oncologic safety of salvage radiation therapy (sRT) is still based on retrospective studies [10], [11], [12], and [13]. A substantial proportion of patients who received salvage treatment in these retrospective studies had PSA values >0.5 ng/ml, whereas the PSA level at sRT was shown to be an important predictor of oncologic outcomes [14]. In these retrospective studies, the outcome was biochemical recurrence (BCR) following sRT, and the evaluation of hard clinical end points, such as clinical recurrence and survival, is still lacking [10], [11], [12], and [13].

To address these shortcomings, we evaluated MFS and OS at long-term follow-up using a multi-institutional series of pT3pN0 patients who underwent aRT versus initial observation followed by esRT in case of PSA relapse. We hypothesised that aRT was associated with better cancer control and survival compared with initial observation.

2.1. Patient population

After institutional review board approval, we identified 764 patients treated with RP and pelvic lymph node dissection at seven tertiary referral centres between 1996 and 2009. Retrospective chart reviews were used at four institutions. All patients had histologically confirmed pT3pN0 R0–R1 adenocarcinoma of the prostate. No patient received any neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as <0.1 ng/ml).
Patients who were initially observed and then treated with sRT at a serum PSA >0.5 ng/ml were excluded from our analyses (n = 127). Patients with missing information on pathologic stage (n = 24), pathologic Gleason score (n = 47), or surgical margin status (n = 56) were likewise excluded. These selection criteria yielded 510 evaluable individuals with complete clinical, pathologic, and follow-up data.

Patients were stratified into two groups according to the postoperative management: aRT (group 1: n = 243; 48%) versus initial observation followed by esRT in case of PSA relapse (group 2: n = 267; 52%). Specifically, aRT was administered within 6 mo after RP to patients. On the contrary, esRT was administered at a PSA level ≤0.5 ng/ml. The PSA relapse after surgery that led to esRT in group 2 was defined as postoperative undetectable PSA with a subsequent PSA increase within two or more determinations, according to the definition provided by the National Comprehensive Cancer Network (NCCN) guidelines [6]. Patients who did not develop PSA relapse in group 2 underwent oncologic follow-up that consisted of a PSA test every 3 mo for the first year, biannually between the second and the fifth years after surgery, and annually thereafter.

2.2. Radiation therapy technique

Radiation therapy consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 MV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 65 Gy (interquartile range [IQR]: 60–67). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians to the CTV definition. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error.

2.3. Variable definition

Clinical data consisted of patient age at radiation therapy (RT), preoperative PSA level, time from surgery to RT, and pre-RT PSA level. Pathologic data included pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive).

2.4. Outcome definition

The primary outcome of the study was distant metastasis. Distant metastases in bones, parenchymal organs, or soft tissues were identified by radiologic imaging and confirmed with biopsy per the treating clinicians’ discretion. The secondary outcome of the study was OS. Follow-up time was defined as the time between RP and distant metastasis diagnosis or last follow-up (for the primary outcome), and the time between RP and patient death or last follow-up (for the secondary outcome).

2.5. Statistical analysis

Our statistical analyses consisted of three main steps. First, the Kaplan-Meier method was used to compare distant MFS and OS between the aRT and the observation followed by esRT cohorts. The log-rank test was used for the hypothesis that aRT provided better cancer control and OS compared with initial observation followed by esRT.

Second, multivariable Cox regression analysis tested the association between groups and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). The year of surgery was included in the multivariable model because the postoperative management of patients may vary over time.

Third, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. As an example, aRT may provide better cancer control only in patients affected by locally advanced disease (eg, pathologic stage pT3b or higher), more aggressive disease (eg, pathologic Gleason score ≥8), and/or positive surgical margins. Therefore, we tested an interaction with groups (aRT vs observation followed by esRT) and baseline pathologic risk. The latter was derived by multivariable Cox regression analysis. The predictors consisted of pathologic stage, pathologic Gleason score, and surgical margin status. The nonparametric curve fitting method was used to explore graphically the relationship between distant MFS and OS at 8 yr after surgery and baseline patient risk.

All statistical analyses were performed using Stata software v.12.0 (StataCorp LP, College Station, TX, USA).

Pathologically advanced PCa after RP is associated with worse oncologic outcomes because concomitant adverse pathologic features are often present [15] and [16]. Postoperative RT may improve disease control and patient survival when administered either immediately after surgery (aRT) or at PSA relapse (sRT) [9], [13], [17], and [18]. Three randomised clinical trials evaluated the impact of aRT on pT3pN0 patients, showing better biochemical outcomes at long-term follow-up. However, conflicting results were shown when clinical recurrence and patient survival were considered [7], [8], and [9]. In contrast, previous retrospective studies showed an oncologic benefit for patients affected by BCR following RP treated with sRT [11], [12], [18], and [19].

The real relevant clinical question still remains whether postoperative RT should be administered in an adjuvant setting or could be postponed and reserved only for patients who will experience PSA relapse. According to the European Association of Urology and the NCCN guidelines, two options can be essentially offered to pT3 node-negative patients with undetectable postoperative PSA: immediate aRT to the prostatic fossa or initial biochemical monitoring followed by esRT before PSA level exceeds 0.5 ng/ml [5] and [6].

The hypothesis of the current study was that aRT provided better cancer control and OS compared with observation followed by esRT in pT3pN0 patients who achieved an undetectable postoperative PSA. Our results did not confirm that hypothesis because statistically significant differences in terms of distant metastasis and mortality were not observed between the groups. Several facets of our findings deserve attention.

First, these results corroborate the previous comparative study by Briganti et al, who found no significant difference between aRT and initial observation followed by esRT was found in terms of BCR [10]. However, the current study provides two main additional strengths: (1) The evaluated outcomes were distant MFS and OS, harder clinical end points compared with BCR; and (2) median follow-up was significantly longer compared with the previous study (93 vs 47 mo). These strengths were essential for the evaluation of these outcomes.

Second, baseline patient characteristics were comparable among groups. A similar proportion of advanced pathologic stage and high Gleason score were detected in both adjuvant and observational groups. At the same time, patients showed comparable age at surgery and preoperative PSA level. Conversely, a significantly different rate of positive surgical margin was observed between group 1 and 2 (74% vs 52%, respectively). However, positive margins did not affect the risk of distant metastasis at both univariable and multivariable analyses. When considering only patients who received esRT, the status of surgical margins (negative vs positive) did not significantly influence median time from surgery to esRT (29 mo; IQR: 15–43 mo) versus 23 mo (IQR: 14–44 mo; p = 0.7) and median PSA level at esRT (0.2 ng/ml; IQR: 0.1–0.3 ng/ml) versus 0.2 ng/ml (IQR: 0.1–0.3 ng/ml); p = 0.4. Similarly, it was not significantly associated with MFS (HR: 0.56; 95% CI, 0.18–1.76; p = 0.3). This finding was consistent with previous reports in which surgical margin status did not correlate with oncologic outcomes [12] and [20]. Taken together, these observations suggest that patient characteristics were substantially unlikely to alter our results.

Third, RT dose was significantly different between the two groups (60 vs 67 Gy; p < 0.0001). However, it was not associated significantly with the risk of distant metastasis at univariate analysis (HR: 0.98; 95% CI, 0.65–1.39; p = 0.4). The reason could be related to the relatively low dose administered in the salvage setting. Retrospective evidence indicates that oncologic outcomes following sRT are better by increasing radiation dose [21]. The hypothesis that dose escalation may improve biochemical outcome is currently under investigation by the SAKK–SWISS group for clinical cancer research that is randomising patients between 64 and 70 Gy (NCT01272050).

Fourth, the current study addressed a relevant clinical question recently investigated by three randomised clinical trials [7], [8], and [9]. Conflicting results emerged from these studies regarding the risk of clinical recurrence. The main reason for such a discrepancy may be related to the inclusion criteria. The EORTC trial, in contrast to the other two studies, included a significant proportion of pT2 R1 patients, and excellent prognosis was demonstrated for this category of patients [22]. An undetectable postoperative PSA was considered by the ARO study only; approximately 30% of patients had PSA persistence after surgery in both the EORTC and the SWOG trials. Finally, PSA level at RT was >0.5 ng/ml in a significant proportion of patients receiving salvage treatment in all three studies. The delay in sRT administration may have importantly affected patient prognosis because PSA level at RT was shown to be a crucial predictor of oncologic outcomes [11], [12], and [14]. In contrast to the three trials just mentioned, in this study we included pT3pN0 patients who had achieved an undetectable postoperative PSA while sRT was administered at a PSA level ≤0.5 ng/ml. These inclusion criteria represent an important strength of the study. However, currently ongoing randomised trials (RADICALS NCT00541047 and RAVES NCT00860652) are needed to corroborate our findings.
Finally, we tested the hypothesis that the impact of aRT versus observation followed by esRT differed by pathologic characteristics. We found that aRT may be associated with an oncologic benefit only in patients with several adverse pathologic features at RP. However, a different impact of aRT according to pathologic characteristics was not observed. The reason may be related to the low number of patients with advanced and aggressive disease.
The current study has important clinical implications regarding postoperative RT administration. Approximately 40–50% of patients who were randomised to the observational arm in previous prospective randomised trials never recurred. Therefore, such patients would have been overtreated and exposed to treatment-related toxicity if aRT was administered in a blanket fashion following RP [23]. On the contrary, the restriction of esRT to only recurrent patients might potentially reduce overtreatment-related complications. Immediate aRT may potentially have a negative impact on functional outcomes recovery because urinary continence and sexual function recovery occurs mostly within the first 12 mo following surgery [24].

Despite its strengths, our study is not devoid of limitations. First, the relatively small size of the patient population may have influenced our results because the lack of significant differences among groups may be related to the number of patients included in the study. However, to the best of our knowledge, this is the first comparative study with stringent inclusion criteria evaluating distant metastasis and OS at long-term follow-up. Second, the retrospective nature of the study may also represent an important limitation. The decision whether to propose immediate postoperative aRT versus initial observation was left to the treating physician. This point may represent an important selection bias. However, as we previously specified, baseline patient characteristics were similar among groups, reducing the importance of such a selection bias. Finally, concomitant androgen-deprivation therapy was at the discretion of the referring urologist/radiation oncologist. Therefore, there was no standardised treatment schedule concerning type and duration of hormonal therapy. This may represent a further limitation of the study. However, a recent randomised trial did not show a significant survival benefit of goserelin in patients treated with sRT [25].

At long-term follow-up, no significant differences between aRT and esRT were observed in terms of MFS and OS. Our study, although based on retrospective data, suggests that a management approach to patients with adverse pathology at RP with initial observation and then esRT if biochemical relapse is diagnosed does not compromise cancer control and potentially reduces the overtreatment associated with a strategy of administering aRT to all such patients. The current ongoing randomised clinical trials are needed to corroborate our findings.

Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fossati, Briganti.

Acquisition of data: Fossati, Moschini, Morlacco, Seisen, Chiorda, Gandaglia, Dell’Oglio, Tosco, Goldner.

Analysis and interpretation of data: Fossati, Karnes, Boorjian, Bossi, Seisen, Cozzarini, Fiorino, Gandaglia, Dell’Oglio, Joniau, Shariat, Hinkelbein, Haustermans, Tombal, Briganti.

Drafting of the manuscript: Fossati, Karnes, Boorjian, Moschini, Morlacco, Bossi, Seisen, Cozzarini, Fiorino, Chiorda, Gandaglia, Dell’Oglio, Joniau, Tosco, Shariat, Goldner, Hinkelbein, Bartkowiak, Haustermans, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Critical revision of the manuscript for important intellectual content: Karnes, Boorjian, Bossi, Joniau, Shariat, Bartkowiak, Tombal, Montorsi, Van Poppel, Wiegel, Briganti.

Statistical analysis: Fossati, Gandaglia, Dell’Oglio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Tombal, Montorsi, Van Poppel, Wiegel.

Other (specify): None.

Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.