Improving postoperative radiotherapy following radical prostatectomy

ABSTRACT

Introduction: Prostate cancer has one of the highest incidences in the world, with good curative treatment options like radiotherapy and radical prostatectomy. Unfortunately, about 30% of the patients initially treated with curative intent will develop a recurrence and need adjuvant treatment.

Five randomized trials covered the role of postoperative radiotherapy after radical prostatectomy, but there is still a lot of debate about which patients should receive postoperative radiotherapy.

Areas covered: This review will give an overview on the available literature concerning post-operative radiotherapy following radical prostatectomy with an emphasis on the five randomized trials. Also, new imaging techniques like prostate-specific membrane antigen positron emission tomography (PSMA-PET) and multiparametric magnetic resonance imaging (mp-MRI) and the development of biomarkers like genomic classifiers will be discussed in the search for an improved selection of patients who will benefit from postoperative radiotherapy following radical prostatectomy. With new treatment techniques like Intensity Modulated Radiotherapy, toxicity profiles will be kept low.

Expert commentary: Patients with biochemical recurrence following radical prostatectomy with an early rise in prostate-specific antigen (PSA) will benefit most from postoperative radiotherapy. In this way, patients with only high risk pathological features can avoid unnecessary treatment and toxicity, and early intervention in progressing patients would not compromise the outcome.

KEYWORDS:

• Prostatectomy
• recurrence
• postoperative radiotherapy
• imaging
• PSMA-PET
• genomics

1. Introduction

Prostate cancer has one of the highest incidences in men with an estimated 1.1 million new patients worldwide in 2012 according to the World Health Organization. It accounts for 15% of cancers diagnosed in men, with 70% of men diagnosed in developed countries. This is partly because of the widespread availability of prostate-specific antigen (PSA) in developed countries. Approximately 300,000 men die every year, accounting for 6.6% of deaths in men. (http://globocan.iarc.fr/old/FactSheets/cancers/prostate-new.asp) The most widely used curative treatment options consist of radical prostatectomy and radiotherapy. In a recent meta-analysis performed by Roach et al., there was no difference in treatment outcome between both options [1]. This was confirmed by the ProtecT trial randomizing 1643 patients with PSA detected tumors (low- and intermediate-risk) between monitoring (N = 545), surgery (N = 553), and radiotherapy (N = 545), showing no significant difference in disease progression between radiotherapy and surgery [2]. Although the outcome appears to be good after radical prostatectomy, approximately 20–25% of patients will develop a biochemical recurrence (BCR), with up to 40–50% in high grade prostate cancer [3–5]. In case of BCR, the overall mortality rate is 46% after 15 years. Unfortunately, 77% of deaths can be attributed to prostate cancer recurrence [6]. Different treatment options have been proposed in an attempt to prevent these deaths, like adjuvant radiotherapy and salvage radiotherapy with or without hormonal therapy. In this article, we give an overview of these different postoperative treatment options and describe which patients that will benefit most from each treatment. Additionally new imaging modalities like prostate-specific membrane antigen positron emission tomography (PSMA-PET) and multi-parametric MRI (mpMRI) will be discussed as well as new risk scores based on genetic profiles.

2. Risk factors for recurrence

2.1. How to localize site of recurrence?

A PSA rise following radical prostatectomy suggests a relapse of disease locally, regionally, or distantly. A BCR is defined after two consecutive PSA levels ≥ 0.2 ng/ml and rising after previous undetectable PSA levels according to the American Urological Association (AUA) (http://www.auanet.org/guidelines/radiation-after-prostatectomy-(astro/aua-guideline-2013) and European Association of Urology (EAU) guidelines http://uroweb.org/guideline/prostate-cancer/#7. Although with new ultrasensitive PSA measurements even lower PSA levels > 0.01 ng/ml can be measured and some regard a consecutive rise even in this range a BCR. These low PSA levels are indicative of subclinical disease, local, regional, or distant, which is difficult to detect. Until recently, imaging studies failed to demonstrate the localization of subclinical disease and local biopsy lack sensitivity, even if the recurrence is local [7–10]. New imaging techniques like mpMRI and PSMA-PET will hopefully give us the possibility to better detect the site of recurrence, these new techniques will be discussed below. A positive surgical margin (PSM) might predict local recurrence after radical prostatectomy, but the importance of a PSM and location and risk for recurrence is still a subject of debate, other prognostic parameters seem to be as important such as histology, PSA, and lymph node involvement or a combination of those [11].

2.2. PSM and location following radical prostatectomy

The incidence of overall PSMs has declined from around 40% in the eighties of the last century to 10–25% in recent years, although the rate of PSM in pT3 tumors did not decrease and remained around 25%, with some series reporting PSMs up to 50% [3,12,13]. Histological proof of PSMs seems difficult because several situations at histological examination can be found suggesting possible PSMs: (1) extra capsular extension beyond the surgical resection margin, (2) organ-confined disease in an area where there is no prostatic capsule suggesting an incomplete removal, (3) iatrogenic incision into the prostate through the tumor giving a false positive margin. The only true PSM is the first situation in which the resection has gone through tumor tissue. In patients operated with robotic-assisted laparoscopic prostatectomy (RALP) the rate of iatrogenic intraprostatic incision seems higher because of the lack of tactile feedback from the robotic arms [14]. A positive surgical resection margin finding also depends on the technique of the pathologist used to examine the specimen. Sakr et al. showed an increased positive margin detection of 12% when going from 5 mm to 2–3 mm sections [15]. Another problem is the interobserver variability in case of a positive margin. Van der Kwast et al. examined the prostatectomy specimens of 552 patients treated in the EORTC 22911 trial and found a high concordance index of 94% between the review pathologist and local pathologist on prostate specimen regarding seminal vesicle invasion [16]. Considering extraprostatic extension and PSM the concordance was much lower, 57.5% and 69.4%, respectively [16]. In an analysis from Swanson et al., the surgical margin is a negative predictor with a 5-year disease-free survival ranging between 36–84% in case of positive margins compared to 78–95% in margin negative patients [11]. The extensive review by Fontenot et al. reported that only 6 out of 44 studies found an increased risk of BCR in margin positive patients on multivariate analysis [17]. The length of a PSM seems to be correlated with failure rate: extensive positive margins versus focal positive margins about 70% and 20%, respectively. In most series, a focal positive margin is defined as a solitary positive margin, whereas extensive consists of multiple positive areas. The increased risk has also been demonstrated in seven other studies, with two studies on univariate analysis, three on multivariate analysis, and two when there were more than three PSMs [18–23]; however, in seven other studies no increased risk was demonstrated [24–30]. Several trials have looked into the length of the PSM. Eleven of 15 studies demonstrated an increased risk with a trend that a PSM of >3mm increased the risk on BCR [18,20,24,25,31–36].

2.2.1. Apex

One of the most difficult regions to examine histologically is the apex. This is the most caudal part of the prostate, with close proximity to the venous complex, external sphincter, and neurovascular bundle. It contains almost no prostatic capsule in contrast to the body of the prostate and therefore is difficult to differentiate between prostate and surrounding tissue. Because of this difficulty making a distinction between organ-confined tumors (pT2) and extraprostatic extension (pT3) is also complex, resulting in higher rate of false PSMs [14,37]. The EAU guidelines state that tumors at the apex mixed with skeletal muscle does not constitute extra prostatic extension (https://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf).

Because the surgeon tries to preserve as much urethral length as possible for reanastomosis, it is the most common location of a PSM. Also the traction on the prostate is mentioned as a reason of more PSMs in the apex compared to other locations. In case of a laparoscopic approach, a higher incidence of a positive margin in this region has been reported [38]. In a comprehensive review by Fontenot et al. [17], a PSM in the apex was found to be the most frequent localization reported in literature. However, it is still unclear if a PSM at the apical site is prognostic for recurrence. Fesseha et al. reported the same outcome in patients with a PSM in the apex compared to organ-confined disease [39]. A study by Ohor et al. showed a 5-year disease-free survival of 70% in positive margins at the apex compared to 81% in other areas, suggesting an increased risk of recurrence in apical positive margins [40]. Fontenot et al. reported the risk of BCR in patients with a PSM at the apex on multivariate analysis in literature, with 4 studies reporting an increased risk at multivariate analysis and 11 not.

2.2.2. Posterior side

The posterior site is the second most common localization for a positive margin reported by Fontenot et al. [17]. This area consists of the true prostate capsule; a thin layer of connective tissue and three layers of prostatic fascia; anterior, lateral, and posterior with the nerves in between. When trying to spare the neurovascular bundle, the risk of a positive margin increases. In patients treated with RALP, the chance of a PSM in the posterior side seems higher, with the idea that the traction of the nondominant arm causes capsular sheering. Also, the improved visualization seems to increase the chance of a PSM in RALP patients, because improved nerve sparing could encourage closer prostatic incision [14]. An increased risk of a BCR in case of a positive surgical at the posterior side has been reported in three studies, this could not be confirmed in one study according to Fontenot et al. [17].

2.2.3. Bladder neck

A PSM at this site is often a result of an attempt to preserve the bladder neck for urinary continence. Poulus et al. showed a recurrence risk of 36% in bladder neck positive tumors compared to 11% in other areas [41]. Aydin et al. reported a 5-year progression-free survival (PFS) decrease from 70% to 33% when bladder neck invasion was found [42]. Others did not find evidence of increased risk [43–46]. Fontenot et al. reported only one out of four studies with an increased risk of BCR on multivariate analysis in case of a PSM at the bladder neck [32].

2.2.4. Anterior

The chance of a PSM at the anterior side is considered low 5–14%, because of the presence of the anterior fibromuscular stromal region and absence of relevant structures [24,26,32,47]. An increased risk has been reported in three recent papers [18,26,32], but two other studies could not confirm this [24,47].

2.3. What are risk factors for a PSM?

The occurrence of a positive resection margin depends on the clinical tumor stage. In the meta-analysis performed by Novara et al. in 2012 a PSM of 9% in pT2 tumors, 37% in pT3 tumors and in half of the cases in pT4 tumors has been demonstrated. Ficarra et al. evaluated predictive values for PSM and found that clinical stage cT2 (HR 2.2; p = 0.008) and prostate volume > 40 ml on transrectal ultrasound(TRUS) (HR 0.4; p = 0.002) were clinically associated with PSMs. The pT3-4 stage was the only pathological predictor for PSM (HR 11.9; p < 0.001). The Gleason score 8–10 versus 6 or less was predictive for multiple PSMs (HR 6.9; p < 0.001). Surgical experience seems to influence the risk of a PSM: with the open and laparoscopic approach, the experience plateau seems to be reached at 200–250 cases [48,49], and with RALP, the plateau seems even higher with around 1000–1500 cases [50]

2.4. Prognostic factors for BCR

The involvement of seminal vesicle invasion seems to increase the recurrence rate in patients with PSM, with a disease-free survival of 14% compared to 49% in seminal vesicle negative patients [51]. In another trial, the disease-free survival in seminal vesicle positive patients was 36%, when they had also a PSM it dropped to 21% compared to 56% in negative PSMs [52]. The negative prognostic factor of seminal vesicle invasion was confirmed by the SWOG 8794 trial for 10-year biochemical failure-free survival (BFFS), overall survival, and metastasis-free survival. The role of extracapsular extension in margin positive patients showed a 5-year disease-free survival ranging from 33% to 64% in margin positive patients with extracapsular extension compared to 74–78% in margin positive without extracapsular extension patients [11]. In the comprehensive search by Fontenot et al., 18 out of 23 studies showed that extra prostatic extension significantly increased the BCR rate [17]. Another prognostic factor is the Gleason score, a higher score is prognostic unfavorable for BCR [53,54].In the ARO 96-02/AUO Gleason >6, ≥pT3b and PSM were factors influencing PFS both in the wait-and-see group and the adjuvant radiotherapy group [55]. To predict the BCR rate, several factors seem relevant and therefore nomograms have been proposed. Kattan et al. have proposed one of the first nomograms in 1999, incorporating preoperative PSA levels, Gleason score, extracapsular extension, seminal vesicle invasion, and lymph node involvement which has been updated in 2005 and 2009, with a concordance index ranging between 0.77 and 0.79 for BCR [56]. Another widely used model is the CAPRA-S. Different studies showed a concordance index for BCR ranging between 0.73 and 0.80 and for prostate cancer-specific survival ranging between 0.75 and 0.88 [57]. Also the Stephenson nomogram with a CI index of 0.78–0.81 and Suardi nomogram with a CI index of 0.77–0.83 have been proposed [58,59]. With these models, an attempt is made to select patients who will develop a BCR and select individually adjuvant treatment.

3. Treatment options following radical prostatectomy

3.1. Immediate postoperative radiotherapy versus wait and see?

Three randomized controlled trials compared immediate postoperative radiotherapy with delayed radiotherapy in case of recurrence in high-risk prostate cancer patients. The Southwest Oncology Group (SWOG 8794) conducted the first trial between 1988 and 1997 in the USA. They included 425 patients with pT3N0M0 with extracapsular extension, positive margins, or seminal vesicle invasion [60]. Radiotherapy was delivered to the prostatic fossa with a dose of 60–64 Gy. The PSA progression rate was higher in the delayed arm compared to the immediate postoperative radiotherapy group, 77–55%. The metastasis-free survival differed between the two groups, with 71% after 10 years in the immediate postoperative radiotherapy group versus 61% in the delayed arm. One of the prognostic factors for BCR was the PSA following prostatectomy, with a PSA of ≤0.2 ng/ml having the most favorable outcome and PSA ≥ 1.0 ng/ml with the worst outcome. The Gleason score had also an impact on BCR, but this was less important compared to PSA. The overall survival at a median follow-up of 12.6 years was in favor of the immediate group, 74% after 10 years compared to 66% in the delayed arm, with a HR of 0.72 (p = 0.023). Both the local and metastatic failure were less in the radiotherapy group, local failure 8% versus 22% and metastases 7% versus 16% in the immediate versus delayed arm, respectively [61]. The second trial was the EORTC 22911 performed between 1992 and 2001. One thousand and five patients with pT2-3 prostate cancer were randomized with one of three findings: extracapsular extension, PSM, or seminal vesicle invasion. The treatment dose was 50 Gy with an infield boost up to 60 Gy. Biochemical progression was 39.4% in the radiotherapy group compared to 61.8% in the delayed arm (p = 0.0001), although clinical PFS and overall survival were not significantly different after 10 years. The proportion of loco regional progression was 16.5% in the delayed radiotherapy group compared to 7% in the immediate group with the same metastasis rate of 7.2%. In the delayed arm, 6.8% of the patients died from prostate cancer compared to 5% in the immediate radiotherapy group [62].

The third randomized controlled trial is the ARO 96–02/AUO AP 09/05 [55]. In this trial, only high-risk patients with undetectable PSA levels following radical prostatectomy were randomized between immediate postoperative radiotherapy versus delayed treatment. In total, 388 patients were randomized 2 weeks following prostatectomy. Because undetectable PSA levels are normally achieved within 2–6 weeks, 78 patients having detectable PSA levels after the randomization were not analyzed. Three patients were ineligible and the remaining 307 patients were eventually analyzed. The 10-year PFS was 35% in the delayed group compared to 56% in the immediate postoperative radiotherapy group (HR 0.71). Especially the subgroup of patients with PSM seemed to benefit the most with 10 years PFS of 27% in the delayed group compared to 57% in the immediate postoperative radiotherapy group. In the multivariate analysis positive margins, pT3b or higher and Gleason > 6 were found as statistical significant prognostic factors [55]. In the Cochrane analysis by Daly et al., the pooled analysis of these three trials showed an improved overall survival at 10 years, with a number needed to treat of 10 [63].

3.2. Salvage radiotherapy versus adjuvant radiotherapy

In spite of the results of these three published trials, immediate postoperative radiotherapy did not result in wide acceptance. Kalbasi et al. reported that only 9% of patients were referred for immediate postoperative radiotherapy between 2004 and 2011 based on data from the National Cancer Database [64]. This was in the same period when the results of the three randomized clinical trials were published. Most patients are still being treated with so-called salvage radiotherapy.

No randomized controlled trials have been published yet investigating if salvage radiotherapy will yield the same result as immediate postoperative radiotherapy. In the SWOG trial, a small number of patients in the wait-and-see group eventually received salvage radiotherapy, they were matched with the adjuvant radiotherapy group on PSA levels into two groups: PSA levels ≤ 0.2 ng/ml and between 0.2 and 1.0 ng/ml. The 5-year PSA-failure rate in the group with PSA levels ≤ 0.2 ng/ml was 77% in the adjuvant radiotherapy group versus 38% in the wait and see group that received salvage radiotherapy. In patients with PSA between 0.2 and 1.0 ng/ml, the 5-year PSA-failure rate was 34% in the adjuvant radiotherapy group compared to 17% in the wait and see group that received salvage radiotherapy [61]. In a meta-analysis performed in 2014, adjuvant and salvage radiotherapy were compared including 18 studies; 2 matched control studies and 16 retrospective studies. In this study, the 5-year BFFS was improved for the adjuvant radiotherapy group compared to the salvage radiotherapy group. Also disease-free survival and overall survival were better in the adjuvant radiotherapy group [65]. One of the major drawbacks is that the PSA prior to adjuvant or salvage radiotherapy was either not reported or ranged between <0.1 and 4.5 ng/ml. Therefore, Fossati et al. [66] compared adjuvant radiotherapy with salvage radiotherapy in a multi-institutional cohort of seven tertiary referral centers. Five hundred and ten patients with undetectable PSA levels following radical prostatectomy were stratified into adjuvant radiotherapy (243 patients) or early salvage radiotherapy (267 patients) with PSA levels ≤ 0.5 ng/ml. Although a higher number of patients with pT3b/pT4 and PSM were in the adjuvant radiotherapy group, no difference was found in metastasis-free survival and overall survival. Multivariate Cox regression analysis showed that Gleason score ≥ 8 and pT3b were both adverse prognostic factors in predicting overall mortality in the 510 patients. The matched-control analysis performed by Briganti et al. also showed no difference in BCR between adjuvant radiotherapy versus salvage radiotherapy in case of PSA ≤ 0.5 ng/ml at least 6 months following radical prostatectomy [67]. Ost et al. performed a matched-control analysis of 178 patients receiving adjuvant or salvage high-dose radiotherapy following radical prostatectomy. Patients were matched based on preoperative PSA levels, Gleason score, and pT stage. The 3-year biochemical relapse-free survival (bRFS) was 91% in the adjuvant radiotherapy and 79% in the salvage radiotherapy group (p < 0.05), although on multivariate analysis salvage radiotherapy was no longer an independent prognostic factor for worse bRFS. The only independent prognostic factors for reduced bRFS were Gleason grade ≥ 4 + 3, perineural invasion and omission of androgen deprivation therapy (ADT) [68]. Abugharib et al. investigated the best timing of salvage radiotherapy following radical prostatectomy based on PSA nadir levels [69] and found that PSA levels before salvage radiotherapy predicted outcome. PSA levels between 0.01 and 0.2 ng/ml resulted in the highest bRFS compared to patients with higher levels. Even a significant difference in overall survival was found. In patients with PSA levels 0.01–0.2ng/ml, >0.2–0.5 ng/ml, and >0.5 ng/ml at time of salvage radiotherapy it was 84%, 82%, and 61%, respectively [69]. This suggests that a BCR defined as two consecutive PSA levels > 0.2 ng/ml by the AUA and EAU guidelines might be too high and that earlier intervention is needed. Fossati et al. showed that PSA levels before postoperative radiotherapy were also dependent on adverse pathologic findings. In patients with two adverse factors: pT3b/T4, Gleason ≥ 8, or negative surgical margin, postoperative radiotherapy should be given at the earliest sign of PSA rise. In the group of patients with 2 or more adverse findings, the 5-year BCR dropped 10% with every PSA increment of 0.1 ng/ml compared to only a 1.5% drop in patients with only one or no adverse findings [70].

One of the reasons that early salvage radiotherapy seems more effective than delayed radiotherapy could be the introduction of lead-time bias. In most studies, BCR were calculated from the start of salvage radiotherapy until relapse, thereby not taking into account the time from the radical prostatectomy and the start of radiotherapy. In case of a patient that is irradiated 5 months following radical prostatectomy and develops a second recurrence after 6 months has the same overall recurrence time compared to a patient that is irradiated 7 months following radical prostatectomy and develops a second recurrence after 4 months, both the second recurrence time is 11 months after the operation [71]. In an attempt to define other prognostic factors than pretreatment PSA levels that influence the impact of postoperative radiotherapy, a retrospective study was performed by Trock et al. Patients receiving salvage radiotherapy were compared with a wait-and-see group and they found that patients with a PSA doubling time of less than 6 months had the most benefit from salvage radiotherapy with an increased prostate specific survival when the radiotherapy was given ≤2 years after radical prostatectomy [72]. However, in patients irradiated >2 years after radical prostatectomy, no significant association was found in prostate cancer-specific survival and PSA doubling time. Stephenson et al. performed a retrospective analysis on patients treated with salvage radiotherapy and found that patients with a PSA doubling time of less than 10 months had a worse progression-free probability compared to a PSA doubling time of more than 10 months [73]. The impact of a PSM and postoperative radiotherapy has been reported in the retrospective study by Mauermann et al, where only a benefit in BCR was found with a 10-year BCR of 82% in margin negative compared to 72% in margin positive patients. On hard end-points like time to metastasis, prostate-specific survival, and overall survival, no benefit was found between margin positive and negative patients [74].

In an attempt to select patients that would benefit most from adjuvant radiotherapy, different risk scores were proposed. Abdollah et al. constructed a nomogram for patients treated with adjuvant radiotherapy; they found a survival benefit for patients receiving adjuvant radiotherapy with two or more of the following factors: Gleason score ≥ 8 and/or pT3b-T4 and/or positive lymph nodes. The overall mortality-free survival with 2 or more risk factors was 75.6% in the adjuvant radiotherapy group compared to 62.7% in the group that received no radiotherapy [75]. In their multivariate Cox regression analysis, a PSM was not statistical significant in predicting cancer-specific mortality (CSM) and was therefore not used in their nomogram. Again, the role of a PSM on disease progression seems controversial, which already has been mentioned by Fontenot et al. [17]. Gandaglia et al. validated this risk score in a group of 7616 patients from the SEER database treated with radical prostatectomy. Adjuvant radiotherapy reduced CSM in patients with two or more risk factors as found by Abdollah et al. In this group, there was a CSM reduction of 9.3% at 10 years [76]. In a recent meta-analysis by Jia et al., Gleason score ≥ 7 and ≥pT3a were negative prognostic factors for BCR following salvage radiotherapy. Salvage radiotherapy with ADT had a positive effect on BCR with an odds ratio (OR) of 0.63 [77]. Two ongoing randomized controlled trials, the RADICALS (NCT00541047) [78] and the RAVES (NCT00860652) [79] trials, will hopefully determine optimal timing of radiotherapy following radical prostatectomy. The RAVES trial randomizes between adjuvant radiotherapy and early salvage radiotherapy in high-risk prostate cancer patients following radical prostatectomy. The RADICALS also randomizes between adjuvant radiotherapy and early salvage radiotherapy with an extra randomization for both arms into no adjuvant hormonal deprivation therapy for 6 months or 2 years [78,79].

3.3. Radiotherapy following radical prostatectomy with or without ADT

Shipley at al. randomized 760 patients with pT2 and PSM or pT3 and a detectable PSA of 0.2 ng/ml up to 4.0 ng/ml between postoperative (64.8 Gy) radiotherapy with 24 months of bicalutamide 150 mg or a placebo. With a median follow-up of 13 years, this resulted in an increased overall survival benefit of 5% in the bicalutamide group. The 12-year overall survival was 76.3% in the bicalutamide group compared to 71.3% in the placebo group (p = 0.04). Also the incidence of distant metastasis was lower in the bicalutamide group compared to the placebo group; 14.5% versus 23.0%, respectively. On multivariate analysis a statistical significant benefit was found for overall survival in patients with Gleason score 7, PSA levels of 0.7 ng/ml or higher and PSM. In a subgroup analysis, a lower rate of distant metastasis was found in patients with Gleason score 8–10, those with a PSA level > 1.5 ng/ml and those with PSM in the bicalutamide group compared to the salvage radiotherapy group [80].

Solely for patients with a PSA of >0.7 ng/ml contributed the overall survival benefit, this is rather high by today’s standard as discussed by Abugharib [69]. With the slightly higher, although not significant HR of 1.13 for the risk of death in the PSA < 0.7 ng/ml group, the use of bicalutamide could potentially be avoided if patients are treated with low PSA levels, without the potential extra risk of dying other than due to prostate cancer.

In the GETUG-AFU 16 trial, 743 patients were randomized between salvage radiotherapy when BCR was detected with or without 6 months of ADT using goserelin acetate [81]. The PFS with a median follow-up of 63 months was 62% in the radiotherapy group compared to 80% in the radiotherapy group with ADT. One hundred ninety patients developed disease progression following salvage radiotherapy, 157 (83%) had a local progression event with or without biochemical progression as their first progression event, 104/124 (84%) in the salvage radiotherapy group combined with ADT, and 53/66(80%) in the salvage radiotherapy group only. The multivariate analysis showed that PSM, PSA doubling time < 6 months, seminal vesicle involvement, and PSA at relapse were negative prognostic factors for relapse. The overall survival was not different between the two groups, with only 7% and 5% deaths

3.4. Selecting patients for immediate postoperative radiotherapy based on genetic profile

Traditionally patients are categorized in risk groups based on clinical and pathological data. In an attempt for a more individualized risk assessment, new models have been proposed based on genetic data. These so called genomic classifiers have been tested in different retrospective studies.

Zhao et al. used a 24-gene expression signature and formulated a Post-Operative Radiation Therapy Outcomes Score (PORTOS) to select patient who would benefit from immediate postoperative radiotherapy [82]. They created a high-risk PORTOS group and a low-risk PORTOS group of developing distant metastasis. In both their training and validation set, patients with a high PORTOS score had benefit from radiotherapy following prostatectomy. In the validation set with 330 patients, the use of radiotherapy reduced the risk of metastasis from 35% to 4% only in the high-risk group. In the low-risk PORTOS group, there was no benefit from radiotherapy with 32% of patients developing metastasis in both groups. No clear reason for the high incidence of distant metastasis in the low-risk group is provided, so the results should be interpreted with caution and the usage of the PORTOS should be evaluated in a prospective trial. Unfortunately, no distinction between adjuvant and salvage radiotherapy was made in the model. To address the role of adjuvant versus salvage radiotherapy following prostatectomy, Den et al. used a 22-gene classifier on high-risk prostate cancer patients. This genomic classifier is a continuous risk score between 0 and 1, with a higher score indicating higher risk of metastasis [83]. The Genomic Classifier (GC) had a concordance index of 0.83 in predicting the incidence of metastasis after 5 years, compared to 0.66 for the CAPRA-S. The GC downgraded 43% of the intermediate- and high-risk CAPRA-S group into low-risk GC group, 96% of these reclassified patients remained metastatic-free on study follow-up. The incidence of metastasis was 0%, 9%, and 29% in the low-, intermediate-, and high-risk group, respectively. In patients with a score of 0.4 or less, the incidence of metastasis in the adjuvant radiotherapy group and salvage radiotherapy group was both 0%. In the group with a GC of 0.4 or more, the incidence of metastasis was 6% in the adjuvant radiotherapy group compared to 23% in the salvage radiotherapy group [83]. This cohort of 188 patients had a relative low concordance index of 0.66 for metastatic disease, whereas Tilki et al. showed a concordance index of 0.85 in a cohort of 14,532 patients [84]. Thus the real value of genomic classifiers has to be explored prospectively.

4. Toxicity of adjuvant and salvage radiotherapy

One of the problems in adopting adjuvant radiotherapy is the increased toxicity. The meta-analysis performed by Daly et al. showed an increase in acute and late gastrointestinal toxicity, urinary stricture, and incontinence in patients treated with adjuvant radiotherapy in the RTOG, EORTC, and SWOG trial.

Although more severe late gastrointestinal and genitourinary toxicity, grade III toxicity was low with only 4.2% in the adjuvant radiotherapy group compared to 2.6% in the delayed group in the EORTC trial. Rectal bleeding and proctitis were reported in 3.2% of patients in the adjuvant radiotherapy group compared to 0% in the delayed group in the SWOG trial. The percentage of urethral stricture and urine incontinence was 10% and 6.8% in the adjuvant radiotherapy group compared to 5.8% and 2.6% in the delayed group in the ARO and SWOG trial. Erectile function and quality of life were not affected. Feng et al. reported the toxicity outcome in 959 patients from a multi-institutional database, with 19% of patients receiving adjuvant radiotherapy and 81% salvage radiotherapy. In the multivariate analysis adjuvant radiotherapy was a predictor for late grade 2 or higher genitourinary (GU) toxicity (p = 0.03). Cozzarini et al. performed a retrospective analysis on 742 patients treated with immediate (N = 566) and delayed (N = 186) postoperative radiotherapy on clinical factors predicting late grade 3 GU toxicity. There was no difference in grade 3 GU toxicity between both groups. In the multivariate analysis acute grade 2 toxicity, hypertension, whole pelvis irradiation, and age above 62 year were predictors for late grade 3 toxicity in the immediate postoperative radiotherapy group. In the delayed group acute grade 2, radiation dose > 72 Gy and age > 71 were predictors for late grade 3 toxicity [85].

5. Improving radiotherapy

5.1. Dose and technique?

In the three randomized trials with immediate postoperative radiotherapy, the mean dose was 60–64 Gy, with a local recurrence of 8% in the SWOG 8794 trial and locoregional failure of 7% in the EORTC 22911 trial. In a subgroup of patients in the SWOG 8794 trial with PSA > 1.0 ng/ml, the local recurrence was only 9%, although only 11 patients belonged to this group. No information was provided on local or regional recurrence in the ARO96-02/AUO AP 09/0. The GETUG-16 data showed that following salvage radiotherapy 21% developed a local recurrence [81]. This is much higher than the 8% in the SWOG (60–64Gy) trial, while the dose in the GETUG-16 trial (66 Gy) was slightly higher with the addition of ADT. These figures may indicate that in case of a rising PSA a higher dose should be applied. A dose response curve was plotted in the meta-analysis of King et al., showing a 2.0% increase in relapse-free survival (RFS) per Gy dose increase. The RFS was 38.5% in the 60 Gy group compared to 58.4% in the 70 Gy group [86]. The EORTC 22911, SWOG 8794 and ARO96-02/AUO AP 09/0 used three or four field conformal techniques for dose delivery. This resulted in increased acute and late gastrointestinal toxicity, urinary strictures, and incontinence according to the Cochrane analysis by Daly et al. [63]. With new treatment techniques like volumetric arc radiotherapy or intensity modulated radiotherapy (IMRT), a high focused boost can be given on macroscopic disease, without compromising normal tissue tolerance. A study by Riou et al. compared 3D conformal radiotherapy with IMRT planning to a dose of 68 Gy. A significant reduction in rectal dose and bladder dose for IMRT was noticed without grade 2 or higher acute or late adverse effects [87]. Ost et al. showed that a dose of >70 Gy is feasible in 104 patients treated with radiotherapy following radical prostatectomy with a bRFS of 93% at 5 years follow-up [88]. With no acute and late grade 3 gastrointestinal toxicity and only 8% developing acute and 4% late genitourinary toxicity. Recently, D’Angelillo et al. reported a focal boost of up to 80 Gy to the 18F-Choline PET/CT positive region, with only 3 patients experiencing grade 3 acute GI toxicity, no grade 3 late toxicity was reported [89]. Ghadjar et al. showed similar result in 102 patients treated with 80 Gy using IMRT and daily image guidance, with no grade 3 acute or late GI toxicity and 5% developing acute GU toxicity and 1% late GU toxicity [90]. It seems that fraction dose is more important for toxicity. Cozzarini et al. reported an increased GU toxicity in patients treated with a mean fraction dose of 2.5 Gy instead of 1.8 Gy in a cohort of 1176 patients treated between 1993 and 2010.

These data supported the feasibility of higher radiotherapy dose without compromising toxicity when treated with conventional (1.8–2.0 Gy) fractionated radiotherapy [91]. With up to date techniques like MR-linac and MRIdian® (Viewray), more precise irradiation can be delivered with daily MRI-based image guidance, with the possibility of escalating the dose even further without compromising normal tissue tolerance. The role of brachytherapy for salvage radiotherapy is limited, with only a few studies presenting small numbers of patients treated with brachytherapy. In the studies presented the mean PSA ranged from 1.43 to 5.02 ng/ml, with biopsy proven local relapse. Techniques reported used I-125 or HDR brachytherapy with or without external beam radiotherapy [92–99]. One of the advantages of brachytherapy would be an even higher local dose without compromising normal tissue, because of the steep dose falloff, but the drawback is that a visible lesion is needed to place the I-125 sources or HDR needles [100,101].

5.2. Target definition for postoperative radiotherapy

The exact target definition for postoperative radiotherapy is still under debate, four different guidelines for target volume contouring have been published: (1) The European Organization for Research and Treatment of Cancer (EORTC) [102], (2) Radiation Therapy Oncology Group (RTOG) [103], (3) Faculty of Radiation Oncology Genito-urinary group (FROGG) [104], and (4) Genito-urinary Radiation Oncologists of Canada (GUROC) [105]. All these groups use the vesicourethral anastomosis as the starting point for delineation, with 8–12 mm extension caudally for the RTOG group, 8 mm caudally for the GUROC group, and 5 mm margin for the FROGG. The EORTC suggests the caudal border to be 15 mm above the penile bulb. One of the problems of these guidelines is the interobserver variation in contouring the prostate bed. Ost et al. performed an interobserver analysis between six radiation oncologist delineating the same prostatic fossa and seminal vesicle remnant according to the EORTC delineation guideline. There was only moderate agreement, with a kappa of 0.49 for delineating the prostate bed and a kappa of 0.42 for delineating the seminal vesicle remnant. One of the explanations could be the use of CT-based contouring instead of MRI; they suggested refining the guidelines based on MRI delineation [106]. Park et al. determined local recurrence on MRI findings and found that 78% of recurrences were at the anastomotic site besides 18% at the bladder neck for T2-3a and 21.7% at the retrovesical area for T3b tumors. They used the lower border of the pubic symphysis as a reference point and found that the recurrences were between 8 mm caudally of this reference point and 43 mm cranially of this reference point [107]. None of the consensus guidelines requires a urethrogram for determining the vesicourethral anastomosis; therefore, Manji et al. used a urethrogram to adequately localize the vesicourethral anastomosis and compared this to the delineated vesicourethral anastomosis based on the most inferior urine-containing bladder slice on the CT-scan. An average distance of 16.1 mm (range 6.8–34.2 mm) was found between the two methods. They suggested that a 25 mm margin caudally to the reference CT would be required to cover in 90% all vesicourethral anastomoses when a urethrogram is absent [108]. With these findings, some of the local failures in the SWOG 8794 and EORTC 22,911 trial could partly be explained by inadequate coverage [61]. The role of whole pelvic irradiation compared to the irradiation of the prostate bed alone was investigated by Spiotto et al. who found that high-risk patients with ADT would benefit from WPRT, with a 5-year bRFS of 47% in the WPRT group compared to 21% in the prostate bed group [109]. This was confirmed by Song et al. who also found a benefit in bRFS in high-risk patients receiving whole pelvic radiotherapy (WPRT) compared to prostate-bed only radiotherapy [110]. Moghanaki et al. found that whole pelvic irradiation significantly improved biochemical PFS in patients with a PSA level of ≥0.4 ng/ml prior to radiotherapy

Deville et al. performed an IMRT dosimetric analysis comparing toxicity of whole pelvis irradiation with a boost to the prostate bed to treatment of the prostate bed only. Despite dosimetric differences especially for bowel, bladder, and rectum, only acute gastrointestinal toxicity was significantly higher in the whole pelvic group, with no difference for late gastrointestinal toxicity [111]. Alongi et al. compared IMRT with 3DCRT in patients treated with WPRT to reduce toxicity. They found that upper gastrointestinal toxicity according to the RTOG/EORTC grading system of 2 or higher was significantly reduced from 22.2% to 6.6%. The reduced gastrointestinal toxicity could probably be attributed to a lower V30-V50 dose to the intestine [112]. With IMRT, WPRT seems possible in selected patients without adding extra toxicity. Hopefully, the RTOG 0534 trial (NCT00567580) will give the answers to who will benefit from WPRT. This phase III trial consist of three arms, randomizing patients with a rising PSA following radical prostatectomy into prostate bed radiotherapy, prostate bed radiotherapy with 6 months ADT and pelvic lymph node and prostate bed radiotherapy with 6 months ADT.

6. Imaging techniques

6.1. Role of MRI following radical prostatectomy to identify locoregional recurrence

The role of 3T-MRI was studied in 90 patients following radical prostatectomy who were referred for salvage radiotherapy. There was a positive finding for recurrence on MRI in 22.2% of patients, although not histologically proven. In the group with a PSM, 33% had a positive finding for recurrence, contrary to 11% in the negative margin group. In 9 of the 12 patients, there was an association between the location of the MRI findings and the location of the PSM following prostatectomy. The treatment was changed in 7 of 18 patients due to the MRI findings; these changes consisted of an extra boost up to 77.4 Gy to the detected lesion on MRI or pelvic lymph nodes that were also irradiated. So, it seems that in case of a PSM a MRI can aid with the localization of the target volume for salvage treatment in some patients [113], but it is still unclear if this approach will influence outcome. Müller et al. verified the positive findings on mpMRI with ultrasound-registered biopsies. In total, 39 patients were examined; 21 having a positive finding on MRI, 11 patients were excluded from analysis because 4 had already metastatic disease and 7 patients were treated without biopsy proven recurrence in the lesion. Eight out of 10 biopsies were positive for local recurrence [114]. In a pooled analysis by Yu et al., the pooled sensitivity and specificity for dynamic contrast-enhanced MRI in detecting residual or recurrent disease following prostatectomy was 0.88 and 0.87, respectively, in the 12 studies reviewed [115]. In most studies, patients with positive MRI findings had higher PSA levels [113]. Dirix et al. found a PSA level of 1.4 ng/ml in the patients with positive findings on MRI compared to 0.4 ng/ml in the negative group [116]. They also found that patients with a positive finding on MRI have a lower biochemical disease-free survival compared to the group with negative findings in multivariate analysis.

Meijer et al. examined the pattern of lymph node spread in 65 patients with a BCR using MRI with a lymph node-specific contrast agent called ferumoxtran-10 (Sinerem; Guerbet, Paris, France). In normal lymph nodes, this tracer will be accumulated in macrophages resulting in a low T2-MRI images and in metastatic lymph nodes this tracer will be blocked, with a high signal on T2-MRI. They reported an aberrant positive lymph node in 79% of the patients when comparing their result with the RTOG-CTV delineation guideline for pelvic lymph nodes [117]. The distribution was 47% at the proximal common iliac artery, 23% para-aortal, and 43% at the pararectal region. The only correlation for para-aortal and common iliac region was the median PSA at the time of lymphographic MRI, the mean PSA was 2.49 ng/ml in the para-aortal and proximal common iliac positive group compared to 0.82 ng/ml in the absent group. The lymphographic MRI showed a different lymph node distribution in patients following radical prostatectomy compared to the treatment-naïve patient and suggested a different delineation in patients treated with WPRT [118].

6.2. Choline PET-CT

Two slightly different tracers are commonly used, ¹¹C-choline and ¹⁸F-choline. In a pooled analysis for all sites of disease, a lower sensitivity for ¹¹C-choline and similar specificity was found compared to 18F [119]. In a recent meta-analysis, the overall detection rate of ¹¹C-choline for local recurrence was 27% with a sensitivity and specificity of 61% and 97%, respectively [120]. The overall detection rate of lymph node or distant metastasis was 36%, no sensitivity or specificity analysis had been performed because only three studies reported outcomes. In the meta-analysis of Evangelista et al., both ¹¹C-choline and ¹⁸F-choline were pooled and showed a sensitivity and specificity for lymph node metastasis detection of 100% and 81.8%, respectively. A major drawback is the relatively low sensitivity of less than 50% in case of PSA levels below 1.0 ng/ml and PSA doubling time longer than 6 months [121,122]. With most data suggesting that salvage radiotherapy should be performed at a PSA level of 0.5 ng/ml or less makes this imaging model less useful in detecting recurrence.

6.3. Prostate-specific membrane antigen-positron emission tomography

Bluemel et al. assessed the role of PSMA-PET in 45 patients with persistent or recurrent prostate cancer following radical prostatectomy. Twenty-four patients had positive findings; 11 a local recurrence, 8 lymph node metastasis, 1 both local and lymph node metastasis, and 4 bone or rectal metastasis. This changed treatment in 19 patients ranging from dose escalation on the positive lesion, irradiating lymph node metastasis or ADT [123]. A drawback of PSMA-PET is the clearance through the kidneys, thereby potentially obscuring local recurrence in the area of the bladder neck. In a retrospective study, Freitag et al. evaluated patients that received both ⁶⁸Ga-PSMA-11-PET/CT and mpMRI in an integrated PET/MRI scanner. They found local recurrences in 18 patients, with only 9 ⁶⁸Ga-PSMA-11-PET/CT positive lesions. Only the uncertain cases were histologically proven otherwise follow-up scans or PSA decrease following salvage therapy were used to determine if the positive lesion was a true recurrence. This mismatch between MRI and ⁶⁸Ga-PSMA-11-PET/CT was statistically significant and they suggested using multimodality imaging to enhance the detection of local recurrence [124]. In an attempt to address PSA kinetics when using of ⁶⁸Ga-PSMA-11-PET/CT, Eiber et al. retrospectively studied 248 patients with a BCR. They found in 57.9% of patients with PSA levels between 0.2 and 0.5 ng/ml a positive result, which increased to 96.8% in patients with PSA ≥ 2.0 ng/ml. The detection rate increased from 81.8% in patients with a PSA velocity of <1 ng/ml per year to 100% in patients with a PSA velocity of ≥5ng/ml per year. The detection rate was 82.7% in patients with a PSA doubling time of >6 months, 96.2% in PSA doubling time between 4 and 6 months and 90.7% in patients with a PSA doubling time of <4 months. Another prognostic factor for detecting recurrence using ⁶⁸Ga-PSMA-11-PET/CT is histological differentiation. The detection rate of ⁶⁸Ga-PSMA-11-PET/CT increased from 86.7% in patients with Gleason ≤ 7 to 96.8% in Gleason ≥ 8 [125]. Schwenk et al. compared the detection rate of ⁶⁸Ga-PSMA-11-PET/CT and ¹¹C-Choline PET/CT in 123 patients with 103 biochemical relapses with a median PSA of 2.7 ng/ml. They found a local relapse in 27 of 103 patients; three were only detected with ⁶⁸Ga-PSMA-11-PET/CT and one local recurrence only with ¹¹C-Choline PET/CT. The only statistical difference was a much higher standard uptake value on ⁶⁸Ga-PSMA-11-PET/CT compared to ¹¹C-Choline PET/CT, this enabled a better visualization of the relapse. Especially in the detection of lymph node metastasis, the ⁶⁸Ga-PSMA-11-PET/CT performed better, with 39% of the lesions only been detected by ⁶⁸Ga-PSMA-11-PET/CT, and 6% only by ¹¹C-Choline PET/CT. The average lymph node size being detected by ⁶⁸Ga-PSMA-11-PET/CT was smaller compared to the ¹¹C-Choline PET/CT, 6.0 mm versus 11.7 mm. The differences between both techniques seems to be greater in PSA levels < 1.0 ng/ml [126]. These data show promising results and may help in selecting patients treated with radiotherapy to the prostatic fossa or pelvic lymph nodes or systemic treatment.

7. Expert commentary

Radical prostatectomy is one of the potential curative treatment modalities for prostate cancer. About 30% of the patients will, however, develop a recurrence [127]. Because of the availability of PSA, most recurrences are diagnosed based on a rise in serum PSA without evidence of clinical disease on standard imaging. Three randomized trials investigated the role of adjuvant radiotherapy compared to delayed treatment [55,61,62]. All three trials demonstrated a reduction in BCR rate following adjuvant postoperative radiotherapy. Only the SWOG 8794 trial demonstrated a statistical significant difference in overall survival for the adjuvant radiotherapy group, this benefit was also found when the three trials were pooled together. One of the problems in the five randomized clinical trials different cutoff values for BCR were used in patients receiving direct radiotherapy following radical prostatectomy, and also PSA measurements were not done very consistently (Table 1). Another criticism is that only about one-third of patients in the SWOG 8794 and EORTC 22911 trials received salvage radiotherapy in the delayed group, with a median PSA of 0.75–1.7 ng/ml. These patients were potentially undertreated because some retrospective studies suggest that patients with PSA levels up to 0.5 ng/ml following radical prostatectomy have the same outcome with delayed radiotherapy compared to direct postoperative radiotherapy. The RAVES [79] and RADICALS trials [78] will hopefully give an answer about the timing of radiotherapy following radical prostatectomy. Use of biomarkers will potentially help to categorize patients even better in different risk groups for developing biochemical relapse, thereby selecting the more aggressive tumors that necessitate a multimodality treatment. New imaging modalities possibly can differentiate between local recurrence and regional/distant metastasis. In case of a local recurrence, salvage techniques like brachytherapy can potentially control the disease [92] and in case of limited metastatic disease these lesions can be irradiated with high dose precision radiotherapy. Ost et al. showed in a group of 72 patients a median PFS of 21 months in patients treated with three or less lymph node metastases [128]. Therefore, more research is needed for the role of PSMA-PET and mpMRI to make the distinction between locoregional recurrence and distant metastases. Patients with regional/distant micrometastasis would probably not benefit from local radiotherapy alone and systemic therapy would be needed as has been shown by Shipley et al. [80]. Because postoperative radiotherapy enhances the risk of urinary and gastrointestinal toxicity and thereby increasing the risk of hospitalization, better selection of patients who will benefit from salvage therapy is necessary. With delayed radiotherapy, large patient groups can be spared the side effects and also the side effects seem to be less in case of delayed radiotherapy. Until now, the 2017 EAU guidelines recommend to offer patients with a PSA rise from the undetectable range and favorable prognostic factors (≤pT3a, time to BCR >3 years, PSA doubling time > 12 months, Gleason score ≤ 7), active surveillance, and possibly delayed radiotherapy. They also advise to treat patients with a PSA rise from the undetectable range with salvage radiotherapy and the total dose of salvage radiotherapy should be at least 66 Gy and should be given early (PSA < 0.5 ng/ml). These advices are somewhat contradictory. A restaging may be considered. A bone scan or abdominopelvic CT scan should only be performed in patients with a PSA level > 10 ng/ml and Choline PET-CT in patients with PSA levels above 1.0 ng/ml. No recommendations are made for mpMRI or PSMA-PET. The 2013 AUA guidelines recommend a detailed discussion with the patient regarding the risk and benefits of adjuvant radiotherapy. Especially patients with adverse pathologic findings like seminal vesicle invasion, PSM, and extraprostatic extension should be informed that adjuvant radiotherapy following radical prostatectomy reduces the risk of BCR and local recurrence, but the impact on distant metastasis and overall survival is still unclear. A personal interest lies in more clinical trials. Because only five randomized clinical trials have been performed until now concerning postoperative radiotherapy following radical prostatectomy although prostate cancer has one of the highest incidences in the world only. And by the time these trials were published, the clinical relevance seemed disputable. A good future perspective would be for long-lasting multicenter collaboration to perform randomized clinical trials. This could be organized in a way that after completing a trial, a new one could be started that elaborate on the previous one, thereby creating a continuous cycle of evolving trials. In this way, trials can be adapted to modern standards like genomic classifiers of PSMA-PET more easily and with the multicenter approach trials can be completed in a shorter amount of time. One of the biggest challenges is getting a research network of multiple centers to participate in this trials with enough funding.

Table 1. Comparison of the five randomized clinical trials concerning postoperative radiotherapy following radical prostatectomy.

	SWOG 8794 N = 425	EORTC 22911 N = 1005	ARO 96-02 N = 307	GETUG-16 N = 743	RTOG 9601 N = 840
Year	1988–1997	1992–2001	1997–2004	2006–2010	1998–2003
Inclusion	pT3R1/R0 (any PSA)	pT2 R1 or pT3R1/R0	pT3 R0/R1 (undetectable PSA)	pT2, pT3, pT4 with PSA rise 0.2–2.0 -g/ml	pT2 R1, pT3 R0/R1 detectable PSA 0.2–4.0 -g/ml > 8 weeks RP
Treatment	Radiotherapy vs. wait-and-see	Radiotherapy vs. wait-and-see	Radiotherapy vs. wait-and-see	Radiotherapy with goserolin (6 months) vs. radiotherapy	Radiotherapy with bicalutamide (24 months) vs. radiotherapy
Dose	60–64 Gy	60 Gy	60 Gy	66 Gy	64.8 Gy
Median FU	12.6 years	10.6 years	10 years	5.3 years	12 years
Timing of radiotherapy	<17.5 weeks after RP	<16 weeks after RP	6–12 weeks after RP	with PSA rise 0.2–2.0 -g/ml	with PSA rise 0.2–4.0 -g/ml
Relapse	>0.4 ug/ml PSA after undetectable	Increase PSA > 0.2 ug/ml two times	2 increases in PSA after undetectable	0.5 -g/ml increase from lowest PSA	0.3 -g/ml increase from lowest PSA
BR	10.3 years (RT) 3.1 years (WS) Median (p < 0.001)	13.2 years (RT) 6.12 years (WS) Median (p < 0.0001)	NA	NA	44% (RT + HT) 67.9% (RT) At 12 years
PFS	NA	60.6% (RT) 41.1% (WS) 10 years (p < 0.0001)	56% (RT) 35% (WS) 10 years (p < 0.0001)	80% (RT+ Go) 62% (RT) 5 years (p < 0.001)	NA
Overall survival	74% (RT) 66% (WS) 10 years (p = 0.023)	76.9% (RT) 80.7% (WS) 10 years (NS)	82% (RT) 85% (WS) 10 years (NS)	96% (RT + Go) 95% (RT) 5 years NS	76.3% (RT + Bi) 71.3% At 12 years (p = 0.04)
MFS	71% (RT) 61% (WS) 10 years (p = 0.016)	76.5% (RT) 71.3% (WS) 10 years (NS)	80% (RT) 84% (RT) 10 years (NS)	NA	14.5%(RT + Bi) 23% (RT) (p = 0.005) Incidence of a distant recurrences

Go: gosereline; Bi: bicalutamide; MFS: metastatic-free survival; PFS: progression-free survival; BR: biochemical relapse; WS: wait and see.

8. Five-year view

In 5 years, imaging and possibly genomic classifiers will better select patients for radical prostatectomy and thereby reducing the chance of recurrence. In the event of PSA progression, patients that benefit from adjuvant radiotherapy and at what time will be better defined. Patient profiling with genomics on circulating tumor DNA will give us much more detailed information on tumor biology and tell us who will recur locally or will metastasize. These genomic profiles will also predict the radiosensitivity of tumors, resulting in a more tailored dose of radiotherapy. Until now, there is no imaging modality or blood test that will give us information on treatment response during radiotherapy. Park et al. performed a feasibility study to see if changes on diffusion weighted MR images can be used as a biomarker for tumor response during radiotherapy, one drawback is that the study is done in visible tumors on MRI with the prostate in situ, while most patients following radical prostatectomy will have microscopic disease not visible on MRI [129]. Therefore, circulating DNA/RNA will give us information on effectiveness of radiotherapy during treatment, and if an extra dose is needed. This circulating tumor DNA/RNA will show in case of disease progression if tumors are changing their biology from moderate aggressive to highly aggressive disease. Even in a single patient different grades of tumors can be seen and targeting therapy to these different tumors with a multimodality approach will hopefully be possible. Another development is a more precise delivery of radiotherapy, especially in avoiding organs at risk during treatment. With MRI-based linear accelerators day to day variations and even variations during treatment will be visible, thereby making individualized plans based on real time information. This will help reducing toxicity even more.

Key issues

• Adjuvant radiotherapy following radical prostatectomy improves biochemical recurrence and overall survival in a pooled analysis of three randomized trials.

• There is growing evidence that salvage radiotherapy in case of PSA levels ≤0.5 ng/mL is as good as adjuvant radiotherapy, the ongoing RAVES and RADCIALS trials will give the final answers.

• The addition of 2 years of bicalutamide 150 mg to adjuvant radiotherapy gives a 5% survival benefit in patients treated with salvage radiotherapy following radical prostatectomy. The survival benefit was most evident in patients treated with high PSA levels.

• Even in low PSA levels between 0.2–0.5 ng/mL the detection rate to identify recurrences on PSMA-PET seems higher than choline-PET, with a detection rate of 57%.

• With new treatment techniques like IMRT high precision dose can be delivered without serious side effects.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

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