Salvage radiotherapy with or without hormonal therapy for biochemical recurrence after radical prostatectomy: A systematic review and meta-analysis.

RADICALS-HD: Reflections before the Results are Known

Assessing the Role and Optimal Duration of Hormonal Treatment in Association with Salvage Radiation Therapy After Radical Prostatectomy: Results from a Multi-Institutional Study

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Adding hormone therapy to definitive radiotherapy in localised prostate cancer improves overall survival, but whether it similarly improves overall survival in the context of postoperative radiotherapy (PORT) after radical prostatectomy is unclear. Herein, we report an individual patient data (IPD) meta-analysis of randomised trials aimed at quantifying the benefit of adding hormonal therapy to PORT. This was an IPD meta-analysis that identified randomised, phase 3 trials of PORT with or without hormone therapy. A systematic literature search of MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was done on Dec 15, 2024. IPD were available via the MARCAP consortium. The primary outcome was overall survival. Meta-analyses evaluated the benefit of adding hormone therapy, short-term hormone therapy (4-6 months), or long-term hormone therapy (24 months) to PORT. Tests for interaction based on pre-PORT prostate-specific antigen (PSA) and duration of hormone therapy were evaluated and non-linear associations between pre-PORT PSA and overall survival were modelled. This study was done under the master protocol of the MARCAP Consortium (PROSPERO registration CRD42019134376). IPD were available for six randomised trials including 6057 patients with a median follow-up of 9·0 years (IQR 7·2-10·7 years). Adding hormone therapy to radiotherapy did not significantly improve overall survival (hazard ratio [HR] 0·87, 95% CI 0·76-1·01, p=0·06). There was no significant interaction between hormone therapy duration and this effect (pinteraction=0·17), although there was a significant interaction with pre-PORT PSA greater than 0·5 ng/mL versus 0·5 ng/mL or less (pinteraction=0·02). For all pre-PORT PSA values, the upper bounds of the 95% CI of the HR for overall survival crossed 1·0 for patients randomly assigned to PORT with or without short-term hormone therapy (n=3938). For patients randomly assigned to PORT with or without long-term hormone therapy (n=1088), the upper bounds of the 95% CI for overall survival HR fell below 1·0 at PSA greater than 1·6 ng/mL. Our findings, we believe, provide the strongest level of evidence to date suggesting there might be no meaningful overall survival benefit to adding hormone therapy, either short-term or long-term hormone therapy, to PORT for PSA 0·5 ng/mL or less, with no apparent difference in efficacy for short-term versus long-term hormone therapy. There is an unmet need to identify biomarkers to predict potential hormone therapy benefit. National Institutes of Health.

Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit. To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982-2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n = 397), salvage radiotherapy alone (n = 160), or salvage radiotherapy combined with hormonal therapy (n = 78). Prostate cancer-specific survival defined from time of recurrence until death from disease. With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19-0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17-0.69]; P = .003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.

1. Prostate cancer-specific survival following salvage radiotherapy vs. observation in men with biochemical recurrence after radical prostatectomy: Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC, Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD

Positive Surgical Margins After Radical Retropubic Prostatectomy: The Influence of Site and Number on Progression

130 Background: To describe metastasis-free survival (MFS) in patients with biochemical recurrence following radical prostatectomy (RP), and to define clinical prognostic factors for metastasis. Methods: From our institutional database, 1,408 patients underwent primary RP between 2005 and 2011. Of these, 267 patients who had biochemical recurrence (two consecutive PSA ≥ 0.2 ng/mL) and had post-biochemical recurrence follow-up greater than 12 months were used as the study cohort. As an initial management for biochemical recurrence, salvage radiotherapy (SRT) combined with or without androgen deprivation therapy (ADT) was administered to 186 patients, while 33 patients received salvage ADT alone. Remaining 48 patients had been observed without any treatments. We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression. Results: Median follow-up after RP was 6.0 years, and after biochemical recurrence was 4.2 years. At last follow-up, 28 of 267 patients (10.5%) had developed metastasis, while 5-year MFS rate was 88.6%. No one developed metastasis in patients under observation. SRT resulted in an improved 5-year MFS rate (89.3% vs. 76.7%; p =0.022) compared with salvage ADT alone. This inferiority of salvage ADT alone compared with salvage SRT was marginally significant in the multivariate analysis (hazard ratio [HR] 2.24; 95% confidence interval [CI] 0.93–5.36; p = 0.071). Gleason score ≥8 (HR 4.10; 95% CI 1.77–9.51; p = 0.001) and seminal vesicle invasion (HR 2.37; 95% CI 1.06–5.30; p = 0.036) were significantly associated with MFS in the multivariate analysis. Conclusions: In patients undergoing prostatectomy, MFS after biochemical recurrence is variable and is most strongly influenced by Gleason score and seminal vesicle invasion. These parameters serve to stratify patients into different risk groups with respect to metastatic progression. Salvage ADT alone should be used with caution with select patients.

In this issue of CUAJ, the Genito-Urinary Radiation Oncologists of Canada (GUROC) group addresses several very important issues relating to salvage radiotherapy following biochemical relapse after radical prostatectomy.1 With the published results from the EORTC (European Organisation for Research and Treatment of Cancer) 229112 and SWOG (Southwest Oncology Group) 8794 (NCIC PR-2)3 studies and the recent update of the latter trial showing metastasis-free and overall survival benefit for adjuvant radiotherapy for pT3 disease,4 the questions relating to salvage radiotherapy deserve more discussion. A fundamental issue is the attitude of urologists toward the use of local salvage radiotherapy. There is a wide range of opinions among practitioners in various countries about whether radiotherapy should be recommended for prostate-specific antigen (PSA) relapse after radical prostatectomy, with those in favour ranging from 13% to 91%. A safe assumption is that the Canadian position is more moderate and intermediate. The dichotomy in practice pattern stems largely from the lack of evidence from randomized controlled trials. The GUROC consensus meeting included a discussion on 2 retrospective multi-institutional analyses by Stephenson and colleagues5,6 that revealed some surprising results. The 6-year progression-free probability was 32% for all participants, and even the most unfavourable group (those with a Gleason score of 8–10, negative margins or a serum PSA level doubling time of < 10 mo, i.e., those with a high probability of distant metastatic disease) had a 1 in 5 chance of achieving sustained progression-free response provided the local salvage radiotherapy was delivered when the serum PSA level was less than 2.0 μg/L. Remarkably, when such patients were treated when the serum PSA level was less than 0.5 μg/L, 41% were disease-free at 6 years. These findings have led to the very reasonable recommendation by the GUROC for much earlier referral for salvage radiation consideration, even for patients with high-risk features. Another potential consequence of earlier radiotherapy may be obviation or deferral of androgen ablation (demonstrated in the SWOG 8794, NCIC PR-2 adjuvant radiotherapy trial3,4), with the inherent benefits of avoiding hormonal therapy. Although multivariable analysis from the retrospective multicentre study suggested a benefit for neoadjuvant androgen ablation6 the role of adjunctive hormonal therapy with salvage radiotherapy remains unsettled. The upcoming MRC (Medical Research Council) (NCIC PR-13) study hopes to answer some of the questions, including the timing and duration of hormonal therapy. The trial design appears somewhat complicated and imposing at first glance, but is in fact very logical and straightforward, and by providing an opportunity for most radical prostatectomy patients to participate at some point in the variable clinical course, the MRC will hopefully maximize accrual and eventually provide some valuable answers. Sia and colleagues referred to the potential role of endorectal magnetic resonance imaging in guiding and planning salvage radiotherapy. Another imaging modality is the ProstaScint (Cytogen Corporation) capromab pendetide scan.7 More promising would be the fusion or coregistration of ProstaScint with another imaging modality such as CT.8,9 Ongoing studies with newer imaging techniques will assist radiation oncologist with making decisions about and fine-tuning salvage radiotherapy for the patient with biochemical relapse after radical prostatectomy. The recommendations by GUROC, with acceptance and participation from urologists, should clarify the role of salvage radiotherapy after radical prostatectomy.

BackgroundThe addition of endocrine therapy to salvage radiotherapy (SRT) is expected to further improve the prognosis of patients with biochemical recurrence of prostate cancer after radical prostatectomy (RP). The quantitative synthesis of clinical outcomes of SRT combined with endocrine therapy is limited. Whether salvage radiotherapy plus endocrine therapy remains inconclusive. We performed a systematic review and meta-analysis of existing randomized controlled trials to evaluate the efficacy and safety of salvage radiotherapy combined with endocrine therapy in patients with biochemical recurrence after radical prostatectomy.MethodsA systematic search of PubMed, EMBASE, and the Cochrane library was performed for articles published between January 1, 2012 and October 10, 2022. Data were analyzed using Review Manager 5.4.1 (Cochrane Collaboration Software). Main outcome and measures included biochemical progression-free survival (bPFS), metastasis free survival (MFS), overall survival (OS), and Grade 3 or higher adverse events (3+AEs), including acute and late adverse events.ResultsIn this systematic review and meta-analysis, 4 randomized controlled studies enrolling 2731 male (1374 of whom received SRT combined with endocrine therapy and 1357 controls) met the inclusion criteria. SRT combined with endocrine therapy were related to significantly improve bPFS (HR=0.52; 95% CI: 0.46 0.59; p<0.00001) and MFS (HR=0.75; 95% CI: 0.64 0.88; p<0.001). Compared with SRT alone, the combination therapy tended to be associated with prolong OS (HR=0.83; 95% CI: 0.69-1.01; p=0.06), but not statistically significant. At early follow-up, the risk of acute AEs was comparable in the two groups (RR=1.04; 95% CI: 0.22-4.85). However, the risk of late AEs was higher in the combination group at later follow-up (RR=1.33; 95% CI: 1.09-1.62).ConclusionsThis systematic review and meta-analysis found superior efficacy associated with adding endocrine therapy to SRT compared with SRT alone in patients with biochemical recurrence after RP. Additional endocrine therapy is safe and feasible for patients with biochemical recurrence after RP.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier (CRD42022365432).

Salvage radiotherapy (sRT) after radical prostatectomy (RP) is the standard of care treatment for prostate cancer (PCa) patients experiencing biochemical recurrence (BCR). Delivery of early sRT (initiated at prostate-specific antigen (PSA) level below 0.25 ng/mL) is associated with a reduction in all-cause mortality risk compared to men who received sRT when PSA levels are above this threshold [1] . Treatment intensification is needed for this latter group of patients and those with other unfavorable disease characteristics (such as a rapid PSA doubling time -PSA-DT and ISUP group ≥ 4) to improve clinical outcomes. In contrast to the primary radiotherapy setting, the benefit of hormone therapy in the sRT setting is less well-defined. Four randomized controlled trials (RCTs) investigated the benefit of adding hormone therapy to sRT (GETUG-AFU 16, RTOG 9601, SPPORT/RTOG 0534, RADICALS-HD). The GETUG-AFU 16 and SPPORT trials showed that the addition of a short-term androgen deprivation therapy (ADT) to sRT delays PSA progression-free survival (PFS). A post-hoc analysis of the GETUG-AFU 16 also demonstrated a 6% improvement in metastasis-free survival (MFS) at 5 and 10 years but no overall survival (OS) benefit [2] . The RTOG 9601 was the only RCT demonstrating an OS benefit from adding hormone therapy [3] . Interestingly, it didn't use ADT but bicalutamide 150 mg, a first-generation androgen receptor pathway inhibitor (ARPI) for two years. Twelve years OS was 76.3% in the bicalutamide group and 71.3% in the placebo group (HR 0.77; 95% CI 0.59-0.99; p = 0.04). Finally, RADICALS-HD randomized 2839 patients with BCR to postoperative RT with none, 6, or 24 months of ADT [4, 5] . The authors reported that adding 6 months of ADT to postoperative RT did not improve MFS compared with no ADT while adding 24 months of ADT improved MFS when compared to 6 months of ADT. The benefit remained marginal, with the 10-year MFS being 71.9% in the 6-month ADT group and 78.1% in the 24-month ADT group. Overall, the DADSPORT metaanalysis on these 4 trials showed no evidence of an OS benefit with hormone therapy vs. none, irrespective of whether 6 months or 24 months of hormonal suppression [6] . ARPI have profoundly impacted the management of metastatic PCa. Recent studies indicate that they will likely impact the treatment of high-risk localized PCa. Abiraterone increased OS of very high-risk or node-positive PCa treated by RT and ADT [7, 8] . In the EMBARK trial, enzalutamide, in monotherapy or with ADT, increased MFS of high-risk BCR patients, i.e. with a PSA-DT ≤ 9 months and a PSA ≥ 2 ng/mL above nadir after RT or ≥ 1 ng/mL after RP with or

Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer in the Context of Novel Therapies.

MP62-17 PREDICTIVE FACTORS OF OUTCOME FOLLOWING SALVAGE RADIOTHERAPY ALONE FOR PATIENTS WITH BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY

367 Background: Salvage radiotherapy (SRT) alone or in combination with androgen deprivation therapy (ADT) is the only curative treatment option for patients with biochemical recurrence after radical prostatectomy (RP) for prostate cancer. An undetectable post SRT PSA in patients without ADT (&lt;0.1 ng/ml) has been shown retrospectively to correlate significantly with long-term freedom from progression, metastasis free survival and overall survival. The aim of this study was to investigate whether the predictive power of a post SRT-nadir &lt;0.1 ng/ml extends to all subgroups of SRT patients. Methods: Between 1998 and 2018, 698 patients (all pN0/cN0) with persisting PSA or increasing PSA out of the undetectable range (&lt;0.1 ng/ ml) of two German university hospitals received SRT alone without ADT. Exclusion criteria were distant metastases and/or ADT in the interval between RP and/or in combination with SRT. ADT before RP was allowed. All patients received 3D-conformal or intensity-modulated SRT to a median dose of 70.2 Gy. The impact of post-SRT nadir &lt;0.1 ng/ml on biochemical progression free survival (BPFS), freedom from metastases (FFM) and on overall survival (OS) was analyzed by Kaplan-Meier analysis and multivariate Cox regression analysis. 9 subgroups with at least 30 patients per group were analyzed separately (pT2 + R0, pT3 + R0, pT3 + R1, pT2 + Gleason Score ≤ 7, pT3 + Gleason Score ≤ 7, pT3 + Gleason Score ≥ 8, pT3 + Gleason Score ≥ 7 + R1, pT3 + Gleason Score ≥ 7 + pre-SRT-PSA-Wert ≤1,0 ng/ ml and pT2/3 + Gleason Score ≥ 8 + pre-SRT-PSA-Wert ≤1,0 ng/ ml). Results: Median follow-up was 5.6 years. Median PSA before SRT was 0.30 ng/ ml. A post SRT PSA &lt;0.1ng/ml was achieved by 76.6% of patients. In univariate analysis of the entire cohort, post SRT PSA &lt;0.1 ng/ ml was a significant predictor of BPFS (p&lt;0.001), FFM (p&lt;0.001) and OS (p=0.01). Regarding univariate analysis of the subgroups, post SRT PSA &lt;0.1ng/ml was a significant predictor of BPFS in all subgroups (p&lt;0.001), FFM in 6 subgroups (p&lt;0.001 to p=0.03) and for OS in 3 subgroups (p&lt;0.001 to p=0.02). In multivariate analysis of the entire cohort, post-SRT PSA &lt;0.1ng/ml was an independent predictor for BPFS (HR: 7.25, 95%-CI: 5.36-9.81, p&lt;0.001), FFM (HR: 4.21, 95%-CI: 2.00-8.84, p=0.002) and OS (HR: 2.59, 95%-CI: 1.28-5.23, p=0.008). Conclusions: Achieving an undetectable PSA after SRT is an independent predictor of BPFS, FFM and OS. This effect is present in subgroups with favorable (pT2+Gleason score ≤ 7) as well as in those with unfavorable characteristics (pT3+ Gleason score &gt;8). Our findings indicate that ADT could be withheld in a proportion of patients that are candidates for ADT based on their risk factors but achieve an undetectable PSA after SRT. Prospective studies are needed to confirm these results.

To evaluate the oncological outcome and to assess prognostic factors of salvage radiotherapy alone in patients with biochemical recurrence after radical prostatectomy. We reviewed our single institution, prospectively maintained database of 2043 patients who underwent radical prostatectomy between September 1995 and December 2011. In this cohort, 149 patients who developed biochemical recurrence after radical prostatectomy and received salvage radiotherapy alone after pelvic magnetic resonance imaging were included. Three-dimensional conformal radiotherapy or intensity-modulated radiotherapy was delivered with a median dose of 70.0 Gy (66.0-78.0 Gy) or 67.2 Gy (64.8-70.0 Gy). Kaplan-Meier and Cox regression analyses were carried out. With a median follow up of 82 months (range 20-153 months), 55 patients (36.9%) failed salvage radiotherapy. The 5-year salvage radiotherapy failure-free probability was 53.6%. On multivariate analysis, pre-salvage radiotherapy prostate-specific- antigen ≥ 1.0 ng/mL (P = 0.003, hazard ratio 3.592, 95% confidence interval 1.522-8.579), pathological stage ≥ T3a (P = 0.004, hazard ratio 2.261, 95% confidence interval 1.290-3.833), pathological Gleason score ≥ 7 (P = 0.018, hazard ratio 5.501, 95% confidence interval 1.577-21.221), prostate-specific antigen doubling time < 12 months (P = 0.014, hazard ratio 2.243, 95% confidence interval 1.177-4.275) and no visible lesion on pelvic magnetic resonance imaging (P = 0.016, hazard ratio 2.068, 95% confidence interval 1.268-3.501) were independent prognostic factors of salvage radiotherapy failure after radical prostatectomy. Pre-salvage radiotherapy prostate-specific antigen ≥ 1.0 ng/mL, pathological stage ≥ T3a, pathological Gleason score ≥ 7, prostate-specific antigen doubling time < 12 months and no visible lesion on pelvic magnetic resonance imaging are prognostic factors of salvage radiotherapy failure after radical prostatectomy. We should consider additional treatment in patients with these factors for favorable outcomes.