pre-SRT Prostate-specific Antigen Research Articles

Undetectable PSA predicts outcome after salvage radiotherapy for biochemical recurrence following radical prostatectomy

Background and purposeSalvage radiotherapy (SRT) is a curative treatment option in patients with biochemical recurrence after radical prostatectomy (RP). Undetectable prostate-specific antigen (PSA) < 0.1 ng/mL following SRT predicts biochemical progression-free survival (BPFS). The aim of this large retrospective study was to evaluate whether this effect persists in an extended follow-up of >5 years. Materials and methodsA total of 678 patients treated with SRT for biochemical recurrence after RP were included. Exclusion criteria were lymph node or distant metastases, pre-SRT PSA > 3 ng/mL, and receipt of androgen deprivation therapy (ADT) between RP and SRT. All patients received a median dose of 70.2 (range 59.4–72.0) Gy to the prostatic fossa. The log-rank test (Kaplan–Meier) and Cox regression analysis were used to evaluate the impact of disease- and treatment-related parameters on BPFS, metastasis-free survival (MFS), and overall survival (OS). ResultsMedian follow-up after SRT was 5.6 (range 0.1–14.5) years. The 5-year BPFS was 77.8 % in patients with a PSA nadir < 0.1 ng/mL (undetectable) and 16.3 % in the remaining cohort (p < 0.001). Five-year MFS was 95.3 % with undetectable PSA versus 84.0 % with detectable PSA (p < 0.001), and 5-year OS values were 97.5 % and 92.7 % with undetectable versus detectable PSA, respectively (p = 0.04). In multivariate analysis, undetectable PSA was the strongest predictor of BPFS (HR = 0.122; 95 %CI: 0.080–0.187; p < 0.001) and MFS (HR = 0.262; 95 %CI: 0.136–0.594; p < 0.001), but was not significant for OS (HR = 0.615; 95 %CI: 0.298–1.269; p = 0.189). ConclusionPSA < 0.1 ng/mL following SRT without ADT is a significant predictor of BPFS and MFS. The results suggest that it might be feasible to withhold ADT in selected patients if they have undetectable PSA after SRT. Prospective studies are warranted to confirm these findings.

Salvage Radiotherapy for Relapsed Prostate Cancer after Radical Prostatectomy Is Associated with Normal Life Expectancy

In patients with prostate cancer (PCa), salvage radiotherapy (SRT) for biochemical progression (BP) after radical prostatectomy (RP) improves PCa-specific survival. However, no prospective randomized trials have compared the effect of SRT with untreated patients. In this analysis of 151 patients who received SRT for post-RP BP, we compared their overall survival (OS) with virtual, age-matched controls (n = 151,000) retrieved from government life tables. We also investigated the risk factors associated with BP and OS and compared the prostate-specific antigen (PSA) doubling times (DTs) before and after SRT for patients with BP. The median follow-up was 9.3 years for BP and 17.4 years for OS. The risk factors significantly affecting BP were Gleason score (p &lt; 0.001), pre-SRT PSA (p = 0.003), and negative surgical margins (p = 0.003). None of these risk factors were associated with OS. In 93 patients with BP after SRT, the median PSADT was significantly prolonged compared with pre-SRT values (3.7 vs. 8.3 months, p &lt; 0.001). The OS did not differ between patients and controls (p = 0.112), and life expectancy was similar, likely due to the survival benefit of SRT. The prolonged PSADT after SRT further supports the beneficial role of SRT in this patient population. However, subsequent treatments were not systematically recorded, which may have affected the results.

Predictive factors for disease progression after salvage radiation therapy in biochemical recurrent patients treated by radical prostatectomy.

Salvage radiation therapy (SRT) is standard treatment for patients after radical prostatectomy (RP). However, the optimal timing of SRT remains to be elucidated. We retrospectively reviewed 133 prostate cancer (PCa) patients who underwent SRT for biochemical recurrenceafter RP. Disease progression was defined as repeated prostate-specific antigen (PSA) level more than 0.2ng/mL, greater than the post-SRT nadir or radiographic progression. A receiver operating characteristic curve analysis was used to identify the optimal pre-SRT PSA level for predicting progression after SRT. Cox regression analyses were performed to elucidate the association between clinicopathologic characteristics and disease progression. Fifty-one PCa patients (38.4%) experienced disease progression after SRT. The optimal cutoff value of the pre-SRT PSA for predicting disease progression was 0.44ng/mL. In multivariable analysis, pre-SRT PSA >0.44ng/mL was a significant independent predictor of post-SRT disease progression [hazard ratio (HR): 2.02, P=0.02]. Although the pre-SRT PSA >0.44ng/mL did not maintain its independent association with disease progression in the multivariable analysis of patients with adverse pathology (HR: 1.63, P=0.22), PSA within 4weeks after RP as a continuous variable was significantly associated with disease progression (HR: 1.19, P=0.04). Our results highlight thatin PCa patients who undergo RP, SRT should be performed before their PSA reaches 0.44ng/mL. In patients with adverse pathology disease, a high PSA level within the 4weeks after RP might identify those who are likely to have disease progression, andthese patients might require systemic therapy.

Multi-institutional Development and External Validation of a Machine Learning Model for the Prediction of Distant Metastasis in Patients Treated by Salvage Radiotherapy for Biochemical Failure After Radical Prostatectomy

BackgroundUp to 40% of patients with prostate cancer may develop biochemical recurrence after surgery, with salvage radiation therapy (SRT) being the only curative option. In 2016, Tendulkar et al. (Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J Clin Oncol 2016;34:3648–54) published a nomogram to predict distant metastasis in a cohort of patients treated with SRT with pre-SRT prostate-specific antigen (PSA) of 0.5 ng/ml after radical prostatectomy. In modern practice, SRT is delivered at lower PSA values. ObjectiveTo train and externally validate a machine learning model to predict the risk of distant metastasis at 5 yr in a contemporary cohort of patients receiving SRT. Design, setting, and participantsWe trained a machine learning model on data from 2418 patients treated with SRT at one institution, with a median PSA value of 0.27 ng/ml. External validation was done in 475 patients treated at two different institutions. Patients with cM1, pN1, or pT4 disease were excluded, as were patients with PSA >2 ng/ml or PSA 0, and patients with radiation dose <60 or ≥80 Gy. Outcome measurements and statistical analysisModel performance was assessed using calibration and time-dependent area under the receiver operating curve (tAUC). Results and limitationsOur model had better calibration and showed improved discrimination (tAUC = 0.72) compared with the Tendulkar model (tAUC = 0.60, p < 0.001). The main limitations of this study are its retrospective design and lack of validation on patients who received hormone therapy. ConclusionsThe updated model can be used to provide more individualized risk assessments to patients treated with SRT at low PSA values, improving decision-making. Patient summaryUp to 40% of patients with prostate cancer may develop biochemical recurrence after surgery, with salvage radiation therapy as the only potentially curative option. We trained and validated a machine learning model using clinical and surgical data to predict a patient’s risk of distant metastasis at 5 yr after treatment. Our model outperformed the reference tool and can improve clinical decision-making by providing more personalized risk assessment.

The impact of salvage radiotherapy initiation at PSA ≤ 0.5 ng/mlon metastasis-free survival in patients with relapsed prostate cancer following prostatectomy.

Salvage radiation therapy (SRT) is indicated for biochemical failure after radical prostatectomy. Prior data have shown that initiation of SRT at lower PSA levels improves subsequent biochemical control, yet given the long natural history of prostate cancer questions remain regarding optimal timing of SRT. We analyzed the impact of prostate specific antigen (PSA) level at time of salvage radiotherapy with regard to both biochemical relapse-free (bRFS) as well as metastasis-free survival (MFS) in patients with biochemically recurrent prostate cancer. Using prospective institutional tumor registry data, univariate and multivariable-adjusted Cox proportional hazards models were constructed to assess association between outcomes and clinical and pathologic prognostic features, including pre-SRT PSA, interval from prostatectomy to SRT, androgen deprivation therapy (ADT), and adverse pathologic features. We identified 397 patients who received salvage RT between 1985 and 2016: 187 (45.8%) received SRT initiated when pre-RT PSA was ≤0.5 ng/ml; 212 (52.0%) patients had pre-SRT PSA > 0.5 ng/ml. Independent of pathologic risk status and ADT use, pre-SRT PSA ≤ 0.5 ng/mlwas the most significant predictor of bRFS (HR 0.39, 95% CI [0.27, 0.56]) as well as MFS (HR = 0.58, 95% CI [0.37, 0.91]). Seminal vesicle invasion was also associated with shorter interval to biochemical failure, HR = 1.79, 95% CI [1.07, 2.98], and eventual metastases, HR = 2.07, 95% CI [1.14, 3.740]. Initiation of salvage RT while PSA levels remain ≤0.5 ng/ml was associated with improved MFS. Consideration for salvage RT initiation while PSA levels remain low is warranted to minimize risk of future prostate cancer metastasis.

Anti-Androgen Therapy Overcomes the Time Delay in Initiation of Salvage Radiation Therapy and Rescues the Oncological Outcomes in Men with Recurrent Prostate Cancer After Radical Prostatectomy: A Post Hoc Analysis of the RTOG-9601 Trial Data.

BackgroundIt is unknown whether the addition of anti-androgen therapy (AAT) to late salvage radiation therapy (sRT) can lead to oncological outcomes equivalent to that of early sRT in men with recurrent prostate cancer (CaP) after surgery.MethodsData on 670 men who participated in the Radiation Therapy Oncology Group (RTOG)-9601 trial and who experienced biochemical recurrence were extracted using the National Clinical Trials Network (NCTN) data archive platform. Patients were stratified into four treatment groups: early sRT (pre-sRT prostate-specific antigen [PSA] < 0.7 ng/mL) and late sRT (pre-sRT PSA ≥ 0.7 ng/mL) with/without concomitant AAT, based on cut-offs reported in the original trial. Time-varying Cox proportional hazards and Fine–Gray competing-risk regression analyses assessed the adjusted hazards of overall mortality, CaP-specific mortality, and metastasis among the four treatment groups.ResultsAt 15-years (median follow-up of 14.7 years), for patients treated with early sRT, early sRT with AAT, late sRT, and late sRT with AAT, the overall mortality, CaP-specific mortality, and metastasis rates were 22.9, 22.8, 40.1, and 22.9% (log-rank p = 0.0039), 12.1, 3.9, 22.7, and 8.0% (Gray’s p = 0.0004), and 18.8, 14.6, 35.9, and 19.5% (Gray’s p = 0.0004), respectively. Time-varying multivariable adjusted analysis demonstrated increased hazards of overall mortality in patients receiving delayed sRT versus early sRT (hazards ratio [HR] 1.49, 95% confidence interval [CI] 1.02–2.17); however, no difference remained after the addition of concomitant AAT to late sRT (HR 0.85, 95% CI 0.55–1.32, referent early sRT). Likewise, the hazards of cancer-specific mortality and metastatic progression were worse for late sRT when compared with early sRT, but were no different after the addition of AAT to late sRT.ConclusionsPoorer outcomes associated with late sRT in men with recurrent CaP may be rescued by delivery of concomitant AAT.

Clinical Outcome of Salvage Radiotherapy for Locoregional Clinical Recurrence After Radical Prostatectomy.

Objectives: To assess the clinical outcomes of prostate cancer patients treated with salvage radiotherapy (SRT) for locoregional clinical recurrence (CR) after radical prostatectomy (RP). Methods: Records of 60 patients with macroscopic locoregional recurrence after prostatectomy and referrals for SRT were retrospectively investigated in the multi-institutional database. The median radiation dose was 70.2 Gy. Biochemical failure was defined as the prostate-specific antigen (PSA) ≥ nadir + 2 or initiation of androgen deprivation therapy (ADT) for increased PSA. Results: Median recurrent tumor size was 1.1 cm and pre-radiotherapy PSA level was 0.4 ng/ml. At a median follow-up of 83.1-month after SRT, 7-year biochemical failure-free survival (BCFFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were 67.0%, 89.7%, 83.6%, and 91.2%, respectively. Higher Gleason's scores were associated with unfavorable BCFFS, DMFS, and OS. Pre-SRT PSA ≥0.5 ng/ml predicted worse BCFFS, LRFFS, and DMFS. In multivariate analyses, a Gleason's score of 8 to 10 was associated with decreased BCFFS (hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.11-8.74, P = .031) and OS (HR 17.72, 95% CI 1.75-179.64, P = .015), and combined ADT decreased the risks of distant metastasis (HR 0.18, 95% CI 0.04-0.92, P = .039). Two patients (3.3%) experienced late grade 3 urinary toxicity. Conclusions: SRT for locoregional CR after RP achieved favorable outcomes with acceptable long-term toxicities. Higher Gleason's scores and pre-radiotherapy PSA level were unfavorable prognostic variables. Combined ADT may decrease the risks of metastases.

Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer

In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05). These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. ClinicalTrials.gov Identifier: NCT00002874.

Salvage Radiotherapy for Recurrent Prostate Cancer: Can the Prognostic Grade Group System Inform Treatment Timing?

In order to better time salvage radiotherapy (SRT) for post-radical prostatectomy biochemical failure, we examined the association between pre-SRT prostate-specific antigen (PSA) and PSA control as a function of the new prognostic grade group (PGG) system. Using the Shared Equal Access Regional Cancer Hospital database, we identified men after radical prostatectomy with PSA > 0.2 ng/mL and without cancer involvement of lymph nodes who underwent SRT alone. SRT failure was defined as post-SRT PSA nadir+ 0.2 ng/mL or receipt of post-SRT hormone therapy. Men were stratified by pre-SRT PSA (0.2-0.49, 0.5-0.99, and≥ 1.0 ng/mL). Multivariable Cox models were used to test the association between pre-SRT PSA and SRT failure, stratified by PGG. A total of 358 men met the inclusion criteria and comprised our study cohort. Median post-SRT follow-up was 78 months. A total of 174 men (49%) had pre-SRT PSA 0.2-0.49 ng/mL, 97 (27%) PSA 0.5-0.99 ng/mL, and 87 (24%) PSA≥ 1.0 ng/mL. On multivariable analysis among men with PGG 1-2, pre-SRT PSA 0.2-0.49 ng/mL had similar outcomes as PSA 0.5-0.99 ng/mL; those with PSA≥ 1.0 ng/mL had higher recurrence risks (hazard ratio= 2.78, P< .001). Among PGG 3-5, PSA 0.5-0.99 ng/mL or≥ 1.0 ng/mL had a higher recurrence risk (hazard ratio= 2.15, P= .021; and hazard ratio= 2.49, P= .010, respectively) versus PSA 0.2-0.49 ng/mL. In men with higher-grade prostate cancer (PGG 3-5), SRT should be provided earlier (PSA< 0.5 ng/mL), while among men with lower-grade disease (PGG 1-2), SRT results in equal PSA control up to PSA 1.0 ng/mL.

Salvage radiotherapy for biochemical recurrence after radical prostatectomy: does the outcome depend on the prostate cancer characteristics?

ABSTRACTObjective:To build a model to evaluate the impact of salvage radiotherapy (SRT) in men with PSA rise or persistent PSA after undergoing radical prostatectomy (RP).Materials and Methods:The study included 107 node-negative patients treated with SRT after RP at a single institution. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP. All patients received local radiation to the prostate / seminal vesicle bed. The primary measured outcome was the biochemical recurrence (BCR) free survival. Multivariable Cox regression analysis was used to develop a risk-stratification group to identify predictive factors associated with the probability of BCR at 5yr.Results:At a median follow-up of 52 months, the BCR free survival rate and overall survival in 5 years was 73% and 94%, respectively. At multivariable analysis, pre-SRT PSA level > 0.35ng / mL (p = 0.023), negative margins (p = 0.038), and seminal vesicles invasion (p = 0.001) were significantly associated with BCR free survival. Three risk groups using regression analysis for SRT administration was built. Low-, intermediate- and the high-risk groups had a BCR free survival in 5-years of 96%, 84%, and 44% (p = 0.0001), respectively.Conclusions:We developed a risk group stratification to show the impact of SRT based on prostate cancer characteristics. SRT showed to be extremely beneficial for patients with low- and intermediate-risk tumors. Moreover, the risk-group built could identify patients classified as high-risk who might benefit from more aggressive treatment for SRT.

Disease Control With Delayed Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy.

Purpose: To retrospectively assess clinical outcomes and toxicity profile of prostate cancer patients treated with delayed dose-escalated image-guided salvage radiotherapy (SRT) for macroscopic local recurrence after radical prostatectomy (RP).Material and Methods: We report on a cohort of 69 consecutive patients with local recurrence after RP and no evidence of regional or distant metastasis who were referred for salvage radiotherapy between 2007 and 2016. SRT consisted of 64–66 Gy (2 Gy/fraction) to the prostatic bed followed by dose escalation to 72–74 Gy (2Gy/fraction) to the macroscopic disease. All patients received concurrent short-term androgen deprivation therapy (ADT). Biochemical recurrence-free survival (bRFS) and clinical progression-free-survival (cPFS) were depicted using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predictors of survival outcomes. Baseline, acute, and late urinary and gastrointestinal (GI) toxicity rates were reported using CTCAE v4.03.Results: Median time from RP to SRT was 66 months (IQR: 32–124). Median pre-SRT prostate-specific antigen (PSA) was 2.7 ng/ml (IQR: 0.9–6.5). Median follow-up after SRT was 38 months (IQR: 24–66). The 3- and 5-year bRFS were 58 and 44%, respectively. The 3- and 5-year cPFS were 91 and 76%, respectively. Median time from SRT to clinical disease progression was 102 months (IQR 77.5–165). At baseline, 3 patients (4%) had grade 3 urinary symptoms. Six patients (9%) developed acute and six patients (9%) developed late grade 3 urinary toxicity. Five patients (7%) had acute grade 2 GI toxicity. No acute grade 3 GI toxicity was reported. Late grade 3 GI toxicity was reported in one patient (1.5%).Conclusions: Delayed dose-escalated SRT combined with short-course ADT for macroscopic LR after RP was associated with 44% bRFS and 76% cPFS at 5 years. Albeit improved patient stratification is warranted, these data suggest that delayed SRT provides inferior tumor control compared to early intervention.

Salvage radiation therapy for prostate cancer patients after prostatectomy

The aim of this study was to identify risk factors to predict a biochemical recurrence (BCR) in patients treated with salvage radiation therapy (SRT) after radical prostatectomy (RP). We retrospectively reviewed 122 Japanese patients who received SRT for BCR after RP. Using uni- and multivariate Cox proportional hazard models, we identified the predictive factors of BCR after SRT. With a median follow-up of 61.3 months, 45.9% of the patients showed BCR after SRT, with 61.5 and 41.8% of non-BCR rates at the second and fifth years. Univariate proportional hazards analysis demonstrated that extraprostatic disease (P = 0.029), seminal vesicle invasion (P = 0.005), microvascular invasion (P = 0.001), postoperative Gleason score (P = 0.008) and pre-SRT prostate-specific antigen (PSA) (P = 0.005) were significantly associated with BCR after SRT. However, only the presence of microvascular invasion and a higher pre-SRT PSA were significant predictors in the multivariate analysis. The non-BCR rate in the second year after SRT for 15 patients with microvascular invasion and pre-SRT PSA > 1.2 ng/ml was only 21% compared to 72.5% of 72 patients with negative microvascular invasion and a pre-SRT PSA of <1.2 ng/ml (P = 0.000031). While SRT is the most important secondary treatment option for patients with BCR after RP, the effectiveness of SRT may not be uniform. The combination of risk factors such as microvascular invasion in RP specimens and pre-SRT PSA may provide a better way to stratify the risk of BCR after SRT.

Evaluating the Impact of Lead-Time Bias on the Observed Efficacy of Early Salvage Radiation Therapy in Prostate Cancer: A Post-Hoc Analysis of the RTOG 9601 Trial

Background: To evaluate the potential impact of lead-time bias on the reported beneficial role of early salvage radiotherapy (sRT), defined as delivering radiation at a relatively low pre-sRT prostate-specific antigen (PSA) value, in treating prostate cancer patients with biochemical recurrence after radical prostatectomy (RP). Methods: All available demographic, tumor-specific, and overall survival data from 760 men who participated in the RTOG 9601 trial were extracted using the Project Data Sphere platform. Patients were stratified based on pre-sRT PSA ( 1.5-4.0 ng/mL [n=118]) as reported in the original trial. Cox regression analysis assessed the impact of pre-sRT PSA on overall mortality, after controlling for covariates. To ascertain the role of lead-time bias, survival time zero was set to the time of (1) initiation of sRT, and (2) RP. Findings: There were no statistically significant differences amongst men within the three groups, except for a greater proportions of African-American patients and men with post-RP PSA nadirs ≥0.5 ng/mL within the higher pre-sRT PSA groups. For men with pre-sRT PSA 1.5-4 ng/mL, estimated 15-year overall mortality was 39%, 45%, and 50%, respectively (p=0.005) when calculated from time since sRT, and 23%, 29%, and 36% respectively (p=0.08) when assessed from time since RP. On multivariable regression analyses, pre-sRT PSA >1.5-4.0 ng/mL was significantly associated with overall mortality only when measured from time of initiation of sRT (HR 1.61, 95% confidence interval [CI] 1.13-2.28; p=0.008), but not from time since RP (HR 1.24, 95% CI 0.87-1.76; p=0.2). Interpretation: Our findings suggest that the putative survival benefit with early sRT instituted at lower PSA thresholds is mitigated when measured from time since surgery, highlighting the role of lead-time bias. These findings need further validation given their significant clinical implications. Funding Statement: There was no funding for this study. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Declaration of Interests: Firas Abdollah is a consultant for GenomeDx Biosciences. Ethics Approval Statement: An institutional review board waiver was obtained before the study was conducted, in accordance with institutional regulation when dealing with de-identified previously collected data.

Outcomes of salvage radiotherapy for recurrent prostate cancer after radical prostatectomy.

Salvage radiotherapy (SRT) provides effective biochemical control for patients with prostate cancer who have prostate specific antigen (PSA) failure after radical prostatectomy. However, the effect of SRT on long-term clinical outcomes remains unknown. Therefore, we report the natural history of patients treated with SRT. We identified 84 Chinese patients with prostate cancer treated with SRT to the prostatic fossa alone during 2006-2017 at Tuen Mun Hospital, Hong Kong. Survival was calculated using Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters with outcomes. Median SRT dose given was 70 Gy (range, 64-76 Gy). Median pre-SRT PSA level was 0.4 ng/mL (0.2-7.4 ng/mL). After SRT, 47 (56%) patients had undetectable (<0.1 ng/mL) PSA levels. After median follow-up of 48 months (2 months to 10 years), 25 (30%) patients had further biochemical progression. Subsequently, 12 patients received androgen deprivation therapy and nine (11%) developed distant metastasis. The 5-year biochemical progression-free survival, androgen deprivation therapy-free survival and metastasis-free survival were 62.7%, 83.5% and 86.7%, respectively. Early PSA failure after radical prostatectomy (hazard ratio 7.4), negative surgical margin (hazard ratio 2.7), positive extracapsular extension (hazard ratio 4.6), and detectable PSA levels after SRT (hazard ratio 17.3) were associated with lower biochemical progression-free survival after SRT. High-dose SRT with intensity-modulated radiotherapy/volumetric modulated arc radiotherapy is an effective local treatment that can prevent distant metastasis and avoid the need for androgen deprivation therapy in Chinese patients who have PSA failure after radical prostatectomy.

Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy.

Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago. In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters. The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y). Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.

Prostate-specific antigen after salvage radiotherapy for postprostatectomy biochemical recurrence predicts long-term outcome including overall survival

Background: For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) is a second chance of cure. However, depending on risk factors, 40–70% of the patients experience further progression. With a focus on the pre- and post-SRT serum level of the prostate-specific antigen (PSA), we assessed the determinants of the long-term outcome after SRT.Patient and methods: Between 1997 and 2011, 464 patients received 3D-conformal SRT with median 66.6 Gy. The median PSA level before SRT was 0.31 ng/ml. In our retrospective analysis, post-SRT progression was defined as either a rising PSA >0.2 ng/ml above the nadir, or the application of anti-androgens or clinical recurrence. A PSA <0.1 ng/ml was termed undetectable. We analyzed the data with the Kaplan–Meier method (Logrank test) and multivariable Cox regression.Results: The median follow-up was 5.9 years. Overall, 178 patients had recurrence, 13 developed distant metastases and 30 died. Univariate, a pre-RP PSA <10 ng/ml, pathological stage pT <3, Gleason score <8, positive surgical margins, a pre-SRT PSA <0.2 ng/ml and a post-SRT PSA nadir <0.1 ng/ml correlated with fewer and later second recurrences. In a multivariable Cox model, pT, Gleason score, margin status and pre-SRT PSA were significant covariates of progression. If the post-SRT PSA response was included in the regression analysis, then a nadir ≥0.1 ng/ml was the strongest risk factor. Initiating SRT at a PSA <0.2 ng/ml correlated with a post-SRT PSA <0.1 ng/ml. Men who achieved an undetectable post-SRT PSA nadir also had lower rates of metastases and a better overall survival. However, there were too few events for Cox regression analysis of these two endpoints.Conclusions: Early SRT at a PSA <0.2 ng/ml correlates with re-achieving an undetectable PSA, which predicts improved freedom from progression and metastases and better overall survival.

Risk Factors for Disease Progression After Postprostatectomy Salvage Radiation: Long-term Results of a Single-institution Experience.

Salvage radiotherapy (SRT) has been successfully used for recurrent prostate cancer after radical prostatectomy; however, the optimal timing of SRT remains controversial. Our objective was to identify the risk factors for disease progression after SRT, with a focus on the pre-SRT prostate-specific antigen (PSA) levels in the modern era of PSA testing. We performed a retrospective review of 551 consecutive patients who had undergone postradical prostatectomy SRT for recurrent prostate cancer from 2000 to 2013. The exclusion criteria were hormonal therapy before or concurrent with SRT, adjuvant RT, distant metastases, and missing data. Disease progression was defined as a repeat PSA level of≥ 0.2 ng/mL greater than the post-SRT nadir, a continued increase in the PSA level despite SRT, initiation of systemic therapy, local recurrence, nodal failure, and/or distant metastases. Univariate and multivariable Cox regression analysis were performed to identify the predictors of disease progression. Secondarily, PSA kinetics were evaluated in the model and compared using the Akaike information criterion. Of the 551 patients, 307 underwent SRT, of whom 134 experienced subsequent disease progression. The median interval to recurrence was 6.03 years (95% confidence interval, 3.74-8.36 years). On multivariable analysis, Gleason score, Tstage, positive surgical margins, and pre-SRT PSA level were associated with progression; PSA kinetics did not independently predict for progression. When the pre-SRT PSA level was stratified (≤ 0.30, 0.31-0.50, 0.51-1.00, and > 1 ng/mL), incremental elevations were associated with an increased risk of disease progression. Multiple factors predict for progression after SRT. These risk factors could help identify those who would derive the greatest benefit from additional systemic treatment. The findings of the present study also support initiation of early SRT, irrespective of the PSA kinetics.

Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy

BackgroundSalvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. ObjectiveWe aimed to identify the optimal candidates for early SRT after RP. Design, setting, and participantsThe study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. Outcome measurements and statistical analysisThe primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. Results and limitationsAt a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.06, p<0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. ConclusionsWe developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. Patient summaryIn patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified.

Improved Metastasis-Free and Survival Outcomes With Early Salvage Radiotherapy in Men With Detectable Prostate-Specific Antigen After Prostatectomy for Prostate Cancer.

Purpose To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify associations with outcomes. Patients and Methods A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < .05 for retention. Results In multiple variable analyses, pathologic tumor stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P < .001), DM (HR, 1.32; P < .001), CSM (HR, 1.40; P < .001), and all-cause mortality (HR, 1.12; P = .02). Using a pre-SRT PSA cutoff ≤ 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% ( P < .001), DM 7% versus 14% and 13% versus 25% ( P < .001), CSM 1% versus 4% and 6% versus 13% ( P < .001), and OS of 94% versus 92% and 83% versus 73% ( P > .05). Conclusion SRT outcomes are in part affected by factors associated with prostatectomy findings but may be positively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all-cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT.

Prostate Cancer–Specific Mortality and Survival Outcomes for Salvage Radiation Therapy After Radical Prostatectomy

Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. Using a consortium database including data from 10 academic institutions, we assessed the impact of SRT initiation at lower prostate specific antigen (PSA) levels on prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM). In this IRB-approved retrospective study, 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA (≥0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (n/c ADT) were included. Exclusion criteria included previous ADT or incomplete treatment, staging, or follow up details. Cumulative incidence method of Fine-Gray and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression (CRR) and Cox proportional hazards (CPH) methods for PCSM and ACM, respectively. Median follow-up was 5.1 years following SRT end-date; 597 pts (24%) had pathologic Gleason score (GS) of ≤6, 1383 (56%) GS 7, and 474 (19%) GS ≥8. There were 1365 (56%) with extraprostatic extension, 451 (18%) seminal vesicle invasion, 1430 (58%) positive surgical margins, and 390 (16%) received n/c ADT for a median of 6 months. Median age at RP and SRT were 61 years (IQR = 56-66) and 64 years (59-69), respectively. Median SRT dose to the prostate bed was 66 Gy (IQR = 64.8-68) and median pre-SRT PSA was 0.5 ng/mL (IQR = 0.3-1.1). The 5 and 10-year PCSM rates were 3% and 6%, respectively. The 10 year PCSM rate was 5% for pre-SRT PSA ≤0.2 ng/mL, 6% for 0.21-0.50 ng/mL, 8% for 0.51-1.0 ng/mL, 18% for 1.01-2.0 ng/mL, and 22% for >2.0 ng/mL, P < 0.0001. The 5 and 10-year ACM rates were 7% and 23%, respectively, and at 10 years was 14% for pre-SRT PSA ≤0.2, 16% for 0.21-0.50, 23% for 0.51-1.0, 30% for 1.01-2.0, and 38% for >2.0, P < 0.0001. On MVA, higher pre-SRT PSA (HR = 2.13, P < 0.0001), higher GS (GS 7 vs. ≤6: HR = 2.01, P = 0.0012; GS ≥8 vs. 6: HR = 3.34, P < 0.0001), seminal vesicle invasion (HR = 2.48, P < 0.0001), and year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR = 2.87, P = 0.021, HR = 2.50, P = 0.0097, HR = 3.58, P = 0.0016, respectively) were significantly associated with higher PCSM, while extraprostatic extension, surgical margins, ADT use, SRT dose, age at SRT, and age at RP were not. These same variables were significantly associated with higher ACM on MVA, in addition to advanced age at RP (HR = 1.06, P < 0.0001). Initiation of early SRT at low PSA levels compared to higher PSA levels following RP is associated with reduced risk of PCSM and ACM. Other factors significantly associated with PCSM include higher GS, seminal vesicle invasion, and earlier year of SRT.