post-RP Prostate-specific Antigen Research Articles

Radiotherapy after radical prostatectomy for prostate cancer: clinical outcomes and factors influencing biochemical recurrence.

Radiotherapy (RT) after radical prostatectomy (RP) includes adjuvant radiotherapy (ART) and salvage radiotherapy (SRT), which can prevent or cure biochemical recurrence. To evaluate long-term outcomes of RT after RP and to examine factors affecting biochemical recurrence-free survival (bRFS). Sixty-six received ART and 73 received SRT between 2005 and 2012 were included. The clinical outcomes and late toxicities were evaluated. Univariate and multivariate analyses were performed to examine factors affecting bRFS. Median follow-up from RP was 111months. Five-year bRFS and 10-year distant metastasis-free survival from RP were 82.8% and 84.5% in ART, and 74.6% and 92.4% in SRT, respectively. The most frequent late toxicity was hematuria, which was higher in ART (p = .01). No recurrence within RT field was occurred. On univariate analysis, pelvic RT was associated with favorable bRFS in ART (p = .048). In SRT, post-RP prostate-specific antigen (PSA) level (< 0.05ng/mL), PSA nadir after RT (≤ 0.01ng/mL), and time to PSA nadir (≥ 10months) were associated with favorable bRFS (p = .03, p < .001, and p = .002, respectively). On multivariate analysis, post-RP PSA level and time to PSA nadir were independent predictive factors for bRFS in SRT (p = .04 and p = .005). ART and SRT had favorable outcomes with no recurrence within RT field. In SRT, the time to PSA nadir after RT (≥ 10months) was found to be a new predictor for favorable bRFS and useful in assessing treatment efficacy.

Development and validation of a multi-institutional nomogram of outcomes for PSMA-PET–based salvage radiotherapy in recurrent prostate cancer.

355 Background: We aimed to develop and to validate a multi-institutional nomogram of outcomes for PSMA-PET based salvage radiotherapy (sRT) following radical prostatectomy (RP) for patients with recurrent or persistent prostate cancer (PCa). Methods: Data from patients with a detectable post-RP prostate-specific antigen (PSA) treated with sRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 11 academic institutions from 5 countries. All patients had a PSMA-PET scan prior sRT and patients with distant metastases on PET were excluded from this analysis. The freedom from biochemical failure (FFBF) rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse (BR) was defined as PSA nadir +0.2 ng/ml after sRT. Results: Overall, 1029 patients (training set n=821, external validation set n=208) with a median follow-up of 33 months were included. On PSMA-PET, 427 (42%) and 313 (30%) patients had local and nodal recurrences, respectively. Elective pelvic lymphatics were irradiated in 368 (36%) patients. All patients received sRT to the prostatic fossa receiving a dose of &lt;66 Gy, 66-70 Gy and &gt;70 Gy in 103 (10%), 551 (54%) and 375 (36%) patients, respectively. Androgen deprivation therapy (ADT) was given in 325 (32%) patients. On multivariable Cox regression analysis, pre-SRT PSA, ISUP grade, pT stage, surgical margins, ADT use, sRT dose and nodal recurrence on PSMA PET were associated with FFBF. The nomogram concordance index was 0.7 for FFBF in external validation. Conclusions: We present an externally validated contemporary nomogram which can estimate individual patient outcomes after PSMA-PET guided sRT. Positive lymph nodes on PSMA-PET seem to be a new risk factor for BR after sRT.

GETUG-AFU 22 Phase II Randomized Trial Evaluating Outcomes of Post-Operative Immediate Salvage Radiation Therapy with or without ADT for Patients with Persistently Elevated PSA Level

<h3>Purpose/Objective(s)</h3> Radical prostatectomy (RP) is one of the recommended option for localized prostate cancer (PCa) treatment but no clear recommendations guide post-operative treatment patients with persistently elevated prostate-specific antigen (PSA) after RP. The aim of this trial was to compare immediate salvage radiation therapy (iSRT) with or without short-term androgen deprivation therapy (ADT) in these patients. <h3>Materials/Methods</h3> RP patients with nonmetastatic PCa on conventional preoperative imaging, and with a post-RP PSA level between 0.2 and 2 ng/mL were randomized (1:1) to iSRT alone (iSRT arm) or 6 months of ADT (degarelix) with iSRT (iSRT+ADT arm). ISRT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Biochemical progression-free survival (bPFS), metastates-free survival (MFS), overall survival (OS), quality of life, and toxicities were evaluated as secondary endpoints. <h3>Results</h3> From Jan-2013 to Sept-2015, 125 pts were included (iSRT arm: 64 pts; iSRT+ADT arm: 61). Median follow up was 75.0 months (95% CI: 74.1-76.6). The baseline characteristics were well-balanced between the two arms. Median PSA was 0.6 ng/mL (0.12-3.65) at randomization. All patients received the planned iSRT and 98.4% in the arm iSRT+ADT received ADT as planned. The efficacy results were analyzed at 5 years. EFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 63.5% (95% CI: 49.9-74.2) in iSRT+ADT arm (HR=0.83; 95%CI: 0.47-1.47; p=0.528). bPFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 66% (95% CI: 52.3-76.6) in iSRT+ADT arm (HR=0.76; 95%CI: 0.44-1.31; p=0.322). MFS was in favor of the iSRT+ADT arm with HR=0.51 (95% CI: 0.26-0.99; p=0.048). OS data were not mature at the time of analysis. Multivariate analysis demonstrated that PSA level <0.6 ng/ml at randomization and tumor ≤pT3a were associated with increased bPFS (HR=1.84; 95%CI: 1.02-3.33; p=0.05 and HR=2.96; 95%CI: 1.66-5.25; p=0.0002, respectively). PSA level <0.6 ng/ml at randomization was associated with improved MFS (HR=2.82; 95%CI: 1.14-6.95; p=0.019). No grade 4 toxicities were observed. Overall, no difference in acute toxicity were observed between the 2 arms and more late toxicities (≥6 months after iSRT) were observed in the iSRT+ADT than the iSRT arm (53.1% vs 70.5%; p=0.046). At 12 months ADT-related symptoms were more important in the iSRT+ADT arm (QLQ-PR25; p=0.04). At 24 months, no difference in QLQ-C30 or QLQ-PR25 analysis was reported. After an initial 25-fold decrease in blood testosterone level, all patients recovered to normal level 12 months after starting ADT. <h3>Conclusion</h3> Despite the lack of differences in terms of EFS between the two arms, this study demonstrated that iSRT+ADT improved MFS without impaired quality-of-life for patients with persistently elevated PSA after RP.

Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401)†

BackgroundNo standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). ObjectiveTo determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients. Design, setting, and participantsThis study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) ± SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr. Outcome measurements and statistical analysisThe primary endpoint was time to treatment failure (TTF) of BCL. Results and limitationsTTF of BCL was significantly longer in the SRT ± SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40–0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT ± SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT ± SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions. ConclusionsInitial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT ± SHT is more beneficial than SHT alone. Patient summaryPatients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy.

Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy

BackgroundProstate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. ObjectiveTo evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. Design, setting, and participantsA multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml. Outcome measurements and statisitical analysisCumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. Results and limitationsThe median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. ConclusionsDespite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Patient summaryDecipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

Adjuvant radiation therapy, androgen deprivation, and docetaxel for high-risk prostate cancer postprostatectomy: Results of NRG Oncology/RTOG study 0621.

Phase 3 trials have demonstrated a benefit from adjuvant radiation therapy (ART) for men who have adverse factors at radical prostatectomy (RP). However, some patients have a high risk of progression despite ART. The role of systemic therapy with ART in this high-risk group remains to be defined. Patients who had either a post-RP prostate-specific antigen (PSA) nadir > 0.2 ng/mL and a Gleason score ≥7 or a PSA nadir ≤0.2 ng/mL, a Gleason score ≥8, and a pathologic tumor (pT) classification ≥ pT3 received 6 months of androgen-deprivation therapy (ADT) plus radiotherapy and 6 cycles of docetaxel. The primary objective was to assess whether the addition of ADT and docetaxel to ART resulted in a freedom from progression (FFP) rate ≥ 70% compared with an expected rate of 50%. Multivariate logistic and Cox regression analyses were used to model associations between factors and outcomes. In total, 74 patients were enrolled. The median follow-up was 4.4 years. The pathologic tumor classification was pT2 in 4% of patients, pT3 in 95%, and pT4 in 1%. The Gleason score was 7 in 18% of patients and ≥8 in 82%. Post-RP PSA levels were ≤0.2 ng/mL in 53% of patients and >0.2 ng/mL in 47%. The 3-year FFP rate was 73% (95% confidence interval, 61%-83%), and the 3-year cumulative incidence of biochemical, distant, and local failure was 26%, 7%, and 0%, respectively. In multivariate models, postprostatectomy PSA nadir was associated with 3-year FFP, Gleason score, and PSA with biochemical failure. Grade 3 and 4 neutropenia was common; however, only 3 episodes of febrile neutropenia occurred. Late toxicities were not impacted by the addition of systemic therapy. Combined ADT, docetaxel, and ART for men with high-risk prostate cancer after prostatectomy exceeded the prespecified study endpoint of 70% 3-year FFP. Phase 3 trials assessing combined local and systemic therapies for these high-risk patients are warranted. Cancer 2017;123:2489-96. © 2017 American Cancer Society.

Gleason grade grouping of prostate cancer is of prognostic value in Asian men

AimThe International Society of Urological Pathology made recommendations for the use of Grade Groups (GG) originally described by Epstein and colleagues over Gleason score (GS) alone in 2014, which was...

Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy.

We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

Assessing guideline impact on referral patterns of postprostatectomy patients to radiation oncologists

Adjuvant radiotherapy (aRT) can improve biochemical progression-free survival in patients with high-risk features (HRF) after radical prostatectomy (RP). Guidelines from Alberta and the Genitourinary Radiation Oncologists of Canada (GUROC) recommend that patients with HRF be referred to radiation oncologists (RO) based on the findings from three randomized, controlled trials (RCT). Our study examines the impact of these recommendations both pre- (2005) and post- (2012) publication of RCT and GUROC guideline establishment. Patients undergoing RP during 2005 and 2012 were identified from the provincial cancer registry. Charts were retrospectively reviewed and variables of interest were linked to the registry data. RO referral patterns for each year were determined and variables influencing referral (extracapsular extension, positive margin, seminal vesicle invasion, and post-RP prostate-specific antigen [PSA]) were compared. Median time to referral was 26.4 months in 2005 compared to 3.7 months 2012 (p<0.001). Among patients referred post-RP, a higher proportion was referred within six months in 2012 (21%) as compared to 2005 (13%) (p=0.003). Among eligible patients in 2012, 30% were referred for discussion of aRT compared to 24% in 2005 (p=0.003). There was a marked drop in patients referred for salvage radiation therapy beyond six months and a rise in the number of patients who are never referred. Despite an increase in referral rates to RO post-RP from 2005-2012, more than 50% of those patients with HRF did not receive a referral. Initiatives aimed at improving multidisciplinary care and guideline adherence should be undertaken.

Dual-timing PSA as a biomarker for patients with salvage intensity modulated radiation therapy for biochemical failure after radical prostatectomy.

We investigated the outcomes and the associated clinical-pathological factors in patients with prostate cancer (PCa) undergoing salvage intensity modulated radiation therapy (IMRT) for post-radical-prostatectomy (RP) biochemical failure. We report clinical outcomes of post-RP salvage IMRT, and describe chronic toxicity in these patients.Fifty patients with PCa underwent post-RP salvage IMRT. The median dose of IMRT was 70 Gy to the prostatic and seminal vesicle bed. Clinical-pathological and toxicity information were collected. The prostate cancer-specific survival (PCSS), disease-free survival (DFS), and biochemical-failure-free survival (BFFS) were calculated. Prognostic factors were analyzed for their association with disease control.The median follow-up time was 74 months. The 5-year PCSS, DFS, and BFFS after salvage IMRT were 95%, 88%, and 60%, respectively. Two patients (4%) experienced late gastrointestinal toxicity ≥ grade 3, and 5 patients (10%) had late genitourinary toxicity ≥ grade 3. On multivariate analysis, post-RP prostate-specific antigen (PSA) nadir ≤0.1 ng/ml (P=0.018) and PSA ≤0.5 ng/ml at salvage IMRT (P=0.016) were independent factors predicting better BFFS. Patients with both post-RP PSA nadir ≤0.1 ng/ml and PSA ≤0.5 ng/ml at salvage IMRT had a 5-year BFFS of 83% as compared with 43% in other patients (P=0.001).In conclusion, with hormonal therapy in most PCa patients, the addition of salvage IMRT for post-RP biochemical failure can achieve a good outcome with low toxicity. Patients with a post-RP PSA nadir ≤0.1 ng/ml and PSA ≤0.5 ng/ml at salvage IMRT could benefit the most from salvage IMRT.

Gleason Score ≤ 6 Prostate Cancer at Radical Prostatectomy: Does a High-Risk Setting Truly Exist? A Recursive Partitioning Analysis

BackgroundThe purpose of this study was to determine whether a “high-risk” subpopulation of low-grade (Gleason score ≤6) prostate cancer defined by lower prostate-specific antigen (PSA) relapse-free survival (bRFS) might be identified within a large population of men who underwent radical prostatectomy (RP) alone, with mature follow-up. Patients and MethodsPatients were retrospectively identified for inclusion by cT1-2 prostate cancer managed with RP alone. Exclusion criteria were: Gleason score ≥7 at RP, any pre- or post-RP radiotherapy or hormone therapy, or PSA follow-up <12 months. The Kaplan–Meier method was used for survival estimates; recursive partitioning by conditional inference analysis was applied to identify variables associated with bRFS. ResultsFrom 2002 through 2010, 284 eligible patients were identified. Median age was 60 years (range, 44-76 years), 233 (82%) were cT1c, and median PSA was 5.3 ng/dL (92% ≤10). The median biopsy to RP interval was 50 days (range, 11-410, with 97% <180 days). Eighty patients (28%) had positive margin (M+). At a median follow-up of 92.6 months (range, 16.9-160.9, with 45% followed ≥ 8 years), 32 patients (11%) had PSA failure, with an estimated 8-year bRFS rate of 89%. In univariate analysis, M+, extraprostatic extension, detectable initial post-RP PSA, and longer biopsy to RP interval were significantly associated with lower bRFS. M+ and longer biopsy to RP interval remained significant in multivariable analysis. Recursive partitioning analysis identified M+ as the only stratification factor, with 8-year bRFS estimates of 74% versus 95% for M+ versus margin-negative. ConclusionGleason score ≤6 prostate cancer managed using RP alone is associated with high rates of bRFS; however, margin positivity predicts early PSA failure rates in >20% of patients.

Observation Following Radical Prostatectomy (RP) With Positive Margin(s) (PM): Does a Low-Risk Subgroup Exist?

Following RP for prostate cancer (PC), PM is a well-established risk factor for prostate-specific antigen (PSA) failure. Despite phase 3 evidence confirming benefit of adjuvant radiation therapy (RT) in this setting, many patients are not referred owing to the observation that not all patients with PM recur. The primary objective of this study is to determine whether expanded pathologic factors may permit substratification of risk within a well-defined cohort of PM RP patients who did not undergo adjuvant RT. Multi-institutional retrospective analysis of patient- and tumor-specific factor associations with disease control. Eligible patients underwent RP for clinically localized PC, without pathologic involvement of seminal vesicles or lymph nodes and >1 positive surgical margin (defined as ink on tumor). Patients were excluded for pre-RP PSA >30 or adjuvant (nonsalvage) RT or hormone therapy. PSA failure was defined as >0.2 ng/mL and rising. Cox regression was used to assess the effects of demographic and clinicopathologic variables on freedom from failure (FFF). Kaplan-Meier method was employed for disease control estimates. Ad hoc substratifications within post-RP PSA and pathologic features were examined using log-rank. From 2002 to 2010, 215 patients were eligible for this analysis. There was no difference in outcome or follow-up between institutions. Median age at diagnosis was 61 years (range, 43-76 years), and pre-RP PSA 5.8 (1.6-26). At median follow-up of 78 months (14-155 months), 85 patients had experienced PSA relapse. On univariate analysis, PSA failure was associated with higher primary Gleason grade (4-5 vs 3) and total Gleason score (7-9 vs 6) at RP, presence of capsule invasion at positive margin site, and higher initial post-RP PSA (<0.1 vs >0.1, performed within 6 months of RP), with initial post-RP PSA remaining significant at multivariate analysis. Multiple comparisons analysis yielded 4 discrete risk groups (Table). Of note, 45 patients underwent salvage RT, of whom 38 remained without evidence of PSA rise at last follow-up. Within the present study, high 5-year FFF rates were observed for the subgroup of PM RP patients with Gleason score 6 and initial post-op PSA <0.1, without further therapy. These findings are hypothesis-generating, and longer follow-up is needed to determine if this group of PC patients may be safely observed, with RT reserved for the salvage setting.Poster Viewing Abstracts 2515 Table 1Group5 Year FFF95% CIUnadjusted P valueInitial post-op PSA <0.1, GS 686%75-92%-Initial post-op PSA <0.1, GS 7-964%53-73%.06Initial post-op PSA ≥0.1, GS 633%6-66%<.01Initial post-op PSA ≥0.1, GS 7-97%<1-25%<.01 Open table in a new tab

Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men

BackgroundRadical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. ObjectiveTo evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. Design, setting, and participantsRetrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. Outcome measurements and statistical analysisThe primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. Results and limitationsNinety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer–specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. ConclusionsIn a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. Patient summaryThe Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy.

A genomic classifier to improve prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy.

154 Background: Surgery is a standard first line therapy for most intermediate-high risk men diagnosed with prostate cancer. While clinical factors such as tumor grade, stage and prostate specific antigen (PSA) are currently used to identify patients at risk of cancer recurrence, novel biomarkers that can improve risk stratification and distinguish local from systemic recurrence are needed. The Decipher Genomic Classifier (GC) is a validated model for predicting men at risk of metastasis. We evaluated its performance in predicting metastatic disease within 5 years after surgery (rapid metastasis, RM) in an independent cohort. Methods: Tumors and clinicopathologic data were obtained from a cohort of 2,641 RP patients treated between 1987-2008 at Cleveland Clinic. The final study cohort consisted of 15 RM patients and 154 patients as non-RM controls who met the following criteria: 1) preoperative PSA&gt;20 ng/mL, stage pT3 or margin positive, or Gleason score ≥8; 2) pathologic node negative; 3) undetectable post-RP PSA; 4) no neoadjuvant or adjuvant therapy; and 5) minimum 5 year follow-up for the controls. Results: RM patients developed metastasis with a median of 2.3 (IQR: 0.8-5) years. In multivariable analysis, GC was a significant predictor of RM (OR=1.48, p=0.018) after adjusting for clinical risk factors. GC had the highest c-index, 0.77, compared to the Stephenson model (c-index 0.75) and CAPRA-S (c-index 0.72) as well as a panel of previously reported prostate cancer biomarkers unrelated to GC. Integration of GC into the Stephenson nomogram increased the c-index from 0.75 (95% CI: 0.65-0.85) to 0.79 (95% CI: 0.68-0.89). Conclusions: GC was independently validated as a genomic metastasis signature for predicting RM in a cohort of high-risk men treated with RP and managed conservatively without any adjuvant therapy. Integration of GC into clinical nomograms led to improvement in prediction of RM. GC may further allow identification of men most at risk for metastatic progression who should be considered for multimodal therapy or inclusion in clinical trials.

Prostate-Specific Antigen Persistence After Radical Prostatectomy as a Predictive Factor of Clinical Relapse-Free Survival and Overall Survival: 10-Year Data of the ARO 96-02 Trial

The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option.

A Genomic Classifier Improves Prediction of Metastatic Disease Within 5 Years After Surgery in Node-negative High-risk Prostate Cancer Patients Managed by Radical Prostatectomy Without Adjuvant Therapy

BackgroundSurgery is a standard first-line therapy for men with intermediate- or high-risk prostate cancer. Clinical factors such as tumor grade, stage, and prostate-specific antigen (PSA) are currently used to identify those who are at risk of recurrence and who may benefit from adjuvant therapy, but novel biomarkers that improve risk stratification and that distinguish local from systemic recurrence are needed. ObjectiveTo determine whether adding the Decipher genomic classifier, a validated metastasis risk–prediction model, to standard risk-stratification tools (CAPRA-S and Stephenson nomogram) improves accuracy in predicting metastatic disease within 5 yr after surgery (rapid metastasis [RM]) in an independent cohort of men with adverse pathologic features after radical prostatectomy (RP). Design, setting, and participantsThe study population consisted of 169 patients selected from 2641 men who underwent RP at the Cleveland Clinic between 1987 and 2008 who met the following criteria: (1) preoperative PSA >20 ng/ml, stage pT3 or margin positive, or Gleason score ≥8; (2) pathologic node negative; (3) undetectable post-RP PSA; (4) no neoadjuvant or adjuvant therapy; and (5) minimum of 5-yr follow-up for controls. The final study cohort consisted of 15 RM patients and 154 patients as non-RM controls. Outcome measurements and statistical analysisThe performance of Decipher was evaluated individually and in combination with clinical risk factors using concordance index (c-index), decision curve analysis, and logistic regression for prediction of RM. Results and limitationsRM patients developed metastasis at a median of 2.3 yr (interquartile range: 1.7–3.3). In multivariable analysis, Decipher was a significant predictor of RM (odds ratio: 1.48; p=0.018) after adjusting for clinical risk factors. Decipher had the highest c-index, 0.77, compared with the Stephenson model (c-index: 0.75) and CAPRA-S (c-index: 0.72) as well as with a panel of previously reported prostate cancer biomarkers unrelated to Decipher. Integration of Decipher into the Stephenson nomogram increased the c-index from 0.75 (95% confidence interval [CI], 0.65–0.85) to 0.79 (95% CI, 0.68–0.89). ConclusionsDecipher was independently validated as a genomic metastasis signature for predicting metastatic disease within 5 yr after surgery in a cohort of high-risk men treated with RP and managed conservatively without any adjuvant therapy. Integration of Decipher into clinical nomograms increased prediction of RM. Decipher may allow identification of men most at risk for metastatic progression who should be considered for multimodal therapy or inclusion in clinical trials. Patient summaryUse of Decipher in addition to standard clinical information more accurately identified men who developed metastatic disease within 5 yr after surgery. The results suggest that Decipher allows improved identification of the men who should consider secondary therapy from among the majority that may be managed conservatively after surgery.

Salvage Radiotherapy for Patients with PSA Relapse Following Radical Prostatectomy: Issues and Challenges

A progressively rising level of serum prostate specific antigen (PSA) after radical prostatectomy (RP) invariably indicates the recurrence of prostate cancer. The optimal management of patients with post-RP PSA relapse has remained uncertain due to a wide variability in the natural course of post-RP PSA relapse and the inability to separate a recurrent disease confined to the prostate bed from that with occult distant metastasis. Management uncertainty is further compounded by the lack of phase III clinical studies demonstrating which therapeutic approach, if any, would prolong life with no significant morbidity. Radiotherapy has been the main therapeutic modality with a curative potential for patients with post-RP PSA relapse. This review article depicts issues and challenges in the management of patients with post-RP PSA relapse, presents the literature data for the efficacy of salvage radiotherapy, either alone or in combination of androgen ablation therapy, and discusses future directions that can optimize treatment strategies.

Predicting PSA failure following salvage radiotherapy for a rising PSA post-prostatectomy: From the CaPSURE™ database

Background The role of radiotherapy (RT) for rising PSA after radical prostatectomy (RP) is debatable. We analyzed a large database of men to evaluate for predictors of prostate-specific antigen (PSA) failure after salvage RT. Methods Data from the Cancer of the Prostate Strategic Urologic Research Endeavor database (CaPSURE™) identified 4,563 men with RP between 1989 and 2004; 194 underwent salvage RT ≥6 months after RP. PSA failure following RT was defined as a PSA >0.2 ng/ml. The association between clinical and pathologic characteristics and PSA failure was examined using a χ-square metric. A multivariable analysis of predictors for time to PSA failure was performed using a Cox proportional hazard regression model. Results After a median follow-up of 66 months, 121 (62%) men experienced PSA failure at a median 20 months. Significant associations for PSA failure were found for the clinical T category ( P < .01), race/ethnicity ( P = 0.04), pT3 disease ( P < 0.01), seminal vesicle invasion ( P < 0.01), and pre-RT PSA level ( P < 0.01). The pre-RT PSA level ( P = 0.07) was the only factor to approach significance as an independent predictor of PSA failure on multivariable analysis. Pre-RT PSA doubling time was calculated for 131 men but did not predict for PSA failure on univariate ( P = 0.38) or multivariate analyses ( P = 0.13) for ≤12 vs. >12 months. Conclusions Salvage RT provided the greatest benefit in PSA control in men with the lowest pre-RT PSA levels. Post-RP PSA doubling time >12 months trended toward predicting for PSA failure but was not significant likely owing to limited sample size. Together, these findings would suggest that salvage RT is optimal at low pre-RT PSA and long doubling times with favorable pathologic features.

The Long-Term Clinical Impact of Biochemical Recurrence of Prostate Cancer 5 or More Years After Radical Prostatectomy

Information regarding the clinical impact of delayed (5 years or greater) biochemical failure (BF) after radical prostatectomy (RP) is lacking. We undertook an investigation to differentiate the innocuous recurrence of serum prostate specific antigen (PSA) from that which heralds an eventual clinical failure (CF), and to determine if there is a period following RP when a patient is cured of clinical disease. Men with clinically localized prostate cancer (PCA) undergoing RP (1987 to 1995) were identified from our longitudinal PCA registry. Outcome measurements were based on the detection of post-RP serum PSA 0.4 ng/ml or greater, clinical identification of cancer recurrence and disease related death. Following RP in 3,903 eligible men, 33% had a detectable PSA (median followup 8.8 years). Of these BFs 27% occurred after 5 or more disease-free years. Currently, 29% of all men with BF have clinical evidence of PCA, with 8% dying of PCA (median actuarial survival time from CF to death 9.8 years). Progression from BF to CF was not significantly altered by the disease-free interval (p = 0.544). A PSA doubling time less than 12 months significantly increased the risk of CF regardless of the interval from surgery. Risk factors for BF were significant throughout the duration of followup. Patients are at prolonged risk for BF and CF following RP. Regardless of the timing of the initial PSA recurrence the PSA doubling time is the most powerful predictor of progression, stratifying patients with BF into high and low risk groups for CF.