The impact of biochemical recurrence (BCR) after radical treatment of prostate cancer on oncological outcomes remains unclear. A new European Association of Urology BCR risk stratification (low and ...high risk) has been proposed. To validate these risk groups, we retrospectively analyzed data for 1125 post-radical prostatectomy (RP) BCR patients (surgery between 1992 and 2006). Univariable Kaplan-Meier plots and multivariable Cox regression models with time-dependent covariates were used to test the independent predictor status of the risk grouping on metastatic progression (MP) and prostate cancer-specific mortality (PCSM). The 5-yr MP-free and PCSM-free survival rates were significantly higher among patients with low BCR risk compared to their high-risk counterparts. In multivariable analyses, the BCR risk grouping reached independent predictor status for MP (hazard ratio HR 3.46; p<0.001) and PCSM (HR 5.12; p<0.001). Salvage radiation therapy, especially when delivered at prostate-specific antigen <0.5ng/ml, was highly protective. Our findings corroborate the validity of this novel BCR risk grouping, which is easily applicable in daily practice and could be valuable in decision-making for salvage therapy and clinical trials.
The European Association of Urology grouping for the risk of biochemical recurrence of prostate cancer after radical prostatectomy was valid when applied in a European study cohort.
Our findings corroborate the validity of the novel European Association of Urology biochemical recurrence risk grouping, which is easily applicable in daily practice and could be valuable in decision-making for salvage therapy and clinical trials.
Persistent prostate-specific antigen (PSA) represents a poor prognostic factor for recurrence after radical prostatectomy (RP).
To investigate the impact of persistent PSA at 6wk after RP on ...long-term oncologic outcomes and to assess patient characteristics associated with persistent PSA.
Within a high-volume center database we identified patients who harbored persistent (≥0.1ng/ml) versus undetectable PSA (<0.1ng/ml) at 6wk after RP. Patients with neo- and/or adjuvant androgen-deprivation therapy (ADT) were excluded.
Logistic regression models tested for prediction of persistent PSA. Kaplan–Meier analyses and Cox regression models tested the effect of persistent PSA on metastasis-free survival (MFS), overall survival (OS), and cancer-specific survival (CSS) rates. Propensity score matching (PSM) was performed to test the impact of salvage radiotherapy (SRT) on OS and CSS in patients with persistent PSA.
Of 11 604 identified patients, 8.8% (n=1025) harbored persistent PSA. At 15yr after RP, MFS, OS, and CSS were 53.0% versus 93.2% (p<0.001), 64.7% versus 81.2% (p<0.001), and 75.5% versus 96.2% (p<0.001) for persistent versus undetectable PSA, respectively. In multivariable Cox regression models, persistent PSA represented an independent predictor for metastasis (hazard ratio HR: 3.59, p<0.001), death (HR: 1.86, p<0.001), and cancer-specific death (HR: 3.15, p<0.001). SRT was associated with improved OS (HR: 0.37, p=0.02) and CSS (HR: 0.12, p<0.01) after 1:1 PSM. Main limitation is missing data on postoperative PSA and duration of salvage ADT.
Persistent PSA is associated with worse oncologic outcome after RP, namely, metastasis, death, and cancer-specific death. In patients with persistent PSA, SRT resulted in improved OS and CSS.
We assessed the impact of persistent prostate-specific antigen (PSA) at 6wk after radical prostatectomy on oncologic outcomes. Early persistent PSA was associated with worse metastasis-free survival, overall survival, and cancer-specific survival. Salvage radiotherapy may result in a survival benefit in well-selected patients.
Persistent prostate-specific antigen (PSA; ≥0.1ng/ml) at 6wk after radical prostatectomy represents an independent predictor for worse long-term oncological outcome after radical prostatectomy in patients with nonmetastatic prostate cancer. Specifically, persistent PSA is associated with death and development of metastasis. In selected patients, salvage radiotherapy may lead to a survival benefit in patients with persistent PSA.
Adjuvant compared with early salvage radiation therapy (sRT) following radical prostatectomy (RP) has not been shown to reduce progression-free survival in randomized controlled trials. However, ...these trials might have missed a benefit in men with adverse pathology at RP given that these men were under-represented and immortal time bias might have been present; herein, we investigate this possibility.
We evaluated the impact of adjuvant versus early sRT on all-cause mortality (ACM) risk in men with adverse pathology defined as positive pelvic lymph nodes (pN1) or pGleason score 8-10 prostate cancer (PC) and disease extending beyond the prostate (pT3/4). We used a treatment propensity score to minimize potential treatment selection bias when estimating the causal effect of adjuvant versus early sRT on ACM risk and a sensitivity analysis to assess the impact that varying definitions of adverse pathology had on ACM risk adjusting for age at RP, PC prognostic factors, site, and the time-dependent use of post-RP androgen deprivation therapy.
After a median follow-up (interquartile range) of 8.16 (6.00-12.10) years, of the 26,118 men in the study cohort, 2,104 (8.06%) died, of which 539 (25.62%) were from PC. After excluding men with a persistent prostate-specific antigen, adjuvant compared with early sRT was associated with a significantly lower ACM risk among men with adverse pathology at RP when men with pN1 PC were excluded (0.33 0.13-0.85;
= .02) or included (0.66 0.44-0.99;
= .04).
Adjuvant radiation therapy should be considered in men with pN1 or pGleason score 8 to 10 and pT3/4 PC given the possibility that a significant reduction in ACM risk exists.
The role of subcellular survivin compartmentalization in the biology and prognosis of prostate cancer is unclear. We therefore investigated subcellular localization of survivin in more than 3000 ...prostate cancer patients by quantitative immunohistochemistry and performed transcriptomics of 250 prostate cancer patients and healthy donors using publicly available datasets. Survivin (BIRC5) gene expression was increased in primary prostate cancers and metastases, but did not differ in recurrent vs non-recurrent prostate cancers. Survivin immunohistochemistry (IHC) staining was limited exclusively to the nucleus in 900 prostate cancers (40.0%), and accompanied by various levels of cytoplasmic positivity in 1338 tumors (59.4%). 0.5% of prostate cancers did not express survivin. Nuclear and cytoplasmic survivin staining intensities were strongly associated with each other, pT category, and higher Gleason scores. Cytoplasmic but not nuclear survivin staining correlated with high tumor cell proliferation in prostate cancers. Strong cytoplasmic survivin staining, but not nuclear staining predicted an unfavorable outcome in univariate analyses. Multivariate Cox regression analysis showed that survivin is not an independent prognostic marker. In conclusion, we provide evidence that survivin expression is increased in prostate cancers, especially in metastatic disease, resulting in higher aggressiveness and tumor progression. In addition, subcellular compartmentalization is an important aspect of survivin cancer biology, as only cytoplasmic, but not nuclear survivin accumulation is linked to biological aggressiveness and prognosis of prostate cancers.
Abstract Background Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤6, 3 + 4, 4 + 3, 8, and 9–10, but there is variability within ...these subgroups. For example, Gleason 4 components may range from 5–45% in a Gleason 3 + 4 = 7 cancer. Objective To assess the clinical relevance of the fractions of Gleason patterns. Design, setting, and participants Prostatectomy specimens from 12 823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. Outcome measurements and statistical analysis To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. Results and limitations Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. Conclusions Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. Patient summary Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤3 + 3, 3 + 4, 4 + 3, 8, 9–10. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making.
Abstract Background A key prerequisite for urinary continence after radical prostatectomy (RP) is the functional length of the urethral sphincter and the stabilisation of its anatomic position within ...the pelvic floor. Objective We describe our modified surgical technique for full functional-length urethra (FFLU) preservation during RP. Design, setting, and participants We analysed 691 consecutive patients who underwent RP over a 12-mo period (285 without and 406 with the FFLU technique). Surgical procedure The full functional urethra length was preserved by performing an individualised apical preparation strictly along anatomic landmarks, respecting the individual length of the intraprostatically located proportion of the urethral sphincter. Anatomic fixation of the sphincter was reached by a thorough preservation of the pelvic floor and anatomic restoration of the Mueller's ligaments. Measurements Continence rates were assessed at 7 d and 12 mo after removal of the catheter. Continence was defined as the use of no pads and no urinary leakage. Results and limitations The continence rates were 50.1% and 30.9% 1 wk after catheter removal ( p < 0.0001) and 96.9% and 94.7% ( p = 0.59) at 12 mo after surgery in patients operated on with the FFLU technique versus the non-FFLU technique. In multivariate regression analysis, only the surgical technique correlated significantly with the continence status 1 wk after catheter removal. Neither the overall positive surgical margin rates nor the number of positive margins at the urethral resection border differed significantly between the FFLU and non-FFLU groups (13.6% and 0.5% vs 14.9% and 1.3%, respectively). Although the patients’ baseline characteristics were similar in the two surgical groups, the patients were not preoperatively randomised, and the number of patients in the groups was asymmetric. Conclusions The combination of an FFLU preparation and improved preservation of the anatomic fixation of the urethral sphincter complex resulted in significantly increased early urinary continence results.
Abstract Objectives As life expectancy increases, functional outcomes in elderly patients after radical prostatectomy (RP) become a more important factor to consider in treatment selection. The aim ...of this study was to determine age-dependant differences in functional outcomes after RP. Patients and methods A total of 8,295 patients who underwent RP from January 2009 to July 2013 were analyzed. Univariate and multivariate logistic regressions were used to estimate the effect of age and other covariates on 3- and 12-month continence and potency rates. Continence was achieved if no more than one safety pad was used per day. Potency was defined as an international index of erectile function (IIEF)-5 score of 18 or higher. Results In the entire cohort, 12-month (3-mo) continence and potency rates were 91.0% (76.1%) and 54.6% (40.9%), respectively. The 1-year continence rates for age groups<65,≥65 and<70,≥70 and<75, and≥75 years were 93.2%, 90.8%, 86.0%, and 86.5%, respectively. The corresponding 1-year potency rates were 59.3%, 46.9%, 44.4%, and 31.3%. In both, univariate and multivariate analyses, older age had a significant negative effect on functional outcomes. Moreover, nerve sparing, pT category, and patients’ body mass index were significantly associated with continence. Nerve sparing, pT category, patients’ body mass index, and use of PDE5 inhibitor or intracavernous injection therapy significantly influenced potency. Conclusions Older age has a significant adverse effect on recovery of continence and potency. Although functional outcomes in elderly patients and especially in patients aged 75 years or older are still good, they should be educated about the increased risk of incontinence and impotence after RP.
Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete.
To study the prognostic value of lymphatic invasion (L1) and whether it ...might complement or even replace lymph node analysis in clinical practice.
Retrospective analysis of pathological and clinical data from 14 528 consecutive patients.
Radical prostatectomy.
The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint.
Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values (p<0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas (p<0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas (p<0.0001). Both N1 and L1 were linked to PSA recurrence (p<0.0001 each). This was also true for 17 patients with isolated tumor cells (ie, <200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients.
Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence.
Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis.
To replace morbidity-prone lymph node analysis, we tested immunohistochemical analysis of lymphatic vessels to predict prognosis after radical prostatectomy. We found that minimal lymphatic invasion had a pivotal prognostic impact.
It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with ...EBRT, brachytherapy, and ADT (termed MaxRT).
To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) risk.
The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017.
Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both.
Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index.
The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%.
Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM.
A pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and ...variation in pathology reporting may miss aggressive disease.
The 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4.
Adjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67; p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26; p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630-0.660) within GG 3 + 3, but not GG 3 + 4.
The 4Kscore can help guide the clinical decision whether additional risk assessment-such as confirmatory biopsy-is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.
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