Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa

Background Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8–10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3 + 4 = 7 and 4 + 3 = 7 are often considered the same prognostic group. Objective To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. Design, setting, and participants Between 2005 and 2014, 20 845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. Outcome measurements and statistical analysis Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. Results and limitations In the surgery cohort, we found large differences in recurrence rates between both Gleason 3 + 4 versus 4 + 3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3 + 4, 4 + 3, 8, and 9–10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five–grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. Conclusions The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. Patient summary We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

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RRP can be performed with excellent survival outcomes. Favorable clinicopathological parameters and treatment in the PSA era are associated with improved cancer control.

Purpose Long-term prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen-detected cancers and the pathological risk factors for PCSM are needed for treatment decision-making. Methods Using Fine and Gray competing risk regression analysis, the clinical and pathological data and follow-up information of 11,521 patients treated by radical prostatectomy at four academic centers from 1987 to 2005 were modeled to predict PCSM. The model was validated on 12,389 patients treated at a separate institution during the same period. Results The overall 15-year PCSM was 7%. Primary and secondary pathological Gleason grade 4–5 (P < 0.001 for both), seminal vesicle invasion (P < 0.001), and year of surgery (P = 0.002) were significant predictors of PCSM. A nomogram predicting 15-year PCSM based on standard pathological parameters was accurate and discriminating with an externally-validated concordance index of 0.92. Stratified by patient age, 15-year PCSM for Gleason score ≤ 6, 3+4, 4+3, and 8–10 ranged from 0.2–1.2%, 4.2–6.5%, 6.6–11%, and 26–37%, respectively. The 15-year PCSM risks ranged from 0.8–1.5%, 2.9–10%, 15–27%, and 22–30% for organ-confined cancer, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis, respectively. Only 3 of 9557 patients with organ-confined, Gleason score ≤ 6 cancers have died from prostate cancer. Conclusions The presence of poorly differentiated cancer and seminal vesicle invasion are the prime determinants of PCSM after radical prostatectomy. The risk of PCSM can be predicted with unprecedented accuracy once the pathological features of prostate cancer are known.

Purpose Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome fluorescence in situ hybridization (FISH) spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemical (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease. Experimental Design PTEN IHC was validated by employing formalin fixed and paraffin embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution SNP microarray analysis was performed on a subset of these cases. Results PTEN protein loss, as assessed as a dichotomous IHC variable, was highly reproducible, correlated strongly with adverse pathologic features (e.g. Gleason score and pathological stage), detected between 75% and 86% of cases with PTEN genomic loss, and was found at times in the absence of apparent genomic loss. In a cohort of 217 high risk surgically treated patients, PTEN protein loss was associated with decreased time to metastasis. Conclusions These studies validate a simple method to interrogate PTEN status in clinical specimens and support the utility of this test in future multi-center studies, clinical trials and ultimately perhaps for routine clinical care.

Using 3 preoperative or postoperative parameters, these nomograms can easily be used to determine the 3, 5, 7 and 10-year biochemical recurrence-free survival probabilities among men who undergo radical retropubic prostatectomy for clinically localized prostate cancer in the modern era.

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