Cryosurgery Versus Primary Androgen Deprivation Therapy for Locally Recurrent Prostate Cancer After Primary Radiotherapy: A Propensity-Matched Survival Analysis.
ABSTRACT: Background Optimal management of isolated local recurrence of prostate cancer after primary radiotherapy remains to be defined. Up-front androgen deprivation therapy (ADT) is widely used but may adversely affect the quality of life and is essentially a palliative treatment. Local salvage carries a different side-effect profile and is potentially curative, but it has not been compared to ADT. Materials and methods We conducted a propensity-matched analysis of cohorts of men treated with either whole gland cryotherapy (CRYO) or primary ADT following the diagnosis of locally recurrent prostate cancer. Our specific objectives were to compare overall survival (OS) and prostate cancer-specific mortality (PCSM) between CRYO vs. ADT. Results After a one-to-one matching, 169 patients from each cohort were included in comparisons. Median follow-up time was 6.7 years (ADT) vs. 18 years (CRYO). The 10-year PCSM was 18.5% (ADT) vs. 16.2% (CRYO), which was not statistically different [hazard ratioo (HR): 0.69, 95% CI: 0.36-1.34, p=0.27]. The median OS was 12.3 years (CRYO) versus 10.2 years (ADT) (HR: 0.63, 95% CI: 0.42-0.95, p=0.03). Conclusions While PCSM was similar between the two strategies, CRYO was associated with a longer OS compared to primary ADT. Given the retrospective nature of the trial, these results should be considered hypothesis-generating, and phase III trials comparing these two options are required to further explore these findings.
Project description:<h4>Background</h4>Serine-arginine protein kinase 1 (SRPK1) has been implicated in prostate cancer (PCa) progression. However, its prognostic value and association with ERG and PTEN expression, two of the most common genetic alterations, have not been explored fully.<h4>Objective</h4>We assessed the prognostic value of SRPK1 in association with ERG and PTEN in a cohort of patients managed nonsurgically by androgen deprivation therapy (ADT) for advanced disease.<h4>Design setting and participants</h4>The study cohort consisted of men diagnosed with PCa by transurethral resection of the prostate (TURP; <i>n</i> = 480). The patients were divided into three main groups: incidental (patients with Gleason score [GS] ≤7 with no prior ADT), advanced (patients with GS ≥8 with no prior ADT), and castrate-resistant PCa (patients with prior ADT).<h4>Outcome measurements and statistical analysis</h4>A total of 480 TURP samples were assessed by immunohistochemistry for SRPK1, ERG, and PTEN, and results were correlated with Gleason grade group (GG), overall survival (OS), and PCa-specific mortality (PCSM).<h4>Results and limitations</h4>High SRPK1 expression was noted in 105/455 (23%) available patient cores. Expression of SRPK1 was associated with Gleason grade grouping (<i>p</i> < 0.0001) with high expression detected in 22/74 (33%) with GG 5. High SRPK1 was not associated with ERG positivity (<i>p</i> = 0.18) but was significantly associated with PTEN intensity (<i>p</i> = 0.001). High SRPK1 was associated with OS (hazard ratio [HR] 1.99; confidence interval [CI]: 1.57-2.54, <i>p</i> < 0.0001) and PCSM (HR 1.64; CI: 1.19-2.26, <i>p</i> < 0.002). Adjusting for Gleason score, patients with high SRPK1 and negative PTEN had the worst clinical outcome for both OS and PCSM compared with other patients (<i>p</i> < 0.0001, HR: 3.02; CI: 1.87-4.88 and HR: 6.40, CI: 3.19-12.85, respectively).<h4>Conclusions</h4>High SRPK1 is associated with worse OS and PCSM. Moreover, patients with high SRPK1 expression and loss of PTEN had the worst clinical outcome for OS and cancer-specific mortality. Combined status of SRPK1 and PTEN may provide added value in stratifying patients into various prognostic groups.<h4>Patient summary</h4>The expression of serine-arginine protein kinase 1 (SRPK1) combined with PTEN has a significant prognostic role in prostate cancer patients. Patients with high SRPK1 expression and negative PTEN had the worst clinical outcome for overall survival and cancer-specific mortality.
Project description:Importance: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). Objective: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. Design, Setting, and Participants: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. Exposures: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. Main Outcomes and Measures:Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index. Results: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%. Conclusions and Relevance: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.
Project description:PURPOSE:We aimed to study the associations between androgen-deprivation therapy (ADT)-induced weight changes and prostate cancer (PC) progression and mortality in men who had undergone radical prostatectomy (RP). METHODS:Data from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort were used to study the associations between weight change approximately 1-year post-ADT initiation and metastases, castration-resistant prostate cancer (CRPC), all-cause mortality (ACM), and PC-specific mortality (PCSM) in 357 patients who had undergone RP between 1988 and 2014. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) using covariate-adjusted Cox regression models for associations between weight loss, and weight gains of 2.3 kg or more, and PC progression and mortality post-ADT. RESULTS:During a median (IQR) follow-up of 81 (46-119) months, 55 men were diagnosed with metastases, 61 with CRPC, 36 died of PC, and 122 died of any cause. In multivariable analysis, weight loss was associated with increases in risks of metastases (HR 3.13; 95% CI 1.40-6.97), PCSM (HR 4.73; 95% CI 1.59-14.0), and ACM (HR 2.16; 95% CI 1.25-3.74) compared with mild weight gains of ??2.2. Results were slightly attenuated but remained statistically significant in analyses that accounted for competing risks of non-PC death. Estimates for the associations between weight gains of ??2.3 kg and metastases (HR 1.58; 95% CI 0.73-3.42), CRPC (HR 1.33; 95% CI 0.66-2.66), and PCSM (HR 2.44; 95% CI 0.84-7.11) were elevated, but not statistically significant. CONCLUSIONS:Our results suggest that weight loss following ADT initiation in men who have undergone RP is a poor prognostic sign. If confirmed in future studies, testing ways to mitigate weight loss post-ADT may be warranted.
Project description:BACKGROUND:Androgen deprivation therapy (ADT) remains a primary treatment for localized prostate cancer (PCa) even though there is no evidence that its use is beneficial in the absence of curative treatment. METHODS:Men aged ?70?years (n?=?16,534) diagnosed with localized PCa from 1985 to 2014 and managed either with primary observation or ADT in the absence of curative treatment were included. The cases were identified from the population-based Finnish Cancer Registry. We estimated the standardized mortality ratios (SMR) for overall mortality by treatment group. We determined the relative risk (RR) of PCa-specific mortality (PCSM) and other-cause mortality between the two treatment groups. Survival was determined using the life table method. Two age groups (70-79?years and???80?years) and three calendar time cohorts (1985-1994, 1995-2004, and 2005-2014) were compared following adjustment of propensity score matching between the treatment groups with four covariates (age, year of diagnosis, educational level, and hospital district). Follow-up continued until death or until December 31, 2015. RESULTS:Patients in the observation group had lower overall SMRs than those in the ADT group in both age cohorts over the entire study period. PCSM was higher in men aged 70-79?years undergoing primary ADT compared to those managed by observation only (RR: 1.70, 95% confidence interval [CI]: 1.29-2.23 [1985-1994]; RR 1.55, 95% CI: 1.35-1.84 [1995-2004]; and RR 2.71, 95% CI: 2.08-3.53 [2005-2014]); p?=?0.005 for periodic trend. A similar trend over time was also observed in men aged >?80?years; (p for age-period interaction?=?0.237). Overall survival was also higher among men in their 70's managed by observation compared to those undergoing ADT. CONCLUSIONS:Primary ADT within four months period from diagnosis is not associated with improved long-term overall survival or decreased PCSM compared to primary conservative management for men with localized PCa. However, this observational study's conclusions should be weighted with confounding factors related to cancer aggressiveness and comorbidities.
Project description:<h4>Background</h4>Most men who die of prostate cancer are older than 70 years. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel demonstrating an overall survival (OS) benefit for docetaxel.<h4>Methods</h4>In a post-hoc analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years ("older men") versus <70 years ("younger men") with Cox proportional hazards models. In addition, we compared adverse events, therapy completion rate, and subsequent treatment patterns between these two groups using Chi-squared tests.<h4>Results</h4>177 (22.4%) patients were ≥70 years. Docetaxel + ADT resulted in improved OS in both older and younger men (Hazard Ratio [HR] 0.45, 95%CI: 0.25-0.80 for older men; HR 0.71, 95%CI: 0.53-0.95 for younger men). This treatment benefit was seen for subgroups of older men with high volume disease (HR 0.43, 95%CI 0.23-0.79) and de novo metastatic disease (HR 0.36, 95%CI 0.19-0.69). A similar proportion of older and younger men completed six cycles of docetaxel (82.6% vs. 87.1%, p = 0.28). Rates of grade 3-5 adverse events were similar between older and younger men (36.8% vs. 26.8%, respectively, p = 0.069). The rate of any Grades 4-5 adverse events did not differ significantly between older and younger men (14.9% vs. 11.9%, respectively, p = 0.46). In the control arm, a smaller proportion of older men received subsequent cancer treatments (34.4% vs. 51.5%, p = 0.017) or subsequent docetaxel (25.6% vs. 37.6%, p = 0.035) compared to younger men.<h4>Conclusions</h4>Older men with mHSPC had similar OS benefit and clinical outcomes compared to younger men when receiving docetaxel + ADT. Oncologists should consider docetaxel chemotherapy as a favorable treatment option for older men with mHSPC who are fit for chemotherapy.
Project description:<h4>Introduction</h4>Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments.<h4>Methods</h4>This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events.<h4>Results</h4>Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT.<h4>Conclusion</h4>This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile.<h4>Trial registration</h4>ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.
Project description:<h4>Importance</h4>Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer.<h4>Objective</h4>To validate the GC in the context of a randomized phase 3 trial.<h4>Design, setting, and participants</h4>This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019.<h4>Intervention</h4>Salvage radiotherapy (sRT) with or without 2 years of bicalutamide.<h4>Main outcomes and measures</h4>The preplanned primary end point of this study was the independent association of the GC with the development of DM.<h4>Results</h4>In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%).<h4>Conclusions and relevance</h4>This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT.<h4>Trial registration</h4>ClinicalTrials.gov identifier: NCT00002874.
Project description:<h4>Introduction</h4>Approximately 50% of patients with non-metastatic prostate cancer are treated with radical prostatectomy (RP). While some men will be cured with surgery alone, a substantial proportion will experience cancer recurrence. Androgen-directed therapy (ADT) is an effective adjuvant therapy for patients treated with prostate radiation. Comparatively, the efficacy of ADT in surgical patients has not been well-studied.<h4>Methods</h4>A systematic search of MEDLINE, Embase, and the Cochrane Library from inception to July 2020 was performed. Randomized trials comparing ADT with RP vs. prostatectomy alone in patients with clinically localized prostate cancer were included. Neoadjuvant ADT and adjuvant ADT interventions were assessed separately. The primary outcomes were cancer recurrence-free survival (RFS) and overall survival (OS). Pathological outcomes following neoadjuvant ADT were also evaluated.<h4>Results</h4>Fifteen randomized trials met eligibility criteria; 11 evaluated neoadjuvant ADT (n=2322) and four evaluated adjuvant ADT (n=5205). Neoadjuvant ADT (three months of treatment) did not improve RFS (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.74-1.11) or OS (HR 1.22, 95% CI 0.62-2.41). Neoadjuvant ADT significantly decreased the risk of positive surgical margins (relative risk [RR] 0.48, 95% CI 0.41-0.56) and extraprostatic tumor extension (RR 0.75, 95% CI 0.64-0.89). Adjuvant ADT improved RFS (HR 0.65, 95% CI 0.45-0.93) but did not improve OS (HR 1.02, 95% CI 0.84-1.24).<h4>Conclusions</h4>Neoadjuvant ADT causes a pathological downstaging of prostate tumors but has not been found to delay cancer recurrence nor extend survival. Few studies have evaluated adjuvant ADT. Trials are needed to determine the benefits and harms of intermediate- or long-term adjuvant ADT for RP patients.
Project description:Evidence supporting radical prostatectomy (RP) for men with clinically node-positive (cN+) prostate cancer (PC) is limited. In a US national database, we identified 741 men with cN+ nonmetastatic PC diagnosed during 2000-2015 who underwent definitive local therapy with RP (n=78), radiotherapy (RT) with neoadjuvant androgen deprivation therapy (ADT) (n=193), or nondefinitive therapy with ADT alone (n=445) or observation (n=25). We compared PC-specific mortality (PCSM) and all-cause mortality (ACM) using multivariable Fine-Gray competing risk regression and Cox regression, respectively. Compared to nondefinitive therapy, RP was associated with significantly better PCSM (subdistribution hazard ratio [SHR] 0.32, 95% confidence interval [CI] 0.16-0.66; p=0.002) and ACM (HR 0.36, 95% CI 0.21-0.61; p<0.001). Compared to RT, RP was not associated with a significant difference in PCSM (SHR 0.47, 95% CI 0.19-1.17; p=0.1) or ACM (HR 0.88, 95% CI 0.46-1.70; p=0.71). These data suggest that RP is associated with favorable survival outcomes that appear to be superior to those for patients who did not receive definitive therapy and comparable to those for patients receiving definitive ADT/RT. Randomized trials of surgery with multimodal therapy are needed. PATIENT SUMMARY: We found that in clinically node-positive prostate cancer, radical prostatectomy was associated with a cancer-specific and overall survival benefit compared to nondefinitive therapy. Randomized clinical trials are required to determine the best treatment approach in this patient population.