Disease control outcomes of stereotactic body radiation therapy or moderate hypo-fractionation for prostate cancer: Real-world experience at two Canadian centers.

BACKGROUND: Advantages of using stereotactic body radiation therapy to treat prostate cancer include short treatment times, decreased costs, and limited toxicity. Randomized trial outcomes comparing 5-fraction stereotactic body radiation therapy to conventionally fractionated radiotherapy or hypo-fractionated radiation therapy are pending. OBJECTIVE: We report the 10-year experience with 5-fraction stereotactic body radiation therapy and hypo-fractionated radiation therapy at two Canadian centers. MATERIAL AND METHODS: Patients with low- or intermediate-risk prostate cancer treated with stereotactic body radiation therapy alone (35-40 Gy in 5 fractions) or hypo-fractionated radiation therapy alone (60-62 Gy in 20 fractions) in the period of July 2010 and June 2020. The biochemical relapse-free survival, PSA nadir, interval time to PSA nadir, time to biochemical recurrence (2 ng/ml above PSA nadir) and overall survival were reviewed. Outcomes between treatment groups were compared after propensity-matching by patient baseline characteristics. Kaplan-Meier curves were used to assess biochemical relapse-free survival and overall survival. RESULTS: We identified 205 and 513 patients with low or intermediate-risk prostate cancer who were treated with stereotactic body radiation therapy or hypo-fractionation, respectively. Intermediate-risk category composed 81% and 95% of the stereotactic body radiation therapy and hypo-fractionated radiation therapy cohorts, respectively. After a median follow up of 58.6 months for the stereotactic body radiation therapy cohort and 45.0 months for the hypo-fractionated cohort, biochemical relapse-free survival and overall survival were not significantly different between treatment groups. The 5-year biochemical relapse-free survival rates were 92.1% and 93.6% and overall survival rates were 96.4% and 95.0% for the stereotactic body radiation therapy and hypo-fractionated cohorts, respectively, after propensity-matching. Stereotactic body radiation therapy resulted in a significantly lower PSA nadir (0.18 ng/ml) compared to hypo-fractionated radiation therapy (0.48 ng/ml) in patients with low-risk prostate cancer. Mean time to biochemical recurrence was not different between treatment groups. CONCLUSIONS: Stereotactic body radiation therapy is an effective treatment option for low and intermediate-risk prostate cancer with encouraging biochemical relapse-free survival and overall survival rates comparable with hypo-fractionated radiation therapy.

Prediction of biochemical recurrence after laparoscopic radical prostatectomy.

BACKGROUND: Radical prostatectomy (RP) has been considered primary treatment for localized prostate cancer. Biochemical recurrence (BCR) occur approximately 20-30% in five year after RP. We aim to develop a novel nomogram to predict BCR-free survival (BCRFS) and performed external validation using a validation cohort that may help clinicians to make better decision for tailoring adjuvant treatment to specific group of patients. MATERIALS AND METHODS: This retrospective cohort study included 370 localized and regional prostate cancer patients who underwent laparoscopic radical prostatectomy (LRP) in Songklanagarind hospital between January 2010 and December 2019, the patients were divided into two groups (primary cohort and validation cohort). BCR-free survival was created using Kaplan-Meier curve. Predictive factors for BCR were identified with univariable and multivariable analysis using Cox proportional hazards model. Predictive nomogram was created using these identified factors and developed for the prediction of biochemical recurrence free survival (BCRFS) at 1 and 5 years after LRP. RESULTS: For primary Songklanagarind cohort, BCR was found in 105 patients (44.7%). Overall 1-year BCR-free survival was 52.8%, and 5-year BCR-free survival was 45.7% with median time to BCR of 18.1 months. Multivariable analysis identified unfavorable factor to BCRRF which are high initial serum PSA (> 20) (p < 0.001; HR 3.2), ISUP Gleason grade group > = 3 (p 0.033; HR 2.2), positive surgical margins (p 0.046; HR 1.5), and seminal vesicle involvement (p < 0.001; HR 5.2) and using for develop a novel nomogram to predict BCR. Concordance index 0.78. CONCLUSION: Prostate cancer patients with unfavorable factors, including high initial PSA (> 20), ISUP Gleason grade group > = 3, positive margin and extra-prostatic tumor extension are considered high risks and independent predictors of biochemical recurrence. This predictive models could potentially improve the 1 and 5-year BCR prediction after RP, according to the study's findings and will aid medical professionals in achieving the goal of clinical prediction and creating a proper management for the localized treatment of prostate cancer underwent laparoscopic radical prostatectomy.

Prostate-specific antigen nadir and testosterone level at prostate-specific antigen failure following radiation and androgen suppression therapy for unfavorable-risk prostate cancer and the risk of all-cause and prostate cancer-specific mortality.

BACKGROUND: Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping. METHODS: Seventy-five men treated with RT with or without 6 months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors. RESULTS: After a median follow-up of 15.34 years (interquartile range, 6.66-16.88 years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P = .04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P = .05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P < .01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P < .01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure. CONCLUSIONS: Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk. LAY SUMMARY: This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

PSA nadir and time to PSA nadir during initial androgen deprivation therapy as prognostic factors in metastatic castration-resistance prostate cancer patients treated with docetaxel.

Prostate-specific antigen nadir (nPSA) and time to nPSA (TTN) have been proved to be associated with the prognosis of prostate cancer. In this study, we explored the prognosis effect of nPSA and TTN during initial androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel-based chemotherapy. The data of 153 mCRPC patients received docetaxel followed by ADT were retrospectively reviewed. Multivariate Cox regression analysis demonstrated that TTN (overall survival (OS): Hazard ratio [HR] 0.096, 95% confidence interval [CI] 0.045-0.206, p < .001; progression-free survival (PFS): HR 0.128, 95% CI 0.078-0.211, p < .001) and nPSA (OS: HR 2.849, 95% CI 1.318-6.157, p = .008; PFS: HR 1.573, 95% CI 1.008-2.454, p = .046) acted as independent predictors of chemotherapy prognosis. Kaplan-Meier analysis showed that patients with nPSA ≥ 0.2 ng/ml or TTN < 6.5 months had shorter OS and PFS. These results suggest that TTN and nPSA during ADT can affect the prognosis of docetaxel-based chemotherapy prognosis post-castration resistance in patients with mCRPC, and higher nPSA and shorter TTN lead to poor chemotherapy prognosis. What is more, TTN has a greater impact during ADT on the prognosis of chemotherapy than nPSA.

[The correlation of PSA-nadir PS recurrence after total HIFU-ablation in patients with localized prostate cancer].

OBJECTIVE: To study the survival rate of patients without biochemical recurrence according to the Stuttgart and Phoenix criteria in terms of their correlation with four different PSA nadir values as predictors of clinical recurrence in patients with localized prostate cancer who underwent total HIFU prostate ablation. MATERIAL AND METHODS: The object of the study was patients with morphologically proven localized RP by biopsy results, who were treated with prostate cancer by HIFU ablation on the Ablatherm Integrated Imaging apparatus (EDAP TMS, France). The study included 658 patients in whom HIFU ablation was used as primary treatment of localized prostate cancer (stages T1 - T2) without previous use of other methods (hormonal, radiation therapy) For the analysis, a continuous sample of patients was selected, which were divided into four groups depending on the PSA nadir level: less or equal 0.2 ng / ml (1 group), 0.21-0.5 ng / ml (group 2), 0.51-1 ng / ml (group 3) and> 1 ng / ml (group 4). sensitivity, specificity, predictive value, and 5-year biochemical relapse-free survival according to the Stuttgart definition and the Phoenix definition in the PSA nadir groups. RESULTS: The median (range) of the observation period for the patients was 5.3 (3-7) years, the mean time to reaching PSA nadir was 14.5+/-2.6 weeks. PSA nadirs less or equal 0.2, 0.21-0.5, 0.51-1.0 and > 1 ng/ml were achieved in 231 (35.1%), 132 (20.0%), 105 (15, 9%) and 190 (28.8%) patients, respectively. Survival without biochemical relapse in accordance with the Stuttgart definition in the four groups allocated for the PSA nadir was 82, 65, 43 and 32%, respectively (p<0.001), according to the Phoenix definition - 94, 74, 66 and 47% (p<0.001) respectively. According to the results of the control biopsy, 601 (91.3%) patients in the 1st and 2nd groups had a negative oncological status (approximately 85%). CONCLUSION: This study confirms that PSA nadir after HIFU ablation predicts biochemical recurrence-free survival and is a reliable marker that is easy to integrate into routine clinical practice.

Impact of nadir PSA level and time to nadir during initial androgen deprivation therapy on prognosis in patients with metastatic castration-resistant prostate cancer.

PURPOSE: We determine whether the nadir prostate-specific antigen level (PSA nadir) and time to nadir (TTN) during initial androgen deprivation therapy (ADT) are prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: We reviewed the Michinoku Japan Urological Cancer Study Group database, including 321 mCRPC patients. Optimal cutoff values for PSA nadir and TTN on survival were calculated with the receiver operating characteristic (ROC) curve. Patients were stratified into unfavorable (higher PSA nadir and/or shorter TTN) and favorable (lower PSA nadir and longer TTN) groups. The inversed probability of treatment weighing (IPTW)-adjusted Cox proportional hazard model was performed to evaluate the impact of the unfavorable group on overall survival (OS) after CRPC diagnosis. RESULTS: Median age and follow-up period were 71 years and 35 months, respectively. ROC curve analysis demonstrated cutoffs of PSA nadir > 0.64 ng/mL and TTN < 7 months. The unfavorable group included 248 patients who had significantly shorter OS after mCRPC. The IPTW-adjusted multivariate model revealed that the unfavorable group had a negative impact on OS in mCRPC patients [hazards ratio (HR) 2.98, P < 0.001]. CONCLUSIONS: Higher PSA nadir and shorter TTN during the initial ADT are poor prognostic factors in patients with mCRPC.

Predictors of survival outcomes in native sub Saharan black men newly diagnosed with metastatic prostate cancer.

BACKGROUND: Though it is well established that black men are at higher risk of prostate cancer (PCa) very little is known about the disease in native sub Saharan black men. Newly diagnosed metastatic PCa patients treated with primary androgen deprivation therapy were identified and predictors of progression-free survival (PFS) assessed. METHODS: Patients diagnosed with metastatic PCa between 2010 and 2015 in a sub Saharan black population were included in the study. Primary outcome measure was PFS defined as time from primary androgen deprivation therapy to clinical progression or death. Demographic, clinical and PSA kinetic variables were evaluated for their prognostic power using Cox proportional hazard regression models. RESULTS: Seventy-nine patients met the eligibility criteria and were analyzed. Median age, median overall survival and PFS was 69 years, 40 months and 27 months respectively. A PSA nadir >4 ng/mL was found to predict an earlier clinical progression. Median PFS was shorter in those with PSA nadir >4 ng/mL (15 months) compared to those with PSA nadir ≤4 ng/mL (29 months); log rank p value = 0.003. CONCLUSIONS: The PSA nadir achieved following primary androgen deprivation therapy predicts progression-free survival in sub Saharan black men newly diagnosed with metastatic PCa. PSA nadir >4 ng/mL was found to be associated with a more rapid clinical progression.

Clinical significance of PSA dynamics in castration-sensitive prostate cancer treated with ARSI doublet therapy: A multicenter study.

BACKGROUND: Androgen receptor signaling inhibitors (ARSIs) have revolutionized the treatment of metastatic castration-sensitive prostate cancer (mCSPC). Prostate-specific antigen (PSA) dynamics, including PSA nadir, PSA response rate, and time to PSA nadir (TTN), are well-established markers of disease control. We evaluated the clinical significance of these PSA dynamics using data from a multicenter clinical database for mCSPC patients. METHODS: We conducted a multicenter retrospective study including 552 mCSPC patients treated with ARSI and ADT, and 262 patients treated with combined androgen blockade (CAB). PSA nadir, PSA response rate, and TTN were evaluated using predefined cut-offs. Clinicopathological data were collected and subsequently analyzed using multivariate Cox regression models to investigate impact of the PSA dynamics on oncological outcomes, including castration resistant prostate cancer free survival (CRPCFS), cancer-specific survival (CSS), and overall survival (OS). Propensity score matching (PSM) was used to minimize selection bias and balance baseline characteristics between treatment the groups. The achievement rates of low PSA nadir and high PSA response were then evaluated. RESULTS: In the ARSI cohort, 36.4% of patients achieved a PSA nadir of ≤ 0.02 ng/mL, and 65.8% attained a PSA response rate of ≥ 99 %. Notably, patients with a PSA nadir of ≤ 0.02 ng/mL, a PSA response rate ≥ 99%, and TTN > 12 months demonstrated significantly improved oncological outcomes. Multivariate analyses confirmed that these PSA dynamics were independent predictors of favorable oncological outcomes. A PSA nadir of ≤ 0.02 ng/mL was as an independent predictor of improved oncological outcomes compared to a nadir of > 0.2 ng/mL (CRPCFS: HR, 0.063; CSS: HR, 0.12; OS: HR, 0.15; P < 0.001). A PSA response rate of ≥ 99% compared to < 95%, also independently predicted more favorable outcomes (CRPCFS: HR, 0.29; CSS: HR, 0.26; OS: HR, 0.30; P < 0.001). Furthermore, a TTN > 12 months was also an independent predictor of improved survival compared to TTN ≤ 3 months (CRPCFS: HR, 0.12; CSS: HR, 0.08; OS: HR, 0.12; P < 0.001). PSM with a 1:1 ratio was associated with significantly higher rates of PSA nadir ≤ 0.02 ng/mL and PSA response rate ≥ 99% in the ARSI doublet group compared to the CAB group. CONCLUSIONS: Our study demonstrates that achieving a PSA nadir ≤ 0.02 ng/mL, a PSA response rate ≥ 99%, and a longer TTN are associated with significantly improved oncological outcomes. Furthermore, we elucidated how PSA dynamics differ between ARSI doublet therapy and CAB, highlighting the distinct characteristics of each. These findings provide valuable clinical information for guiding the management and prognosis of mCSPC in routine clinical practice.

Prostate-Specific Antigen as an Ultrasensitive Biomarker for Patients with Early Recurrent Prostate Cancer: How Low Shall We Go? A Systematic Review.

Serum prostate-specific antigen (PSA) needs to be monitored with ultrasensitive PSA assays (uPSAs) for oncologists to be able to start salvage radiotherapy (SRT) while PSA is <0.5 µg/L for patients with prostate cancer (PCa) relapsing after a radical prostatectomy (RP). Our systematic review (SR) aimed to summarize uPSAs for patients with localized PCa. The SR was registered as InPLASY2023110084. We searched for studies on Google Scholar, PUBMED and reference lists of reviews and studies. We only included studies on uPSAs published in English and excluded studies of women, animals, sarcoidosis and reviews. Of the 115 included studies, 39 reported PSA assay methods and 76 reported clinical findings. Of 67,479 patients, 14,965 developed PSA recurrence (PSAR) and 2663 died. Extremely low PSA nadir and early developments of PSA separated PSAR-prone from non-PSAR-prone patients (cumulative p value 3.7 × 1012). RP patients with the lowest post-surgery PSA nadir and patients who had the lowest PSA at SRT had the fewest deaths. In conclusion, PSA for patients with localized PCa in the pre-PSAR phase of PCa is strongly associated with later PSAR and survival. A rising but still exceedingly low PSA at SRT predicts a good 5-year overall survival.

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

BACKGROUND: Radiotherapy (RT) after radical prostatectomy (RP) includes adjuvant radiotherapy (ART) and salvage radiotherapy (SRT), which can prevent or cure biochemical recurrence. AIMS: To evaluate long-term outcomes of RT after RP and to examine factors affecting biochemical recurrence-free survival (bRFS). METHODS: 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. RESULTS: Median follow-up from RP was 111 months. 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 (< 0.05 ng/mL), PSA nadir after RT (≤ 0.01 ng/mL), and time to PSA nadir (≥ 10 months) 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). CONCLUSIONS: ART and SRT had favorable outcomes with no recurrence within RT field. In SRT, the time to PSA nadir after RT (≥ 10 months) was found to be a new predictor for favorable bRFS and useful in assessing treatment efficacy.

Prostate-specific antigen kinetics and metastasis-free survival in patients treated with external beam radiotherapy combined with high-dose-rate brachytherapy boost and androgen deprivation therapy for localized prostate cancer.

PURPOSE: Serum prostate-specific antigen (PSA) kinetics has been linked to prognosis in prostate cancer (PCa) patients. Our goal was to analyze the association between PSA kinetics and metastasis-free survival (MFS) in patients with localized PCa treated with high-dose-rate (HDR) brachytherapy (BT) boost combined with external beam radiotherapy (EBRT). MATERIAL AND METHODS: We retrospectively analyzed multiple PSA kinetics related to PSA nadir (nPSA), PSA bouncing, and biochemical recurrence (BCR) in 186 PCa patients treated with neoadjuvant androgen deprivation therapy (ADT), followed by EBRT combined with HDR-BT boost. Uni- and multivariate Cox regression models were calculated to assess the value of PSA-related parameters for the prediction of MFS. RESULTS: 5- and 10-year MFS were 95% and 84%, respectively. Median nPSA was 0.011 (IQR, 0.007-0.057) ng/ml and predicted MFS in multivariable analysis. Implementation of nPSA improved c-index of baseline model from 0.8 to 0.68. nPSA of 0.2 ng/ml offered the most optimal discriminatory ability for identifying patients with better prognoses. Time to nPSA (median, 11 months; IQR, 8-18 months) and PSA bounce, which occurred in 12.4% of patients, were not significantly associated with MFS. CONCLUSIONS: Lower values of nPSA are significantly associated with decreased risk of developing metastases in patients treated with EBRT combined with HDR-BT boost and ADT, and improve the accuracy of a clinical model for MFS.

High Dose "HDR-Like" Prostate SBRT: PSA 10-Year Results From a Mature, Multi-Institutional Clinical Trial.

Purpose/Objectives: Although ample intermediate-term prostate stereotactic body radiotherapy (SBRT) outcomes have been reported, 10-year results remain relatively sparse. Materials/Methods: Eighteen institutions enrolled 259 low- and intermediate-risk patients. Median follow-up is 5.5 years, with 66 patients followed ≥ 10 years. This SBRT regimen specifically emulated an existing HDR brachytherapy dose schedule and isodose morphology, prescribed to 38 Gy/4 fractions, delivered daily by robotic SBRT, mandating > 150% dose escalation in the peripheral zone. Androgen deprivation therapy was not allowed, and a hydrogel spacer was not available at that time. Results: Median pre-SBRT PSA 5.12 ng/mL decreased to 0.1 ng/mL by 3.5 years, with further decrease to a nadir of < 0.1 ng/mL by 7 years, maintained through 10 years. Ten-year freedom from biochemical recurrence measured 100% for low-risk, 84.3% for favorable intermediate risk (FIR), and 68.4% for unfavorable intermediate (UIR) cases. Multivariable analysis revealed that the UIR group bifurcated into two distinct prognostic subgroups. Those so classified by having Gleason score 4 + 3 and/or clinical stage T2 (versus T1b/T1c) had a significantly poorer 10 year freedom from biochemical recurrence rate, 54.8% if either or both factors were present, while UIR patients without these specific factors had a 94.4% 10-year freedom from biochemical recurrence rate. The cumulative incidence of grade 2 GU toxicity modestly increased over time - 16.3% at 5 years increased to 19.2% at 10 years-- while the incidence of grade 3+ GU and GI toxicity remained low and stable to 10 years - 2.6% and 0%, respectively. The grade 2 GI toxicity incidence also remained low and stable to 10 years - 4.1% with no further events after year 5. Conclusion: This HDR-like SBRT regimen prescribing 38 Gy/4 fractions but delivering much higher intraprostatic doses on a daily basis is safe and effective. This treatment achieves a median PSA nadir of <0.1 ng/mL and provides high long-term disease control rates without ADT except for a subgroup of unfavorable intermediate-risk patients.

PSA nadir predicts biochemical recurrence after external beam radiation therapy combined to high dose rate brachytherapy in the treatment of prostate cancer.

INTRODUCTION: Prostate cancer (PCa) is the second most prevalent neoplasm among men in the world. Its treatment has a wide spectrum of alternatives and variables, ranging from active surveillance through radio and/or brachytherapy, to surgery. OBJECTIVE: The present work aimed to identify the predictive factors for biochemical recurrence and to evaluate the toxicity of the treatment using the association of external beam radiation therapy (EBRT) with high dose rate brachytherapy (HDR-BT) applied in the treatment of patients with prostate cancer. METHODS: Longitudinal retrospective study, using a prospectively collected database between 2005 and 2014 of 186 consecutive patients records with a diagnosis of low, intermediate, or high-risk prostate cancer treated with EBRT combined with HDR-BT, in a single medical institution located in the city of Campinas, SP, Brazil (Radium Institute). PSA increase over 2 ng/ml above the nadir PSA was considered as biochemical recurrence, following the definition of the Phoenix Consensus. Continuous and clinically relevant categorical variables (age, initial PSA, delivered dose in EBRT, number of implants, number of positive cores in transrectal biopsy, use of hormone blockade, Gleason score, TNM staging, post treatment PSA and PSA Nadir) were evaluated with absolute (n) and percentage (%) values using multiple logistic regression and validated our previously described optimal PSA nadir as predictor of biochemical recurrence. RESULTS: Post treatment PSA was the only independent predictor of biochemical recurrence, P<0.0001. The lower the PSA nadir the lower the biochemical recurrence risk (P=0.0009). PSA nadir >1 was the best cutoff (P=0.018) determinant of biochemical recurrence. The incidence of grade 3 late toxicity to the genitourinary tract was 0.6%, and there were no cases of severe complications to the gastrointestinal tract. CONCLUSION: External Beam Radiation Therapy conjugated to Brachytherapy in the treatment of Prostate Cancer has demonstrated low biochemical recurrence rates, mainly when PSA nadir <1, with low toxicity into both GU and GI tracts.

Predictors of poor response to first-generation anti-androgens as criteria for alternate treatments for patients with non-metastatic castration-resistant prostate cancer.

PURPOSE: There are no criteria for administering first- or second-generation anti-androgens (FGA and SGA, respectively) to patients with non-metastatic castration-resistant prostate cancer (nmCRPC). This study aimed to assess the efficacy of alternative FGA therapy in nmCRPC patients and the prognosis of these patients and to identify factors for predicting patients potentially responsive to FGA. METHODS: Data from 63 men with nmCRPC who underwent alternative FGA therapy (bicalutamide, flutamide, or chlormadinone acetate) as first-line therapy after failure of primary androgen-deprivation therapy (PADT) between 2004 and 2017 at Hiroshima University Hospital and affiliated hospitals were retrospectively investigated. The associations of clinicopathological parameters with overall survival (OS) and prostate-specific antigen (PSA) progression-free survival (PFS) of alternative FGA-treated patients were analyzed. RESULTS: Time to CRPC [p = 0.007, hazard ratio (HR) = 4.77], regional lymph node involvement at the diagnosis of CRPC (p = 0.022, HR = 2.42), and PSA-PFS of alternative FGA therapy ≤ 6 months (p = 0.020, HR = 2.39) were identified as prognostic factors using a multivariate analysis. Additionally, Cox proportional hazard models revealed that PSA nadir value > 1 ng/mL during PADT (p = 0.034, HR = 2.40) and time from starting PADT to PSA nadir ≤ 1 year (p = 0.047, HR = 1.85) were predictive factors for worse PSA-PFS in alternative FGA therapy. CONCLUSIONS: Shorter time to CRPC, regional lymph node involvement, PSA nadir during PADT > 1 ng/mL, and time from starting PADT to PSA nadir ≤ 1 year might suggest the potential benefit of immediate commencement of SGA, compared to FGA administration after nmCRPC diagnosis.

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: Multicenter validation in patients from the Chinese Prostate Cancer Consortium.

OBJECTIVE: Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China. We have previously shown that time to nadir (TTN) of prostate-specific antigen (PSA) is an important prognostic factor in patients from a single center in Northwestern China. In this study, we performed a multicenter validation of the prognostic role of TTN in additional Chinese patients with mCRPC receiving docetaxel treatment. MATERIALS AND METHODS: The data were gathered from 170 eligible Chinese patients who received docetaxel chemotherapy from January 2007 to October 2018 in 11 Chinese Prostate Cancer Consortium member hospitals in China. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS). RESULTS: Patients with a TTN ≥ 15 weeks had a longer OS and PFS compared to those with a TTN < 15 weeks (43 vs. 15 months, P < 0.001; 24 vs. 6 months, P < 0.001, respectively). In addition, Patients with a TTN ≥ 15 weeks and PSA nadir <4.55ng/ml were associated with longer OS than others (HR 0.093, 95% CI 0.044-0.188, P < 0.001; HR 4.002, 95% CI 1.890-8.856, P = 0.001, respectively) and TTN, PSA nadir, PSA baseline (optimal threshold 56.07 ng/ml), and PSA reduction (optimal threshold 50%) were associated with PFS (HR 0.238, 95% CI 0.149-0.382, P < 0.001; HR 1.676, 95% CI 1.033-2.722, P = 0.037; HR 1.770, 95% CI 1.134-2.763, P = 0.012; HR 0.573, 95% CI 0.428-0.756, P < 0.001; respectively). Furthermore, patients with a PSA nadir <4.55 ng/ml had longer OS and PFS compared to other patients when TTN was ≥15 weeks. CONCLUSION: In this multicenter validation study, TTN and PSA nadir remain important prognostic markers in predicting therapeutic outcomes in Chinese men who receive chemotherapy for mCRPC.

Radical dose escalation by high-dose-rate brachytherapy for localized prostate cancer-Significance of prostate-specific antigen nadir level within 18 months as correlation for long-term biochemical control.

PURPOSE: High-dose-rate brachytherapy (HDR-BT) for dose escalation in localized prostate cancer has been established as one standard treatment option. However, long-term results at followup (FU) ≥5 years are usually needed to ensure robustness of reported outcomes. Potential benefit of salvage therapy is, nevertheless, higher when relapse is diagnosed early. This study aimed to solve this dilemma by evaluating the prostate-specific antigen (PSA) nadir for early prediction of long-term biochemical control. METHODS AND MATERIALS: Combined pelvis-external beam radiation/HDR-BT boost to EQD2 >100 Gy (α/ß = 3) was performed in 459 consecutively treated patients. These patients with an FU ≥ 24 months were analyzed and stratified in PSA nadir (nPSA)-groups by PSA nadir within 18 months after radiotherapy (nPSA18). Kaplan-Meier/log-rank tests and Cox-regression models were used to compare the study endpoints. RESULTS: The mean FU was 77 months. A PSA nadir within 18 months (nPSA18) <0.5 ng/mL was achieved in 222 patients with median time to reach nPSA18 of 7 months. The 5-year American Society of Therapeutic Radiology and Oncology (ASTRO) biochemical control (prostate-specific antigen disease-free survival) for the nPSA18 group <0.5 ng/mL was 89% and for the group ≥ 0.5 ng/mL, it was 78.6% (p = 0.011). nPSA18 was an independent predictor of cancer-specific survival, distant metastasis-free survival, and biochemical control (ASTRO) (p = 0.026, p = 0.020, and p = 0.01, respectively). CONCLUSIONS: The present results suggest that the PSA nadir level within 18 months after radiotherapy may serve as an early parameter for long-term biochemical control according to ASTRO definitions following radical dose escalation by HDR-BT for prostate cancer. Excellent outcomes were associated with nPSA18 < 0.5 ng/mL.

A comparison of early prostate-specific antigen decline between prostate brachytherapy and different fractionation of external beam radiation-Impact on biochemical failure.

PURPOSE: The aim of this study was to compare early prostate-specific antigen (PSA) decline patterns and PSA nadirs between low-dose-rate seed prostate brachytherapy (LDR-PB) and different fractionations of external beam radiotherapy (EBRT) and their predictive importance for biochemical failure (bF). METHODS AND MATERIALS: Patients with D'Amico low- or intermediate-risk prostate cancer who underwent a single-modality treatment without androgen deprivation were included in this study. Three different treatment groups were compared: (1) normofractionation EBRT up to 70.2-79.2 Gy/1.8-2.0 Gy, (2) LDR-PB, and (3) EBRT with hypofractionation 60 Gy/3 Gy daily or 5-7.25 Gy once a week over 9-5 weeks, to a total dose of 45-36.25 Gy, respectively. The log-rank test, Cox regression analysis, and nonparametric tests were used. RESULTS: We analyzed 892 patients: the median followup for patients without bF was 84 months (interquartile range 60-102 months), with 12% of patients experiencing bF. The PSA decline within the first 15 months was generally exponential. LDR-PB showed a faster early exponential decline compared with EBRT treatments, but whether decline was fast or slow had no influence on recurrence. The only factors that were positive predictive factors in univariate and multivariate analyses were the time to nadir >48 months (median), PSA nadir <0.5 ng/mL, and <0.2 ng/mL (all p < 0.001). CONCLUSIONS: Although there are significant differences in early exponential PSA decline between different treatments, only the PSA nadir and longer time to nadir were predictive factors for bF.

Risk factors for biochemical recurrence after a tissue-ablative prostate-specific antigen <0.2 ng/mL.

PURPOSE: A prostate-specific antigen (PSA) nadir <0.2 ng/mL is generally considered as tissue ablative and at low risk for recurrence. After attaining such a low PSA nadir, we analyzed risk factors for recurrence. METHODS AND MATERIALS: We identified patients from our institutionalized database with either D'Amico low- or intermediate-risk prostate cancer that was treated with either low-dose-rate prostate brachytherapy or external beam radiotherapy as monotherapy. We compared patients who attained a nadir <0.2 ng/mL and subsequently developed biochemical failure to patients who did not experience biochemical failure by using χ2 test and Student t test. Survival analysis was performed using the Kaplan-Meier method (log-rank test). RESULTS: Of 892 patients, 560 (63%) achieved a nadir <0.2 ng/mL. Only 23 (4.1%) later developed a biochemical recurrence. The 7-year Kaplan-Meier biochemical recurrence-free survival after a PSA nadir of <0.2 ng/mL was 96%. Patients who later experienced biochemical recurrence were more likely to have Cancer of the Prostate Risk Assessment Score intermediate- or high-risk cancer: (74% vs. 40%, p < 0.001). Patients were more likely to have a diagnostic PSA >6.0 ng/mL: (66% vs. 43% p < 0.001) and have a Gleason score ≥ 3  + 4: (52% vs. 34%, p = 0.005). They were also more likely to be older (p = 0.003): mean (SD) 70.3 (6.4) vs. 66.2 (6.5) and have a time to PSA nadir that was significantly shorter (p = 0.013): mean (SD) 51.8 (29.6) vs. 65.2 (25.1). CONCLUSIONS: Biochemical recurrence after attaining a PSA nadir <0.2 ng/mL is rare and more frequent in patients with intermediate risk cancer and older patients. These patients can benefit from a prolonged followup with specialized physicians.

The Importance of Time to Prostate-Specific Antigen (PSA) Nadir after Primary Androgen Deprivation Therapy in Hormone-Naïve Prostate Cancer Patients.

Prostate-specific antigen (PSA) is currently the most useful biomarker for detection of prostate cancer (PCa). The ability to measure serum PSA levels has affected all aspects of PCa management over the past two decades. The standard initial systemic therapy for advanced PCa is androgen-deprivation therapy (ADT). Although PCa patients with metastatic disease initially respond well to ADT, they often progress to castration-resistant prostate cancer (CRPC), which has a high mortality rate. We have demonstrated that time to PSA nadir (TTN) after primary ADT is an important early predictor of overall survival and progression-free survival for advanced PCa patients. In in vivo experiments, we demonstrated that the presence of fibroblasts in the PCa tumor microenvironment can prolong the period for serum PSA decline after ADT, and enhance the efficacy of ADT. Clarification of the mechanisms that affect TTN after ADT could be useful to guide selection of optimal PCa treatment strategies. In this review, we discuss recent in vitro and in vivo findings concerning the involvement of stromal⁻epithelial interactions in the biological mechanism of TTN after ADT to support the novel concept of "tumor regulating fibroblasts".

Association of Nadir Prostate-specific Antigen >0.5 ng/mL after Dose-escalated External Beam Radiation with Prostate Cancer-specific Endpoints.

Objective Prior studies have suggested that prostate-specific antigen (PSA) nadir of 0.5 ng/mL is an important surrogate endpoint for prostate cancer-specific and all-cause mortality. This study analyzed our well-followed patient cohort to assess whether this endpoint was associated with differences in prostate cancer-specific endpoints in patients receiving dose-escalated radiation. Methods Patients with intermediate- or high-risk prostate cancer (≥T2b, or prostate-specific antigen >10 ng/mL, or Gleason score ≥7) who were treated with external beam radiation to a minimum dose of 7560 cGy +/- androgen deprivation between 2003 and 2011 were identified. Biochemical control, distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were compared between those who achieved a nadir PSA ≤0.5 ng/mL with those who did not via Kaplan-Meier analysis. Univariable and multivariable Cox regression was performed on all endpoints to assess their impact on OS. Results There were 367 patients identified with a median follow-up of 99.5 months. Two hundred five patients (55.9%) received androgen deprivation for a median of 24 months (range 1-81 months). Most patients (n = 308, 83.9%) achieved a nadir PSA ≤0.5 ng/mL, which was associated with improvement across all endpoints at 10 years. This included biochemical control (68.0% versus 24.0%, p < 0.001), DMFS (89.6% versus 80.8%, p = 0.019), PCSS (91.1% versus 85.7%, p = 0.01), and OS (55.7% versus 45.8%, p = 0.048). On multivariable analysis, nadir PSA >0.5 ng/mL remained strongly associated with worse outcomes across all endpoints. Conclusions Achievement of nadir PSA ≤0.5 ng/mL after completion of dose-escalated radiation therapy was associated with improvement of all prostate cancer endpoints.