The State of Intermediate Clinical Endpoints as Surrogates for Overall Survival in Prostate Cancer in 2024.

In the past, selection of intermediate clinical endpoints (ICEs) in prostate cancer (PCa) trials largely depended on qualitative assessments; however, the advancing quality of research necessitates a robust correlation with overall survival (OS). This review summarises the results from several high-quality meta-analyses that explored the validity of ICEs as surrogates for OS. We found strong evidence that metastasis-free survival can serve as an ICE in localized PCa. In advanced disease, valid ICEs were identified only within the context of metastatic hormone-sensitive PCa, including radiological and clinical progression-free survival; however, concerns remain regarding their use owing to the limited generalisability of the data used to validate their surrogacy. PATIENT SUMMARY: Intermediate clinical endpoints can reduce the costs of trials and allow earlier introduction of new treatment methods. This article summarises results from studies verifying the validity of these endpoints as surrogates for overall survival.

The effect of dose-escalation radiotherapy with simultaneous-integrated-boost on the use of short-term androgen deprivation therapy in patients with intermediate risk prostate cancer.

PURPOSE: To compare the biochemical failure (FFBF) and prostate cancer specific survival (PCSS) rates of patients with intermediate-risk prostate cancer (IR-PC) who were treated with 6 months of androgen deprivation therapy (ADT) with 78 Gy to the prostate, those treated with ADT and focal boost (FB) of 86 Gy to intraprostatic lesion (IPL) using the simultaneous-integrated boost (SIB) technique, and those treated with SIB alone. MATERIALS AND METHODS: A retrospective analysis of 320 IR-PC patients treated between January 2012 and April 2021 was performed. Patients were divided into three groups based on their treatment arm: 78 + ADT (109 patients, 34.1%), 78/86 (102 patients, 31.8%), and 78/86 + ADT. Univariable and multivariable analyses were used to determine prognostic factors for FFBF and PCSS. RESULTS: Median follow-up was 8.8 years. The 8-year FFBF and PCSS rates were 88.6% and 99.0%. Patients who received ADT had significantly higher pretreatment PSA levels and clinical tumor stage. Disease progression occurred in 45 patients (7.3%) at a median of 41.9 months after definitive radiotherapy (RT). Younger age, positive core biopsy (PCB) ≥ 50%, and the absence of ADT were all independent predictors of poor FFBF in multivariate analysis, whereas patients with PCB < 50% who were also given ADT had better PCSS. Patients treated with 78/86 Gy alone had worse FFBF than those treated with 78 Gy and ADT (Hazard ratio [HR] = 3.39 [95% CI = 1.46-7.88]; p = 0.005), as well as than those treated with 78/86 Gy and ADT (HR = 3.21 [95% CI = 1.23-6.46]; p = 0.009). However, FB to IPL has no effect on PCSS in multivariable analysis. There was no significant difference between treatment groups in terms of acute and late Grade ≥2 genitourinary or gastrointestinal toxicity. CONCLUSIONS: Our findings demonstrated that patients who received 78/86 alone did worse than patients who received ADT with either 78 or 78/86 Gy. However, because IR-PC patients are so diverse, additional prospective trials are needed to validate our findings.

Brachytherapy for favorable prognostic prostate cancer in men up to 60 years of age: Long term follow-up.

PURPOSE: Brachytherapy (BT) is a standard treatment for low- and favorable intermediate-risk prostate adenocarcinoma. Few studies have focused on young patients. We therefore evaluated long-term efficacy and toxicity of BT in patients aged ≤ 60 years with low- and favorable intermediate-risk prostate cancer. MATERIALS AND METHODS: This retrospective study included patients aged ≤60 years with low- or favorable intermediate-risk prostate adenocarcinoma treated with iodine BT alone between 1999 and 2014 at the Institut de Cancérologie de Lorraine. Follow-up assessment included incidence of biochemical failure (BF) at 10 and 15 years after BT, as well as survival data and late toxicities. RESULTS: A total of 177 patients of median age 56 years (54-58) were analyzed, with a median follow-up of 126 months (97-172). Incidence of BF at 10 and 15 years after BT was 5.4% and 11.7% respectively. PSA nadir (HR = 51.8 [95% CI 6.69-277], p < 0.001), age at treatment (HR = 1.78 [95% CI 1.19-2.65], p = 0.005) and prostate D90% (HR = 1.08 [95% CI 1.01-1.15], p < 0.021) were identified as predictive factors of BF. Overall survival at 10 and 15 years after BT was 92.8% and 84.4% respectively. Cancer-specific survival at 10 and 15 years after BT was 99.3% and 97.7% respectively. No major toxicity was recorded. CONCLUSIONS: Exclusive BT is a long-term effective treatment for patients aged ≤ 60 years with low- or favorable intermediate-risk prostate adenocarcinoma.

Combination of [18F]FDG and [18F]PSMA-1007 PET/CT predicts tumour aggressiveness at staging and biochemical failure postoperatively in patients with prostate cancer.

PURPOSE: [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limitations in prostate cancer (PCa) detection owing to low glycolysis in the primary tumour. Recently, prostate-specific membrane antigen (PSMA) PET/CT has been useful for biochemical failure detection and radioligand therapy (RLT) guidance. However, few studies have evaluated its use in primary prostate tumours using PSMA and [18F]FDG PET/CT. This study aimed to evaluate [18F]PSMA-1007 and [18F]FDG PET/CT for primary tumour detection and understand the association of metabolic heterogeneity with clinicopathological characteristics at staging and postoperatively. METHOD: This prospective study included 42 index tumours (27 acinar and 15 ductal-dominant) in 42 patients who underwent [18F]PSMA-1007 and [18F]FDG PET/CT and subsequent radical prostatectomy. All patients were followed for a median of 26 mo, and serum prostate-specific antigen levels were measured every 3 mo to evaluate biochemical failure. One-way analysis of variance, Tukey's multiple comparison test, and Fisher's exact test were performed. RESULTS: All 42 index tumours were detected on [18F]PSMA-1007 PET/CT, whereas only 15 were detected on [18F]FDG PET/CT (62.3% vs. 37.7%, p < 0.0001). A high SUVmax for [18F]PSMA-1007 was observed in tumours with high Gleason scores (GS 6-7 vs. GS 8-10; 12.1 vs. 20.1, p < 0.05). Tumours with [18F]FDG uptake were mostly ductal dominant (acinar-dominant 4/27; ductal-dominant; 11/15, p < 0.001), with lower [18F]PSMA-1007 uptake than tumours without [18F]FDG uptake (SUVmax 16.58 vs. 11.19, p < 0.001). There were 16.6% (7/42) of patients with pStage IV in whom the primary tumours were [18F]FDG positive. Biochemical failure was observed in 14.8% (4/27) of patients with [18F]FDG negative tumours but in 53.3% (8/15) of patients with [18F]FDG positive tumours (p = 0.013). CONCLUSIONS: [18F]PSMA-1007 PET/CT was superior to [18F]FDG PET/CT in detecting primary PCa. In contrast, tumours with [18F]FDG uptake are associated with larger size, a ductal-dominant type, and likely to undergo metastasis at staging and biochemical failure postoperatively.

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.

Primary Total Prostate Cryoablation for Localized High-Risk Prostate Cancer: 10-Year Outcomes and Nomograms.

The role of prostate cryoablation was still uncertain for patients with high-risk prostate cancer (PC). This study was designed to investigate 10-year disease-free survival and establish a nomogram in localized high-risk PC patients. Between October 2008 and December 2020, 191 patients with high-risk PC who received primary total prostate cryoablation (PTPC) were enrolled. The primary endpoint was biochemical recurrence (BCR), defined using Phoenix criteria. The performance of pre-operative and peri-operative nomograms was determined using the Harrell concordance index (C-index). Among the cohort, the median age and PSA levels at diagnosis were 71 years and 12.3 ng/mL, respectively. Gleason sum 8-10, stage ≥ T3a, and PSA > 20 ng/mL were noted in 27.2%, 74.4%, and 26.2% of patients, respectively. During the median follow-up duration of 120.4 months, BCR-free rates at 1, 3, 5, and 10 years were 92.6%, 76.6%, 66.7%, and 50.8%, respectively. The metastasis-free, cancer-specific, and overall survival rates were 89.5%, 97.4%, and 90.5% at 10 years, respectively. The variables in the pre-operative nomogram for BCR contained PSA at diagnosis, clinical stage, and Gleason score (C-index: 0.73, 95% CI, 0.67-0.79). The variables in the peri-operative nomogram for BCR included PSA at diagnosis, Gleason score, number of cryoprobes used, and PSA nadir (C-index: 0.83, 95% CI, 0.78-0.88). In conclusion, total prostate cryoablation appears to be an effective treatment option for selected men with high-risk PC. A pre-operative nomogram can help select patients suitable for cryoablation. A peri-operative nomogram signifies the importance of the ample use of cryoprobes and helps identify patients who may need early salvage treatment.

Salvage high-dose-rate interventional radiotherapy (brachytherapy) for locally relapsed prostate cancer after radical prostatectomy and subsequent external irradiation.

Purpose: To report the use of high-dose-rate (HDR) interventional radiotherapy (brachytherapy, IRT) as a salvage treatment for macroscopic histologically confirmed local relapse of prostatic cancer after prostatectomy and subsequent external irradiation. Material and methods: A retrospective study of patients with prostate adenocarcinoma, treated with HDR-IRT for an isolated local relapse after prostatectomy and external irradiation at our institution (2010-2020). Treatment results and treatment related-toxicity were recorded. Clinical outcomes were analyzed. Results: Ten patients were identified. The median age was 63 years (range, 59-74 years), and the median follow-up time was 34 months (range, 10-68 months). Four patients had a biochemical relapse, and the mean time to prostate specific antigen (PSA) increase was 13 months. One-year biochemical failure-free survival (bFFS), 3-year bFFS, and 4-year bFFS were 80%, 60%, and 60%, respectively. Most of the treatment-related toxicities were grade 1-2. Two patients experienced grade 3 late genitourinary toxicity. Conclusions: HDR-IRT seems to be an effective treatment option showing acceptable toxicity for prostate cancer patients with isolated macroscopic histologically confirmed local relapse after prostatectomy and subsequent external irradiation.

Mesorectal nodal metastasis with seminal vesicle invasion in biochemically recurrent prostate cancer.

OBJECTIVES: To determine the prevalence and predictors of mesorectal lymph node (MLN) metastases on prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) in patients with biochemically recurrent prostate cancer (PCa) following radical therapy. MATERIALS AND METHODS: This was a cross-sectional analysis of all PCa patients with biochemical failure following radical prostatectomy or radiotherapy who underwent an 18 F-DCFPyL-PSMA-PET/CT at the Princess Margaret Cancer Centre between December 2018 and February 2021. Lesions with PSMA scores ≥2 were considered positive for PCa involvement (PROMISE classification). Predictors of MLN metastasis were evaluated using univariable and multivariable logistic regression analyses. RESULTS: Our cohort consisted of 686 patients. The primary treatment method was radical prostatectomy and radiotherapy in 528 (77.0%) and 158 patients (23.0%), respectively. The median serum PSA level was 1.15 ng/mL. Overall, 384 patients (56.0%) had a positive scan. Seventy-eight patients (11.3%) had MLN metastasis, with 48/78 (61.5%) having MLN involvement as the only site of metastasis. On multivariable analysis, presence of pT3b disease (odds ratio 4.31, 95% confidence interval 1.44-14.2; P = 0.011) was significantly associated with increased odds of MLN metastasis, whereas surgical factors (radical prostatectomy vs radiotherapy; performance/extent of pelvic nodal dissection), surgical margin positivity, and Gleason Grade were not. CONCLUSIONS: In this study, 11.3% of PCa patients with biochemical failure had MLN metastasis on 18 F-DCFPyL-PET/CT. pT3b disease was associated with 4.31-fold significantly increased odds of MLN metastasis. These findings suggest alternate drainage routes for PCa cells, either via alternate lymphatic drainage from the seminal vesicles themselves or secondary to direct extension from posteriorly located tumours invading the seminal vesicles.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

PURPOSE: We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). METHODS: The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). RESULTS: All but one patient responded with a 98.8% reduction in serum PSA (21.8 ng/mL vs. 0.3 ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1 months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6 months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. CONCLUSION: These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

Role of magnetic resonance imaging for preoperative prediction of early biochemical failure in localized prostate cancer.

Background: The purpose of our study was to assess preoperative clinical biological and Magnetic Resonance Imaging (MRI) predictive factors of early biochemical failure (BF), defined as persistence of significant post-operative plasmatic prostate specific antigen (PSA) level after radical prostatectomy (RP) in patients with localized prostate cancer (PCa). Methods: In a retrospective cohort study we included 142 patients from our university hospital with newly diagnosed PCa, who underwent 3T multiparametric MRI prior to RP. Only the MRI target lesions [Prostate Imaging Reporting and Data System (PIRADS) ≥3] with histological correspondence were considered significant. Clinical, biological, MRI and pathological preoperative data were studied. We performed univariate and multivariate logistic regression analysis to identify significant parameters associated with early BF. Results: Early BF occurred in 14% of patients (20/142). Patients with BF had higher PSA level at diagnosis, Gleason score, number of positive biopsies, size of the largest positive biopsy and higher National Comprehensive Cancer Network (NCCN) risk score (P<0.001 for all). According to MRI, they also had higher T stage and a higher size of capsular contact (P<0.001 for all). In contrast, there was no difference concerning neither ADC value, perfusion profile and zonal location of the index lesion. In multivariate analysis, the best combination of predictive factors of early BF was the association of preoperative Gleason score ≥4+3 [odds ratio (OR) =6.8 (1.4-32.5); P=0.002] and T stage ≥3 on preoperative MRI [OR =17.4 (3.2-94.9); P<0.001] with an area under the curve (AUC) of 0.89 [99% confidence interval (CI): 0.77-1], a negative predictive value of 94% and a positive predictive value of 75%. Conclusions: Combination of simple preoperative biomarkers as Gleason score and T stage according to MRI accurately stratify the risk of early BF following RP. These results emphasize the pivotal role of preoperative MRI for the management of localized PCa.

The Prognostic Value of DCE-MRI Findings before Salvage Radiotherapy after Radical Prostatectomy.

BACKGROUND: To investigate the predictive role of dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) findings before salvage radiotherapy after radical prostatectomy (RP). METHODS: This retrospective study selected patients with biochemical failure (BF) after RP restaged with DCE-MRI. Patients underwent sRT in 30 fractions delivering 66-69 Gy and 73.5 Gy to the prostatic fossa and to the local failure as per DCE-MRI, respectively. Pelvic nodes were treated to 54 Gy in selected patients. The endpoint was BF after sRT. RESULTS: In total, 236 patients were analyzed and 146 (61.9%) had presumed local failure at DCE-MRI: 54.8%, 23.8% and 21.4% were found at the vesico-urethral anastomosis (VUA), the bladder neck and the retro-vesical space, respectively. The presence of a local failure at DCE-MRI halved the risk of BF; VUA-only location and lesion volume were independently correlated with survival without evidence of biochemical failure (bNED) at multivariable analysis. For patients with VUA-only disease up to 0.4 cc, the 4-year-bNED was 94.6% (95%CI: 80.2-98.6%) as opposed to 80.9% (95%CI: 71.6-87.4%) and 73.7% (95%CI: 63.1-81.8%) for other lesions and no macrodisease, respectively. CONCLUSIONS: DCE-MRI at restaging for BF after RP provides predictive and therapeutic information. Patients with small lesions at the VUA have an excellent prognosis after sRT.

Biochemical outcomes and toxicities in young men with prostate cancer after permanent iodine-125 seed implantation: Prospective cohort study in 6662 patients.

PURPOSE: We evaluated the effect of age, <60 and ≥60 years, on biochemical outcomes and toxicities in patients with prostate cancer who underwent permanent seed implantation (PI) ± external beam radiation therapy ± hormone therapy in a national Japanese prospective cohort study (J-POPS). METHODS AND MATERIALS: The safety and efficacy analyses included 6721 and 6662 patients, respectively. We categorized patients into two age groups: <60 (n = 716) and ≥60 (n = 6,005) years. We used propensity score matching (PSM) to estimate the marginal effect of age on biochemical freedom from failure (bFFF) using a Phoenix definition and Cox proportional hazard models. RESULTS: The median followup period was 60.0 months. Without PSM, men <60 years demonstrated similar 5-year bFFF (96.3%) compared with men ≥60 years (95.6%; p = 0.576); percent positive biopsies, biologically effective dose, Gleason score, risk classification, and supplemental external beam radiation therapy (p <0.001, <0.001, <0.001, 0.008, and <0.001) were significantly associated with bFFF while age was not (p = 0.576). With PSM, bFFF was not significantly different between age groups (p = 0.664); however, men <60 years showed a significantly lower incidence of declining erectile function, grade ≥2 all urinary toxicities, urinary frequency/urgency, and rectal bleeding (p <0.001, 0.024, 0.031, and 0.010) than men ≥60 years. CONCLUSIONS: After PI, men <60 years achieved a comparable 5-year biochemical control rate and showed a lower incidence of several toxicities compared to men ≥60 years. This suggests that PI should be an excellent treatment option for men <60 years with prostate cancer.

Feasibility of MRI targeted single fraction HDR brachytherapy for localized prostate carcinoma: ProFocAL-study.

PURPOSE: A potential method for focal therapy in locally advanced prostate cancer is focal brachytherapy (F-BT). The purpose of this research was to evaluate midterm F-BT oncologic, functional, and toxicological results in men who had therapy for prostate cancer. MATERIALS AND METHODS: Between 2016 and 2020, F-BT was used to treat 37 patients with low- to intermediate-risk prostate cancer. The recommended dosage was 20 Gy. Failure was defined as the existence of any prostate cancer that has persisted in-field after treatment. The F-BT oncologic and functional outcomes served as the main and secondary objectives, respectively. RESULTS: A median 20-month follow-up (range 14-48 months). 37 patients received F-BT and enrolled in the study; no patient experienced a biochemical recurrence in the first 24 months, according to Phoenix criteria. In the control biopsies, only 6 patients showed in-field failure. The median initial IPSS was 6.5, at 6 months was 6.0, and at 24 months was 5.0. When the median ICIQ-SF score was 0 at the baseline, it remained 0 at 6-, 12-, and 24 months. Overall survival and biochemical disease-free survival after 3 years were all at 100% and 86.4%, respectively. There was no notable acute gastro-intestinal (GI) or genitourinary (GU) adverse effects. No intraoperative or perioperative complications occurred. CONCLUSIONS: For selected patients with low- or intermediate-risk localized prostate cancer, F-BT is a safe and effective therapy.

Analysis of biochemical failure rate and its influencing factors in patients with high-risk localized prostate cancer after radical prostatectomy / 中华泌尿外科杂志

Objective:To analyze the biochemical failure rate and its predictive factors after radical prostatectomy (RP) in patients with high-risk localized prostate cancer.Methods:The data of 166 patients with high-risk localized prostate cancer who underwent RP surgery in Peking university cancer hospital from January 2015 to November 2021 were retrospectively reviewed. The average age was 65.4±6.2 years old, and the average body mass index (BMI) was 24.86±3.23 kg/m 2. The median prostate-specific antigen (PSA) was 19.84 (10.98, 44.47) ng/ml, PSA density was 0.68 (0.34, 1.32)ng/ml 2, and prostate volume was 31.20 (25.58, 40.23) ml. Biopsy pathology Gleason score according to the International society of Urological Pathology(ISUP) grade group: 18 cases of group 1, 33 cases of group 2, 30 cases of group 3, 51 cases of group 4, and 33 cases of group 5, 1 case was unknown. The percentage of puncture positive needles was (55.4±25.7)%, and the largest linear length of positive lesions was 80.0% (60.0%, 90.0%). Preoperative clinical stage : 14 cases in ≤T 2b stage, 117 cases in T 2c stage, 13 cases in T 3a stage and 22 cases in ≥T 3b stage; 157 cases in N 0 stage, 9 cases in N 1 stage. One hundred and three patients (62.0%) were assessed by traditional imaging and 63(38.0%) were assessed by PSMA PET-CT. The patients underwent laparoscopic radical prostatectomy. 64 patients (38.6%) received neoadjuvant therapy, including 37 received neoadjuvant therapy for 1-3 months, 23 for 4-6 months and 4 for over 6 months. The postoperative pathological characteristics, treatment and prognosis of the patients were analyzed. The primary endpoint was biochemical failure, including biochemical persistence(BCP, defined as PSA≥0.1ng/ml at 4-6 weeks after operation, and confirmed by re-examination at least 1 week interval) and biochemical recurrence(BCR, PSA falling below 0.1ng/ml after operation and then rising ≥0.2 ng/ml without adjuvant therapy or after the end of adjuvant treatment). Results:Compared with preoperative clinicopathological characteristics, 48(28.9%) cases had postoperative pathological ISUP upgrade, 98 (59.0%)cases had T stage upgrade, and 13 (7.8%) cases had N stage upgrade. The rate of positive margins was 53%, and apex margin was the most common positive site (65.9%). The postoperative PSA in 114 patients (68.7%) decreased to less than 0.1ng/ml, of which 74 patients didn't receive the therapy and 40 patients received adjuvant therapy. 52 patients (31.3%) had postoperative PSA more than 0.1ng/ml and among them, 51 cases received salvage treatment. 5 patients (3.0%) underwent PSA progression during adjuvant or salvage endocrine therapy and were considered to have castration resistance. After a median follow-up time of 25.5 (12.0, 40.0) months, 78 patients (48.4%, 78/161) experienced biochemical failure, including 49 BCP and 29 BCR, the median time of biochemical failure was 30.0 (95% CI 14.5-45.5) months. Adjuvant therapy could reduce the rate of BCR (31.1% and 15.8%, P=0.08). Baseline PSA, PSA density, proportion of pathological ISUP ≥4, proportion of pathological T stage ≥T 3a, adjuvant therapy, and positive surgical margins were significantly associated with biochemical failure ( P=0.034, 0.002, 0.004, 0.025, <0.001and 0.047). Multivariate Cox regression analysis showed that adjuvant therapy ( P<0.001, OR=0.12), PSA density ( P=0.03, OR=1.19) and positive surgical margins ( P=0.034, OR=1.80) were independent factors for biochemical failure. Conclusions:Patients with high-risk localized prostate cancer have a high rate of biochemical failure after RP and need to receive RP-based multimodal therapy. Adjuvant therapy, PSA density and positive surgical margins are independent factors associated with postoperative biochemical failure.

Radiation Therapy for Recurrent or Residual Pituitary Macroadenoma Invading Extrasellar Structures.

PURPOSE: This study aimed to evaluate the efficacy of radiation therapy (RT) for recurrent or residual pituitary macroadenoma (PMA) invading extrasellar regions. MATERIALS AND METHODS: Patients from 2000 to 2020 who received RT with conventional fractionation for recurrent or residual PMA were included. The patients were divided according to the type of tumor [functioning (fx) or non-fx] and the aim of RT (salvage RT alone, immediate postoperative RT, delayed postoperative RT). Local and biochemical failure-free rates (FFR) were calculated using the Kaplan-Meier method. RESULTS: With a median follow up of 82 months (IQR; 42-132 months), 36 patients treated with conventional RT (total 45-54 Gy in 1.8 or 2 Gy per fraction) for recurrent or residual PMA were analyzed. The 10-year local FFRs after RT for non-fx and fx tumor were 100% and 74.4%, respectively (p=0.047). In the immediate postoperative RT group, the 10-year local FFR was 100%, which was higher than the 90% FFR for salvage RT alone or 80% FFR for the delayed postoperative RT group (overall p=0.043, immediate vs. salvage; p=0.312, immediate vs. delayed; p=0.072). The local FFR was compared according to size of tumor with a cut-off value of 4 cm, and there was no significant difference (10-year local FFR 100% vs. 84.7% for >4 cm vs. <4 cm, p=0.320). The extents of extrasellar region invasion were not predictive of local failure after RT. We found no grade ≥3 acute toxicities or newly developed visual impairments as a late toxicity of RT. CONCLUSION: Conventional RT is safe and effective for the local control of recurrent or residual PMA. Our data suggest that immediate postoperative RT can be beneficial in recurrent or residual PMA, although further studies to evaluate risk factors of treatment failure in terms of treatment and disease characteristics are required.

Computer classification and construction of a novel prognostic signature based on moonlighting genes in prostate cancer.

Advanced prostate cancer (PRAD) patients have poor prognosis and rising morbidity despite the ongoing iteration of molecular therapeutic agents. As newly discovered proteins with several functions, Moonlighting proteins have showed an important role in tumor progression but has not been extensively investigated in PRAD. Our study aimed to identify moonlighting-related prognostic biomarkers and prospective PRAD therapy targets. 103 moonlighting genes were gathered from previous literatures. A PRAD classification and multivariate Cox prognostic signature were constructed using dataset from The Cancer Genome Atlas (TCGA). Subsequently, we tested our signature's potential to predict biochemical failure-free survival (BFFS) using GSE21032, a prostate cancer dataset from Gene Expression Omnibus (GEO). The performance of this signature was demonstrated by Kaplan-Meier (KM), receiver operator characteristic (ROC), areas under ROC curve (AUC), and calibration curves. Additionally, immune infiltration investigation was conducted to determine the impact of these genes on immune system. This signature's influence on drug susceptibility was examined using CellMiner's drug database. Both training and validation cohorts demonstrated well predictive capacity of this 9-gene signature for PRAD. The 3-year AUCs for TCGA-PRAD and GSE21032 were 0.802 and 0.60 respectively. It can effectively classify patients into various biochemical recurrence risk groups. These genes were also assessed to be connected with tumor mutation burden (TMB), immune infiltration and therapy. This work created and validated a moonlighting gene signature, revealing fresh perspectives on moonlighting proteins in predicting prognosis and improving treatment of PRAD.

Biochemical failure and toxicity in treatment with brachytherapy and external beam radiotherapy compared with radical prostatectomy in localized prostate cancer.

Background: Localized prostate cancer (T1-3N0M0) has therapeutic options such as radical prostatectomy (RP), external beam radiation therapy (EBRT) and brachytherapy (BT). However, the evidence of the outcome of these treatments is limited and no studies have been conducted comparing biochemical failure (BF) and toxicity associated with surgical treatment and EBRT + high-dose brachytherapy (HDBT) in the region. Materials and methods: Retrospective cohort study, clinical records of patients diagnosed with localized prostate cancer between 2014 and 2018 were reviewed at one of the main private neoplasm centers in Lima, Peru; Cox regression was used for both the BF outcome and the grade 2 toxicity outcome, calculating the hazard ratio (HR) with 95% confodence interval (CI). Results: Of 549 patients, 76.3% (419) received RP as primary treatment, and 72% were between 50 and 70 years old at the time of diagnosis. The patients treated with EBRT + HDBT presented worse characteristics. The EBRT + HDBT group had a 40% lower risk of presenting BF (HR = 0.6; 95% CI: 0.4-0.9), and also a 50% greater risk of presenting toxicity greater than or equal to grade 2 (HR = 1.5; 95% CI: 1.0-2.0) than the group treated with RP. Conclusion: Our results show that when comparing patients treated with EBRT + HDBT and RP, BF was greater in RP, and post-treatment toxicity was greater in EBRT + HDBT.

The CAPRA-S Score and Immune Dysfunction as a Guide to Outcome in Men Treated with Prostatectomy Radical as Mono-Therapy for Prostate Cancer.

OBJECTIVE: Incorporate the immune function as determined by the absolute lymphocyte count (ALC) into the CAPRA-S risk stratification score to determine if predictive values could be improved. MATERIALS AND METHODS: The clinical pathological findings in the surgical specimen and total PSA were used to define the three CAPRA-S risk groups. One month after surgery and at each follow up total PSA and the ALC were determined, until biochemical failure (BF) or the end of the study period. A cut off value of <1,000 lymphocytes/mm3 was used to define lymphocytopenia (LCP). Each CAPRA-S group was sub-divided based on the presence or absence of LCP. Kaplan-Meier biochemical failure free survival (BFFS) curves and restricted mean biochemical failure free survival times were calculated for each group. RESULTS: 404 patients participated of whom 103 (25.5%) underwent BF. 270 men were CAPRA-S low risk (LR), 89 intermediate risk (IR) and 45 high risk (HR), of whom LCP was found in 22 (8%) of low risk, 24 (27%) of intermediate risk and 17 (38%) of high risk men. LCP was significantly associated with a higher PSA, higher Gleason and CAPRA-S scores and BF. HRs were 1.76 for IR, 2.49 for HR and 1.29 for LCP. Five-year BFFS for men without LCP, LR 93.5%, IR 61% and HR 36%, for those with LCP, LR 55%, IR 25% and HR 6%. All patients with LCP and IR or HR scores relapsed within 6 years. 10 year BFFS for men without LCP were 71% LR, 43% IR and 23% HR, LR with LCP 16%. Men with BF had increasing LCP approximately 18 months before BF. CONCLUSIONS: The incorporation of the ALC taken one month after surgery with the CAPRA-S improves risk stratification; decreases in the ALC suggest that BF is occuring. These results need to be confirmed with larger studies.

The CAPRA-S Score and Immune Dysfunction as a Guide to Outcome in Men Treated with Prostatectomy Radical as Mono-Therapy for Prostate Cancer

Objective: Incorporate the immune function as determined by the absolute lymphocyte count (ALC) into the CAPRA-S risk stratification score to determine if predictive values could be improved. Materials and Methods: The clinical pathological findings in the surgical specimen and total PSA were used to define the three CAPRA-S risk groups. One month after surgery and at each follow up total PSA and the ALC were determined, until biochemical failure (BF) or the end of the study period. A cut off value of <1,000 lymphocytes/mm3 was used to define lymphocytopenia (LCP). Each CAPRA-S group was sub-divided based on the presence or absence of LCP. Kaplan-Meier biochemical failure free survival (BFFS) curves and restricted mean biochemical failure free survival times were calculated for each group. Results: 404 patients participated of whom 103 (25.5%) underwent BF. 270 men were CAPRA-S low risk (LR), 89 intermediate risk (IR) and 45 high risk (HR), of whom LCP was found in 22 (8%) of low risk, 24 (27%) of intermediate risk and 17 (38%) of high risk men. LCP was significantly associated with a higher PSA, higher Gleason and CAPRA-S scores and BF. HRs were 1.76 for IR, 2.49 for HR and 1.29 for LCP. Five-year BFFS for men without LCP, LR 93.5%, IR 61% and HR 36%, for those with LCP, LR 55%, IR 25% and HR 6%. All patients with LCP and IR or HR scores relapsed within 6 years. 10 year BFFS for men without LCP were 71% LR, 43% IR and 23% HR, LR with LCP 16%. Men with BF had increasing LCP approximately 18 months before BF. Conclusions: The incorporation of the ALC taken one month after surgery with the CAPRA-S improves risk stratification; decreases in the ALC suggest that BF is occuring. These results need to be confirmed with larger studies (AU)

Objetivo: Establecer el riesgo de recidiva bioquímica(RBQ) basado en la puntuación CAPRA-S (riesgo bajo(RB) , riesgo intermedio (RI) y riesgo alto (RA) y recuentoabsoluto de linfocitos (RAL) ≤1000 por mm3(definidiacomo linfocitipenia LCP).Material y Métodos: Entre 2005 y 2020, se realizaun estudio observacional prospectivo de sujetos con cáncerpróstatico tratado con cirugia. Se registran los hallazgos delespécimen quirúrgico y el PSA para definir la CAPRA-S.Un mes pos-cirugía y durante el seguimiento el PSA y RALfueron determinados hasta la RBQ o final del estudio. Seconstruye un modelo de supervivencia flexible paramétrico(FP) para predecir la RBQ a 5 años utilizando la puntuaciónCAPRA-S y la LCP. Se evalúan mediante regresión localponderada mediciones repetidas de los RAL y el tiempo aRBQ o fin del estudio.Resultados: De los 404 participantes observaron 103(25,5%) RBQ. Puntajes de la CAPRA-S: 270 RB, 89 RI y45 RA. La LCP estaba asociada con niveles elevados delPSA, puntuación Gleason, márgenes comprometidos, extensión extracapsular, invasión de vesículas seminales ynodos linfáticos. El modelo FP incorporo en forma independiente y significativa ( coeficiente con valor P<0,01) laLCP ( 1,29), RA (2,49), RI (1,76) y RB (1); mostrando unaC de Harrell de 0,81 con adecuada validez. la media restringida en años (MR) para ocurrencia de RBQ, como lasupervivencia predicha (SP) a 5 años fueron: sin LCP RA(MR: 3,63; SP 42,1%) RI (MR 4,3; SP 63,1%) RB (MR4,83; SP 91,7%) con LCP RA (MR 2,1; SP 4,34%) RI (MR3,14; SP 18,9%) y RB (MR 4,42; SP 73,1%). Los sujetoscon RBQ tuvieron LCP 18 meses previo a la RBQ. LCP más CAPRA-S predicen la RB en sujetos tratado con cirugia (AU)

Increasing Immune Dysfunction is Associated with Increasing Matrix-Metalloproteinase-2 Expression and Predicts Biochemical Failure in Men with Bone Marrow Micro-Metastasis Positive Localized Prostate Cancer.

INTRODUCTION: To determine if there was an association of the ALC (absolute lymphocyte count) and LCP (lymphocytopenia) with the expression of MMP-2 in bone marrow micro-metastasis, the changes occurring during follow-up and association with biochemical failure. METHODS AND PATIENTS: One month after surgery blood and bone marrow samples were taken to determine the presence of micro-metastasis, the presence of circulating prostate cells (CPCs) and ALC. CPCs and micro-metastasis were detected using immunocytochemistry and MMP-2 expression determined in micro-metastasis. Only men positive for micro-metastasis participated in the study. At end follow blood was taken for serum PSA, ALC and CPCs, if the ALC decreased by more than 10% bone marrow sampling was repeated and MMP-2 expression determined, similarly for men with BF. Men who had stable ALCs had an end of study evaluation of the bone marrow. RESULTS: 402 men underwent radical prostatectomy, one month post surgery 79 men were positive for only bone marrow micro-metastasis and formed the study group; of whom 36/79 (45%) underwent BF. Clinical pathological findings were not significantly different between men with or without BF. In men with BF the ALC was significantly lower one-month post surgery. The 5 and 10 year Kaplan-Meier survival was 100% at 5-years and 65% at 10-years for the whole cohort. Men without BF had stable ALCs. A decrease of >10% in the ALC was associated with increasing MMP-2 expression in the micro-metastasis and surrounding stromal tissue, the appearance of CPCs 6-12 months later and BF. CONCLUSIONS: the immune host-tumour cell interaction in the microenvironment is dynamic and changes with time. A decreasing ALC may be a valuable marker in identifying men with high risk of BF and changes in immune mediated dormancy before the PSA rises.