OBJECTIVE: Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes.
METHODS: We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment.
UNASSIGNED: A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data.
CONCLUSIONS: This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics.
RESULTS: We summarize the data from previously reported clinical trials on the topic of which factors predict worse cancer outcomes for patients who recur with prostate cancer after their initial treatment.

BACKGROUND: Some authors propose extended pelvic lymph node dissection (ePLND) to enhance diagnostic and therapeutic outcomes in patients with localized prostate cancer. However, recent evidence found no difference in biochemical recurrence (BCR).
OBJECTIVE: To stratify and analyze available evidence on ePLND and its impact on BCR in patients with localized prostate cancer.
METHODS: We systematically reviewed the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to identify studies up to November 2023. We identified original articles that presented statistical comparisons through Cox regressions reported as hazard ratio (HR) or survival curve data reported as Kaplan-Meier curve differences in BCR in patients undergoing radical prostatectomy and stratified by the extent of lymph node dissection for localized prostate cancer.
RESULTS: We identified 12 studies, with two being randomized controlled trials (RCTs). The RCTs showed no benefit of ePLND with an HR of 1.03 ([0.92, 1.14], p = 0.61). A combined analysis with the ten retrospective studies revealed a notable reduction in BCR with an HR of 0.68 ([0.52, 0.88], p = 0.003). A subgroup analysis based on the extent of dissection demonstrated that studies focusing on the more conservative extended template of dissection did not show significant BCR benefit (HR 0.97 [0.72, 1.32], p = 0.86). In contrast, dissections that expanded the anatomical extent showed decreased BCR (HR 0.56 [0.41, 0.75], p < 0.0001). A Bayesian network analysis highlights significant differences in BCR reduction between different dissection approaches, indicating the potential benefits of specific dissection templates.
CONCLUSIONS: Available literature on the extent of pelvic lymph node dissection needs to be improved in quality and varying definitions of the ePLND template. Dissection of the common iliac nodes may be beneficial.
RESULTS: There is a potential benefit in removing more lymph nodes during radical prostatectomy. However, more research is needed to determine whether this strategy benefits certain patient groups.

UNASSIGNED: Correlation between zonal origin of clinically localized prostate cancer (PC) and biochemical recurrence (BCR) after treatment is still controversial.
UNASSIGNED: We performed a meta-analysis of published articles to investigate the prognostic value of zonal origin in clinically localized PC. Literature was searched from Medline, Embase, Scopus, and Web of Science, from inception to Nov 1st, 2022. The risk of BCR was compared between PC originating from transition zone with peripheral zone. Relative risk (RR) was pooled in a random-effects model. Subgroup analysis and meta-regression were conducted to assess the source of heterogeneity.
UNASSIGNED: 16 cohorts and 19,365 patients were included. PC originating from transition zone was associated with a lower risk of BCR (RR, 0.79, 95%CI; 0.69-0.92, I2, 76.8%). The association was consistent in studies with median follow-up time ≥60 months (RR, 0.65; 95%CI, 0.48 to 0.88, I2 56.8%), studies with NOS score ≥8 (RR, 0.70; 95%CI, 0.62 to 0.80, I2 32.4%), and studies using multivariate regression model (RR, 0.57; 95%CI, 0.48 to 0.69, I2 23%).
UNASSIGNED: This meta-analysis supported that transition zone origin was an independent prognostic factor of a better biochemical result in clinically localized prostate cancer after treatment.
UNASSIGNED: 10.37766/inplasy2023.11.0100, identifier INPLASY2023110100.

After primary radiotherapy, biochemical recurrence is defined according to the Phoenix criteria as a prostate-specific antigen (PSA) value >2 ng/ml relative to the nadir. Several studies have shown that prostate-specific membrane antigen (PSMA)-ligand positron emission tomography/computed tomography (PET/CT) can help in detecting recurrence in patients with low PSA values. This study aimed to assess the detection rate and patterns of PSMA-ligand PET/CT uptake in patients with suspected biochemical recurrence after primary radiotherapy and with PSA levels below the Phoenix threshold.
The meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Articles providing data on patients with suspected prostate cancer recurrence after primary radiotherapy with a PSA value below the Phoenix threshold and who underwent PSMA-ligand PET/CT were included. Quality assessment was carried out using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2).
In total, five studies were included, recruiting 909 patients (202 with PSA ≤2 ng/ml). The PSMA-ligand detection rate in the patients with ≤2 ng/ml ranged from 66 to 83%. The most frequent source of PSMA-ligand PET/CT uptake was local recurrence, followed by lymph node metastasis and bone metastasis. PSMA-ligand PET/CT uptake due to local-only recurrence was more likely in patients with PSA ≤2 ng/ml compared with PSA > 2 ng/ml: risk ratio 0.72 (95% confidence interval 0.58-0.89), P = 0.003. No significant differences were observed in the detection of PSMA-ligand uptake in other areas. Limitations include a lack of biopsy confirmation, cohort reports with small sample sizes and a potentially high risk of bias.
A significant detection of PSMA-ligand-avid disease was observed in patients with PSA levels below the Phoenix threshold. There was a higher likelihood of detecting local-only uptake when the PSA value was ≤2 ng/ml. The findings suggest that a critical review of the Phoenix criteria may be warranted in the era of PSMA-ligand PET/CT and highlight the need for further prospective trials.

Despite the acknowledged diagnostic detection rate of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging in prostate cancer, little is known about the quality of evidence, particularly focusing on prospective studies. Most systematic reviews are based on retrospective reports.
To conduct systematic review and meta-analysis of prospective studies reporting the diagnostic detection rate of PSMA PET (computed tomography (CT) and MR) for the detection of biochemically recurrent metastatic prostate cancer.
We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database until March 1, 2023 for randomized controlled trials and prospective studies using PSMA PET imaging in prostate cancer. The primary endpoint was to assess diagnostic detection rate of PSMA PET imaging in the detection of recurrent prostate cancer in men with biochemical relapse following radical treatment. We calculated the pooled overall diagnostic detection rate with 95% CI using a random-effects model and assessed the heterogeneity between the studies including risk of biases estimation.
A total of 6800 patients from 32 articles were included in this study. The overall detection rate of PSMA PET for prostate cancer was 0.67 (95% CI, 0.63, 0.71). For histologically confirmed lymph nodes, the PPV from 13 prospective studies containing 1496 patients was 0.96 (95% CI, 0.93, 0.99). We performed a subgroup analysis of PSMA PET detection rates according to categorically grouped Prostate Specific Antigen (PSA) values of 0-0.5, 0.5-1.0, 1.0-2.0, and >2.0 ng/ml and obtained detection rates of 0.44, 0.63, 0.82, and 0.94, respectively. The detection rate of 18F PSMA was better in men with a PSA between 1 ng/ml and 2 ng/ml in comparison to 68Ga PSMA (0.91 with 95% CI 0.81-0.99 vs. 0.79 with 95% CI 0.73, 0.85).
PSMA PET imaging provides a good detection rate for the metastatic recurrence of prostate cancer in men with biochemical relapse following radical treatment. The detection rate improves significantly above a serum PSA value of 1 ng/ml. The diagnostic detection rate of 18F-PSMA is best at PSA values between 1 and 2 ng/ml, in comparison to 68Ga PSMA. This conclusion is heavily biased, further research needs to focus on better methodology to minimize the risk of biases.

OBJECTIVE: To draw inferences from a retrospective evaluation of PSMA PET CT scans performed for the evaluation of biochemical recurrence.
METHODS: A retrospective analysis of 295 PSMA PET CT scans spanning 3 years between 2020 and 2022 was undertaken.
RESULTS: Of 295 PET CT scans, 179 were positive, 66 were negative and 50 had indeterminate findings. In the positive group, 67 had radical prostatectomy and PSMA avid lesions were seen most commonly in pelvic lymph nodes. The remaining 112 positive scans were in the non-radical prostatectomy group; 25 had recurrence only in the prostate, 17 had recurrence involving the prostate bed; 28 had no recurrence in the prostate gland, while 42 had recurrence in the prostate as well as in extra-prostatic sites. Overall, in the non-prostatectomy group, 75% of the population was harboring a PSMA avid lesion in the prostate gland while in the remaining 25% of the population, recurrence did not involve the prostate gland. The majority of indeterminate findings were seen in small pelvic or retroperitoneal lymph nodes or skeletal regions (ribs/others) and in nine patients indeterminate focus was seen in the prostate bed only. Follow-up PSMA PET CT was helpful in prior indeterminate findings and unexplained PSA rise.
CONCLUSIONS: A higher recurrence in the prostate bed while evaluating biochemical recurrence prompts the following: question: should prostatectomy be offered more proactively? Follow-up PSMA PET CT is helpful for indeterminate findings; a PSA rise of 0.7 ng/mL in 6 months can result in positive PSMA PET CT while negative scans can be seen up to a 2 ng/mL PSA rise in 6 months.

BACKGROUND: After initial treatment of prostate cancer, increases in prostate-specific antigen (PSA) levels commonly signify potential relapse or metastasis. 18F-labeled prostate-specific membrane antigen (PSMA) is considered a promising treatment due to its favorable physical properties.
OBJECTIVE: To investigate the diagnostic value of 18F-PSMA PET/CT for the recurrence and/or metastasis of biochemical recurrence of prostate cancer (BRPca).
METHODS: A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library databases. Combined sensitivity and specificity values for the use of 18F-PSMA PET/CT in patients with BRPca were obtained. The quality of the studies was tested using the Diagnostic Accuracy Research Quality Assessment tool. Meta-analysis was performed using STATA 15 software, and heterogeneity was subsequently tested.
RESULTS: A total of 16 studies (1162 patients) were enrolled and had significant heterogeneity. The pooled sensitivity, specificity, and AUC values for 18F-PSMA PET/CT in the diagnosis of prostate recurrence and/or metastasis were 0.93 (0.89-0.95), 0.94 (0.85-0.98), and 0.96 (0,94-0.98), respectively. Meta-regression analyses showed that the sources of heterogeneity did not relate to ligands, study designs, or participants. The pooled sensitivity and specificity values of 18F-DCFPyL PET/CT were 0.90 (0.85-0.94) and 0.89 (0.85-0.93), respectively. The pooled sensitivity and specificity values of 18F-PSMA-1007 PET/CT were 0.89 (0.85-0.93) and 0.93 (0.70-0.99), respectively. The per-patient pooled sensitivity and specificity values were 0.92 (0.86-0.96) and 0.83 (0.41-0.97), respectively. The per-lesion pooled sensitivity and specificity values were 0.91 (0.86-0.94) and 0.91 (0.86-0.94), respectively.
CONCLUSIONS: According to our meta-analysis, 18F-PSMA PET/CT has the potential to be critical for the diagnosis of recurrence and/or metastasis in patients with BRPca.

Piflufolastat F-18 (18F-DCFPyL) prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is approved by the US food and drug administration for initial staging of high-risk prostate cancer, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Here, we sought to assess how its integration into clinical care may have impacted the management of patients.
We identified 235 consecutive patients who underwent an 18F-DCFPyL PET scan from August 2021 to June 2022. The median prostate-specific antigen at the time of imaging was 1.8 ng/mL (Range: 0-3740 ng/mL). Descriptive statistics were used to analyze its impact on clinical care for a subset of 157 patients with available treatment information: 22 for initial staging, 109 with BCR, and 26 patients with known metastatic disease.
PSMA-avid lesions were detected in 154/235 (65.5% of) patients. In patients undergoing initial staging, 18/39 (46.2% of) patients had extra-prostatic metastatic lesions; 15/39 (38.5% of) scans were negative and 6/39 (15.4%) had equivocal results. 12/22 (54.5% of) patients had a change in their treatment plan post-PSMA PET scan while 10/22 (45.5%) had no change in their treatment plan. In the BCR cohort, 93/150 (62.0%) had a local recurrence or metastatic lesions. Equivocal and negative scans accounted for 11/150 (7.3%) and 46/150 (30.7%) of scans, respectively. 37/109 (33.9% of) patients had a change in their treatment plan, while treatment was not altered in 72/109 (66.1% of) cases. In patients with metastatic disease, 43/46 (93.5%) had PSMA-avid lesions identified; equivocal and negative scans accounted for 2/46 (4.3%) and 1/46 (2.2%) of scan results, respectively. 6/26 (23.1%) had their tentative treatment plan adjusted after the PSMA PET scan. No change in the treatment plan was observed in 20/26 (76.9% of) cases.
Integration of F-18 PSMA PET imaging impacted clinical decision-making and subsequent management across all stages of prostate cancer. It remains to be seen whether this translates into superior survival outcomes.

Context: Systematic reviews (SR) have always been used as the best evidence to compare three radical prostatectomy (RP) techniques: retropubic radical prostatectomy (RRP), laparoscopic radical prostatectomy (LRP), and robotic radical prostatectomy (RARP). Despite the superiority of minimally invasive surgery in relation to perioperative outcomes, the literature still cannot establish which technique is superior in relation to oncological outcomes. A new methodology called Reverse Systematic Review (RSR) was created to gather the best evidence in the literature based on a heterogeneous sample, allowing the comparison of oncological outcomes from a population point of view. Objective: To apply the RSR to compare RP techniques in relation to oncological outcomes: positive surgical margin (PSM) and biochemical recurrence rate (BCR). Evidence Acquisition: A search was carried out in eight databases between 2000 and 2020 through SR studies referring RRP, LRP, or RARP (80 SR). All references used in these SR were captured referring to 1724 reports. Preoperative and oncological outcomes were compared and correlated among RRP, LRP, and RARP. Evidence Synthesis: Five hundred fifty-nine (32.4%) reports for RRP, 413 (23.9%) for LRP, and 752 (43.7%) for RARP, and a total of 1,353,485 patients were found. Regarding PSM, 284 reports were collected for RRP, 324 for LRP, and 499 for RARP, with rates of 23.6%, 20.7%, and 19.2%, respectively, and only the RRP with statistical difference (p < 0.001). Using a nonlinear regression model, the BCR was correlated with follow-up time at 1, 2, 3, 5, 7, and 10 years: 10%, 15%, 18%, 20%, 23%, and 38% for RRP; 6%, 9%, 13%, 20%, 23%, and 10% for LRP; and 8%, 12%, 16%, 23%, 27%, and 19% for RARP. The absence of long-term work for RARP prevented more accurate projections of BCR. Conclusions: RSR proved to be effective in generating a population and heterogeneous sample capable of demonstrating better oncological results for minimally invasive surgery (LRP and RARP) compared to RRP. It demonstrated the maturity of temporal follow-up data for RRP and LRP and the impact of absence of late follow-up from RARP studies on the long-term rate of BCR. Patient Summary: After 20 years of coexistence of the three main radical prostatectomy techniques, the RSR was able to detect better results from minimally invasive surgery in relation to PSMs and long-term BCRs.

The introduction of prostate-specific membrane antigen positron emission tomography (PSMA-PET) had a substantial impact on the management of prostate cancer (PCa) patients with a stage migration phenomenon and consequent treatment changes.
To summarise the role of PSMA-PET to define the burden of disease through an accurate location of metastatic site(s) in PCa patients, describing the most common locations at PSMA-PET in the primary staging and recurrence setting, and to assess the clinical impact in the decision-making process.
A comprehensive nonsystematic literature review was performed in April 2022. Literature search was updated until March 2022. The most relevant studies have been summarised, giving priority to registered clinical trials and multicentre collaborations.
PSMA-PET showed higher diagnostic accuracy than conventional imaging both in newly diagnosed PCa and in recurrent disease. This greater accuracy led to a migration of a higher proportion of patients identified with metastatic disease. Bone metastases were reported as the most frequent site of metastatic spread in staging (up to 17%) and restaging (up to 18%). In staging, considering the suboptimal sensitivity in lymph node metastasis detection prior to radical surgery, PSMA-PET should be performed in patients with high risk or unfavourable intermediate risk only, and it is not recommended to routinely avoid pelvic lymph node dissection in case of a negative scan. In case of prostate-specific antigen relapse, PSMA-PET had higher diagnostic accuracy than other diagnostic procedures in the early detection of the sites of recurrence, thus influencing the therapy decision-making process.
PSMA-PET detects a higher number of lesions than conventional imaging or other PET radiotracers, especially metastatic lesions unseen with other modalities. The high diagnostic accuracy of PSMA-PET leads to a significant patient upstage and thus an impact in clinical management, even if the overall impact on cancer mortality is still to be assessed.
Prostate-specific membrane antigen positron emission tomography (PSMA-PET) identifies metastatic lesions with higher accuracy than conventional imaging, both in primary prostate cancer and during disease recurrence. Skeletal metastasis and extrapelvic lymph nodes are the most common sites of metastatic spread. The high accuracy of PSMA-PET in the detection of metastatic disease led to a significant impact on patient management, even if the overall impact on cancer mortality is still to be assessed.