Comparison between different neoadjuvant chemotherapy regimens and local therapy alone for bladder cancer: a systematic review and network meta-analysis of oncologic outcomes.

PURPOSE: The present systematic review and network meta-analysis (NMA) compared the current different neoadjuvant chemotherapy (NAC) regimes for bladder cancer patients to rank them. METHODS: We used the Bayesian approach in NMA of six different therapy regimens cisplatin, cisplatin/doxorubicin, (gemcitabine/cisplatin) GC, cisplatin/methotrexate, methotrexate, cisplatin, and vinblastine (MCV) and (MVAC) compared to locoregional treatment. RESULTS: Fifteen studies comprised 4276 patients who met the eligibility criteria. Six different regimes were not significantly associated with a lower likelihood of overall mortality rate compared to local treatment alone. In progression-free survival (PFS) rates, cisplatin, GC, cisplatin/methotrexate, MCV and MVAC were not significantly associated with a higher likelihood of PFS rate compared to locoregional treatment alone. In local control outcome, MCV, MVAC, GC and cisplatin/methotrexate were not significantly associated with a higher likelihood of local control rate versus locoregional treatment alone. Nevertheless, based on the analyses of the treatment ranking according to SUCRA, it was highly likely that MVAC with high certainty of results appeared as the most effective approach in terms of mortality, PFS and local control rates. GC and cisplatin/doxorubicin with low certainty of results was found to be the best second options. CONCLUSION: No significant differences were observed in mortality, progression-free survival and local control rates before and after adjusting the type of definitive treatment in any of the six study arms. However, MVAC was found to be the most effective regimen with high certainty, while cisplatin alone and cisplatin/methotrexate should not be recommended as a neoadjuvant chemotherapy regime.

Quality indicators for the management of muscle-invasive bladder cancer in the perioperative setting of radical cystectomy: a narrative review.

Background and Objective: Identifying evidence-based and measurable quality-of-care indicators is crucial for optimal management of patients requiring radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). RC with urinary diversion and lymphadenectomy is the standard treatment for patients with MIBC. Preoperatively, neoadjuvant chemotherapy (NAC) with cisplatin-based combinations improves survival outcomes and is the recommended standard of care for eligible patients. Intraoperatively, lymph node dissection (LND) by, at least, following a standard pelvic lymph node template improves overall- and recurrence-free survival and allows for accurate tumour staging. Avoiding positive soft tissue surgical margins (STSM) should be a main target intraoperatively since they are almost universally associated with mortality. Implementing enhanced recovery after surgery (ERAS) programs can reduce lengths of hospital stay (LOS) and postoperative complication rates without increasing readmission rates after RC. Moreover, several studies have shown that smoking negatively affects local and systemic treatment outcomes in bladder cancer (BC) patients. Therefore, smoking cessation counselling for smokers should be an essential part of bladder cancer management regardless of the disease state. Methods: We performed a comprehensive, non-systematic review of the latest literature to define indicators representing the best evidence available for optimal care of MIBC patients treated with RC. Key Content and Findings: In this review, we propose five major quality indicators that are easily implementable for optimized management of MIBC patients treated with RC, including: usage of cisplatin-based NAC in eligible patients, ensurance of negative STSM, performance of (at least) a standard pelvic template LND, implementation of ERAS strategies, and professional smoking cessation counselling. Conclusions: Optimal management of MIBC needs to be framed by evidence-based, reproducible, and measurable quality indicators that will allow for guidance and comparative effectiveness assessment of clinical practices; adherence to them is likely to improve patients' prognoses by a tensible margin. For the treatment of MIBC patients with RC, we identified five essential quality indicators. Keywords: Assessment; bladder cancer (BC); muscle-invasive bladder cancer (MIBC); cystectomy; radical cystectomy (RC); quality.

Radiation therapy compared to radical prostatectomy as first-line definitive therapy for patients with high-risk localised prostate cancer: An updated systematic review and meta-analysis.

Objective: To present an update of the available literature on external beam radiation therapy (EBRT) with or without brachytherapy (BT) compared to radical prostatectomy (RP) for patients with high-risk localised prostate cancer (PCa). Methods: We conducted a systematic review and meta-analysis of the literature assessing the survival outcomes in patients with high-risk PCa who received EBRT with or without BT compared to RP as the first-line therapy with curative intent. We queried PubMed and Web of Science database in January 2021. Moreover, we used random or fixed-effects meta-analytical models in the presence or absence of heterogeneity per the I2 statistic, respectively. We performed six meta-analyses for overall survival (OS) and cancer-specific survival (CSS). Results: A total of 27 studies were selected with 23 studies being eligible for both OS and CSS. EBRT alone had a significantly worse OS and CSS compared to RP (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.16-1.65; and HR 1.55, 95% CI 1.25-1.93). However, there was no difference in OS (HR 1.1, 95% CI 0.76-1.34) and CSS (HR 0.69, 95% CI 0.45-1.06) between EBRT plus BT compared to RP. Conclusion: While cancer control affected by EBRT alone seems inferior to RP in patients with high-risk PCa, BT additive to EBRT was not different from RP. These data support the need for BT in addition to EBRT as part of multimodal RT for high-risk PCa.Abbreviations: ADT: androgen-deprivation therapy; BT: brachytherapy; CSS: cancer-specific survival; HR: hazard ratio; MFS, metastatic-free survival; MOOSE: Meta-analyses of Observational Studies in Epidemiology; OR: odds ratio; OS: overall survival; PCa: prostate cancer; RR: relative risk; RP: radical prostatectomy; RCT: randomised controlled trials; (EB)RT: (external beam) radiation therapy.

Prognostic impact of insulin-like growth factor-I and its binding proteins, insulin-like growth factor-I binding protein-2 and -3, on adverse histopathological features and survival outcomes after radical cystectomy.

OBJECTIVES: Insulin-like growth factor-I and its binding proteins are involved in cancer development, progression, and metastasis. In urothelial carcinoma, the impact of this pathway is still poorly investigated. The present large cohort study aimed to evaluate the association of preoperative circulating levels of insulin-like growth factor-I, insulin-like growth factor-I binding protein-2 and -3 on outcomes after radical cystectomy. METHODS: A retrospective cohort study of the plasma specimens from 1036 consecutive urothelial carcinoma patients who were treated with radical cystectomy. The primary and secondary outcomes were adverse histopathological features and survival outcomes. Binominal logistic regression and multivariable Cox regression analyses were performed to assess the association of plasma levels of insulin-like growth factor-I, insulin-like growth factor-I binding protein-2 and -3 with outcomes. RESULTS: On multivariable analysis adjusting for the effects of preoperative variables, lower insulin-like growth factor-I binding protein-2 levels were associated with an increased risk of lymph node metastasis and (any non-organ confined disease) any non-organ confined disease. Insulin-like growth factor-I binding protein-3 levels were also inversely independently associated with lymph node metastasis. Receiver operating characteristic curve analysis showed that the addition of insulin-like growth factor-I binding proteins biomarkers to a reference model significantly improved the discriminating ability for the prediction of lymph node metastasis (+10.0%, P < 0.001). On multivariable Cox regression models, lower levels of both insulin-like growth factor-I binding protein-2 and -3 plasma levels were associated with recurrence-free survival, cancer-specific survival, and overall survival. insulin-like growth factor-I binding protein-2 and -3 levels and improved the discrimination of a standard reference model for the prediction of recurrence-free survival, cancer-specific survival, and overall survival (+4.9%, 4.9%, 2.3%, respectively). CONCLUSIONS: Preoperative insulin-like growth factor-I binding protein-2 and -3 are significantly associated with features of biologically and clinically aggressive urothelial carcinoma. These biomarkers improved prognostic urothelial carcinoma models.

Comparison of Clinicopathologic and Oncological Outcomes Between Transurethral En Bloc Resection and Conventional Transurethral Resection of Bladder Tumor: A Systematic Review, Meta-Analysis, and Network Meta-Analysis with Focus on Different Energy Sources.

Introduction: It has been hypothesized that transurethral en bloc (TUEB) of bladder tumor offers benefits over conventional transurethral resection of bladder tumor (cTURBT). This study aimed to compare disease outcomes of TUEB and cTURBT with focus on the different energy sources. Methods: A systematic search was performed using PubMed and Web of Science databases in June 2021. Studies that compared the pathological (detrusor muscle presence), oncological (recurrence rates) efficacy, and safety (serious adverse events [SAEs]) of TUEB and cTURBT were included. Random- and fixed-effects meta-analytic models and Bayesian approach in the network meta-analysis was used. Results: Seven randomized clinical trials (RCTs) and seven non-RCTs (NRCT), with a total of 2092 patients. The pooled 3- and 12-month recurrence risk ratios (RR) of five and four NRCTs were 0.46 (95% CI 0.29-0.73) and 0.56 (95% CI 0.33-0.96), respectively. The pooled 3- and 12-month recurrence RRs of four and seven RCTs were 0.57 (95% CI 0.25-1.27) and 0.89 (95% CI 0.69-1.15), respectively. The pooled RR for SAEs such as prolonged hematuria and bladder perforation of seven RCTs was 0.16 (95% CI 0.06-0.41) in benefit of TUEB. Seven RCTs (n = 1077) met our eligibility criteria for network meta-analysis. There was no difference in 12-month recurrence rates between hybridknife, laser, and bipolar TUEB compared with cTURBT. Contrary, laser TUEB was significantly associated with lower SAEs compared with cTURBT. Surface under the cumulative ranking curve ranking analyses showed with high certainty that laser TUEB was the best treatment option to access all endpoints. Conclusion: While NRCTs suggested a recurrence-free benefit to TUEB compared with cTURBT, RCTs failed to confirm this. Conversely, SAEs were consistently and clinically significantly better for TUEB. Network meta-analyses suggested laser TUEB has the best performance compared with other energy sources. These early findings need to be confirmed and expanded upon.

The Efficacy and Safety of Relugolix Compared with Degarelix in Advanced Prostate Cancer Patients: A Network Meta-analysis of Randomized Trials.

CONTEXT: Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients. OBJECTIVE: This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix. EVIDENCE ACQUISITION: A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis. EVIDENCE SYNTHESIS: Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses. CONCLUSIONS: We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available. PATIENT SUMMARY: We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.

The role of lymph node dissection in salvage radical prostatectomy for patients with radiation recurrent prostate cancer.

PURPOSE: To examine the effect of lymph node dissection on the outcomes of patients who underwent salvage radical prostatectomy (SRP). MATERIAL AND METHODS: We retrospectively reviewed data from radiation-recurrent patients with prostate cancer (PCa) who underwent SRP from 2000-2016. None of the patients had clinical lymph node involvement before SRP. The effect of the number of removed lymph nodes (RLNs) and the number of positive lymph nodes (PLNs) on biochemical recurrence (BCR)-free survival, metastases free survival, and overall survival (OS) was tested in multivariable Cox regression analyses. RESULTS: About 334 patients underwent SRP and pelvic lymph node dissection (PLND). Lymph node involvement was associated with increased risk of BCR (p < .001), metastasis (p < .001), and overall mortality (p = .006). In a multivariable Cox regression analysis, an increased number of RLNs significantly lowered the risk of BCR (hazard ratio [HR] 0.96, p = .01). In patients with positive lymph nodes, a higher number of RLNs and a lower number of PLNs were associated with improved freedom from BCR (HR 0.89, p = .001 and HR 1.34, p = .008, respectively). At a median follow-up of 23.9 months (interquartile range, 4.7-37.7), neither the number of RLNs nor the number of PLNs were associated with OS (p = .69 and p = .34, respectively). CONCLUSION: Pathologic lymph node involvement increased the risk of BCR, metastasis and overall mortality in radiation-recurrent PCa patients undergoing SRP. The risk of BCR decreased steadily with a higher number of RLNs during SRP. Further research is needed to support this conclusion and develop a precise therapeutic adjuvant strategy based on the number of RLNs and PLNs.

Impact of enhanced optical techniques at time of transurethral resection of bladder tumour, with or without single immediate intravesical chemotherapy, on recurrence rate of non-muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized trials.

OBJECTIVE: To assess whether single immediate intravesical chemotherapy (SIIC) adds value to bladder tumour management in combination with novel optical techniques: enhanced transurethral resection of bladder tumour (TURBT). METHODS: A systematic search was performed using the PubMed and Web of Science databases in September 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) extension statement for network meta-analyses. Studies that compared recurrence rates among intervention groups (TURBT with photodynamic diagnosis [PDD] ± SIIC, narrow-band imaging [NBI] ± SIIC, or white-light cystoscopy [WLC] + SIIC) and a control group (TURBT with WLC alone) were included. We used the Bayesian approach in the network meta-analysis. RESULTS: Twenty-two studies (n = 4519) met our eligibility criteria. Out of six different interventions including three different optical techniques, compared to WLC alone, blue-light cystoscopy (BLC) plus SIIC (odds ratio [OR] 0.349, 95% credible interval [CrI] 0.196-0.601) and BLC alone (OR 0.668, 95% CrI 0.459-0.931) were associated with a significantly lower likelihood of 12-month recurrence rate. In the sensitivity analysis, out of eight different interventions compared to WLC alone, PDD by 5-aminolevulinic acid plus SIIC (OR 0.327, 95% CrI 0.159-0.646) and by hexaminolevulinic acid plus SIIC (OR 0.376, 95% CrI 0.172-0.783) were both associated with a significantly lower likelihood of 12-month recurrence rate. NBI with and without SIIC was not associated with a significantly lower likelihood of 12-month recurrence rate (OR 0.385, 95% CrI 0.105-1.29 and OR 0.653, 95% CrI 0.343-1.15). CONCLUSION: Blue-light cystoscopy during TURBT with concomitant SIIC seems to yield superior recurrence outcomes in patients with non-muscle-invasive bladder cancer. The use of PDD was able to reduce the 12-month recurrence rate; moreover, concomitant SIIC increased this risk benefit by a 32% additional reduction in odds ratio. Although using PDD could reduce the recurrence rate, SIIC remains necessary. Moreover, ranking analysis showed that both PDD and NBI, plus SIIC, were better than these techniques alone.

Association of statins use and mortality outcomes in prostate cancer patients who received androgen deprivation therapy: a systematic review and meta-analysis.

INTRODUCTION: While several recent studies investigated the influence of statins on survival outcomes in prostate cancer (PCa) patients on androgen deprivation therapy (ADT), definitive conclusions are still missing. The present systematic review and meta-analysis aimed to develop an overarching framework for the association of statins use and survival outcomes in PCa patients who receive ADT. MATERIAL AND METHODS: We conducted a systematic review and meta-analysis of the literature assessing the survival outcomes for statin compared to non-statin users in PCa patients who received ADT. We searched PubMed and Web of Science for studies published before March 1, 2021. We used the random effect model in the presence of heterogeneity and the fixed-effects model in the absence of heterogeneity per the I 2 statistic. We did two meta-analyses; the primary meta-analysis was accomplished for articles reporting cancer-specific survival (CSS) as an outcome. A secondary meta-analysis was completed for articles reporting overall survival (OS) as an outcome. RESULTS: Ten studies were eligible for inclusion. Nine studies included in the first meta-analysis comprising 136,285 patients showed no statistically significant difference in CSS (HR 0.77; 95% CI 0.49-1.21) between statin users and non-users in PCa patients who received ADT. In four studies included in the second meta-analysis comprising 95,032 patients, statin users had a significantly better OS compared to non-users (HR 0.67; 95% CI 0.62-0.73). CONCLUSIONS: Although the combination of statins and ADT in PCa patients significantly improves OS, it seems not to be through an effect on cancer-specific factors.