Predicting Recurrence and Progression in Patients with Non-Muscle-Invasive Bladder Cancer: Systematic Review on the Performance of Risk Stratification Models


BACKGROUND: Several classifications have been reported to stratify non-muscle-invasive bladder cancer (NMIBC) in risk groups according to the probability of recurrence and progression.

OBJECTIVE: To systematically review the current evidence regarding risk stratification of NMIBC.

METHODS: The systematic review was performed in accordance with the PRISMA statement. Studies providing data on development and/or external validation cohorts of models and risk stratification tables for recurrence and/or progression for patients with NMIBC, reporting at least one discrimination measure (AUC or C-Index) were included.

RESULTS: Twenty-five studies involving 22,737 patients were included. Six classifications were identified, three of them were predictive models (EORTC, CUETO, EAU 2021) and three were based on expert opinion (EAU 2020, AUA, NCCN). A high risk of bias was present in the majority of the studies. Certain heterogenicity was found among the studies regarding adjuvant therapy, postoperative instillation or second resection. The definition of oncological outcomes was not standardized in the included studies. CUETO and EORTC scoring systems are the most validated. In general, validations showed a poor discrimination capability to predict recurrence, slightly better for progression. The EAU 2021 model overestimates the risk of progression in patients treated with BCG. Carcinoma in situ is underrepresented in all the studies analyzed.

CONCLUSIONS: The existing classifications show poor discrimination capability for recurrence and possibly helpful discrimination capability for progression in NMIBC patients. These results highlight the unmet need to develop novel accurate risk models for patients with NMIBC, which could be improved with the combination of clinicopathological and molecular information.

Switch Maintenance Therapy for Metastatic Urothelial Carcinoma


INTRODUCTION: While switch maintenance therapy is being increasingly investigated in solid tumors, it is a standard in only a few. We conducted a systematic review on switch maintenance therapy for metastatic urothelial carcinoma.

EVIDENCE ACQUISITION: In this systematic review, we conducted a literature search in PubMed and Cochrane databases up to 2021, based on PRISMA statement guidelines. One hundred and fifty eight articles were identified and after a three-step selection process and six articles, using different agents were included in evidence synthesis. The primary end points were effect on overall survival, progression free survival, safety and tolerability.

EVIDENCE SYNTHESIS: In the pre-immunotherapy era, targeted therapies like sunitinib, lapatinib and vinflunine were studied as switch maintenance therapy in metastatic urothelial carcinoma but did not show any overall survival benefit. Use of anti-PD-1/PD-L1 agents have shown promise as switch maintenance therapy; pembrolizumab showed improvement in progression free survival in a phase 2 trial and avelumab showed improvement in overall survival and progression free survival in the phase 3 JAVELIN Bladder 100 trial.

CONCLUSION: Immunotherapy with anti-PD-1/PD-L1 agents has emerged as an effective switch maintenance strategy in patients with metastatic urothelial carcinoma. Intensification of the immunotherapy backbone in this setting can potentially further enhance outcomes. Emerging evidence shows a potential role of Poly (ADP-ribose) polymerase (PARP) inhibitors in this setting as well. Results from ongoing and planned studies will help us understand which switch maintenance approaches would be most effective for improving outcomes in metastatic urothelial carcinoma.

Combination of Two T1 Substaging Systems (T1a/b/c and T1m/e) Better Predicts Tumor Outcomes in Patients with T1 High Grade Bladder Cancer


BACKGROUND: T1 substaging is a predictive factor for non-muscle-invasive bladder cancer, and two types of T1 substaging systems (T1a/b/c and T1m/e) are currently in use. However, the predictive ability of both systems is poor, and there is debate over which system is better.

OBJECTIVE: To confirm whether combination of two T1 substaging systems can improve the predictive ability of T1 substaging for tumor outcomes.

METHODS: Patients with primary pT1 high-grade bladder cancer from three centers were included. All tumors were assessed with T1a/b/c and T1m/e substaging. A new variable named COMB was developed in which patients were stratified into T1a/b&T1m, T1a/b&T1e, T1c&T1m or T1c&T1e subgroups. A time-dependent receiver operating characteristic curve (ROC) analysis was used to test whether the accuracy of prediction could be improved with COMB.

RESULTS: A total of 239 patients with primary pT1HG were analyzed. No tumor was T1c&T1m, and therefore, only three types of combinations were evaluated: T1a/b&T1m (62 patients), T1a/b&T1e (124 patients) and T1c&T1e (53 patients). Regardless of all patients or those treated with Re-TURBt and adequate BCG, patients with T1a/b&T1m have the best prognosis, and those with T1c&T1e have the poorest prognosis. The time-dependent ROC showed that, for both recurrence and progression, COMB had a higher AUC than T1a/b/c and T1m/e, regardless of population.

CONCLUSIONS: Compared with either system alone, the combination of two T1 substaging systems improves the predictive ability of T1 substaging for tumor outcomes.

A Multicenter Study of 2-year Outcomes Following Hyperthermia Therapy with Mitomycin C in Treating Non-Muscle Invasive Bladder Cancer: HIVEC-E


INTRODUCTION: High grade, non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical Bacillus Calmette–Guérin. Chemohyperthermia therapy (CHT) may be a novel alternative therapy for the treatment of NMIBC.

OBJECTIVE: To evaluate the recurrence-free survival (RFS) of patients treated with CHT using the Combat bladder recirculation system (BRS) for NMIBC.

METHODS: This was a prospective multi-institutional study of 1,028 consecutive patients with NMIBC undergoing CHT between 2012 and 2020. A total of 835 patients were treated with CHT with Mitomycin C (MMC). Disease was confirmed on transurethral resection of bladder tumor (TURBT) prior to starting CHT. Follow-up included cystoscopy and subsequent TURBT if recurrence/progression was suspected. The primary endpoint was RFS. Secondary endpoints were progression-free survival (PFS) and adverse events from CHT.

RESULTS AND LIMITATIONS: Median follow up was 22.4 months (Interquartile range (IQR): 12.8 –35.8). Median age was 70.4 years (IQR: 62.1 –78.6). A total of 557 (66.7%), 172 (20.6) and 74 (8.9%) of patients were classified to BCG naïve, BCG unresponsive and BCG failure, respectively. The RFS at 12 months and 24 months for BCG naïve was 87.6% (95% CI 85.0% – 90.4%) and 75.0% (95% CI 71.3% – 78.8%), respectively. The RFS at 12 months and 24 months for BCG unresponsive cohort was 78.1% (95% CI 72.0% – 84.7%) and 57.4% (95% CI 49.7% – 66.3%), respectively. The RFS at 24 months for the BCG unresponsive cohort for CIS with/without papillary disease and papillary only disease were 43.6% (95% CI 31.4% –60.4%) and 64.5% (95% CI 55.4% – 75.1%), respectively. Minor adverse events occurred in 216 (25.6%) patients and severe events occurred in 17 (2.0%) patients.

CONCLUSIONS: CHT with MMC using the Combat BRS is effective in the medium term and has a favorable adverse event profile.

Physical Activity and Health-related Quality of Life from Diagnosis to One Year After Radical Cystectomy in Patients with Bladder Cancer: A Longitudinal Cohort Study


BACKGROUND: Emerging evidence shows a positive impact of physical activity (PA) on health-related quality of life (HRQoL) in cancer patients. However, longitudinal evidence on PA and HRQoL in patients with bladder cancer (BC) undergoing radical cystectomy (RC) is lacking.

OBJECTIVES: To investigate PA levels, HRQoL outcomes and their relationship from diagnosis to one year after RC in BC patients.

METHODS: A longitudinal cohort study in 90 BC patients was conducted at Ghent and Leuven University Hospitals between April 2017 and December 2020. The Godin Leisure-Time Exercise Questionnaire (GLTEQ) and the EORTC QLQ-C30 and BLM30 were used to measure PA and HRQoL, respectively, before RC, one, three, six and twelve months after RC. Linear mixed models were used for statistical analyses.

RESULTS: The majority was physically inactive before RC (58%), at month one (79%), three (53%), six (61%) and twelve (64%). Among (moderately) active patients, light-intensity activities (mainly walking) were important contributors to the total amount of PA. Clinically important and low HRQoL outcomes in different domains were identified with lowest scores at diagnosis and one month after RC. Active patients before RC have better physical functioning (mean difference (MD) -22.7, standard error (SE) 8.7, p = 0.011), global health status (MD -15.9, SE 6.9, p = 0.023) and fatigue (MD 19.9, SE 9.5, p = 0.038) one month after RC, compared to inactive patients. Active patients at month have better physical functioning (MD -16.2, SE 6.9, p = 0.023) and sexual functioning (MD -16.8, SE 5.4, p = 0.003; MD -13.5, SE 5.5, p = 0.017) at month six and twelve, respectively, compared to inactive patients.

CONCLUSIONS: Higher PA levels are associated with better HRQoL outcomes for BC patients undergoing RC. The data suggests that PA interventions could be an asset to improve BC patients’ HRQoL, but should be tested in future trials.

Adjuvant Chemotherapy Plus Radiotherapy versus Chemotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy


BACKGROUND: Survival with locally advanced bladder cancer (LABC) following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small, randomized trial has suggested a potential survival benefit when combined with post-operative radiotherapy (PORT).

OBJECTIVE: We examined the association of AC + PORT with overall survival (OS) in patients with LABC after RC.

METHODS: Using a prior phase 2 trial to inform design, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18–79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial bladder carcinoma following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006–2015 in the NCDB. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment with OS were evaluated using multivariable Cox regression.

RESULTS: 1,684 patients were included, with 66 receiving AC + PORT and 1,618 AC alone. Compared to patients treated with AC alone, those treated with AC + PORT were more likely to have pT4 disease (52% vs 26%; p < 0.01), positive surgical margins (44% vs 17%; p < 0.01), and be treated at a non-academic facility (75% vs 53%; p < 0.01). Crude 5-year OS was 19% for AC + PORT versus 36% for AC alone (p = 0.01). Adjusted 5-year OS was 33% for AC + PORT versus 36% for AC alone (p = 0.49). After adjusting for baseline characteristics including pathologic features, AC + PORT was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82–1.51).

CONCLUSIONS: Although infrequently utilized, the addition of radiotherapy to AC is not associated with improved OS in LABC. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes.