Validation of non-muscle-invasive bladder cancer risk stratification updated in the 2021 European Association of Urology guidelines

Abstract

Objective: The objective of this study is to validate the predictive ability of the 2021 European Association of Urology (EAU) risk model compared to that of existing risk models, including the 2019 EAU model and risk scoring tables of the European Organization for Research and Treatment of Cancer, Club Urologico Espanol de Tratamiento Oncologico, and Japanese Nishinihon Uro-oncology Extensive Collaboration Group.

Patients and methods: This retrospective multi-institutional database study included two cohorts-3024 patients receiving intravesical bacillus Calmette-Guerin (BCG) treatment (BCG cohort) and 789 patients not receiving BCG treatment (non-BCG cohort). The Kaplan-Meier estimate and log-rank test were used to visualize and compare oncological survival outcomes after transurethral surgery among the risk groups. Harrell's concordance index (C-index) was used to evaluate the predictive ability of the models.

Results: We observed a risk shift from the 2019 EAU risk grouping to the 2021 EAU risk grouping in a substantial number of patients. For progression, the C-index of the 2021 EAU model was significantly higher than that of the 2019 EAU model in both the BCG (0.617 vs. 0.572; P = 0.011) and non-BCG (0.718 vs. 0.560; P < 0.001) cohorts. According to the 2021 EAU model, 731 (24%) and 130 (16%) patients in the BCG and non-BCG cohorts, respectively, were considered to have a very high risk. Survival analysis showed no significant differences among the five very high-risk subgroups in both cohorts. A major limitation was potential selection bias owing to the retrospective nature of this study.

Conclusions: The updated 2021 EAU model showed better stratification than the three existing risk models, especially for progression, in both cohorts, determining the most appropriate postoperative treatment and identifying patients requiring intensified surveillance or early cystectomy.

Keywords: prediction; prognosis; progression; recurrence; risk; urinary bladder neoplasms.

FIGURE 1

Flow chart for the patient's cohort data sets and schematic design of this study. Two independent datasets are used for external validation: the BCG cohort receiving intravesical BCG treatment and the non‐BCG cohort that did not receive BCG treatment. From the original datasets, the cohorts excluded patients with critically missing data for risk stratification in each model. BCG, bacillus Calmette‐Guerin; CUETO, Club Urologico Espanol de Tratamiento Oncologico; EAU, European Association of Urology; EORTC, European Organization for Research and Treatment of Cancer; J‐NICE, Japanese Nishinihon Uro‐oncology Extensive Collaboration Group; NMIBC, non‐muscle‐invasive bladder cancer.

FIGURE 2

Shift of the risk grouping from the 2019 EAU model to the 2021 EAU model in the BCG (A) and non‐BCG (B) cohorts. Sankey diagrams (left panels) connecting the risk grouping from the CUETO or EORTC models (based on the progression score) to the 2019 EAU model and from the 2019 EAU model to the 2021 EAU model. Each vertical bar represents stratified risks: blue, low risk; yellow, intermediate risk; red, high risk; purple, highest risk; or very high risk. Tabulation of risk grouping by the 2019 EAU model and the 2021 risk model (right panels) shows patients with a reduced risk (yellow), an increased risk (orange) and a risk agreement (grey). CUETO, Club Urologico Espanol de Tratamiento Oncologico; EAU, European Association of Urology; EORTC, European Organization for Research and Treatment of Cancer.

FIGURE 3

Recurrence‐free survival curves and comparison of predictive ability among risk models in the BCG (A) and non‐BCG (B) cohorts. Survival curves stratified by each stratification model were compared using the log‐rank test, and the predictive ability was evaluated using the C‐index. The overall C‐index values for the prediction of progression were compared using the CompareC package in the R software. The p values indicated by the double arrows represent the differences between C‐indices. BCG, bacillus Calmette‐Guerin; CUETO, Club Urologico Espanol de Tratamiento Oncologico; EAU, European Association of Urology; EORTC, European Organization for Research and Treatment of Cancer; J‐NICE, Japanese Nishinihon Uro‐oncology Extensive Collaboration Group; NMIBC, non‐muscle‐invasive bladder cancer.

FIGURE 4

Progression‐free survival curves and comparison of predictive ability among risk models in the BCG (A) and non‐BCG (B) cohorts. Survival curves stratified by each stratification model were compared using the log‐rank test, and the predictive ability was evaluated using the C‐index. The overall C‐index values for the prediction of progression were compared using the CompareC package in the R software. The p values indicated by the double arrows represent the differences between C‐indices. BCG, bacillus Calmette‐Guerin; CUETO, Club Urologico Espanol de Tratamiento Oncologico; EAU, European Association of Urology; EORTC, European Organization for Research and Treatment of Cancer; J‐NICE, Japanese Nishinihon Uro‐oncology Extensive Collaboration Group; NMIBC, non‐muscle‐invasive bladder cancer.

FIGURE 5

Subgroup survival analysis of very high‐risk group in the 2021 EAU risk model in the BCG (A) and non‐BCG (B) cohorts. The 2021 EAU risk model defines five subgroups as the very high‐risk population based on the T category, WHO 1973 tumour grade, WHO 2004/2016 and three additional clinical factors (Table 1). Survival curves are compared among the five subgroups in the BCG cohort (A). There are only two and three patients with ‘Ta HG/G3 and CIS with all three risk factors’ and ‘T1 G2 and CIS with at least two risk factors’ subgroups, respectively. Thus, survival curves are compared among the remaining three subgroups in the non‐BCG cohort (B). BCG, bacillus Calmette‐Guerin; CIS, carcinoma in situ; HG, high‐grade.