Vesical imaging reporting and data system (VI-RADS) could predict the survival of bladder-cancer patients who received radical cystectomy

Vesical Imaging Reporting and Data System (VI-RADS) shows good potential in determining muscle-invasive bladder cancer (MIBC) patients. However, whether VI-RADS could predict the prognosis of radical cystectomy (RC) patients has not been reported. Our purpose is to determine whether VI-RADS contributed to predict oncologic outcomes. In this retrospective study, we analysed the information of bladder cancer patients who admitted to our centre from June 2012 to June 2022. All patients who underwent multiparametric magnetic resonance imaging (mpMRI) and underwent RC were included. VI-RADS scoring was performed by two radiologists blinded to the clinical data. Patients’ clinical features, pathology data, and imaging information were recorded. Kaplan–Meier method was used to estimate patients' overall survival (OS) and progression-free survival (PFS). Log-rank test was used to assess statistical differences. COX regression analysis was used to estimate risk factors. Ultimately, we included 219 patients, with 188 males and 31 females. The median age was 66 (IQR = 61–74.5) years. The VI-RADS scores were as follows: VI-RADS 1, 4 (1.8%); VI-RADS 2, 68 (31.1%); VI-RADS 3, 40 (18.3%); VI-RADS 4, 69 (31.5%); and VI-RADS 5, 38 (17.4%). Patients with VI-RADS ≥ 3 had poorer OS and PFS than those with VI-RADS < 3. The AUC of VI-RADS predicting 3-year OS was 0.804, with sensitivity of 0.824 and negative predictive value of 0.942. Multivariate COX analysis showed that VI-RADS ≥ 3 was risk factors for OS (HR = 3.517, P = 0.003) and PFS (HR = 4.175, P < 0.001). In the MIBC subgroup, patients with VI-RADS ≥ 4 had poorer OS and PFS. In the non-muscle invasive bladder cancer (NMIBC) subgroup, the prognosis of patients with VI-RADS ≥ 3 remained poorer. VI-RADS scores could effectively predict the survival of patients after RC.

Bladder cancer is the tenth most common cancer around the world, with more than 500,000 new cases and over 200,000 deaths annually 1,2 .The management of bladder-cancer patients is based on tumour invasion and histological grade.Non-muscle invasive bladder cancer (NMIBC) is primarily treated with transurethral resection of bladder tumour (TURBT), whereas muscle invasive bladder cancer (MIBC) is treated by radical cystectomy (RC) 3,4 .
Multiparametric magnetic resonance imaging (mpMRI) is a non-invasive and convenient examination method for bladder-cancer patients.It comprises of the sequence of T2-weighted images (T2W), diffusionweighted images (DWIs), and dynamic contrast enhanced (DCE) 5 .Vesical Imaging Reporting and Data System (VI-RADS) based on the three sequences is used as an important guideline to determine clinical staging [5][6][7] .A meta-analysis has shown that VI-RADS score is good at detecting the muscle invasiveness of bladder cancer with AUC > 0.90 when using VI-RADS 3 or VI-RADS 4 as the cutoff value 8 .
Clinical treatment should be based on patient prognosis, which is actually the most important thing that patients consider.Several studies have shown that the five-year cancer specific survival rate of MIBC patients is about 65% 9,10 .The use of imaging examination to predict the treatment outcomes of tumour patient is emerging.

Pathological diagnosis
The surgical specimens were diagnosed by an attending physician in the department of pathology, and the diagnosis results were reviewed by a chief physician.

Statistical analyses
We performed Kaplan-Meier (K-M) method to estimate patients' overall survival (OS) and progression-free survival (PFS), as well as log-rank test to assess statistical differences.To evaluate the performance of VI-RADS in predicting prognosis, a time-dependent ROC curve was constructed.The optimal cutoff value was determined based on the Youden index, and the AUC for predicting survival at 1, 3, and 5 years was calculated.Univariate COX regression analysis was conducted to estimate the hazard ratio (HR) and 95% confidence of each variable.A nomogram was plotted for clinicians to compute the survival, using "rms" package.All statistical analyses were performed in SPSS (version 26.0) and R (version 3.6.3)software, and P < 0.05 was considered statistically significant.

Ethical approval and consent to participate
This study was approved by the Ethics Committees of the First Affiliated Hospital of Nanjing Medical University (2020-SR-252), and have been performed in accordance with the Declaration of Helsinki.All written informed consent to participate in the study was obtained from the patients.
The median follow-up was 36.5 (IQR: 30.3-43.2) months.Overall, 25 (11.4%)patients developed tumour progression, and 42 (19.2%)patients died.Patients with VI-RADS ≥ 3 had significantly lower OS and PFS than those with VI-RADS < 3 (Fig. 2A,B), with the 5-year OS of 61.7% vs. 87.7% and 5-year PFS of 55.6% vs. 84.1%.We further divided the groups into two with a cutoff of VI-RADS 4 and found the same trends (Figure S1A,B).Subsequently, we plotted time-dependent ROC curves (Fig. 3 and S2), and determined the best cutoff value according to Youden index.The AUC of VI-RADS for predicting 3-year OS was 0.804, the sensitivity was 0.824, and the negative predictive value was 0.942 (Table S2).

Discussion
VI-RADS score system has given great reliability and clinical usefulness for distinguishing muscular invasion in bladder cancer.The AUC of VI-RADS for determining MIBC was 0.94, with a sensitivity of 0.871, specificity of 0.965, and accuracy of 0.941 17 .However, previous studies have mostly focused on the use of VI-RADS to estimate the degree of invasion.Herein, we used this system to predict the prognosis of RC patients and constructed a nomogram to broaden its clinical use.We enrolled 219 bladder-cancer patients.Our results demonstrated a significant difference in oncology outcomes between the two groups with VI-RADS 3 or 4 as a cutoff.Specifically, with a cutoff score of 3, patients with VI-RADS < 3 had a longer mean OS time (101.5 vs. 83.9months) and mean PFS time (100.3 vs. 72.9months) compared with those having VI-RADS ≥ 3.This finding can serve as a theoretical basis for previous research showing that patients with VI-RADS ≥ 3 are more inclined to be MIBCs [17][18][19] .Conversely, Metwally MI et al. pointed that VI-RADS 4 and 5 have a high performance in defining surgical treatment, whereas VI-RADS 2 and 3 require further modification 7 .Some studies showed that in patients with intradiverticular bladder tumours, MRI features could significantly predict the overall survival 15 .In addition, Woo S, et al. enrolled 41 patients and found that VIRADS were associated with prognosis 16 .
The AUCs of VI-RADS scores in predicting the survival of RC patients all exceeded 0.7, showing its good ability.In particular, in predicting 3-year PFS, the AUC was 0.822, with a sensitivity of 0.832, specificity of 0.716, positive predictive value (PPV) of 0.512, and negative predictive value (NPV) of 0.923.With regard to the low PPV, we considered that the VI-RADS score system was designed to evaluate the primary lesion and did not take into account the status of lymph nodes.Several studies have proven that pelvic lymph-node metastasis induces cancer recurrence 9,20 .Therefore, patients who are predicted not to recur by judging the primary lesion may have some recurrence due to the presence of positive lymph node.How to effectively predict pelvic metastatic lymph nodes before surgery is also crucial.
In the MIBC subgroup, VI-RADS with the cutoff of 4 was more valuable.A total of 22 (17.5%)MIBC patients had a VI-RADS score of 3. Accordingly, we speculated that patients with a score of 3 would have a better prognosis even if the pathology was MIBC.The K-M curve showed no significant difference in prognosis between MIBC and NMIBC when the VI-RADS score was 3.However, in the NMIBC subgroup, the prognosis of patients with VI-RADS ≥ 3 was significantly poorer than that of patients with VI-RADS < 3. Some patients with NMIBC undergo RC because of BCG-unresponsive.Ferro M, et al. showed that in patients treated with TURBT, the recurrence rate of patients with BCG-unresponsive is significantly higher than that of patients with BCG-responsive 21 .Therefore, new risk stratification based on VI-RADS may better serve NMIBC patients.
Our study also had some limitations.First, this study was a retrospective one, with existing inherent bias.Second, some of the patients (7 patients, 3.2%) in our study had received TURBT in other centres, which may increase the difficulty for judging VI-RADS scores.Even so, our study obtained some useful results and provided guidance for clinical practice in the real world.

Table 1 .
Patient characteristics and VI-RADS evaluation.a 15 patients were not received lymph nodes dissection.

Table 2 .
Univariable and multivariate Cox regression models predicting OS and PFS.