Comparison of trimodality therapy and neoadjuvant chemotherapy combined with radical cystectomy for the survival of muscle-invasive bladder cancer: a population-based analysis

Bladder cancer is the ninth most common cancer worldwide and the most common urinary tumor [1]. At the preliminary diagnosis, approximately one-third of patients are diagnosed with muscle-invasive bladder cancer (MIBC), and approximately 15% to 20% of nonmuscle-invasive bladder cancer (NMIBC) eventually progresses to MIBC [2]. Radical cystectomy (RC) has been considered the mainstay therapy for MIBC, with a reported 5-year overall survival (OS) of approximately 50% [3, 4]. Cisplatin-based neoadjuvant chemotherapy (NAC) has been applied in clinical practice to improve the survival benefits of RC [5]. However, about 59–70% of older patients with MIBC have age-related comorbidities such as renal impairment and cardiovascular or respiratory disease, which makes them unsuitable for surgery or chemotherapy [6] [7]. Considering the possible complications, about 1/3 of patients would choose bladder preservation rather than RC [8, 9].

For those patients with MIBC who rejected RC or NAC, trimodality therapy (TMT) has been investigated as an alternative, in which external beam radiotherapy (RT) and radiosensitizing chemotherapy are delivered after maximal transurethral bladder tumor resection (TURBT) [10]. Most patients receiving TMT could achieve a complete clinical response (cCR) of 70–80%, avoid salvage radical cystectomy, and provide long-term survival comparable to contemporary radical cystectomy series [11‐14]. Although patients who experienced NAC + RC exhibited significant survival benefits compared to patients treated with RC only [5], the comparative effectiveness of TMT and NAC + RC remains unreported.

Therefore, based on the Surveillance, Epidemiology, and End Results (SEER) database, we aimed to compare the survival benefits of NAC + RC and TMT to provide an alternative treatment for clinicians and patients.

RC has shown great survival effectiveness for MIBC patients but may not be eligible for all patients due to some patients having reached quite advanced stages or preferring to retain the bladder [15, 16]. In recent decades, TMT has been increasingly considered as an alternative to RC [17, 18]. However, the clinical benefits of TMT compared with NAC + RC are not yet clear. To provide solid evidence to guide clinicians and patients in choosing therapies, we compared the survival benefits of MIBC patients who were treated by NAC + RC and TMT.

In this research, we found that TMT was more commonly applied in elderly patients, whereas NAC + RC was preferred in younger patients (age ≥ 68: 75.9% vs. 38.5%, P < 0.001). Patients with more advanced T stages were more likely to receive NAC + RC rather than TMT (T3–4a: 26.3% vs. 7.5%, P < 0.001). This may be caused by selection bias in clinical practice. It is not difficult to understand that patients with older age may have poorer surgical tolerance, and patients with more advanced T stage need to receive a more thorough surgical procedure. Because patients with MIBC exhibited heterogeneity between the NAC + RC and TMT groups, we performed propensity matching to reduce selection bias. After PSM, all characteristics were balanced between the two groups, including age (age ≥ 68: 51.8% vs. 55.1%, P = 0.464), T stages (T3–4a: 18.4% vs. 18.4%, P = 0.257), etcetera. We also identified elder age, unmarried, advanced T stages, and received TMT instead of NAC + RC were independent poor prognostic factors for MIBC patients. Age has been reported to be correlated with more adverse outcomes and poor prognosis among patients received RC [19]. Previous studies have reported that T stage is the second most vital predictor of MIBC survival outcome after RC [20‐22]. Based on the high risk of mortality in patients with advanced T stages, neoadjuvant therapy should be considered.

Our results indicated that both the 5-year CSS and OS were better in patients who underwent NAC + RC than in those who underwent TMT. Then, we performed a subgroup analysis to determine the group of patients best suited for each type of local treatment. The analysis further revealed that among most patients, NAC + RC was correlated with a better prognosis, except for black patients and patients with grade III/IV, which showed no significant difference between TMT and NAC + RC. These results suggested that NAC + RC is still a more effective treatment for most patients.

In most patients with high surgical risk or who are unwilling to resect the bladder, treatments that could preserve the bladder are recognized as optional treatments for RC [23, 24]. It is now believed that among these treatments for bladder preservation, TMT not only exhibits the best oncological effect but can also be selected to improve QOL by retaining bladder function in the elderly population [11, 25, 26]. Another retrospective study has previously reported that the elder patients were more likely to take TMT instead of RC (percentages of patients with age ≥ 80: 45.9% vs. 24.7%) [27], which is consistent with our study. The choice of patients with TMT has gradually increased, and most of them were elderly people with possibly more comorbidities, which may be the underlying reason for the low survival rates of TMT in our research. However, as our results indicated, NAC + RC still has a better prognosis even after population propensity matching (OS: HR, 0.33; 95% CI 0.27–0.48). Previous research based on SEER database of 3200 older adults (aged ≥ 66 years) with clinical stage T2 to T4a bladder cancer also stated that compared with RC, patients who underwent TMT had significantly decreased OS and CSS (OS: HR, 1.49, 95% CI 1.31–1.69), and the median total costs were substantially higher for TMT than for RC [27]. Another retrospective research of MIBC patients also suggested that TMT was associated with a significant adverse impact on long-term OS (HR 1.37, 95% CI 1.16–1.59) [28]. In addition, the effectiveness of TMT requires not only professional oncologists and radiotherapists but also specialists in bladder surgeries who can successfully perform a TURBT. Therefore, for those patients who meet the requirements of TMT, there should be an opportunity to discuss all possible treatment regimens.

Although NAC + RC has shown considerable efficacy in our study, around 50% of patients cannot receive cisplatin chemotherapy due to various reasons such as other health conditions, impaired kidney function, or previous contraindications [29, 30]. Current studies also indicated the possible vital role of neoadjuvant or adjuvant immunotherapy including PD-1, PDL-1, and CTLA-4 inhibitors has shown efficacy in treating MIBC [30, 31]. So far, many clinical trials discovering the efficacy of adjuvant or neoadjuvant immunotherapy alone or in combination with chemotherapy have shown promising results with acceptable safety profiles in MIBC [32‐36]. As reported, neoadjuvant immunotherapy achieved a higher pathological complete response rate than neoadjuvant chemotherapy (42–46% vs 20–40%) [32, 33]. The increasing use of immunotherapy in the neoadjuvant treatment of MIBC indicates its potential role in TMT, either as a standalone treatment or in combination with chemotherapy. Relevant clinical studies have been carried out and the results are worth expected (NCT05072600, NCT05531123).

However, the study contains limitations. First, the lack of external verification by other populations may reduce the universality of our conclusion. Second, our study is retrospective, and excluding some patients with MIBC due to missing data could introduce bias, although we tried to control potential bias by using propensity score matching. Third, SEER doesn't have disease-free survival data, so we chose CSS and OS as alternatives. Finally, the SEER database does not contain specific information on the doses, techniques, or sites of radiotherapy, either the exact chemotherapy drugs.

In general, compared with patients receiving TMT, patients receiving NAC + RC had a markedly better prognosis. Older patients and patients with earlier T stages were more likely to take TMT than NAC + RC. Being older than 68 years old, being unmarried, grade III/IV, T3–4a stage, and undergoing TMT were identified as independent poor prognostic factors in all MIBC patients. These findings are primary and underline the requirement for randomized controlled trials to compare TMT with NAC + RC.