Muscle-invasive bladder cancer (MIBC) is an aggressive disease with high mortality if left untreated [1,2]. Radical cystectomy (RC) with pelvic lymph node dissection is the guideline-recommended gold standard for curative treatment for MIBC [3,4]. However, RC is associated with significant morbidity and mortality, with a meta-analysis finding a pooled 90-day overall complication rate of 59% and high-grade complication rate of 15% [5]. RC may also cause a decrease in quality of life (QOL) due to removal of the patient's natural bladder [6]. Patients with MIBC tend to be older and may have multiple comorbidities, putting them at even higher risk of complications and possibly rendering them unfit for major surgery [7,8].

Trimodality therapy (TMT) has thus emerged as a viable alternative treatment modality, with an aim to improve quality of life through bladder preservation while not compromising oncological outcomes [9]. TMT consists of maximal transurethral resection of bladder tumor (TURBT) followed by the concurrent use of radiotherapy and systemic chemotherapy [10], and has been endorsed as an alternative to RC in nonmetastatic MIBC for select patients by American Urological Association and European Association of Urology guidelines [4,11]. Several meta-analyses have been performed to compare survival outcomes between TMT and RC [[12], [13], [14]] but outcomes were conflicting, possibly due to frequent use of indirect comparisons and low quality of included studies.

Despite recent research that aims to expand the indication for TMT to include node-positive nonmetastatic MIBC [15], concerns about reduced survival without radical surgery prevail [14]. The SPARE randomized controlled trial (RCT) directly comparing the RC and TMT closed early due to recruitment difficulties, and was marred by high rates of protocol deviation [16]. In view of these challenges, there appears to be a low likelihood that further RCTs will be initiated [17]. Retrospective comparisons exist in literature, but there appear to be vast differences in populations referred to both treatment modalities in terms of age and fitness. Another important factor leading to bias in the comparison is the discordance between clinical and pathological staging. Pathological staging provides pertinent information through microscopic examination of the bladder specimen following cystectomy, and the lack of this definitive staging in the TMT group may introduce misclassification bias by underestimating the degree of muscle invasion or lymph node involvement [18].

Bearing in mind the difficulties of conducting proper RCTs in the field, as well as the limitations of retrospective studies, we aimed to further characterize this comparison by using retrospective studies which performed statistical adjustments in order to emulate RCTs. These study types include propensity score-matched (PSM) studies and case-control studies, which account for baseline patient and tumor characteristics and hence represent the next-best level of evidence.

Hence, the aim of this systematic review and meta-analysis was to evaluate survival outcomes of TMT versus RC in patients with MIBC using studies of the highest quality evidence to date.