title: A systematic review and meta-analysis of clinical trials of bladder-sparing trimodality treatment for muscle-invasive bladder cancer (MIBC).
abstract: OBJECTIVE
  Despite the numerous prospective and retrospective studies published during the last 2 decades aiming at testing the safety and the efficacy of trimodality therapy (TMT) as a conservative treatment, an optimal therapeutic strategy has not yet been identified. We made a systematic overview of the 5-year outcomes from 31 trials of combined chemotherapy and radiation (CRT) after transurethral resection of muscle-infiltrating bladder tumours (TURBT), the so-called trimodality therapy. We took into consideration the results of each trial i.e. the rate of complete response (CR), local muscle-invasive local failure (LF), salvage cystectomy (SC), 5-year overall survival (OS) and 5-year bladder intact survival (BIS) from 3315 patients.
  
  
  RESULTS
  About half of the patients were treated with a preliminary induction followed by a consolidation CRT course in CR, or SC in non-CR patients (split treatment). The remaining half of the patients underwent an upfront full-dose CRT course (continuous treatment) with SC reserved to non-CR patients. Excellent results were obtained by trimodality therapy (TMT), with 78% CR, 28% muscle infiltrating LF and 21% SC in patients with MIBC. The 5-year OS and BIS rates were 56% and 42%, respectively. At univariate analysis, CR, and SC rates appeared to be significantly better in the continuous than in the split treatment group. Multivariate analysis confirmed the former regimen as a significant prognostic variables only for CR, while CP-based regimen was a significant prognostic factor for SC. The subgroup analysis revealed a significant improvement in 5-year OS rate of continuous over split treatment in later stage tumours. No relevant benefit was observed with the addition of other drugs to cisplatin (CP) or neo-adjuvant chemotherapy (NATC) to CRT, although, in patients receiving NACT, significantly better CR and OS rates were seen in the continuous than split treatment.
  
  
  CONCLUSIONS
  The results of this overview seem to indicate that TMT is able to produce excellent 5-year OS rates, no matter how it is done (continuous or split). No significant difference in 5-year OS rates could be observed between the two treatment regimens, although the continuous may offer some advantage compared to split treatment in terms of higher CR and, likely lower SC rates. The highest benefit might be achieved in later stage tumours, using a total radiation equivalent dose when delivered in 2Gy/fraction (EQD2) of more than 60Gy in combination with CP based regimes and preceded by 2-3 NACT cycles. Appropriate randomized trials should be addressed to confirm the results of the present review.
authors.affiliation: Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Arcangeli
authors.affiliation: Department of Radiotherapy, Azienda Ospedaliera S. Camillo-Forlanini, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Arcangeli
authors.affiliation: Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy. Electronic address: strigari@ifo.it.
authors.forename: Lidia
authors.initials: L
authors.lastname: Strigari
mesh_terms: D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D006801:Humans; D009361:Neoplasm Invasiveness; D059351:Organ Sparing Treatments; D011379:Prognosis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*
keywords: Bladder-sparing trimodality; Muscle invasive bladder cancer; Radio-chemotherapy