title: Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation?
abstract: BACKGROUND
  The European Association of Urology non-muscle-invasive bladder cancer (NMIBC) guidelines recommend that all low- and intermediate-risk patients receive a single immediate instillation of chemotherapy after transurethral resection of the bladder (TURB), but its use remains controversial.
  
  
  OBJECTIVE
  To identify which NMIBC patients benefit from a single immediate instillation.
  
  
  METHODS
  A systematic review and individual patient data (IPD) meta-analysis of randomized trials comparing the efficacy of a single instillation after TURB with TURB alone in NMIBC patients was carried out.
  
  
  RESULTS
  A total of 13 eligible studies were identified. IPD were obtained for 11 studies randomizing 2278 eligible patients, 1161 to TURB and 1117 to a single instillation of epirubicin, mitomycin C, pirarubicin, or thiotepa. A total of 1128 recurrences, 108 progressions, and 460 deaths (59 due to bladder cancer [BCa]) occurred. A single instillation reduced the risk of recurrence by 35% (hazard ratio [HR]: 0.65; 95% confidence interval [CI], 0.58-0.74; p<0.001) and the 5-yr recurrence rate from 58.8% to 44.8%. The instillation did not reduce recurrences in patients with a prior recurrence rate of more than one recurrence per year or in patients with an European Organization for Research and Treatment of Cancer (EORTC) recurrence score ≥5. The instillation did not prolong either the time to progression or death from BCa, but it resulted in an increase in the overall risk of death (HR: 1.26; 95% CI, 1.05-1.51; p=0.015; 5-yr death rates 12.0% vs 11.2%), with the difference appearing in patients with an EORTC recurrence score ≥5.
  
  
  CONCLUSIONS
  A single immediate instillation reduced the risk of recurrence, except in patients with a prior recurrence rate of more than one recurrence per year or an EORTC recurrence score ≥5. It does not prolong either time to progression or death from BCa. The instillation may be associated with an increase in the risk of death in patients at high risk of recurrence in whom the instillation is not effective or recommended.
  
  
  RESULTS
  A single instillation of chemotherapy immediately after resection reduces the risk of recurrence in non-muscle-invasive bladder cancer; however, it should not be given to patients at high risk of recurrence due to its lack of efficacy in this subgroup.
authors.affiliation: EORTC Headquarters, Department of Biostatistics, Brussels, Belgium. Electronic address: richard.sylvester@skynet.be.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sylvester
authors.affiliation: Ghent University Hospital, Department of Urology, Ghent, Belgium.
authors.forename: Willem
authors.initials: W
authors.lastname: Oosterlinck
authors.affiliation: University of Gothenburg, Department of Urology, Gothenburg, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Holmang
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, Department of Cancer and Other Non-Infectious Diseases, London, UK.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.affiliation: Royal Preston Hospital, Rosemere Cancer Centre, Preston, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Birtle
authors.affiliation: Skane University Hospital, Department of Urology, Malmo, Sweden.
authors.forename: Sigurdur
authors.initials: S
authors.lastname: Gudjonsson
authors.affiliation: Ospedale Sant'Andrea, University "La Sapienza," Department of Urology, Rome, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: De Nunzio
authors.affiliation: Higashi Nagoya Hospital, Department of Urology, Nagoya, Japan.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Okamura
authors.affiliation: Hyvinkaa Hospital, Department of Urology, Hyvinkaa, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Kaasinen
authors.affiliation: Valencia Oncology Institute, Department of Urology, Valencia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Solsona
authors.affiliation: Urology and Nephrology Center, Mansoura University, Department of Urology, Mansoura, Egypt.
authors.forename: Bedeir
authors.initials: B
authors.lastname: Ali-El-Dein
authors.affiliation: Turkiye Yuksek Ihtisas Education and Research Hospital, Department of Urology, Ankara, Turkey.
authors.forename: Can Ali
authors.initials: CA
authors.lastname: Tatar
authors.affiliation: Duke University Medical Center, Division of Urology, Durham, NC, USA.
authors.forename: Brant A
authors.initials: BA
authors.lastname: Inman
authors.affiliation: University of Aberdeen, Academic Urology Unit, Aberdeen, UK.
authors.forename: James
authors.initials: J
authors.lastname: N'Dow
authors.affiliation: Jeroen Bosch Hospital, Department of Urology, 's-Hertogenbosch, The Netherlands.
authors.forename: Jorg R
authors.initials: JR
authors.lastname: Oddens
authors.affiliation: Hospital Motol and Second Faculty of Medicine, Charles University, Department of Urology, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Babjuk
mesh_terms: D000283:Administration, Intravesical; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002295:Carcinoma, Transitional Cell / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015251:Epirubicin / Q000008:administration & dosage; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D015996:Survival Rate; D013852:Thiotepa / Q000008:administration & dosage; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*
chemical_list: D015251:Epirubicin; D016685:Mitomycin; D004317:Doxorubicin; D013852:Thiotepa; C027260:pirarubicin
keywords: Chemotherapy; Meta-analysis; Non–muscle-invasive bladder cancer; Single instillation; Systematic review