title: Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209.
abstract: BACKGROUND
  This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy.
  
  
  METHODS
  Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm.
  
  
  RESULTS
  Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC.
  
  
  CONCLUSIONS
  This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment.
  C000000093.
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, Sapporo hkitamu@sapmed.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, Sapporo.
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Japan Clinical Oncology Group Data Centre, Multi-institutional Clinical Trial Support Centre, National Cancer Centre, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, Sapporo.
authors.forename: N
authors.initials: N
authors.lastname: Masumori
authors.affiliation: Department of Urology, National Cancer Centre Hospital, Tokyo.
authors.forename: H
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Urology, Nara Medical University, Kashihara.
authors.forename: Y
authors.initials: Y
authors.lastname: Hirao
authors.affiliation: Department of Urology, Nara Medical University, Kashihara.
authors.forename: K
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Department of Urology, Niigata Cancer Centre Hospital, Niigata.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Urology, Yamagata University Faculty of Medicine, Yamagata.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Urology, Shizuoka Cancer Centre Hospital, Shizuoka.
authors.forename: K
authors.initials: K
authors.lastname: Tobisu
authors.affiliation: Department of Urology, Shizuoka Cancer Centre Hospital, Shizuoka.
authors.forename: M
authors.initials: M
authors.lastname: Niwakawa
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka.
authors.forename: S
authors.initials: S
authors.lastname: Naito
authors.affiliation: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto.
authors.forename: M
authors.initials: M
authors.lastname: Eto
authors.affiliation: Department of Urology, Kagawa University Faculty of Medicine, Kagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kakehi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000601:surgery; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D015653:Cystectomy; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016016:Proportional Hazards Models; D011788:Quality of Life; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000601:surgery; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate
keywords: bladder cancer; neoadjuvant chemotherapy; radical cystectomy