title: Sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial.
abstract: BACKGROUND
  Intravesical bacillus Calmette-Guérin (BCG) is an effective therapy in non-muscle-invasive bladder cancer (NMIBC), but it has limitations in terms of recurrence and toxicity.
  
  
  OBJECTIVE
  To determine whether the sequential combination of mitomycin C (MMC) and BCG is superior to BCG alone in increasing a disease-free interval (DFI).
  
  
  METHODS
  We conducted a prospective randomized trial including 407 patients with intermediate- to high-risk NMIBC and allocated 211 to the MMC and BCG arm and 196 to the BCG-alone arm.
  
  
  METHODS
  The trial was designed to provide concurrently a power of 80% for the detection of a relative risk reduction of 35% (hazard ratio [HR]: 0.65) of disease relapse with a type I error of 0.05. Times to events were estimated using cumulative incidence functions and compared using the Cox regression model. We used the Kaplan-Meier technique to estimate survival curves.
  
  
  CONCLUSIONS
  In the intention-to-treat analysis at 5 yr, DFI was significantly improved by the sequential scheme (HR: 0.57; 95% confidence interval [CI], 0.39-0.83; p=0.003), reducing the disease relapse rate from 33.9% to 20.6%. Higher toxicity was observed with the combination, even reducing the MMC dose, especially in G3 local toxicity compared with BCG with a difference of 17.4% (95% CI, 7.6-27.2; p<0.001). In recurrent T1 tumors, the potential benefit of the sequential scheme was more evident than in the remaining subgroup (18.8% vs 12.8%), with a number needed to treat of five versus eight to avoid an event and with similar toxicity.
  
  
  CONCLUSIONS
  Although the sequential scheme is more effective than BCG alone in reducing disease relapse, due to higher toxicity it could be offered only to patients with a high likelihood of recurrence, such as those with recurrent T1 tumors.
  
  
  RESULTS
  We analyzed the outcomes of a randomized trial demonstrating that in intermediate- to high-risk non-muscle-invasive bladder cancer, mitomycin C and bacillus Calmette-Guérin (BCG) reduced disease relapse compared with BCG alone but was more toxic. Consequently, it could be offered only to patients with recurrent T1 tumors.
  
  
  BACKGROUND
  CUETO 93009.
authors.affiliation: Department of Urology, Instituto Valenciano de Oncología, Valencia, Spain. Electronic address: solsona@pulso.com.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Solsona
authors.affiliation: Department of Statistics, Hospital La Paz, Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Madero
authors.affiliation: Department of Urology, Complejo Hospitalario Universitario a Coruña, La Coruña, Spain.
authors.forename: Venancio
authors.initials: V
authors.lastname: Chantada
authors.affiliation: Department of Urology, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Fernandez
authors.affiliation: Department of Urology, Hospital Cruces, Bilbao, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Zabala
authors.affiliation: Department of Urology, Hospital Universitario Marques de Valdecilla, Santander, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Portillo
authors.affiliation: Department of Urology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Alonso
authors.affiliation: Department of Urology, Hospital de Galdakao, Bilbao, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Astobieta
authors.affiliation: Department of Urology, Hospital de Basurto, Bilbao, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Unda
authors.affiliation: Department of Urology, Hospital Princesa Sofia, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Piñeiro
authors.affiliation: Department of Urology, Hospital de la Princesa, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Rabadan
authors.affiliation: Department of Urology, Hospital Xeral, Vigo, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ojea
authors.affiliation: Department of Urology, Hospital Universitario de San Carlos, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Rodriguez-Molina
authors.affiliation: Department of Urology, Hospital General, Jerez de la Frontera, Spain.
authors.forename: Pastora
authors.initials: P
authors.lastname: Beardo
authors.affiliation: Department of Urology, Hospital Alvarez Buylla, Mieres, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Muntañola
authors.affiliation: Department of Urology, Hospital Negrin, Las Palmas de Gran Canaria, Spain.
authors.forename: Matias
authors.initials: M
authors.lastname: Gomez
authors.affiliation: Department of Urology, Hospital Virgen del Camino, Pamplona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Montesinos
authors.affiliation: Department of Urology, Clínica La Luz, Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez Piñeiro
mesh_terms: D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001500:BCG Vaccine / Q000009:adverse effects*; D017024:Chemotherapy, Adjuvant; D015653:Cystectomy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D001500:BCG Vaccine; D016685:Mitomycin
keywords: BCG; Intermediate- to high-risk groups; MMC plus BCG; Randomized trial; Subgroup analysis