title: Standard versus continuous administration of capecitabine in metastatic breast cancer (GEICAM/2009-05): a randomized, noninferiority phase II trial with a pharmacogenetic analysis.
abstract: BACKGROUND
  The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy.
  
  
  METHODS
  We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed.
  
  
  RESULTS
  The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3-4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3-4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5' untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival.
  
  
  CONCLUSIONS
  Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.
authors.affiliation: Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain; mmartin@geicam.org.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.affiliation: Hospital Universitario Ramón y Cajal, Madrid, Spain;
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez
authors.affiliation: Centro Oncológico Galicia, A Coruña, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramos
authors.affiliation: Complejo Hospitalario A Coruña (CHUAC), A Coruña, Spain;
authors.forename: Lourdes
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Hospital Clínico Universitario de Valencia, Valencia, Spain;
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain;
authors.forename: Pilar
authors.initials: P
authors.lastname: Zamora
authors.affiliation: Hospital Clinic de Barcelona, Barcelona, Spain;
authors.forename: Montserrat
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: GEICAM (Spanish Breast Cancer Group), San Sebastián de los Reyes, Madrid, Spain;
authors.forename: Eva
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: GEICAM (Spanish Breast Cancer Group), San Sebastián de los Reyes, Madrid, Spain;
authors.forename: Rosalía
authors.initials: R
authors.lastname: Caballero
authors.affiliation: Hospital Clínico San Carlos, Madrid, Spain;
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: García-Sáenz
authors.affiliation: Hospital Universitario Ramón y Cajal, Madrid, Spain;
authors.forename: Eva
authors.initials: E
authors.lastname: Guerra
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain;
authors.forename: Daniela
authors.initials: D
authors.lastname: Caronia
authors.affiliation: Hospital Clínico San Carlos, Madrid, Spain;
authors.forename: Antonio
authors.initials: A
authors.lastname: Casado
authors.affiliation: Hospital Universitario Virgen del Rocío, Sevilla, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruíz-Borrego
authors.affiliation: Hospital General Yagüe, Burgos, Spain;
authors.forename: Blanca
authors.initials: B
authors.lastname: Hernando
authors.affiliation: Hospital Virgen de la Salud, Toledo, Spain;
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Chacón
authors.affiliation: Hospital Clínico San Carlos, Madrid, Spain;
authors.forename: Julio César
authors.initials: JC
authors.lastname: De la Torre-Montero
authors.affiliation: GEICAM (Spanish Breast Cancer Group), San Sebastián de los Reyes, Madrid, Spain;
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Jimeno
authors.affiliation: Hospital General De Hospitalet, Hospitalet de Llobregat, Barcelona, Spain;
authors.forename: Lucía
authors.initials: L
authors.lastname: Heras
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain;
authors.forename: Rosario
authors.initials: R
authors.lastname: Alonso
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain;
authors.forename: Juan
authors.initials: J
authors.lastname: De la Haba
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain;
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.affiliation: Complejo Hospitalario de Pontevedra, Pontevedra, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Constenla
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D060831:Hand-Foot Syndrome / Q000209:etiology / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D016896:Treatment Outcome
chemical_list: D000069287:Capecitabine; D005472:Fluorouracil