Intended for healthcare professionals


30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study

BMJ 2005; 330 doi: (Published 27 January 2005) Cite this as: BMJ 2005;330:217
  1. Gianni Bonadonna, consultant, Department of Medical Oncology (gianni.bonadonna{at},
  2. Angela Moliterni, senior staff, Division of Medical Oncology A1,
  3. Milvia Zambetti, senior staff, Division of Medical Oncology A1,
  4. Maria Grazia Daidone, director, Determinant of Prognosis and Treatment Response Unit1,
  5. Silvana Pilotti, director, Division of Pathology C1,
  6. Luca Gianni, director, Division of Medical Oncology A1,
  7. Pinuccia Valagussa, head, Operations Office, Department of Medical Oncology1
  1. 1 Istituto Nazionale Tumori, 20133 Milan, Italy
  1. Correspondence to: G Bonadonna
  • Accepted 15 November 2004


Objective To assess the long term effectiveness of adjuvant treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of relapse, on the basis of three successive randomised trials and one observational study conducted from June 1973 to December 1980.

Design Cohort study.

Setting Istituto Nazionale Tumori in Milan, Italy.

Main outcome measures Relapse free and overall survival, measured by univariate and multivariate analyses.

Results After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04). Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years.

Conclusions When delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups.


  • Contributors GB developed the protocols, secured initial funding, implemented the studies, and wrote the original draft. AM and MZ directed the clinical studies and helped with the final draft. MGD and SP directed the pathobiological studies and granted quality control for all assays. LG obtained long term funding, supervised the long term follow up, and helped with the final draft. PV organised the studies, assured the quality control of the data entry, carried out the statistical analysis, and wrote the original draft. GB, LG, PV are guarantors.

  • Funding These studies were supported in part by contracts (N01-CM-33714 and N01-CM-07338) with the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Md.

  • Competing interest None declared.

  • Ethical approval Research and Ethics Committee of the Istituto Nazionale Tumori of Milan.

View Full Text