Skip to main content

Adjuvant chemotherapy for operable breast cancer: old vs new schema

In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate and fluorouracil (CMF) as adjuvant treatment for node-positive breast cancer. Thirty years later, the results of this study demonstrate that the significant advantage in both relapse-free (reduction in relative risk for relapse of 29%) and overall survival (reduction in relative risk for death of 21%) persists over the years and that adjuvant CMF can exert a moderate but worthwhile suppression of micrometastases, regardless of anatomical sites [1].

With the aim of further improving the prognosis of operable breast cancer patients, in the early 1980s many research groups designed and carried out new randomized trials including anthracyclines. Despite the fact that many individual trials failed to observe a true benefit for the tested anthracycline regimen, the arithmetic construction on which the international overview is based (i.e. the summing up of many individual trials to increase the statistical power) allowed it to be estimated that there was a reduction in the risk for disease relapse and death of approximately 10%, corresponding to an absolute difference of approximately 3% [2].

At the Milan Cancer Institute we designed two different studies to test the effectiveness of sequential non-cross-resistant regimens containing anthracyclines. Briefly, in patients with moderate risk for relapse the sequential delivery of CMF followed by adriamycin was compared with CMF alone, whereas in a second study conducted in high-risk patient the inverse sequence (adriamycin followed by CMF) was tested. The rationale behind these studies was that switching to another regimen early in the administration of chemotherapy could overcome drug resistance. The updated 20-year results confirmed that the relative merits of anthracycline-containing adjuvant programs can also depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighted against potential risks [3].

The treatment results observed after sequential adriamycin followed by CMF in a poor risk subset could probably be explained by an increased density of the anthracycline, which was delivered at full dose within the first 9 weeks of treatment. The value of dose density was recently confirmed by the National Cancer Institute's Breast Intergroup INT C9741 trial, in which patients who received the dose-dense regimens had significantly improved early treatment outcome compared with their counterparts who did not receive these regimens.

The role of sequential non-cross-resistant regimens was tested in many other trials, both in the adjuvant and neoadjuvant settings. Of note, the 3-year joint efficacy analysis of the National Epirubicin Adjuvant Trial (NEAT) and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential regimen, supporting the hypothesis that the sequential administration of single-agent anthracyclines given upfront before CMF can indeed improve treatment outcome. Also, the addition of taxanes after delivery of adriamycin and cyclophosphamide contributed to improving therapeutic results over the nontaxane regimen both in the adjuvant and neoadjuvant settings. By contrast, in the INT C9741 trial no difference was detected in treatment outcome between the concurrent or sequential schedules of adriamycin, cyclophosphamide and paclitaxel. Similarly, the MD Anderson randomized study failed to detect superiority of the sequential arm.

Thirty years ago, treating patients who were free of identifiable metastatic disease with systemic adjuvant therapy because some of them might eventually develop distant disease was a revolutionary departure from prior treatment approaches [4]. It has been estimated that improvements since the 1970s in the way in which breast cancer is managed must have prevented about 25–30% of the breast cancer deaths in middle-aged women that would otherwise have occurred in the year 2000.


  1. Bonadonna G, Molterni A, Zambetti M, Daidone MG, Pilotti S, Gianni L, Valagussa P: 30 years' follow up of randomized studies of adjuvant CMF in operable breast cancer: cohort study. BMJ. 2005, 330: 217-220. 10.1136/bmj.38314.622095.8F.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Early Breast Cancer Trialists' Collaborative Group.: Polychemotherapy for rearly breast cancer. Lancet. 1998, 352: 930-942. 10.1016/S0140-6736(98)03301-7.

    Article  Google Scholar 

  3. Bonadonna G, Zambetti M, Gianni L, Valagussa P: Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and fluorouracil operable breast cancer. J Clin Oncol . 2004, 22: 1614-1620. 10.1200/JCO.2004.07.190.

    Article  CAS  PubMed  Google Scholar 

  4. Fisher B: The evolution of paradigms for the management of breast cancer: a personal perspective. Cancer Res. 1992, 52: 2371-2383.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Valagussa, P., Gianni, L. & Bonadonna, G. Adjuvant chemotherapy for operable breast cancer: old vs new schema. Breast Cancer Res 7 (Suppl 1), S21 (2005).

Download citation

  • Published:

  • DOI:


  • Anthracyclines
  • Adriamycin
  • Operable Breast Cancer
  • Overcome Drug Resistance
  • Operable Breast Cancer Patient