BMJ  2005;330:217 (29 January), doi:10.1136/bmj.38314.622095.8F (published 13 January 2005)

Paper

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

¹ Istituto Nazionale Tumori, 20133 Milano, Italy

Abstract

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.

Introduction

In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for node positive breast cancer.¹ A worldwide overview of chemotherapy for breast cancer confirmed that when the long term benefits of treatment are balanced against its risks, adjuvant chemotherapy can be worth while in many patients.² Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients.^{3 4} We report the results of 30 years of experience with adjuvant CMF in a series of successive clinical trials.

Methods

The study designs of the randomised trials were reported earlier (see bmj.com)^{1 5-7} and are summarised in table 1. The study populations consisted of patients admitted to the Istituto Nazionale Tumori in Milan, Italy. All women who had had surgery (radical mastectomy or conservative surgery and full axillary clearance) for unilateral breast cancer were considered for inclusion in the studies if they had histological evidence that one or more axillary nodes were affected (first three studies) or if they had histologically negative axillary nodes and oestrogen receptor negative tumours (fourth study).

View this table: [in this window] [in a new window]   Table 1 CMF studies carried out at the Istituto Nazionale Tumori in Milan

 

Patients with locally advanced or metastatic disease, those with a history of previous cancer, and those with concomitant severe non-malignant systemic disease were not eligible.

With the exception of the fourth study, assessment of the hormone receptors was not mandatory and was done retrospectively.

Adjuvant treatment
In patients with node positive breast cancer, CMF consisted of cyclophosphamide (100 mg/m² orally from day 1 to 14), methotrexate (40 mg/m² intravenously on days 1 and 8), and fluorouracil (600 mg/m² intravenously on days 1 and 8), repeated every four weeks for either six or 12 cycles.¹ In this subset of patients, women older than 60 were to receive reduced doses of methotrexate (30 mg/m²) and fluorouracil (400 mg/m²).

In the fourth study, 12 cycles of cyclophosphamide (600 mg/m²), methotrexate (40 mg/m²), and fluorouracil (600 mg/m²) were given intravenously on day 1 and repeated three weeks later. No dose reductions for older patients were planned.⁷

In all studies, treatment with CMF was started two to four weeks after surgery. No other adjuvant treatments, in particular no endocrine treatment, were allowed, with the exception of breast irradiation for patients who had had conservative surgery. Breast irradiation had to be initiated within six to eight weeks from surgery and was administered alongside CMF in women allocated to receive adjuvant chemotherapy.

Study variables
Details on baseline studies and follow up programmes are reported elsewhere (see bmj.com).^{1 5-7} We considered treatment to have failed when the first evidence of new manifestations of disease in locoregional areas (including ipsilateral supraclavicular adenopathy), distant sites, the contralateral breast, or any combination of these sites was documented. We considered neither second primary cancers nor deaths owing to causes other than breast cancer treatment failures.

Statistical analysis
We calculated relapse free survival from the date of surgery to the first documented evidence of treatment failure. We used death from all causes as the end point for overall survival, which we also measured from the date of surgery. We analysed whether drug induced amenorrhoea in women menstruating at study entry was able to influence the outcome of treatment, excluding all patients who had a relapse within the first nine months after surgery. We tested the null hypothesis concerning the differential effects of treatment or of some prognostic factors in univariate analyses. We used a Cox regression model to investigate the joint effects of treatment and of prognostic indicators. We estimated the relative risks as hazard ratios and calculated the rate of the sites of disease relapse as first event. We analysed the data that were available as of 28 February 2003. Only two patients in complete clinical remission were lost to follow up (see bmj.com).

Results

First CMF study
In the first study, after a median follow up of 28.5 years and a minimal follow up of 25.4 years, both relapse free survival and overall survival remained significantly superior in women receiving adjuvant CMF than in women treated with surgery alone (figure). Patients who received optimal doses of CMF ( 85% of the planned doses) showed a longlasting, superior benefit (relapse free survival 42%, 95% confidence interval 26% to 59%; overall survival 40%, 26% to 55%) compared with patients who received lower doses (26%, 19% to 33%; 21%, 14% to 26%). See bmj.com for details of rates of relapse free and overall survival relative to main characteristics. Further investigation using regression analyses of the joint effects of treatment and prognostic indicators confirmed the significant benefit of adjuvant chemotherapy (table 2).

View larger version (19K): [in this window] [in a new window]   Treatment outcome in the first randomised CMF study after a median observation of 28.5 years. Left: Relapse free survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.71 (95% confidence interval 0.56 to 0.91; P=0.005). Right: Overall survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.79 (0.63 to 0.98; P=0.04)

 

View this table: [in this window] [in a new window]   Table 2 Multivariate analysis of the first CMF study in 337 patients with known oestrogen receptor status. Final model

 

As reported in table 2, CMF contributed to reducing the relative risk of disease relapse by 34% and of death from all causes by 22%. The extent of nodal involvement remained a significant prognostic factor; patients with three or more positive nodes were also at an increased risk of relapse and death in this long term analysis. Neither age group nor menopausal status, oestrogen receptor status, or tumour size influenced relapse free survival significantly. As far as overall survival is concerned, patients aged 50 or more years at study entry had a significantly higher risk of dying than younger women. The lower rates of overall survival in these older women can be explained by deaths not due to progression of breast cancer or new primary malignancies.

The cumulative incidence of first relapse according to anatomical sites showed that the main therapeutic effect of adjuvant CMF was to reduce the incidence of distant metastases (an absolute difference of 11% between patients who received CMF and those who did not).

New malignancies other than contralateral breast cancers were documented in 12 patients with no prevailing distinctive pattern in either treatment group.

CMF for six cycles compared with 12 cycles in premenopausal patients
After a median follow up of 25 years, the outcome of treatment was not improved with a longer duration of adjuvant CMF. The estimated relapse free survival rates were 39% after 12 cycles and 38% after six cycles of CMF. At 25 years, the overall survival rates were 40% in both treatment arms. In the multivariate analysis, the only variable able to influence treatment outcome was the extent to which axillary nodes were affected; patients with three or more affected nodes had a significantly higher risk of disease relapse and death (hazard ratio 2.3, 95% confidence interval 1.61 to 3.16, P = 0.0001).

CMF and amenorrhoea
Grouping together all patients given CMF, a total of 397 women had monthly periods before starting the 12 cycle regimen, and 145 had monthly periods before starting the six cycle regimen. Overall, drug induced amenorrhoea was reported more often in the longer regimen (75% v 62%) than in the shorter one. However, in women aged 45 or older the incidence of amenorrhoea was unrelated to the duration of treatment (97% v 96%).

We assessed whether amenorrhoea induced by CMF could influence the outcome of treatment. We looked at relapse free survival in patients who had monthly periods before starting 12 cycles of CMF and found only a modest and non-significant advantage favouring patients with CMF induced amenorrhoea (P = 0.2). A multivariate analysis including amenorrhoea, extent of nodal involvement, oestrogen receptor status, and age group confirmed that ovarian suppression induced by adjuvant CMF had no significant role in treatment outcome (hazard ratio 1.13, 95% confidence interval 0.69 to 1.57, P = 0.6); the only significant prognostic indicator remained the extent of nodal involvement. See bmj.com.

Intravenous CMF in node negative tumours
When we looked at treatment outcome in patients with node negative and oestrogen receptor negative tumours, after a median follow up of 19.2 years, we found that CMF reduced the relative risk of both disease relapse and death by 35%. Premenopausal and postmenopausal women benefited equally from adjuvant CMF, and small (£ 2.0 cm) and large tumours (> 2.0 cm) were equally affected. CMF had the greatest effect on highly undifferentiated tumours (relapse free survival 32% after surgery alone v 63% after intravenous CMF), but it also affected differentiated tumours (57% v 64%) (see bmj.com).

Discussion

Our long term analysis of the trials we started three decades ago shows that the significant advantage in both relapse free and overall survival has persisted throughout the years and that adjuvant chemotherapy can suppress micrometastases to a moderate but worthwhile extent, regardless of their anatomical sites.

Benefit of CMF and menopausal status
The magnitude of benefit of adjuvant CMF as given in our studies was apparently different between premenopausal and postmenopausal women. Although this different effect may be, at least in part, attributable to the lower doses of CMF delivered in women older than 60 years,^{1 5} many investigators believed that the predominant effect of chemotherapy was chemical castration. Data from two randomised studies comparing the effects of CMF with endocrine manipulations in premenopausal women reinforce this interpretation.^{3 8 9} Our analysis of the influence of drug induced amenorrhoea, supported by many individual trials and the worldwide overview,² shows that adjuvant chemotherapy benefits hormone responsive and hormone unresponsive tumours. Endocrine therapy has no worthwhile benefit in oestrogen receptor negative subpopulations.¹⁰ Our findings indicate that adjuvant chemotherapy has cytotoxic effects regardless of the putative hormone dependency of the tumour cells. The worldwide overview indicated that in hormone responsive tumours, the delivery of chemotherapy and endocrine therapy further reduces the relative risk of disease relapse and death compared with either modality alone.^{2 10}

What is already known on this topic At a median follow up of about 15 years, adjuvant systemic therapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) can benefit patients with operable breast cancer What this study adds Adjuvant systemic therapy has longlasting effects even after 30 years, and these are achieved at the cost of minimal long term sequelae The poor prognosis associated with unfavourable indicators in patients treated locoregionally alone was improved by administration of adjuvant CMF

Benefit of CMF and prognostic subsets
The goal to tailor adjuvant treatment to characteristics of individual tumours, the subject of current trials, was inconceivable at the time when we designed our studies. The role of new biological variables, including c-erb-b2 expression, was retrospectively assessed in the first randomised trial.¹¹ The poor prognosis associated with unfavourable indicators in the untreated group was overcome by adjuvant CMF, and our analysis confirms these results.

Conclusion
New drugs available today include anthracyclines and taxanes, and these have improved outcomes of treatment over the CMF regimen.² Although technological advances will further improve our understanding of breast cancer and will contribute to tailoring treatment to the individual patient, our experience with adjuvant CMF over 30 years confirms that the effects of such a regimen are long lasting and may benefit patients with favourable and unfavourable prognostic indicators, at the cost of minimal long term sequelae.

---

This is the abridged version of an article that was posted on bmj.com on 13 January 2005: http://bmj.com/cgi/doi/10.1136/bmj.38314.622095.8F

We thank all the patients who have participated in our clinical trials, and the many associates, in particular medical oncologists, surgeons, radiation therapists, pathologists, and research nurses, for their cooperation during the studies and follow up. We also thank George Canellos, Paul P Carbone, and Steve Carter for their invaluable advice during the planning and conduct of the studies.

Contributors: See bmj.com

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 interests: None declared.

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

References

1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294: 405-10.[Abstract]
2. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of randomised trials. Lancet 1998;352: 930-42.[CrossRef][Web of Science][Medline]
3. Pritchard KI. Adjuvant therapy for premenopausal women with breast cancer: is it time for another paradigm shift? J Clin Oncol 2002;20: 4611-4.[Free Full Text]
4. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998;16: 413-28.[Web of Science][Medline]
5. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332: 901-6.[Abstract/Free Full Text]
6. Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983;1: 2-10.[Abstract]
7. Zambetti M, Bonadonna G, Valagussa P, Daidone MG, Coradini D, Bignami P, et al. Adjuvant CMF for node-negative and estrogen receptor-negative breast cancer. J Natl Cancer Inst Monogr 1992;11: 79-85.
8. Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group trial 5. J Clin Oncol 2002;20: 4621-7.[Abstract/Free Full Text]
9. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex early breast cancer research association study. J Clin Oncol 2002;20: 4628-35.[Abstract/Free Full Text]
10. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: 1451-67.[CrossRef][Web of Science][Medline]
11. Ménard S, Valagussa P, Pilotti S, Gianni L, Biganzoli E, Boracchi P, et al. Response to CMF in lymph-node positive breast cancer according to HER2 overexpression and other tumours biologic variables. J Clin Oncol 2001;19: 329-35.[Abstract/Free Full Text]

(Accepted 15 November 2004)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

CMF adjuvant chemotherapy for breast cancer achieves good long term results
BMJ 2005 330: 0. [Full Text] [PDF]

A tough nut to crack

Kamran Abbasi
BMJ 2005 330: 0. [Extract] [Full Text] [PDF]

Reduction in mortality from breast cancer

Alison L Jones
BMJ 2005 330: 205-206. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Bretzel, R. L. Jr, Cameron, R., Gustas, M., Garcia, M. A., Hoffman, H. K., Malhotra, R., Miller, K., Prime, J., Favret, A. (2009). Dose Intensity in Early-Stage Breast Cancer: A Community Practice Experience. J Oncol Pract 5: 287-290 [Abstract] [Full text]  
• Marks, L. B., Zeng, J., Prosnitz, L. R. (2008). One to Three Versus Four or More Positive Nodes and Postmastectomy Radiotherapy: Time to End the Debate. JCO 26: 2075-2077 [Full text]  
• Pachmann, K., Camara, O., Kavallaris, A., Krauspe, S., Malarski, N., Gajda, M., Kroll, T., Jorke, C., Hammer, U., Altendorf-Hofmann, A., Rabenstein, C., Pachmann, U., Runnebaum, I., Hoffken, K. (2008). Monitoring the Response of Circulating Epithelial Tumor Cells to Adjuvant Chemotherapy in Breast Cancer Allows Detection of Patients at Risk of Early Relapse. JCO 26: 1208-1215 [Abstract] [Full text]  
• Ng, R., Pond, G. R., Tang, P. A., MacIntosh, P. W., Siu, L. L., Chen, E. X. (2008). Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006. Ann Oncol 19: 481-486 [Abstract] [Full text]  
• Bonadonna, G., Valagussa, P., Veronesi, U. (2008). Lessons From the Initial Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil Studies in Operable Breast Cancer. JCO 26: 342-344 [Full text]  
• Ozer, H., Mirtsching, B., Rader, M., Luedke, S., Noga, S. J., Ding, B., Dreiling, L. (2007). Neutropenic Events in Community Practices Reduced by First and Subsequent Cycle Pegfilgrastim Use. The Oncologist 12: 484-494 [Abstract] [Full text]  
• Oettle, H., Post, S., Neuhaus, P., Gellert, K., Langrehr, J., Ridwelski, K., Schramm, H., Fahlke, J., Zuelke, C., Burkart, C., Gutberlet, K., Kettner, E., Schmalenberg, H., Weigang-Koehler, K., Bechstein, W.-O., Niedergethmann, M., Schmidt-Wolf, I., Roll, L., Doerken, B., Riess, H. (2007). Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer: A Randomized Controlled Trial. JAMA 297: 267-277 [Abstract] [Full text]  
• Sonmezer, M., Oktay, K. (2006). Fertility preservation in young women undergoing breast cancer therapy.. The Oncologist 11: 422-434 [Abstract] [Full text]  
• Colozza, M., de Azambuja, E., Cardoso, F., Bernard, C., Piccart, M. J. (2006). Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era.. The Oncologist 11: 111-125 [Abstract] [Full text]  
• Goldhirsch, A., Glick, J. H., Gelber, R. D., Coates, A. S., Thurlimann, B., Senn, H.-J., and Panel Members, (2005). Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 16: 1569-1583 [Abstract] [Full text]  
• (2005). Screening and Adjuvant Therapy Improve Breast Cancer Outcome. Journal Watch Dermatology 2005: 12-12 [Full text]  
• (2005). Screening and Adjuvant Therapy Improve Breast Cancer Outcome. JWatch General 2005: 5-5 [Full text]  
• Jones, A. L (2005). Reduction in mortality from breast cancer. BMJ 330: 205-206 [Full text]  

Rapid Responses:

Read all Rapid Responses

Humiliating effect of biological predeterminism

Srinivasan Ravi
bmj.com, 3 Feb 2005 [Full text]

Re: Humiliating effect of biological predeterminism

Francis Lopez
bmj.com, 24 Feb 2005 [Full text]

Online poll

Find out more>>