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Lessons From the Initial Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil Studies in Operable Breast Cancer

Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milano, Italy

Umberto Veronesi

European Institute of Oncology, Milano, Italy

In 1975, we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) delivered in 1-month cycles for 12 months as adjuvant treatment for node-positive breast cancer.^1,2 These results, along with those reported in a similar patient population by the National Surgical Adjuvant Breast and Bowel Project,³ raised hopes that chemotherapy could have a more central role in the primary management of this common cancer, and were of seminal importance for all the studies on adjuvant systemic therapy conducted throughout the world.

Among the numerous questions to be answered after the first CMF study was the optimal duration of treatment. In fact, a relatively short-term effective adjuvant chemotherapy would spare the patients a considerable amount of toxicity. For this reason, in September 1975, we started a new randomized study with the intent of evaluating the possibility of reducing the duration of CMF without compromising its therapeutic effects. The 5-year results of the study⁴ showed that 1-month cycles for 6 months of CMF yielded results that were identical to those obtained with 12 cycles. The long-term analysis after a median follow-up of 25 years confirmed that a longer duration of the same drug regimen was unable to improve treatment outcome.⁵ The pattern of relapse-free survival was superimposable in the two treatment groups, the estimated relapse-free survival rates were 39% after 12 cycles and 38% after six cycles of CMF, and 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 of axillary node involvement; patients with more than three involved nodes were at a significantly higher risk of disease relapse and death (hazard rate, 2.3; P = .0001). Neither estrogen-receptor status nor size of the primary tumor was able to affect therapeutic outcome significantly.

In response to the early results observed in the above-mentioned study,⁴ in the early 1980s our own research group tested in a random fashion whether the inclusion of a non–cross-resistant agent such as doxorubicin (DOX) could be of benefit in patients with positive nodes. The choice of DOX was based on its great efficacy in metastatic and locally advanced breast cancer⁶ and on the low reported incidence of congestive heart failure when the total dose was less than 400 mg/m² of the body-surface area.⁷

In women at high risk of disease relapse because of extended axillary involvement (> three positive nodes), we reasoned that DOX, either given first and followed sequentially by CMF or interspersed with CMF, had the potential to improve treatment outcome.⁸ A 20-year analysis confirmed the superiority of the sequential delivery of DOX as first treatment for four cycles followed by intravenous CMF (DOXCMF) compared with the alternating delivery of the same regimens (CMF/DOX). In fact, after DOXCMF, the risk of developing disease relapse was reduced by approximately 32% (P = .0017) and the risk of dying as a result of all causes was reduced by approximately 26% (P = .018). The improved outcome in the sequential arm was not impaired by the occurrence of congestive heart failure.⁹

It is important to note that the 5-year joint efficacy analysis of the National Epirubicin Adjuvant Trial and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential administration of epirubicin for four cycles followed by CMF compared with CMF alone,¹⁰ supporting the hypothesis that single-agent anthracyclines given first, before CMF, can indeed improve treatment outcome.

In patients with one to three involved axillary nodes, we randomly assessed whether the addition of single-agent DOX for four cycles administered after intravenous CMF given for approximately 6 months could overcome resistance putatively induced by the alkylating regimen alone.¹¹ The 20-year analysis showed that approximately half of the patients in this study were alive and disease free regardless of whether they received CMF alone or CMF sequentially followed by DOX.⁹ Although available long-term results failed to detect any statistically significant difference from the addition of DOX in the overall population of patients enrolled onto the study, a retrospective analysis on the predictive relevance of the status of human epidermal growth factor receptor (HER2) showed a trend for an increased benefit of the DOX combination in patients with HER2-positive tumors.¹² This observation further emphasizes the need for a priori characterization of markers predicting for response, and for eventually tailoring adjuvant treatment to individual patients—a goal that is currently being pursued, but was inconceivable at the time when the study protocol was designed.

In all clinical trials, what is measured is indeed an average effect, and the experience gained through the past decades led us to a growing recognition that not all breast cancers with seemingly similar clinical and morphologic features have the same biologic behavior.¹³ Because of this heterogeneity, adjuvant systemic therapy involves both the possibility of overtreating certain patient subsets who have truly localized disease cured by surgery, or of an ineffective treatment for other patients subsets whose cancer is not sensitive to the delivered drug treatments.

As both physicians and investigators, our ultimate goal is to tailor treatment approaches so that only patients who are at risk of disease relapse will receive adjuvant systemic treatments with drugs that can achieve complete eradication of metastatic cells. During the last few decades, hundreds of biochemical markers have been tested and individual markers in individual studies have raised great promise about their abilities to predict either breast cancer prognosis or treatment responsiveness.¹³ Unfortunately, and because of the biases inherent to many of the research designs (eg, specimen assessment, use of continuous or discrete values, lack of definition of inclusion criteria, and adequacy of statistical power, analysis, and data interpretation), the results of many of these studies failed to be reproducible between different research groups and, at times, also within the same research group when the same markers were tested on independent case series or after a prolonged period of observation. Thus, we continued our clinical studies by using the old standards of tumor stage, grade, and axillary involvement for predicting prognosis and of hormone receptor status and, in the last few years, on HER2 expression for predicting sensitivity to endocrine therapy and trastuzumab treatment, respectively. However, the many studies of single markers published during the last decades have made it amply clear that there is no single marker that provides reliable prognostic information for an individual patient, nor can it predict response or resistance to specific treatments with a high degree of accuracy.

More recently, the development of molecular genetic techniques has allowed the identification and analysis of molecular factors that have an important role in normal cell growth and differentiation.¹⁴ Such factors have also been shown to influence the behavior of tumors with respect to cellular differentiation, growth rate, metastatic pattern, and response to therapy. Furthermore, they will be instrumental in developing new agents for targeted therapies.

Using molecular markers to select, among effective available regimens, the one with the highest probability of cure for the individual patient is an appealing way to conduct new research. The ability to predict who will need adjuvant medical therapy and who will or will not respond to a given drug or drug regimen has important challenges able to influence clinical decision making and treatment recommendations. Although predictive accuracy may not be an all-or-none phenomenon, patients can be spared treatments that are devoid of efficacy, but are associated with toxicity. Furthermore, delivering treatments that are associated with a more pronounced antitumor activity against tumors with specific molecular features will lead to improved benefit, making the real difference between cure and palliation for patients.

Recent reports on small case series have suggested that this approach may be a valid one.^15-17 All of these experiences have been carried out in limited case series treated with primary chemotherapy, a treatment modality in use since the late 1980s also for patients with operable breast cancer.¹⁸ These observations need to be confirmed in large validation trials, performed with statistical rigor and reported clearly and with unbiased statistics. The important goal of the next generation of genetic profiles will also be to test whether the predictive accuracy is specific to a defined drug therapy or whether it simply predicts response to a variety of regimens with different drug associations. Only if there is a regimen-specific predictive accuracy will we have in our hands a powerful tool to tailor treatment to individual patients.

The major lesson learned from all our CMF-containing studies is that prolonging the delivery of the same drug regimen for longer that 4 to 6 months does not translate into a benefit for our patients, and that different sequencing of non–cross-resistant regimens has different clinical relevance.⁹ We also learned that selecting optimal treatment from all existing options and alternatives must come from well-designed, well-conducted, and well-analyzed clinical trials before such therapies and technologies can be adopted into daily standard practice. We can be of more help to our patients by fully informing them about ongoing clinical trials and supporting their participation in these studies.

Authors’ Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

Author Contributions

Conception and design: Gianni Bonadonna, Umberto Veronesi,

Collection and assembly of data: Gianni Bonadonna, Pinuccia Valagussa, Umberto Veronesi

Data analysis and interpretation: Gianni Bonadonna, Pinuccia Valagussa

Manuscript writing: Pinuccia Valagussa

Final approval of manuscript: Gianni Bonadonna, Pinuccia Valagussa, Umberto Veronesi

ACKNOWLEDGMENTS

Supported in part by Contract Nos. N01-CM-33714 and N01-CM-07338 with the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD.

REFERENCES

1. Bonadonna G, Brusamolino E, Valagussa P, Veronesi U: Adjuvant study with combination chemotherapy in operable breast cancer. Proc Am Assoc Cancer Res Am Soc Clin Oncol 16:254, 1975 (abstr 1135)

2. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976[Abstract]

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4. Tancini G, Bonadonna G, Valagussa P, et al: Adjuvant CMF in breast cancer: Comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1:2-10, 1983[Abstract]

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This Article Full Text (PDF) From JCO 1983 Publisher's Note Erratum (v26,p1773) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bonadonna, G. Articles by Veronesi, U. Search for Related Content PubMed Articles by Bonadonna, G. Articles by Veronesi, U.