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Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer

From the Department of Medical Oncology, Istituto Nazionale Tumori, Milano, Italy.

Address reprint requests to Gianni Bonadonna, MD, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy; e-mail: gianni.bonadonna{at}istitutotumori.mi.it

	ABSTRACT

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PURPOSE: To assess the clinical relevance of different sequences of doxorubicin (DOX) and cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of disease relapse.

PATIENTS AND METHODS: Two randomized trials were activated in the early 1980s. The first study, in patients with one to three involved nodes, was intended to assess the effectiveness of intravenous (IV) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose DOX (CMFDOX). The second study, in patients with more than three involved nodes, compared four courses of full-dose DOX sequentially followed by eight courses of IV CMF (DOXCMF) versus alternating two courses of the same CMF regimen with one course of DOX (CMF/DOX) for a total of 12 courses.

RESULTS: After a median observation of 210 months, no statistically significant difference was documented in the first study (relapse-free survival hazard rate [HR], 1.06; total survival HR, 1.03). In contrast, the delivery of DOX first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54 to 0.87; P = .0017) and death (HR, 0.74; 95% CI, 0.57 to 0.95; P = .018) compared with the alternating regimen.

CONCLUSION: Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.

	INTRODUCTION

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Long-term results of the early adjuvant chemotherapy trials confirmed that this treatment strategy has undoubtedly contributed to the prevention of breast cancer deaths that would otherwise have occurred in middle-aged women diagnosed with moderate- to high-risk operable breast cancer.¹

Our own research group, after assessing the relative merits of using classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy for 12 or 6 monthly cycles in node-positive breast cancer (Bonadonna, submitted for publication)^2-4 questioned whether the inclusion of doxorubicin (DOX [Adriamycin]; Pharmacia Italia, Milan, Italy) within the adjuvant program could improve treatment results. The choice of DOX was based on its great efficacy in metastatic and locally advanced breast cancer⁵ and on the low reported incidence of congestive heart failure (CHF) when the total dose was less than 400 mg/m² of the body surface area.⁶

To avoid overlapping toxicity of concomitant administration of the four agents and maintain full active doses of CMF and DOX, we devised to deliver either single-agent DOX sequentially before or after CMF, or alternating DOX and CMF regimens in two different trials. In women with limited nodal involvement (ie, one to three positive axillary nodes), in whom CMF by itself could achieve good eradication of micrometastases, we were interested in assessing whether the sequential delivery of DOX after approximately 6 months could overcome CMF-induced resistance. Although humanely worthwhile, the effects of CMF alone in women with extended axillary involvement (> three positive nodes) were unsatisfactory and we reasoned that DOX, either given first, and sequentially followed by CMF or interspersed with CMF, had the potential to improve treatment outcome. In this article, we report the 20-year results of the above-described trials.

	PATIENTS AND METHODS

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Study designs of the two randomized trials have been detailed in previous publications.^7-9 Briefly, the study on patients with one to three positive axillary nodes was activated in November 1981, and by July 1990 a total of 552 eligible patients were centrally allocated to receive either 12 courses of intravenous (IV) CMF every 3 weeks or eight courses of the same CMF regimen followed by four courses of DOX.⁷ The study on patients with more extended (> three nodes) axillary involvement was activated in February 1982, and by June 1990 a total of 403 eligible patients were randomly assigned to receive either DOX for four courses followed by IV CMF for eight courses or alternating two courses of CMF and one course of DOX up to a total of 12 courses of chemotherapy.^8,9

The study populations consisted of patients admitted to the Istituto Nazionale Tumori (Milan, Italy). All women who had had surgery (radical mastectomy or conservative surgery and full axillary clearance) for unilateral carcinoma of the breast were considered for inclusion in the studies if they had histologic evidence of involvement of one or more axillary nodes. All women had to be 70 years of age or younger. Patients with locally advanced or metastatic disease, those whose tumors were fixed to the underlying pectoral fascia or muscle, or those with a history of previous cancer or with concomitant severe nonmalignant systemic disease were not eligible.

Determination of the hormonal receptors was not mandatory and was assessed using the dextran-coated charcoal technique. The study designs were approved by the members of the institute's research and ethics committees and, according to the Italian rules at the time, all patients had to give their verbal informed consent before enrollment onto each of the studies.

Adjuvant Treatment
To avoid problems of patient adherence with oral cyclophosphamide, as documented in our first trials,^3,10 we devised an IV administration of CMF that consisted of cyclophosphamide 600 mg/m², methotrexate 40 mg/m², and fluorouracil 600 mg/m², all given by IV push on day 1 and repeated 3 weeks later. DOX was planned at the full dose of 75 mg/m² by IV push on day 1 every 3 weeks. No dose reductions for age were planned and adjuvant chemotherapy was started 2 to 4 weeks after surgery. In the presence of myelosuppression, treatment delivery was delayed in the attempt to avoid dose reduction.

No other adjuvant treatments (in particular, no adjuvant tamoxifen) were allowed, with the exception of breast irradiation for patients who underwent conservative surgery. Breast irradiation (40 Gy plus a boost of 10 Gy in 4 to 6 weeks) was planned to start within 6 to 8 weeks after surgery and was administered concomitantly with chemotherapy. A total of 12 patients did not receive breast irradiation after conservative surgery.

Study Parameters
Details on baseline studies and follow-up programs were previously reported^7-9 and they can be summarized as follows. Before surgery, all patients underwent a complete physical examination; radiologic studies of chest, bone, and liver; bilateral mammography; ECG; a differential blood count with platelet count; and biochemical tests. In the absence of symptoms, during the first year, physical examination was performed on day 1 of each treatment cycle and every 3 months on its discontinuation. Physical examination was then performed every 6 months for the next 4 years, and every 12 months for the following 10 years. Biochemical tests and radiologic studies were performed every 6 to 8 months during the first 5 years, and once a year thereafter. Liver ultrasonography was performed only if there were clinical or biochemical findings suggestive of liver disease. Mammography, bilateral in patients subjected to conservative surgery, was planned once a year. After the 15th year of follow-up, examinations were planned every 12 to 24 months, and when they were not directly performed in the outpatient clinic of the Institute, contacts were periodically maintained with the patients and with their family doctors. In patients with findings that were controversial or suggestive of disease, examinations were performed more often. Repeat ECGs were planned at the conclusion of all drug therapy, and subsequently once a year for the first 5 years, and every 2 years thereafter. In the presence of individual clinical indications, ECGs were repeated more often, and when abnormalities were present, multiple-gated angiographic scan or cardiac echography was used to evaluate left ventricular ejection fraction.

Treatment failure was considered to have occurred with the first documented evidence of new disease manifestations in locoregional areas (including ipsilateral supraclavicular adenopathy), distant sites, contralateral breast, or any combination of these sites. Neither second primary cancers nor deaths from causes other than breast cancer were considered treatment failures.

Statistical Analysis
Relapse-free survival was calculated from the date of surgery to the first documented evidence of treatment failure. Death as a result of all causes was used as the end point for overall survival, which was also measured from the date of surgery. The Kaplan-Meier product limit method was adopted.¹¹ The null hypothesis concerning the differential effects of treatment or of some prognostic factors in univariate analyses was tested by means of the log-rank test,¹² and all P values were two tailed. In addition, the joint effects of treatment and of prognostic indicators were investigated by a Cox regression model using a backward-selection procedure, which retained only the variables that reached the conventional significance of the 5% level.¹³ The null hypothesis of the regression analysis was tested by the Wald statistics.¹⁴ The relative risks were estimated as hazard rate ratios (HRs).

All data relative to the studies herein reported have been managed and analyzed according to the standard operating procedures of the Operations Office of the Istituto Nazionale Tumori. Present analysis was carried out on data available as of February 28, 2003. Only one patient in complete clinical remission was lost to follow-up (after 11.2 years).

	RESULTS

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Patients With One to Three Positive Nodes
Main characteristics of the 552 women eligible for this randomized trial were fairly well balanced in the two treatment arms and are summarized in Table 1. In contrast to our previous studies, postmenopausal women accounted for approximately one third of the entire patient series. Primary tumors measured up to 2 cm at pathologic examination in two thirds of the patients and were classified as estrogen receptor-negative in 23% of the patients allocated to receive CMF and in 19% of those allocated to sequential CMFDOX, with no difference between premenopausal and postmenopausal women.

View larger version (12K): [in this window] [in a new window]   Fig 1. Treatment outcome in patients with one to three positive axillary nodes: (A) relapse-free survival; (B) total survival. CMF, cyclophosphamide, methotrexate, and fluorouracil; DOX, doxorubicin; IV, intravenous.

Second malignancies other than contralateral breast cancer developed as first disease manifestation in 28 patients (CMF, 11 of 275 [4%]; CMFDOX, 17 of 277 [6%]). Various types of second malignancies were documented, with a prevailing pattern for gastrointestinal and gynecologic tumors. No patients developed acute leukemias, whereas chronic lymphatic leukemia was documented in one woman at the age of 53 years.

Deaths unrelated to breast cancer progression or second malignancies accounted for eight events after CMF (3%; median age at death, 68 years; range, 38 to 87 years) and for 11 events after CMFDOX (4%; median age at death, 61 years; range, 34 to 76 years). Four of these women, two in each treatment group (median age, 40 years at study entry), committed suicide during the course of disease. One patient given CMFDOX died because of cardiac failure at the age of 76 years. This woman, aged 64 years at study entry and with a history of controlled hypertension, was subjected to conserving surgery and irradiation of the left breast. After 11.5 years, she presented with systolic dysfunction and a left ventricular ejection fraction of 42%. Four months after this event, she developed an ipsilateral breast recurrence and received tamoxifen. Despite appropriate treatment for her cardiac conditions, fatal CHF developed 7 months later.

Patients With More Than Three Involved Nodes
The main characteristics of the 403 women eligible for this second randomized trial are summarized in Table 2. Apart from a greater proportion of patients with more than 10 nodes involved in the alternating CMF/DOX regimen (38% v 29%, respectively; P = .08), all other characteristics were fairly well balanced. In addition, in this study, postmenopausal women accounted for one third of the patient series. Approximately 25% of the tumors were classified as estrogen receptor–negative in either treatment group, with no substantial difference between premenopausal and postmenopausal patients.

View larger version (13K): [in this window] [in a new window]   Fig 2. Treatment outcome in patients with more than three positive axillary nodes: (A) relapse-free survival; (B) total survival. CMF, cyclophosphamide, methotrexate, and fluorouracil; DOX, doxorubicin.

CHF was recorded in six patients, for an absolute incidence of 1.5%. All patient cases have already been described in a previous publication.¹⁵ Briefly, four patients developed CHF during or within 1 month from the end of chemotherapy, whereas in the remaining two patients cardiac disease was documented during scheduled follow-up examinations, at 6 and 11 years after chemotherapy discontinuation, respectively. Of note, four of the six women underwent conserving surgery and left breast irradiation. CHF was the cause of death in three patients (at 32, 86, and 113 months after diagnosis of the cardiac event, respectively). One of the other women died 7 years later at the age of 80 years as a result of an intervening nonmalignant condition, whereas a second patient died as a result of progression of a primary gynecologic cancer after receiving additional chemotherapy for this second malignancy. The remaining patient is alive at 189 months after the diagnosis of the iatrogenic cardiopathy.

Deaths unrelated to breast cancer progression, second primary cancers, or iatrogenic cardiac diseases were observed in four women (1%) at a median of 10 years (range, 6.5 to 14.5 years) from breast cancer surgery.

	DISCUSSION

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Results of the initial randomized studies confirmed that the early benefits of adjuvant systemic chemotherapy with alkylating agents were maintained during the years and that improvements in relapse-free survival were translated into worthwhile benefits for total survival.^2,3,16,17

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. The international overview¹⁷ published in 1998 confirmed that anthracyclines were able to achieve a modest but humanely worthwhile benefit in decreasing the annual odds of recurrence and death compared with so-called CMF-like regimens. Such findings were confirmed at the updated but yet unpublished overview held in September 2000 (Oxford, United Kingdom). Of note, the many anthracycline-containing regimens used in the studies that were part of the international effort consisted mainly of the substitution of either methotrexate alone or of both methotrexate and fluorouracil with either DOX or epirubicin (eg, cyclophosphamide, doxorubicin, and fluorouracil; fluorouracil, epirubicin, and cyclophosphamide; doxorubicin and cyclophosphamide; and epirubicin and cyclophosphamide). The anthracyclines were given at different doses (from 30 to 60 and 90 mg/m² for DOX; 50 or 100 mg/m² for epirubicin) and the new regimens were administered at various intervals and for a different number of cycles. Although many individual trials failed to observe a true benefit for the anthracycline regimen, the arithmetic construction on which the meta-analysis is based (ie, the summing up of many individual trials to increase the statistical power) allowed researchers to assess that there was a reduction in the risk of disease relapse and death of approximately 10%, corresponding to an absolute difference of approximately 3%.

For a new regimen to be used in clinical practice, however, it is of paramount importance to assess whether in individual patients the benefits of a given combination warrant the relative risks. This is especially true when anthracyclines are used in an adjuvant setting: although the total dose of the drug is maintained below the threshold dose for cardiac toxicity, it is possible that coexisting nonmalignant conditions might place the individual patient at an increased risk of developing this iatrogenic effect, thus abrogating the value of the potential minimal benefit.

The results of our studies better exemplify the above-described situation. After assessing that continuing the delivery of the same drug regimen for more than six cycles was unable to improve treatment outcome (Bonadonna, submitted for publication),⁴ we tested in a random fashion whether changing to a non–cross-resistant agent could be of benefit in patients with one to three positive nodes. Approximately half of the patients in this study are alive and disease free after a median follow-up of 210 months, regardless of whether they received CMF alone or CMF sequentially followed by DOX. Although a recently published retrospective analysis on the predictive relevance of the status of HER2 showed a trend for an increased benefit of the DOX combination in patients with HER2-positive tumors,¹⁸ present long-term results failed to detect any statistically significant difference by the addition of DOX in the overall population of patients enrolled onto the study. 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 we designed the present studies.

In patients with more than three axillary nodes involved, present analyses confirm the superiority of the sequential delivery of DOX as first treatment for four cycles followed by IV CMF compared with the alternating delivery of the same regimens. It is important to emphasize that both regimens included the same drugs, at the same doses, and for identical treatment duration, and that the received dose-intensity for all drugs was the same in both regimens. This improved outcome in the sequential arm was not impaired by the occurrence of CHF. Of the total six patient cases of CHF documented in our study, three (1.5%) occurred in patients who were given DOX first, and received concomitant radiation to the left breast. This last observation prompted us to a more accurate screening of cardiac risk factors in women candidates for adjuvant DOXCMF and to the delivery of breast irradiation at the end of the chemotherapy program both in our ongoing studies and in clinical practice.

The treatment results observed after sequential DOX and CMF in a poor-risk subset could probably be explained by an increased density of DOX that was delivered within 9 weeks, whereas in the alternating regimen it was spread over 27 weeks. The concept of dose density has been confirmed recently by the National Cancer Institute's Breast Intergroup INT C9741 trial, in which patients who received the dose-dense regimens had a significantly improved early treatment outcome compared with their counterparts.¹⁹

The actual contribution of CMF in the sequential arm is difficult to assess in an adjuvant setting. We previously reported that in a small case series of metastatic breast cancer, CMF delivered after four cycles of DOX could achieve additional objective regression in 64% of the patients.²⁰ Recently, the results of the effects on locoregional disease achieved in an European cooperative trial in operable breast cancer more than 2 cm in largest diameter confirmed the above-mentioned observations.²¹ Primary sequential chemotherapy with DOX plus paclitaxel for four cycles followed by four cycles of CMF was delivered in a total of 327 patients. The rate of objective remission achieved with the anthracycline regimen (60%) was further increased by CMF (81%), which also doubled the rate of complete clinical response (27% after DOX and paclitaxel; 52% after CMF).

The role of sequential non–cross-resistant regimens was tested in many other trials. Of note, the 3-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,²² supporting the hypothesis that single-agent anthracyclines given first, before CMF, can indeed ameliorate treatment outcome. The addition of taxanes after delivery of DOX and cyclophosphamide contributed to improve therapeutic results compared with the nontaxane regimen both in the adjuvant^23,24 and neoadjuvant settings.^25,26 In contrast, in the previously mentioned INT C9741 trial,¹⁹ no difference was detected in treatment outcome between the concurrent or sequential schedules of DOX, cyclophosphamide, and paclitaxel. Similarly, The M.D. Anderson Cancer Center (Houston, TX) randomized study failed to detect a superiority of the sequential arm.²⁷

In summary, the long-term results of our trials indicate that the sequential delivery of two effective non–cross-resistant regimens such as DOX and CMF is a valid, safe, and reproducible treatment approach²⁸ to attain an improved outcome. Although we await more mature results of the modern adjuvant taxane studies, we conclude that DOX sequentially followed by CMF represents a recommended treatment option for moderate- to high-risk patients with operable breast cancer, in whom the significant improvement in the reduction of the odds of recurrence and death is not counterbalanced by an increased risk of life-threatening sequelae.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
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 Dr George Canellos, Dr Paul P. Carbone, and Dr Steve Carter for their invaluable advice during the planning and the conduct of the studies, and Rossella Vio and Sabina Innocenti for their assistance in data management.

	NOTES

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

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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14. Miller RG: Survival Analysis. New York, NY, John Wiley, 1981

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18. Moliterni A, Menard S, Valagussa P, et al: HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer. J Clin Oncol 21:458-462, 2003[Abstract/Free Full Text]

19. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431-1439, 2003[Abstract/Free Full Text]

20. Zambetti M, Giacobone A, Terenziani M, et al: Sequential adriamycin and CMF in metastatic breast cancer. Oncologist 2:223-227, 1997[Abstract/Free Full Text]

21. Gianni L, Baselga J, Eiermann W, et al: First report of the European Cooperative Trial in operable breast cancer (ECTO): Effects of primary systemic therapy (PST) on local-regional disease. Proc Am Soc Clin Oncol 21:34a, 2002 (abstr 132)

22. Poole CJ, Earl HM, Dunn JA, et al: NEAT (National Epirubicin Adjuvant Trial) and SCTBG BR9601 (Scottish Cancer Trials Breast Group) phase III adjuvant breast trials show a significant relapse-free and overall survival advantage for sequential ECMF. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 13)

23. Henderson CI, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003[Abstract/Free Full Text]

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Submitted July 25, 2003; accepted February 20, 2004.

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