Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group

M. Martin1,+, A. Villar2, A. Sole-Calvo3, R. Gonzalez4, B. Massuti5, J. Lizon6, C. Camps7, A. Carrato8, A. Casado1, M. T. Candel2, J. Albanell3, J. Aranda4, B. Munarriz9, J. Campbell10 and E. Diaz-Rubio1

1 Hospital Universitario San Carlos, Madrid; 2 Hospital Arnau de Vilanova, Valencia; 3 Hospital Vall d’Hebron, Barcelona; 4 Hospital Reina Sofia, Cordoba; 5 Hospital General Universitario, Alicante; 6 Hospital Universitario San Juan, Alicante; 7 Hospital General Universitario, Valencia; 8 Hospital General Universitario, Elche; 9 Hospital La Fe, Valencia; 10 Department of Biostatistics, GEICAM, Madrid, Spain

Received 17 February 2003; revised 28 March 2003; accepted 31 March 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to determine the relative efficacy of doxorubicin versus methotrexate in combination with intravenous cyclophosphamide and 5-fluorouracil (FAC versus CMF) as adjuvant chemotherapy for operable breast cancer.

Patients and methods:

Over a 4-year period, 985 women undergoing curative surgery for breast cancer (T1–3 N0–2 M0, stage I–IIIA, UICC) from nine hospitals were stratified with respect to axillary node involvement (node positive versus node negative) and randomized to receive either FAC (500/50/500/m2) every 3 weeks for six cycles or CMF (600/60/600/m2) every 3 weeks for six cycles.

Results:

The relative dose intensities of FAC and CMF were 87% and 85% of planned doses, respectively. Unadjusted data indicated a non-significant trend towards better results with FAC. In the prospectively formed subset of node-negative patients, disease-free survival and overall survival were statistically superior in the FAC treatment arm (P = 0.041 and 0.034, respectively), but this advantage was not seen in the subset of node-positive patients, probably because of a difference in the percentage of patients with four or more positive nodes. Adjusting data for size of treatment effect and potential interactions (number of positive nodes, tumor size, treatment center), the overall relative risk (RR) of disease recurrence and death were significantly lower with FAC treatment (RR 1.2, P = 0.03, and RR 1.3, P = 0.05, respectively). This result was mainly due to the difference observed in the node-negative patient population. Toxicity was mild: FAC induced more alopecia, emesis, mucositis and cardiotoxicity; this last was of clinical concern, but was infrequent and manageable. CMF induced more conjunctivitis and weight gain. There were no toxic deaths.

Conclusions:

Doxorubicin in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil is superior to methotrexate in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for operable breast cancer. A treatment effect is particularly evident in the node-negative patients. Although the clinical toxicity of FAC is greater than that of CMF, the levels were manageable and clinically acceptable.

Key words: adjuvant chemotherapy, anthracyclines, operable breast cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In 1976, Bonadonna et al. [1] from the Istituto Nazionale Tumori in Milan presented the results of the first randomized phase III study of adjuvant polychemotherapy versus control in node-positive breast cancer. With a follow-up of 20 years, this trial provides unequivocal evidence that CMF increases disease-free survival (DFS) and overall survival (OS) in these patients [2]. Results of similar studies performed by other cooperative groups have been coincident with those of the Milan trial and, additionally, the meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have confirmed that adjuvant CMF (methotrexate, cyclophosphamide, 5-fluorouracil) improves DFS as well as OS in all subsets of patients with operable breast cancer [3].

Since these early studies, CMF-like protocols have been considered the gold standard for adjuvant chemotherapy in operable breast cancer. Doxorubicin, a topoisomerase II inhibitor, was introduced into the clinical setting in the 1970s and was observed to be the most active drug in metastatic breast cancer at that time. Hence, several groups began randomized trials that compared doxorubicin-containing combinations with CMF-like regimens as adjuvant treatment for operable breast cancer.

In 1987, the Spanish Breast Cancer Research Group (GEICAM, Grupo Español de Investigación en Cáncer de Mama) began a phase III trial comparing an all-intravenous CMF protocol with a similar regimen in which methotrexate was substituted with doxorubicin: the FAC (doxorubicin, cyclophosphamide, 5-fluorouracil) regimen. We present here the final results of this trial.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Women aged between 18 and 72 years with histological diagnosis of breast carcinoma who had undergone appropriate primary surgery (either mastectomy or tumorectomy with free margins, plus axillary lymphadenectomy) were considered eligible for inclusion in the trial. Patients had to have had operable unilateral disease. Only patients with T1, T2 and T3 tumors and N0, N1 and N2 axillary disease (stage I–IIIA Union International Contre le Cancer) were eligible, while T4 and N3 patients were not. Prior to randomization, chest X-ray, bone scan and biochemistry analyses were performed. In case of elevation of liver enzymes, a computed tomography scan or sonography of the liver was mandatory. Patients with suspected or demonstrable metastatic disease were excluded from the study. Additional exclusion criteria were: previous history of other cancers (except for basocellular carcinoma of the skin and in situ carcinoma of the cervix); serum creatinine >1.5 mg/dl; serum bilirubin >1.5 mg/dl; major psychiatric disease; and prior history of significant cardiac disease (i.e. myocardial infarction, cardiac insufficiency or uncontrolled arrhythmia). Since hormone receptor assays were not available in most of the participating institutions at the time of the study’s inception, these determinations were not mandatory for inclusion. The study was approved by the ethics committees of the participating institutions. All patients gave informed consent and the ethical considerations conformed to Spanish legislation.

Randomization, stratification and treatment
Eligible patients were stratified according to axillary status (node positive versus node negative) and institution and randomly assigned to receive either CMF or FAC according to the following schedules. CMF: cyclophosphamide 600 mg/m2 i.v. day 1, methotrexate 60 mg/m2 i.v. day 1 and 5-fluorouracil 600 mg/m2 i.v. day 1, every 3 weeks for six cycles. FAC: 5-fluorouracil 500 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1 and cyclophosphamide 500 mg/m2 i.v. day 1, every 3 weeks for six cycles

Assignment of patients to FAC or CMF was done in blocks of eight patients according to a table of random numbers.

Both treatments were administered every 21 days for six courses. Dose modifications were included in the protocol according to the following criteria. (i) A 50% dose reduction of all drugs in case of grade 4 myelosuppression on day 21. (ii) In case of grade 1–3 myelosuppression on day 21, the treatment was delayed until recovery and the administration of the dose was 100% of that scheduled. (iii) A 50% dose reduction of doxorubicin in the FAC regimen in case of serum bilirubin of between 2 and 3 mg/dl and a 50% dose reduction of methotrexate in the CMF regimen in case of serum creatinine of between 1.5 and 2 mg/dl. (iv) Treatment was stopped in case of serum bilirubin >3 mg/dl (FAC treatment arm) or serum creatinine >2 mg/dl (CMF treatment arm).

Since hormone receptor assays were not available in the majority of centers at the time of the study commencement, administration of adjuvant tamoxifen was not part of the study protocol.

In patients undergoing tumorectomy, radiotherapy of the residual breast was mandatory. Radiotherapy was not mandatory in the remaining patients, although most institutions administered it to patients with large tumors (>5 cm) and/or more than four axillary lymph nodes undergoing mastectomy.

Study objectives, evaluation of efficacy and toxicity
Efficacy parameters in the study were DFS and OS, which were calculated from the day of primary surgery until local/distant/contralateral relapse (DFS) or death from any cause (OS). Patients free from disease at last contact who were lost to follow-up were censored for OS calculations. Patients with known recurrence but who were lost to follow-up were considered as having died at the date of last contact.

The primary end point of the study was 5-year DFS. Secondary end points were 5-year OS and toxicities.

Laboratory toxicity was evaluated on day 20–21 of the cycle. A full cell count and general biochemistry was mandatory immediately before each new cycle. Clinical toxicity was evaluated carefully on day 21. The parameters evaluated were alopecia, nausea, vomiting, mucositis, diarrhea, constipation, skin changes, dyspnea, edemas and amenorrhea (in premenopausal patients). Toxicity was graded according to the WHO criteria [4].

Statistical considerations
Sample size calculations were based on a two-sided, 0.05 type I error level log-rank test with a 90% power to detect an expected absolute difference of 10% (65% versus 55%) in 5-year DFS between treatment arms. The planned final sample size was of 996 patients (498 per treatment arm).

Time functions (DFS and OS) were compared by the log-rank test and regression analysis (Cox’s proportional hazard) was used to describe the relative risk (RR) of CMF versus FAC. This analysis was performed in the overall population and in the two prospective strata (N0 and N1). The 95% confidence intervals (CIs) were constructed for the model’s RR. Multivariate analysis for the study of prognostic effect on the primary end point also required proportional hazard model procedures.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between November 1987 and December 1991, 989 patients were recruited. Four of these patients were randomized but subsequently excluded from analysis because of age >72 years or stage IIIB disease. The remaining 985 patients were fully eligible for survival analysis and toxicity evaluation. Both treatment arms were well balanced regarding most prognostic and demographic factors (Table 1), although the number of patients with tumors at stage T3 and those with four or more positive axillary lymph nodes were slightly over-represented in the FAC arm. Of the 415 node-negative patients, at least 322 (78%, 161 in CMF and 161 in FAC) fulfilled the criteria for high risk according to the St Gallen Consensus Conference definitions (age <35 years and/or histological grade 2–3 and/or negative hormone receptors and/or tumors of >2 cm). Among the remaining 93 patients, the histological grade and/or the hormone receptor status were unknown in 82 cases. Therefore, the population of node-negative patients included in this trial was, essentially, at high risk according to the St Gallen criteria.


View this table:
[in this window]
[in a new window]
 
Table 1. Characteristics of the patient study population
 
Table 2 depicts the dose intensity of drugs actually received by the patients. Overall, patients received nearly 85% of planned doses in the CMF arm and nearly 87% in the FAC arm. The actual dose intensity of the agents that were common to both protocols (cyclophosphamide and 5-fluorouracil) was 17% higher in the CMF arm.


View this table:
[in this window]
[in a new window]
 
Table 2. Chemotherapy: actual dose intensity of drugs
 
After a median follow-up of 77.7 months, 441 patients have disease recurrence (200 in the FAC arm and 241 in the CMF arm) and 298 patients have died (136 in the FAC arm and 162 in the CMF arm). The sites of first recurrence (defined as the organ in which the first signs of recurrence were observed) are shown in Table 3. Patients in the FAC arm presented an incidence of loco-regional relapse lower than that in the CMF arm (64/480 versus 94/505; P <0.05). Recurrences in liver and bone were also lower with FAC, but the differences were not statistically significant.


View this table:
[in this window]
[in a new window]
 
Table 3. Sites of first recurrence (main sites per treatment arm)a
 
Survival
Survival curves for the overall population and the two prospective strata (node-negative and node-positive patients) are shown in Figures 1, 2 and 3. Table 4 depicts the corresponding 5-year and 7.5-year survival parameters.



View larger version (16K):
[in this window]
[in a new window]
 
Figure 1. (A) Overall survival and (B) disease-free survival in the study population. FAC, doxorubicin, cyclophosphamide, 5-fluorouracil; CMF, methotrexate, cyclophosphamide, 5-fluorouracil.

 


View larger version (16K):
[in this window]
[in a new window]
 
Figure 2. (A) Overall survival and (B) disease-free survival in node-positive patients. FAC, doxorubicin, cyclophosphamide, 5-fluorouracil; CMF, methotrexate, cyclophosphamide, 5-fluorouracil.

 


View larger version (15K):
[in this window]
[in a new window]
 
Figure 3. (A) Overall survival and (B) disease-free survival in node-negative patients. FAC, doxorubicin, cyclophosphamide, 5-fluorouracil; CMF, methotrexate, cyclophosphamide, 5-fluorouracil.

 

View this table:
[in this window]
[in a new window]
 
Table 4. Survival parameters (%) at 5-year and 7.5-year follow-up
 
Overall patient population (Figure 1)
In the overall population, there was a clear trend that almost reached statistical significance (P = 0.056) towards a better DFS in patients treated with FAC. The 5-year and 7.5-year DFS were, respectively, 58% and 55% for FAC, and 50% and 47% for CMF. OS was slightly better with FAC (75% versus 69% at 5 years), but the difference was not significant.

Node-positive patient population (Figure 2)
DFS and OS were not different between FAC and CMF in the subgroup of node-positive patients, although there was a slight trend towards a better DFS with FAC.

Node-negative patient population (Figure 3)
In the prospective strata of 415 node-negative patients, DFS was statistically higher in the women allocated to FAC than in CMF-treated patients (P = 0.046). The 5-year and 7.5-year DFS were, respectively, 75% and 73% for FAC, and 67% and 62% for CMF. OS was also statistically better with FAC (P = 0.0378).

Cox regression analysis
Unadjusted models for the overall and main strata patient populations were consistent with log-rank analysis, and revealed a generalized increase in OS and DFS for the FAC arm in node-negative patients (Table 5A and 5B). Multivariate tests confirmed expected significance for standard predictors such as tumor size, positive nodes and menopausal status. Other variables (type of surgery, receptor status, Eastern Cooperative Oncology Group performance status, previous radiotherapy) did not reach significance and were excluded from the final model.


View this table:
[in this window]
[in a new window]
 
Table 5A. P values from Cox regression analysis: overall population
 

View this table:
[in this window]
[in a new window]
 
Table 5B. P values from Cox regression analysis: main strata (multivariate)
 
Upon evaluation of the size of the treatment effect when adjusted for potential interaction terms (positive nodes, tumor size, treatment center) the overall risk for CMF for OS and DFS in the overall patient population increased significantly (OS RR 1.3, P = 0.05; DFS RR 1.2, P = 0.03, respectively). The size of the treatment effect was also calculated in separate analyses for negative and positive node data subsets, and showed significantly higher RR for CMF-treated patients in the node-negative strata (OS RR 1.7, P = 0.04; DFS RR 1.4, P = 0.047), but not in the node-positive strata. These same analyses were repeated with center and tumor size included as interaction terms, with similar results.

Relative risk of death
Figure 4 shows the relative risk of death according to the number of axillary lymph nodes. The superiority of FAC over CMF is inversely related to the number of positive axillary lymph nodes.



View larger version (13K):
[in this window]
[in a new window]
 
Figure 4. Relative risk of death by nodal status.

 
Toxicity
Both regimens were equi-myelotoxic (Table 6), as reported earlier [5]. Myelotoxicity was mild and no patients had severe infection due to myelosuppression.


View this table:
[in this window]
[in a new window]
 
Table 6. Laboratory toxicities (percentage of patients with WHO grade 3–4 toxicity)
 
The clinically manifest toxicities are summarized in Table 7. FAC treatment induced significantly more emesis, mucositis, alopecia and cardiotoxicity, while CMF treatment induced significantly more conjunctivitis and weight gain. Cardiotoxicity was infrequent. Only three patients (0.6%) in the FAC arm had grade 3 cardiotoxicity; two of them are alive with minor symptoms and the other died from disease progression 3 years after the end of the FAC chemotherapy. Amenorrhea, defined as absence of three or more consecutive menses, occurred in the majority of patients in both treatment arms.


View this table:
[in this window]
[in a new window]
 
Table 7. Clinical toxicities (WHO worst grade occurrence/patient)
 
No toxic deaths occurred in this study.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our study clearly suggests that doxorubicin in combination with cyclophosphamide and fluorouracil as intravenous infusion is superior to methotrexate in combination with the same two drugs when administered as adjuvant therapy for operable breast cancer. The overall RR of CMF-treated patients reached statistical significance (RR of recurrence 1.2, P = 0.03, and RR of death 1.3, P = 0.05). The superiority of FAC over CMF was mainly due to the results obtained in the subgroup prospectively formed of patients with negative axillary lymph nodes. In this subgroup, the RRs for recurrence and death with CMF were 1.4 and 1.7, respectively.

The superiority of FAC over CMF in the subpopulation of patients with node-negative disease is intriguing and warrants further analysis. One explanation could be that the benefit of the antitumor drugs is limited, essentially, to patients with a lower tumor load, i.e. patients with negative ganglia involvement. These patients could have tumors with a higher growth fraction and a lower level of acquired resistance to drugs than the node-positive patients, and could be more sensitive to the action of doxorubicin. In our study, FAC was clearly better than CMF in terms of DFS and OS in the patients with negative ganglia. Analyses of survival in the subgroup retrospectively formed of women with one to three axillary ganglia indicated that there was a clear tendency towards better DFS and OS in the women treated with FAC. This trend was not evident in the women with four or more axillary ganglia involved (Figure 4). One reason could be that the superiority of FAC over CMF is progressively decreased with increasing tumor load, i.e. very evident in the node-negative patients, doubtful in the patients with one to three positive ganglia and practically none in those with four or more positive ganglia. Confirmation of this hypothesis requires phase III studies to be conducted with prospective stratification with respect to axillary status (zero nodes, one to three nodes, four or more nodes). Indeed, the Istituto Nazionali Tumori of Milano had adopted this strategy after observing that CMF adjuvant chemotherapy provided a clear survival benefit mainly in those women with one to three positive nodes [2]. These findings were subsequently extended in two studies of adjuvant therapies with different designs; one in patients with one to three positive nodes and the other in patients with four or more positive nodes [6, 7].

Because of concerns regarding cardiotoxicity, anthracyclines had not been tested in the adjuvant setting until 10–15 years ago. These concerns have been somewhat alleviated with the demonstration that 6 months of adjuvant therapy is as effective as more prolonged treatment [8]. This allows for the administration of cumulative doses of anthracyclines without reaching the maximum recommended dose. Over the past few years several studies have compared anthracycline-containing combinations with CMF-like combinations as adjuvant therapy for operable breast cancer. The results of these trials are difficult to interpret as many of them were not designed to answer the specific question of the role of the anthracycline versus methotrexate. Individual trials differed in the number of drugs used, schedules and dose intensities. The final results observed might be due to the superiority of the anthracycline over methotrexate, to the different number of drugs or to the different dose intensities of the other drugs in the combinations. Another problem with many of these studies is the small number of patients treated. Nearly 1000 patients need to be included in a trial to demonstrate a 20% reduction in mortality with an anthracycline-containing regimen. Many of these trials did not reach such a sample size. These trials can be classified into two groups: those in which the relative merits of the anthracycline against methotrexate, both in combination with cyclophosphamide and 5-fluorouracil, were assessed and those in which regimens with and without anthracyclines were compared. The studies of the former group (design similar to the present study, and more appropriate to define the role of anthracyclines as adjuvant therapy for breast cancer) are summarized in Table 8.


View this table:
[in this window]
[in a new window]
 
Table 8. Randomized studies testing the role of doxorubicin/epirubicin versus methotrexate as adjuvant chemotherapy for operable breast cancer
 
Carpenter and the Southeastern Oncology Group [9] compared intravenous CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2) and CAF (cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, 5-fluorouracil 500 mg/m2) as adjuvant chemotherapy for node-positive breast cancer. All the drugs were administered on day 1 every 3 weeks for six cycles. In both treatment arms, each subsequent dose was escalated or decreased by 15% or maintained unchanged depending on the neutrophil nadir 2 or 3 weeks after the previous treatment (the nadir goal was 800 to 1200 neutrophils/µl). The 5-year survivals were 74% (CAF) and 68% (CMF), a difference that was not statistically significant. However, as the authors pointed out, this trial did not rule out a slightly better survival (~10%) with the CAF regimen, since the study had only a power of 77% to detect a 10% difference in survival. The study did not report on DFS.

Coombes and the International Collaborative Cancer Group [10] performed a multicenter, multinational trial comparing CMF with FEC (5-fluorouracil, epirubicin, cyclophosphamide) as adjuvant chemotherapy for premenopausal women with axillary node-positive breast cancer. The study was composed of two different trials since the participating institutions were allowed to choose between two alternative schedules of CMF and FEC. Twelve institutions selected randomization between the classical CMF regimen (cyclophosphamide 100 mg/m2/day orally, days 1–14; and methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2, both intravenously on days 1 and 8, administered every 4 weeks for six cycles) and the FEC regimen (5-fluorouracil 600 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 600 mg/m2, all drugs given intravenously on day 1 every 3 weeks for eight cycles). This design does not permit an evaluation of the relative value of anthracycline compared with methotrexate, since the rest of the drugs in the combinations were administered in different schemes and the number of cycles were also different. The results of this part of the study have not been included in Table 8. In this part of the trial, no evidence of a benefit was observed for either regimen in terms of DFS or OS. In the second substudy, chosen by three of the institutions, a comparison was made between intravenous CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2; all drugs given on days 1 and 8 of an every 4 week cycle for six cycles) and FEC (same schedule except that epirubicin 50 mg/m2 was administered on days 1 and 8). The results of this substudy have been included in Table 8, since the design allows for an estimation of the relative value of epirubicin against methotrexate in combination with cyclophosphamide and 5-fluorouracil. In this substudy, FEC was superior to CMF in terms of DFS (P = 0.03) and OS (P = 0.02).

The first results of the American Intergroup Trial INT 0102 were reported in 1998 [11]. This study compared the classical CMF regimen with CAF (cyclophosphamide, doxorubicin, fluorouracil) in 2691 high-risk node-negative breast cancer patients. To be classified as high risk, node-negative patients had to have had at least one of the following criteria: tumors ≥2 cm, negative estrogen and progesterone receptors or high S-phase fraction in flow cytometry. CAF was marginally superior to CMF in terms of DFS and OS (5-year absolute survival benefit of 2%).

A study reported by Mouridsen et al. [12] compared CEF (oral cyclophosphamide, epirubicin, 5-fluorouracil) with CMF in three different subsets of patients: (i) premenopausal node negative, grade 2–3; (ii) premenopausal node positive, hormone receptor negative, or hormonal status unknown; and (iii) postmenopausal node positive, hormone receptor negative. Drugs were administered intravenously and treatment arms differed only by the substitution of methotrexate (40 mg/m2) with epirubicin (60 mg/m2). OS was statistically superior with CEF in the combined premenopausal groups, but not in postmenopausal women.

Levine et al. [13] compared the classical CMF regimen (oral cyclophosphamide 100 mg/m2/day on days 1–14, methotrexate 40 mg/m2 i.v. on days 1 and 8 and 5-fluorouracil 600 mg/m2 i.v. on days 1 and 8) with the CEF regimen (oral cyclophosphamide 75 mg/m2/day on days 1–14, epirubicin 60 mg/m2 on days 1 and 8 and 5-fluorouracil 500 mg/m2 i.v. on days 1 and 8) in 710 premenopausal, node-positive patients. Both regimens were given every 4 weeks for six cycles. Relapse-free survival and OS were statistically superior with CEF (63% versus 53%, and 77% versus 70%, respectively, at 5 years).

Meta-analysis by the EBCTCG confirms the superiority of the combinations containing anthracyclines over the CMF-like combinations, even though it includes not only the trials described in Table 8, but also other trials where the anthracycline-containing combinations included only two drugs [3]. There have been 11 trials in which CMF-type combinations were compared with an anthracycline-containing combination, in approximately 6000 patients followed-up for at least 5 years. Overall, there was a 4% absolute risk reduction for recurrence and death above that seen with CMF after 10 years of follow-up (11% and 16% relative improvements in relapse and death; P <0.001).

Our study was designed to answer the specific question of the relative value of doxorubicin versus methotrexate, both administered in combination with cyclophosphamide and 5-fluorouracil, as adjuvant treatment of operable breast cancer. The drugs were administered intravenously every 21 days in both arms. The doses of cyclophosphamide and 5-fluorouracil were set higher (17%) in the CMF treatment arm with the objective of comparing schemes of equivalent myelotoxicity. Despite this handicap, FAC was superior to CMF, especially in node-negative women, which indicates that doxorubicin is superior to methotrexate in combination with cyclophosphamide and 5-fluorouracil as adjuvant therapy for node-negative breast cancer.

Figure 5 shows the ratios of survival rates for CMF and CF plus doxorubicin/epirubicin in the studies included in Table 8. The meta-analysis of these studies (n = 6507 patients) demonstrates a clear advantage of CAF/CEF versus CMF.



View larger version (21K):
[in this window]
[in a new window]
 
Figure 5. Comparison of randomized trials testing the role of doxorubicin/epirubicin (A/E) versus methotrexate, combined with cyclophosphamide (C) and 5-fluorouracil (F), as adjuvant chemotherapy for operable breast cancer. Survival rates ratios for CMF (methotrexate, cyclophosphamide, 5-fluorouracil) versus CF + A/E are shown. The areas of the shaded boxes are proportional to the number of patients. See Table 8 for details.

 
GEICAM has adopted the FAC schedule as standard adjuvant therapy in women with operable axillary-negative breast cancer. Currently, GEICAM is testing the value of taxotere as adjuvant therapy for high-risk axillary-negative breast cancer. In 1998 we initiated the TARGET 0 study (Taxotere Adjuvant Rhône-Poulenc-GEICAM Trial in high-risk N-0 patients) comparing the TAC combination (taxotere, doxorubicin, cyclophosphamide) with FAC in women with axillary-negative breast cancer and high-risk criteria according to the 1998 St Gallen conference.


    Acknowledgements
 
Editorial assistance was provided by Dr Peter R. Turner of t-SciMed (Reus, Spain). The authors would like to thank Esther Mahillo, María José Escudero and Juan Manuel Lopez Alcorocho (GEICAM) for their assistance in the preparation of the manuscript.


    Footnotes
 
+ Correspondence to: Dr M. Martin, Servicio de Oncologia Medica, Hospital Universitario San Carlos, C/ Dr Martín Lagos s/n 28040 Madrid, Spain. Tel: +34-91-3303546; Fax: +34-91-5436623; E-mail: mmartin{at}geicam.org or mmartin.hcsc{at}madrid.salud.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Bonadonna G, Brusamolino E, Valagussa P. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976; 294: 405–410.[Abstract]

2. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 1995; 332: 902–906.

3. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 1998; 352: 930–942.[CrossRef][ISI][Medline]

4. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[ISI][Medline]

5. Martin M, Villar A, Sole-Calvo A et al. A randomized trial comparing CMF with FAC in breast cancer adjuvant treatment. Toxicity analysis. Ann Oncol 1994; 5 (Suppl 8): (Abstr 21).

6. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten year results. JAMA 1995; 273: 542–547.[Abstract]

7. Moliterni A, Bonadonna G, Valagussa P et al. Cyclophosphamide, methotrexate, and fluororouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 1991; 9: 1124–1130.[Abstract]

8. 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 1983; 1: 2–10.[Abstract]

9. Carpenter JT, Velez-Garcia E, Aron BS et al. Five-year results of a randomized comparison of cyclophosphamide, doxorubicin (adriamycin) and fluorouracil (CAF) vs cyclophosphamide, methotrexate and fluorouracil (CMF) in node positive breast cancer: a Southeastern Cancer Study Group study. Proc Am Soc Clin Oncol 1994; 13: (Abstr 66).

10. Coombes RC, Bliss JM, Wils J et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol 1996; 14: 35–45.[Abstract]

11. Hutchins L, Green S, Ravdin P et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients. First results of Intergroup trial INT 0102. Proc Am Soc Clin Oncol 1998; 17: 1a (Abstr).

12. Mouridsen HT, Andersen J, Andersson M et al. Adjuvant anthracycline in breast cancer. Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol 1999; 18: 68a (Abstr).

13. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 1998; 16: 2651–2658.[Abstract]