In 1976, Bonadonna et al. [
13] 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 followup of 20 years, this trial provides unequivocal evidence that CMF increases disease free survival (DFS) and overall survival (OS) in these patients [
14]. As the classical CMF and CMF-like protocols have been considered the gold standard for adjuvant chemotherapy for operable breast cancer, between 1990-1999, 32.9% of our patients (n=98) were treated with CMF. Because of concerns regarding cardiotoxicity, anthracyclines had not been tested in the adjuvant setting until 10-15 years ago. After the demonstration of effectiveness of 3-6 months of adjuvant therapy, this allowed for the administration of cumulative doses of anthracyclines without reaching the maximum recommended doses [
13,
15-
17]. So, 53% of the study population (n=158) received anthracycline-based regimens. Only 14.1% of patients (n=42) with good prognostic features such as node negative, ER and/or PR positive, postmenopausal ones received endocrine therapy alone.
In the present study, 5-year DFS and OS for nodenegative, node-positive and all patients were 82%, 90%; 61%, 72%; and 67%, 78%, respectively. With a statistically significant difference between the survival rates of node negative and positive patients, our results were compatible with those obtained from the randomized trials with CMF and anthracycline-based chemotherapies for operable breast cancer [18-23]. But the limitation of the present study was being a retrospective analysis. A multidisciplinary team approach, as well as, prognostic factors and evidence-based guidelines were the core of treatment selection.
In regard to systemic chemotherapy, as our study was not a prospective randomized trial, CMF and anthracyclinebased chemotherapy groups are not well-balanced according to known prognostic factors. There were statistically significant differences among the groups with respect to age, menopausal status, involvement of lymph nodes and vascular invasion favoring CMF group. To avoid problems of patient adherence with oral cyclophosphamide, as documented in the first trials of Gianni Bonadonna et al., we preferred IV administration of CMF [14,24,25]. In regard to anthracyclines; FEC, FAC, AC and EC regimens were all devised for both node negative and positive patients in the 1990s. Dose intensity and duration of adjuvant chemotherapy are also important issues affecting survival improvement [26]. 1998 and 2000 Oxford Overviews, 2000 NIH and 2001 St Gallen Consensus Panels concluded that adjuvant chemotherapy should be given 4-6 cycles (3-6 months) and superiority of FEC/FAC over CMF was shown in the randomized clinical trials (10). Today, it is well-known that 6 cycles of FEC(50) (FASG 01) used in our treatment protocol is inferior than 6 cycles of FEC(100) (FASG 05) for node-positive breast cancer patients with poor prognostic factors; but it was an acceptable regimen in the early and mid-1990s [27,28]. Conventional dose escalations above standard doses will not be beneficial for doxorubicin or cyclophosphamide, while an epirubicin dose of 90-100 mg/m2 given every third week in polychemotherapy regimens results in overall survival gains [10].
Multivariate analysis revealed that the only significant variable both for DFS and OS was presence of four or more positive axillary lymph nodes in the overall study population.
The benefit of antitumor drugs is limited, essentially, to patients with a lower tumor load, i.e. patients with negative and one to three axillary ganglia involvement. These patients could have tumors with a higher growth fraction and a lower level of acquired resistance to drugs than the four or more positive ganglia. A prospective randomized study by the GEICAM group comparing CMF with FAC chemotherapy regimens confirmed statistically better DFS and OS rates with FAC in the node-negative patient population, but not in the subgroup of positive axillary ganglia. While superiority of FAC over CMF could be the reduced dose intensity of the CMF regimen used in that study compared with classical CMF or the unknown biological features of tumor, the reason for the progressively decreased superiority of FAC over CMF in the node-positive subgroup could be increasing tumor load [23]. American Intergroup Trial INT 0102 revealed the marginally better survival rates with FAC than classical CMF in the highrisk node-negative breast cancer patients [20]. The International Collaborative Cancer Group Study and French Adjuvant Study Group 05 Trial pointed out the importance of dose-intensity of anthracycline which led to a significant benefit in terms of DFS and OS among node-positive patients with poor prognostic factors [19,27].
A decade of randomized clinical trials has established the level 1 evidence-based superiority of anthracyclinebased CT over CMF-like regimens. This superiority is smaller than expected, however, on average not exceeding a 4% absolute gain in 10-year survival for node-positive and a 1.7% gain at 5 years for node-negative breast cancer patients [10-12]. In the last update of the EBCTCG Overview (September 2000), the results regarding anthracycline benefit, based on 14,000 women enrolled in 15 trials, continue to show the benefit of anthracycline regimens when compared with CMF in terms of reductions in recurrence (11% greater relative reduction, two-sided pvalue= 0.0005) and death (16% greater relative reduction, two-sided p-value<0.00001). For the node positive subset, these benefits persist for at least 10 years, with absolute gains of around 4% in recurrence and in survival. The advantage of anthracycline-based CT was found almost exclusively when a three-drug regimen was used (either CEF or CAF) [29-31].
Not only the increased risk of relapse and death associated with increasing lymph node metastasis to the ipsilateral axilla but even with endocrine-responsive disease, the higher risk of relapse and the presence of endocrine-resistant clones within the tumor have in general been taken as indications for the inclusion of cytotoxic chemotherapy in the treatment regimen.
Unfortunately, our current understanding of the optimal adjuvant chemotherapy regimen for the individual patient is still very limited. In clinical practice, the decision whether to use an anthracycline-based treatment in a given patient must always depend on the balance between the expected survival benefits for that patient and the potential risk factors for increased toxicity (i.e., mainly pre-existing heart disease) [10-12,31,32].
Solid data are still lacking with regard to what is considered as the optimal anthracycline, optimal regimen (2- or 3-drug) and optimal number of cycles (4 or 6) [11,12,31,33,34].
In conclusion, the importance of our study was not only to answer the specific question of the impact of adjuvant systemic therapies received in daily clinical practice on operable breast cancer patients, but also to recognize the weakness of standard chemotherapy regimens for women with four or more positive lymph nodes. Because of concerns regarding high percentage of patients with ≥4 positive axillary ganglia, it might be very important to stress the necessity of early recognition by well-designed national breast cancer screening and educational programs for the avoidance of high numbers of involved lymph nodes besides new effective treatment modalities, i.e. taxanes and biological therapies.
ACKNOWLEDGEMENTS
The authors would like to acknowledge the contribution of the following investigators and departments: Dr. Cavit Çehreli (Retired Professor, Hematologist/Oncologist, the founder of Hematology/Oncology Division); Dr. Uğur Yılmaz, Dr. İlhan Öztop (Department of Internal Medicine, Division of Hematology/Oncology); Dr. Mehmet Ali Koçdor (Department of General Surgery); Dr. Hatice Durak and Dr. Erkan Derebek (Department of Nuclear Medicine), Dr. Gül Ergör (Department of Public Health), Dr. Hilmi Alanyalı (Department of Radiation Oncology).
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