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© 2003 American Society for Clinical Oncology
In Reply:University of California at Los Angeles, Los Angeles, CA There is increasing evidence that anthracycline-containing regimens are more effective than polychemotherapy regimens without anthracyclines in women with node-positive breast cancer, in particular, when the dose-intensity and the exposure to anthracyclines are maintained at an optimal level. The National Cancer Institute of Canada (NCIC) MA5 trial1 demonstrated a significant improvement in disease-free survival (DFS) and overall survival (OS) for six cycles of well-dosed cyclophosphamide, epirubicin, and fluorouracil (CEF; epidoxorubicin: 60 mg/m2 day 1 and 8) over cyclophosphamide, methotrexate, and fluorouracil (CMF). The French Adjuvant Study Group-05 trial (FASG-05)2 showed clearly that fluorouracil, epirubicin, and cyclophosphamide (FEC) 100 regimen was superior to FEC 50 in an adjuvant setting mostly for patients with four or more positive nodes, while results from a Cancer and Leukemia Group B (CALGB) study3 indicate that lower doses of doxorubicin (cyclophosphamide, doxorubicin, and fluorouracil [CAF] 30 and CAF 40 regimens) are significantly inferior to higher doses (CAF 60 regimen) in an adjuvant setting. These data indicate that decreasing dose-intensity of anthracyclines is most likely detrimental to patient outcome. Inversely, there is no evidence that increasing dose-intensity of doxorubicin beyond 60 mg/m2 (75 or 90 mg/m2) improves the outcome of patients in adjuvant setting, as seen in the CALGB 9344 trial.4 These observations indicate that the FEC 50 regimen may contain a suboptimal dose of anthracycline, whereas six cycles of FEC 100 (6 FEC 100) regimen might represent an optimal use of epirubicin. In addition, the true ratio dose/efficacy between doxorubicin and epidoxorubicin is still open to debate. The results of the metastatic trial performed by the French Group comparing fluorouracil, doxorubicin, and cyclophosphamide (FAC) to FEC at equimolar doses should be interpreted with caution, as the statistical power of this trial limits conclusions of true equivalence between the two anthracycline-containing regimens.5 The integration of taxanes in an adjuvant setting is presently a subject of intense discussion. The results of the first interim analysis of the Breast Cancer International Research Group (BCIRG) 001 trial, comparing docetaxel, doxorubicin, and cyclophosphamide (TAC) to FAC, showed at 33 months follow-up that TAC regimen was superior to FAC in terms of the primary end point, disease-free survival (DFS; relative risk [RR] TAC/FAC, 0.68; P = .0011).6 These results were most striking in patients with one to three involved nodes (prospectively defined) in whom the relative risk of relapse was 0.50 (P = .0002). In patients with four or more nodes, there was not a statistically significant difference in DFS (RR, 0.86; P = .33). These differences translated into significant differences in the absolute number of patients surviving disease-free at 33 months (TAC, 82%; FAC, 74%). Among those with one to three positive nodes, 90% in the TAC group remained disease-free, compared with 79% treated with FAC. There was a trend toward improved overall survival in the TAC group, but this trend did not achieve statistical significance (RR, 0.76; P = .11) In patients with one to three involved nodes, however, TAC was superior to FAC (RR of death, 0.46; P = .006). There was no difference in OS in patients with four or more axillary nodes. Overall, 92% of those treated with TAC remained alive at the time of the interim analysis, compared with 87% treated with FAC. The primary analyses with respect to DFS and OS were confirmed by an analysis unadjusted for nodal status and by a multivariate Cox model. In addition, the superiority of TAC in terms of DFS was also observed in other selected cohorts of patients. In particular, TAC appeared to provide benefit regardless of tumor hormone receptor status or HER2 expression level. Beside the fact that retrospective side-by-side comparisons of subgroups of different randomized prospective trials could be debatable, it is clear that the FASG-05 involved mostly a subgroup of a node-positive breast cancer population (four or more positive nodes). In the BCIRG 001 trial, the planned analysis of DFS and OS by nodal status was prospectively defined and statistically powered and did not show a significant difference between TAC and FAC for patients with more than three nodes, while the significant largest difference in favor of TAC was clearly seen in patients with one to three nodes. In addition, when analyzing DFS for patients with more than three nodes retrospectively stratified to four to nine nodes and more than 10 nodes, RRs for TAC/FAC were 0.78 and 1.06, respectively, indicating that patients with more than 10 nodes do not get any benefit from TAC over FAC. This also may indicate a potential linear relation between the number of positive nodes and the potential benefit expected from TAC over FAC (a lower number of nodes, a higher potential benefit and vice versa), with the number of nodes as a continuous variable. In addition, talking today about chemotherapy of reference for node-positive breast cancer patients should not only be viewed for limited subgroups of patients (those with four or more positive nodes). As we know, during the last decade, the implemented screening programs have induced an important shift in initial breast cancer patient presentation; today, a large majority of patients present with either node-negative or one to three positive nodal status. The patient population seen in the BCIRG 001 trial, performed at the end of the 1990s, reflects this fact (62%, one to three nodes), as opposed to that of the FASG-05 trial, performed earlier in the 1990 decade. In terms of safety profile, the main toxicity of TAC is indeed hematologic, with an incidence of febrile neutropenia (FN) of 23.9% but, interestingly enough, with very low documented infection and no septic death. This was known from phase II–III trials in advanced disease using docetaxel/doxorubicin based combinations (AT and TAC).7–9 Thus, when designing the BCIRG 001 trial, we did not use any primary prophylactic hematopoietic support (granulocyte colony-stimulating factor [G-CSF]): G-CSF was only prescribed for subsequent cycles of TAC after a first episode of FN. However, aware of the potential issue related to the incidence of FN, we conducted a prospective randomized trial in which we studied the hematologic safety profile of TAC using primary prevention with G-CSF in advanced breast cancer patients. Recently published results of this study showed a 6.7% incidence of FN in a clinical setting known for a worse hematologic tolerance than in an adjuvant situation. Nonhematologic toxicity was mild with no significant difference between TAC and FAC. Of note, no leukemia has been reported in the BCIRG 001 trial.10 Overall, there is no doubt that regimens such as FEC 100 and the Canadian CEF are optimal anthracycline-containing combinations and at present remain a choice for patients with node-positive breast cancer, mostly for those with more than three nodes. However, TAC represents a clear option for patients in an adjuvant setting, knowing that the added benefit may be inversely proportional to the number of positive nodes. Consequently, this benefit of TAC over FAC is maximal for patients with one to three positive nodes, then appears to decrease linearly as the number of positive nodes increases from four to nine to become nonexistent for patients with more than ten positive nodes. There is a need for more data and more follow-up from trials investigating the integration of taxanes and docetaxel in particular, as we are foreseeing shifts in reference therapy for early breast cancer patients. REFERENCES 1. 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 16:2651–2658, 1998[Abstract]
2. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-years follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19:602–611, 2001
3. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253–1259, 1994 4. Henderson IC, Berry D, Demetri G, et al: Improved disease-free survival (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (pts) with node positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17:390 A, 1998 (abstr 390A) 5. French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil and either doxorubicin or epirubicin. J Clin Oncol 6:679–688, 1998 6. Nabholtz JM, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:141, 2002 (abstr 141).
7. Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 19:314–321, 2001 8. Nabholtz JM, Falkson G, Campos D, et al: Docetaxel and doxorubicin (AT) compared to doxorubicin and cyclophosphamide (AC) as first-line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968–975 9. Mackey J, Paterson A, Dirix L, et al: Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first-line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:137, 2002 (abstr 137). 10. Nabholtz JM, Cantin J, Chang, et al: Randomized double-blind phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide: Results of the BCIRG 004 trial. Clinical Breast Cancer 3:268–275, 2002.[Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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