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© 2001 American Society for Clinical Oncology
Anthracycline Adjuvant Chemotherapy: How Much Is Enough?Cancer Care Ontario Hamilton Regional Cancer CentreMcMaster UniversityHamilton, Ontario, Canada OVER THE LAST 30 years, thousands of women with early breast cancer have participated in clinical trials that have established the role of adjuvant chemotherapy in reducing breast cancer recurrence and improving survival.1 The knowledge gained has been incremental, with results from one trial serving as a foundation for the next. Trials have examined many different questions, including, for example, single agent versus multiple drugs, chemotherapy dose and duration, and anthracycline- versus nonanthracycline-containing regimens. The critical role that data from randomized trials plays in establishing treatment practices is highlighted by two recent events that occurred in the fall of 2000: the Fifth Main Meeting of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) and the National Institutes of Health (NIH) Consensus Development Conference on Adjuvant Therapy for Breast Cancer. At both of these meetings, results of trials evaluating anthracycline chemotherapy regimens were discussed. In the results of the 1995 EBCTCG meta-analysis, anthracycline regimens were associated with a 12% reduction in the annual odds of recurrence and an 11% reduction in mortality compared with cyclophosphamide/methotrexate/fluorouracil (CMF)–type regimens.1 In individual trials, CMF and doxorubicin/cyclophosphamide (AC) were equivalent in terms of disease-free survival (DFS) and overall survival (OS),2,3 whereas cyclophosphamide, epirubicin, and fluorouracil–containing regimens (CEF/FEC)4,5 and cyclophosphamide, doxorubicin, and fluorouracil (CAF)6 were superior to CMF. It is possible that the failure to detect an advantage of AC over CMF may be related to the relatively short duration of the AC therapy. In the consensus statement from the NIH Conference, a recommendation was made for anthracycline-containing regimens.7 Doxorubicin is the anthracycline that oncologists in the United States are most familiar with for use in early breast cancer. The consensus statement from the recent NIH Conference concluded that there is a threshold dose effect for doxorubicin in the adjuvant setting.7 This is based on two trials conducted by Cancer and Leukemia Group B. In the first trial, by Wood et al,8 three dose levels of CAF chemotherapy were compared in women with node-positive breast cancer. In the high- and intermediate-dose treatment arms, the cumulative doxorubicin dose was 240 mg/m2, now accepted as standard. The DFS and OS in the high- and intermediate-dose arms were equivalent and were superior to those of the low-dose arm. This trial demonstrated that giving less than the threshold dose results in a worse outcome. The subsequent trial in node-positive patients posed two questions: What is the value of escalating the dose of doxorubicin in the AC regimen above the "threshold" dose? And is the addition of paclitaxel to doxorubicin and cyclophosphamide beneficial?9 While the answer to the latter question is controversial,7 the former can be answered unequivocally: at 18 months, the DFS and OS were the same for doxorubicin 60 mg/m2, 75 mg/m2, and 90 mg/m2 when administered every 3 weeks for four cycles. This issue of the Journal of Clinical Oncology contains the results of two randomized trials that provide valuable insights into the therapeutics of nondoxorubicin-containing anthracycline chemotherapy (epirubicin and mitoxantrone) in early breast cancer.10,11 Epirubicin, the 4&|-epimer of doxorubicin, has been widely used throughout the world (except in the United States) since 1985, both as adjuvant therapy for early breast cancer and in metastatic breast cancer. Recently, the United States Food and Drug Administration approved epirubicin for use as a component of adjuvant therapy in women with early-stage breast cancer. The structural differences between epirubicin and doxorubicin may account for the different safety profiles of the two agents; larger doses of epirubicin are required to produce the same degree of toxicity as doxorubicin.12 This increased safety profile potentially allows for greater dose escalation that can be achieved safely. Much has been learned about the dose-response relationship, optimal dose, and duration of administration of epirubicin. Bastholt et al13 conducted a randomized trial in which women with metastatic breast cancer were randomized to one of four different doses of epirubicin administered every 3 weeks: 40 mg/m2, 60 mg/m2, 90 mg/m2, and 135 mg/m2. The corresponding response rates were 20%, 18%, 38%, and 36% respectively, suggesting a dose-dependent relationship up to 90 mg/m2. The French Epirubicin Study Group has conducted a series of trials in women with metastatic breast cancer. In the first trial, FEC 75 mg/m2 was associated with a higher complete response rate than FEC 50 mg/m2.14 In a second trial, FEC 100 mg/m2 was superior to FEC 50 mg/m2,15 and in a third trial, response rates were higher with FEC 100 mg/m2 than with FEC 75 mg/m2.16 In the adjuvant setting in women with node-positive breast cancer, an earlier trial by the French Adjuvant Study Group demonstrated that six cycles of FEC 50 mg/m2 were superior to three cycles of FEC 75 mg/m2 or FEC 50 mg/m2.17 In the subsequent study by Bonneterre et al,10 which appears in this edition of the Journal, women with node-positive breast cancer were randomized to FEC 50 mg/m2 or FEC 100 mg/m2; both regimens were administered every 3 weeks for six cycles. There was a statistically significant improvement in both DFS and OS in favor of the higher dose regimen. These data are consistent with a dose-threshold hypothesis, which argues that an adequate dose of epirubicin is necessary.
The trial by Fumoleau et al11 that appears in this issue of the Journal further tests the hypothesis that escalating the anthracycline above the standard dose might lead to improved outcome in a population at very high risk of recurrence, namely, women with 10 or more positive lymph nodes. In this randomized trial of 150 patients, four cycles of standard AC were compared with four cycles of a dose-intense regimen of mitoxantrone and cyclophosphamide given with granulocyte colony-stimulating factor. Mitoxantrone has been well studied in the metastatic setting,18 but it is not commonly used to treat early-stage breast cancer. With a median follow-up of 60 months, there was no significant difference in either DFS or OS between the treatment groups. A post hoc subgroup analysis of the highest risk patients (those with The failure to detect a difference in favor of the high-dose regimen may have been due to the relatively small sample size of the trial. The results of this trial, however, are consistent with those of other trials of drug escalation to a level requiring growth factor but not stem-cell support. In these trials, the dose of chemotherapy drugs (eg, doxorubicin, epirubicin, and cyclophosphamide) above a certain threshold did not improve outcome9,19-21 but can be associated with significant toxicity.22,23 At the NIH Consensus Development Conference, the invited experts were asked to define the standard adjuvant therapy regimen for patients with early-stage breast cancer. How do these two trials contribute to that task? The study by Bonneterre et al10 strengthens the case for a minimum threshold dose of anthracycline below which treatment outcomes are inferior. For oncologists in the United States, it is further evidence that epirubicin-containing regimens are safe and effective. The trial by Fumoleau et al11 adds to the growing body of evidence that dose escalation of anthracyclines above a critical dose is not beneficial. Although the 1995 overview confirmed the superiority of anthracyclines in the adjuvant therapy of breast cancer, the optimal regimen has yet to be determined and should continue to be evaluated in clinical trials. REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 352:930-942, 1998 2. Fisher B, Brown A, Dimitrov N, et al: Two months of doxorubicin-cyclophosphamide with and without interval re-induction therapy compared with 6 months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer patients with tamoxifen-non-responsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483-1496, 1990[Abstract] 3. Fisher B, Anderson S, Wolmark N, et al: Chemotherapy with and without tamoxifen for patients with ER negative breast cancer and negative nodes: Results from NSABP B23. Proc Am Soc Clin Oncol 19: 72, 2000 (abstr 277) 4. 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] 5. Mourisden H, 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 18: 68, 1999 (abstr 254) 6. 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 17: 1, 1998 (abstr 1) 7. Adjuvant Therapy for Breast Cancer: NIH Consensus Statement Online. Http://consensus.nih.gov. 17:1-23, 2000
8.
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 9. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (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) (meeting abstract). Proc Am Soc Clin Oncol 17: 101, 1998 (abstr 390) 10. French Adjuvant Study Group: Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: Five year follow-up results of FASF 05 randomized trial. J Clin Oncol 19:602-611, 2000
11.
Fumoleau P, Chauvin F, Namer M, et al: Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes. J Clin Oncol 19: 612-620, 2000 12. Ormrod D, Holm K, Goa K, et al: Epirubicin: A review of its efficacy as adjuvant therapy and in the treatment of metastatic disease in breast cancer. Drugs Aging 15: 389-416, 1999[Medline]
13.
Bastholt L, Dalmark M, Gjedde SB, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 14: 1146-1155, 1995 14. French Epirubicin Study Group: A prospective trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9:305-312, 1991
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Focan C, Andrien JM, Closon MT, et al: Dose-response relationship of epirubicin based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol 11: 1253-1263, 1993 16. Bastit P, Roche H, Namer M, et al: Final results of a randomized trial comparing three epirubicin based regimens as first line chemotherapy in metastatic breast cancer (MBC) patients (PTS). Proc Am Soc Clin Oncol 18: 128, 1999 (abstr 487) 17. Fumoleau P, Bremond A, Kerbrat P, et al: Better outcome of premenopausal node positive breast cancer patients treated with six cycles vs three cycles of adjuvant chemotherapy: Eight year follow-up results of FASG01. Proc Am Soc Clin Oncol 18: 67, 1999 (abstr 252) 18. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic breast cancer, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the Breast. Philadelphia, PA, Lippincott Williams &Wilkins, 2000, pp 775-776 19. Therasse P, Mauriac L, Welnicka M, et al: Neo-adjuvant dose intensive chemotherapy in locally advanced breast cancer (LABC): An EORTC-NCIC-SAKK randomized phase III study comparing FEC (5FU, epirubicin, cyclophosphamide) vs high dose intensity EC + G-CSF (filgrastim). Proc Am Soc Clin Oncol 17: 124, 1998 (abstr 472)
20.
Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15: 1858-1869, 1997
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Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17: 3374-3388, 1999 22. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomised trial. Lancet 356: 1384-1391, 2000[Medline] 23. DeCillis A, Anderson S, Wickerham DL, et al: Acute myeloid leukemia (AML) in NSABP B25. Proc Am Soc Clin Oncol 14: 98, 1995 (abstr 92)
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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15 positive nodes) suggested an improvement in outcome with the high-dose treatment; however, this observation can only be considered hypothesis-generating. There were three cases (4%) of acute leukemia or myelodysplastic syndrome in the high-dose treatment group. 
