Overview: Progress in Systemic Chemotherapy of Primary Breast Cancer

Gabriel N. Hortobagyi, M.D., FACP

Improved understanding of the natural history of breast cancer led to the systematic evaluation of adjuvant chemotherapy. Progress has been based on knowledge derived from randomized clinical trials (EBCTCG, 1998). The following paragraphs report salient points of progress.

Adjuvant chemotherapy significantly reduces the annual odds of recurrence and death for patients with primary breast cancer. The relative reduction in risk is similar regardless of initial tumor burden or prognostic category. The magnitude of benefit is greater in women less than 50 years of age than in those at or older than 50. Combination chemotherapy with two or more agents is more effective than single-agent therapy.

The optimal duration of chemotherapy has also been addressed in prospective clinical trials (Henderson, Gelman, Harris, et al., 1986). Prolonged chemotherapy for 4 to 6 months is superior to a single perioperative dose. The administration of chemotherapy for more than 6 months, utilizing the same cytotoxic regimen, is not superior to 6 months or less.

The initial clinical trials used cyclophosphamide-methotrexate-5-flourouricil (CMF) and related regimens. The second generation clinical trials of adjuvant chemotherapy evaluated the role of anthracyclines in the management of micrometastases (EBCTCG, 1998). Several individual randomized trials and the Oxford overview of randomized trials demonstrated that anthracycline-containing regimens were superior to nonanthracycline-containing regimens, and that the addition of an anthracycline resulted in an incremental reduction in odds of recurrence and death (EBCTCG, 1998; Levine, Bramwell, Pritchard, et al., 1998). Although the incremental benefit of an anthracycline-containing regimen was smaller in magnitude than that of polychemotherapy in relation to no adjuvant treatment, it became evident in retrospect that several of the randomized trials utilized suboptimal doses of anthracyclines. More recent information suggests that anthracycline-containing regimens may be particularly effective in patients with tumors that overexpress the HER-2/neu oncogene (Paik, Bryant, Park, et al., 1998; Ravdin, Green, Albain, et al., 1998).

These same studies suggest that the utility of anthracyclines would be marginal (compared to nonanthracycline-containing regimens) for patients whose primary breast cancer had a normal expression of HER-2/neu. These data and correlations, however, must be confirmed prospectively.

Over the past 20 years, much energy and resources have been expended on the evaluation of dose-intensive chemotherapy in the adjuvant setting. The results of multiple clinical trials suggest that there is a threshold effect for several of the commonly used regimens and that doses that fall below such a threshold result in less or no benefit. However, there is no clinical evidence at this point that continued increase in dose intensity above the threshold dose results in improved outcome (Hortobagyi, 1999; Rahman, Hortobagyi, Buzdar, et al., 1998).

The preliminary results of randomized clinical trials exploring the value of high-dose chemotherapy and autologous stem cell support in the adjuvant setting have not demonstrated a reproducible and significant clinical benefit superior to that of standard dose chemotherapy (Hortobagyi, 1999).

The role and value of adjuvant hormonal therapy is reviewed elsewhere. The addition of chemotherapy to hormonal therapy for patients with estrogen receptor-positive tumors has been shown to result in incremental reductions in odds of recurrence and death for both pre- and postmenopausal patients. Similar results have been found for patients with node-positive and node-negative breast cancer.

Recently published results suggest that the addition of paclitaxel to an anthracycline cyclophosphamide-containing regimen results in a greater reduction in odds of recurrence and death than those obtained with the anthracycline regimen alone (Henderson, Berry, Demetri, et al., 1998).

Several randomized trials have produced results suggesting that the introduction of a second noncross-resistant regimen after a course of primary adjuvant chemotherapy would improve the therapeutic results (Perloff, Norton, Korzun, et al., 1996). The trial with paclitaxel following the anthracycline cyclophosphamide regimen falls in this category, and continued evaluation of sequential, noncross-resistant regimens should produce results of great interest.

Another important topic in designing optimal adjuvant regimens is the timing of systemic chemotherapy. The majority of the data (on which current management is based) were derived from prospective randomized trials comparing surgery alone with surgery followed by postoperative adjuvant chemotherapy. More recently, preoperative chemotherapy (utilizing regimens similar to those employed in postoperative adjuvant treatment) has been evaluated in several prospective randomized trials (Fisher, Brown, Mamounas, et al., 1997; Kuerer, Newman, Smith, et al., 1999).

It is apparent that combination chemotherapy results in objective regression in the great majority of tumors. This reduction in tumor size increases the proportion of patients who are candidates for breast-conserving surgery and also results in substantial downstaging in the breast and regional lymph nodes. Not surprisingly, preoperative chemotherapy does not confer improved survival when compared to the same regimen used postoperatively. However, additional benefits-including preoperative evaluation of sensitivity to chemotherapy-are associated with preoperative chemotherapy (Fisher, Brown, Mamounas, et al., 1997; Kuerer, Newman, Smith, et al., 1999). Ongoing trials will determine whether this information can be translated into improved therapeutic results by the timely introduction of noncross-resistant systemic therapy.

References

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930-42. Abstract

Fisher B, Brown A, Mamounas E, Wieand S, Fisher E, Robidoux A, et al. Effect of preoperative therapy for primary breast cancer on local-regional disease, disease-free survival (DFS) and survival (S): results from NSABP B-18.. Proc Am Soc Clin Oncol 1997;16:A449. Abstract

Henderson IC, Berry D, Demetri G, Cirrincione C, Goldstein L, Martino S, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proc Am Soc Clin Oncol 1998;17,390a. Abstract

Henderson IC, Gelman RS, Harris JR, Canellos GP. Duration of therapy in adjuvant chemotherapy trials. NCI Monogr 1986;95-8. Abstract

Hortobagyi GN. High-dose chemotherapy for primary breast cancer: facts versus anecdotes. J Clin Oncol 1999;17:25-9.

Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17:460-9. Abstract

Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, 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. [National Cancer Institute of Canada Clinical Trials Group.] J Clin Oncol 1998;16:2651-8. Abstract

Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361-70. Abstract

Perloff M, Norton L, Korzun AH, Wood WC, Carey RW, Gottlieb A, et al. Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study. J Clin Oncol 1996;14:1589-98. Abstract

Rahman ZU, Hortobagyi GN, Buzdar AU, Champlin R. High-dose chemotherapy with autologous stem cell support in patients with breast cancer. Cancer Treat Rev 1998;24:249-63.

Ravdin PM, Green S, Albain KS, Boucher V, Ingle J, Pritchard K, et al. Initial report of the SWOG biological correlative study of C-erbB-2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with tamoxifen alone. Proc Am Soc Clin Oncol 1998;17:374. Abstract

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