One of the most important developments in the history of solid tumor treatment is the use of systemic adjuvant therapy following local management of breast cancer. More than 25% of women who would otherwise die of metastatic disease remain free of disease when treated with the appropriate adjuvant therapy. Studies from all over the world have contributed to the knowledge that forms the basis for treatment recommendations. One of the major contributors has been the National Surgical Adjuvant Breast and Bowel Project (NSABP) under the leadership of Bernard Fisher. In a series of carefully designed and executed studies, NSABP has defined what types of therapy are effective and in what settings. Their recent report of their 20th large, multicenter, randomized breast cancer study broadens the indications for adjuvant chemotherapy and raises some important questions about standard management.
NSABP B-20 randomly assigned women with histologically negative axillary nodes and estrogen-receptor positive primary breast cancer to one of three treatment groups: tamoxifen alone (10 mg PO bid for 5 years), tamoxifen plus methotrexate (M) and 5-fluorouracil (F) (M, 100 mg/m2 IV; F, 600 mg/m2 both given by IV bolus on days 1 and 8 every 4 weeks for 6 cycles; F was given one hour after M, and leucovorin 15 mg/m2 was given orally q6h for six doses beginning 24 hours after M), or tamoxifen plus cyclophosphamide, methotrexate, and 5-fluorouracil (the standard Milan regimen of CMF was given; C, 100 mg/m2 orally days 1-14; M, 40 mg/m2 intravenously days 1 and 8; and F, 600 mg/m2 intravenously days 1 and 8CMF was given every 4 weeks for 6 cycles). Tamoxifen was started at the same time as the chemotherapy. Radiation therapy was administered to patients whose primary tumor was treated by lumpectomy after one course of therapy on the MF arm and within a week of the day eight drugs on the CMF arm.
A total of 2363 patients were randomly assigned to the three treatment groups following surgery. Patients were stratified according to age (< 50 vs ³ 50), tumor size (£ 2 cm, 2.1-5.0 cm, > 5 cm), and tumor estrogen receptor level (10-49, 50-99, or > 99 fmol/mg of cytosolic protein). Only 2.2% of randomly assigned patients were found to be ineligible for analysis usually either because of advanced disease at study entry or unacceptable delay in initiating adjuvant therapy after surgery. The median follow-up of patients was 6.5 years (range, 4-9 years). Only 6% of patients in the study were of African descent.
Patients on both arms that included combination chemotherapy had significantly improved disease-free survival, freedom from distant relapse, and overall survival compared to patients who received tamoxifen alone. Disease-free survival at five years was 85% for tamoxifen alone, 90% for MFT, and 89% for CMFT. Freedom from distant relapse at five years was 87% for tamoxifen alone, 92% for MFT, and 91% for CMFT. Overall survival at five years was 94% for tamoxifen alone, 97% for MFT, and 96% for CMFT. In all pairwise comparisons between the chemotherapy arms and tamoxifen alone, the chemotherapy-containing arms were significantly better. There were no significant differences between the two chemotherapy-containing arms. Significant reductions in local, regional, and distant recurrences were observed with both types of chemotherapy, but the reduction in local-regional recurrences was greater in the CMFT group. Addition of chemotherapy had no effect on risk of contralateral breast cancer, second primary tumors (not breast cancer), or deaths from causes other than breast cancer.
Analysis of the results according to patient age found that both chemotherapy regimens reduced the risk of relapse in both groups, but the benefit of the chemotherapy was greater in the group 49 years and younger. Those 49 years old and younger receiving MFT had a 46% reduction in risk of relapse compared to those receiving tamoxifen alone, and those receiving CMFT had a 44% reduction in risk of relapse. Risk of death was 50% lower in younger patients receiving MFT and was 28% lower in younger patients receiving CMFT. In patients older than 49 years, the benefit of adding chemotherapy to tamoxifen was not as great as in the younger group, and CMFT seemed relatively more effective than MFT, but not significantly so; MFT reduced relapse risk by 10%, and CMFT reduced relapse risk by 26% compared to tamoxifen alone in the group older than 49 years. Mortality in the older group was reduced 20% by MFT and 43% by CMFT. In all subgroup analyses performed, there was no subgroup of patients that failed to benefit from chemotherapy.
Toxic deaths occurred in 0.3% of patients on MFT and 0.1% of patients on CMFT; grade 3 or 4 toxicity was noted in 17% of patients on MFT and 25% of patients on CMFT. However, 90% of patients assigned to MFT and 85% of patients assigned to CMFT received all six courses of adjuvant therapy. (Fisher B, et al. J Natl Cancer Inst 1997;89:1673-1682.)
COMMENTARY
Treatment recommendations for adjuvant therapy of breast cancer have been controversial, though meta-analysis and consensus conferences have helped to minimize the discord. In general, younger women have been noted to benefit more from adjuvant chemotherapy than older women, and older women have been noted to benefit more from tamoxifen than younger women. Thus, estrogen receptor status has been important in older women; older women with node-negative estrogen receptor-positive breast cancer often receive tamoxifen alone, and those with node-negative estrogen receptor-negative may or may not receive any adjuvant therapy but certainly do not usually receive tamoxifen. Older patients with node-positive disease receive adjuvant therapy based on their estrogen receptor status; estrogen receptor-positive tumors lead to tamoxifen therapy with or without chemotherapy depending on the extent of node involvement, and estrogen receptor-negative tumors lead to chemotherapy alone. In younger patients, the role of tamoxifen adjuvant therapy has not been clear.
In 1982, NSABP began a clinical trial (B-14) in which patients with node-negative estrogen receptor-positive tumors were randomly assigned to receive tamoxifen or no therapy. Analysis of B-14 in 1988 (published in 1989) showed a significant reduction in relapse rates on the tamoxifen arm, but the survival benefit was not significant.1 The NSABP investigators wondered whether the benefits associated with tamoxifen might be improved by the addition of chemotherapy, and they began B-20 to address this question. The result of the study, after more than six years of follow-up, is that chemotherapy added to tamoxifen improves disease-free survival about 5% and overall survival about 3%. A 1990 meta-analysis of 133 randomized trials undertaken by the Early Breast Cancer Trialists’ Collaborative Group reached similar conclusions based upon indirect comparisons of tamoxifen alone and tamoxifen plus chemotherapy.2 Importantly, B-20 suggests that in addition to its value in premenopausal women with node-positive or node-negative disease and postmenopausal women with multiple positive nodes, combination chemotherapy added to tamoxifen appears to benefit postmenopausal women with node-negative disease.
Who does that leave who should not receive adjuvant chemotherapy or chemohormonal therapy? Patients with noninvasive cancers and those with very small primary tumors detected by mammography are the only ones in whom no benefit from adjuvant therapy has been shown. Yet, it must be acknowledged that the level of benefit is "significant" but small. Many women will be treated to benefit very few. Is the benefit worth the cost? Certainly women with breast cancer generally think so. Slevin and colleagues noted that most patients with breast cancer would accept transient, severe toxicity in order to achieve as little as a 1% increase in survival.3 What will managed care companies conclude?
It is not completely clear that the cost of caring for breast cancer patients will increase as a consequence of the more widespread use of adjuvant combination chemotherapy. Why not? Well, given that nearly all subgroups of patients now appear to benefit from adjuvant therapy, what exactly is the rationale for axillary lymph node dissection? We know that axillary dissection does not have any therapeutic benefit based on a prior NSABP study (B-04).4 More conservative primary surgery (lumpectomy) is generally given with radiation therapy to the primary site and the axilla. In the absence of palpable axillary adenopathy, it is not clear whether axillary dissection should continue to be a required component of definitive therapy.
Where do we go from here? It would be of interest to see whether other chemotherapy regimens would be more effective than MF and CMF. It is interesting to consider whether neoadjuvant therapy (i.e., delivery of chemotherapy before definitive surgery) might increase the number of women whose tumors could be adequately managed by breast-conserving surgery. Furthermore, tumors that respond to neoadjuvant chemotherapy by shrinkage may be more likely to respond to adjuvant chemotherapy as well. A critical goal of future work is to attempt to identify in advance those patients who are cured with their local therapy and to use biologic and molecular features of tumors in individual patients to assess prospectively which patients might be expected to benefit most from systemic therapy.
References
1. Fisher B, et al. N Engl J Med 1989;320:479-484.
2. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1992;339:1-15.
3. Slevin ML, et al. Br Med J 1990;300:1458-1460.
4. Fisher B, et al. N Engl J Med 1985;312:674-681.
A 45-year-old woman presents with a 2 cm primary breast cancer that is estrogen receptor-positive. Axillary dissection reveals no tumor involving lymph nodes. What, if any, adjuvant therapy is indicated?
a. None
b. Adjuvant tamoxifen for five years and six months of combination chemotherapy
c. Adjuvant tamoxifen for five years
d. Adjuvant tamoxifen for 10 years
e. Adjuvant combination chemotherapy alone for six months