A Randomized Clinical Trial Evaluating Sequential Methotrexate and Fluorouracil in the Treatment of Patients with Node-Negative Breast Cancer Who Have Estrogen-Receptor-Negative Tumors

Abstract

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

The association between population-based treatment guidelines and adjuvant therapy for node-negative breast cancer

“…Because benefits have been modest with respect to both recurrence rates and survival, and both chemotherapy and tamoxifen have associated toxicities, it has been suggested that adjuvant systemic therapy be restricted to women with NNBC who, by virtue of the presence of adverse clinical and pathological features, have a moderate or high risk of recurrence (Scottish Cancer Trials Office, 1987; CRC Adjuvant Breast Trial Working Party, 1988;Fisher et al, 1988Fisher et al, , 1989aLudwig Breast Cancer Study Group, 1989;McGuire, 1989;Mansour et al, 1989;McGuire et al, 1992;Early Breast Cancer Trialists' Collaborative Group, 1992). Several treatment guidelines for adjuvant systemic therapy for NNBC have been developed and distributed, but the actual impact of these guidelines on consistency of care is uncertain.…”

Epidermal growth factor receptor (EGFr); results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup

“…Tumour recurrence and death due to breast cancer, however, affects a significant proportion of patients with node-negative disease (Fisher et al, 1989c). Recurrence rates of up to 43% and mortality at 10 years of 32% have been reported (Fisher et al, 1989b), suggesting a need for effective adjuvant systemic therapy for selected patients in this supposedly good prognostic subgroup.It is now recognised that there is a need for a marker (or markers) capable of discriminating patients with axillary node-negative disease at high risk of recurrence and death. Tumour oestrogen receptor (ER) content has been proposed but there is disagreement about its value (Cooke et al, 1979;Fisher et al, 1988 Valagussa, 1987).…”

“…Tumour recurrence and death due to breast cancer, however, affects a significant proportion of patients with node-negative disease (Fisher et al, 1989c). Recurrence rates of up to 43% and mortality at 10 years of 32% have been reported (Fisher et al, 1989b), suggesting a need for effective adjuvant systemic therapy for selected patients in this supposedly good prognostic subgroup.…”

West Midlands Oncology Association trials of adjuvant chemotherapy in operable breast cancer: results after a median follow-up of 7 years. II. Patients without involved axillary lymph nodes

“…Patients were asked how long they were unwell, how long they were unable to go to work (or perform housework) and how long they were confined to bed if they The results of other trials comparing the use of prolonged combination chemotherapy with a no treatment control arm in node negative patients are shown in Table V (Koyama et al, 1980;Senn et al, 1986;Semiglazov et al, 1986;Jakesz et al, 1987;Ludwig Breast Cancer Study Group, 1989;Espie et al, 1987;Bonadonna et al, 1987;Williams et al, 1987;Mansour et al, 1989;Fisher et al, 1989). In most, low dose oral or intravenous treatments have been studied in node (Jakesz, 1987), there have been no reported improvements in survival in this type of study, which is not surprising in view of the small absolute improvement possible in this good prognosis group and the small sample sizes.…”

“…These studies have all demonstrated highly significant improvements in relapse free survival. In the NSAPB study (Fisher et al, 1989), 741 node negative, ER negative patients…”