1998 Guideline
A draft of the practice guideline report was discussed at the Breast Cancer Disease Site Group (DSG) meeting in April 1997. Feedback, particularly in two areas (i.e., definition of histologic grade and inclusion of lymphatic/vascular invasion as a poor prognostic factor) led to changes in the report. The report was discussed again at a DSG meeting in November 1997 and approved, on condition that minor refinements in the wording of the treatment recommendations be made.
At the Breast Cancer Disease Site Group (DSG) meeting of April 1998, the results of the practitioner feedback survey were discussed and addressed in the practice guideline report. The results of the 1995 Early Breast Cancer Trialists' meta-analysis had become available and were discussed and incorporated into the guideline report.
Some members of the Site Group felt that the results of the MA.5 trial that established the superiority of cyclophosphamide, epirubicin, fluorouracil (CEF) over cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in premenopausal, node-positive patients could be extrapolated to node-negative women.
The use of the combination of chemotherapy and tamoxifen was discussed at length. The results of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 trial were reviewed, and their demonstration of the superiority of chemotherapy plus tamoxifen versus tamoxifen alone was found to be consistent with other trials. In the recently reported Intergroup study comparing tamoxifen with tamoxifen plus cyclophosphamide/doxorubicin/5-fluorouracil (CAF), in postmenopausal node-positive women the disease-free survival was 72% in the tamoxifen patients versus 79% in the CAFT patients (p=0.01). No difference was detected in survival. In the 1995 Early Breast Cancer Trialists' meta-analysis, the relative reduction in recurrence in the chemotherapy plus tamoxifen arm compared with tamoxifen alone was 19% (standard deviation [SD] 3) and for mortality 11% (SD 4) for women >50 years of age. The data for women <50years of age were 21% (SD 13) and 25% (SD 14), respectively. In summary, the evidence from the NSABP B-20 trial is consistent with the results of other studies comparing chemotherapy plus tamoxifen versus tamoxifen alone in patients with node-positive breast cancer.
The 1995 Early Breast Cancer Trialists' meta-analysis detected a relative reduction in recurrence of 54% (SD 8) in women >50 years of age who received chemotherapy plus tamoxifen compared with chemotherapy alone and a reduction in mortality of 49% (SD 10) in this age group. The relative reductions for women <50 years were 40% (SD 19) for recurrence and 39% (SD 22) for mortality. (Note: The number of women in this subgroup was relatively small.)
If one accepts that the inclusion of chemotherapy provides an additional benefit to tamoxifen alone, then the question is which chemotherapy to use? In the NSABP B-19 trial, pre- and postmenopausal estrogen-receptor-negative, node-negative patients were randomized to MF for six months versus CMF for six months. The five-year disease-free survival (DFS) rate was 73% for the methotrexate, fluorouracil (MF) patients versus 82% for the CMF patients (p<0.001). The five-year survival rate was 85% in the former group compared with 88% in the latter group (p=0.06). There was increased toxicity in patients who received CMF. It is interesting to note that in the B-19 trial CMF was superior to MF. In the B-20, trial there has been no difference detected yet between CMFT patients and MFT patients. Of importance is the fact that there were mostly premenopausal women in the B-19 trial, whereas the B-20 trial included many postmenopausal women. It is conceivable that in the older women the toxicity of oral cyclophosphamide resulted in lower drug absorption and consequently, reduced effect from the inclusion of cyclophosphamide in this regimen. In the NSABP B-15 trial, CMF was compared with adriamycin and cyclophosphamide (AC) in node-positive patients, and no difference was detected in disease-free survival.
The DSG addressed the question of whether chemotherapy should be added for tamoxifen-responsive patients, and if so, whether to all subgroups. The agreement was that there was still a low-risk group for whom no adjuvant therapy should be recommended (e.g., <2 cm, all prognostic factors favourable). However, these women should be made aware that systemic therapy is offered to women at higher risk of recurrence.
The addition of chemotherapy to tamoxifen for high risk (>3 cm, or grade III) estrogen-receptor-positive postmenopausal women was also agreed upon. (Note: Tamoxifen is considered standard therapy in this situation based on a large body of evidence in node-negative and node-positive disease from the Early Breast Cancer Trialists' meta-analysis.) Reasonable chemotherapy regimens in this situation are CMF or adriamycin/cyclophosphamide (AC). Although AC was found to be equivalent to CMF in node-positive patients, its use in node-negative disease is by extrapolation. These two regimens have different toxicity profiles; for example, AC is associated with complete alopecia in all patients versus 40% occurrence in CMF patients. MF was not favoured because of its observed inferiority in the NSABP B-19 trial.
The DSG agreed that in high risk (>3 cm, or grade III) estrogen-receptor-positive premenopausal women, chemotherapy would remain as the systemic adjuvant therapy of choice. There are insufficient data at the present time to recommend the addition of tamoxifen to chemotherapy in this subgroup. (The evidence from the Early Breast Cancer Trialists' meta-analysis is based on small numbers of patients and the results for survival are not statistically significant.) In addition, there is an ongoing clinical trial being conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) examining the additional benefit of tamoxifen after adjuvant chemotherapy in this subgroup of patients.
The DSG was less clear on what should be done with patients at moderate risk of recurrence. There was less enthusiasm for adding chemotherapy to tamoxifen for this group of patients compared to the high risk group. The moderate risk group would be an ideal group in which to evaluate a decision aid. If a decision board cannot be used, then tamoxifen should be recommended. However, these women should be made aware that chemotherapy plus tamoxifen is offered to women at higher risk of recurrence.
2003 Update
The information above remains current.
