Early Initiation of Adjuvant Chemotherapy for Premenopausal Breast Cancer

Abstract & Commentary

Synopsis: It appears that there is a survival advantage for premenopausal patients who have ER-negative tumors if they were treated within 21 days of initial surgery, compared to those in whom adjuvant chemotherapy was started later (i.e., after 21 days).

Source: Colleoni M, et al. J Clin Oncol 2000;18:584.

The initiation of adjuvant breast cancer chemotherapy varies for a number of factors and it had not been clearly demonstrated that earlier treatment is beneficial. This question was addressed by the International (Ludwig) Breast Cancer Study Group (IBCSG). Using data from trial V at a median follow-up of 11 years, there was a suggestion that earlier treatment was associated with better outcomes. Thus, a larger analysis was undertaken.

The experience of node-positive, premenopausal patients (n = 1788) treated on IBCSG trials I, II, and VI was examined to address the relationship between early initiation of adjuvant chemotherapy, estrogen receptor (ER) status, and prognosis. The disease-free survival for 599 patients (84 ER-negative) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for the remainder of the group (1189 patients, 142 of which were ER- negative) who started their chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years.

Among those with ER-negative tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group. This difference was statistically significant and remained so after multiple regression analysis which factored out the influence of number of positive nodes, tumor size, patient age, vessel invasion, or treating center. Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with ER-positive tumors.

COMMENT by William B. Ershler, MD

Although it makes sense that early therapy is prudent, published experience from large trials has been inconclusive. There have been a few trials that would suggest that early intervention with adjuvant chemotherapy was beneficial.1,2 The experience from the National Surgical Adjuvant Breast and Bowel Project (NSABP), particularly Trial B-18, would seem to be in conflict. However, the current examination revealed a survival benefit only for a distinct subgroup, those premenopausal patients who were ER-negative. The NSABP trial, which demonstrated comparable survival for patients who received preoperative or postoperative chemotherapy, did not report the data in terms of ER status.3

Perioperative chemotherapy has been shown to benefit some subgroups of patients, and it might be these same subgroups that would benefit from early adjuvant therapy. A recent meta-analysis of published reports on perioperative chemotherapy indicated that this approach reduced the risk of relapse by 17% for women less than 50 years of age.4 Here too, the ER status was not reported. Yet, there has been at least one study that showed that the subgroup most positively influenced by perioperative therapy was the ER-negative group.5

A theoretical rationale for early intervention can be derived from animal models in which surgical excision of primary tumors results in an increased growth fraction and angiogenesis in metastatic lesions.5,6 Thus, shortly after surgery, metastatic cells might be more susceptible to cycle-specific chemotherapy or even anti-angiogenic agents.

This was a retrospective examination and all the caveats regarding overinterpretation of such are in effect. Nonetheless, the finding of enhanced survival in those ER-negative, premenopausal, early-treated patients was quite robust, and the analysis was appropriately balanced with regard to other prognostic factors. The conclusion that early adjuvant therapy is likely to benefit this group is probably correct, but a prospective study would likely settle the issue.

References

1. Brooks RJ, et al. Proc Am Soc Clin Oncol 1983;2:110.

2. Pronzato P, et al. Am J Clin Oncol 1989;12:481-485.

3. Fisher B, et al. J Clin Oncol 1998;16:2672-2685.

4. Fisher B, et al. Cancer Res 1983;43:1488-1492.

5. Folkman J. J Natl Cancer Inst 1990;82:4-6.

Which of the following statements about the initiation of adjuvant chemotherapy for breast cancer patients is true?

a. Early treatment (within three weeks of surgery) has been shown to improve survival for all patients, regardless of nodal status, ER status, age, or tumor size.

b. Early treatment (within three weeks of surgery) has been shown to improve survival for premenopausal ER-positive patients regardless of nodal status or tumor size.

c. Early treatment (within three weeks of surgery) has been shown to improve survival for premenopausal ER-negative patients regardless of nodal status or tumor size.

d. Early treatment has not been associated with any demonstrable survival advantage when issues such as tumor size, nodal status, age, and comorbidities are controlled.