ArticlesPolychemotherapy for early breast cancer: an overview of the randomised trials*
Introduction
In women with “early” breast cancer, all detectable cancer is, by definition, restricted to the breast (and, in women with node-positive disease, the local lymph nodes) and it can be removed surgically. However, undetected micrometastatic deposits of the disease may remain and subsequently, perhaps after a delay of several years, develop into a clinically detectable recurrence that eventually causes death. Previous systematic overviews (meta-analyses) of the randomised trials showed that some months of adjuvant chemotherapy with two or more cytotoxic drugs (polychemotherapy) can improve 10-year survival for some such women.1, 2, 3 But uncertainty has remained about which women derive most benefit and which regimens are most effective. This overview addresses these questions by updating the randomised evidence on recurrence and survival, including data from new trials and additional follow-up from trials that were already included in the previous overviews.
Section snippets
Methods
Every 5 years since 1984–85, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has undertaken systematic overviews of all randomised trials of any aspect of the treatment of early breast cancer.1, 2, 3, 4, 5, 6 This paper is based on data that were collected and finalised in 1995–97. The trial identification and data-checking procedures have been described previously.1, 2, 3, 4, 5, 6 For the analyses presented here, data were sought for all randomised trials that began before 1990
Results
The general structure of Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 is similar: the left-hand side describes recurrence and the right-hand side describes mortality. In Figure 3, Figure 4, Figure 5, Figure 8, the upper and lower parts describe the results separately for women aged under 50 and 50–69 when randomised (excluding the relatively small numbers, only about 600, aged 70 or over); other figures include women of any age.
Discussion
This collaboration has now continued for over 10 years, accumulating more randomised evidence on the effects of chemotherapy than is available for the treatment of any other type of cancer patient, and these updated results for polychemotherapy are essentially complete, at least for the mature trials (see Methods). What is new is the widening range of women for whom some months of polychemotherapy is now known to be protective, including not only women aged under 50 but also those aged 50–69 (
Age
With the longer follow-up and larger numbers of events now available for review, it is clear that polychemotherapy has an effect on recurrence and on long-term survival not only in women aged under 50 but also in those aged 50–59 and 60–69 (figure 2). Hence, the present results indicate that, at least up to the age of 70, being over 50 should not be a barrier to the use of adjuvant polychemotherapy in those women who would otherwise be at substantial risk of recurrence. Too few women aged 70 or
Nodal status
Both for recurrence and for mortality, the proportional risk reductions with polychemotherapy appeared (after standardisation for age and time since randomisation) to be about the same for women with node-negative disease as for those with node-positive disease. At least in terms of 10-year outcome, the same proportional benefit for node-negative as for node-positive disease would generally imply a greater absolute benefit for the latter. Figure 8 illustrates this by applying the overall
Addition of polychemotherapy to tamoxifen
Irrespective of whether there were greater or lesser effects of cytotoxic chemotherapy in the trials of polychemotherapy plus tamoxifen versus tamoxifen alone than in the trials of polychemotherapy on its own, the addition of chemotherapy to tamoxifen certainly produced some additional benefits. Similarly, tamoxifen has been shown to add to the benefits of chemotherapy.6 Certain forms of chemotherapy might be expected to be more effective in the absence of a drug, such as tamoxifen, that slows
Different polychemotherapy regimens
Indirect comparisons of the reductions in recurrence and in mortality produced by different polychemotherapy regimens did not indicate that any particular regimen was more or less effective than any other, either overall (subtotals of figure 1) or separately among women aged under 50 or 50–69 at entry (figure 5). These indirect comparisons are based on large numbers of events (and, hence, involve only small random errors), but they may be affected by systematic differences in the patient
Conclusions
The proportional benefits of polychemotherapy appeared to be largely unaffected by menopausal status, nodal status, or tamoxifen use—and, even though the proportional effect diminished with increasing age, there was clear evidence of benefit not just for women aged under 50 at the start of treatment but also for those aged 50–69 (with insufficient evidence among women aged 70 or over). The proportional mortality reductions among women aged 50–69 appeared, however, to be only about one-third as
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