Elsevier

The Lancet

Volume 352, Issue 9132, 19 September 1998, Pages 930-942
The Lancet

Articles
Polychemotherapy for early breast cancer: an overview of the randomised trials*

https://doi.org/10.1016/S0140-6736(98)03301-7Get rights and content

Summary

Background

There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented.

Methods

In 1995, information was sought on each woman in any randomised trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. Analyses involved about 18 000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil).

Findings

For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p<0·00001) and among those aged 50–69 (20% [SD 3] reduction; 2p<0·00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p<0·00001) and among those aged 50–69 (11% [SD 3] reduction; 2p=0·0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50–69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0·05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0·89 [SD 0·09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3–6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0·006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0·02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available.

Interpretation

Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7–11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2–3% for those aged 50–69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated.

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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