27
oestrogen-receptor poor. Among younger women the effects of tamoxifen are less definite, but both ovarian ablation and cytotoxic chemotherapy lengthen survival, and these benefits are likewise discernible in several clinicopathological subgroups. How then should adjuvant systemic therapy be used in early breast cancer? The 10-year data suggest that the smaller the risk of relapse for the individual patient, the smaller will be the absolute benefit of adjuvant therapy and so the greater will be the relative importance of any toxic side-effects of that therapy. With this principle in mind, some simple guidelines might emerge. For example, a premenopausal woman judged to have a poor prognosis, either because of nodal status or because of biological variables decoded from the primary tumour, would benefit from at least six cycles of polychemotherapy or some form of ovarian ablation; whereas in a premenopausal woman with a very good prognosis the side-effects of these treatments might not be justified. In postmenopausal women, "hormonal therapy" has low toxicity and high efficacy, so even in a woman who has a good prognosis one might consider adjuvant tamoxifen for
or
EDITORIALS
2
Adjuvant systemic therapy for early breast cancer From a remarkable worldwide collaboration between 133 randomised trials involving 75 000 women with early breast cancer, clear evidence emerges that adjuvant therapy can enhance 10-year survival. The improvements recorded in this overview (split between this week’s issue and the next) are not large-about a dozen extra 10-year survivors for every 100 women with stage II disease, and about another dozen for every 200 women with stage I-but every decade millions of women are treated for early breast cancer, and for every 1 million such women improvements like these could result in an extra 100 000 10-year survivors. About a third of this benefit may be ascribed to the judicious use of polychemotherapy, yet the remainder can be obtained just by "hormonal therapy" (with some years of tamoxifen or, for younger women, with ovarian ablation). It was already known that these treatments led to a small but definite improvement in 5-year survival;l what is new is the demonstration that they provide a larger difference in 10-year survival. About 4 in every 5 new patients with breast cancer are aged 50 or more, and among such women tamoxifen has little toxicity and defmite benefits. The choice of which of these women to treat is made easier by the fact that the effects of tamoxifen on survival are to be seen in women of different ages (50-59, 60-69, or 70 + ), and different stages of disease (I or II), whether receiving concurrent chemotherapy or not, whether
premenopausal or postmenopausal, and, remarkably, whether their tumours are oestrogen-receptor positive
or more
years.
These are the simple conclusions one can draw from the results. The overview process, however, threw up some less predictable findings. For example, in postmenopausal women it is commonly supposed that if the oestrogen receptor protein is not detectable in the primary tumour then any adjuvant therapy should consist only of chemotherapy rather than of tamoxifen. It turns out that these treatments are of approximately the same efficacy for such "ERnegative" postmenopausal women, so if only one is to be given tamoxifen might be preferred. Furthermore, in premenopausal women the studies of tamoxifen in the absence of chemotherapy show distinct risk reductions, even though tamoxifen induces very high levels of unopposed oestradiol.Another intriguing observation is that, on long-term follow-up, ovarian ablation shows an advantage of the same order as that achieved by polychemotherapy-further evidence for the notion3that chemotherapy in premenopausal women acts largely via chemical castration (the subject of a further editorial next week). The finding that the benefits of hormonal adjuvant therapy and, still more so, of cytotoxic adjuvant therapy improve with time must have surprised the collaborating trialists whose ideas were based on conventional biological models. So, the world overview has done more than show us that adjuvant treatment improves 10-year survival, it has also suggested directions for the next generation of trials. Early Breast Cancer Trialists’ Collaborative Group. Treatment of early breast cancer. Vol 1: worldwide experience 1985-1990. Oxford: Oxford University Press, 1990. 2. Sunderland MC, Osbourne CK. Tamoxifen in premenopausal patients 1.
with metastatic breast cancer: a review. Clin Oncol 1991; 9: 1283-97. 3. Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhoea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 1991; 63: 799-803.
oestrogen-receptor poor. Among younger women the effects of tamoxifen are less definite, but both ovarian ablation and cytotoxic chemotherapy lengthen survival, and these benefits are likewise discernible in several clinicopathological subgroups. How then should adjuvant systemic therapy be used in early breast cancer? The 10-year data suggest that the smaller the risk of relapse for the individual patient, the smaller will be the absolute benefit of adjuvant therapy and so the greater will be the relative importance of any toxic side-effects of that therapy. With this principle in mind, some simple guidelines might emerge. For example, a premenopausal woman judged to have a poor prognosis, either because of nodal status or because of biological variables decoded from the primary tumour, would benefit from at least six cycles of polychemotherapy or some form of ovarian ablation; whereas in a premenopausal woman with a very good prognosis the side-effects of these treatments might not be justified. In postmenopausal women, "hormonal therapy" has low toxicity and high efficacy, so even in a woman who has a good prognosis one might consider adjuvant tamoxifen for
or
EDITORIALS
2
Adjuvant systemic therapy for early breast cancer From a remarkable worldwide collaboration between 133 randomised trials involving 75 000 women with early breast cancer, clear evidence emerges that adjuvant therapy can enhance 10-year survival. The improvements recorded in this overview (split between this week’s issue and the next) are not large-about a dozen extra 10-year survivors for every 100 women with stage II disease, and about another dozen for every 200 women with stage I-but every decade millions of women are treated for early breast cancer, and for every 1 million such women improvements like these could result in an extra 100 000 10-year survivors. About a third of this benefit may be ascribed to the judicious use of polychemotherapy, yet the remainder can be obtained just by "hormonal therapy" (with some years of tamoxifen or, for younger women, with ovarian ablation). It was already known that these treatments led to a small but definite improvement in 5-year survival;l what is new is the demonstration that they provide a larger difference in 10-year survival. About 4 in every 5 new patients with breast cancer are aged 50 or more, and among such women tamoxifen has little toxicity and defmite benefits. The choice of which of these women to treat is made easier by the fact that the effects of tamoxifen on survival are to be seen in women of different ages (50-59, 60-69, or 70 + ), and different stages of disease (I or II), whether receiving concurrent chemotherapy or not, whether
premenopausal or postmenopausal, and, remarkably, whether their tumours are oestrogen-receptor positive
or more
years.
These are the simple conclusions one can draw from the results. The overview process, however, threw up some less predictable findings. For example, in postmenopausal women it is commonly supposed that if the oestrogen receptor protein is not detectable in the primary tumour then any adjuvant therapy should consist only of chemotherapy rather than of tamoxifen. It turns out that these treatments are of approximately the same efficacy for such "ERnegative" postmenopausal women, so if only one is to be given tamoxifen might be preferred. Furthermore, in premenopausal women the studies of tamoxifen in the absence of chemotherapy show distinct risk reductions, even though tamoxifen induces very high levels of unopposed oestradiol.Another intriguing observation is that, on long-term follow-up, ovarian ablation shows an advantage of the same order as that achieved by polychemotherapy-further evidence for the notion3that chemotherapy in premenopausal women acts largely via chemical castration (the subject of a further editorial next week). The finding that the benefits of hormonal adjuvant therapy and, still more so, of cytotoxic adjuvant therapy improve with time must have surprised the collaborating trialists whose ideas were based on conventional biological models. So, the world overview has done more than show us that adjuvant treatment improves 10-year survival, it has also suggested directions for the next generation of trials. Early Breast Cancer Trialists’ Collaborative Group. Treatment of early breast cancer. Vol 1: worldwide experience 1985-1990. Oxford: Oxford University Press, 1990. 2. Sunderland MC, Osbourne CK. Tamoxifen in premenopausal patients 1.
with metastatic breast cancer: a review. Clin Oncol 1991; 9: 1283-97. 3. Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhoea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 1991; 63: 799-803.
