A meta-analysis of 123 randomised trials involving some 100,000 women with breast cancer over the past 40 years shows that, in a wide range of patients, modern chemotherapy regimens reduce breast cancer mortality by around one third compared with no chemotherapy. The findings appear in an article published Online First, and in an upcoming Lancet, by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) at the Clinical Trial Service Unit, University of Oxford, UK.
The researchers studied the trials of various older chemotherapy regimens, finding that standard 1980s chemotherapy regimens could produce a reduction of almost a quarter in breast cancer mortality. They also studied recent trials of more modern regimens versus these older regimens, finding a further reduction of about one-sixth in breast cancer mortality. They conclude that, compared with no chemotherapy, modern regimens reduce breast cancer mortality rates by about a third in a wide range of patients.
Among the best of the older chemotherapy regimens were standard CMF and standard 4AC. These two 1980s regimens were roughly equivalent to each other, reducing annual breast cancer mortality rates by 20-25%. Other regimens with lower doses of chemotherapy were somewhat less effective, whereas modern regimens with substantially more chemotherapy than standard 4AC (but which were not so intensive as to require stem-cell rescue) were somewhat more effective. The modern regimens tested in these trials included some that just had higher cumulative dosage (eg, CAF or CEF) and some that consisted of an older regimen plus a taxane (see note below).
The reduction of one-third in breast cancer mortality appeared to apply to all women, irrespective of age (although few in these trials were over 70 years old), of how big the tumour was, of whether it had started to spread to the local lymph nodes and of whether or not it was oestrogen-receptor (ER)-positive.
The risk of an ER-positive breast cancer causing death can be reduced substantially by 5 years of endocrine therapy, which is generally much less toxic than chemotherapy. The present results showed, however, that in ER-positive disease chemotherapy plus endocrine therapy was more effective than endocrine therapy alone. The absolute gain from a one-third breast cancer mortality reduction depends on the absolute risk without chemotherapy (which, for ER-positive disease, is the risk remaining with appropriate endocrine therapy).
Sir Richard Peto, one of the leaders of this worldwide collaboration, said "Most breast cancers are ER-positive, and for ER-positive disease that appears to have been completely removed by surgery the 10-year risk of recurrence and death from breast cancer can be reduced by at least half by giving a few months of modern chemotherapy plus 5 years of endocrine therapy."
All of these chemotherapy regimens can have severe side-effects while they are being given and can sometimes cause permanent damage, so they are given only if there would be a substantial risk of the cancer recurring without them. Tumour characteristics such as size and invasiveness can help predict the risk of recurrence without chemotherapy, and hence can help predict the absolute gain from a one-third reduction in that risk. Otherwise, however, the characteristics recorded in these trials could not predict sensitivity to chemotherapy.
In a linked Comment, Dr Carlo Palmieri, Division of Cancer, Imperial College London, UK, and Dr Alison Jones, Department of Medical Oncology, University College Hospital, London, UK conclude: "The EBCTCG meta-analyses continue to show that polychemotherapy saves lives (and that it can, on average, reduce breast cancer mortality by about a third). Clearly, the actual benefit and harm of polychemotherapy will be determined by the individual future risk of relapse and coexisting comorbidities. The challenge now is not only to save more lives, but to reduce the number of women given polychemotherapy unecessarily. It is with such hope that the results of ongoing oncomolecular trials are awaited. We look forward to the day when treatment of fewer women with a personalised approach achieves more."
Professor Sir Richard Peto, for the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), University of Oxford Clinical Trial Service Unit (CTSU), UK. T) 44-777-196-0329 E) RPeto@CTSU.ox.ac.uk
Dr Carlo Palmieri, Division of Cancer, Imperial College London, UK. T) 44-7787-505098 E) c.palmieri@imperial.ac.uk
Note for editors: The letters refer to the names of the cytotoxic drugs used in these regimens: C=cyclophosphamide, M=methotrexate, F=fluorouracil, A=doxorubicin, E=epirubicin. Taxanes were originally extracted from Pacific yew tree bark, but are now synthetic. The other cytotoxic drugs have been widely used for decades to treat various types of cancer.
Journal
The Lancet