Problems associated with randomized controlled clinical trials in breast cancer

The domination of the randomized controlled clinical trial in clinical research in breast cancer is questioned in the context of adjuvant therapy. The criteria for selection of cases by TNM classification are shown to be poorly related to tumour behaviour. The factors that determine outcome--the presence or absence of metastases, their size at the time of presentation of the primary cancer and their growth rate--are not measured. Metastases cannot be detected at sizes below about 10 mm in diameter. This represents about 30 doublings of volume or three-quarters of the life span of the tumour. There is no identifiable starting point for a trial. It is possible to estimate growth rates from the rates of shrinkage in response to primary medical treatment. Modelling of the times at which metastases may appear in the clinic from different possible starting sizes reveals that the usual end points of time from primary diagnosis to metastasis or death have an enormous intrinsic variability. Treatment is merely another confounding variable. The randomized controlled clinical trial is shown to be a poor tool for the investigation of adjuvant treatments. An alternative approach, based upon observation of individual tumour response to primary medical treatment, is commended.