Reduced recurrence-free survival after reduced doses of adjuvant chemotherapy in breast cancer: Are groups selected after randomization comparable?
In a recent issue Bonadonna et al. presented a summary of their results with adjuvant chemotherapy of breast cancer (1). The retrospective analysis of dose-response based on ten-year results confirmed previous findings which had suggested that reduced doses of chemotherapy were associated with higher likelihood of recurrence compared to 'optimal doses' (2). This hypothesis has been criticized from various aspects and methodologic problems were recently discussed (3). On the other hand, the concept of a dose-related response is attractive and fits theoretical and experimental models (4). One major question, however, is whether groups that are selected by a post-randomization differentiation by doses of chemotherapy are equivalent to each other and to non-treated patients in relevant aspects. We have analyzed interim results of an on-going trial of adjuvant chemotherapy in breast cancer in Stockholm. A total of 242 patients were eligible for the current analysis. They had been randomised to chemotherapy which was similar to that of the Milan trial (1). Like Bonadonna et al., we found a better recurrence-free survival for patients who had received >84 per cent of the planned dose compared to those who had tolerated <65 per cent of that dose. These percentages were calculated as the ratio of the total dose received to the maximum protocol dose possible prior to treatment failure or death. The doses were mainly reduced due to low WBC or platelet counts. Interestingly, we found that there was a significant correlation between the doses of chemotherapy and the initial WBC (r = 0.29, P<0.001) and platelet count ( r=0 .23 , P<0.01), i.e. the counts before any drug was given. The table gives the mean values of the blood counts by level of dose of chemotherapy in 153 patients who received the planned 12 courses. There is no indication that the blood cell counts are related to prognosis and, even though statistically significant, the correlation coefficients were both small. Despite these circumstances, our findings show that the groups of patients that were distinguished after randomization by the dose of chemotherapy, differed at least in one respect. This, of course, does not rule out the possibility of a dose-related response. It only points to the difficulties in proving this in a retrospective analysis of a prospective trial.