Reduction in new metastases in breast cancer with adjuvant clodronate treatment
CommentIn this study, clodronate was administered orally for two years to patients with breast cancer, without evidence of metastatic disease but with tumor cells found on bone marrow biopsy. During a mean follow-up of 36 months, there was a significant decrease in the incidence of new bony metastases and an increase in the time to appearance of this complication. Surprisingly, a similar effect was noted on visceral metastases and on overall survival.
Complications from breast cancer can occur many years later. Thus, as the authors point out, it is impossible to tell whether their results indicate definitive prevention of metastasis and death for some women, or a delay in the occurrence of these events. Looking at the shape of the Kaplan-Meier curves in the article, one has the impression that the divergence is due to a delay in the occurrence of events. However, even if cure is preferable to delay, a significant delay is much better than no delay.
It is surprising that this trial was randomized but not blinded or placebo-controlled. It is not stated that the radiologists who interpreted the bone scans were blinded to the treatment assignment. This in troduces some concern about observer bias in interepretation of results and symptoms, when patients came for follow-up.
There is another aspect of the study design that I find troubling. In order to participate, women had to undergo an iliac-crest bone-marrow aspirate. It is specifically stated that adjuvant chemotherapy decisions did not take into account the results of the bone-marrow biopsy. Thus, it would seem that those women who were randomized to the control group received no benefit from this procedure and the information it provided. This is particularly troubling since the presence of tumor cells in the bone marrow indicates a worse prognosis and thus might justify a more aggressive adjuvant therapy approach. Despite the presence of tumor cells in the marrow, 19% of the women received no adjuvant therapy at all, including tamoxifen. Would more aggressive adjuvant therapy in all patients have diminished the magnitude of clodronate's effect seen in this study? Unfortunately, the authors do not give any data on the effect of clodronate therapy in the various subgroups of adjuvant therapy.
Finally, since all patients in this study had documented tumor cells in the bone marrow, it is not clear how the results would apply to large proportion of women (up to 70% of those with negative axillary nodes) who do not have tumor cells in their marrow.
These objections aside, the role of bisphosphonates in the treatment of breast cancer is likely to increase, with many questions that remain to be answered concerning the effectiveness of various agents, their combination with other therapies and the appropriate target populations.
September 4, 1998
ReferencesReferences related to this article from the NLM's PubMed database.
to the editor about this article, from the New England Journal of Medicine.