At first glance, high-dose chemotherapy for breast cancer makes sense. The disease is often sensitive to chemotherapy, potentially curable, and highly prevalent, which means that even a modest benefit would be tremendously important. Unfortunately, multiple clinical trials have failed to demonstrate that high-dose therapy is more effective than other chemotherapeutic approaches. Thus far, no prospective study has demonstrated a benefit based on its planned primary objective and planned analysis, and none has shown a survival advantage (see Table 1).[1-5]
Hence, the studies to date would be best used for hypothesis generation and not for guidance in treating patients. On the other hand, this does not mean that high-dose therapy could never be superior or that it could not be superior in a selected cohort of patients. It does mean, however, that one should be careful and conservative with regard to the further use and study of this technique. Treatment outside of appropriate prospective studies cannot be supported, and studies should be limited.
It is instructive to compare our view of chemotherapy with our view of surgery earlier in the past century. There are remarkable parallels in our thinking on these two topics over time. "More" treatmentmeaning more extensive surgerywas presumed to be better than "less" treatment, and some surgeons perfected and popularized extended radical mastectomies with seemingly better outcomes compared to their own and contemporaneous nonrandomized controls.
Later, multiple randomized trials finally convinced practitioners that this widely accepted concept was incorrect and that as many patients could be cured with "lesser" surgery as with the more extensive procedures. This paved the way for the broad use of breast-conserving surgery, which may be appropriate for the vast majority of patients with early-stage disease. Yet, there are selected patients for whom mastectomy is still recommended, so we are not yet convinced that breast conservation is always the appropriate option.
Almost the same story could be told regarding high-dose therapy. Knowing that chemotherapy is effective, many of us were motivated to develop high-dose regimens based on the hypothesis that "more" would be better. Remarkable and important advances in supportive care resulted from the high-dose experience with significant collateral benefit. But as with more extensive surgery, we later showed that it was not clearly superior and, indeed, offers no advantages in the majority of patients.
Perhaps the two stories now diverge in that we do not yet have any useful way to predict which subset of patients might benefit from higher-than-standard-dose treatment, just as we have no reliable way to predict which patients do not need systemic chemotherapy at all. In contrast, we continue to rationally select some patients for mastectomy instead of breast conservation. This is where our efforts concerning high-dose therapy should be focused.