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Editorial

High dose, high risk? What updated evidence tells us about chemotherapy dosing in early breast cancer

Annabel Goodwin, Melina Willson, Nicholas Wilcken
Editorial Article

In the 1990s, chemotherapy was established as an effective therapy for early breast cancer, reducing recurrence rates and improving survival. Therefore, it was postulated that higher doses of treatment might be more effective. Indeed, uncontrolled studies of highly selected patients suggested that better rates of survival were achieved by giving doses of chemotherapy so high that bone marrow transplant or other forms of stem cell support were required. There was even a time when the commonest indication for bone marrow transplant in the USA was not leukaemia (where it cures disease) but breast cancer.[1] However, randomized trials were initiated, and we now have an updated systematic review of these trials with mature follow-up.[2]

This review has been updated with new data in the form of extended follow-up from the existing trials. The answer we have now could not be more definitive: there is high-quality evidence that high-dose chemotherapy does not improve survival in breast cancer. The effect sizes are remarkably consistent, the results statistically secure, and follow-up is now available for up to 12 years post-randomization. Increased doses of chemotherapy also carry an increased risk of toxicity, including treatment-related deaths: a lose-lose situation.

How did we come to believe that high-dose chemotherapy might work in the first place, and how can we explain why it doesn’t? The answer to the initial question is human nature. We wanted it to work; there were some preclinical data, and the early 'trials' we had suggested a very good outcome with a high-tech glamorous treatment. However, we simply failed to do due diligence. By definition, women fit enough to undergo high-dose treatment and bone marrow transplantation were very fit and likely to fare better in comparison to historical controls. It transpired that our optimism was based on results that proved too good to be true. Two of those early randomized trials were found to be fabrications of a fraudulent study investigator.[3]

The reasons why this approach doesn’t work must remain speculative. Presumably there is a proportion of cancer cells that remain intrinsically chemo-resistant no matter what the dose is. Additionally, the drugs traditionally used to achieve ablation of the bone marrow (cisplatin, carmustine, thiotepa, etoposide) are not frontline breast cancer drugs. Lastly these trials were done in an era before we understood how subtype-specific breast cancer can be: breast cancers that are sensitive to endocrine therapy or anti-HER2 therapy are lumped in together with tumours that lack hormone and other receptor overexpression. There may indeed be a subtype of breast cancer that is somewhat dose-sensitive, although it seems unlikely that bone marrow ablation would be required.

The review conclusions are definitive, and we believe that the review question can now effectively be closed off. More recent reviews have opened up potential for other therapeutic approaches. In contrast to the high-dose approach, real and valuable progress has been made over the last two decades with the better-defined use of endocrine therapy[4], the use of taxane chemotherapy[5], and the use of anti-HER2 therapy [6]. Taken together the message for us in treating breast cancer seems clear: get smarter, not tougher.

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