The disconnection between tumor response and survival
Indraneel Mittra
This article has no abstract so we have provided the first paragraph of the full text.
Epithelial cancers account for more than 80% of all cancer deaths worldwide. While the rising global mortality from these cancers is largely attributable to the challenges in implementing established public health measures, it also brings into focus the unfulfilled promise of cancer treatment. This is particularly the case for the treatment of epithelial cancers with systemic chemotherapy. Extensive clinical experience has shown that while chemotherapy of advanced epithelial cancers frequently leads to dramatic tumor responses, these do not translate into commensurate improvement in patient survival. This realization has led to a search for newer systemic therapies, including biological and targeted therapies, without a critical appraisal of the reasons underlying the failure of potent cytotoxic agents to cure these cancers. The disconnection between significant downstaging and subsequent patient survival is best exemplified by the lack of benefit from myeloablative chemotherapy in metastatic breast cancer,1 and begs for an explanation that might also be universally illuminating. The well-established Goldie and Coldman hypothesis posits that the failure of chemotherapy to eradicate cancer is because of the persistence of a few mutated chemo-resistant cancer cells. More recently, residual stem cells have been implicated in resistance to chemotherapy. While these hypotheses might explain why cancer may not be cured, they do not explain why the relatively small number of cancer cells that remain following myeloablative chemotherapy do not result in significantly longer survival compared with the very large tumor cell numbers remaining after conventional chemotherapy. The Gompertzian model of tumor growth kinetics refined by Norton and Simon argues that the smaller the residual tumor volume following chemotherapy the more rapid is its regrowth rate, and unless cancer cells are completely eradicated a cure is not possible.2 Could there be another explanation?
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