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Why does cytotoxic chemotherapy cure only some cancers?

Nature Clinical Practice Oncology volume 6, pages 43–52 (2009)Cite this article

Abstract

Despite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors. By contrast, in testicular cancer, gestational choriocarcinoma, Hodgkin disease and high-grade lymphomas, chemotherapy is routinely curative, even for patients who present with widely disseminated disease. In the common advanced cancers, however, over 40 years of cytotoxic drug development has brought no significant change in cure rates. One interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. We suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells. A common property of such curable malignancies is that they arise from cells that undergo major genetic rearrangements or recombination as part of their normal physiology. The absence of further genetic and epigenetic changes in genes that regulate apoptosis, DNA repair and senescence allows these cells to maintain their intrinsic sensitivity to chemotherapy. This process allows the cells, when challenged with chemotherapy, to undergo the natural apoptotic pathways that contribute to their intrinsic qualities of chemosensitivity and high curability.

Key Points

  • Curability with cytotoxic chemotherapy is restricted to a very few types of cancer

  • Cancers currently curable by chemotherapy include testicular and ovarian germ-cell tumors, high-grade non-Hodgkin lymphoma (B cell and T cell), Hodgkin disease and gestational choriocarcinoma

  • Clinical and experimental evidence implies that curability results from the biological properties of specific cancers rather than properties of the drugs used to treat them

  • Chemotherapy-curable cancers all arise in cell types whose normal physiological function involves complex rearrangement and/or recombination of genomic DNA

  • Chemotherapy-curable cancers have an intrinsic hypersensitivity to DNA damage, associated with a low threshold to undergo apoptosis, which reflects the function(s) of the cell types they are derived from

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Acknowledgements

Work in the laboratory of T Crook is funded by Breakthrough Breast Cancer, The Institute of Cancer Research and Cancer Research UK. T Crook is a clinical scientist of Cancer Research UK.

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Authors and Affiliations

  1. P Savage and J Stebbing are both Consultant Medical Oncologists at the Department of Medical Oncology, Imperial College School of Medicine, London.,

    Philip Savage & Justin Stebbing

  2. M Bower is a Professor of Medical Oncology in the Department of Medical Oncology, Chelsea and Westminster Hospital, London.,

    Mark Bower

  3. T Crook is a Specialist Registrar in the Department of Medical Oncology, Charing Cross Hospital, and at the Laboratory of Cancer Genetics and Epigenetics, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.,

    Tim Crook

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  1. Philip Savage
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Correspondence to Philip Savage.

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Savage, P., Stebbing, J., Bower, M. et al. Why does cytotoxic chemotherapy cure only some cancers?. Nat Rev Clin Oncol 6, 43–52 (2009). https://doi.org/10.1038/ncponc1260

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