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Reply to “Limitations of combination anti-angiogenesis and chemotherapy”

Nature Reviews Cancer volume 2, page 804 (2002)Cite this article

Andrew Millar raises an important issue in his letter. He points out that despite promising preclinical efficacy and toxicity data, combining conventional chemotherapy with an angiogenesis inhibitor, or alternatively an oncogene signalling inhibitor, can lead to unexpected toxicities and/or lack of increased efficacy. Millar cites important and sobering results. However, the question of whether and how to combine angiogenesis inhibitors with chemotherapy was not overlooked in our discussion of this issue. For example, as noted in our review, we, and subsequently others have previously reported that angiogenesis inhibitors can be combined with chemotherapeutic drugs in which the latter are administered on an 'antiangiogenic' or 'metronomic' dose and schedule — that is, more frequently than most conventional schedules and at significantly lower than maximum tolerated doses1,2,3,4,5,6. Administration of chemotherapeutic drugs in this manner is designed to maximize their anti-angiogenic effects, while at the same time reducing the severe and acute toxicities that are often associated with conventional, maximum tolerated dose regimens7.

Clinical trials of antiangiogenic (metronomic) chemotherapy are underway at present8,9. Depending on their outcome, such trials — along with additional preclinical studies — might conceivably lead to a fundamental re-appraisal of how targeted anticancer drugs, including angiogenesis inhibitors, should be combined with chemotherapeutic agents. Perhaps as implied by Millar, nothing less than a new paradigm might be required for these sorts of combination treatments10, at least when these two therapies are administered concurrently. Nevertheless, we feel that it is too early to make a recommendation about which type of chemotherapy to use with an angiogenesis inhibitor, if any, until more data has been obtained. In fact, Millar highlights the crucial need for small-animal tumour-therapy models which will provide a much better idea of what will happen in the clinical setting11. In this regard, a good start would be the use of experimental tumour models in which treatment of advanced (high tumour burden) metastatic disease is undertaken, as opposed to treatment of primary tumours or of only microscopic (low tumour burden) disease.

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References

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Authors and Affiliations

  1. Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, S-218, 2075 Bayview Avenue, Toronto, M4N 3M5, Ontario, Canada

    Robert S. Kerbel

  2. Department of Surgery, Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Judah Folkman

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  1. Robert S. Kerbel
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  2. Judah Folkman
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Kerbel, R., Folkman, J. Reply to “Limitations of combination anti-angiogenesis and chemotherapy”. Nat Rev Cancer 2, 804 (2002). https://doi.org/10.1038/nrc905-c2

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