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Antiangiogenic therapy: impact on invasion, disease progression, and metastasis

A Correction to this article was published on 01 June 2011

This article has been updated

Abstract

Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies—in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development.

Key Points

  • Successful clinical trials with various VEGF-pathway inhibitors have been accompanied by numerous phase III failures

  • Trial failures in adjuvant disease, and ongoing trials in early-stage settings, could highlight differences in antiangiogenic drug efficacy depending on disease stage

  • There is a gap between how antiangiogenics are usually tested in the clinic (late-stage metastatic) and in preclinical mouse models (localized primary tumors)

  • There is debate whether anti-VEGF therapy may lead to 'rebound growth' when halted or if it may fuel more invasive and metastatic disease phenotypes

  • Future testing of antiangiogenic therapies should be conducted in clinically relevant animal models of all disease stages

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Figure 1: Clinical results of combinations of PFS and overall survival.
Figure 2: Variable efficacy of VEGF pathway-targeted therapies: exposing the gap between preclinical and clinical testing.

Change history

  • 08 March 2011

    In the version of this article initially published online, the title of Table 2 should have read 'Unsuccessful or terminated phase III trials with anti-VEGF pathway agents'; in the last row of Table 2 an asterisk has been added to the PFS column; the title of Box 3 should have read 'Possible mechanisms influencing invasion and metastasis after therapy'; the sentence on page 7, column 2 beginning 'In both trials, the rapid change in PFS after bevacizumab was halted, which requires...' should have read 'Regardless, in both trials, the fact that PFS changed rapidly after bevacizumab was halted requires...'; and in Table 3 'CAPOX' has been deleted. The errors have been corrected for the print, HTML and PDF versions of the article.

  • 04 May 2011

    In the Review article published in the April issue of Nature Reviews Clinical Oncology there were errors in the clinical data presented in Tables 1 and 2. In addition, the primary end point of the adjuvant AVANT and NSABP-C-08 trials should have been disease-free survival (DFS) instead of progression-free survival (PFS). The errors have been corrected for the HTML and PDF versions of the article.

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Acknowledgements

The authors thank David Reardon for editorial comments and permission to use the concept in Figure 1, and William Cruz-Munoz and Christina R. Lee for critically reading the manuscript.

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Authors and Affiliations

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Contributions

J. M. L. Ebos researched the data for the article and wrote the manuscript. Both authors had a substantial contribution to discussion and editing of content.

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Correspondence to John M. L. Ebos.

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Competing interests

R. S. Kerbel is a consultant for GlaxoSmithKline, MetronomX, MolMed, and Taiho Pharmaceutical. In addition, he receives grants or research support from GlaxoSmithKline, MolMed, Pfizer and YM Biosciences and is a stock holder or director at MetronomX. J. M. L. Ebos declares no competing interests.

Supplementary information

Supplementary Box 1

Emerging trend where patient response rate and PFS does not translate into significantly increased overall survival in phase III trials (DOC 35 kb)

Supplementary Box 2

Bevacizumab monotherapy exceptions (DOC 31 kb)

Supplementary Box 3

Methods employed to disrupt VEGF-pathway (DOC 31 kb)

Supplementary Box 4

Preclinical mouse models of GBM (DOC 31 kb)

Supplementary Box 5

The tumor microenvironment (DOC 37 kb)

Supplementary Box 6

Neoadjuvant therapy (DOC 31 kb)

Supplementary Box 7

Dearth in neoadjuvant-model therapy testing (DOC 30 kb)

Supplementary Table 1

Examples of therapy-induced metastasis in preclinical models (DOC 75 kb)

Supplementary Table 2

Preclinical testing of VEGF pathway targeted agents in mouse models of metastasis (DOC 139 kb)

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Ebos, J., Kerbel, R. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8, 210–221 (2011). https://doi.org/10.1038/nrclinonc.2011.21

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