Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

Abstract

Purpose: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth. Experimental Design: We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density. Results: Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates. Conclusions: In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped. Clin Cancer Res; 16(15); 3887–900. ©2010 AACR.

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

“…However, whether tumor regrowth occurs after discontinuation of antiangiogenic therapy is controversial. Results from a study using various different cell lines indicate that tumors that relapsed after cessation of therapy did not grow faster compared with untreated tumors (46). However, most of this work was done by injecting cancer cells subcutaneously where tumor-related angiogenesis is highly different from that at orthotopic sites (47).…”

Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model

“…Select mice received anti-VEGF at a dose of 10 mg/kg 24 hours before dosing radiolabeled trastuzumab or its control mAb. The dose of anti-VEGF mAb was based on previously reported xenograft growth inhibition activity (16,38), whereas the time interval was based on reported statistically significant reductions in vascular density of human xenografts in mice at 24 hours following anti-VEGF administration (28). Furthermore, a pharmacokinetic model simulation indicated that either a 5 mg/kg twice a week or 10 mg/kg weekly dosing regimen would result in a minimum trough concentration at steady state of 30 mg/mL, similar to that achieved in more than 90% of bevacizumab patients (38).…”

Protracted inhibition of vascular endothelial growth factor signaling improves survival in metastatic colorectal cancer: A systematic review

“…However, the optimal duration is unclear and there is a biological rationale to hypothesize a survival benefit from post-progression administrations. [10] The TML and the Bebyp trials investigated protracted administration of bevacizumab after progression to a first-line chemotherapy. Both trials were positive, confirming that protracted administration of bevacizumab, beyond progression, leads to survival advantage.…”

“…[9] Some authors have argued that, since resistance is established, the sudden suspension of the antiangiogenic drug can rapidly increase blood vessels formation, with more pronounced angiogenesis and faster prog ression, sug gesting possible benefits from longer treatment durations. [10] Recently, two randomized trials investigated the administration of bevacizumab beyond progression. [11,12] In these studies, patients progressed after the failure of a bevacizumabbased first line chemotherapy were randomized to continuation or suspension of bevacizumab.…”