Vascular Endothelial Growth Factor Levels in Immunodepleted Plasma of Cancer Patients As a Possible Pharmacodynamic Marker for Bevacizumab Activity

Loupakis, Fotios; Falcone, Alfredo; Masi, Gianluca; Fioravanti, Anna; Kerbel, Robert S.; Tacca, M. Del; Bocci, Guido

doi:10.1200/jco.2006.10.3051

Cited by 55 publications

(44 citation statements)

References 14 publications

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“…The other possibility is that anti-VEGF antibodies form inert complexes, causing a false increase in circulating VEGF levels. One study conducted using immunodepleted plasma has supported this assumption by showing a significant decrease in VEGF levels after treatment with bevacizumab (Loupakis et al, 2007). The increase in plasma VEGF concentration in patients treated with anti-VEGF antibodies has also been seen in those receiving low-molecular-weight VEGFR TKis (Table 2b).…”

Section: Circulating Candidate Biomarkers Of Angiogenesissupporting

confidence: 50%

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

2009

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Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs.

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Section: Circulating Candidate Biomarkers Of Angiogenesissupporting

confidence: 50%

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

2009

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“…BV/ER-treated patients showed a significant decrease in plasma VEGF levels after 7 days (median decreased from 134 to 25 pg ml À1 , P ¼ 0.002, data not shown), probably because the used ELISA-kit measures only free VEGF (Loupakis et al, 2007). No correlation was found between pre-treatment plasma VEGF levels and treatment outcome.…”

Section: Plasma Vegf and Epo Levels In Nsclc Patientsmentioning

confidence: 67%

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

et al. 2009

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Background: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. Methods: (VEGFR2 + ) CECs , (CD133 + ) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). Results: At day 7, SO/ER-treated patients showed a three-fold increase in CECs ( P <0.0001) comparable to BV/ER-treated patients ( P <0.01), and the CECs did not change with erlotinib treatment ( P =0.8). At day 7, CD133 + /HPCs decreased with SO/ER treatment ( P <0.0001). HPC numbers did not change with either BV/ER or erlotinib. In SO/ER-treated patients pre-treatment CD133 + /HPCs were significantly lower in responders ( P =0.01) and pre-treatment CD133 + /HPC numbers lower than the median correlated with a longer time-to-progression (TTP) ( P =0.037). Conclusion: Pre-treatment CD133 + /HPCs are a promising candidate biomarker to further explore for use in selecting NSCLC patients who might benefit from SO/ER treatment.

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“…19,20 Protein G-Sepharose 4 Fast Flow beads were washed three times in phosphate buffered Saline (PBS) before being reconstituted to 50% (v/v) protein G-Sepharose in PBS. To deplete plasma samples of the ranibizumab immunoglobulin antibody and ranibizumab-bound VEGF, 100 ml of protein G slurry (50% v/v protein G-Sepharose in phosphate-buffered saline) was added to 200 ml of plasma and incubated with gentle mixing at 10 1C for 10 h. After centrifugation (2 min at 10 000 r.p.m.…”

Section: Methodsmentioning

confidence: 99%

“…ELISAs are unable to differentiate between bevacizumab-VEGF and ranibizumab-VEGF complexes and free VEGF, so it is possible for functional uncomplexed VEGF levels to fall while total VEGF levels remain the same or increased. 19 In this study, we analysed changes in both total (bound and unbound) and free VEGF levels in a child with a choroidal rupture from blunt trauma who developed a secondary choroidal neovascular membrane and was treated with a course of ranibizumab injections.…”

Section: Introductionmentioning

confidence: 99%

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

Shao

Sivagnanavel

Dabbagh

et al. 2015

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Purpose To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. Methods A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre-and post-immunodepletion to remove complexed VEGF. Results Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. Conclusions These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

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Vascular Endothelial Growth Factor Levels in Immunodepleted Plasma of Cancer Patients As a Possible Pharmacodynamic Marker for Bevacizumab Activity

Cited by 55 publications

References 14 publications

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

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