Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI

Abstract

Background:The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI.Methods:Six DCE-MRI and three 18F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (Ktrans, vp, and ve) were examined for correlation with FDG-PET (SUVmax) and association with drug exposure, and evaluated with clinical outcome.Results:Ktrans (P=0.041) and vp (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in vp at day 5 (P=0.04) and week 10 (P=0.02). A lower Ktrans at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034).Conclusions:This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy

“…Metabolic imaging modalities such as dynamic enhanced MRI and positron emission tomography may provide more accurate measurements of tumor response. 23 …”

“…The treatment schema is shown in Figure 1. Bevacizumab was administered 3 days before the first dose of chemotherapy at week 0 to characterize the single-dose single agent pharmacokinetics of the drug in children 22 and to assess the effect of bevacizumab alone on the tumor vasculature using dynamic contrast-enhanced MRI 23 , as previously reported. All subsequent doses of bevacizumab were given on day 1 of chemotherapy.…”

“…Metabolic imaging modalities such as dynamic enhanced MRI and positron emission tomography may provide more accurate measurements of tumor response. 23 The primary mechanism of elimination of methotrexate is by the kidney. Because VEGF targeting agents may cause renal vascular endothelial dysfunction and glomerular epithelial cell dysregulation, 42 we sought to investigate the effect of bevacizumab on renal clearance of methotrexate (CL t ) by analyzing the effect of cumulative bevacizumab exposure effect on methotrexate pharmacokinetics.…”

[18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer

“…Preclinical studies indicate that anti-angiogenic therapies cause vascular normalization, [46,47]. Several studies have suggested that changes in K trans may be an early pharmacodynamic biomarker of clinical response to anti-angiogenics [48][49][50]. However, K trans denotes a context-dependent (including degree of tumor perfusion and MRI acquisition setup/equipment) complex combination of tissue blood flow and permeability weighted to varying extents.…”

Pathologic fracture in childhood and adolescent osteosarcoma: A single-institution experience

“…OS99 involved carboplatin, ifosfamide, and doxorubicin . OS2008 added a monoclonal antibody, bevacizumab, to a combination of cisplatin, doxorubicin, and HDMTX …”