Non-invasive quantification of tumor vascular architecture during docetaxel-chemotherapy

Abstract

New ultrasound parameters, potentially predictive of tumor response to chemotherapy, were sought after analyzing details of vascular architecture of mammary tumors during chemotherapy. Tumor-bearing rats were separated into untreated or docetaxel-treated group (6 mg/kg/week). Power Doppler Index and vascular contrast-enhanced ultrasound (CEUS) reference endpoints (Peak, area under the curve (AUC), blood flow) were evaluated at the beginning (W (0)), and after 2 and 6 weeks of docetaxel treatment (W (+2) and W (+6)). An improved CEUS image analysis, taking advantage of individual pixel intensity, was developed to quantify large, medium, and small vessels of tumors. Standard immunohistochemistry validated this new methodology analyzing tumor vascular architecture. In rats, there was an enrichment of vascularization with large vessels during tumor growth indicative of a vascular adjustment to tumor size. Docetaxel stopped tumor growth, and showed a sequential effect on vascular parameters. After an initial enrichment in larger vessels (by threefold) at W (+2), docetaxel led to a diminution of vascular parameters at W (+6) (-46 % for peak, -55 % for AUC -31 % compared to W (0)) and a vascular remodeling in favor of small vessels. One of the CEUS parameters measured before chemotherapy, the so-called global contrast-enhanced pixels density, was predictive of rat tumor response to treatment (r = 0.80; p < 0.01). The method was then applied in a clinical setting to detect changes of vascular architecture during chemotherapy of human breast carcinoma. The docetaxel chemotherapy of breast carcinomas induced a similar sequential effect, with vessel enlargement after two cycles of docetaxel treatment and an antiangiogenic effect after six cycles. Such vascular remodeling was not noticed when patients were treated with 5-fluorouracil-epirubicin-cyclophosphamide. Taken together, the sharpened analysis of CEUS pixel intensity presented here strengthened the monitoring of breast tumor vasculature with the potential to improve the prediction of docetaxel efficacy.