Tumor Volume Estimation and Quasi-Continuous Administration for Most Effective Bevacizumab Therapy

Abstract

BackgroundBevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol.Materials and MethodsWe have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. In both cases, three groups were compared in the experiments. The first group did not receive therapy, the second group received one 200 μg bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 μg bevacizumab every day (quasi-continuous therapy). Tumor volume measurement was performed by digital caliper and small animal MRI. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The effectiveness of bevacizumab administration was examined by statistical analysis.ResultsIn the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model.ConclusionOur results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration.

A minimal model of tumor growth with angiogenic inhibition using bevacizumab

“…In the case group, mice received 1/18 mg/kg injection each day starting from the third day for 18 days. The tumor volumes were measured with calipers and MRI, the calculation of tumor volume based on these measurements and more details of the experiment can be found in [13], [16]. The parametric identification was done by utilizing the measurement from the control group, while validation of the model was done using the measurements from the case group.…”

“…The parametric identification of the model is done using measurements from C57Bl/6 mice experiments, where the mice were implanted subcutaneously with C38 colon adenocarcinoma, and received treatment with bevacizumab [13]. The mice were separated into a control group and a case group.…”

Modelling Tumor Growth under Angiogenesis Inhibition with Mixed-Effects Models

“…The third dimension should be estimated, and assuming a certain shape, tumor volume can be approximated. Based on different estimation methods, we obtained three different tumor volume values for each measurement point [14]. Measurements with caliper were made on the 0th, 2nd, 4th, 6th, 8th, 10th, 12th, 14th, 16th, 18th and 19th days of the experiment.…”

Potential Benefits of Discrete-Time Controller-based Treatments over Protocol-based Cancer Therapies

“…However, with the current scientific knowledge, there is no medical device which can handle continuous infusion cancer therapy [18]; hence we designed a discretetime control herein.…”