Simulation of metastatic progression using a computer model including chemotherapy and radiation therapy

Abstract

Introduction: Despite considerable research efforts, the process of metastasis formation is still a subject of intense discussion, and even established models differ considerably in basic details and in the conclusions drawn from them. Mathematical and computational models add a new perspective to the research as they can quantitatively investigate the processes of metastasis and the effects of treatment. However, existing models look at only one treatment option at a time.

Methods: We enhanced a previously developed computer model (called CaTSiT) that enables quantitative comparison of different metastasis formation models with clinical and experimental data, to include the effects of chemotherapy, external beam radiation, radioimmunotherapy and radioembolization. CaTSiT is based on a discrete event simulation procedure. The growth of the primary tumor and its metastases is modeled by a piecewise-defined growth function that describes the growth behavior of the primary tumor and metastases during various time intervals. The piecewise-defined growth function is composed of analytical functions describing the growth behavior of the tumor based on characteristics of the tumor, such as dormancy, or the effects of various therapies. The spreading of malignant cells into the blood is modeled by intravasation events, which are generated according to a rate function. Further events in the model describe the behavior of the released malignant cells until the formation of a new metastasis. The model is published under the GNU General Public License version 3.

Results: To demonstrate the application of the computer model, a case of a patient with a hepatocellular carcinoma and multiple metastases in the liver was simulated. Besides the untreated case, different treatments were simulated at two time points: one directly after diagnosis of the primary tumor and the other several months later. Except for early applied radioimmunotherapy, no treatment strategy was able to eliminate all metastases. These results emphasize the importance of early diagnosis and of proceeding with treatment even if no clinically detectable metastases are present at the time of diagnosis of the primary tumor.

Conclusion: CaTSiT could be a valuable tool for quantitative investigation of the process of tumor growth and metastasis formation, including the effects of various treatment options.

Keywords: Chemotherapy; Computer simulation; Metastasis; Radioembolization; Radioimmunotherapy; Radiotherapy.