(296f) A Computational Study of Combined Chemotherapy for a Growing Tumor with Heterogeneous Vasculature

Cancer is a lethal disease affecting millions of patients each year worldwide. Consequently, a significant part of the scientific community is committed to battling this malady by designing novel therapeutic strategies. Modern therapeutic approaches entail the combination of several therapeutic agents, such as radiotherapy, chemotherapeutic drugs, and immunotherapy.

In the present study, we develop and numerically solve a continuum-level, multiphase model [1, 2], where each phase corresponds to a distinct cellular population: cancer cells, healthy cells, capillaries, and the interstitium. The spatiotemporal evolution of cellular species is formulated through mass and momentum balance equations based on the assumption that said phases are non-mixable. In addition, we model the dynamics of chemical species regulating critical cellular processes, including cellular mitosis, the chemotactically driven motion of immature capillaries, and angiogenesis. The chemical species include nutrient species (oxygen) and the vascular endothelial growth factor (VEGF), which mediates angiogenesis and is an essential factor for the growth of endothelial cells. Finally, we incorporate the effect of chemotherapy by treating the therapeutic drug as additional chemical species.

Here, we model the effect of an anti-VEGF and a cytotoxic drug acting independently and in a combined manner. In particular, an anti-VEGF drug (bevacizumab) inhibits the production of new vessels (angiogenesis). Cytotoxic drugs (e.g., docetaxel) infiltrate cancer cells, arresting the cell cycle and enabling apoptosis. The chemotherapeutic agents' dynamics are monitored by developing reaction-diffusion equations in a similar fashion to the rest of modeled chemical species. Our target is to demonstrate the enhanced efficiency of combined chemotherapy over monotherapy, to delve into the underlying mechanisms that yield these results, and to explore the chemotherapy schedule as a possible optimization parameter. In this context, we perform computational experiments on tumors treated with bevacizumab and docetaxel separately and in combination. Finally, we perform a series of simulations with the combination therapy components being administered at different starting dates relative to each other (with either drug's administration start being delayed).

Our computations (performed in COMSOL) show that combination therapy is significantly more effective in suppressing the tumor for a prolonged time period when compared to monotherapy regimens. This behavior can be explained by docetaxel's increased residence time in the tissue in the presence of an anti-VEGF drug, which has also been experimentally observed for the combination of bevacizumab with paclitaxel [3]. Paclitaxel and docetaxel are the principal representatives of taxane drugs. Finally, our simulations show that the therapeutic efficacy becomes maximum when bevacizumab and docetaxel are administered within a time interval of ± one day, which is in line with the usual clinical practice [4, 5].

[1] M. Hubbard, H. Byrne, Multiphase modelling of vascular tumour growth in two spatial dimensions, Journal of Theoretical Biology 316 (2013) 70–89.

[2] I. Lampropoulos, M. Charoupa, M. Kavousanakis, Intra-tumor heterogeneity and its impact on cytotoxic therapy in a two-dimensional vascular tumor growth model, Chemical Engineering Science 259 (2022) 117792.

[3] N. Qi, F. Li, X. Li, H. Kang, H. Zhao, N. Du, Combination use of paclitaxel and avastin enhances treatment effect for the nsclc patients with malignant pleural effusion, Medicine 95 (47) (2016) e5392.

[4] National Health Service, Chemotherapy protocol for advanced (stage IIIc/IV) ovarian, peritoneal or fallopian tube cancer, sub-optimally debulked either at primary or delayed primary (interval) surgery, https://www.uhs.nhs.uk/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ov..., accessed: 2022-11-14.658.

[5] National Health Service, Chemotherapy protocol for the first line treatment of recurrent or metastatic stage IVB cervical cancer not amenable to curative treatment with surgery and / or radiotherapy and where there has been no prior treatment with bevacizumab or other anti-VEGF therapy, https://www.uhs.nhs.uk/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ce..., accessed: 2022-11-14.