Abstract
In the present-day society, cancer has become a challenge that threatens millions of human lives and causes many deaths. Throughout this research, we have developed a mathematical model to describe the radiotherapy treatment. There is a competition between tumor cells and normal cells; we use Lotka-Volterra dynamics to represent that biological idea in a mathematical model. In radiotherapy, ionizing particles attack the DNA of both tumor cells and normal cells. This process occurs in a medium with oxygenated tissues, and it has a saturation level. Previous researchers have not considered the saturation effects of radiotherapy in their models; however, our model incorporates the Michaelis-Menten term to represent these effects, which is the main novelty in this research with respect to previous works. We assume that other reactions are occurring according to the Mass Action Law, and also that radiotherapy targets both tumor cells and normal cells with the same intensity. First, we conduct a stability analysis of the system and then simulate the system by using time series analysis. We observed that in most cases, a stable equilibrium point can occur or periodic behavior may emerge in the population levels. By conducting a local sensitivity analysis, we identified the most sensitive parameters important in clinical treatments. We then conduct a bifurcation analysis for the most sensitive parameters, observing critical values for these parameters that must be maintained within a specific range to achieve an optimal treatment outcome. Primarily, we investigated the optimal range for the killing rate of tumor cells and discussed how the half-saturation constant effects therapy. These results will be crucial for achieving better clinical outcomes in radiotherapy.
References
Hall EJ, Giaccia AJ. Radiobiology for the radiologist. Philadelphia: Lippincott Williams & Wilkins; 2012.
Chabner BA, Longo DL. Cancer chemotherapy and biotherapy: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2011.
Kaur S, Mayanglabam P, Bajwan D. Chemotherapy and its adverse effects. Int J Nurs Edu Res. 2022; 10(2): 113-7. https://doi.org/10.52711/2454-2660.2022.00090
Altun I, Şenkaya A. The most common side effects experienced by patients receiving first cycle of chemotherapy. Iran J Public Health. 2018; 47(8): 1128-35.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646-74. https://doi.org/10.1016/j.cell.2011.02.013
De Pillis LG, Radunskaya AE, Wiseman CL. A validated mathematical model of cell-mediated immune response to tumor growth. Cancer Res. 2005; 65(17): 7950-8. https://doi.org/10.1158/0008-5472.CAN-05-0564
Powathil GG, Gordon KE, Hill LA, Chaplain MAJ. Modelling the effects of cell-cycle heterogeneity on the response of a solid tumour to chemotherapy. Math Biosci. 2013; 245(2): 162-73.
Bertuzzi A, Fasano A, Gandolfi A. A mathematical model for tumor growth: analysis of the role of vascularization. Math Models Methods Appl Sci. 2003; 13(11): 1731-49.
Panetta JC. A mathematical model of drug resistance: heterogeneous tumors. Math Biosci. 1997; 147(1): 41-61. https://doi.org/10.1016/S0025-5564(97)00080-1
Garay T. Competition dynamics in a tumor-immune model with chemotherapeutic treatment. Bull Math Biol. 2013; 75(9): 1460-80.
Naldi A, Carneiro J, Chaouiya C, Thieffry D. Diversity and plasticity of Th cell types predicted from regulatory network modelling. PLoS Comput Biol. 2010; 6(9): e1000912. https://doi.org/10.1371/journal.pcbi.1000912
Świerniak A, Poleszczuk J, Ochab-Marcinek A. Optimal protocols in combined anticancer therapy. Math Biosci Eng. 2009; 6(4): 739-50.
Tracqui P. Biophysical models of tumor growth. Rep Prog Phys. 2009; 72(5): 056701. https://doi.org/10.1088/0034-4885/72/5/056701
Griggs JJ. Reducing the toxicity of anticancer therapy: new strategies. Leuk Res. 1998; 22(1): 17-22. https://doi.org/10.1016/S0145-2126(98)00036-8
Crittiana M. Lotka–Volterra and their model. Didact Math. 2014; 32(2): 45-9.
Lotka AJ. Elements of physical biology. Baltimore: Williams & Wilkins; 1925.
Tahara T, Gavina MKA, Kawano T, Tubay JM, Rabajante JF, Ito H, et al. Asymptotic stability of a modified Lotka–Volterra model with small immigrations. Sci Rep. 2018; 8: 25436. https://doi.org/10.1038/s41598-018-25436-2
Muller H, Schimidit G, Ficher L. Lotka–Volterra model with principal component analysis. J Comput Biol Med. 2024; 4(4): 96-101. https://doi.org/10.71070/jcbm.v4i1.96
Murray JD. Mathematical biology I: an introduction. New York: Springer; 2002. https://doi.org/10.1007/b98868
Gatenby RA, Maini PK. Mathematical oncology: cancer summed up. Nature. 2003; 421(6921): 321. https://doi.org/10.1038/421321a
Liu Z, Yang C. A mathematical model of cancer treatment by radiotherapy. J Appl Math. 2014; 2014: 172923. https://doi.org/10.1155/2014/172923
Freedman HI. Deterministic mathematical models in population ecology. New York: Marcel Dekker; 1980.
Clotilda AMD, Vithanage GVRK, Lakshika DD. A mathematical model to treat cancer using chemotherapy and immunotherapy under mass action kinetics for immunotherapy. Math Comput Model Appl. 2024; 4: 150. https://doi.org/10.37394/232023.2024.4.15
Conocapka M, Rogolinski J, Sochanik A. Can high dose use in radiotherapy change therapeutic effectiveness? Contemp Oncol. 2017; 20(6): 449-52. https://doi.org/10.5114/wo.2016.65603
Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012; 9(3): 193-9. https://doi.org/10.7150/ijms.3635
Vithanage GVRK, Wei HC, Jang SRJ. Bistability in a model of tumor–immune system with oncolytic viral therapy. Math Biosci Eng. 2022; 19(7): 2072. https://doi.org/10.3934/mbe.2022072
Lestari D, Sari ER, Arifash H. Dynamics of a mathematical model with chemotherapy. J Phys Conf Ser. 2018; 1320(1): 012026. https://doi.org/10.1088/1742-6596/1320/1/012026
Prokopiou S, Moros EG, Poleszczuk J, Caudell J, Torres-Roca JF, Latifi K, et al. A proliferation saturation index to predict radiation response and personalize radiotherapy fractionation. Radiat Oncol. 2015; 10: 145. https://doi.org/10.1186/s13014-015-0465-x
Gasull A, Giacomini H. Effectiveness of the Bendixson–Dulac theorem. J Differ Equ. 2021; 305: 283-96. https://doi.org/10.1016/j.jde.2021.10.011
McCluskey C, Muldowney J. Bendixson–Dulac criteria for difference equations. J Dyn Differ Equ. 1998; 10(4): 541-56. https://doi.org/10.1023/A:1022677008393
Azad R, Aghdam EK, Rauland A, Jia Y, Avval AH, Bozorgpour A, et al. Medical image segmentation review: the success of U-net. IEEE Trans Pattern Anal Mach Intell. 2024; 46(2): 1234-52. https://doi.org/10.1109/TPAMI.2024.3435571
Akuzinov AA, Rozhina EE. Resistance to radiotherapy in cancer. Dis. 2025; 13(1): 22. https://doi.org/10.3390/diseases13010022
Abelman S, Patidar KC. Comparison of some recent numerical methods for initial value problems for stiff ordinary differential equations. Comput Math Appl. 2008; 55(4): 1215-25. https://doi.org/10.1016/j.camwa.2007.05.012
Shampine C, Reichelt M. The MATLAB ODE suite. SIAM J Sci Comput. 2006; 18(1): 1-22.
Ashino R, Nagase M, Vaillancourt R. Behind and beyond the MATLAB ODE suite. Comput Math Appl. 2000; 40(4-5): 491-512. https://doi.org/10.1016/S0898-1221(00)00175-9
Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg. 2014; 133(1): 49-56. https://doi.org/10.1097/01
Toulany M. Targeting DNA double-strand break repair pathways to improve radiotherapy response. Genes. 2019; 10(1): 25. https://doi.org/10.3390/genes10010025
Vignard J, Mirey G, Salles B. Ionizing-radiation induced DNA double-strand breaks: a direct and indirect lighting up. Radiother Oncol. 2013; 108(3): 362-9. https://doi.org/10.1016/j.radonc.2013.06.013
Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate cancer review: genetics, diagnosis, treatment options, and alternative approaches. Molecules. 2022; 27(17): 5730. https://doi.org/10.3390/molecules27175730
Vithanage GVRK, Jang SRJ. Optimal immunotherapy interactions in oncolytic viral therapy and adoptive cell transfer for cancer treatment with saturation effects. WSEAS Trans Biol Biomed. 2025; 22: 23. https://doi.org/10.37394/23208.2025.22.23
Buljan I, Benkovic M. Simulation and local parametric sensitivity analysis of a computational model of fructose metabolism. Processes. 2025; 13(1): 125. https://doi.org/10.3390/pr13010125
Mester R, Landeros A, Rackauckas C. Differential methods for assessing sensitivity in biological models. PLoS Comput Biol. 2022; 18(6): e1009598. https://doi.org/10.1101/2021.11.15.468697
Lakrisenko P, Pathirana D, Weindl D, Hasenauer J. Benchmarking methods for computing local sensitivities in ordinary differential equation models at dynamic and steady states. PLoS One. 2024; 19(4): e0312148. https://doi.org/10.1371/journal.pone.0312148
Charzynska A, Nalecz A, Rybinski M, Gambin A. Sensitivity analysis of mathematical models of signaling pathways. Biotechnologia. 2012; 93(3): 245-54. https://doi.org/10.5114/bta.2012.46584
Savatorova V. Exploring parameter sensitivity analysis in mathematical modeling with ordinary differential equations. CODEE J. 2023; 16: 4. https://doi.org/10.5642/codee.CZKZ5996
Burrage K, Burrage PM, Kreikemeyer JN. Learning surrogate equations for the analysis of an agent-based cancer model. Front Appl Math Stat. 2025; 11: 1578604. https://doi.org/10.3389/fams.2025.1578604
Adi-Kusumo F, Aryati L, Risdayati S, Norhidayah S. Hopf bifurcation on a cancer therapy model by oncolytic virus involving the malignancy effect and therapeutic efficacy. Int J Math Math Sci. 2020; 2020: 4730715. https://doi.org/10.1155/2020/4730715
Alqahtani RT. A model of effector–tumor cell interactions under chemotherapy: bifurcation analysis. Mathematics. 2025; 13(7): 1032. https://doi.org/10.3390/math13071032
Burrage K, Burrage PM, Kreikemeyer JN. Learning surrogate equations for the analysis of an agent-based cancer model. Front Appl Math Stat. 2025; 11: 1578604. https://doi.org/10.3389/fams.2025.1578604
Kim Y, Gilbert RM, Armstrong TS, Celiku O. Clinical outcome assessment trends in clinical trials contrasting oncology and non-oncology studies. Cancer Med. 2023; 12(16): 8715-26. https://doi.org/10.1002/cam4.6325

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2025 G.V.R.K. Vithanage, A.R.M. Hasini Parami Wattetenne, K.A. Nirupadhi Divyanjali Jayakody, M. Sawani Dhanushika, Sachith Dassanayaka