Multi-Species Models of Tumor Growth

General Assumptions
The model is composed of the following volume fractions: proliferative (φP ), hypoxic (φH )
and necrotic (φN ) tumor cells, and the nutrients (φσ ). The total tumor (φT ) volume fraction is
giving by
φT = φP + φH + φN . (1)
The models defined below uses the Heaviside function (H ) as a switch. This value of this
function is one for positive arguments and zero otherwise.

1 The Reaction-Diffusion Model

Assuming that the velocities of the constituents are negligible, the following system of mass
balance equation is obtained:
∂φP 
= ∇ · MP ∇φP + SP , 
∂t



∂φH 

= ∇ · MH ∇φH + SH , 

∂t (2)
∂φN
= ∇ · MN ∇φN + SN , 

∂t


∂φσ



= ∇ · Mσ ∇φσ + Sσ , 
∂t
where SP , SH , SN and Sσ are special source terms defined below.
The source terms in our model take the form
= λP φσ φP (1 − φT ) − λP H H (σP H − φσ )φP + λHP H (φσ − σHP )φH

SP 
1


− H (t − Ttreat ) λ d φP ,


1 + λr (t − Ttreat ) k,P




= λP H H (σP H − φσ )φP − λHP H (φσ − σHP )φH − λHN H (σHN − φσ )φH

SH 


1 (3)
− H (t − Ttreat ) λ d φH ,
1 + λr (t − Ttreat ) k,H 


λdk,N


= λHN H (σHN − φσ )φH + H (t − Ttreat ) (λd φH + λdk,P φP ),

SN


1 + λr (t − Ttreat ) k,H




Sσ = −λc φσ (φP + φH ) + λs ktrans ,


where the vector of 17 parameters is given by

θ 1 = {MP , MH , MN , Mσ , λP , λP H , σP H , λHP , σHP , λHN , σHN , λr , λdk,P , λdk,H , λdk,N , λc , λs }, (4)

with the following restrictions

σP H ≥ σHP > σHN , and 0 ≤ λdk,N ≤ 1. (5)

1
2 The Phase-Field Model
Assuming that the velocities of the constituents are negligible, the following system of mass
balance equation is obtained:

∂φT  2 2 2 2 2 2

= ∇ · MP φP (1 − φP ) + MH φH (1 − φH ) + MN φN (1 − φN ) ∇µ + ST , 


∂t 2

2


µ = 2ĒφT 1 − 3φT + 2φT − T ∆φT ,




∂φH 2 2


= ∇ · MH φH (1 − φH ) ∇µ + SH , (6)
∂t
∂φN 
= ∇ · MN φ2N (1 − φN )2 ∇µ + SN ,



∂t



∂φσ 

= ∇ · Mσ ∇φσ + Sσ , 

∂t
where SH , SN and Sσ are defined as in (3) and ST is defined below.
The source terms in our model take the form
1
ST = λP φσ φP (1 − φT ) + H (t − Ttreat ) (λd − 1)(λdk,H φH + λdk,P φP ), (7)
1 + λr (t − Ttreat ) k,N

where the vector of 19 parameters is given by

θ 2 = {Ē, T } ∪ θ 1 , (8)

with the restrictions presented in (5).

3 Generalized Logistic Function (Richard’s curve)

ST = λP φσ φP (1 − φT )ν − λP H H (σP H − φσ )φP + λHP H (φσ − σHP )φH . (9)

4 Michaelis-Menten type

λPc φP + λH
c φH
Sσ = − M
φσ + λs ktrans (10)
φσ + φσ

5 Other hypothesis

MP = αMH , and λH φσ φH (1 − φT ) = βλP φσ φH (1 − φT ). (11)

6 Papers
• Wise et al. [1]: same source terms but tumor = viable + necrotic;

• Liu and Yang [2]: logistic + treatment effects (exponential) just during treatment interval;

• Barazzuol et al. [3]: ODE model + linear-quadratic (LQ) treatment model (survival);

• Bodgi et al. [4]: good historical synopsis, several cell survival/radiation models (Fig 2);

2
 • Borasi and Nahum [5]: reaction-diffusion (RD) model with exponential growth + LQ
model;

• Branco et al. [6]: RD model with chemotherapy;

• Enderling et al. [7]: survival probability × application distance;

• Enderling and AJ Chaplain [8]: ODEs for growth rate (exponential, logistic, Gompertz)
and dynamically carrying capacity;

• Byrne and Chaplain [9]: radially symmetric tumor growth with necrosis;

• Fowler [10]: LQ review (1989) with α and β coefficients;

• Galochkina et al. [11]: RD model with logistic growth (normal and damaged tumor cells),
using also the LQ model (optimization);

• Benzekry et al. [12]: Model selection with AIC, ODE with logistic and Gompertz models,
dynamic carrying capacity, Von Bertalanffy and power law (for volume);

• Xu et al. [13]: Phase-field model which incorporate hypoxic and necrotic through the
chemical potential;

• Kirkby et al. [14]: Radiotherapy effects on cell cycle;

• Liu and Yang [15]: same model as Liu and Yang [2] but added chemotherapy;

• Lo [16]: stochastic ODE with Gompertz growth;

• Marušić [17]: model selection using BIC for several ODE modeling tumor volume;

• Martı́nez-González et al. [18]: Proliferative + hypoxic + necrotic, using Michaelis-Menten

coefficient for oxygen consumption;

• Brenner [19]: Review of LQ model (states that it is good up to 18 Gy / fraction);

• Park et al. [20]: single fraction × several for the LQ model;

• Altrock et al. [21]: good review (examples): ODE, PDE, hybrid models, game theory and
metastasis;

• Adam [22]: 1D RD model with mitotic inhibitor

References
[1] S. M. Wise, J. S. Lowengrub, H. B. Frieboes, V. Cristini, Three-dimensional multispecies
nonlinear tumor growthi: model and numerical method, Journal of theoretical biology 253
(2008) 524–543.

[2] Z. Liu, C. Yang, A mathematical model of cancer treatment by radiotherapy, Computa-

tional and mathematical methods in medicine 2014 (2014).

[3] L. Barazzuol, N. G. Burnet, R. Jena, B. Jones, S. J. Jefferies, N. F. Kirkby, A math-

ematical model of brain tumour response to radiotherapy and chemotherapy considering
radiobiological aspects, Journal of theoretical biology 262 (2010) 553–565.

[4] L. Bodgi, A. Canet, L. Pujo-Menjouet, A. Lesne, J.-M. Victor, N. Foray, Mathematical

models of radiation action on living cells: From the target theory to the modern approaches.
a historical and critical review, Journal of theoretical biology 394 (2016) 93–101.

3
 [5] G. Borasi, A. Nahum, Modelling the radiotherapy effect in the reaction-diffusion equation,
Physica Medica 32 (2016) 1175–1179.

[6] J. Branco, J. Ferreira, P. de Oliveira, Mathematical modeling of efficient protocols to

control glioma growth, Mathematical biosciences 255 (2014) 83–90.

[7] H. Enderling, A. R. Anderson, M. A. Chaplain, A. J. Munro, J. S. Vaidya, Mathematical

modelling of radiotherapy strategies for early breast cancer, Journal of Theoretical Biology
241 (2006) 158–171.

[8] H. Enderling, M. AJ Chaplain, Mathematical modeling of tumor growth and treatment,

Current pharmaceutical design 20 (2014) 4934–4940.

[9] H. M. Byrne, M. Chaplain, Growth of necrotic tumors in the presence and absence of
inhibitors, Mathematical biosciences 135 (1996) 187–216.

[10] J. F. Fowler, The linear-quadratic formula and progress in fractionated radiotherapy, The
British journal of radiology 62 (1989) 679–694.

[11] T. Galochkina, A. Bratus, V. M. Pérez-Garcı́a, Optimal radiation fractionation for low-

grade gliomas: Insights from a mathematical model, Mathematical biosciences 267 (2015)
1–9.

[12] S. Benzekry, C. Lamont, A. Beheshti, A. Tracz, J. M. Ebos, L. Hlatky, P. Hahnfeldt, Clas-

sical mathematical models for description and prediction of experimental tumor growth,
PLoS Comput Biol 10 (2014) e1003800.

[13] J. Xu, G. Vilanova, H. Gomez, A mathematical model coupling tumor growth and angio-
genesis, PloS one 11 (2016) e0149422.

[14] N. Kirkby, N. Burnet, D. Faraday, Mathematical modelling of the response of tumour cells
to radiotherapy, Nuclear Instruments and Methods in Physics Research Section B: Beam
Interactions with Materials and Atoms 188 (2002) 210–215.

[15] Z. Liu, C. Yang, A mathematical model of cancer treatment by radiotherapy followed by

chemotherapy, Mathematics and Computers in Simulation 124 (2016) 1–15.

[16] C. Lo, Stochastic gompertz model of tumour cell growth, Journal of Theoretical Biology
248 (2007) 317–321.

[17] M. Marušić, Mathematical models of tumor growth, Mathematical Communications 1

(1996) 175–188.

[18] A. Martı́nez-González, G. F. Calvo, L. A. P. Romasanta, V. M. Pérez-Garcı́a, Hypoxic cell

waves around necrotic cores in glioblastoma: a biomathematical model and its therapeutic
implications, Bulletin of mathematical biology 74 (2012) 2875–2896.

[19] D. J. Brenner, The linear-quadratic model is an appropriate methodology for determining

isoeffective doses at large doses per fraction, in: Seminars in radiation oncology, volume 18,
Elsevier, 2008, pp. 234–239.

[20] C. Park, L. Papiez, S. Zhang, M. Story, R. D. Timmerman, Universal survival curve and
single fraction equivalent dose: useful tools in understanding potency of ablative radiother-
apy, International Journal of Radiation Oncology* Biology* Physics 70 (2008) 847–852.

[21] P. M. Altrock, L. L. Liu, F. Michor, The mathematics of cancer: integrating quantitative

models, Nature Reviews Cancer 15 (2015) 730–745.

4
[22] J. A. Adam, A simplified mathematical model of tumor growth, Mathematical biosciences
81 (1986) 229–244.