Research Article

Received 3 September 2013 Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI: 10.1002/mma.3887

MOS subject classification: 37-02

A mixed radiotherapy and chemotherapy

model for treatment of cancer with metastasis
A. Ghaffaria , B. Bahmaieb *† and M. Nazaric
Communicated by V. Kravchenko
In this paper, a mathematical model of cancer treatment, in the form of a system of ordinary differential equations, by
chemotherapy and radiotherapy where there is metastasis from a primary to a secondary site has been proposed and ana-
lyzed. The interaction between immune cells and cancer cells has been examined, and the chemotherapy agent has been
considered as a predator on both normal and cancer cells. The metastasis may be time delayed. For better investigation of
the treatment process and based on physical investigation, the immanent effects of inputs on cancer dynamic have been
investigated. It is supposed that the interaction between NK cells and tumor cells changes during the chemotherapy. This
novel approach is useful not only to gain a broad understanding of the specific system dynamics but also to guide the
development of combination therapies. The analysis is carried out both analytically (where possible) and numerically. By
considering such immanent effects, the tumor-free equilibrium point will be stable at the end of treatment, and the tumor
can not recur again, and the patient will totally recover. So, the present analysis suggests that a proper treatment method
should change the dynamics of the cancer instead of only reducing the population of cancer cells. Copyright © 2016 John
Wiley & Sons, Ltd.

Keywords: mathematical model; metastasis; time delay; chemotherapy; radiotherapy

1. Introduction
In the recent decades, the issue of modeling, diagnosis, and treatment of cancer is not only in the focus of attention of clinicians and
biology researchers but also is in interest of scientists, including mathematicians and control engineers. A mathematical model can
provide a suitable context and framework to answer the questions about the behavior of immune cells in the presence of cancer cells
and also the behavior of tumor cells in the presence of drugs. Preparation of anticancer drugs by using human or animal specimens
requires a long time. Also, the medical examination besides high risk has a high cost. Because of these matters, an appropriate mathe-
matical model and suitable control model for the injection of the drugs is required. Developing a mathematical model, in order to help
in analyzing the effectiveness of new drugs, diminishes many of these problems, and this will enable doctors to predict and control the
behavior of the cancerous tumor [1]. Therefore, doctors and biologists are increasingly aware of the role of mathematical modeling as
a new way in order to progress the medical knowledge and present techniques.
There are many points of view in cancer treatment modeling. Some of these models deal with the treatment from an optimization
point of view, from a compartmental point of view, and from a dynamical point of view [2]. We are interested in the dynamical point of
view that examines the interaction between immune cells and cancer cells. A number of mathematical models have been developed
to describe tumor-immune dynamics. A review of non-spatial tumor-immune models can be found in [3]. The interaction between
immune cells and cancer cells can be explored by ordinary differential equation (ODE) models.
Tumors with high variability in humans (and animals) are seen, often were benign and called tumor. The fibrous capsule surrounding
the tumor can prevent its spread. In comparison, a group of tumors that cause cancer they rarely spread in the body called malignant
tumor; prominent characteristics distinguish both benign and malignant tumors. Invasion characteristic is of the most important fea-
ture of malignant tumors. These tumors are not encapsulated and through the metastasis process enter into the bloodstream of the
body and are replaced in new tissues and cause tumors. Independent of the type of cancer, the large majority of cases, there is no sig-
nificant risk of cancer in the primary tumor but is in a secondary tumor that has originated metastasis of tumor. Hence, it is significant

a Mechanical Engineering, Faculty of Mechanical Engineering, Shahrood University of Technology, Shahrood 3619995161, Iran
b Mechanical Engineering, Faculty of Mechanical Engineering, K. N. Toosi University of Technology, Pardis St., Vanak Sq., Tehran 16569 83911, Iran
c Faculty of Mechanical Engineering, K. N. Toosi University of Technology, Pardis St., Vanak Sq., Tehran 16569 83911, Iran
* Correspondence to: Behnaz Bahmaie, Mechanical Engineering, K.N. Toosi University of Technology, Pardis St., Vanak Sq., Tehran 16569 83911, Iran.
† E-mail: behnazbahmaie@gmail.com

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 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

to consider this process in the cancer modeling. This process takes time. This time based on the type of cancer and where secondary
tumors are composed is different. Because of this process, there is often a time delay (sometimes significant) for this to occur [4]. Hence,
it is reasonable to model the interaction between immune cells and cancer cells at two specific sites with metastasis between the
primary and the secondary sites with a time delay.
Several authors have addressed the computation of the probability for metastatic creation on the base of stochastic models [5–14].
Other models dealt with tumor spreading to surrounding tissues in terms of spatial models [15–24]. Iwata et al. proposed a dynamical
model for the growth and size distribution of multiple metastatic tumors [25]. They showed a combined analysis of the theoret-
ical colony size distribution, and clinical data will give useful information on the diagnosis and the therapy for cancer patients.
Pinho et al. presented a chemotherapy model for the treatment of cancer with metastasis. They considered three-differential equations
for the primary tumor and three-differential equations for the secondary tumor. These equations are closely associated with a time
delay term [2]. Greco showed that it may metastatic disease exists without evidence for cells with metastatic potential in the primary
state [26]. Metastatic spread was described in a model by Chen et al. [27], which made use of a large database of Medicare claims. In
another effort, to better understand the patterns of metastasis, Newton et al. proposed an MC model of metastatic patterns of primary
lung cancers [28, 29]. Scott et al. published a review of mathematical modeling of the metastatic process [30].
However, some of the existing studies on cancer therapy are based on the assumption that cancer growth is a time invariant dynamic
system [31]. They have been focused on the following objectives:

(1) To lessen the treatment burden of patients. This method considers some constraints on the treatment policy [32].
(2) To reduce and control the tumor mass such that a specified volume is obtained at the end of the treatment [33–41].
(3) To evaluate the number of injected cells that affect the equilibrium points of the immune system and thus may ultimately be
dangerous [42].

Previous studies have investigated the effects of therapeutic inputs, which are considered to have direct effects on the system states
[32–43]. However, the behavior of cancer changes as the disease progresses [44]. External stresses that represent destructive inputs,
such as environmental and quality of life factors, can cause disability in the DNA repair genes [45]. They can also interfere with, and
alter, the functions of regulatory growth signals (TGF-a), growth-inhibiting signals (TGF-b), and apoptosis (TP53) [44].
In this study, a system of ODE that present interaction between immune cells and cancer cells is considered. This model is based
on the model developed in [34, 46]. Also, the migration of the cancer cells from the primary site to the secondary site with a time
delay has been taken into account. Moreover, a novel approach for finite duration treatment such that at the end of the treatment the
tumor becomes eradicated has been proposed. The proposed treatment method not only reduces the tumor cells but also modifies
the dynamics of the system in order to correct the destructive changes in the system dynamic. This treatment approach is also used for
cancer treatment in [47–50]. In [47], the drug is used in order to stabilize the tumor-free equilibrium point. However, in [48], the cancer
model must be modified because of the lack of stable tumor-free equilibrium point in the first orthant.
The organization of the paper is as follows. In the next section, our model has been developed. In Section 3, the equilibrium points of
the system and their local stabilities in the no treatment case have been examined. In Section 4, the treatment case has been considered.
Then, the effect of mixed radiotherapy and chemotherapy on the system has been examined.

2. The mathematical model

The system by means of thirteen ODEs, altogether simulating the interactions between the normal cells, cancer cells, radiotherapy, and
chemotherapy agent at each site with metastasis of the cancer from the primary to the secondary site has been modeled. The states of
the system are described in Table I.

Table I. The states of the cancer model.

Cell population
Tp .t/ The total tumor cell population at the primary site
Np .t/ The concentration of NK cells per liter of blood (cells/L) at the primary site
Lp .t/ The concentration of CD8CT cells per liter of blood (cells/L) at the primary site
C.t/ The concentration of lymphocytes per liter of blood (cells/L), not including NK cells and active CD8CT
Ts .t/ The total tumor cell population at the secondary site
Ns .t/ The concentration of NK cells per liter of blood (cells/L) at the secondary site
Ls .t/ The concentration of CD8CT cells per liter of blood (cells/L) at the secondary site
Concentrations
M.t/ The concentration of chemotherapy agent per liter of blood (mg/L)
u.t/ The population of cancer cells that have been exposed to radiation
v.t/ The population of NK cells that have been exposed to radiation
x.t/ The population of CD8CT cells that have been exposed to radiation

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M. NAZARI, B. BAHMAIE AND A. GHAFFARI

The effect of radiotherapy is included in the mathematical model by the term D .t/. Also, the effect of chemotherapy is included by
the term M .t/, which vM .t/  0 , is the amount of chemotherapy agent injected per day per liter of blood. The chemotherapy agent
acts like a predator on both normal and cancer cells at each site. Further, there is a possible time delay of length  between the time
cancer cells leave the primary site and begin to interact on the secondary site.
We all know that the system parameters for a healthy and cancerous person are different. Also, the behavior of cancer changes as
the disease progresses [44]. But in all previous studies, the system parameters are fixed during the treatment, while treatments change
the patient’s condition, interaction between cells, cell growth, apoptosis and so on. In [47], different trajectory patterns of a cancerous
person during its life, due to changes in the parameters of its dynamic, are shown.
Hence, in this paper, the effects of chemotherapy on some parameters of the system are considered. The role of chemotherapy
might be as a treatment which changes the system parameters. The rate of changing c1 , c2 is assumed to be proportional to the input
magnitude vM .t/ [47]. c1 and c2 depend on the dynamics of c1 and c2 , respectively. The biotransformation coefficients saturate at a
definite limit kc1 and kc2 , which are related to the biological limits of the body organs and the accumulation of external effect [47]. So,
the modified equations of the system are as follows:

 
dTp   Tp M Llp
D a1 Tp 1  b1 Tp  c1 Np Tp  Dp Tp  ˛1 Tp  D .t/ Tp C 1 u  K1T Dp D d1 (1)
dt W1T C Tp sTpl C Llp

 
dNp Np M
D e1 C  p1 Np Tp  f1 Np  "D .t/ Np C 2 v  K1N (2)
dt W1N C Np
 
dLp Tp Lp M
D m1 Lp C j1 Lp  q1 Lp Tp C r11 Np Tp C r12 CTp  u1 Np L2p  "D .t/ Lp C 3 x  K1L (3)
dt k1 C Tp W1L C Lp
 
dC CM
D ˛  ˇC  K1C (4)
dt W1C C C
 
dTs Ts M Lls
D a2 Ts .1  b2 Ts /  c2 Ns Ts  Ds Ts C ˛2 Tp .t   /  K2T , Ds D d2 (5)
dt W2T C Ts sTsl C Lls
 
dNs Ns M
D e2 C  p2 Ns Ts  f2 Ns  K2N (6)
dt W2N C Ns
 
dLs Ts Ls M
D m2 Ls C j2 Ls  q2 Ls Ts C r21 Ns Ts C r22 CTs  u2 Ns L2s  K2L (7)
dt k2 C Ts W2L C Ls
 
dc1 c1
D c1 vM .t/ 1  (8)
dt kc1
 
dc2 c2
D c2 vM .t/ 1  (9)
dt kc2

dM
D M C vM .t/ (10)
dt

du
D D .t/ Tp  1 u  ıu (11)
dt

dv
D "D .t/ Np  2 v  ıv (12)
dt

dx
D "D .t/ Lp  3 x  ıx (13)
dt

Note also that the system, which is an autonomous system with differentiable functions, satisfies existence and uniqueness of initial
value problems [2, 51].ıIn Eqs (2) and (3), the equations of NK cells and CD8CT cells have undergone two important changes. The
recruitment term gNT 2 .h C T 2 / has been removed from the de Pillis et al. model [34] due to their observed insignificance within the
context of the model, as evidenced by computer simulations and due to the additional complexity of the dynamics they introduce [52].
D2 T 2 Tp
In addition, the term j kCD 2 T 2 L changed to another expression j1 k CT Lp in accordance with the model presented in [52].
1 p

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 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

A concise illustration of each term can be found in Appendix A. Also, the parameters of the system and their values, from experimental
data, are described in Appendix B. All constants are positive except possibly for  , which may be zero.
The growth rate of cancer cells changes over time. In other words, the growth rate is high at first and then reduced by increasing
the tumor size. The cells that transmitted through the blood or lymphocytes create a secondary tumor. They initially located at this
new location and will begin to multiply rapidly if there is a suitable growing environment. Therefore, the growth rate of cancer cells in
the secondary site is higher than the primary site. Moreover, because of this rapid growth of the tumor cells in the secondary site in
comparison with the primary site, the death rate of the tumor cells due to natural killer cells (NK cells) and CD8C cells in the secondary
site is lower than the primary site. Hence, with similar deduction, the coefficients model with some differences in primary and secondary
locations are considered, which is in accordance with [2].

3. The no treatment case

In this section, the system of equations in the absence of treatment has been analyzed. In the absence of radiotherapy and chemother-
apy, the model is reduced to a seven-population system of ODEs. We derive equilibria, analyze the local stability, and present some
numerical results. The no treatment system is given in the following:

dTp   Llp
D a1 Tp 1  b1 Tp  c1 Np Tp  Dp Tp  ˛1 Tp , Dp D d1 l (14)
dt sTp C Llp

dNp
D e1 C  p1 Np Tp  f1 Np (15)
dt

dLp Tp
D m1 Lp C j1 Lp  q1 Lp Tp C r11 Np Tp C r12 CTp  u1 Np L2p (16)
dt k1 C Tp

dC
D ˛  ˇC (17)
dt

dTs Ll
D a2 Ts .1  b2 Ts /  c2 Ns Ts  Ds Ts C ˛2 Tp .t   / , Ds D d2 l s l (18)
dt sTs C Ls

dNs
D e2 C  p2 Ns Ts  f2 Ns (19)
dt

dLs Ts
D m2 Ls C j2 Ls  q2 Ls Ts C r21 Ns Ts C r22 CTs  u2 Ns L2s (20)
dt k2 C Ts

Figure 1 shows the time evolution of the state variables in the absence of the treatment. Without treatment, the cancer cells of both
sites win the competition with the immune cells, which this is consistent with the hypothesis of cancer. It has to be noted that all
variables are positive because negative values for variables are not biologically plausible.

3.1. Equilibria
In order to derive the equilibria of the system, we simultaneously set all Eqs (14)–(20) equal to zero. Equation (17) is decouple from
the others, so we have CE D ˛ ˇ
. By setting (14) equal to zero, we may have two type equilibrium points. One of them is the tumor-
free equilibrium point, that is, TE D TE p C TEs D 0. The second type corresponds to non-zero tumor cell population. The tumor-free
equilibrium point for all seven state variables is given by
 e2 ˛

E0 D 0,e1 ˛ =ˇf1,0,˛ =ˇ ,0, =ˇf2,0 .

The other equilibrium points for the non-zero tumor population, that is TE D TE p C TEs ¤, must be obtained numerically. By setting
(15) and (19) equal to zero and solving for NE p and NE s , we have the following:
e1 C
NE p D (21)
p1 Tp C f1

e2 C
NE s D (22)
p2 Ts C f2
Similarly, by setting (14) and (18) equal to zero gives

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M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Figure 1. The time evolution of the no treatment model.

DE p D a1  a1 b1 Tp  c1 Np  ˛1 (23)

a2 Ts .1  b2 Ts /  c2 Ns Ts C ˛2 Tp
DE s D (24)
Ts

By using the aforementioned expressions, we obtain the following:

!1=l
sDE p Tpl
LE p D (25)
d1  DE p

 1=l
sDE s Tsl
LE s D (26)
d2  DE s

Finally, by setting (16) and (20) equal to zero gives

 
Tp  
u1 Np L2p  m1 C  q1 Tp Lp  r11 Np Tp C r12 CTp D (27)
k1 C Tp

 
Ts
u2 Ns L2s  m2 C  q2 Ts Ls  .r21 Ns Ts C r22 CTs / D 0 (28)
k2 C Ts

Equilibrium points of the system defined by (14)–(20) are founded by intersecting Eqs (25) and (27) and Eqs (26) and (28). Numer-
ical simulation shows that there are two solutions to (21)–(28), which only one of them is positive (Figures 2 and 3). This means
that it is biologically plausible. So, the system has only two equilibrium points with the parameters stated in Appendix B. However,
as a system parameter is changed, other non-zero equilibria may appear, or negative equilibria can become positive and therefore
biologically feasible.
Therefore, the high-tumor equilibrium point is
 
E1 D 1.905107 , 1.993102 , 2.823106 , 6.25  10, 3.764105 , 1.654  104 , 5.430  105

3.2. Local stability

In this section, the stability of the equilibrium points has been examined by linearization the system about that equilibrium point.
Tumor-free equilibrium point is very important from a physiological viewpoint. Treatments actually should be able to push the system
to this point eventually. The Jacobian matrix of the system about the tumor-free equilibrium point E0 is as follows:

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 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Figure 2. The non-zero equilibria from intersecting Eqs (25) and (27).

Figure 3. The non-zero equilibria from intersecting Eqs (26) and (28).

2 3
a1  c1 Np  ˛1 0 0 0 0 0 0
6 p1 Np f1 0 e1 0 0 0 7
6 7
6 r N Cr C 0 m1 0 0 0 0 7
6 11 p 12 7
6 7
JD6
6 0 0 0 ˇ 0 0 0 77
6 ˛ exp. / 0 0 0 a2  c2 Ns 0 0 7
6 2 7
6 7
4 0 0 0 e2 p2 Ns f2 0 5
0 0 0 0 r21 Ns C r22 C 0 m2

It is easy to see that the local stability analysis around any equilibrium point does not depend on the time delay  . The eigenvalues of
the Jacobian matrix around this equilibrium point are as follows:
8
ˆ 1 D a1  c1 Np  ˛1
ˆ
ˆ
ˆ
ˆ 2 D f1 < 0
ˆ
ˆ
ˆ
ˆ
< 3 D m1 < 0
ˆ 
4 D ˇ < 0
ˆ
ˆ
ˆ 5 D a2  c2 Ns
ˆ
ˆ
ˆ
ˆ
ˆ
ˆ 6 D f2 < 0
:̂
7 D m2 < 0

Because f1 , m1 ,ˇ, f2 , and m2 are positive, therefore, the eigenvalues2 , 3 , 4 , 6 , and 7 are always negative, so the tumor-free
equilibrium point E0 is asymptotically stable if and only if
.a1  ˛1 /ˇf1
a1  c1 Np  ˛1 < 0 ! c1 > (29)
e1 ˛

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M. NAZARI, B. BAHMAIE AND A. GHAFFARI

and
a2 ˇf2
a2  c2 Ns < 0 ! c2 > (30)
e2 ˛

Remember that the parameter c represents the interaction between NK cells and tumor cells.
The stability of the high-tumor equilibrium point is also investigated by linearization the system around the equilibrium point E1 :
2 3
0.0084 0.0012 4.8838 0 0 0 0
6 6.8154e  004 65.0212 0 2.0800e  007 0 0 0 7
6 7
6 0.0548 2.3886e C 003 27.5868 0.0012 0 0 0 7
6 7
JD6
6 0 0 0 0.0120 0 0 0 7
7
6 1.0000e  005 0 0 0 1.4491e C 006 3.7640e  007 0.2094 7
6 7
4 0 0 0 2.0800e  007 0.0331 0.7878 0 5
0 0 0 2.8230e  005 4.1480 88.3859 5.9465

So, the eigenvalues are the following:

8
ˆ 1
ˆ
ˆ
D 8.05e C 06
ˆ
ˆ 2 D 1.4491e C 06
ˆ
ˆ
ˆ
< 3 D 65.1
4 D 27.5868
ˆ
ˆ
ˆ 5
ˆ D 0.7878
ˆ
ˆ
ˆ 6 D 5.9465
:̂
7 D 0.0120

This equilibrium point is stable. This means that if the treatment is stopped and the dynamics of the system have not been changed
during the treatment, the system will return to its high-tumor state. So, if the tumor-free equilibrium point is unstable, in order to have
an effective cure, any treatment must not only lessen the tumor volume but it must also change the parameters of the system.

4. Treatment case: combination of radiotherapy and chemotherapy treatments

In order to cause a large tumor to die, a combination of both chemotherapy and radiotherapy is necessary. In fact, with a radiation
protocol over a period of 35 days greatly reduce the initial tumor volume. Then, a rest period of 1 month has been considered. After-
ward, a course of chemotherapy has been started. The chemotherapy agent affects on both the primary and secondary tumor sites and
eradicates it until the end of treatment.

4.1. Numerical results

In this section, the behavior of our model by considering the combination treatment has been simulated. A tumor of size 107 cells is too
large for the immune system to control naturally. So, the first treatment employs several doses of radiotherapy, where is represented
by setting D.t/ in Eqs (1)–(3) for certain days and is given in a 35-day cycle. The dose of this protocol is based on the protocols that
are used in the clinics. The second treatment employs chemotherapy in a period of 70 days. Combination therapy is more effective at
killing a tumor than either individual treatment alone. The radiotherapy and chemotherapy protocols may be one of several modes.
Clinical observations indicate when in each period the dose was gradually reduced the patient’s general health will be better. In this
paper, we consider two styles of protocols for radiotherapy and chemotherapy: constant dosage and decaying dosage.

4.2. The case of constant dosage

Combination treatment is able to eliminate a tumor of 107 cells as shown in Figure 4. The simulation shows the effectiveness of com-
bination therapy. At the end of the first treatment, the tumor cell population has declined to 99  105 . But, the system is still unstable
about its tumor-free equilibrium point. After the end of radiotherapy, tumor cells begin to multiply and grow. Therefore, it is necessary
to prevent the re-growth of tumor cells by using chemotherapy. Chemotherapy for advanced cancer or multiple metastases is used
because it is the only thing that can destroy cancer cells over the body. After a month short rest, we start chemotherapy. Chemotherapy
agent, spreads through the body and by effecting on the tumor growth dynamics and its interaction with the immune system, reduces
the tumor cells populations and will stabilize the system around its tumor-free equilibrium point.
Furthermore, it was hypothesized that at the start of treatment small metastasis occurs in other part of the body. Figure 5 shows the
changes in the cell populations in the new location. As shown over time, the number of tumor cells increase and arrive to a significant
value and then was gradually reduced to zero when chemotherapy started. Also, normal cells reach to a certain amount.
Indeed, radiation therapy may leave a part of the central tumor cells that exist in hypoxic areas, but often radiation therapy
and surgery are poor due to small microscopic metastases in early treatment of clinically unsuspected. Therefore, radiotherapy and
chemotherapy are so important for small metastases. Using the protocol proposed in this paper, small metastases that are not
detectable at treatment time are lost.

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 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Figure 4. Top left: dynamics of the tumor growth during combination treatment. Top right: radiation administration pattern: five doses of radiotherapy over
35 days. Bottom left: changes in the population of immune cells (NK cells and CD8C T cells) during combination treatment. Bottom right: chemotherapy protocol:
drug administration pattern.

Figure 5. Dynamics of the secondary tumor growth during the combination treatment with constant dose.

4.3. The case of decaying dosage

In this section, the previous simulations are performed again when the dose of radiotherapy and chemotherapy varies exponentially.
Figure 6 shows the changes in the cell populations in the primary tumor. As shown, the primary tumor cells population is higher than
before. In fact, this treatment protocol can destroy a small number of tumor cells. But the numbers of CD8CT cells appear too much;
therefore, the patient’s general health is better. These cells directly attack tumor cells. Figure 7 shows the dynamics of the secondary
tumor cells. As indicated in this figure, at the end of treatment, these cells did not reach zero. So, this protocol is weaker than the
previous protocol in removing small metastases at a given time.
As mentioned, most chemo drugs destroy cancerous cells growing rapidly. Because cancerous cells proliferate faster than normal
cells, cancer drugs affect on them more than normal cells. Regulatory mechanisms of cell division stop and prevent success reproduc-
tion, and growth is very irregular. The parameter c represents the interaction of tumor cells and normal cells. Reduction of tumor growth
rate and increase in apoptosis due to damaged DNA can be changed during treatment. According to Eqs (8) and (9), the parameter c
changes due to chemotherapy. We want to know which type of treatment can reach this parameter to its desired value. Figure 8 shows
the changes in c during treatment. As shown in exponential form, the optimal value of this parameter is faster reached. In other words,
exponential dosage protocol corrects the dynamics of the cancer faster than that of constant protocol.
However, if the parameter c is fixed during the treatment, after the end of the treatment, the system comes back to its high-tumor
equilibrium point due to the instability of E0 . In this case, the tumor re-grows after treatment (Figure 9). As shown in Figures 4 and 6,
after the end of the treatment, the tumor cells populations converge to zero. In other words, the treatment procedure changes the

Copyright © 2016 John Wiley & Sons, Ltd. Math. Meth. Appl. Sci. 2016
M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Figure 6. Top left: Dynamics of the tumor growth during combination treatment. Top right: radiation administration pattern: five doses of radiotherapy over
35 days in exponential form. Bottom left: changes in population of immune cells (NK cells and CD8+T cells) during combination treatment. Bottom right:
chemotherapy protocol: drug administration pattern in exponential form.

Figure 7. Dynamics of the secondary tumor growth model during the combination treatment with decaying dose.

Figure 8. Changing the parameter c during the treatment.

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 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Figure 9. Dynamics of the tumor growth after combination treatment with fixed c during treatment.

stability of the tumor-free equilibrium point and pushes the system to its domain of attraction. Hence, after the end of the treatment,
the system converges to tumor-free equilibrium point, although the tumor cells population is not exactly zero.

5. Conclusion
In this paper, previous mathematical models of cancer by mixed radiotherapy and chemotherapy have been extended and analyzed
where metastasis of the cancer cells occurs. First, the system of equations in the absence of treatment has been analyzed; then, the
equilibrium points of the system along with the criteria for stability have been determined. The instability of the tumor-free equilibrium
implies that any successful treatment must be able to change the system parameters in order to force this desirable equilibrium point
to become stable. So, the immanent effect of chemotherapy is considered for changing the parameters c1 and c2 of the system, for
example, by elevating the cytolytic potential of the natural killer cells. Chemotherapy agent has an effect on primary tumor, secondary
tumor, and the interaction between NK cells and tumor cells (the parameters c1 and c2 /. So, it begins to destroy the tumor and with
affect on the system parameters leads to change in the stability of the system around the tumor-free equilibrium point. Therefore, by
pushing the system inside the domain of attraction of this equilibrium point, the tumor cells populations converge to zero. It is shown
that after the end of treatment, although the populations of tumor cells are not zero, due to change in the stability of tumor-free
equilibrium point and pushing the system to its domain of attraction, the system converges to the tumor-free equilibrium point. Also,
it is shown that the decaying dosage protocol is weaker than constant dosage protocol in removing small metastases at a given time.
So, the development of combination radiotherapy–chemotherapy protocols for remedying certain forms of cancer is an appropriate
strategy in cancer treatment research. Also, the present study suggests that a proper treatment method should change the dynamics
of the cancer instead of only reducing the population of tumor cells.

Appendix A. Nomenclature and parameter values

In this section, we list all of the parameters used in the model, their definition, and their estimated values. Table A1 shows the
experiments run to simulate the human experiments from [34].

Table AI. Estimated human parameter values [34].

Parameter Units Description Estimated value Source
1 1
a1 day Primary tumor growth rate 4.31  10 [54]
b1 cells1 1=b is tumor carrying capacity (in primary tumor) 1.02  109 [54]
c1 cell1 day1 Fractional (non)-ligand-transduced tumor cell 6.41  1011 [54]
kill by NK cells in (in primary tumor)
d1 day1 Saturation level of fractional tumor cell kill by 2.34 [54]
CD8C T cells. Primed with ligand-transduced cells,
challenged with ligand-transduced cells (in
primary tumor)

Copyright © 2016 John Wiley & Sons, Ltd. Math. Meth. Appl. Sci. 2016
M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Table AI. Continued.

Parameter Units Description Estimated value Source
C
l None Exponent of fractional tumor cell kill by CD8 T 2.09 [54]
cells. Primed with ligand-transduced cells,
challenged with ligand-transduced cells
(in primary tumor)
s None Steepness coefficient of the tumor-(CD8C T 8.39  102 [54]
cell) lysis term D. Primed with ligand-transduced
cells, challenged with ligand-transduced
cells (in primary tumor)
e1 day1 Fraction of circulating lymphocytes 2.08  107 [55]
that become NK cells (in
primary tumor)
f1 day1 Death rate of NK cells (in primary tumor) 4.12  102 [55]
p1 cell1 day1 NK cell inactivation rate by tumor 3.42  106 [54]
cells (in primary tumor)
m1 day1 Death rate of CD8C T cells (in primary tumor) 2.04  101 [56]
j1 day1 Maximum CD8C T cell recruitment 2.49  102 [55]
rate. Primed with ligand-transduced cells, [54]
challenged with ligand-transduced
cells (in primary tumor)
k1 cell2 Steepness coefficient of the 3.66  107 [55]
CD8CT cell recruitment curve [54]
(in primary tumor)
q1 cell1 day1 CD8C T cell inactivation rate 1.42  106 [55]
by tumor cells (in primary tumor)
r11 cell1 day1 Rate at which CD8C T cells are 1.1  107 [56]
stimulated to be produced as a result
of tumor cells killed by NK cells [57]
(in primary tumor)
r12 cell1 day1 Rate at which CD8C T cells are stimulated to be 6.5  1011 [34]
produced as a result of tumor cells interacting
with circulating lymphocytes (in primary tumor).
u1 cell2 day1 Regulatory function by NK cells of CD8C T –cells 3  1010 [34]
(in primary tumor)
K1T day1 Fractional tumor cell kill by chemotherapy 100 Estimated
(in primary tumor)
K1L K1N day1 Fractional immune cell kill by chemotherapy 10 Estimated
(in primary tumor)
K1C day1 Fractional immune cell kill by chemotherapy 10 Estimated
(in primary tumor)
˛ cellday1 Constant source of circulating 7.5  108 [58]
lymphocytes [59]
ˇ day1 Natural death and differentiation of 1.2  102 [58]
circulating lymphocytes [59]
 day1 Rate of chemotherapy drug decay 9  101 [60]
a2 day1 Secondary tumor growth rate 5 Estimated
b2 cells1 1=b is tumor carrying capacity 1  107 Estimated
(in secondary tumor)

Copyright © 2016 John Wiley & Sons, Ltd. Math. Meth. Appl. Sci. 2016
 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Table AI. Continued.

Parameter Units Description Estimated value Source
1 1 12
c2 cell day Fractional (non)-ligand-transduced tumor cell 6.41  10 Estimated
kill by NK cells in (in secondary tumor)
d2 day1 Saturation level of fractional tumor cell kills by CD8C T 5 Estimated
cells, Primed with ligand-transduced cells, challenged
with ligand-transduced cells (in secondary tumor)
e2 day1 Fraction of circulating lymphocytes that 2.08  107 Estimated
become NK cells (in secondary tumor)
f2 day1 Death rate of NK cells (in secondary tumor) 3.5  102 Estimated
p2 cell1 day1 NK cell inactivation rate 1  106 Estimated
by tumor cells (in secondary tumor)
m2 day1 Death rate of CD8C T cells 1.8  101 Estimated
(in secondary tumor)
j2 day1 Maximum CD8C T cell recruitment 1.6  102 Estimated
rate. Primed with ligand-transduced cells,
challenged with ligand-transduced cells
(in secondary tumor)
k2 cell2 Steepness coefficient of the CD8CT cell 3.66  107 Estimated
recruitment curve (in secondary tumor)
q2 cell1 day1 CD8C T cell inactivation rate 1  106 Estimated
by tumor cells (in secondary tumor)
r21 cell1 day1 Rate at which CD8C T cells are 2  107 Estimated
stimulated to be produced as a result of tumor
cells killed by NK cells (in secondary tumor)
r22 cell1 day1 Rate at which CD8C T cells are tumor cells i 7.5  1011 Estimated
stimulated to be produced as a result of
nteracting with circulating lymphocytes
(in secondary tumor)
u2 cell2 day1 Regulatory function by NK cells of CD8C T –cells 3  1010 Estimated
(in secondary tumor)
K2T day1 Fractional tumor cell kill by chemotherapy (in 100 Estimated
secondary tumor)
K2L K2N day1 Fractional immune cell kill by chemotherapy (in 10 Estimated
secondary tumor)
K2C day1 Fractional immune cell kill by chemotherapy (in 10 Estimated
secondary tumor)
1 cell1 day1 Restoration and recovery rate of damaged cells irradiated 0.04 Estimated
2 cell1 day1 Restoration and recovery rate of damaged cells irradiated 0.1 Estimated
3 cell1 day1 Restoration and recovery rate of damaged cells irradiated 0.1 Estimated
"  Part of radiation to damage healthy cells 0.05 Estimated
˛1  Rate at which cancer leave the primary site 0.0001 Estimated
˛2  Rate at which cancer cells reach and interact 0.00001 Estimated
at the secondary site after having left the primary site
w1T cell2 Determine the speeds at which cancer cells, in the 0.01 Estimated
absence of competition and predation, reaches
carrying capacity in primary
w1N w1L w1L cell2 Determine the speeds at which immune cells, in the 1 Estimated
absence of site competition and predation, reaches
carrying capacity in primary
w2T cell2 Determine the speeds at which cancer cells, in the 1 Estimated
absence of site competition and predation, reaches
carrying capacity in secondary
w2N w2L cell2 Determine the speeds at which immune cells, in the 1 Estimated
absence of site competition and predation, reaches
carrying capacity in secondary

Copyright © 2016 John Wiley & Sons, Ltd. Math. Meth. Appl. Sci. 2016
M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Appendix B. Equation terms descriptions

Table BI. Description of equation terms.

Equation Term Description
dTp  
dt
a1 Tp 1  b1 Tp Logistic tumor growth in primary tumor
c1 Np Tp NK-induced tumor death in primary tumor
Dp Tp CD8CT cell-induced tumor death in primary tumor
˛1 Tp Rate at which cancer leave the primary site
D .t/ Tp Irradiated rate of tumor cells
C1 u Possible recovery of irradiated cancer cells
 
T M
K1T W1TpCTp Chemotherapy-induced tumor death in primary tumor
dNp
dt
e1 C Production of NK cells from circulating lymphocytes in primary tumor
p1 Np Tp NK death by exhaustion of tumor-killing resources in primary tumor
f1 Np NK turnover in primary tumor
"D .t/ Np Irradiated rate of NK cells
C2 v Possible recovery of irradiated NK cells
 
N M
K1N W1NpCNp Death of NK cells due to chemotherapy toxicity in primary tumor
dLp
dt
m1 Lp CD8CT-cell turnover in primary tumor
Tp
Cj1 k1 CT p
Lp CD8CT-cell stimulation by CD8CT cell-lysed tumor-cell debris in primary tumor
q1 Lp Tp CD8CT-cell death by exhaustion of tumor-killing resources in primary tumor
Cr11 Np Tp CD8CT-cell stimulation by NK-lysed tumor-cell debris in primary tumor
Cr12 CTp Activation of native CD8CT cells in the general lymphocyte population in primary tumor
u1 Np L2p Breakdown of surplus CD8CT cells in the presence of IL-2 in primary tumor
"D .t/ Lp Irradiated rate of CD8CT cells
C3 x Possible recovery of irradiated CD8CT cells
 
L M
K1L W1LpCLp Death of CD8CT cells due to chemotherapy toxicity in primary tumor
dC
dt
˛ Lymphocyte synthesis in bone marrow in primary tumor
ˇC Lymphocyte turnover in primary tumor
 
CM
K1C W1C CC
Death of lymphocytes due to chemotherapy toxicity
dTs
dt
a2 Ts .1  b2 Ts / Logistic tumor growth in secondary tumor
c2 Ns Ts NK-induced tumor death in secondary tumor
Ds Ts CD8CT cell-induced tumor death in secondary tumor
C˛2 Tp .t   / Metastasis term
 
K2T W2TTsCT
M
s
Chemotherapy -induced tumor death in secondary tumor
dNs
dt
e2 C Production of NK cells from circulating lymphocytes in secondary tumor
p2 Ns Ts NK death by exhaustion of tumor-killing resources in secondary tumor
f2 Ns NK turnover in secondary tumor
 
K2N W2NNsCN
M
s
Death of NK cells due to chemotherapy toxicity in secondary tumor
m2 Ls CD8CT-cell turnover in secondary tumor
Ts
Cj2 k2 CT s
Ls CD8CT-cell stimulation by CD8CT cell-lysed tumor-cell debris in secondary tumor
dLs
dt
q2 Ls Ts CD8CT-cell death by exhaustion of tumor-killing resources in secondary tumor
Cr21 Ns Ts CD8CT-cell stimulation by NK-lysed tumor-cell debris in secondary tumor
Cr22 CTs Activation of native CD8CT cells in the general lymphocyte population in primary tumor
u2 Ns L2s Breakdown of surplus CD8CT cells in the presence of IL-2 in secondary tumor
 
K2L W2LLsCL
M
s
Death of CD8CT cells due to chemotherapy toxicity in secondary tumor
dM
dt
M Excretion and elimination of chemotherapy in secondary tumor
D .t/ Tp Irradiated rate of tumor cells
du
dt
1 u Possible recovery of irradiated cancer cells
ıu Clearance rate of irradiated dead tumor cells

Copyright © 2016 John Wiley & Sons, Ltd. Math. Meth. Appl. Sci. 2016
 M. NAZARI, B. BAHMAIE AND A. GHAFFARI

Table BI. Continued.

Equation Term Description
"D .t/ Np Irradiated rate of NK cells
dv
dt
2 v Possible recovery of irradiated NK cells
ıv Clearance rate of irradiated dead NK cells
"D .t/ Lp Irradiated rate of CD8CT cells
dx
dt
3 x Possible recovery of irradiated CD8CT cells
ıx Clearance rate of irradiated dead CD8CT cells
 
dc1
dt
c1 vM .t/ 1  kcc11 Changing the c1 parameter with chemotherapy input
 
dc2
dt
—c2 vM .t/ 1 kcc22 Changing the c2 parameter with chemotherapy input

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