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Nonlinear Analysis: Real World Applications 10 (2009) 27092715

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Nonlinear Analysis: Real World Applications


journal homepage: www.elsevier.com/locate/nonrwa

Stability criteria for the cure state in a cancer model with


radiation treatment
H.I. Freedman a, , S.T.R. Pinho b
a

Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Alberta, Canada, T6G 2G1

Instituto de Fisica, Universade Federalde Bahia, 40.210-340, Salvador, Bahia, Brazil

article

info

Article history:
Received 25 August 2008
Accepted 25 August 2008
This paper is written in honour of the 84th
birthday of V. Lakshmikantham
Keywords:
Cancer modelling
Cure state
Equilibria
Ordinary differential equations
Radiation
Stability

a b s t r a c t
In the present paper, a model for treatment by radiation of cancer is developed, where
the radiation affects normal cells proportionately. We consider only the case where the
radiation delivery is constant. In particular, we are interested in the existence and stability
properties of a cure state, i.e. a steady state in which the cancer is absent. We use ordinary
differential equations to model the growth and interactions. We utilize both analytical and
numerical analysis to obtain our results.
2008 Elsevier Ltd. All rights reserved.

1. Introduction

Previously [3], we have modeled the effects of radiation on a cell population with various protocols of radiation delivery.
The effect of radiation is to destroy cells by causing one or more chromosomes to break. Then the cells will be unable to
reproduce, will die off, and eventually will wash out of the system [5,7,912].
In this paper, we will extend our models to interactions between normal and cancer cells subject to radiation. In [1],
radiation was viewed as a control on cancer cells, but the effect of radiation on chromosomes was not taken into account.
In [6,8] the interactions between normal and cancer cells were viewed as competition for bodily resources and modeled by
a system of ordinary differential equations. We adopt the same point of view here.
In [3], three different radiation delivery protocols were considered. Here, due to space limitations, we consider only
constant delivery. We concentrate our analysis on the cure state, i.e. the equilibrium where the cancer is absent.
The organization of this paper is as follows. In the next section we discuss our model. The equilibria are delineated in
Section 3, and their stabilities discussed in Section 4. In Section 5, we obtain criteria for global stability of the cure state
when radiation does not affect the normal cells. In Section 6 we analyze our model numerically, with a brief discussion in
the last section.

Corresponding author. Tel.: +1 780 492 3530; fax: +1 780 492 6826.
E-mail addresses: hfreedma@math.ualberta.ca (H.I. Freedman), suani@ufba.br (S.T.R. Pinho).

1468-1218/$ see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.nonrwa.2008.08.001

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H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

2. The model
We take as our model, the system of ordinary differential equations

u = ru 1

u
K

Du + pv aux,

u(0) = u0 0

v = Du pv v, v(0) = v0 0

x
x = sx 1
Dx + qy bux, x(0) = x0 0

(2.1)

y = Dx qy y,


=

y(0) = y0 0,

dt

where u(t ) is the concentration of unaffected normal cells, v(t ) is the concentration of broken normal cells, x(t ) is the
concentration of unaffected cancer cells, and y(t ) is the concentration of broken cancer cells. The model and constants may
be interpreted as follows.
In the absence of radiation (D = 0) and competition (a = b = 0), normal and cancer cells grow with specific birth rates
r > 0 and s > 0 respectively to their respective carrying capacities, K > 0 and L > 0. a > 0 and b > 0 represent the
competition coefficients between unaffected normal and cancer cells. The radiotherapy treatment is given by D 0 (D = 0
corresponds to no treatment). The radiotherapy is designed so that the full radiation concentration affects the cancer cells.
However, only a small proportion of the radiation, D, affects the normal cells. Hence 0 is small ( = 0 is the ideal, but
impossible to achieve in a practical scenario). Finally, p and q are the probabilities that the broken normal and cancer cells
can recombine into growing cell populations, respectively.
We note that all functions in system (2.1) are sufficiently smooth, so that all solutions exist uniquely for all positive
time [2].
At this time we can prove the following result.
Theorem 2.1. (i) The nonnegative orthant is invariant. (ii) System (2.1) is dissipative with attracting region contained in

A = (u, v, x, y) : 0 u + v + x + y

(r + )K
(s + )L
+
.
4r
4s

Proof. (i) u |u=0 = pv 0; v |v=0 = Du 0; x |x=0 = qy 0; y |y=0 = Dx 0. Hence no solutions can exit the first
orthant.


= (u+v+x+y)+u r + ru +x s + sx (a+b)ux W + (r +)K + (s+)L .
(ii) Let W = u+v+x+y. Then W
K
L
4r
4s
Hence by the Kamke comparison theorem, W (t ) W (0)e t +

(r +)K
4r

(s+)L
4s

, proving the theorem.

Finally, we will assume that the cancer hypothesis holds throughout the remainder of the paper, namely that in the
absence of treatment, cancer always wins. With no treatment, D = 0, our model reduces to

u

K
x

u = ru 1
x = sx 1

aux,

u(0) 0,
(2.2)

bux,

x(0) 0,

since now v and y never occur. It is well known [8] that the cancer hypothesis reduces to
s bK > 0,

r aL < 0,

which we now assume.

(2.3)

3. Equilibria
There are four possible equilibria for system (2.1), namely E0 (0, 0, 0, 0), e
E (e
u,e
v, 0, 0), b
E (0, 0,b
x,b
y ) and E (u , v , x , y ).
E0 , the null state, always exists.
e
E, the cure state exists if the algebraic system

u

Du + pv = 0
K
Du (p + )v = 0
ru 1

(3.1)

has a positive solution (e


u,e
v ). It was shown in [3] that this is so provided that
0 < D <

r (p + )

(3.2)

H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

2711

in which case

(e
u,e
v) =

K [r (p + ) D] K D[r (p + ) D]

r (p + )

r (p + )2

(3.3)

Similarly, b
E, the cancer state exists if
0<D<

s(q + )

(3.4)

in which case

(b
x,b
y) =

L[s(q + ) D] LD[s(q + ) D]
s(q + )

s(q + )2

(3.5)

Precise criteria for E , the internal state, to exist are unknown. We are fairly certain that E exists whenever e
E and b
E both
exist, and are unstable in directions interior to the positive orthant [4].
Note that if = 0 (no radiation on normal cells), e
E = (K , 0, 0, 0). Also note that for > 0 but sufficiently small, e
E exists.
4. Stability
Local stabilities of the various equilibria are functions of the real parts of the eigenvalues of the variational matrices about
the said equilibria. If (u, v, x, y) is a general equilibrium, then the variational matrix about (u, v, x, y) is given by

M =

2ru

D ax
K
D

au

(p + )

bx

2sx
L

D bu

(q + )

From the structure of M, we see that det (M I ) = det (M 1 I ) det (M 2 I ), where

"

M1 =

2ru

D ax
K
D

(p + )

"

#
,

M2 =

2sx
L

D bu
D

(q + )

#
.

Hence the eigenvalues are given by, after some simplifications

"
#1/2
2

1
2ru
2ru
=
r
D ax p
r
D ax + p + + 4 pD

2
K
K

"
#1/2
2

1
2sx
2sx
=
s
.
s
D bu q
D bu + q + + 4qD

2
L
L

(4.1)

Hence all eigenvalues are real.


4.1. The origin
Consider first E0 . Then u = v = x = y = 0 and

01 =
02 =

1n
2
1n
2

1/2 o

r D p (r D + p + )2 + 4 pD

1/2 o

s D q (s + q + )2 + 4qD

(4.2a)
(4.2b)

From [3] we know that all eigenvalues will be negative (and hence E0 will be stable if both (3.2) and (3.4) are violated,
r (p+)
s(q+)
i.e. D > and D > . Otherwise E0 is unstable.

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H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

Fig. 1. Phase sub-space of non-radiated cells (u x). Case where e


E unstable, b
E stable and E does not exist. Parameters: r = 1.0, K = 4.0, p = 1.0,
a = 0.5, = 0.1, s = 5.0, L = 12.0, q = 3.0, b = 0.5, = 92.5, = 105 . The threshold value is th1 = 93.0. Initial conditions:
u(t = 0) = 10.0, v(t = 0) = 0, x(t = 0) = 1.0, y(t = 0) = 0.0. The cancer cells win the competition.

4.2. The other equilibria


For the cure state e
E,

e
1 =

2re
u

r
D p
2
K

"
r

2re
u
K

D + p +

2

#1/2

+ 4 pD

(4.3a)


1/2 o
1n
e
u + q + )2 + 4qD
2 =
s D be
u q (s D be
.
2

(4.3b)

We know from [3] that in the uv plane, e


E is stable. We are therefore interested in e
2 .
We now prove the following theorem.
Theorem 4.1. Let D satisfy
D>

r (s bK q )(p + )

(4.4a)

r (p + ) bK

and
D>

(s bK )r (p + )(q + )
.
[r (p + ) bK (q + )]

(4.4b)

Then e
2 < 0. If either (4.4a) or (4.4b) then e
2 > 0.

1/2 . Then, (4.4a) implies that < 0. Further (4.4b) implies


< 0. If (4.4a) is reversed, then > 0. If (4.4b) is reversed, then | 1/2 | > ||. In either case

Proof. We already know that e


2 is real. Write e
2 =
1/2

that ||
< ||, and so e
2
e
2+ > 0. 

1
2

For the cancer state b


E, there is an analagous result. However, our interest is with the cure state.
Finally, the interior equilibrium, when it exists, is sufficiently complicated that no specific stability results may be given
at this time.
5. Global stability of the cure state
We consider the positive definite function about e
E over the domain R4+ ,
V (u, v, x, y) = u e
u e
u `n

e
u

+ v e
v `n

v
+ x + y,
e
v

(5.1)

H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

2713

Fig. 2. Phase sub-space of non-radiated cells (u x). Case of bi-stability of e


E and b
E stable, E exists. Parameters: r = 1.0, K = 4.0, p = 1.0, a = 0.5, = 0.1,
s = 5.0, L = 12.0, q = 3.0, b = 0.5, = 95.0, = 105 . Initial conditions: u(t = 0) = 10.0, v(t = 0) = 0, y(t = 0) = 0.0. The cancer cells win the
competition when x(t = 0) = 5.0 (line: dash; symbol: up triangle). The normal cells win the competition when x(t = 0) = 1.0 (line: dot; symbol: circle).

Fig. 3. Phase sub-space of non-radiated cells (u x). Case where e


E stable, b
E unstable and E does not exist. Parameters: r = 1.0, K = 4.0, p = 1.0,
a = 0.5, = 0.1, s = 5.0, L = 12.0, q = 3.0, b = 0.5, = 129.2, = 105 . The threshold value is th2 = 129.2. Initial conditions:
u(t = 0) = 10.0, v(t = 0) = 0, x(t = 0) = 1.0, y(t = 0) = 0.0. The normal cells win the competition.

where e
u and e
v are given in (3.3). Then by algebraic manipulation and the equations given by e
u and e
v, we get the derivative
as
along solutions, V = dV
dt




e
u
pv
pe
v
r 1
+

ax(u e
u)
e
K
K
u
u



e
u
u
x
+ (v e
v) D D
+ sx 1
bux y
v
e
v
L




pe
v
r
De
u
sx2
p
D
=
+
(u e
u) 2
(v e
v)2
y +
+
(u e
u)(v e
v)
ue
u
K
ve
v
L
u
v
(a + b)(u e
u)x + (s be
u)x
 

V = (u e
u) r 1

u

= A2 (u e
u)2 B2 (v e
v)2

x2 + (s be
u)x y + C (u e
u)(v e
v) (a + b)(u e
u)x.

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H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

Fig. 4. Phase sub-space of non-radiated cells (u x). Case where E is globally stable. Parameters (a different set from Figs. 13: r = 2.0, K = 5.0, p = 1.0,
a = 0.5, = 0.1, s = 4.0, L = 12.0, q = 3.0, b = 0.25, = 84.0, = 105 . The threshold values are th1 = 82.67 and th2 = 85.25. Initial conditions:
u(t = 0) = 10.0, v(t = 0) = 0, x(t = 0) = 1.0, y(t = 0) = 0.0.

Fig. 5. Time evolution of non-radiates cells: u (line: black, symbol: square), x (line: grey; symbol: down triangle). The same parameters and initial conditions
of Fig. 4, when E is globally stable.

Thus if the following inequalities hold:


C 2 2A2 B2 < 0

(a + b)2

2A s
L

(5.2)

<0

s be
u < 0,

(5.3)
(5.4)

then e
E is globally asymptotically stable.
6. Numerical examples
Here, we illustrate our analysis by means of numerical examples. We illustrate the outcomes for the non-radiated cells,
since they determine the relevant survival or extinction.

H.I. Freedman, S.T.R. Pinho / Nonlinear Analysis: Real World Applications 10 (2009) 27092715

2715

Fig. 1 illustrates the situation where cancer wins, despite the radiation. In Fig. 2, we get bistability, i.e. either cancer or the
normal cells can win depending on initial conditions. In Fig. 3, we show that elimination of cancer is possible, with the cure
state e
E globally stable. Global stability of the interior equilibrium occurs in Fig. 4. Cancer is always present, but controlled.
This is also illustrated in Fig. 5.
7. Discussion
There are times when we hope that cells will survive radiation, such as after an accidental dose or normal cells invaded
by cancer, and times when we hope that the cells will be eradicated, such as with cancer cells. This paper is a first attempt
to model the effect of radiation on cancer and normal cells in competition, taking into account a recombination of irradiated
cells.
In this paper we have shown various outcomes. However, we considered only the constant treatment case. We will
examine other treatment protocols in future research.
References
[1] G. Belostotski, H.I. Freedman, A control theory model for cancer treatment by radiotherapy, Int. J. Pure Appl. Math. 25 (2005) 447480.
[2] E.A. Coddington, N. Levinson, Theory of Ordinary Differential Equations, McGraw-Hill, New York, 1955.
[3] H.I. Freedman, S.T.R. Pinho, Persistence and extinction in a mathematical model of cell populations affected by radiation, Period. Math. Hungar. 56
(2008) 2535.
[4] H.I. Freedman, P. Waltman, Persistence in models of three interacting predator-prey populations, Math. Biosci. 68 (1984) 213231.
[5] L.G. Hanin, L.V. Pavlova, A.Y. Yakovlev, Biomathematical Problems in Optimization of Cancer Radiotherapy, CRC Press, Ann Arbor, 1994.
[6] F.K. Nani, H.I. Freedman, A mathematical model of cancer treatment by immunotherapy, Math. Biosci. 163 (2000) 159199.
[7] J.A. Nickoloff, M.E. Hoekstra, DNA Damage and Repair, in: DNA Repair in Higher Eukaryotes, vol. II, Humana Press, Totowa, New Jersey, 1998.
[8] S.T.R. Pinho, H.I. Freedman, F. Nani, A chemotherapy model for the treatment of cancer with metastasis, Math. Comput. Modelling 36 (2002) 773803.
[9] R.K. Sachs, P.L. Chen, P.J. Hahnfeldt, L.R. Hlatky, DNA damage caused by ionizing radiation, Math. Biosci. 112 (1992) 271303.
[10] R.K. Sachs, L.R. Hlatky, P. Hahnfeldt, Simple ODE models of tumor growth and anti-angiogenic or radiation treatment, Math. Comput. Modelling 33
(2001) 12971305.
[11] H. Schllnberger, M. Kotecki, D. Crawford-Brown, W. Hofmann, P. Eckl, Adaptive response plateaus for initiation in a state-vector model of
carcinogenesis, Int. J. Radiat. Biol. 75 (1999) 351364.
[12] H.D. Thames, J.H. Hendry, Fractionation in Radiotherapy, Taylor and Francis, New York, 1987.

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