Int. J. Enterprise Network Management, Vol. 4, No.

4, 2011

367

Multistage tumour growth through stochastic model

with continuous time
P. Tirupathi Rao*, T. Ganesh and
P.R.S. Reddy
Department of Statistics, SV University,
Tirupati 517 502, A.P., India
E-mail: drtrpadi@gmail.com
E-mail: ganimsc2007@gmail.com
E-mail: putharsr@gmail.com
*Corresponding author
Abstract: In this paper, we develop the continuous time stochastic model for
multi stage malignant tumours with non-homogeneous Poisson process. The
statistical measures like expected number and variance of malignant and
normal cells were derived through a probability distribution, which developed
through a stochastic model. Sensitivity analysis was carried out and the model
behaviour was studied including with certain special cases. This model is useful
in understanding the tumour behaviour of a patient during the treatment of
treatment chemotherapy at any point of time.
Keywords: stochastic multistage model; SMM; non-homogenous Poisson
process; NHPP; chemotherapy; tumour growth; decision support systems; DSS.
Reference to this paper should be made as follows: Rao, P.T., Ganesh, T. and
Reddy, P.R.S. (2011) Multistage tumour growth through stochastic model with
continuous time, Int. J. Enterprise Network Management, Vol. 4, No. 4,
pp.367379.
Biographical notes: P. Tirupathi Rao works as an Associate Professor at
Department of Statistics, Sri Venkatewsara University, Tirupati A.P., India. His
areas of research include stochastic modelling, operations research, bio
statistics, statistical computing, etc. He has more than 20 years of teaching
experience in the disciplines of mathematical statistics, applied statistics,
operations research, research methodology, bio statistics and statistical
computing. He had contributed 24 research papers and nine books of study
materials for publication. He had delivered 30 invited talks, presented 35
research papers, and organised 22 conferences/workshops of national
and international levels. He taught various course programmes including BSc
in Mathematical Statistics, MCA, MBA, MTech, MPharm, MSc in Statistics,
Bio Technology, Bio Informatics, Nursing, Home Science, etc. He finished his
academic degree from Andhra University, Vishakhapatnam, A.P.
T. Ganesh is presently a Research Scholar at the Department of Statistics,
SV University. He obtained his MSc in Statistics from SV University, Tirupati.
Currently, he is working as a Research Fellow at UGC BRS. His areas of
research include stochastic processes, biostatistics and operations research. He
has attended ten conferences and presented four research papers.

Copyright 2011 Inderscience Enterprises Ltd.

368

P.T. Rao et al.

P.R.S. Reddy is working as a Professor of Statistics at SV University,
Tirupati. His areas of research include optimisations methods, mathematical
programming, stochastic programming, bio statistics and manpower planning,
etc. He is a Fellow of Royal Society of Statistics and of ISPS. He is the
President of ISPS, Vice President of ORSI and of SERQOM. He had more than
30 years of teaching and research experience and published a good number of
research articles. He also served as a Lecturer, Reader, Associate Professor and
taught the subjects of real analysis, operations research, mathematical
programming, etc. He had completed several research projects sponsored by
UGC, DRDO, DST and similar agencies.

Introduction

A mutant cell, after a number of stages of transformation shall be converted into a

malignant cell; from then onwards the cell division will be at faster growth. The model is
developed by considering assumption that a mutant cell will be transformed into
premalignant cell and further it will be converted into malignant cell as a full fledged
cancerous cell. It is assumed that the parameters namely the arrival/transformation rates
from the stage of mutant to premalignant; from stage of premalignant to malignant and
from stage of mutant to malignant follows Poisson process. A multivariate time
dependent Poisson process is developed. The differential equations and statistical
measures are derived from the process. A state and time dependent multivariate Poison
process is developed by assuming the drug absence as state zero and the drug presence as
state one.
There is much literature evidence on the construction of stochastic models for
understanding the tumour growth and its behaviour. With the pioneering works of
Mayneord (1932).The mathematical modelling is a conventional approach in developing
functional relationship between the causing factors and the tumour growth. The attempt
of applying birth and death process to study cancer cell growth was made by Kendall
(1960). The kinetics of solid tumour was studied through stochastic processes by Witte
et al. (1974). Immunological feedback of carcinogenesis were analysed through
stochastic models by Dubin (1976). The phenomena of stochastic numerical models are
applied on analysis of breast cancer growth by Speer et al. (1984). Two stage stochastic
model with the time dependent parameters for carcinogenesis was developed by Serio
(1984). Stochastic differential equations were used for tumour growth models by
Rosencrantz (1988). Stochastic models for cancer cell growth with assumption of in
activation of allele genes and spontaneous mutation of cells by Rao and Rao (2004c,
2006). They have also developed a two stage stochastic model for cancer cell growth.
Pattern formulation in stochastic models for cancer growth was studied by Marcinek
(2005). Cancer risk drug resistance studies through stochastic model were carried out by
Rinaldo and Komorova (2006). Tumour growth were modelled as stochastic non-linear
Gompertz by Lo (2009). Optimal drug administration for cancer treatment through
chemotherapy was modelled using stochasticity by Rao et al. (2010)
Mathematical modelling is a conventional tool for model construction, by assuming
the probabilities of changing pattern of cell growth and loss rates among various stages
are constants. Opting stochastic modelling is the most suitable way for studying the
cancer growth as the behaviour of tumour growth is influenced by many random factors.

Multistage tumour growth through stochastic model with continuous time

369

The growth and loss rates of mutant cells, premalignant cells and malignant cells are
varying with numerous unexplained reasons. The process of cell division, growth and
loss of mutant cells, malignant cells have to be understood by developing suitable
stochastic processes. Hence the theme of cell division or growth process is more
probabilistic rather than deterministic. Rao and Rao (2006) have developed two stage
stochastic models by assuming the arrivals of cells to both mutant and malignant cells are
independent. As the cancer growth is influenced by many transformations and stages in
the growth. The work of Rao and Rao (2006) has more restrictions and practical
limitations. The growth rate of cancer cell depends on the growth status in previous
stages. Dependence in relation between the stages from mutant to malignant stages is
more rational. Considering two stage transformation cancer cell growth may not
sufficient in understanding the tumour dynamics properly. Keeping in view of the above
mentioned gap, we have developed a three stage stochastic model for cancer growth.

Stochastic model

In this model, we have considered that the rate of mutant cell growth per unit time is .
The rate of premalignant cell growth per unit time is and it depends on the number of
existing mutant cells in the tumour. The growth of malignant cells per unit time is ,
and they also depends on the existing size of premalignant cells in the tumour. The model
has considered that , , are the death rates of mutant, pre malignant, malignant cells
respectively. All are non-negative and they are dynamic rather than static.
The events occurred in non-overlapping intervals of time are assumed as statistically
independent. Let t be an infinitesimal interval of time. Let there be n mutant cells and
m premalignant cells, k malignant cells initially at time t. Let ,,, ,,
respectively be the rate of generation of mutant cells, rate of transformation of mutant
cells to premalignant cells, rate of transformation from premalignancy to malignancy,
rate of death of mutant cells without transforming to premalignant stage, rate of death of
premalignant cells without transforming to malignant stage, rate of death of malignant
cells. All the events follow poisson process with the mentioned parameters. With the
above assumptions, the postulate of the model are, the probability of arrival of one
mutant cell during an infinitesimal interval of time t is n t + 0(t). The probability of
arrival of transformation from mutant cell to premalignant cell during an infinitesimal
interval of time t, provided there exist n mutant cells already at time t is
n t + 0(t); The probability of transformation of premalignant cell to malignant cell
during an infinitesimal interval of time t, provided there exist m premalignant cells at
time t is m t + 0(t). The probability of death of a mutant cell without transforming to
premalignancy during an infinitesimal interval of time t, provided there exist n mutant
cells already at time t is nt + 0(t). The probability of death of a premalignant cell
without transforming to malignancy during an infinitesimal interval of time t, provided
there exist m premalignant cells at time t is mt + 0(t). The probability of death of a
malignant cell during an infinitesimal interval of time t, provided there exist n mutant
cells already at time t is kt + 0(t). The probability of no arrival to mutant cell, no
transformation from mutancy to premalignancy, no transformation from premalignancy
to malignancy, no death of mutant cell, no death of premalignant cell, no death of
malignant cell during an infinitesimal interval of time t is 1 [ + n( + ) + m( + ) +

370

P.T. Rao et al.

k]t + 0(t). The probability of occurrence of other than the above events during an
infinitesimal interval of time t is 0(t)2.

The difference-differential equation of the model is:

Let pn,m,k(t) be the probability that there are n mutant cells, m premalignant cells, k
malignant cells at time t
pn,m, k (t + t ) = pn, m,k (t ) 1 + n ( + ) + m ( + ) + k t + 0(t )

+ pn 1,m, k (t ) [t + 0(t ) ] + pn +1,m, k (t ) ( n + 1) t + 0(t )

+ pn +1,m 1,k (t ) ( n + 1) t + 0(t )

+ pn, m +1, k (t ) ( ( m + 1) t + 0(t ) )

(2.1)

+ pn, m +1, k 1 (t ) ( m + 1) t + 0(t )

+ pn, m,k +1 (t ) ( k + 1) t + 0(t ) + 0(t ) 2
for n, m 1

pn ,m, k (t ) = + n ( + ) + m ( + ) + k pn,m,k (t )
+ ( ) pn 1,m,k (t ) + (n + 1) pn +1,m, k (t )
+ (n + 1) pn +1, m 1, k (t ) + (m + 1) pn, m +1, k 1 (t )

(2.2)

+ (k + 1) pn,m,k +1 (t )
for n, m, k 1

(t ) = ( + + ) p1,0,0 (t ) + p0,0,0 (t ) + 2 p2,0,0 (t ) + p1,1,0 (t ) + p1,0,1 (t ) (2.3)

p1,0,0
(t ) = ( + + ) p0,1,0 (t ) + p1,1,0 (t ) + p1,0,0 (t ) + 2 p0,2,0 (t ) + p1,1,0 (t ) (2.4)
p0,1,0
(t ) = ( + ) p0,0,1 (t ) + p1,0,1 (t ) + p0,1,1 (t ) + 2 p0,0,2 (t ) + p0,1,0 (t )
p0,0,1
(t ) = ( + + + + ) p1,1,0 (t ) + p0,1,0 (t ) + 2 p2,1,0 (t )
p1,1,0
+ 2 p2,0,0 (t ) + 2 p1,2,0 (t ) + p1,1,1 (t )
(t ) = ( + + + + ) p1,0,1 (t ) + p0,0,1 (t ) + 2 p2,0,1 (t )
p1,0,1
+ p1,1,1 (t ) + p1,1,0 (t ) + 2 p1,0,2 (t )
(t ) = ( + + + ) p0,1,1 (t ) + p1,1,1 (t ) + p1,0,1 (t ) + 2 p0,2,1 (t )
p0,1,1
+ 2 p0,2,0 (t ) + 2 p0,1,2 (t )
(t ) = p0,0,0 (t ) + p1,0,0 (t ) + p0,1,0 (t ) + p0,0,1 (t )
p0,0,0

(2.5)
(2.6)

(2.7)

(2.8)
(2.9)

Multistage tumour growth through stochastic model with continuous time

371

The initial conditions of the model are

pN0 , M 0 , K0 (t ) = 1, pi , j ,k (0) = 0

For every i N 0 , j M 0 , k K 0

Let p(x, y; t) be the joint probability generating function of pn,m,k(t) where

p ( x, y , z ; t ) =

x n y m z k pn,m,k (t )

(2.10)

m =0 n =0 n =0

Multiplying the equation (2.1) to (2.8) by xnymzk and summing overall n, m and k we
obtain

x n y m z k pn,m, k (t )

m =0 n =0 n =0

{ [ + n( + ) + m( + ) + k ] x

m =0 n =0 n =0

m =0 n =0 n =0

+
+
+

(m + 1) x n y m z k pn +1,m 1, k (t )

(m + 1) x n y m z k pn,m +1,k (t )

(m + 1) x n y m z k pn,m +1,k 1 (t )

(k + 1) x n y m z k pn,m,k +1 (t )

m =0 n =0 n =0

m =0 n =0 n =0

y z pn 1,m, k (t )

(n + 1) x n y m z k pn +1, m,k (t )

m =0 n =0 n =0

y z pn,m, k (t )

n m k

m =0 n =0 n =0

n m k

m =0 n =0 n =0

p
p
p
d
p ( x, y, z; t ) = ( ) p( x, y; t ) ( + ) x ( + ) y z
x
y
z
dt
p
p
p
p
p
+ y +
+ z +
+ xp( x, y; t ) +
x
x
y
y
z
p
p
d
p ( x, y, z; t ) = [ ( + ) x + + y ] + [ ( + ) y + + z ]
x
y
dt
p
+ [ (1 z ) ] + ( x 1) p( x, y, z; t )
z

(2.11)

372

P.T. Rao et al.

We can obtain the characteristics of the model by using the joint cummulant generating
function of pn,m,k(t).
Taking x = eu, y = ev and z = ew and denoting k(u, v, w; t) as the joint cummulant
generating function of pn,m,k(t), we can obtain the following:

k
k
k (u , v, w; t ) = ( + ) + eu + v + ( + ) + ev + ev + w
t
u
v
k
+ e w 1
+ eu 1 k ( u , v, w; t )

(2.12)

Statistical measures

Let mi,j,k(t) denotes the moments of order (i, j, k) of mutant cells, premalignant cells and
malignant cells at time t. Then the characteristics of the model are obtained as follows:
Average number of mutant cells during time t is,
m1,0,0 (t ) =

1 e
+

( + )

(1 N 0 )

(3.1)

Average number of premalignant cells at time t is,

N0

( + )

m0,1,0 (t ) =

e
(
)(
)
(
)

+
+

N0

M 0 e ( + )
(
)(
)
(
)

+
+

(3.2)

( + )( + )

Average number of malignant cells at time t is,

N 0

e ( + )

m0,0,1 (t ) =

M 0
( + )( + ) ( + )
( + )
N 0

M 0
( + ) ( + )( + )
( + )

e
e( + )

+ K0
+ N 0

( + )
+ ( + )( + )
+

( + )( + )

(3.3)

Multistage tumour growth through stochastic model with continuous time

373

Covariance of number of mutant and premalignant cells at time t

N0
e2( + ) e( + + + )

( + )

m1,1,0 (t ) =

(3.4)

Covariance of number of mutant and malignant cells at time t

m1,0,1 (t ) =

N0

e( + + + ) e( + + )

( + )
( + )

e2( + ) e( + + )

( + )

(3.5)

Covariance of number of premalignant and malignant cells at time t

e ( + + )
1
e ( + )

( + ) 2 ( + + ) ( + ) ( + )
N 0 2

m0,1,1 (t ) =

e ( + + )

e 2( + )

( + ) ( + ) (2 + 2 )
1

2( + )

1
e ( + + ) +
e 2( + ) e ( + + )
e

(
)
+

(3.6)
N0
e ( + ) e ( + )

( + ) ( + )

M0
e2( + ) e ( + + )

( + )

N 0 2
e ( + + )
( + )( + )(2 + 2 )

Variance of number of mutant cell

m2,0,0 (t ) =

1 e
+

( + )

+ N 0 e ( + ) 1 e ( + )

(3.7)

Variance of number of premalignant cell

N0

m0,2,0 (t ) =
M 0 e ( + )

( + ) ( + )( + )

2( + )
N0 2
N0 2
M

+
i
i e 2( + )
e

0
2
( + ) 2
( + )

2 N0 2

+
+
+ e ( + + + )
( + )( + ) ( + )

e ( + )
+
N0
( + )
( + )

(3.8)

374

P.T. Rao et al.

Variance of number of malignant cell

N 0

M 0 1
m0,0,2 (t ) =

+
+

(
)(
)
(
)
(
)

e ( + ) e 2

( + 2 )

N 0

+
+

(
)
(
)(
)

e2

e ( + ) e2

1
( + ) ( + 2 ) + ( + ) + 1
(
)

N 0

M 0 K 0

( + ) ( + )( + )

e e 2 e 2( + )
N 0 2 2
+ M 0

+
2
( + ) 2( + ) ( + )

e 2( + ) e 2
2 N 0 2 2

2( + ) ( + )( + )( + )
e ( + + ) e 2 e ( + + + ) e 2
M0

(
)
(
2
)
(
)
+

+
+
+

e ( + + ) e 2
2 N 0 2 2 e ( + + ) e 2

( + )
( + )

( + )

1
1
2( + )( + ) + ( + )( + )

(3.9)

( + )(2 + 2 )
1

Numerical illustration and sensitivity analysis

The numerical data was presented in Table 1 to understand the model behaviour, a
simulated and hypothetical data is applied on the developed model. the statistical
measures like average number of mutant cells m011, average number of premalignant cells
m0,1,0, average number of malignant cells m0,0,1, variance of mutant cells m2,0,0, variance of
premalignant cells m0,2,0, variance of malignant cells m0,0,2; covariance of mutant and
premalignant cells m1,1,0, covariance of premalignant and malignant cells m0,1,1 and
covariance of malignant and mutant cells m1,0,1 are obtained for varying values of initial
sizes of mutant cells N0, premalignant M0 and malignant K0 cells. The above mentioned
statistical measures are also obtained for varying values of time periods when other
parameters are constants. From equations (3.1) to (3.9) the values of m1,0,0(t), m1,0,1(t),
m0,0,1(t), m1,1,0(t), m1,0,1(t), m0,1,1(t), m2,0,0(t), m0,2,0(t), m0,0,2(t) are computed for various
hypothetical values of the , , , , , , N0, M0, K0, t, using MATHCAD 6.0, presented
in Table 1.

4.9
4.9
4.9
4.9

0.21
0.23
0.25

0.426

1.2
0.19

0.488

1
4.9

0.599

0.8

0.17

0.867

4.9

0.61

0.6

4.9

0.59
1.716

4.9

0.57

0.4

4.9

0.55

1.396

0.95
4.9

1.716

0.9

0.53

2.16

37.112

40.052

43.283

46.836

50.745

21.89

24.081

27.243

32.115

40.238

35.742

38.548

41.63

45.017

48.744

47.637

48.843

50.179

51.655

2.781

0.8

0.85

55.163

55.141

55.118

55.096

55.073

m0,1,0

53.277

5.512

m1,0,0

3,248

2,990

2,792

2,637

2516

601.95

662.8

761.47

938.71

1,314

4,135

3,651

3,273

2,970

2,720

1,461

1,569

1,703

1,875

2,103

2,419

2,419

2,419

2,419

2,419

m0,0,1

0.139

0.149

0.16

0.172

0.185

0.0001

0.0005

0.002

0.0088

0.04

0.134

0.144

0.154

0.166

0.178

0.037

0.051

0.072

0.101

0.141

0.199

0.199

0.199

0.199

0.199

m1,1,0

1.857

1.904

1.954

2.005

2.06

0.0025

0.0093

0.035

0.134

0.526

2.238

2.219

2.199

2.177

2.154

0.506

0.676

0.901

1.2

1.596

2.117

2.117

2.117

2.117

2.117

m1,0,1

358.145

315.115

286.124

266.146

252.378

21.086

24.85

31.623

45.69

82.712

399.128

341.381

303.349

277.453

259.628

88.199

101.816

120.137

145.762

183.489

243.152

243.152

243.152

243.152

243.152

m0,1,1

5.381

5.381

5.381

5.381

5.381

0.432

0.508

0.657

1.025

2.085

5.381

5.381

5.381

5.381

5.381

1.702

2.085

2.593

3.271

4.174

5.492

5.47

5.447

5.425

5.403

m2,0,0

3.07

4.965

6.52

7.836

8.965

4.807

5.673

6.887

8.618

10.834

1.942

4.069

5.777

7.204

8.421

13.963

13.944

13.744

13.227

12.138

5.694

6.542

7.39

8.237

9.085

m0,2,0

1,856,000

1,376,000

1,038,000

789,200

600,200

37,510

53,880

82,300

136,300

249,800

1,859,000

1,367,000

1,035,000

801,300

630,900

216,200

239,500

269,500

309,700

366,400

451,600

451,600

451,700

451,700

451,800

m0,0,2

Table 1

3.657

0.75

0.9

K0

5.39

M0

0.88

N0

5.267

0.86

5.145

5.022

0.84

0.82

Multistage tumour growth through stochastic model with continuous time

375

The values of m1,0,0, m0,1,0, m0,0,1, m1,1,0, m1,0,1, m0,1,1, m2,0,0, m0,2,0, m0,0,2, for varying
values of the parameters

0.933

11

3.404

5.568

9.602

1.158
0.998

9
10

30.656
17.054

55.051

2.52

4.9

412

55.051

1.552

4.9

312

55.051

4.9

212

55.051

55.051

56.063

55.86

55.658

55.455

55.253

57.252

56.812

56.372

55.931

55.491

55.051

55.051

55.051

55.051

4.9

112

4.9

550
4.9

4.9

540
102

4.9

530

5.1

1,050
4.9

5.06

1,040

520

5.02

1,030

4.9

4.98

1,020

510

4.94

4.9

0.2

m0,1,0
55.051

m0,0,1

1,922

2,018

2,117

2,219

2,321

2,804

2,681

2,557

2,434

2,421

2,449

2,443

2,437

2,431

2,425

2,519

2,499

2,479

2,459

2,439

1,509

1,644

1,800

1,979

2,184

m1,1,0

0.0001

0.0005

0.0022

0.01

0.045

0.199

0.199

0.199

0.199

0.199

0.199

0.199

0.199

0.199

0.199

0.209

0.207

0.205

0.203

0.201

0.199

0.199

0.199

0.199

0.199

m1,0,1

0.02

0.051

0.131

0.335

0.848

2.117

2.117

2.117

2.117

2.117

2.117

2.117

2.117

2.117

2.117

2.222

2.201

2.18

2.159

2.138

1.268

1.399

1.547

1.714

1.903

m0,1,1

10.426

19.737

37.253

70.038

130.99

243.152

243.152

243.152

243.152

243.152

244.367

244.124

243.881

243.638

243.395

254.701

252.391

250.082

247.772

245.462

888.44

560.18

412.472

329.616

277.671

m2,0,0

0.939

1.012

1.192

1.634

2.72

5.381

5.381

5.381

5.381

5.381

5.381

5.381

5.381

5.381

5.381

5.606

5.561

5.516

5.471

5.426

5.381

5.381

5.381

5.381

5.381

m0,2,0

1.662

2.232

3.213

4.825

7.252

9.933

9.933

9.933

9.933

9.933

6.442

7.14

7.838

8.536

9.235

12.098

11.665

11.232

10.799

10.366

9.933

9.933

9.933

9.933

9.933

m0,0,2

491,100

504,700

510,900

506,800

488,800

451,900

451,900

451,900

451,900

451,900

472,300

468,300

464,200

460,100

456,000

487,800

480,500

473,300

466,100

459,000

39,410

95,310

164,500

249,500

348,800

Table 1

1,010

4.9

0.17

m1,0,0

4.9

t
4.9

K0

0.14

M0

0.11

N0
4.9

0.08

376
P.T. Rao et al.

The values of m1,0,0, m0,1,0, m0,0,1, m1,1,0, m1,0,1, m0,1,1, m2,0,0, m0,2,0, m0,0,2, for varying
values of the parameters (continued)

Multistage tumour growth through stochastic model with continuous time

377

From Table 1 it is observed that average mutant cells, average number of premalignant
cells are increasing function of ; average number of malignant cells are invariant of . It
is also observed that variance of mutant cells is and increasing function of , where as
variance of premalignant cells and variance of malignant cells are the decreasing
functions of ; it is further observed that covariance of mutant cells , premalignant cells;
premalignant and malignant cells; mutant and malignant cells are invariant of . Hence it
may be interpreted as the arrival rate of mutant cells shall have the positive impact on
m1,0,0, m0,1,0, and also it has negative impact on m2,0,0, and m0,2,0.
It is observed that average number of mutant cells, average number of premalignant
cells and average number of malignant cells are decreasing functions of ; it is also
observed that variance of mutant cells, variance of malignant cells are decreasing
functions of where as variance of premalignant cells is increasing function of ; it is
further observed that covariance of mutant cells and pre malignant cells; premalignant
and malignant cells; mutant and malignant cells are decreasing functions of . Hence it
may be interpreted as the arrival rate of mutant cells shall have the negative impact on the
m1,0,0, m0,1,0, m0,0,1, m2,0,0, m0,0,2, m1,1,0, m1,0,1, m0,1,1, and positive impact on m0,2,0.
It is observed that average number of mutant cells is invariant function of . Average
number of premalignant cells is decreasing function of ; average number of malignant
cells is increasing function of ; it is also observed that variance of mutant cells is
invariant function of ; variance of premalignant cells is decreasing function of ;
variance of malignant cells is increasing function of ; it is further observed that
covariance of premalignant and malignant cells is increasing function of . Hence it may
be interpreted as the arrival rate of mutant cells shall have the negative impact on m0,1,0,
m0,2,0, m1,1,0, and positive impact on m0,0,1, m1,0,1, m0,1,1, m0,0,2.
It is observed that average number of mutant cells, average number of premalignant
cells, average number of malignant cells, variance of mutant cells, variance of
premalignant cells, variance of malignant cells, covariance of mutant and premalignant
cells, covariance of premalignant and malignant cells, covariance of mutant and
malignant cells are decreasing function of . Hence it may be interpreted as the arrival
rate of mutant cells shall have the negative impact on m1,0,0, m0,1,0, m0,0,1, m2,0,0, m0,0,2,
m1,1,0, m1,0,1, m0,1,1, m0,2,0.
It is observed that average number of mutant cells is invariant function of ; average
number of premalignant cells is decreasing function of and average number of
malignant cells is increasing function of . It is also observed that variance of mutant
cells is invariant function of , variance of premalignant cells is decreasing function of ;
variance of malignant cells is increasing function of ; it is further observed that
covariance of mutant and premalignant, covariance of mutant and malignant cells are
decreasing functions of ; covariance of premalignant and malignant cells is increasing
function of ; hence it may interpreted as the arrival rate of mutant cells shall have the
negative impact on m0,1,0, m1,1,0, m1,0,1, m0,2,0 and positive impact on m0,0,1, m0,1,1, m0,0,2.
It is observed that average number of mutant cells , average number of premalignant
cells are invariant functions of ; average number of malignant cells is a decreasing
function of ; it is also observed that variance of mutant cells , variance of premalignant
cells are invariant functions of . Variance of malignant cells is decreasing function of ;
it is also further observed that covariance of mutant cells and premalignant cells is
invariant function of , covariance of mutant and malignant cells is decreasing function
of , covariance of premalignant and malignant cells is increasing function of ; hence it

378

P.T. Rao et al.

may interpreted as the arrival rate of mutant cells shall have the negative impact on m0,0,1,
m1,0,1, m0,0,2 and positive impact on m0,1,1.
It is observed that average number of mutant cells, average number of malignant
cells, variance of mutant cells, variance of premalignant cells, variance of malignant
cells, covariance of mutant cells and premalignant cells, covariance of premalignant cells
and malignant cells, covariance of mutant and malignant cells are increasing functions of
N0. Average numbers of premalignant cells is decreasing function of N0. Hence it may be
interpreted as the arrival rate of mutant cells shall have the positive impact on all the
values except m0,1,0.
It is observed that average numbers of mutant cells is invariant function of M0.
Average numbers of premalignant cells, average numbers of malignant cells are
decreasing functions of M0. It is also observed that variance of mutant cells is invariant.
Variance of premalignant cells is decreasing and variance of malignant cells is,
increasing function of M0. It is further observed that covariance of mutant and
premalignant cells, covariance of mutant and malignant cells are invariant functions of
M0. Covariance of premalignant and malignant cells is increasing function of M0; hence it
may be interpreted as the arrival rate of mutant cells shall have the positive impact on
m0,1,0, m0,0,1, m0,1,1, m0,0,2 and negative impact on m0,2,0.
It is observed that average numbers of malignant cells is increasing function of K0.
Average number of mutant cells, average number of premalignant cells, variance of
mutant cells, variance of premalignant cells, variance of malignant cells, covariance of
mutant and premalignant cells, covariance of premalignant and malignant cells,
covariance of mutant cells and malignant cells are invariant functions of K0. Hence it may
be interpreted as the arrival rate of mutant cells shall have the positive impact on m0,0,1,
and reaming are invariant.
It is observed that average number of mutant cells , average number of premalignant
cells, average number of malignant cells are decreasing functions of t; it is also
observed that variance of mutant cells, variance of premalignant cells are decreasing
functions of t. It is further observed that covariance of mutant and premalignant cells ,
covariance of premalignant and malignant cells, covariance of mutant and malignant cells
are decreasing functions of t; hence it may be interpreted as the arrival rate of mutant
cells shall have the negative impact.

Conclusions

This work is organised on theoretical means through mathematical model developments

of cancer growth. Model construction was based on most practical and real life
assumptions. Stochasticity is considered to study the behaviour of tumour growth as it is
influenced by various random factors. The derivations for statistical measures are
obtained through mathematical means and the model behaviour was analysed through
numerical illustration to have more accessibility to non-mathematical users. This work
can be developed as a device of decision support systems (DSS) for health care takers.
Desktop animations and DSS template development will have good scope for this work.
The future work can also be extended in statistical inference and parameter estimations
through method of maximum likelihood estimation.

Multistage tumour growth through stochastic model with continuous time

379

Acknowledgements
The authors are very much grateful to the reviewers and editors of IJENM for their
valuable suggestions on our paper for better presentation and to improve the quality of
the paper.

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