Comparison of Transarterial Chemoembolization as a Selective Drug Delivery Mechanism to Traditional Chemotherapy

1. BME 150 Challenge Based Learning
Group 26
Amanda Hong
Ronald Luu
Roland Moder
Tony Nguyen
Calvin Song

2.  64-year-old male. Coming into the
Emergency Department with chief complaint
of abdominal swelling.
 Patient X seems to have a yellow pigment
which he says is abnormal.
 Upon physical examination, patient has an
enlarged liver.
 Past medical history indicates patient has
compensated cirrhosis.

3.  Ultrasound and CT scans
◦ Indicate a single large tumor mass that has not
metastasized
◦ Diameter >5 cm
L. Criotti et al.: Peri-intraprocedural
imaging: US, CT, and MRI

4.  Liver cancer or hepatocellular
carcinoma
◦ Is an increasingly common tumor
◦ With a poor prognosis
◦ Limited systemic treatment
options
◦ Approximately 80% of patients
die within a year of diagnosis
◦ In men, it is the fifth most
common cancer worldwide and
the third leading cause of cancer-
related death

5.  Describes the severity of the cancer – size,
metastasis, etc.
 Tells physicians survival rates and cancer
treatment
 Many staging systems for hepatocellular
carninoma including:
◦ Cancer of the Liver Italian Program Score
◦ Chinese University Prognostic Index
◦ Barcelona Liver Clinic

6.  Useful because it integrates liver function and
tumor features into classification.
O'Neil, B. H. et al. Oncologist 2007;12:1425-1432

7.  Model the drug transport from the
microsphere into the tumor mass.
 Decide whether TACE is an appropriate
treatment over traditional chemotherapy.
 Treat patient X successfully and thoroughly.

8.  Catheter through the leg up to the hepatic
artery
◦ Hepatic artery chosen since ~90% of blood supplied
to liver is from hepatic artery during cancer.
◦ During procedure, use imaging device to locate
specific arteries that lead to the tumor.

11. 1. How are conventional chemotherapy and
TACE drug delivery similar/different?
2. How do the two methods deliver drugs
similarly/differently (in terms of drug
concentration/delivery rate/time), how does
this affect their models?
3. How do the drugs travel through the
occluded blood vessel to the tumor cell?
4. At what rate does the microsphere elute the
drug?

12. Conventional chemotherapy TACE
 Chemotherapeutic agents end up in the  Embolization blocks all the
Difference rest of the body. small blood vessels.
 Systemic side effects  No blood flow can take
 Liver failure can be developed with chemotherapeutic agents to other
advanced cirrhosis patients. part of the body.
 Increased concentration of
chemotherapy.
 Cutting off blood flow leads to
tumor cell apoptosis
 Future attempts at intra-arterial
infusions are impossible.
 Takes advantage of the fact that liver cancer is very vascularized and the blood
Similarity supply exclusively from the hepatic artery.
 Drugs are delivered by inserting catheter into hepatic artery which supplies the
liver tumor.
 The type and frequency of complications are simular.

13. Conventional Chemotherapy TACE
Higher Dosage Necessary % of drug that reaches the
tumor
Immediate delivery, some gets Slow paced elution of drugs over
processed by liver, the rest is a long period of time
toxic throughout the body
Modeled with mass convective Modeled with constant elution
surface boundary that will rate, decreasing concentration
decrease exponentially over time over time

14.  Occluded blood vessel: a blood vessel that is
closed or stopped due to an obstruction
 Assume that the blood after the microsphere
is not moving.
 Model can be simplified, drug travels through
blood follows diffusion principles.

16. Tumor Mass
5 cm

18.  1D or 2D?
 Analytical or Numerical?
 Simplifications
◦ No mass generation/consumption
◦ Storage is not equal to 0
 Boundary Condition possibilities
◦ Convective?
◦ Constant surface concentration?
◦ Constant mass flux?

20. 1) 1D, not 2D
2) Transient, not steady state
◦ model drug release over long period of time
◦ consider initial release of drug from microsphere as fast
and, over a long duration of time, a slow release of drug
3) Not semi-infinite
◦ drug needs reach a certain depth of the tumor cell 
cannot neglect the distance that the drug travels through
the tumor cell compared to the entire length of the tumor
cell
4) Numerical, not analytical  finite difference,
5) No consumption of drug within tumor cell  Eg = 0
6) Constant mass flux (j‖)
7) The microsphere approaches tumor cell as close as
possible such that the drugs are release directly
into tumor cell and does not pass through the
blood (fluid)

21. Therefore, no diffusion occurs through the
layer of blood in the vessel, but directly to
the tumor cell from the microsphere.
This is the best case scenario for maximum
drug diffusion.

22. 1-D transient Finite
difference model with
constant mass flux as
a boundary condition

23. Surface node:
C0p+1 = (1-2Fom)C0p+2*Fo((∆x/D)j‖+C1p)
Internal nodes:
Cip+1 = (1-2Fom)Cip+Fo(Ci-1p+Ci+1p)
Where Fom is Fourier’s number for mass transfer
and it is defined as Fom = (D*∆t)/((∆ x)^2)

24.  How to create a simple model that can be
remodeled easily.
◦ Use Excel – label all constants and variables, link
values to the equations
 To qualitatively show the effectiveness of
TACE.
◦ Find [Dox] where cell death occurs
 How is Dox transport across membranes
affect rate of diffusion?
◦ Success of clinical trials show that it doesn’t greatly
affect the rate of diffusion => model without
internal membranes

25. Value Description
0 cm Minimum depth
0.1 cm Depth interval
0 g/cm3 Uniform initial concentration
1.50E-06 cm2/s Mass diffusivity
0 hours Initial Time Point
0.92592593 hours Time interval
6.32E-07 g/cm2 s Constant mass flux
1.83E-01 cm2 Area of hepatic artery
0.5 Mass Fourier number
1.16E-07 g/s Drug elution rate
5.80E+02 g/mol Molecular Mass of Doxorubicin
2.25E-05 g/cm3 Cell Death Concentration

26. 1D Transient Finite Difference Constant Mass Flux Model
0.5 Depth (cm)
0.45 0.000
Concentration (g/cm^3)
0.4 0.200
0.35 0.500
0.3 0.900
0.25
1.400
0.2
2.000
0.15
0.1
0.05
0
0 24 48 72 96 120 144 178
Time (Hours)

27. 1D Transient Finite Difference Constant Mass Flux Model (From 4.4 to 5 cm)
1.80E-04 Depth (cm)
4.4
1.58E-04
Concentration (g/cm^3)
4.5
1.35E-04
4.6
1.13E-04 4.7
9.00E-05 4.8
4.9
6.75E-05
5
4.50E-05
2.25E-05 Cell Death
0.00E+00
Concentration
96 120 144 169
Time (Hours)

29.  Our model with no limitations or
consumption predicts:
Cell at center of tumor will die in 6.40
days.
 Compare this to conventional chemotherapy
with necrosis in less than 50% of patients.
 In scenarios close to ideal, TACE works
extremely well.
 Microspheres absorbed into tumor tissue
increases drug delivery.

30.  TACE is a good option for patient X
◦ Localized, Semi-Specific (Doxorubicin is more
prone to affect proliferating cells)
◦ Small concentrations of Dox in blood stream will
quickly be nullified by the liver => no systemic
damage
◦ Dual action – drug elution and blocking
transmission of nutrients to the tumor
Chance of great success with minimal risk.
Patients have longer lifespan after diagnosed, when
treated with TACE instead of standard Chemotherapy
and less severe side affects

31.  Different possible models:
◦ Drugs flow into interstitial space (2D and infinite sink
as side boundary conditions) then to cancerous cell and
normal cell.
◦ Constant convective flow of mass (probably lower
concentration) with diffussion directly to the
center(nucleus) of the cancer cell.
 Permeability of the drug into the tumor mass. If that
would slow or speed up the mass transport model.
 Consumption term, how drug is used as it travels through
the tumor.
 Also we would model the conventional chemotherapy for
comparison.

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