Design and Testing of Water-Filled Bolus Structure to Improve

DESIGN AND TESTING OF WATER-FILLED BOLUS STRUCTURE TO IMPROVE

HEATING UNIFORMITY IN RF HYPERTHERMIA SYSTEM FOR CANCER

TREATMENT

A Project

Presented to the faculty of the Department of Electrical and Electronic Engineering

California State University, Sacramento

Submitted in partial satisfaction of the requirements for the degree of

MASTER OF SCIENCE

Electrical and Electronic Engineering

Meshari Alshehri

SUMMER 2020

Meshari Alshehri

DESIGN AND TESTING OF WATER-FILLED BOLUS STRUCTURE TO IMPROVE

HEATING UNIFORMITY IN RF HYPERTHERMIA SYSTEM FOR CANCER

TREATMENT

A Project

Meshari Alshehri

Approved by:

, Committee Chair Dr. Preetham B. Kumar

, Second Reader Dr. Fethi Belkhouche

Date

iii

Meshari Alshehri

I certify that this student has met the requirements for format contained in the University format manual, and that this project is suitable for electronic submission to the Library and credit is to be awarded for the project.

, Graduate Coordinator Dr. Preetham Kumar Date

Department of Electrical and Electronic Engineering

Abstract

DESIGN AND TESTING OF WATER-FILLED BOLUS STRUCTURE TO IMPROVE

HEATING UNIFORMITY IN RF HYPERTHERMIA SYSTEM FOR CANCER

TREATMENT

Meshari Alshehri

Thermal therapy, thermotherapy or Hyperthermia are names of cancer treatment using heat. Researchers have found that high temperatures are able to destroy cancer cells using Radio Frequency (RF) radiation focused on malignant tumors. In addition, as the cancer cells try to recover themselves or reproduce, they die, and cancer tumor shrinks. In comparison, regular or normal cells recover or reproduce without any long-term damage.

Hyperthermia therapy uses different tools to destroy cancerous cells such as Radio

Frequency (RF) heating.

One of the main challenges in hyperthermia treatment is the ability to obtain uniform heating across the tumor volume. This project will focus on one method to obtain uniform heating using a device called the water bolus, which is a hemispherical surface filled with water. This bolus is attached to the RF applicator and distributes the

RF energy equally across the tumor volume. Experimental studies have been performed in this project to test the efficacy of the bolus structure. The testing will be done on synthetic foam material, with and without bolus to evaluate the heating efficiency and

heating time to a temperature of ~ 42 degrees C. The results show that the bolus structure achieves its desired purpose of uniform heating over a period of 5-30 minutes.

, Committee Chair Dr. Preetham Kumar

Date

DEDICATION

To my father Ali, my mother Nessern and my Wife Leena

vii

ACKNOWLEDGEMENTS

First, I would like to thank my advisor Dr. Preetham Kumar, my professor and my monitor throughout my educational career for his support and guidance, words would never be enough to describe my feeling. Many love and respect not the professor but the father I worked with. He was father to, further he knows I have a rare disease that I am struggling with, although he held my hand and made me stand up and face every single obstacle, thank you from the bottom of my heart Dr. Preetham Kumar.

Many thanks to the department of Electrical and Electronic Engineering, on top of them

Dr. Fethi Belkhouche for his time and effort he gives the students throughout the years he worked as an instructor or as a chairman of the department.

Special thanks to the Ministry of Education at Saudi Arabia for sponsoring my study either bachelor or master at CSUS. I also would like to thank the Saudi Arabian

Cultural Mission for their help throughout the years I have been study in USA.

Finally, I would like to thank my mom Nessern for her support, my father Ali and my beloved wife Leena.

viii

TABLE OF CONTENTS Page

Dedication ...... vii

Acknowledgements ...... viii

List of Tables ...... xi

List of Figures ...... xii

Chapter

1. INTRODUCTION ...... 1

2. HYPERTHERMIA IN CANCER TREATMENT ...... 4

2.1 Comparison between the United States and Europe in hyperthermia

treatment development ...... 4

2.2 Mechanism behind hyperthermia therapy: ...... 4

2.3 Technical Use of Hyperthermia Therapy ...... 6

2.4 Hyperthermia Therapy Challenges ...... 6

3. DESIGN OF HEMISPHERICAL WATER BOLUS FOR HYPERTHERMIA

APPLICATION ...... 8

3.1 Heating distribution of the Mettler diathermy system ...... 9

3.2 Structure and properties of a water bolus ...... 10 ix

4. EXPERIMENTAL HEATING RESULTS USING WATER BOLUS

ATTACHMENT TO RF SYSTEM ...... 12

4.1 Testing the RF system without the water bolus with low power close

and 2 inches away from the surface ...... 12

4.2 Testing the RF system without the water bolus with mid power close

and 2 inches away from the surface ...... 16

4.3 Testing the RF system with the water bolus with low, mid and high

power close to the surface ...... 20

5. CONCLUSIONS ...... 26

Appendix A...... 27

References ...... 46

LIST OF TABLES

Tables Page

1. Time for testing the hyperthermia in low power without the water bolus,

applicator close to surface ...... 13

2. Time for testing the hyperthermia in low power without the water bolus,

applicator 2 inches away from the surface ...... 15

3. Time for testing the hyperthermia in mid power without the water bolus,

applicator close to surface ...... 17

4. Time for testing the hyperthermia in mid power without the water bolus,

applicator 2 inches away from the surface ...... 18

5. Time for testing the hyperthermia in low power with the water bolus, applicator

close to surface ...... 21

6. Time for testing the hyperthermia in mid power with the water bolus, applicator

close to surface ...... 22

7. Time for testing the hyperthermia in high power with the water bolus,

applicator close to surface ...... 24

LIST OF FIGURES

Figures Page

1. Red Blood Cells and Oxygen Transfer during Hyperthermia Therapy...... 5

2. Expansion of Blood Vessels Due to Elevated Temperature ...... 6

3. Mettler diathermy system ...... 8

4. Veterinary application of Mettler system ...... 9

5. Mettler RF system with empty bolus structure ...... 10

6. Mettler RF system with water-filled bolus structure ...... 11

7. Plot for RF system without the water bolus in low power, applicator close

to the surface...... 14

8. Plot for RF system without the water bolus in low power, applicator 2

inches away from the surface ...... 16

9. Plot for RF system without the water bolus in mid power, applicator close

to the surface...... 18

10. Plot for RF system without the water bolus in mid power, applicator 2

inches away from the surface ...... 20

11. Plot for RF system with the water bolus in low power, applicator close to

the surface ...... 22

12. Plot for RF system with the water bolus in mid power, applicator close to

the surface ...... 24

xii

13. Plot for RF system with the water bolus in high power, applicator close to

the surface ...... 25

xiii

CHAPTER 1

INTRODUCTION

By 2030 the number of cancer patients in United States will increase by 45% which means number of cancer patients will rise from 1.7 million to 2.3 million, based on the American Society Clinical Oncology (ASCO). Furthermore, according to American

Cancer Society, the number of women dying from cancer will rise by 60% all over the world. These numbers show us that doctors and engineers in the medical field have to cooperate to create additional ways of treatment to manage these large numbers of new patients and decrease patient mortality.

Nowadays, there are many effective cancer treatments like surgery, chemotherapy and radiation, but another useful treatment is Hyperthermia Therapy as the oncology specialists call it. The definition of Hyperthermia Therapy is “a cancer treatment that allows the body to absorb heat and raise the body temperature up to ~ 42 °C to kill the cancer cells” according to the National Institute of Health (NIH)[1]. The mechanism of

Hyperthermia Therapy is to weaken the cancer cells and make them more sensitive to radiation or chemotherapy.

Several clinical studies have been carried out using Hyperthermia as a tool in cancer treatment [2-7]. In [2], this cancer was treated by the combination of

Chemotherapy (Pazopanib) and Hyperthermia that both can act strongly in inheriting

uterine leiomyosarcoma (LMS) cell growth which is cancer cells. Furthermore, a 50- year-old female patient had a successful cancer treatment course with Hyperthermia

Therapy, [4]. In addition, Hyperthermia Therapy, combined with chemotherapy, was used mainly on children and a teenager with sarcomas or germ cell tumors located in the abdomino-pelvic region [5]. For example, a 54- year old male patient was diagnosed as hilar cholangiocarcinoma, with many symptoms such as fatigue, dyspepsia, epigastralgia, and jaundice, and since radiation and chemotherapy combination was not effective, the next decision was for the patient to be treated with Hyperthermia Therapy and

Chemotherapy as a second treatment course. The second treatment was given to the patient 32 times over 4 months. During the time the patient did not experience any critical complications, and his health and condition improved. The scan showed that the cholangiocarcinoma had not progressed [7].

Hyperthermia is usually administered by using Radio Frequency (RF) devices at

27 MHz or 900 MHz, due to the increased absorption by tissue at these frequencies. One device that we have been using in our work is the Mettler Autotherm© system at 27

MHz, whose design and performance are detailed in Appendix A. RF devices have shown good ability to achieve heating in the tumor up to the required hyperthermia temperature of ~ 42 degrees C (107 degrees F); however, the challenge is to obtain uniform heating across the tumor volume and this results in undesired hot spots in some sections of the tumor and reduced heating in other parts of the tumor. One approach to resolving this problem is the use of a water bolus, which is a hollow hemispherical

container that is made of dielectric material such as plexiglass. Hence, the focus of this project has been to study the heating properties of the Mettler RF system, with and without the bolus structure and to compare the results. The results show that the bolus structure does indeed achieve uniform heating as compared to using the RF system alone

CHAPTER 2

HYPERTHERMIA IN CANCER TREATMENT

2.1 Comparison between the United States and Europe in hyperthermia treatment development

Germany is one of the most developed countries in the world in the medical sector. Further, many clinics around the region treat cancer with hyperthermia therapy

[14]. Not every everyone diagnosed with cancer can be treated either with radiation therapy or chemotherapy as they believe. Many patients in the country such as children and adult with different types of cancer can be treated fully with hyperthermia therapy and the result shows a brilliant progress with a positive acceptance of the treatment. In contrast, the approval by the Food and Drug Administration (FDA) in the United State of

American to treat cancer patients with hyperthermia therapy can be given only if the treatment used along with radiation therapy to boost the tumor response, or to decrease the amount of the radiation therapy and replace it with hyperthermia therapy. In addition, this approach minimize the side effects of the radiation therapy, while it is not helpful to use this therapy with the chemotherapy dose, because some clinical trials have proofed that using hyperthermia with chemotherapy can boost the concentration of the drug and the blood flow to the cancer tumor [16]. Furthermore, hyperthermia therapy does not harm the body organs or create toxification to the tissue. Side effects of the hyperthermia depends on what part of body is treated, for example if it is for the whole body this can cause like nausea, vomiting, and diarrhea [17].

2.2 Mechanism behind hyperthermia therapy:

Hyperthermia therapy boost the body temperature to ~ 107 degrees °F and

make the red blood cells have more oxygen through the vessels and to the tumor as

shown in the figure 1 below.

Figure 1: Red Blood Cells and Oxygen Transfer during Hyperthermia Therapy

Hyperthermia therapy basically targets the blood vessels and inflate them while this

therapy beams frequency focuses on the cancer area. This inflation gives more chance to

the chemotherapy to attack the cancer cells as shown in the figure 2 below. This therapy

weakens the cancer cells and can helps to target the cancer cells easily [18]

Figure 2: Expansion of Blood Vessels Due to Elevated Temperature 2.3 Technical Use of Hyperthermia Therapy

Clinical trials believe that radiation therapy should be given to the patients after

hour of the hyperthermia therapy for more effective attack on the cancer cells. In

addition, they advise the cancer trials that hyperthermia therapy cannot be given every

single day, it needs two days at least between each season for more effective result, in

order to avoid the thermotolerance. Also, studies show that this therapy cannot be given

each day due the biological structure of the human body system. Further, the human body

system is able to create a strong shield for its cells against the heat alleviation, which is

called thermotolerance where the body resists the heat and try to stabilize the body

temperature. Tumor physiology studies prove that there is a strong bond between the

tumor cells and the thermotolerance, and these cells can survive between 4-24 hours. This

studies also proofed that the thermotolerance can be developed quickly and decays in the

next five day. Thermotolerance can push and stress the human cells and can cause tissue

poisoning in the long term, this problem decreases the progression of the engineering

revolution and increases the conflict of the use of hyperthermia therapy [15].

2.4 Hyperthermia Therapy Challenges

The mechanism and duration of heating in the hyperthermia therapy are the

most negative factors. While the hyperemia devices deal with two issues, human body

temperature and room temperature, they lose heat which means the devices resist the heat

and weaken the efficiency of the devices. The department of Electrical and Electronic

Engineering at CSUS focused on the following goals previously and presently:

• Reducing the heating time and studying the efficiency of the devices after a long

time of usage.

• Studying how heat gets absorbed in the human body, and relation between the

thickness of human tissues and absorption.

• Studying how to improve the heating mechanism.

CHAPTER 3

DESIGN OF HEMISPHERICAL WATER BOLUS FOR HYPERTHERMIA

APPLICATION

This chapter discusses the design and fabrication of a hemispherical water bolus that will be used in conjunction with the Mettler RF diathermy system, to improve the uniformity of the temperature distribution over a typical surface area. Figure 3 below shows the default Mettler RF diathermy system that we are currently using for veterinary hyperthermia therapy of cancerous tumors. Basically, the RF system produces heating in the tumor volume, which can be controlled to the therapy range of ~ 107 degrees F.

Figure 3: Mettler diathermy system

3.1 Heating distribution of the Mettler diathermy system

The Mettler system, shown in Figure 3, can generate substantial heating in the

patient treatment surface, when applied as shown below in Figure 4. Several veterinary

feline and canine patients with cancerous growths have been treated using the Mettler

system, with beneficial results [19]. However, simulation and experimental studies have

shown that the heating distribution over the Mettler applicator (as shown in Figure 4) is

not uniform. This may generate non-uniform heating over the treatment surface, resulting

in occurrence of uneven hot spots with temperature higher than the recommended

hyperthermia treatment range of ~ 107 degrees F. In addition, non-uniform heating of the

treatment surface would not raise some areas of the tumor to the required therapy

temperature range.

Figure 4 :Veterinary application of Mettler system

In order to improve the heating pattern and make it more uniform across the

tumor volume, one approach is to use a water bolus, as will be discussed in the next

section.

3.2 Structure and properties of a water bolus

A water bolus used in superficial hyperthermia couples the electromagnetic (EM)

or acoustic energy into the target tissue and cools the tissue surface to minimize thermal

hotspots and patient discomfort during treatment [1]. Several designs and studies have

evolved for the bolus in hyperthermia application [2-5].

A bolus is a simple structure; a typical design is shown below in Figure 5. The

figure shows the bolus structure attached to the applicator surface of the Mettler system.

Figure 5 : Mettler RF system with empty bolus structure

The bolus consists of a hemispherical glass or plastic structure and by itself does not modify the heating properties of the Mettler diathermy system. However, when it is filled with material such as water or gel, it can distribute the RF power over the treatment surface, creating a more uniform heating pattern. The water-filled bolus structure is shown below in Figure 6.

Figure 6: Mettler RF system with water-filled bolus structure.

CHAPTER 4

EXPERIMENTAL HEATING RESULTS USING WATER BOLUS

ATTACHMENT TO RF SYSTEM

This chapter will discuss the experimental study of heating of the Mettler RF system, when applied on a foam absorber material, which is dampened with water.

Further, for obtaining comparative results, we tested the RF system with the water bolus and without it as shown in the earlier chapter respectively in figures 5 and 6.

Specifically, four different tests were made with different amounts of power such as low power and mid power, and for each test the applicator was positioned in two different ways: first one was close to the surface and the second was 2 inches away from the surface. Also, each test result was tabulated and tested using the Matlab© software for clear visualization. Furthermore, the heating process or hyperthermia with the water bolus was more practically effective and the heating was steady and distributed uniformly. The next sections will show all results.

4.1 Testing the RF system without the water bolus with low power close and 2 inches away from the surface:

The first test was without the water bolus with low power and applicator was close to the surface, and the test result are summarized in Table 1 below:

Time (min) Temperature (F) Absorption unit*

5 93.2 2

10 136.2 2.5

15 115.7 2

20 143.4 2.5

25 130.8 2.5

30 120.7 2

*The meter is calibrated using standard loads to indicate the total patient input units. The meter will read below 5 until the applicator drum is placed on a patient load regardless of the DOSAGECONTROL setting. The meter will only read full scale with a heavy load such as a chest or back and with full intensity on the DOSAGE CONTROL

Table 1: Time for testing the hyperthermia in low power without the water bolus,

applicator close to surface

For more visually illustrative results, Matlab software was used to show the variation in the time and temperature. The temperature was measured remotely using an infrared thermometer, and the Power Absorption, shown in Table 1 is read from the Mettler equipment meter.

Shown below is the Matlab test code and plot in Figure 7 below:

%Matlab test 1: clc; clear all;

close all;

%LOW power (Applicator close to surface):

temp = [93.2,136.2,115.7,143.4,130.8,120.7]; t = [5 10 15 20 25 30];

stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)')

grid on;

Figure 7: Plot for RF system without the water bolus in low power, applicator close to the

surface

In the second test the applicator was 2 inches away from the surface. In this test, same period of time was used as the first test, and summarized results are shown below in

Table 2:

Time ( min) Temperature (F) Absorption unit

5 62.9 1

10 86.9 1

15 88.3 1

20 88.1 1

25 88.7 1

30 89.2 1

Table 2 : Time for testing the hyperthermia in low power without the water bolus,

applicator 2 inches away from the surface

For more accurate results, Matlab software was used to the show the variations in the time and temperatures as shown in the Matlab test code and figure 8 below:

%Matlab test 2: clc; clear all; close all;

%LOW power (Applicator close to surface): temp = [62.9,86.9,88.3,88.1,88.1,89.2]; t = [5 10 15 20 25 30];

stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 8 : Plot for RF system without the water bolus in low power, applicator 2 inches

away from the surface

4.2 Testing the RF system without the water bolus with mid power close and 2 inches away from the surface:

The third test was without the water bolus with mid power and applicator was close to the surface, and the test results are summarized in table 3 below:

Time ( min) Temperature (F) Absorption unit

5 97.5 3

10 129.7 4

15 134.9 5

20 124.5 5

25 149 5

30 130.1 5

Table 3: Time for testing the hyperthermia in mid power without the water bolus,

applicator close to surface

As before, Matlab software was used to the show the variation in the time and temperatures; Matlab test code is shown below and the resulting graph in Figure 9:

%Matlab test 3: clc; clear all; close all;

%MID power (Applicator close to surface): temp = [97.5,129.7,134.9,124.5,149,130.1]; t = [5 10 15 20 25 30]; stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 9 : Plot for RF system without the water bolus in mid power, applicator close to

the surface

In the fourth test the applicator was 2 inches away from the surface at mid power. In this test same period time was used as in previous tests, and results are shown below table 4:

Time ( min) Temperature (F) Absorption unit

5 82.2 2

10 83.6 2

15 86.1 2

20 87.8 2

25 93.2 2

30 91.2 2

Table 4: Time for testing the hyperthermia in mid power without the water bolus,

applicator 2 inches away from the surface

The temperature was measured remotely using an infrared thermometer, and the

Power Absorption, shown in Table 1 is read from the Mettler equipment meter. The

Matlab test code is given below along with the temperature graph in Figure 10:

%Matlab test 4:

clc; clear all; close all;

%LOW power (Applicator close to surface): temp = [82.2,83.6,86.1,87.8,93.2,91.2]; t = [5 10 15 20 25 30]; stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 10 : Plot for RF system without the water bolus in mid power, applicator 2 inches

away from the surface

4.3 Testing the RF system with the water bolus with low, mid and high power close to the surface:

This test was with the water bolus with low, mid and high power and applicator was close to the surface, and the test results are summarized in Tables 5, 6 and 7 respectively. The associated graphs for the low, mid and high-power temperature variation are shown correspondingly in Figures 11, 12 and 13 respectively.

Time ( min) Temperature (F) Absorption unit

5 82.5 0

10 82.2 0.5

15 81.6 1

20 81.5 1

25 81.2 1

30 82 1

Table 5: Time for testing the hyperthermia in low power with the water bolus, applicator

close to surface

%Matlab test 5: clc; clear all; close all;

%LOW power (Applicator close to surface): temp = [82.5,82.2,81.6,81.5,81.2,82]; t = [5 10 15 20 25 30]; stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 11 : Plot for RF system with the water bolus in low power, applicator close to the

surface

For the mid power:

Time ( min) Temperature (F) Absorption unit

5 88.7 1

10 87.8 2

15 86.9 2

20 86.7 2

25 86.7 2

30 86.7 2

Table 6: Time for testing the hyperthermia in mid power with the water bolus, applicator

close to surface

%Matlab test 6: clc; clear all; close all;

%LOW power (Applicator close to surface): temp = [88.7,87.8,86.9,86.7,86.7,86.7]; t = [5 10 15 20 25 30]; stairs(t,temp,'r'), xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 12 : Plot for RF system with the water bolus in mid power, applicator close to the

surface

For the high power:

Time ( min) Temperature (F) Absorption unit

5 83.4 1.5

10 83.1 2

15 82.2 2

20 82 2

25 82 2

30 82 2.5

Table 7: Time for testing the hyperthermia in high power with the water bolus, applicator

close to surface

%Matlab test 7: clc; clear all; close all;

%LOW power (Applicator close to surface): temp = [83.4,83.1,82.2,82,82,82]; t = [5 10 15 20 25 30]; stairs(t,temp,'r'),

xlabel('Time (mins)'), ylabel('Temperature (°F)') grid on;

Figure 13 : Plot for RF system with the water bolus in high power, applicator close to the

surface

As shown above through the results, Tables 1-7 illustrate the heating results at different stages of the diathermy machine testing, and Figures 7-13 show the graphical variation of the heating in the absorber material as a function of time. These results showed and prove that RF system with water bolus at different amount of power made the temperature distribution more uniform than the case of the RF system without the water bolus.

26 CHAPTER 5

CONCLUSIONS

In this project, we have focused on one of the important technical issues in RF hyperthermia applicators for cancer treatment, which is the non-uniform distribution of heat over the tumor volume. One solution that has been attempted in this work is the addition of a water bolus to the existing RF system, to distribute the heat uniformly over a time period of 30 minutes. Results show that, with water bolus we were able to conduct heating uniformly as shown in the last part of chapter 4 and illustrated with Matlab software code.

In addition, cancer patients deserve more time and effort in working in such a project, and these types of projects need the cooperation of doctors and engineers, to create new inventions and new ideas. We hope in the future to hear of a new treatments or medicines for cancer patients that can help those heroes to live their life fully and with good quality.

Appendix A.

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