General Word For Collection Of Different Diseases Biology Essay

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CHAPTER 1

Cancer is a general word for collection of different diseases; it involves malignant tumor or growth caused when cells multiply without control destroying healthy tissues. It is the third most common cause of certified deaths in Ministry of Healthy Malaysia hospitals (www.moh.gov.my). The World Health Organization statistics (W.H.O) shows that cancer accounted for 7.9 million deaths in 2007 (13% of all deaths worldwide) and predicted about 12 million in 2030. The most common cancers for men it is lung, prostate, colon, head and neck, and bladder whereas for women are breast, uterus, colon, lung and ovary (Lemoigne and Caner 2009).

1.2 Head and Neck Cancer

Head and neck cancer represents a difficult collection of tumors involving mucosal surfaces of the upper aero-digestive tract (Adelstein 2005). Cell carcinoma of the head and neck affects more than 40,000 people each year in the U.S. This represents 4% to 5% of the total number of cancers diagnosed per annum and at least 13,000 people each year die of this disease (Brockstein and Masters 2003). Carcinomas of the nasopharynx are more frequently diagnosed as a head and neck malignancy in Southeast Asia. Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma (SCC) that usually develops around the ostium of the Eustachian tube in the lateral wall of the nasopharynx (Sham, Choy et al. 1990). The first published of 14 cases of NPC was in 1901 and characterized clinically in 1922 (Wei and Sham 2005). However, they represent a relatively rare disease in Western countries (Lu, Cooper et al. 2009). Malaysian Chinese have the second highest incidence of NPC in the world http://thestar.com.my.

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According to the world Health Organization (WHO), NPC is classified into three types, WHO type 1 is keratinizing SCC, WHO type 2 is transitional cell and WHO type 3 is undifferentiated. WHO type 1 is similar in appearance to SCC in other sites throughout the upper aero-digestive tract. The other two types of NPC are nonkeratinizing and represent less differentiated forms of NPC. These undifferentiated forms, WHO types 2 and 3, are more common in the endemic region.

The incidence of NPC is lower than 1/105 in most areas. High-incidence areas are centralized in the southern part of China (including Hong Kong) as shown in table 1.1. The highest incidence is found in Guangdong province, and the incidence in male can reach 20-50/100000 (Wei and Sham 2005; Lu, Cooper et al. 2009). Furthermore, the incidence of NPC is higher in male than female and the ratio is 2-3: 1 (Parkin, Muir et al. 1992; Wei and Sham 2005). Dietary as well as genetic factors affect to partial decrease in risk to the development of NPC (Bland, Daly et al. 2001). The incidence of NPC is increased with age after 30 years which the peak is between 40 and 59 years in the high incident areas (Lu, Cooper et al. 2009). Patients with WHO types 2 and 3 have a significantly higher 5- year survival rate (60% to 7o %) compared to patients with WHO type 1, keratinizing SCC (20% 5-year survival) (Wen-Zhan, Dao-Lan et al. 1989). The factor that has the most serious impact on survival is the presence and characteristic of lymph node. The head and neck region has a rich network of lymphatic vessels, and SCC originated from the head and neck area including NPC can metastasize to regional cervical neck lymph nodes even in its early stages. Therefore, understanding of the normal anatomy of the neck lymph nodes is crucial for the treatment of head and neck cancers. To ensure effective communication, a standard terminology is needed in the discussion of the complex lymph node regions. Various classifications have been developed for this purpose as shown in table 1.2 and Fig. 1.1 (Lu, Cooper et al. 2009). The mere presence of regional lymph node involvement, especially nodal involvement that is large is related with a poor survival (Bland, Daly et al. 2001).

Table 1.1: incidence of nasopharyngeal carcinoma (NPC) in some cancer registries of five continents in 1998-2002 (N,1/105) (Lu, Cooper et al. 2009)

Region and population

Age -standard incident rate

Male

Female

China

China Zhongashan

26.9

10.1

China Gaungzhou

22.2

9.8

China Hong Kong

17.8

6.7

China Shanghai

4.1

1.5

China Nangang District Harlin city

1.1

0.5

Southeast Asia

Malaysia, Sarawak

15.0

6.5

Malaysia, Penang

9.3

3.3

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Singapore

11.0

3.6

Singapore: Chinese

12.8

4.1

Singapore: Indian

1.8

0.1

Singapore: Malay

5.5

2.0

Philippines, Manila

5.8

2.4

Thailand, Chiang Mai

3.9

1.5

Thailand, Songkhla

2.7

0.9

Thailand, Lampang

2.5

1.5

USA

USA, Hawaii: Chinese

9.9

1.1

USA, Hawaii: Filipino

3.3

1.3

USA, Hawaii: Hawaiian

2.0

0.2

USA, San Francisco: Chinese

8.1

4.0

USA, San Francisco: Filipino

3.1

1.0

USA, Los Angeles: Chinese

6.0

1.9

USA, Los Angeles: Filipino

3.8

0.8

Middle East/North Africa

Algeria, Setif

5.4

1.7

Tunisia, Sousse

4.6

1.9

Uganda, Kyadondo

2.3

1.3

Kuwait: Kuwaitis

1.7

0.8

Europe

Austria

0.4

0.2

Finland

0.3

0.1

Arctic

Canada, Northwest Territories

4.3

1.3

USA, Alaska

1.5

0.9

Table 1.2: Staging of nasopharyngeal carcinoma

(a) (b)

Figure 1.1: (a) Lymph glands are joined together by a network of lymph channels. Lymph is a fluid that forms between the cells of the body. (b) The lateral wall of nasopharynx. (http://standardlifehealthcare.medi-health.info)

1.3 Role of radiation Therapy in treatment cancer

Radiation therapy (RT) is the treatment of cancer patients with medium energy x-ray, high energy x-ray, gamma ray, proton, neutron or electron beams. Radiation may be delivered to tumor sites from an external source (i.e. Teletherapy or Linear Accelerators) or at a short distance to the sites of tumor by using sealed radioactive sources called internal radiotherapy or Brachytherapy (Khan 2009). The biological effects of ionizing radiation originate primarily from damage to the DNA of normal and tumor cells. Normal tissue cells suffer the same type of damage, but have better capacity to repair and control mechanisms. Any uncertainty on delivered dose may either result in an under dosage of the tumor or a complication for normal tissue. ICRU Report No. 50 (Units and Measurements 1993) recommends a target dose uniformity within +7% and -5% of the dose delivered to a well-defined prescription point within the target. Patient setup, organ motion and deformation and machine uncertainty e.g. gantry angle and field sizes of the beam are the sources of the errors that degrade the exact dose delivery in PTV (ICRU-83). With the modern radiotherapy equipment and quality assurance program, the machine errors are small compared to patient setup deviations and organs motion. Therefore, treatment with external beam radiation therapy should be done carefully and precisely to achieve conformal dose distribution to the tumor site and sharp dose fall off to normal tissues.

Patients with malignant tumors can be treated with radiation therapy only or as compliments of other treatments such as surgery or chemotherapy as shown in Fig. 1.2. Roughly one third of patients still fail locally after curative Radiation Therapy (RT) with the improvement in cancer cure observed in the last 2-3 decades. In order to improve local tumor control rates with RT the delivery of high doses to the tumor volume may be necessary (Lemoigne and Caner 2009).

Figure 1.2: About half of all cancer patients receive radiotherapy, either as part of their primary treatment or in connection with recurrences or palliation. For Europe it was found that radiotherapy (alone/in combination) is successful in 18% (Lemoigne and Caner 2009).

1.3.1 Three-Dimensional Conformal Radiation Therapy (3D CRT) of Nasopharyngeal Carcinoma

Three dimensional conformal radiation therapy (3-D CRT) is used to represent computers and special imaging techniques such as CT, MRI or PET scans to show the size, shape and location of the tumor as well as surrounding organs. It depends on three-dimensional imaging to define the target (tumor) and to distinguish it from normal tissues. Therefore, this technique is to be able to maximize the target dose and to minimize the dose to neighbored organs at risk by multiple radiation beams and multileaf collimator MLCs. Once a suitable dose distribution has been reached, various other parameters relevant to the treatment can be used, such as monitor units and patient setup parameters. Modern, high-precision radiotherapy (RT) techniques are needed in order to implement the goal of optimal tumor destruction and to deliver the minimal dose to the surrounding tissues.

Nasopharyngeal carcinoma (NPC) is highly sensitive to ionizing radiation, and radiation therapy is the support treatment modality for non-metastatic disease (Kam, Chau et al. 2003). For decades, NPC radiation therapy uses conventional treatment utilizing two-dimensional and lately three-dimensional techniques. Both techniques mainly use opposed lateral fields with or without an anterior field focused to the primary tumor (En-Pee, Pei-Gun et al. 1989; Waldron, Tin et al. 2003). Disease control using conventional radiotherapy techniques has been acceptable; however, insufficient dose to parts of the targets and insufficient to protect critical structures such as optic chiasm, middle/inner ear, eyes, spinal cord, and/or brainstem may result in reduced disease control in advanced NPC. The comparison between intensity-modulated radiotherapy (IMRT) treatment plans and 3DCRT treatment plans for number of nasopharyngeal carcinoma cases using the dose-volume histograms of target volumes and dose to the sensitive normal tissue structures (Xia, Fu et al. 2000; Cozzi, Fogliata et al. 2001; Hunt, Zelefsky et al. 2001; Kam, Chau et al. 2003; Poon, Xia et al. 2007). Their results showed that IMRT demonstrated better target coverage and sparing to a number of organs at risk (OAR) including parotid glands, brainstem, eye, middle and inner ear and spinal cord than that of 3D CRT. There are limitations for using 3DCRT such as

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Need large number of beams unless target shape is very simple.

Optimal beam angles often non-axial and difficult or impossible to use.

In head and neck area, large number of sensitive tissues. So few beam directions work.

No acceptable plan for concave target.

So, head and neck cancers, especially NPC is ideally suited for treatment with IMRT to spare of critical normal structures and better target coverage (Laskar, Bahl et al. 2008).

1.3.2 Intensity Modulated Radiotherapy (IMRT)

Intensity-modulated radiation therapy (IMRT) is capable of generating complex three-dimensional dose distributions to conform closely to the target volume, even in tumors with concave isodose shapes (30% of tumor) (Nutting, Dearnaley et al. 2000). It represents one of the most significant technical advances in radiation therapy(Ezzell, Galvin et al. 2003). In the IMRT, the intensity of the incident fluence radiation field can be varied and each field can be consisted of several small intensity modulated beams (beamlets) to match the projection of the planning target volume (PTV). So, the fluence from each beam creates acceptable uniform dose within the PTV and low dose to OARs. The subsequent dose distributions from IMRT are highly conformal and uniquely. It can produce a concave dose distribution and results in steep dose gradients between planning target volumes (PTV) and organs at risk (OAR) (Nutting, Dearnaley et al. 2000). An acceptable treatment plan is one in which planning target dose uniformity is within +7% and -5% of the dose delivered to a well defined prescription point within the target, and the doses to OAR are low. Furthermore, by using this technique it is Possible to distribute the dose homogeneity to fit tumors with complex shape (e.g. concave shape) while sparing critical normal tissues (Dogan, Leybovich et al. 2002; Kam, Chau et al. 2003).

Figure 1.3: Comparison of 3DCRT (left) and IMRT (right). The ability for 3DCRT to alter isodose lines was limited to shaping of field boundaries with MLCs or blocks, the use of wedges or compensators for missing tissues, and central blocks for shielding critical structures. The IMRT beams can have highly non-uniform beam intensities (fluences) and are capable of producing a more concave-shaped absorbed-dose distribution (Cheung 2006).

1.4 Treatment planning methods

The software code used to calculate dose distributions in a patient or phantom is called the "treatment planning system" (TPS). There are two methods of TPSs. The first is called « Forward planning » used in 3DCRT. For this method of treatment planning, the planner defines the beam parameters like beam (direction, number of beams, and size of the beam), collimator setting (position of MLCs), beam weighting factors of each field, the use of wedges, compensators or blocks. Next, the dose is calculated for each isodose profile or point dose using the treatment planning system. For the worse case, the planner shall modify some parameters of the beam manually till he gets a satisfactory plan (Eisbruch, Marsh et al. 1998; Fogliata, Cozzi et al. 1999). The second method is called « Inverse planning » used in IMRT. The inverse treatment planning is the method of planning where objectives such as target volumes and OARs are allowed for automatically calculation dose distribution according to a preselected algorithm. The algorithm is used to determine beam parameters like number of beamlets, position of MLCs and number of MUs in order to get a better dose distribution that corresponds as much as possible to the initially defined objectives.

In fact there is a large difference between the two treatment planning techniques: The forward planning is a manual iterative process by the planner till he obtains an acceptable result. In inverse treatment planning system, the planner inquires the PC what it would want to obtain as dose distribution to the target (tumor) and OARs. The algorithm will carry out these objectives to obtain the desired dose distribution. The inverse treatment planning seems to be more efficient. However, one should be careful because it implies also many difficulties in comparison with forward planning. This difficulties include (Jiang, Earl et al. 2005):

Treatment time of a patient is more than 3D CRT.

Increased quality assurance efforts.

• The leakage through tongue and groove could become significant in IMRT (Huq, Das et al. 2002).

• Increased shielding requirements due to increased leakage radiation and neutron contamination.

1.5 Different IMRT delivery techniques

All intensity-modulated treatments are performed by changing the multi-leaf collimator (MLC) shape to irradiate different sections of the target volume. By changing the shape of sub-field and monitor units (dose) associated with each MLC segment. Different portions of the target are irradiated separately. The summation of these MLC patterns makes the total dose to the irradiated volume. This combination of beam angles, intensity of dose and MLC segments is designed to deliver highly conformal dose distributions. (Wu, Yin et al. 2010). So, the multi‐leaf collimator (MLC) based IMRT techniques are most currently used and fall into three categories:

- The segmented MLC (SMLC) mode, often referred to as the step and shoot mode.

- The dynamic MLC (DMLC) mode sometimes referred to as the sliding window mode.

- Intensity modulated arc therapy (IMAT)

The segmented MLC (static IMRT) mode referred to as step and shoot, in this technique the beam is only turned on when the MLC leaves are stationary in each of the prescribed beamlet during delivery. The intensity modulated fields are delivered with a sequence of small segments or beamlets, each beamlet with a uniform intensity. To achieve maximum conform dose to the target volume 4 to 9 beam directions may be required depending on the complexity of the PTV (Jiang, Earl et al. 2005). Static IMRT technique is used in Mt Miriam Hospital in Pulau Penang for treatment number of tumor especially NPC cases. The individual fields may consist of 3 to 20 beamlets, which are delivered in succession. The number of beamlets result in the increase of treatment time for IMRT to about 2.5 times more than 3D - CRT3 (Nutting, Dearnaley et al. 2000). To reduce delivery times of inverse planning systems, direct aperture optimization (DAO) should be used. It is used to reduce the monitor units of the beamlet and/or reduce the number of beamlets (Ludlum and Xia 2008; McGarry C K and R 2011; McGarry, Butterworth et al. 2011).

In the dynamic MLC mode (dynamic IMRT) the delivery of the intensity modulated fields are carried out while the leaves of the MLC are moving during patient treatment in a dynamic way. In this mode IMFs (intensity modulated fields) are created by means of moving corresponding leaves independently with a different velocity as a function of time, while the beam is on. Desirable dose can be got by changing the position of MLCs and speed of them. The dynamic IMRT treatment time is much faster than static IMRT technique; typical delivery time for a five ‐ field prostate treatment is 14 min (Nutting, Dearnaley et al. 2000).

Figure 1.4: Dynamic IMRT technique (Schlegel and Mahr 2001)

The intensity modulated arc therapy (IMAT) delivery method uses the sliding window approach while the gantry rotates around the patient. The advantage of using IMAT technique includes; faster delivery time than dynamic MLC (estimated at 5 - 10 min) and the capability of using fewer intensity levels than dynamic MLCs (Boyer and Yu 1999). The Sliding window IMRT and IMAT produce better target dose homogeneity compared to step & shoot IMRT (Wiezorek, Brachwitz et al. 2011). The main difference between IMAT and IMRT is that IMRT consists of a few gantry angles with number of beamlets for each beam direction while IMAT has a single MLC segment at each of many beam direction, but the segment shapes are restricted by the MLCs leaves and gantry rotation speeds. Fig. 1.5 (a) and (b) show the distribution of beams and beamlets for the IMRT and the IMAT techniques, respectively (Wu, Yin et al. 2010).

Figure 1.5: beams direction and beamlets for IMRT and IMAT distribute around a patient. (a) For IMRT, a few beams distributed around the patient, with number of beamlets associated for each beam. (b) For IMAT, many beams distributed around the patient, with one MLC segment connected with one beam (Wu, Yin et al. 2010).

1.5 IMRT verification

A conformal treatment plan consists of two to four open fields, each with a homogeneous dose profile. These fields are applied from different directions. In the other hand, IMRT uses non-uniform radiation beam intensities which are determined using computer-based optimization techniques. The dose distribution on the target can be further shaped by modulating the intensity of each field used. Due to the complexity of the technique, verification of the dose delivery is important. In IMRT, it is necessary to verify the calculated dose distribution from TPS and the actual dose distribution in patient via phantom. There are several methods available for IMRT verification. The most widely used are films which have good spatial resolution but the films have to be calibrated against dose. Gafchromic films which were developed for industrial radiation monitoring have been refined for clinical radiotherapy dosimetry (Chu, Lewis et al. 1990; Devic, Seuntjens et al. 2004). These films are self-developing and require no physical/chemical processing. The optical density of the irradiated film is measured using optical measuring systems such as densitometers and document scan- ners (Devic, Seuntjens et al. 2005; Sankar, Ayyangar et al. 2006). Electron portal imaging devices (EPIDs) do have good spatial resolution but require calibration and they age with radiation. EPIDs are available on treatment machines and are used for position verification of patients. EPID dosimetry using deconvolution methods are used to estimate dose in a patient (Wendling, Louwe et al. 2006; Wendling, McDermott et al. 2009). The 2‐D detector array that can be placed on top of the treatment couch or attached to the accelerator head can improve verification time compared to film measurements. 2D array of pixel ionization chambers do have poorer resolution but provide direct measurement of dose without frequent calibration (Spezi, Angelini et al. 2005; Herzen, Todorovic et al. 2007). The measurements are in real time.

1.6 Objectives of the Study

To study the characteristics of a commercialized array of 2D pixel ionization chambers I'mRT MatriXX from Scanditronix Wellhöfer using Siemens Artist LINAC (6 and 10 MV).

To implement I'mRT MatriXX for IMRT quality assurance in NPC IMRT treatment plan verification using Siemens Artist LINAC (6 and 10 MV).

To evaluated the capability of a commercialized array of 2D pixel ionization chambers Seven29TM (PTW, Freiburg, Germany) with the objective to implement for IMRT quality assurance for NPC IMRT treatment plan verification on Varian clinac 2300 EX (6 and 18 MV).

To correct the response of the I'mRT MatriXX in high gradient region using Deconvolution correction method.

To apply the deconvolution method, the true beam profile for different field sizes and IMRT plans were measured using small ionization chamber (IC03) and Gafchromic films (EBT2 films) and calculated using Monte Carlo simulation BEAMnrc/DOSXYZnrc.

To study the effect of inhomogeneity of head and neck shape, a semi cylindrical phantom was designed for number of NPC IMRT QA cases.

To simulate semi-cylindrical phantom for different field sizes using BEAMnrc/DOSXYZnrc (Linux version).

Structure of this Thesis

This thesis contains eight chapters having the common theme; evaluation of an array of 2D pixel ionization chambers (I'mRT MatriXX) for nasopharynx cases (NPC) for intensity modulated radiation therapy (IMRT) verification. Chapter 1 provides background information on external NPC radiation therapy, spread of lymphatic routes of NPC anatomy, description of treatment types, and the main objectives of this research.

A literature review ; evaluation of an array of 2D pixel ionization chambers (I'mRT MatriXX) for nasopharynx cases (NPC) for intensity modulated radiation therapy (IMRT) verification in chapter 2. It is divided into four broad categories: i) characteristics of 2D Array detectors and Film Dosimeters and Their capabilities to implement for IMRT QA, ii) Detector Size Effects for small field sizes, iii) deconvolution correction method, iv) Monte Carlo Simulation EGSnrc (BEAMnrc/DOSXYZnrc). Chapter 3 describes a basic physics of interaction of photon with matter. Chapter 4 describes the instrumentation utilized in this research. There were two main categories of instruments used, namely the detectors and their software with the ancillary equipments. The detectors employed included I'mRT MatriXX and Seven29TM. The software of the I'mRT MatriXX is called OmniPro-I'mRT Software and Seven29TM has two software called MatrixScan Software and VeriSoft Software. Also Gafcromic films and two types of ionization chamber were used. Three types of phantoms were described, namely the solid water phantom and the Perspex phantom for Nasopharynx. As a treatise in instrumentation, the simulator and linear accelerator (LINAC) is also described. Validation of the experimental work for dose calculations and measurements is provided in the following four chapters. Chapter 5 presents represent study of the characteristics of the 2D array (I'mRT MatriXX and Seven29TM). Deconvolution method to correct detector response function for small fields in 2D array I'mRT MatriXX was applied in chapter 6. It includes measurements for beam profiles using Gafcromic films and Monte Carlo simulation. In chapter 7 was about clinical Application of the I'mRT MatriXX and Seven29TM for Quality Assurance in IMRT Treatments. Finally, chapter 8 concludes the thesis providing a summary of the major results and potential avenues for future work.