CHAPTER : 1 INTRODUCTION 1.1 Carcinoma of the Cervix (Cervical Cancer)

Transcription

1 CHAPTER : 1 INTRODUCTION The curative management of carcinoma of the cervix is significantly enhanced when intracavitary Brachytherapy (BT) is used as an integral component in the treatment of cervical cancer. There have been several studies demonstrated increased in survival rate and decreased in disease recurrence rate when brachytherapy was used in treatment of locally advanced cervical cancer (1-4). Brachytherapy is an advanced cancer treatment where radioactive seeds or sources are placed in or near tumor itself, delivering a high radiation dose to the tumor while reducing the radiation exposure in the surrounding healthy tissues. The term brachy is Greek term for short distance; Brachytherapy is a short distance radiation therapy, also called internal radiation therapy, used to treat cancer and it is very precise and localized. 1.1 Carcinoma of the Cervix (Cervical Cancer) Cancer is a disease when cells of the body start growing out of control. If this abnormal cell growth starts in and from the cervix, it s called Cervical Cancer. Cervix is the lower, narrow end of the uterus. The cervix connects the vagina to the body of the uterus. The uterus (or womb) is the organ where fetus grows during woman s pregnancy. The part of the cervix that is close to the uterus is called endocervix and the other part which is close to vagina is called exocervix. Figure 1.1 shows a female reproductive system diagram (5). There are mainly two types of cells in cervix; squamous cells, these cells are located on exocervix and glandular cells; these cells are located on endocervix area. The place where these two types of cell are met is called transformation zone. Cervical cancer usually originates in the cells located in this transformation zone also called squamous columnar junction. The malignant process breaks through the basement membrane of the epithelium and invades the cervical stroma (6). 1

2 International Federation of Gynecology and Obstetrics (FIGO) staging scheme is used to classified the stage of the disease and dependent on the spread of the tumor around the cervix and in surrounding locations. Cervical cancer can be divided mainly in two types; Squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas generally start in the transformation zone where exocervix joins the endocervix whereas adenocarcinomas are developed from the glandular cells; mucus producing cells of the endocervix (7). Figure 1.1:- Female Reproductive System (Image from reference 5) Majority of the cervical cancers (80% - 90%) are squamous cell carcinomas. These cancer cells start developing in transformation zone and spread. Remaining majority of the cervical cancers are adenocarcinoma and less commonly there are some cervical cancers those have properties of both; adenocarcinoma and squamous cell carcinoma and such cervical cancers are called adenosquamous carcinomas. 2

3 Normal cervix cells do not suddenly change to cancerous cells, those cells first start with pre-cancerous cell changes and if not discovered and treated, those changes can then turn into cancer. 1.2 Statistics of Cervical Cancer Cervical cancer is one of the most common cancers in women worldwide. Statistical data shows number of cases diagnosed and death occurred per year. Below data shows the numbers of cases diagnosed and deaths from the cervical cancer Worldwide, United States and in Indian population. Worldwide: Per most recent available report published in 2012, 528,000 cases were diagnosed for cervical cancer. It s about 4% of the all cancer cases diagnosed worldwide (8). This is the third most common cancer among women worldwide and second leading cause of cancer deaths in the developing world (9). United States: In Untied States, American Cancer Society s estimates for cervical cancer for 2016 is about 12,990 new cases will be diagnosed and estimated death from cervical cancer would be 4,120 (about 32%) (10) India: Per Human Papillomavirus and Related Cancers, Fact Sheet 2016; 122,844 women are diagnosed with cervical cancer and expectedly 67,477 deaths from cervical cancer which is about 55%. (11) 1.3 Cervical Cancer Screening and Prevention A regular screening is necessary to prevent cervical cancer. Its recommended to start a Pap smear test to begin at age 21 years or 3 years after the onset of sexual activities, whichever comes first (12). The American Cancer Society advocates annual screening for women under age 30 (biennial if using liquid-based testing). This screening frequency can be reduced to every two to three years for women aged 30 and older who have had three consecutive normal Pp tests, or every three years if they also are tested for HPV DNA (6). Women population of age 30 years and older are average risk category and should be screened with a combination of Pap smear and HPV testing. Combination screening should 3

4 be performed every three years if both tests are negative. Women with a positive HPV test and with a negative cytology should repeat both test in 6 to 12 months period. (6). An HPV vaccine was recently approved by the FDA ( U S Food and Drug Administration) in 2006 for certain HPV types and it's found to be very effective in clinical trials (13). 1.4 Cervical Cancer Staging The process to determine how far the disease/cancer has spread is called staging (14). Patient general physical examination and diagnostic tests are used to determine the tumor size and disease spread in and around the cervix and further spread to regional lymph nodes or at distant organs. Staging is the key factor in determining the optimum treatment plan to treat the cervical cancer. There are two main staging systems used to stage the extent of the cervical cancer; AGCC (American Joint Committee on Cancer) TNM System and FIGO (International Federation of Gynecology and Obstetrics) System. The AGCC TNM system classifies the cancer staging on the basis of three key factors; Tumor extent (T), Lymph node spread (N) and whether the disease has spread to distant sites, Distance spread (M). FIGO system uses the similar TNM information but classifies the diseases in stage 0 through IV. Recently FIGO staging recommendations were revised in 2009 and decided to delete stage 0 from the staging of all tumors. Updated FIGO staging classifies staging I through IV. Staging system is necessary for the members of cancer care team to summarize and standardized the extent of disease spread. Staging is based on the attending physicians clinical findings rather than surgical findings. AJCC staging starts with T0 (No evidence of primary tumor) to T4 (Tumor invades mucosa of bladder or rectum), Nx to N1 (No regional lymph node involved to metastasis to regional nodes), M0 to M1 (No distance metastasis to distance metastasis spread of the disease). FIGO staging starts with I ( Cervical carcinoma confirmed) to IVB (Distance metastasis) (6). FIGO stages are the same as AJCC staging system with only difference is FIGO staging doesn't include the lymph nodes until stage III (14). 4

5 1.5 Survival rates by Stage Survival rate is refers to the percentage of patient who lived after their cancer is diagnosed. For example, 5-year survival rate refers to the percentage of patients survived or who lived at least 5 years from the time their cancer is diagnosed. Table 1.1 shows the five year observed survival rate based on staging. This data was published in 2010 in 7th edition of the AJCC staging manual and is based on data collected by the National Cancer Data Base from people diagnosed between 2000 and 2002 (15). People with cancer in this observed population may have died from other unknown causes and this published data does not include those death rate into account. Stage Five Year Observed Survival Rate 0 93% IA 93% IB 80% IIA 63% IIB 58% IIIA 35% IIIB 32% IVA 16% IVB 15% Table 1.1:- Five Year Survival Rate By Stage (data from reference 15) 1.6 Therapeutic Measures for Cervical Cancer Cervical cancer treatment depends on the cancer stage and its spread in and around cervix. There are multiple modalities to treat cervical cancer but the common treatment 5

6 technique includes are; Surgery, Radiation Therapy, Chemotherapy and Targeted Therapy. Radiation therapy is the main component in the management of cervical cancer treatment. In very early stage of cervical cancer, radiation therapy or surgery in combination with chemotherapy is typically used but for advanced cases, radiation therapy with chemotherapy is the main course of treatment. 1.7 Radiation Therapy Radiation therapy is the technique that uses high energy radiation X rays/gamma rays or particles to kill cancerous cells. Radiation therapy can be used alone or used with other modality such as chemotherapy or surgery for cancer treatment. Radiation therapy uses, ionizing radiation; waves or high energy particles like, x-rays, gamma rays, electrons, protons or heavy particles to kill or damage the tumor cells. Radiation can be delivered externally with external beam irradiation called External Beam Radiation Therapy (EBRT) and/or internally (Brachytherapy) using radioactive sources. 1.8 Basics of Radiation Radiation can be defines as the propagation of energy through matter or space. Radiation can be in the form of energetic particles or electromagnetic waves. In general radiation can be divided into two major categories; Ionizing radiation and Non-ionizing radiation Ionizing radiation Ionizing radiation is such type of form of energy that has enough energy so that during an interaction with an atom, it can remove the tightly bound electrons from its orbit and that causes the atom to become ionized or charged. Ionizing radiation 6

7 can be in the form of waves or particles. Electromagnetic spectrum, shown in Figure 1.2, represents different waves in wavelength and frequency; higher the wave length, lower the wave frequency (heat and radio waves) will have less energy and will not be able to ionize a atom, on the other hand, shorter wave length will have higher frequency waves ( X-rays and gamma rays) will have more energy and has the ability to knock an electron out from the atom. Examples of ionizing radiation include: Alpha particles Beta particles Neutrons X-rays Gamma rays Non-ionizing radiation Non-ionizing radiation does not have enough energy to ionize atoms in the matter it interacts with. Examples of ionizing radiation include: Visible lights Radio waves Microwaves TV waves Ultraviolet radiation 7

8 Figure 1.2: The Electromagnetic Spectrum 1.9 History of Radiation The Discovery of the X-ray Radiation (X-rays) was discovered by Wilhelm Conrad Roentgen on November 8, Roentgen was a German physicist who had been experimenting in his laboratory with the discharge of electricity in vacuum tubes: called cathode ray tube. These tubes are pretty much similar to fluorescent light bulbs. These glass tubes were evacuated, filled it with a special gas, and had metal plated sealed at the ends. These metal plates could then be connected to a battery or an induction coil so that a high electric voltage can be passing through it. This flow of electricity would produce a fluorescent glow. Those rays causing the glow in tube were named as cathode rays. It was demonstrated that cathode rays were not penetrating. On November 8, 1895, Rontgen had covered the cathode tube completely with black cardboard and his laboratory was completely dark. There was a piece of paper, feet away from the tube, covered with barium-platinum cyanide. In dark room Roentgen noticed that screen fluorescing, emitting light. He realized that he had produced an unknown ray that was being emitted from the tube and is capable of passing through the heavy paper covering the tube. With his additional 8

9 experiments, he found that the newly discovered ray would pass through most substances casting shadow of solid objects on piece of film. He named the new unknown rays as X-ray, because in mathematics X is used to define an unknown quantity. In his further experiments Roentgen found that X-ray would pass through the tissues of humans and would identify the bones and metal visible on the films. One of the early human x-ray image was his wife Bertha s hand with a ring on her finger shown in figure 1.3. Roentgen was awarded the Noble Prize in physics in 1901 for this discovery. Figure 1.3: First X-ray image of human body part This discovery of the x-rays was the breakthrough in medical history. In early 1896, X-rays were being utilized clinically in the United States for findings bone fractures and gunshot wounds The Discovery of Radioactivity Soon after the discovery of the X-rays, in 1896 a French scientist Henri Becquerel was experimenting with naturally fluorescent mineral to study the 9

10 properties of the x-rays. One of the minerals he worked on was uranium compound. Part of his experiment procedure was, wrapping photographic film in light proof paper and placing a piece of fluorescent uranium compound on photographic film and leaving this sample in sun light believing that the uranium compound material would absorbed the sun s energy and then emitted as x-rays. One day he prepared the sample for experiment and was ready to leave it out in sun light but the weather was too cloudy and no sun light to expose the sample so he stored the uranium compound and film in a drawer. This sample was not exposed to any sun light at all; however, after couple of days, he decided to develop the film anyways. He was surprised to see the image of uranium sample on the film. He realized that this sample was not exposed to any external light source so this image might have developed by something invisible from uranium compound that could penetrate the heavy paper and exposed the film. This invisible something was named as radiation and it was determined that an element that gives off radiation is called a radioactive element, hence radioactivity was discovered. Henri Becquerel was awarded the Noble Prize in physics in 1903 for this discovery The Discovery of other Radioactive elements Polonium and Radium In late 1897, Polish scientist Marie Curie and her husband Pierre Curie were get interested with the discovery of radioactivity by Becquerel and started working on looking for other elements. In 1898, The Curies discovered a radioactive element in pitchblende. They named it Polonium in honor of Marie Curie s native country. Later in the same year they discovered another radioactive element and they named it Radium. In 1903, the Curies shared the Nobel Prize in physics with Henri Becquerel. In 1911, Marie Curie received a second Noble Prize, this time in Chemistry, for her purification of Radium metal. Marie Curie is the first person ever to have won the Nobel Prize twice. Marie Curie is the one who proposed the word radioactivity to describe the phenomenon. 10

11 1.9.4 Historically Medical Use of X-rays Soon after the discovery of the X-rays, a potential use of x-rays was realized for diagnostic and therapeutic use in medical field. The first diagnostic x-ray was taken within 2 months (February 1896) of x-ray discovery. Indeed, X-rays were used to treat a patient with breast cancer in January 1896 (16) A woman named Ross Lee, suffering from locally advanced breast cancer was treated with X-rays by a medical student in Chicago named Emil Grubbe (17). Ms. Lee greatly benefitted from this invention demonstrating the potential use of x-ray treatment. In few years, patients throughout the United States and Europe were undergoing Radiotheray treatment Radiation Interaction with Cells X-rays, gamma rays and heavy particles, also called ionizing radiation, have enough energy to ionize an atom (removing an electron from atom). The biological effects of radiation is due to radiation interaction with cell and damage to cell's DNA. When human body is exposed to radiation, energy is transferred to the cells atoms. This energy transfer can be explained with two commonly known mechanism called Direct and Indirect effects of radiation Direct Effects of Radiation If radiation interacts with the atoms of the cell s DNA molecule, or some other cellular component that is critical to the survival of the cell is called direct effect. In this process, cell DNA molecules absorbs sufficient energy from particle or photon radiation and break their molecular bonds. This causes the direct modification or destruction of complex molecules. At cellular level, this effect called DNA break. DNA consists of a pair of strands, so a incoming radiation can break the single strand or both strands of the DNA and may affect the ability of the cell to reproduce and its survival. This direct action of radiation is more dominant with high linear energy transfer (LET) radiations like α particles or neutrons. The probability of direct interaction with cell DNA is small comparison to indirect interaction. 11

12 Indirect Effects of Radiation Indirect interaction is more dominant then the direct interaction. The main part of the cell is mostly water. When radiation (photon or a charged particle) interact with water then the water molecule become ionized. H2O -----> H2O + + e - H2O + is an ion radical because it has lost an electron. H2O + is positively charged and has an unpaired electron so it is both; an ion and a free radical. Ion radicals have short lifetime and tends to interact with other molecule and form free radicals. In this reaction ion radical H2O + reacts with another water (H2O) molecule and form hydroxyl (OH - ) radicals. H2O + + H2O -----> H3O + + OH - These hydroxyl radicals are highly reactive free radicals and interacts with the cell DNA. Usually these ions have low energy and quickly recombine to form water; but, at higher energies it can form free radicals and that can produce toxic substances like hydrogen peroxide (H2O2). H2O2 is highly reactive oxidizing compound that can further attack on other molecules like DNA and damage or kill the cell. Depending on the cell damage, cells tend to repair but excessive molecular damage can lead to cellular death or mutation. Figure 1.4 shows the direct and indirect effects of radiation. The indirect action of radiation with cell can be explained with this chain as follows (18): Incident of X-ray photon/radiation ---> Fast electrons (e - ) ---> Ion radical ---> Free radical ---> Chemical changes form the breakage of DNA bonds ---> Biological effects 12

13 Figure 1.4: Direct and Indirect Actions of Radiation The ion radicals and free radicals have very short lifetime but the expression of the biological damage and its effects may be shown in hours, day, months and years depending on the cell damage Radiation Therapy Techniques used for Cancer Treatment In general radiation therapy techniques can be delivered in three ways; External Beam Radiation Therapy, Brachytherapy and Systemic radiation therapy External Beam Radiation Therapy (EBRT) In External Beam Radiation Therapy (EBRT), radiation is delivered from a machine, at distance, outside the patient body. Ionizing radiation photons (X-rays or gamma rays) or particles (electrons, protons) are used for treatment. Majority of the EBRT treatments are delivered using a machine called linear accelerator also 13

14 called LINAC. Linear accelerator high energy microwave power technology to accelerate the electrons. These high energy electrons can itself be used to treat superficial tumor or skin cancer. These high energy electrons can also collide with a heavy metal target located in Linac and produce high energy x-rays. These high energy x-rays can be used to treat cancer. This exit x-ray beam has high penetrating power and can be used to treat deep tumor inside the patient body. X-ray beam can be shaped using beam collimation techniques like multi leaf collimators to treat different shape and sizes of tumor. There are different techniques used in external beam radiation therapy Dimensional Conformal Radiation Therapy (3D CRT) 3D CRT technique required CT/MRI scan of the patient. Patient is scanned in treatment position on CT machine. Patient is setup with proper immobilization devices to reduce the patient motion during treatment. Beam entry/exit points are marked on patient skin so that patient setup can be reproduced on treatment machine during treatment. This process is called CT Simulation. This data set is fed to dedicated computer called treatment planning system. Radiation oncologist mark the tumor and other critical structures on planning system. Planning system is able to display 3D representation of the tumor and normal organs. Patient specific plan is generated such that it delivers prescribed radiation dose to the tumor while keeping normal tissue doses within the limit Intensity Modulated Radiation Therapy (IMRT) In this technique, intensity of the incoming radiation beam can be modulated during treatment so that it deliver precise radiation dose to the tumor and minimize the doses to surrounding normal organs. Beam modulation can be achieved by using a device called multileaf collimator (MLCs) located in Linac. These MLCs are thin leaves those are made up of high Z lead material. These leaves can be stationary or move during the treatment and can take the shape of the tumor and deliver high radiation doses to the tumor and minimize doses to surrounding normal structures. 14

15 Image Guided Radiation Therapy (IGRT) In this technique, imaging scans are taken during treatment. Treatment machines can be equipped with different kind of imaging modality like CT, kv imager, MV imager. These imaging modalities collect images of the tumor prior or during treatment. Collected images are fed to the processing computer and compared with the original planned images. This help in identifying any changes in tumor position and allow user to change in patient position. This process increases the accuracy of the radiation treatment and help in reducing the margin around the tumor. Due to less margin around the tumor, it minimizes the doses to normal tissues around the tumor Tomotherapy Tomotherapy machine is a combination of CT machine and a linear accelerator. This treatment technique is a type of image guided radiation therapy where CT part of the machine capture imaging data of the tumor, this data can then be analyzed to precisely locate the tumor and treatment is then delivered once tumor location is confirmed. Machine is like a CT scanner where patient is set up on treatment couch, and machine rotate around the patient delivering high and precise radiation dose to the tumor Stereotactic Body Radiotherapy (SBRT) Stereotactic body radiation therapy is a technique where very high radiation doses are delivered in fewer fractions. Tumor lying outside the brain e.g. lung, liver etc are mostly treated in this technique. This technique require image guidance so that tumor can be precisely located and very high dose is delivered to the tumor Stereotactic Radiosurgery (SRS) Stereotactic radiosurgery deliver very high dose to brain tumor mostly in one session. This technique is used for small brain tumor(s) and required precise image 15

16 guidance to locate the tumor so that very high dose can be delivered to the target without damaging to surrounding normal tissues Proton Therapy Proton therapy is one of kind external radiation therapy where it uses high energy charged particles protons instead of x-rays to treat cancer. Proton beam has an advantage of depositing the maximum energy at certain depth and the point where it releases its highest energy is called "Bragg peak". Once physician decide the location of the tumor then treatment plan can be designed such that incoming proton beam releases its maximum energy in tumor while sparing normal tissues around. Unlike X-ray beam, which deposit its energy along the path of the beam and deliver relatively more doses to the normal tissues, proton therapy deliver much less doses to normal tissues Other Charged Particle Beams Linear accelerator can also produce electron beams that can be used to treat superficial tumors and skin cancer. Electrons have limitations in travelling deep in tissues so can only be used for superficial lesions Internal (Brachy) Radiation Therapy (BT) Internal radiation therapy (also called Brachytherapy) is a short distance radiation therapy in which radioactive sources are directly inserted in body cavity or placed at a short distance from the tumor. There are several techniques used in Brachytherapy to treat cancer depending on type and location of the disease. Brachytherapy techniques uses encapsulated radioactive sources in the forms of seeds, needles, tubes and wires. Brachytherapy techniques can be generally divided in main two categories; Intracavitary and Interstitial. There are other forms of brachytherapy treatments including surface molds, surface plaque, intraluminal, intraoperative and intravascular. These implant techniques can be further divided in temporary and permanent. Radioactive sources have certain life defined by "Half Life"; Half Life is the life in which source strength is down to half of its original strength. Some radioactive sources 16

17 have very long half life in making it more suitable for temporarily implant uses so that it can be used multiple times for long time in different patient. This also help in reducing the cost of the treatment. Examples of such radioactive sources are 226 Ra, 137 Cs and 192 Ir, these sources have half life of 1600 years, 30 years and 74 days respectively. However, on the other hand, short life radioactive sources are used for permanent implants. Short life sources are placed directly into the tumor and leaving them permanently. After several days or months, the radioactivity level of the sources diminishes to almost nothing delivering most of the dose in short period of time. Such sources have radiation safety and radiobiological advantages. 125 I, 103 Pd and 198 Au with half life of 59.6 days, 17 days and 2.7 days are some of the examples of permanent implant sources. The main advantage of brachytherapy treatments compared to external beam radiation treatment is localized delivery of radiation dose to the tumor itself as radiation is delivered in close proximity of the tumor volume delivering dose to tumor and sparing surrounding normal structures. This therapy can only be executed for well localized and relatively small tumors. This therapy mostly used along with EBRT as a boost dose to the tumor. In a typical radiotherapy department about 10-20% of all scheduled radiotherapy patients are treated with brachytherapy (19) Systemic radiation therapy Systemic radiation therapy uses different types of radioactive drugs to treat cancer. These Radioactive sources are in liquid form made up of a radioactive substance. These radioactive substances are bound to a monoclonal antibody and attaches to the cancer cell. Medicine can be given to patient by mouth or by an injection and then it travel in the blood throughout the body. These substances find the cancer cell and deposit its radiation energy to the affected cells and kill those cells. Radioactive iodine ( 131 I) is a perfect example of systematic radiation therapy that is commonly used to treat thyroid cancer Radiation Therapy Techniques for Cervical Cancer Management 17

18 Radiation therapy is the main component in the management of cervical cancer treatment. Radiation therapy is generally used in combination with chemotherapy for cervical cancer treatment. Different approaches are used how to deliver radiation therapy for cervical treatment and its completely dependent on the disease staging. Cervical cancer can be treated with EBRT alone or combination of EBRT and BT or BT alone depending upon tumor stage and extent of the disease External Beam Irradiation for Cervical Cancer Treatment External radiation is used to treat the whole pelvis and parametria, including common iliac and periaortic lymph nodes. EBRT can be used by itself to treat as the main treatment of cervical cancer for the patients who cannot tolerate chemoradiation. EBRT is delivered before brachytherapy in patients with bulky lesions; exophytic, easily bleeding tumors; tumors with necrosis or infections and parametrial involvement. It is really important to cover the entire cervix and regional pelvic lymph nodes when designing a EBRT irradiation treatment plan for cervix treatment. The pelvic EBRT treatment fields generally extended superiorly up to L4-5 interspace to include all of the external iliac and hypogastric lymph nodes. If common iliac nodes are positive then the superior field border can be extended to the L3-4 interspace. If lateral fields are used then posterior filed border include S2. EBRT is generally given as one treatment per day for five days per week for about six to seven weeks with a radiation dose of 45 to 60 Gy range depending upon tumor stage. It is important to deliver adequate doses to pelvis and pelvis lymph nodes to achieve the therapy outcome. High energy photon beams (10 MV or higher) are generally used for pelvic external beam irradiation. Treatment is given by anteroposterior (AP) and posteroanterior (PA) 2 fields arrangements or four fields (AP and PA with Right and Left laterals ) techniques depending on the disease. There are certain side effects of external beam radiation therapy. External beam radiation passes through the skin and may damage the skin cells. It can cause minor 18

19 skin irritation to temporary redness and peeling of the skin. Patient can develop skin erythema, skin may release fluid and carefully managed over the course of treatment. Other common side effects includes, nausea and vomiting, stomach upset and diarrhea Brachytherapy (BT) Irradiation for Cervical Cancer Treatment Brachytherapy is often used in addition to external beam radiation as a main treatment of the cervical cancer. Brachytherapy is internal radiation therapy that uses radioactive sources placed in or near the tumor. These inserted radioactive sources continuously irradiated the affected area and delivered the required therapy dose. There are mainly two types of brachytherapy treatment technique used for cervical cancer treatment; Interstitial Brachytherapy (ISBT) and Intracavitary Brachytherapy (ICBT) Interstitial Brachytherapy (ISBT) In this technique radioactive sources are implanted within the tumor volume. Radioactive sources are fabricated in the form of wires, needles or seeds and those can directly be implanted into the tissue. ISBT treatments may be temporary or permanent. In a temporary implants, radioactive sources are removed from the implant once the desired radiation dose has been delivered and on the other hand in permanent implant, radioactive sources are left permanently in the tumor/tissue. Interstitial cervical implants are helpful in specific clinical situations like localized residual tumor or parametrial extensions, large bulky tumor and lower vaginal involvement. ISBT implants are used in situations like when it's hard for physicians to perform intracavitary implant because of poor fitting intracavitary geometry. ISBT implant may be use as an alternate choice of intracavitary implants to deliver localized dose to cervical area. Temporary ISBT implants are used for cervical treatment. ISBT implant procedure involve a transperineal template (Syed Template) through which multiples needles and hollow tubes are inserted directly into the tissue. A central vaginal cylinder is also incorporated into the template. Implant is done in operating room. CT or MRI imaging are done after the implant and patient specific plan is generated on treatment planning system. 19

20 This complete ISBT procedure is not very comfortable for the patient, longer planning time and require lots of efforts from clinical staff. Because of this disadvantage ISBT procedure is not very commonly practiced in the clinics. Patients are either treated with intracavitary implants or referred to the specific hospitals/clinics that routinely perform ISBT procedures. Figure 1.5 show a dose distribution of Intracavitary Implant. Figure 1.5:- Dose distribution of an Interstitial Implant Intracavitary Brachytherapy (ICBT) This technique involves placing the radioactive sources in body cavities close to the tumor volume. ICBT treatments are always temporary and radiation sources are removed from the cavity after short period of time depending on the source strength. Combination of external and intracavitary therapy have achieved remarkably high rates of pelvic tumor control and cure of cervical cancer (20). Intracavitary brachytherapy technique for cervical cancer is one of the efficient technique because of its anatomical conditions that allow insertion of applicators and radioactive sources such that radiation sources in contact or very close to the target volume and "inverse square law" allow delivering high doses to the target volume and doses decreases rapidly with the distance from the sources so this minimize doses to surrounding normal organs rectum and bladder (21). 20

21 The ICBT approach to treat cervical cancer depends on if patient had hysterectomy (removal of uterus and cervix) or not. If patient has had uterus removed than the radioactive material is placed using cylinder applicator in the vagina. If uterus is not removed, then either tandem and ovoid or tandem and ring applicator is used to place the radioactive source in the uterus and near the cervix. Tandem is a metal hollow tube closes at the end, that goes in the uterus and ovoids are metal holders surrounded by plastic or tissue equivalent material called "build up caps", size of the caps varies from 1.6cm to up to 3.0 cm diameter. Ovoids are placed in vagina near cervix. Ring is another style, its round like a disk with a build up caps and also placed in vagina near cervix. Ring applicator is preferred for patient with small vagina that cannot hold the ovoids. Figure 1.6 shows dose distribution for a Intracavitary Implant. Figure 1.6:- Dose distribution of an Intracavitary Implant Although there are several radioactive isotopes are available for ICBT treatment but Cs-137 is more commonly used for Low Dose Rate (LDR) brachytherapy treatment and Ir-192 for High Dose Rate (HDR) treatment. 21

22 Brachytherapy treatments can further be classified with respect to dose rate a (dose at specific dose point(s)). Dose Rate Low Dose Rate (LDR) Medium Dose Rate (MDR) High Dose Rate (HDR) Dose rate at the dose specification point(s) Gy/Hour 2-12 Gy/Hour > 12 Gy/Hour Table 1.2:- Brachytherapy Treatment Techniques Classified With Dose Rate (reference 19) ICBT treatment using LDR implant was most popular for cervical cancer until remote after loader HDR therapy introduced in late 1990 or early Most of the clinical experience in cervical cancer treatment gained from the LDR as this was the primary method of cervical implants and treatment. The disadvantage with LDR brachytherapy treatment is the longer treatment time and personal radiation safety. To deliver the desired doses with the LDR technique it take few days to complete the treatment and patient has to be in hospital/clinic during that time. Medium Dose Rate (MDR) is not commonly used and now a day majority of the clinics in USA, India and Worldwide are switched to HDR because of its advantages over the LDR Advantage of HDR Brachytherapy in Cervical Cancer Treatment 22

23 HDR brachytherapy implant can be treated as outpatient treatment as it takes few minutes to deliver the required prescription dose. It would require prolong treatment time and patient hospitalization for LDR treatment. Because of shorter treatment delivery time with HDR brachytherapy, a large patient population can be treated in a clinic where as with LDR only one or two patients can be treated at a time depending on the available resources. HDR treatment delivery reduce the radiation exposure to the radiation staff. HDR treatments are more precise and reproducible HDR Remote Afterloader HDR Unit in Cervical Cancer Treatment HDR remote after loaders treatments are performed in completely shielded room so it minimize the radiation exposure to health care providers. Because of remote after loading technology, it's possible to deliver the high dose more safely and precisely compared to LDR treatments. A single source, Ir 192 (Iridium - 192) radioisotope of high activity ( about10ci) is more commonly used in HDR remote after loader unit. This isotope is produced in a nuclear reactor from stable Ir-191 by absorption of a neutron. Iridium-192 radioisotope has about 74 days half-life with average photon energy of 0.37 MeV. It decays by beta decay (95%) from Ir-192 Pt -192 and by beta capture (5%) from Ir-192 to Os-192 and has complex energy spectrum from 0.1 to 1.1 MeV with an average gamma energy of 0.37 MeV. Ir 192 is is considered best for HDR because of its higher specific activity. Higher specific activity allow to produce smaller sources for the same activity and smaller size sources are always helpful for precise treatment. Its lower average photon energy makes it more popular because of its less shielding requirement. The one disadvantage of Ir 192 source is its shorter half-life of 74 days so it decays about 1% per day. Shorter half-life required a frequent HDR source replacement in every three to four months. 23

24 A single Ir 192 source is welded at the end of flexible steel wire drive cable. This cable is moved by a stepping motor that transport the cable. Source size vary from 0.3 to 0.6 mm in diameter and 3.5 to 10 mm in length depending upon the make and model of the HDR remote afterloader unit. This source is stored in a shielded storage safe inside the HDT unit when not in use. Figure 1.7 shows a Varian VariSource ix HDR remote after loader unit. The source can be precisely programmed and position at any point in the implanted catheter/channel. Dwell time and dwell position (predetermined point) is achieved in treatment planning system to deliver the desired radiation dose. Figure 1.7: Varian VariSource ix Remote After loader HDR Unit There are several channels (20 channel in Varian VariSource ix HDR unit) in HDR unit with an indexer system that direct the source to each channel. A single source travels to the desired channel connected to the implanted catheter as per the treatment plan. For Cervical plan, three catheters are implanted and connected through transfer guide tube to HDR unit. The source position at the programmed dwell position in the connected applicator is precisely achieved by stepper motor. The source position accuracy of HDR remote afterloader is ±1mm. Treatment plan loaded on the treatment console, Source travel to first catheter and stay at programmed dwell location for programmed dwell time and return bank to unit after delivering the programmed dose to that catheter. Similarly source travel to second and third catheter and deliver the planned radiation dose. 24

25 Remote after loader units makes the treatment delivery more precise, reproducible source positioning and dose optimization. A number of safety mechanisms are provided in the HDR treatment room and at treatment console. HDR treatment room are equipped with door interlocks that retract the source when the door is opened during treatment or when emergency button is pressed on the treatment console. Room is also equipped with video monitoring and audio alarm to alert the personals when radiation is on. HDR unit is also equipped with back-up batteries that can retract the HDR source to the safe storage in case of power failure. A manual retractor wheel is also provided on the HDR unit as a secondary back-up that can be used manually in case of source stuck to any position and emergency switch fail to automatically retract the source to a safe position Treatment Planning Approaches in Cervical Cancer Treatment Dimensional Treatment Planning After completing the ICBT or ISBT implant, treatment simulation is necessary to verify the applicator insertion geometry. Traditionally orthogonal (AP and Lateral) x-ray images were taken to verify the applicator insertion. Dose specification reference points (Point A) are defined on X-ray images. Surrounding organ at risks, bladder and rectum, were identified on x-ray films using contrast medium. Treatment planning was performed using 2D image data set. This planning approach worked fine for years and still some clinics who has limited resources around the globe continue to use this approach. The problem with this approach is limited ability to visualize the actual tumor and surrounding normal structures; rectum, bladder and sigmoid. 2D planning approach can only provide the dose to prescription reference point and max point doses to organ at risks. This maximum point dose may not actually represents the dose to tumor and organ at risks Dimensional Treatment Planning 25

26 With the advancement in the technology it's possible to perform three dimensional imaging using CT and MRI. Cross sectional image data set is reconstructed in planning system and provide three dimensional view of area of interest. Tumor volume and organ at risks (bladder, rectum and sigmoid) can be contoured in treatment planning system. Its provide opportunity to prescribed radiation dose to 3D tumor volume. Dose to organ at risks can be evaluated volumetrically. Point doses to rectum, bladder and sigmoid in 2-Dimensional approaches do not always truly estimate the highest doses to organ at risks but 3-dimensional contoured organs accurately estimate the doses to entire organ and location of the maximum dose in the organ itself. 3-Dimensional treatment planning and dosimetric distribution is the state of the art technology in current scenario. National and international brachytherapy bodies like American Brachytherapy Society (ABS) and Groupe Européen Curiethérapie-European Society of Therapeutic Radiology Oncology (GEC-ESTRO) recommend 3D image based 3D treatment planning in cervical cancer (22-24). CHAPTER : 2 AIMS AND OBJECTIVES Cervical cancer is one of the most common cancer in worldwide in women and is the second main cause of cancer deaths in women in the developing countries (25-26). Studies 26

27 have demonstrated that brachytherapy plays an important role in the management of carcinoma of the cervix. Use of brachytherapy in cervical cancer care increases the survival rate with less recurrence rate (27-30). Since the first gynecological brachytherapy treatment started in 1903 and as of today, there has been multiple dosimetry systems designed to guide brachytherapy implant procedures and dose specifications for the treatment of cervical cancer. There have been enormous development and improvements in implantation techniques, applicators and imaging modalities as well as radioactive sources. Improvements in radioactive source, from Radium source to miniature computer controlled source like Ir192, improvements in treatment delivery technique from Low Dose Rate Therapy (LDR) where treatment time was in days to High Dose Rate (HDR) technique, where treatment can be delivered in few minutes. Improvements in imaging modalities, where earlier 2D X-ray radiographs were used to define the point A (Hypothetical point; defined as 2cm superior to the external cervical os and 2 cm lateral to the cervical canal) and critical structures and now CT or MRI imaging is used to delineate the tumor volume and surrounding critical structures. Point A is still considered as the primary dose prescription point to achieve the total outcome of brachytherapy treatment. Aims: This study was designed to investigate the classical definition of Point A and its existence and variation in 3D approach. Prescription dose to Point A will be compared with actual radiation dose delivered to high risk clinical tumor volume (HR-CTV). Dosimetric parameters will be reviewed and data will be evaluated 3 dimensionally on CT data set to see how point prescription (Point A) versus 3D volume (HR-CTV) prescription approaches is impacting the tumor coverage. Objectives: 1. Review of various dosimetric systems and guidelines in the dose prescription and treatment planning of carcinoma of the cervix 27

28 2. Dosimetric evaluation of High Dose Rate brachytherapy treatment planning using American Brachytherapy Society 2011 recommendations 3. Design a new methodology using three dimensional volumetric approach and come up with a hypothetical formalism in a way such that a new anatomical based revised point A can be defined that will provide adequate coverage to the high risk clinical target volume (HR-CTV) when treating cervical cancer using limited sources. 4. Study the dosimetric and spatial variation due to applicator positioning during interfraction high dose rate brachytherapy treatment of cervical cancer. 5. Compare the planned versus decayed calculated treatment plans and evaluate the dose differences to Point A and to HR-CTV volume. CHAPTER : 3 REVIEW OF LITERATURE Intracavitary Brachytherapy (ICBT) is an essential component in the management of cervical cancer. There have been several studies that have indicated that survival rate 28

29 increases with decrease in recurrence rate when intracavitary brachytherapy is used in managing the cervical cancer (27-30). ICBT treatment uses radioactive sources implanted through a suitable applicator close to the tumor to deliver therapeutic radiation dose to the tumor. Dr Margaret A. Cleaves (1903) treated an inoperable cancer of the cervix first time on 15 September 1903 using radium bromide (700 milligrams) sealed in a glass tube (31). Two applications of ten minutes each were planned with an interval of three days in between the two applications to treat the cancer of cervix uteri. This was the first time when brachytherapy was introduced to treat gynecological malignancies. This was early phase of radiation treatment with no knowledge of biological effects of radiation on the tumor and on the normal tissues. The radiation dose prescription was completely experimental due to lack of radiation biology knowledge and understanding about the dose distribution and treatment duration. Initial radiation treatment provided promising results and based in the extensive clinical data and experience on particular applicator and radioactive source. the concept of Dosimetric system was introduced. 3.1 Dosimetric Systems To treat the cancer of cervix using radioactive source, set of rules were defined by different practicing physicians and clinical researchers. These system, called Dosimetric Systems; are set of rules taking into consideration the radioactive isotope source strength, geometry and method of application and its spatial distribution of radiation dose to deliver a defined dose over the volume(s) to be treated. Within any defined dosimetric system, it is necessary to specify the treatment in terms of dose, timing and proper administration technique so that prescribed dose can be delivered in a reproducible manner and dose standardization can be achieved. 29

30 There are various dosimetric systems used in the treatment of cervical cancer. All those available dosimetric systems were reviewed and a brief explanation of such systems are discussed hereunder Stockholm System Gosta Forssell (1913) developed this system in Radiumhemmet, Stockholm. Intracavitary Brachytherapy (ICBT) treatment was reported in terms of the amount of radium radioactive isotope is used in milligrams and the duration of the application in hours i.e. milligramhours (mg-hrs) (32). James Heyman and Hans Kottmeier (1914) later modified this system (33). This system defined delivered dose in fractionations. Two to three fractionated applications were planned to deliver the prescribed radiation dose within about a month duration. Each treatment application lasted for about hours. The amount of Radium radioactive source was unequal in uterus (30-90 mg, in linear tube) and in vagina (60-80 mg, in shielded silver or lead boxes). Vaginal and uterine applicators were not fixed together. Total milligram-hours were usually 6500 to 7100 and out of which 4500 mg were used in vagina. This was the very early phase of cervical cancer treatment using radium radioactive source Paris System Claude Regaud (1922) developed this system in institute du Radium, Paris for cervical cancer treatment. Similar to Stockholm approach, ICBT treatment was reported in terms of the amount of radium radioactive isotope used ( in milligrams) and the duration of the application in hours i.e. milligram-hours (mg-hrs). This system used two applicators, one Intrauterine applicator, (a tube containing three radium sources in the ratio of 1:1:0.5) and other vaginal applicator called vaginal colpostate and cork together containing same strength as the top intrauterine source. Prescription dose was delivered in a single 30

31 application. Treatment delivery time was roughly about one hundred and twenty hours ( 5 days) to deliver the prescribed radiation dose of mg-hrs. Vaginal and uterine applicators were not fixed together and almost equal amounts of Radium source were used in uterus and vagina. Figure 3.1: Paris System loading pattern (image from reference 34) Figure 3.1 shows the typical radium application for a cervical carcinoma treatment consisting of : Three individualized vaginal sources (one in each lateral fornix and one central in front of the cervical os) and one intrauterine source made of three radium tubes. There are possible variations in the loading pattern in case of a narrow uterus and vagina. Loading can include two vagina sources (or may be only one) in case of a narrow vaginal vault, and only two intrauterine tubes (or only one) in case of short uterus Comparison between Stockholm and Paris Dosimetric Systems 31

32 In both systems uterine radium sources were arranged in a line fashion extending from the external os to nearly the top of the uterine cavity. Both systems preferred the longest possible intrauterine tube to increase the dose to paracervical region and pelvic lymph nodes. There was limited use of external beam radiation therapy in Stockholm system whereas Paris system used external beam radiation therapy before the ICBT implant Issues with mg-hrs dosimetric systems Dose specification in mg-hrs is not adequate, It lacks the information on source arrangements, position of tandem relative to the vaginal sources and packing of the applicators. This system also ignored anatomical targets and tolerance organs Manchester System M. C. Todd and W. J. Meredith (1938) developed this system in Holt Radium Institute, Manchester and later revised in (1953). Manchester system is the most extensively used system in the world (35). This system define treatment in terms of dose to a point representative of the target, i.e. uterus, that is more or less reproducible from patient to patient. To define the actual dose and delivered in a meaningful way, Tod and Meredith began to calculate the dose to various sites in the pelvic region by defining a series of points anatomically comparable from patient to patient. They found that dose prescription to cervix itself is not suitable due to the high dose gradient inherently present in that region. They observed that the limiting radiation dose was not the doses to surrounding critical structures i.e. rectum or bladder, but to the area in the medial edge of the broad ligament where uterine vessels cross the ureter. They defined a "Paracervical Triangle"; This is a pyramid shaped area, the base of which rests on the lateral vaginal fornices and apex curves around the anteverted uterus. It was considered that the dose tolerance of this. 32

33 This system was designed to deliver a consistent dose rate to defined reference points near the cervix. Manchester system defined by doses to four points; Point A, Point B and Rectum and Bladder points. These defined reference points were intended to be used in the context of a set of strict rules dictating the relationship, position, and activity of radium sources in the uterine tandem and vaginal applicators. If those rules are followed, then the dose rate at point A was relatively constant for a variety of anatomical situations and source arrangements. Point A:- Point A was defined as 2 cm lateral to the central canal of the uterus and 2 cm superior from the mucous membrane of the lateral vaginal fornix in the axis of the uterus, shown in figure 3.2 (36). In 1953, Point A definition was later modified and redefined as 2cm superior to the external cervical os (or cervical end of the tandem), and 2 cm lateral to the cervical canal (37). The reason for this modification was although original point A was defined in relation to anatomical structures but these structures cannot be revealed on a x-ray radiograph. The flange stops at cervical os and due to its metal material it's easy to define on x-ray image. These flanges provide a reference for tandem end position and 2 cm superior reference would start from here to define point A superiorly. Due to this reference point A sometimes denoted as Ao where o stands for external os. Dose to Point A is considered to be the most useful index of limiting doses that can be given in the treatment of cervix. Radiation dose is prescribed to Point A for cervix treatment. Point B: - It is defined as 5 cm lateral from the mid-line and on the same level as Point A and 2 cm superior from the mucus membrane of the lateral fornix (figure 3.2). This point was chosen because it gives not only the dose in the vicinity of the pelvic wall near the obturator nodes. but also a good measure of the lateral spread of the effective dose. 33

34 The dose at point B depends very little on the actual geometrical distribution of radium, such as the size of the ovoids and intrauterine tubes, but almost entirely on the total amount of radium used. The dose at point B is approximately 25-30% of the dose at point A. Figure 3.2 Original definition of points A and B, according to the Manchester system. (Meredith WJ. Radium dosage: the Manchester system, Edinburgh: Livingstone, 1967) In situation where the uterus does not lie in the mid-line of the body, the tissues in which point "A" lies is considered to be carried with the uterus, but point B, which does not directly depend on the uterus, remain as a fixed point. In the loading rules of the Manchester System, it was recommended that, if possible, largest ovoids be used to carry the radium close to point "B" and increase the depth dose. It was advised to place the ovoids as far laterally as possible in the fornices for the same reason. Figure 3.3 shows the location of point B in reference to tandem and point A location. 34

35 Figure 3.3: Point B in reference to point A and tandem Rectum and Bladder Points: Rectum and bladder are the critical structures in cervical treatment. The dose to rectum and bladder depends on the distribution of sources in a given application. The localization of bladder and rectum is performed using radiographs taken with the contrast material in bladder and rectum. Dose to rectum and bladder be kept less than the 80% of the dose to point A. If the dose is measured or calculated to be too high to these structures than altering the geometry of the sources are the alternative option. Other dose limiting structures:- Vaginal mucosa and recto-vaginal septum are the other dose limiting structures. The tolerance of vaginal mucosa is such that not more than about 40% of the total dose to point A can safely be delivered through the vaginal ovoids and this should be taken into account in planning the different loading patterns. Dose to rectovaginal septum for any technique should be less than that at point A. packing gauge of thickness of at least 1.5 cm to pack ovoids away from the rectum is used to reduce the dose to rectum Applicators 35

36 A pair of ovoids and an intrauterine tube is used for source application to treat cervix cancer. Intrauterine Tubes:- The intrauterine tube was made up of the thin molded rubber or plastic with one end closed and supporting a flange at the other end for aiding fixation. Flange help in identifying the location of the cervical area on x-ray radiograph. Flange at the other end of the tube help in keeping the tube fixed in place such that when it packed into position, the uterine tube did not slip out during the treatment. Intrauterine tubes were available in there lengths, meant for one, two or three radium tubes (1 tube is 2cm long). These tubes were available in 2cm, 4cm and 6cm lengths. Vaginal Ovoids:- The Ovoids were used in pairs, placed in vagina in each lateral fornix. Ovoids were made of hard rubber or plastic with diameter of 2.0, 2.5or 3.0 cm. The ovoids were designed not only to be adaptable to the different sizes of the vagina, but also to take advantage of vaginal capacity to carry the radium laterally. The largest ovoids are placed in the roomiest vagina in order to achieve the best lateral dose throw off Packing Manchester system's applicators do not incorporate rectal and bladder shielding. Gauge pieces are used as packing to pack the applicators firmly and carefully. Gauge packing is used behind the ovoids posteriorly to push the rectum posteriorly and anteriorly between the ovoids and the base of the bladder to push the bladder anteriroly to reduce the rectum and bladder doses. Packing helps to keep the implanted applicators in positions and to reduce the dose to rectum and bladder Implantation Rules 36

37 Tod and Meredith (1953) defined a set implantation rules to deliver required dose for cervical cancer treatment. Prescription dose was defines at point A. Total dose to point A was defined to be 8000 R (Roentgen, a unit of radiation dose). Point A should receive the same dose rate, irrespective of the combination of the applicators used. Not more than one third of the total dose to point A should be delivered by the vaginal ovoids so that tolerance of vaginal mucosa is not exceeded. Ideal implant loading is considered as i.e. 60% of the dose to point A is contributed by intrauterine sources while 40% is contributed by ovoids. Total two applications used with each application of 72 hours with about 4-7 days interval in between applications. The implied dose rate of 55 R per hour at point A which was achieved by the strict loading rules. The amount of Radium to be used was defined in terms of units. 1 Unit is equal to 2.5 mg of Radium source filtered by 1 mm platinum. The loadings were specified in terms of integral multiples of this unit. Long intrauterine tube with 3 sources contained 4, 4, 6 units, medium intrauterine tube with 4, 6 units and short with 8 units. Large, medium and small ovoids were assigned 9, 8, and 7 units in each ovoid Limitations of Manchester System Manchester system was meant for Radium as the radioisotope and its applicators specifically designed to accommodate those sources following a set of strict rules to deliver a constant dose rate at Point A. Any variations in the selection of applicator, radiation source or the set rules would result a different dose delivery to point A. Because of long half life of the Radium radioisotope and other radiation safety hazardous associated with Radium source, Radium as the choice of radiation source started to phase out and soon it was replaced by Cs 137 and Ir 192 radioisotopes The International Commission on Radiation Units and Measurements (ICRU) System 37

38 ICRU (1985), recommended a system of dose specification that relates the dose distribution to the target volume instead of the dose to a specific point (38). The dose is prescribed as the value of an isodose surface that surrounds the target volume. ICRU report number 38, includes recommendations on including various treatment parameters in dose and volume specification for cervix treatment. The ICRU system require to report certain treatment parameters in cervical cancer treatment. The reporting data includes, description of the technique, type of applicator and its geometry and radiation source used for treatment. ICRU defined a new parameter called Total Reference Air Kerma (TRAK). Total reference air kerma (kerma; kinetic energy released in mater) is defined as total air kerma at 1 meter from the implant. This is equal to the air kerma strength times the duration (in hours) of the implant. TRAK is similar to the total milligram-hours of radium or total mg-ra-eq-h except that the sources are calibrated in units of air kerma strength that is µgy m 2 h -1. ICRU report recommended to calculate and report total dose to a reference volume. This reference volume is defined as the volume of the isodose that just surrounds the target volume. The value of the reference isodose surface prescription was based on the Paris experience and was set at 60 Gy. The prescription reference isodose value is determined by two factors; (i) This 60Gy dose includes the dose contribution from the external beam radiation therapy treatment. The contribution of the external beam radiation therapy is subtracted from the 60Gy total dose, then a relevant isodose surface from the intracavitary plan is divided by the duration of the insertion (figure 3.4) 38

39 Figure 3.4: Total volume treated with external beam and brachytherapy (reference from ICRU report number 38) (ii) the intracavitary portion of the treatment in dimensions of height (dh), width (dw) and thickness (dt) of the pear-shaped reference volume should be identified and recorded. The reference volume is approximated by (dh X dw X dt ) cm 3. The reference pear-shaped reference volume parameters can be measured from the oblique frontal and oblique sagittal planes on x-ray radiographs (figure 3.5). 39

40 Figure 3.5: Reference volume treated with ICBT (from ICRU report number 38) Absorbed dose at reference points ICRU recommends recording and reporting doses to these reference points for any intracavitary implant:- Bladder reference point:- The dose to bladder depends on the distribution of sources in a given application. The localization of bladder can be performed using radiographs taken with the contrast material in bladder. The bladder point is identified by using a Foley balloon catheter that is filled with the 7cc radiopaque contrast material. Two X- ray radiographs are used, on Anteroposterior (AP) radiograph, bladder reference point is marked on at the center of the balloon, and on lateral radiograph, bladder point is marked at posterior surface of Foley balloon on AP line through center of balloon, Figure 3.6 (38) shows bladder and rectum reference points. The maximum dose to bladder should be less than 80% of the prescribed dose to point A. Rectal reference point:- The dose to rectum depends on the distribution of sources in a given application. The rectum reference point is identified on the AP radiograph at the intersection of (the lower end of) the intrauterine source through the plane of the vaginal source. On the lateral image, it can be identified at 5 mm behind the vaginal posterior wall. The posterior vaginal wall can be clearly visualized by using radiopaque gauge for the vaginal packing. Rectum ICRU reference point is shown in figure 3.6 (38). The maximum dose to rectum should be less than 80% of the prescribed dose to point A. 40

41 Figure 3.6: Rectum and Bladder Reference Points (from ICRU report number 38) Lymphatic trapezoid:- Lymphatic trapezoid represents dose at lower Para-aortic, common and external iliac lymph nodes. Lymphatic trapezoid pelvic reference points are shown in figure 3.7. A line is drawn from S1-S2 junction to top of symphysis, then a line is drawn from middle of this line to middle of anterior aspect of L4. A trapezoid is constructed in a plane passing through transverse line in pelvic brim plane and midpoint of anterior aspect of body of L4. 41

42 Figure 3.7: Reference AP and LAT image representing Lymphatic Trapezoid (reference from ICRU report number 38) Pelvic wall reference point:- The pelvic wall reference points represents absorbed dose at the distal part of the parametrium and at the obturator lymph nodes. Figure 3.8 shows the AP and Lateral x-ray images to identify the pelvic wall reference points. Reporting dose at reference points related to well defined bony structures and lymph nodes areas is particularly useful when intracvitary brachytherapy is combined with external beam radiation therapy. Pelvic wall reference points can be identified on AP and LAT radiographs. On AP radiograph, the points are located at the intersection of a horizontal tangent to superior aspect of the acetabulum and on LAT radiograph these points are marked as the highest mid-distance points of the right and left acetabulums. 42

43 Figure 3.8: Pelvic Wall Reference Points showing on AP and LAT X-ray film (reference from ICRU report number 38) Time-dose pattern The duration and time sequence of the implant relative to the EBRT should be included, for example one hours of LDR intracavitary implant be scheduled after one week of external beam radiation therapy treatment (EBRT) completion. The duration of the application should also be included in dose reporting Applicators The applicators include, A tandem that is inserted into the uterus. Tandem can be of different lengths that allow for adaptation according to the individual anatomy (with a fixed flange). Tandems are also at varying degree angles (15º, 30º, 45º and 60º). The deliberate angle in the tube draws the uterus, in most patients, into a central position in the pelvis away from the pouch of douglas, the sigmoid colon and the anterior rectal wall. Two ovoids, to be positioned in the vaginal vault abutting the cervix. 43

44 Issues with ICRU dosimetric systems ICRU dosimetric system considered the best in that time as it provides information about doses to pelvic point and doses to reference volume for better tumor control and critcial structures dose management. Issues with the ICRU system is, it does not exactly provide doses to clinical target volume and also doses to critical structures (rectum and bladder) volume. Critical structure doses were point based not to the complete organ volume. Bladder point was defined at the surface of the foley balloon catheter representing the maximum dose to bladder but in reality this is not a true indication of the bladder dose. Sometime foley catheter is displaced and not at perfect location and doses to bladder can be under or over estimated. Similarly, rectum point was defined as 5mm posterior to the vaginal wall, directly posterior to the center of ovoid and ring applicator. These point do not accurately provide doses to these organs. A complete organ volume is necessary to calculate the accurate doses to such critical structures. So for mostly cervical brachytherapy treatment was delivered with Low-Dose-Rate (LDR) brachytherapy. Radium radioactive source was replaces by Cs-137 (LDR) and later Ir192 (HDR) 3.2 Other Dose Specifications Points (Potish, 1987), proposed Point Av ( v stands for vagina) as 2 cm lateral to the midpoint of the cervical collar and 2 cm above the top of the colpostats, measured at their intersection with the tandem midpoint on the lateral radiograph. Madison System (1993), was proposed for HDR brachytherapy of uterine cervix in This system defined a new point called Point "M". It lies 2 cm cephalad along the tandem from a line connecting the center points of the vaginal ovoids and 2 cm perpendicular to the tandem, when using 1cm radius ovoid caps shown in figure 3.9. In this system, the 44

45 uterus is held lower in the pelvis (using tanaculum) to lower the small bowel dose superior to the uterus. in this situation, this point M approximately coincides with original point A of the Manchester system. Figure 3.9: AP and LAT x-ray Images Representing Reference Point M 45

46 3.3 Recent Advancements and Proposed Guidelines All above discussed system utilized Low-Dose-Rate brachytherapy approaches to deliver radiation dose for cervical cancer treatment. LDR brachytherapy techniques had disadvantages as it required mandatory patient hospitalization, longer treatment time, and radiation exposure to care givers. LDR brachytherapy treatment gradually started to shift toward High-Dose-Rate (HDR) approaches. Remote after-loading units were introduced in early Remote after loader unit contained a single Ir-192 source of 10 Curie (Ci). Treatment time came down from hours to minutes. American Association of Physicists in Medicine (AAPM, 1993), published a report (AAPM Report Number 41) on remote after-loading technology as HDR brachytherapy becoming popular worldwide. This report lists commercially available remote afterloader units and their features, reviewed radiological safety aspects, facility requirement and calibration methods. This was the first report published by AAPM discussing all aspects of safe use of HDR in cancer management. AAPM (1998), later published another report (Task Group Number 59 report) discussing High-Dose-Rate brachytherapy treatment delivery techniques. This document provided an extensive quality assurance check list and reviewed all aspects of HDR brachytherapy treatment delivery, including radiation prescription, radiation safety, treatment plan and treatment delivery. 46

47 3.3.1 The American Brachytherapy Society (ABS) recommendations The American Brachytherapy Society (ABS, 2000), published guidelines for HDR brachytherapy for carcinoma of the cervix. In this published ABS report, members with expertise in HDR brachytherapy for cervical cancer performed a review literature, supplemented their clinical experience to formulate guidelines for HDR brachytherapy of cervical cancer. ABS report states that ideally prescription dose should be specified to the individual patient's target volume but sometime it's not practical as institutes may not have capability to determine the volume at risk and also there is not sufficient information in the literature to establish the clinical target volume. ABS 2000, report recommends prescribing the dose to a new point, called Point H to differentiate from any of the other definitions of Point A. ABS system retain the original Manchester system s point A definition and just called it Ao or point H. For tandem and ovoid insertion, Point H can be found by drawing a line connecting the mid-dwell positions of the ovoids. From the intersection of this line with the tandem, move superiorly along the tandem 2 cm plus the radius of the ovoids, and then 2-cm perpendicular to the tandem in the lateral direction as shown in figure 3.10 (39). Figure 3.10 shows the ABS recommended point A (showed as Ao or H in the figure). Ao is point A as defined by original definition of Manchester system. There are other 2 points showed in the figure 3.10A, marked as Af1 and Af2. The position of these 2 points Af1 and Af2 follow the revised definition of Manchester system depending upon the location of the flange/cervical os stopper on radiograph. If flange is found at f1 location the point A will be defined as Af1 and if flange location is as f2 then point A would be marked at Af2. Figure 3.10 also shows the location of Point M that follows the definition of Madison system where the 2 cm superior location would be marker from the central line of the vaginal ovoids. 47

48 Figure 3.10A Figure 3.10B Figure 3.10A&B: Point H on AP X-ray Image (image from reference 39) For tandem and ring application, point H can be identified by drawing a line connecting the mid-dwell positions of the ring. From the intersection of this line with the tandem, move superiorly along the tandem 2 cm plus the thickness of the ring (including the cap), and then 2-cm perpendicular to the tandem in the lateral direction per figure 3.10B (39). For tandem and vaginal cylinder application, point H is defined as 2cm cephalad along the tandem form the cervical flange and 2 cm perpendicular to the tandem in the lateral direction on both sides of AP radiograph. ABS revised its recommendation again in 2011 that was published in In its 2011 ABS recommendations, it is clearly stated that finding point A relative to flange on tandem for tandem and ovoid implant, produces inconsistent dose specification and this method should not be used to define point A (24). 48

49 ABS 2011, guidelines which talks about 3D planning, point A should be determined as follows, Connect a line on treatment planning system through the center of each vaginal ovoid for tandem and ovoid implant or the lateral most dwell position for tandem in ring implant, on tandem, where this line intersects, extend superiorly the radius of the ovoid or for the ring, move superiorly to the top of the ring, and then move 2 cm along the tandem. From that point move 2cm laterally on both sides, on a perpendicular line form this pint and mark right and left point A accordingly, shown in figure 3.11 and 3.12 (24). For tandem and cylinder application, start at the flange/or cervical os level then move 2 cm superiorly along the tandem and 2cm laterally on a perpendicular line, shown in figure 3.13 (24). Fig 3.11: Point A for a Tandem and Ovoid Applicator (image from reference 24 A.N. Viswanathan, B. Thomadsen/ Brachytherapy 11 (2012) 33-46) 49

50 Figure 3.12: Point A for Tandem and Ring Applicator (image from reference 24 A.N. Viswanathan, B. Thomadsen/ Brachytherapy 11 (2012) 33-46) Fig 3.13: Point A for a Tandem and Cylinder Applicator (image from reference 24 A.N. Viswanathan, B. Thomadsen/ Brachytherapy 11 (2012) 33-46) 50

51 3.3.2 Groupe Européen Curiethérapie-European Society of Therapeutic Radiology Oncology (GEC-ESTRO) guidelines GEC-ESTRO 2005, working group released a series of recommendations to support and promote 3D imaging based 3D treatment planning (22). This working group was founded based on experts in the field so that they can establish a common terminology and set of parameters for 3D image based treatment planning in cervix cancer. The recommendations established in GEC ESTRO report were based on clinical experience and dosimetric concepts of different institutions participated in the group (22). These recommendation set a new fundamental guidelines for the cervix treatment that was completely based on 3D concepts using CT/MRI imaging. It is recommended to use CT and/or MRI compatible applicators that allow a sectional image based approach to assess the gross tumor volume (GTV), clinical target volume (CTV) and organs at risk (OARs). GEC-ESTRO working group recommended that dose should be prescribed to a high-risk clinical target volume (HR-CTV) rather than to a point, however its recommended to document conventional point A dose. This working group first time define the clear guidelines of defining the HR-CTV volume. HR-CTV volume is defined as the area of gross residual disease at the time of brachytherapy. HR-CTV includes all the gross disease at the time of implant, the entire cervix and any areas of suspicious residual disease. MRI is preferred for target localization and volume delineation. The optimum dose to this HR- CTV volume was not clearly indicated but its recommended that HR-CTV should receive the complete prescription dose same as it would have been prescribed to point A. A dose of >80Gy should be delivered to this target for better tumor control. This dose include the dose from EBRT and considered sufficient enough to sterilize macroscopic tumor cells. This group also recommend a second target called intermediate risk clinical target volume (IR-CTV), and should be defined at the time of diagnosis. IR-CTV includes HR- CTV volume plus an additional margin of 5-15 mm depending upon potential tumor 51

52 spread and OARs tolerance. GEC-ESTRO guidelines specify to record doses to target volumes (IR-CTV and HR-CTV) and OARs. D90 and D100 should be documented for HR-CTV along with doses to point A, and ICRU rectum and bladder points. For OAR; D0.1cc, D1cc, D2cc, if volumes are delineated; or D5cc, D10cc, if walls are contoured, should be recorded Issues with Recent Guidelines Recent ABS and GEC-ESTRO guidelines are encouraging to use CT/MRI (MRI preferred) based cross sectional imaging to delineating the target volume. Unfortunately, small clinics do not have capability of CT/MRI imaging capability. It is obvious that the CT images fails to provide adequate information of invasion of microscopic tumor cells as compare to MR images. Small clinics with limited resources still use the old Manchester/ICRU technique for Point A definition using AP radiographs. 3.4 Scope of Further Research on the Topic Cervical cancer treatment had gone through several changes from delivering modality (LDR to HDR) to prescription dose specification (Point versus 3D). There has not been a single formalism established yet that can provide a hybrid approaches. There is a need of hypothetical equation that redefine Point A in such a manner that this revised point A can provide adequate coverage to HR-CTV even when 3D imaging is not performed. CHAPTER : 4 MATERIALS AND METHODS 52

53 4.1 Patient Selection Twenty five patients (125 treatment plans) with carcinoma of the cervix were selected for this study. All forty patients had received their high dose rate brachytherapy treatment at radiation oncology department at Texas Oncology located at 1450 Eighth Avenue in Fort Worth, Texas, USA. This study was approved via expedited review by the departmental research committee and by the practice/academic institutional review boards, and used deidentified retrospective data for study analysis. In this study patients treated in or prior to January 2013 were included and high dose rate (HDR) brachytherapy treatment patient log files were thoroughly reviewed and Forty cases were randomly selected who completed their high dose rate brachytherapy treatments prior to January 2013 for two practicing radiation oncologists. All those cervical patients were treated as per national/ international approved guidelines in the management of cervical cancer. Selected twenty five carcinoma of cervix patients were treated during January 2009 to January This study is conducted for cervical cancer so all enrolled patients was female. Patients were in the age group of years with average age of 57 years and median age of 52 years. Abnormal Pap smear test results indicated a potential cervical cancer in these patients. A complete medical physical exam, biopsy and imaging confirm the diagnosis and staging of the cervical cancer. All these patient had pathologically proven locally advanced squamous cell carcinoma or adenocarcinoma with FIGO (International Federation of Gynecology and Obstetrics) staging IB or higher. Patients who completed their course of EBRT and ICBT were included in this study and Patients who couldn't complete the entire course of radiation therapy were excluded from the study. Patient who received ICBT treatment with tandem and ovoid and/or tandem and ring applicator were included. Patient with tandem and cylinder applicator and interstitial implant were excluded from this study. 53

54 CT/MR compatible Titanium Fletcher-style tandem and ovoid and tandem and ring applicators were used for intracavitary brachytherapy (ICBT) implants. Radiation Oncology Department has three T&O applicator sets with reference numbers (AL for all, Lot/Batch Numbers , 10419, and 20408) and one tandem and ring applicator set (Reference Serial Number AL ). These applicators were supplied by Varian Medical Systems, Inc (Palo Alto, California, USA) and were manufactured with Titanium CT/MR compatible material. One applicator set is required per implant so any one of the listed applicator set was used for implant depending upon the availability of the applicator set at the time of implant. Multiple applicator sets are available in department to treat multiple cases per day. Flexible cervical sleeves (Smit Sleeve), supplied by Varian Medical Systems, Inc (Palo Alto, California, USA) with current product number AL , AL , AL , AL for 20mm, 40mm, 60mm and 80mm respectively, were used for all the implants and implanted during first ICBT implant (Smit sleeve helps in identifying and dilating the cervical os and allow easy insertion of the tandem during rest of the implants). GE Healthcare System s Computed Tomography (CT) unit (Model Number: LightSpeed QX/I, Serial Number CN6) was used for patient imaging. Eclipse treatment planning system (BrachyVision version 11.1) was used for brachytherapy treatment planning and Varian VariSource (Model: VariSource 2000, Serial Number H600329) HDR treatment machine was used for brachytherapy treatment delivery. Both, treatment planning system and HDR remote-after loader treatment delivery machine were manufactured and supplied by Varian Medical Systems, Inc (Palo Alto, California, USA). Reusable Transfer Guide Tubes (200 series, Reference Number AL , LOT number ) were used for tandem and ovoids implants. Reusable Click-Fit Style Transfer Guide Tubes (200 series, Reference Number AL , LOT number ) were used for tandem and ring implants. Transfer Guide Tubes (TGTs) connect implanted applicator to the HDR treatment machine and are used during treatment delivery. All TGTs were supplied by Varian Medical Systems, Inc. A universal applicator clamping device (Model GM ), also called 54

55 base plate, is used for all the patient to hold the implant in place. Base plate was also supplied by Varian Medical Systems, Inc. High dose rate brachytherapy treatment, in general, is combined with the external beam radiation therapy treatment. Once staging is finalized and clinical decision is made for patient to receive radiation therapy as part of their cancer care, patient goes through a treatment planning CT simulation prior to external beam radiation therapy treatment. During CT simulation procedure patient goes through pelvic or lower extremities CT scan. The basic difference in regular CT scan and CT simulation procedure is, in CT simulation study, patient is scanned in treatment position, and at least some kind of patient immobilization devices are used to reproduce the setup on treatment machine. Patient setup is aligned with CT lasers that simulate the treatment room laser and laser points are marked on patient skin to reproduce the patient setup on treatment machine. Sometime intravenous contrast, oral contrast or rectum and bladder contrast medium is also used to improve the critical structures delineation. All patients of this study were initially treated with external beam radiation therapy (EBRT) radiation dose of 4500 cgy (cgy = unit of radiation dose) in 25 fractions, 5 fractions per week over a period of 5 weeks to the whole pelvis. External beam radiation is generally delivered daily, Monday through Friday for about 5-6 weeks. Concurrent cisplatin-based chemotherapy was also given to the patient during the course of radiation treatment as per chemotherapy schedule. As the external beam radiation therapy treatment approaches close to completion, a brachytherapy high dose rate brachytherapy boost dose in the range of cgy/fraction in 5 fractions were delivered with intracavitary brachytherapy implants. Two brachytherapy intracavitary implants were done per week so the completed ICBT doses were delivered in about two and half week. It is recommended to complete the overall treatment of cervical cancer with external beam radiation and brachytherapy treatment 55

56 within 8 weeks to limit the chances of tumor cell proliferation, which ensures better local control compared to the patients who received treatment in more than 8 weeks. The survival rate decreases approximately by 1% per day as time increases by more than 8 weeks (43-46). These guidelines were followed for all the patients in the management of cervical cancer treatment. Brachytherapy treatment sometime can be integrated with the external beam radiation therapy treatment but in all our cases, brachytherapy treatment is delivered after the course of external beam radiation treatment. 4.2 Applicator Selection All of the cases in this study were treated using intracavitary implant. Intracavitary brachytherapy implant involves a procedure in which intracavitary applicators are placed in uterus and vagina through the vaginal cavity to treat the cervical cancer. There are varieties of applicators used for intracavitary brachytherapy implant. Tandem and Ovoid and tandem and ring applicators are more commonly used for cervical treatment. Forty percent (40%) of the selected cases were implanted using tandem and ovoid applicator and remaining sixty percent (60%) of the cases were implanted with tandem and ring applicator. Tandem and cylinder applicator is rarely used in our practice. There was not even a single case of tandem and cylinder applicator included in this study Tandem and Ovoid (T&O) Applicator Tandem and Ovoid Applicator:- Tandem and ovoid applicator set consist of one tandem and two ovoids (also called colpostats). Tandem is a metal hollow tube that is inserted through the vaginal cavity and placed through the cervix to the level of the uterine fundus, and two ovoids are placed on either side of the cervix in the lateral vaginal fornices. CT/MR compatible Titanium Fletcher-style tandem and ovoid applicator was used for T&O implant cases. Radiation Oncology Department has 3 T&O applicator sets with reference number (AL for all, Lot/Batch Numbers as , 10419, 20408). 56

57 These applicators are supplied by Varian Medical Systems, Inc (Palo Alto, California, USA) and are manufactured with Titanium CT/MR compatible material. Tandems are attached to two ovoids with interlocking system provided in the applicator set. T&O kit has different sets of tandems that include 15º, 30 º and 45º with variable length options of 4 cm, 6cm and 8cm. Angle and length option help in accommodating the variety of anatomical situation i.e. uterus size and curvature. Tandem intrauterine tubes are 3mm diameter that can easily fit it flexible cervical sleeves. Different smit sleeves are also available to hold the different sizes of the tandems. Ovoids are used in pair, sit in lateral vaginal fornices and are attached to the tandem with locking mechanism. There are 4 options to choose from in T&O kit that includes 16 mm diameter (mini), 20 mm (small), and 25 mm (medium) to up to 30 mm (large) diameters ovoids. These ovoids are also commonly called as Mini, Small, Medium and Large ovoid respectively. Different diameters ovoids are necessary to cover the smaller vaginal cavity to larger cavity. If possible, larger size ovoids are preferred to minimize the vaginal mucosal dose. A titanium cervical stopper is also used along with the T&O applicator set that defines the cervix or end of the tandem channel. Cervical stopper helps in visualizing the cervix location on radiographs. Cervical stopper reduce the risk of perforation. T&O kit with all T&O sets and accessories are steam sterilized prior to each use. A Aluminum sterilization tray that holds all the applicator sets is included as part of the T&O applicator kit. Figure 4.1 shows pictures of tandem and ovoid kit, showing all different parts available in the kit. T&O applicator is connected with transfer guide tubes (200 series, Reference Number AL , LOT number ) and those tubes are connected with HDR remote afterloader unit (SN H600329) as shown in figure 4.1E. 57

58 Figure 4.1A:- Tandem and Ovoid Kit containing different length and angle s tandem and different sizes (mini, small, medium and large) ovoids. 58

59 Figure 4.1B:- Tandem and Ovoids set prior to implantation Figure 4.1C:- Tandem and Ovoid set ready for implantation with transfer guide tubes 59

60 Figure 4.1D:- Complete set of applicator set with TGT connection Figure 4.1E:- T&O applicator set connected with TGT and HDR Unit Figure 4.1(A-E): Tandem and Ovoid Kit (Ref , SN ), Transfer Guide Tubes (Ref AL , LOT ) and Connection with HDR Remote-after loader Machine (SN H600329). 60

61 4.2.2 Tandem and Ring (T&R) Applicator Tandem and Ring combination applicators set can also be used for the cervical cancer treatment. This applicator set includes 32mm diameter rings that can be used in conjunction with interlocking tandems of different lengths 20, 40 and 60 mm. This applicator set comes with a complete range of tandem and ring angles 30º, 45º and 60º. This applicator set also includes two ring build up caps of 5mm and 7.5mm thickness and a rectal retractor. The applicator set is fabricated from space-age titanium tubing for a light yet rigid appliance with very thin tandem tubing for ease of placement. Tandem tubes are 3mm diameter that can easily fit in flexible smit sleeves. T&R kit with all T&R sets and accessories are steam sterilized prior to each use. An Aluminum sterilization tray that holds all the applicator sets is included as part of the T&R applicator kit. Tandem and ring set has advantage of fixed geometry that helps in comparably faster applicator placement and simplifies the treatment planning process. Tandem and ring applicator is more suitable for patients who have to narrow vaginal fornices. T&R applicator set is CT/MR compatible and supplied by Varian Medical Systems. Department has a one complete set of T&R applicator. Figure 4.2 (A-F) shows pictures of Tandem and Ring, quick fit style Transfer Guide Tubes (200 series, Reference Number AL , LOT number ) and their Connection with HDR Remote-afterloader Machine (SN H600329). 61

62 Figure 4.2A: Tandem and ring complete kit showing all parts of tandem and rings Figure 4.2B: Ring applicator with 5mm build up cap 62

63 Figure 4.2C: Tandem and ring applicator set with 5mm build up cap Figure 4.2D: Tandem and ring applicator set with rectal retractor 63

64 Figure 4.2E: Tandem and ring applicator set with transfer guide tubes 64

65 Figure 4.2F: Tandem and ring applicator set connected to HDR machine Figure 4.2(A-F): Tandem and Ring Applicator Kit (Ref SN AL ), Quick Fit Style Transfer Guide Tubes (Ref AL , LOT ) and Connection with HDR Remote-afterloader Unit (SN H600329). 4.3 Applicator Placement/(ICBT) Implant ICBT applicator placement procedure can be performed in operating room or in a clinic depending upon available resources in the clinic setup. It's also physician s personal preference, some physicians prefer all implantation procedures to be performed in operating room under general anesthesia and some physicians can perform the procedure under local anesthesia in clinic itself or in some cases physicians perform the first implant in operating room in association with Ob/Gyn physician and remaining implants are performed in clinic. 65

66 In all of our studied cases, first applicator placement was performed in operating room under general anesthesia. Attending radiation oncologist and Ob/Gyn physician in general, are available to place a Smit Sleeve into the cervical os during first application. Ob/Gyn physician helps radiation oncologist in Smit Sleeve placement as and when needed. Smit sleeve was placed during first implant in operating room for all of the subject cases. Smit sleeve (shown in figure 4.3 A-B) helps in identifying and dilating the cervical os and allow easy insertion of the tandem during rest of the implants (47-48). Smit sleeves also prevent tandem perforation of the uterine wall. Figure 4.3A:- Rigid and reusable Smit Sleeves Figure 4.3B:- Flexible and single use Smit Sleeves Smit Cervical Sleeves 66

67 Figure 4.3 (A-B) shows the picture of commercially available Smit sleeves that can be used with any/all applicators that have tandem, i.e. Tandem and Ovoid/or Ring /or Cylinder applicators. Smit sleeves are available in 30, 40, 50, 60 and 80mm lengths to accommodate the different tandem lengths. These sleeves are CT compatible and MR conditionally (conditional for 1.5 and 3 Tesla) compatible. These sleeves can easily accommodate a 3mm diameter tandem. It can be sutured in place and left in situ for easy repeat treatment. First styles (Figure 4.3A) of smit sleeves are more rigid and come with titanium marking for easy identification and reusable after steam sterilization. Second styles (Figure 4.3B) of sleeves are more flexible with no metal marking. Those are available in 20, 40, 60 and 80 mm lengths and cannot be reused. Flexible cervical smit sleeve (product number AL , AL , AL , AL for 20mm, 40mm, 60mm and 80mm respectively) were used for all of our cases Applicator Placement:- In general, five treatments are delivered with intracavitary brachytherapy. All of the studied cases received five ICBT treatments. Each treatment requires a intracavitary applicator placement procedure prior to treatment. Implantation procedure is same for all 5 implants with slightly difference in first implantation as first implantation is done in operating room and rest of the four implants are done in the clinic ICBT Implantation 1:- First ICBT implantation is done in operating room. Radiation oncologist and Ob/Gyn physician are available to perform this procedure. Patient is under general anesthesia. The patient is placed in the dorsal lithotomy position in stirrups. A Foley catheter is inserted into bladder and balloon is inflated with 7 cc of radio-opaque contrast material per International Commission on Radiation Units and Measurement (ICRU) recommendations to identify the bladder location during imaging. 67

68 A speculum is placed through vaginal cavity for easy visualization of the cervix. A uterine sound is then placed. A single tooth tenaculum is used to control the cervix and to provide counter traction, that help during uterine sound advancement in uterus through cervix. A clamp or forceps is also attached at the level of the cervical os. Once cervix is dilated then uterine sound is inserted in uterine fundus. Once it s fully inserted and there is no further room, then sound is then extracted and the inserted distance is measured from the cervical os position and it help in deciding the appropriate length of the tandem. Smil sleeve is then inserted through the cervical canal into the uterine cavity and sutured properly so it holds the place in uterus as the same Smit sleeve is used for subsequent implants. The Smit sleeve help in keeping the cervical os open during subsequent implants and eliminates the need of cervix dilation. Once Smit sleeve is in the uterus then based on the curvature and length of the uterus, an appropriate angle and proper length tandem is selected from the kit and inserted through vaginal cavity into uterus and it properly sits in Smit sleeve. A transabdominal or transrectal ultrasound can be used to ensure the proper placement of the tandem. After the tandem insertion, Ovoids or ring is then placed in vaginal lateral fornices. Selected size of the ovoids and ring is dependent of the space available in vaginal cavity. If possible, it's always preferred to use the largest size of the ovoids and ring to control the vaginal mucosa doses. Complete applicator set i.e. Tandem and Ovoids/rings are then properly secured and stabilized in place to avoid any movement. Proper techniques is used to displace the surrounding normal structure i.e. bladder and rectum as far as possible to minimize the doses to such structures. Gauze packing with radiopaque lining is used to push the rectum more posteriorly and bladder more anteriorly. Gauge packing can be placed using forceps or fingers. Proper care is taken while placing the gauge packing to make sure packing not crossing over the top of the applicator and displacing the applicator from cervix. 68

69 Tandem and ring applicator has a built in "rectal retractor" (figure 4.2D) that also helps in displacing the rectum. Packing also help in stabilizing the applicator in place and radiopaque lining help in viewing the packing on X-ray images. It's very common to use anteroposterior (AP) and lateral (LAT) radiographs to ensure the applicator position. For 3D planning, a CT or MRI scan is done to verify the applicator position. For all patients, external base plate was used to hold the applicator in place. External fixation device like base plate decreases applicator movement. It's really important to minimize applicator movement and keep the applicator in the proper position from the time of completion of the applicator placement until the treatment delivery for proper treatment ICBT Implantation 2-5 Rest of the applicator placements were done in clinic under local anesthesia. Procedure is almost the same as first implantation as described in section 4.3a(1). The only difference is Smit sleeve is not placed during implantation and already implanted (during first application) Smit sleeve is used and same length and angled tandem is used. Physician take proper caution to displace the bladder and rectum during subsequent implants based on prior implant experience so that the doses to such structures can be kept as low as possible. Subsequent implants goes bit faster as physicians are already aware of the used applicator and patient specific anatomy based on prior implants. 4.4 CT acquisition/imaging Once intracavitary applicator placement is done, all patients undergo pelvic CT scan. Radiation oncology department has in house GE Health Care Systems (Model No. LightSpeed-QX/I, Serial No CN6) four slice Computed Tomography (CT) scanner (figure 4.4). A HDR Gyn pelvic CT scan protocol is followed during CT scan. Pelvic area scanning is performed using helical mode scanning with 3mm slice thickness. Figure 4.4 shows a GE CT scanner used for scanning. CT data set was 69

70 acquired in a manner such that it include at least 3-4 cm margin from the superior to the proximal tandem location and the entire implant inferiorly. Once CT scanning is completed, attending radiation oncologist then review the applicator position to ensure that implanted tandem and ovoids/ring are at the proper location anatomically or in relation to relative to tandem and ovoid/ring itself. If any variations were observed in applicator positioning, radiation oncologist rectify it by adjusting the implant and resecuring the implant. A rescan is necessary and performed after any modification in implant to confirm the implant geometry. If everything looks in place and no further actions are needed from physician then imaging data get approved on CT console and ready to export for treatment planning. Patient is taken down from the CT table and sent to exam room or recovery room until treatment plan is ready for treatment delivery. Acquired CT data is then exported to treatment planning system in DICOM format via institution network. A CD of CT scan can also be burnt and data can then be manually imported in treatment planning system in case of non-network connectivity. Other imaging modalities include X-ray films and MRI scanning. X-ray films were used traditionally where two X-rays; AP and LAT were obtained immediately after the implant procedure. X-ray images have its own limitation in viewing tumor on the films and other critical structures i.e. bladder, rectum and sigmoid. Institutes with limited resources, where CT or MRI scanning machines are not available in house, X-rays are still the best way to localize the applicator and organs at risk. Now a days, per American Brachytherapy Society (ABS) and GEC-ESTRO recent recommendations, when available, cross sectional imaging like computed tomography (CT) or magnetic resonance imaging (MRI) should be used to visualize the tumor size and critical structures. MRI is preferable over CT as MRI is more sensitive for the detection of parametrial involvement and estimation of tumor size (49-50). Issue with MRI imaging is, it's not very common to have in-house MRI scanner even in developed countries. Hence therefore, CT imaging is very commonly used for imaging. CT 70

71 provide all necessary information in term of tumor size and extent of disease and detail about critical structures bladder, rectum and sigmoid. Only issue in CT compare to MRI is CT does not provide better soft tissue contrast and hence bit challenging contouring cervix and high-risk clinical target volume (HR- CTV). Figure 4.4: GE CT Scanner used for ICBT imaging 4.5 Treatment planning Eclipse Brachyvision (version 11.1) treatment planning system supplied by Varian Medical Systems was used for treatment planning of all test cases. Treatment planning and dosimetry was performed after every applicator implantation. Treatment planning methods are further subdivided as follows:- 71

72 4.5.1 DICOM Data Import CT image data set exported to Eclipse treatment planning system through networking. On Brachyvision treatment planning system, CT data set is imported and number of slices, patient orientation and other imaging parameters along with patient name and ID are matched to make sure correct data is imported to correct patient s file. After CT data import, its properly named and labeled in planning system representing the correct implant and treatment session. A strict naming convention protocol is followed in department to avoid accidental planning on incorrect image data set Tumor and OARs Contouring:- Once CT data is imported in the treatment planning system, then next step is to delineate the target volumes and normal tissue structures. Planning system finds the external patient body contour automatically and should be reviewed carefully. This study was conducted retrospectively and planning was initially performed based on Manchester system hence no tumor volume and critical structures existed. Traditionally dose prescription was based on particular "system" and was on point based. Now with the introduction of the 3D image data set its possible to define tumor volume and organ at risk structures on 3D image data set. To perform the 3D dosimetric review on retrospective data, tumor volume and organ at risk contour is necessary. Those required organ and tumor contouring was performed on existing plans. GEC-ESTRO recommends defining 2 Clinical Target Volumes (CTVs); First target volume is defined at the time of cervical cancer diagnosis and related to the extent of the Gross Target Volume (GTV). A 60 Gy dose is prescribed to this target and its called Intermediate Risk CTV (IR-CTV). The intent is to deliver a radiation dose appropriate to cure significant macroscopic disease ( Fig 4.5, from ref 22). 72

73 A second target is defined at the time of Brachytherapy and related to the extent of GTV taking into account tumor extent at diagnosis and recommended dose prescription to this target is Gy and its called High Risk CTV (HR-CTV). This target is considered as a major risk of local recurrence because of residual macroscopic tumor (Fig 4.5, 22). Figure 4.5 shows a schematic diagram for cervix cancer, limited disease, with GTV, high risk CTV and IR CTV for definitive treatment; coronal and transversal view. Figure 4.5:- Schematic diagram for cervix cancer, limited disease, with GTV, high risk CTV and IR CTV for definitive treatment; coronal and transversal view (image from reference 22). Attending physician for all five implants for all the cases contoured high-risk Clinical Clinical-Tumor-Volume (HR-CTV). Bladder, rectum and sigmoid (Organ At Risks) were also contoured on treatment plans retrospectively by physicist. Those contours are later reviewed by attending physicians and modified as necessary and finally approved. 73

74 Figure 4.6:- Treatment plan of a test case showing 3D representation of HR-CTV (red colour), Rectum (blue colour) and Bladder (orange colour) Applicator Tracing:- Once HR-CTV and OARs are contoured in "Contouring" section of the treatment planning system, a new treatment plan is inserted in "Brachytherapy Planning" section. Planning technique and dose prescription is entered. Next very important step is to review the implanted applicator geometry and tracing the applicators; Tandem and Ovoids/Ring. It's really important to review the applicator in 3D view to confirm the implanted geometry. A 2cm tandem reference line created both side of tandem and named "RT Tandem 2cm Ref Line" and "LT Tandem 2cm Ref Line". Similarly Ovoid/Ring surface reference line and Surface+5mm reference line is inserted. These reference lines are necessary to track the vaginal surface dose and dose at 5mm depth Reference Points:- Although CT cross sectional imaging is used for treatment planning still ABS and GEC- ESTRO guidelines (24,41) suggest to record and documents doses to Point A. Right and Left point A is recorded for all the cases. In our test plans, retrospective plans already had 74

75 point A ( RT and LT) but those points were defined based on Manchester System Point A definition. American Brachytherapy Society (ABS 2011) redefined the Point A definition as shown in figures 3.15 & Revised RT and LT point As were defines on all retrospective plans and names as RT Point Aabs and LT Point Aabs. Bladder and rectum reference (ICRU-38) points were already existed on all retrospective plans Dosimetry:- Dose calculation and dose optimization is next step once reference points are defined. Most common dose regimen is to deliver 45 Gy to the pelvis along with 9Gy possible side wall boost delivered by EBRT. 6Gy per fraction for 5 fraction is more commonly delivered with ICBT brachytherapy. In our test cases majority cases received 6Gy/fr X 5 fr dose from brachytherapy. Dose prescription varies from 4-6 Gy for few cases. Attending physician depending upon the doses to normal OAR structures reduces dose prescription. In some cases when OARs are getting really higher doses then prescription dose to point A is reduced to keep the OARs doses in organ tolerance dose limit. HR-CTV, rectum, bladder and sigmoid organ volume was recorded from Dose Volume Histogram. RT and LT point A (Manchester system) and revised RT and LT Point Aabs reference points doses recorded from the planning system. HR-CTV dose and volume data also recorded. Recorded data include, D90, D95, D100 and V100, V125, V150 and V200. For 3D brachytherapy plans now dose prescription is defined to HR-CTV volume instead of point A. It is recommended that 90% of high risk clinical target volume (HR-CTV) D90 to receive at least the prescription dose (51, 52). In this study, we did not re-prescribed dose to HR-CTV volume instead we kept the original Manchester Point A doses as is in the plan but recorded doses to HR-CTV D90 and revised Point Aabs and compared those data and analyzed the variation in all these data. 75

76 In 3D dosimetric review, ICRU rectum and bladder reference dose is replaced by OARs D2cc doses, where D2cc is defined as the minimum dose in the most irradiated 2 cm 3 normal tissue volume. D5cc cc, D1cc and D0.1cc doses were also recorded Dosimetric Analysis:- We divided this study in 5 sub categories. Study 1:- In this study we investigated applicability of various dosimetry systems and guidelines in the dose prescription and treatment planning. This study is more theoretical review of the available literature and the limitation of available guidelines in cervical cancer treatment. Study 2:- In our second study we evaluated tandem based cervical high-dose-rate brachytherapy treatment planning using American Brachytherapy Society 2011 recommendations. Dosimetric and DVH analysis for HR-CTV and OARs were performed for all the plans. Dose distribution with Manchester point A was compared with dose distribution as per ABS Point Aabs Plan. HR-CTV D90 was compared with point doses and coverage index for HR-CTV also evaluated. Figure 4.7 (A&B) shows the HR-CTV, OARs and original point A and revised Point Aabs on different view on treatment planning system. 76

77 Figure 4.7 A: - Manchester and revised ABS Point A (RT and LT) Figure 4.7 B:- Screen shot showing Manchester and revised ABS Point A and 3D view of HR-CTV (red), Rectum (blue), Bladder(orange) and Sigmoid(cyan) 77

78 Study 3:- Third study includes a 3D dosimetric study of spatial variations due to applicator positioning during inter-fraction treatment. In that particular study, first implants CT data set named (CT1) was registered with CT2, CT3, CT4 and CT5 (ICBT implants number 2-5) in Eclipse planning system. This optimum rigid registration involved manually aligning the two CT data sets based on bony anatomy and then used automatic registration tools available in planning system. Spatial, translational and rotational registration coordinated were recorded for all registered CT data sets (Figure 4.8). This image fusion allowed us to move plan 1 reference points to rest of the other plans. All plan 1's Points and OARs points were transferred to rest plan 2-plan 5 keeping the point A location same as it was on plan 1. This exercise provided is dose difference in point A in subsequent implants considering plan 1 as our primary reference plan. Figure 4.8: Fused image data set of CT1 (plan1) and CT2 (plan2) 78

79 Study 4:- In this part of the data analysis we collected HR-CTV volume of all the treatment plans. Patient femoral head distance was measured on AP digitally reconstructed radiograph (DRR) image. Patient pelvic cavity distance was also measured on the AP radiograph as well. It was observed that HR-CTV volume and femoral head distance a co-relation. Based on the relation between HR-CTV volume and femoral head distance, a hypothetical formula was defined that revised the classic point A definition. Figure 4.9A and 4.9B shows the pelvic cavity and femoral head distance on AP DRR. Figure 4.10A & 4.10B and 4.11 shows HR-CTV location and orientation in different radiographic view. 101 This revised point A is based on three dimensional volumetric imaging and provide appropriate coverage to HR-CTV volume even if there are no cross sectional imaging is used. This formula can be utilized in cancer center with limited resources. If the clinic does not have CT capability then utilizing this revised point A location would provide adequate HR- CTV coverage. Figure 4.9A:- AP DRR image of pelvis showing RT and LT point A location and pelvic cavity distance at the level of Point A. 79

80 Figure 4.9B:- AP DRR image of pelvis showing measurements of pelvic cavity distance and femoral head distance. Figure 4.10A: Transverse and sagittal image showing patient orientation in Right (RT), Left (LT), Superior (Sup) and Inferior (Inf) direction. 80

81 Figure 4.10B: Coronal image showing patient orientation in Anterior (Ant) and Posterior (Post) direction. Figure 4.11: HR-CTV (red) on Transverse, Sagittal and Coronal plane with 3D view. 81

82 Study 5:- In this part of the data analysis we evaluated planned versus decay corrected treatment plans for all our cases. First HDR plan was considered as reference plan and decay correction was applied to calculate treatment time for subsequent fractions. This decay time was then applied to already existing plan and compared the actually delivered plan doses. Dose difference to point A, HR-CTV D90, and rectum and bladder doses was recorded. 4.6 Treatment Delivery:- All ICBT treatments were delivered on HDR Varian VariSource 2100 remote afterloader unit (Serial Number H600329). This HDR remote after loader machine is manufactured and supplied by Varian Medical Systems, Inc (Palo Alto, California, USA). Figure 4.12 shows a picture of Varian machine and figure 4.13 shows the picture of treatment console. Treatment plan is programmed and delivered as per planning loaded at treatment console. Figure 4.12: Varian VariSource 2000 series (Serial Number H600329) Machine 82

83 Figure 4.13: Treatment delivery console. Treatment plans are loaded and delivery is controlled form treatment console. 83

84 CHAPTER : 5 RESULTS Analysis of available various dosimetric systems and the dose distributions of Manchester / ICRU systems and ABS HR-CTV based dose prescriptions reveals completely different area coverage. The point based systems like Manchester / ICRU system dose prescriptions cover entire uterus which may have micro-invasive disease and at potential risk of recurrence in the uterus which does not cover in ABS HR-CTV based dose prescription, because the HR-CTV includes the cervix plus tumor extension at the time of brachytherapy, and 1 cm extension above the uterine vessels identified by intravenous contrast or the location where uterus begins to enlarge. On the other hand, there is a significant HR-CTV under coverage, for the patients of large pelvic region and over coverage for small pelvic region if point based prescription system is adopted. Point A is an applicator related point that does not specify anatomical structures. Dose to point A is very sensitive to the position of the ovoid sources relative to the tandem sources, which should not be the determining factor in deciding on implant duration. Depending upon the size of the cervix, point A may lie inside or outside of the cervix (Figure 5.1). Thus, dose prescription to point A could risk under dosage of large cervical cancers or over dosage of small ones. Wide variation in point A, in respect to the ovoids, point A often occurs in a high-gradient region of the isodose distribution. Therefore, minor differences in position can result in large differences in dose. Figure 5.1: Location of point A depending upon patient size 84

85 Normalized Point A abs Dose---> Doses to the original Manchester/Point A plan and ABS/Point A plan were compared and recorded bilaterally. A mean point A dose was calculated for left and right points, and is normalized to the prescription dose. Fig. 5.2 represents the best-fit linear regression line between Manchester/Point A and Point A ABS doses, normalized to the prescription dose, with a slope of 1.644, an intercept on Y axis of and correlation coefficient of The mean prescription dose is 5.51 Gy with standard deviation 0.71 Gy. The mean dose and standard deviation for Point A plan and Point AABS are Gy ± 0.68 Gy, 5.24 Gy ± 1.06 Gy, respectively. Normalized Point A dose vs Normalized Point A abs dose y = 1.644x R² = Normalized Point A Dose---> Figure 5.2: Plot between normalized point A and normalized point A abs doses. Figure 5.3 shows a plot between Manchester/Point A and D90 doses, to the prescription dose, plotted using the method of best-fit linear regression. The slope, intercept on vertical 85

86 Normalized Point A dose---> axis and correlation coefficient, of the best-fit linear regression line, are found to be 0.008, and , respectively. In Fig. 5.3 the Manchester/Point A plan was the original plan used for the treatment, whereas D90 is based on HR-CTV contour and represents the volume dose rather than a point dose. The mean dose and standard deviation for D90 are 6.78 Gy ± 0.54 Gy. Normalized Point A dose vs Normalized D90 dose y = x R² = Normalized D90 dose---> Figure 5.3: Plot between Normalized point A and Normalized D 90 Doses 5.1 Coverage index vs. HR-CTV volume analysis 86

87 V > Coverage index was defined as the ratio between V100 and HR-CTV volume. HR-CTV mean volume and standard deviation is cc ± cc. V100 mean volume and standard deviation is cc ± 9.33 cc. Fig. 5.4 represents a plot between V100 and HR- CTV volume, representing the best-fit regression line with a slope of , intercept on vertical axis of and correlation coefficient of V 100 vs HR-CTV (cc) y = x R² = HR-CTV (cc)---> Figure 5.4: V 100 (coverage index) vs. HR CTV Volume 5.2 D90 dose vs. HR-CTV volume analysis 87

88 Normalized D90 ---> Figure 5.5 shows a power curve between normalized D90 and HR-CTV, with a coefficient of 4.56, power index of and correlation coefficient of The plotted curve comparing normalized D90 and HR-CTV, and demonstrate a better power fit and shows that as HR-CTV volume increases the tumor coverage decrease Normalized D90 vs HR-CTV y = 4.56 x R² = HR-CTV (cc) ---> Figure 5.5: Plot between Normalized D 90 vs. HR CTV volume 5.3 OAR analysis: 88

89 a. Bladder: ICRU Point dose vs. D2cc & D0.1cc dose Bladder ICRU reference point dose, maximum dose point dose, as well as D2cc and D0.1cc, were recorded for each plan. The mean bladder ICRU reference point dose was 3.47 Gy ± 1.04 Gy (95% confidence interval Gy Gy). The mean bladder D2cc dose was 3.81 Gy ± 1.09 Gy. (95% confidence interval Gy Gy). t-test results for ICRU Max reference points doses versus Bladder D2cc and D0.1cc doses wad calculated as t = with sdev = The probability of the t-test results assuming the null hypothesis is less than Mean bladder D0.1cc dose was 5.17 Gy +/ Gy (95% confidence interval Gy Gy). ICRU Max bladder reference points doses and bladder D0.1cc doses and t value was calculated as t = with sdev = The probability of the t-test results assuming the null hypothesis was found to be less than Figures 5.6 &5.7 shows the dose variation ICRU reference point vs. D2cc and D0.1cc dose. 89

90 BladderICRU ref pt dose (Gy)---> Bladder ICRU ref point dose (Gy)---> 7.00 Bladder ICRU ref point dose vs D2cc dose y = x R² = D2cc Bladder (Gy)---> Figure 5.6: Plot between bladder ICRU reference point dose and D2cc dose. Bladder max dose vs. D0.1cc dose y = x R² = Bladder D0.1cc dose (Gy)---> Figure 5.7: Plot between bladder maximum point dose and D0.1cc dose 90

91 (b) Rectum: ICRU Point dose vs. D2cc & D0.1cc dose ICRU rectum max point doses as well as D2cc and D0.1cc were also recorded. Mean rectum ICRU reference point dose was 3.19 Gy +/ Gy (95% confidence interval Gy Gy). Mean rectum D2cc dose was 2.87 Gy +/ Gy (95% confidence interval Gy Gy). ired t-test for rectum ICRU rectum Max reference points doses versus rectum D2cc and D0.1cc doses were calculated as t = 3.52 with sdev = The probability of the t-test results assuming the null hypothesis is less than The mean rectum D0.1cc dose was 3.78 Gy +/ Gy (95% confidence interval Gy Gy). ICRU Max reference points doses and rectum D0.1cc doses and t value was calculated as t = with sdev = The probability of the t-test results assuming the null hypothesis was found to be less than Rectum ICRU reference mean dose was 3.19 Gy ± 0.70 Gy. Rectum D2cc and D0.1cc mean doses were 2.87 Gy ± 0.72 Gy and 3.78 Gy ± 0.98 Gy, respectively. Figures 5.8 & 5.9 compare the dose relationships betweenicru reference points and D2cc and D0.1cc doses. Figures 5.10 represents the 3 D view of HR-CTV and organ at risk; bladder, rectum and sigmoid. Figure 5.11 shows Manchester Point A, ABS Point A abs and HR-CTV on CT image 91

92 Rectum max dose (Gy)---> Rectum ICRU ref dose (Gy)---> Rectum ICRU Ref pt dose and D2cc dose y = x R² = Rectum D2cc dose (Gy)---> Figure 5.8: Plot between rectum ICRU reference point doses and D2cc rectum doses 5.0 Rectum max dose vs D0.1cc Dose y = x R² = Rectum D0.1cc dose (Gy)---> Figure 5.9: Plot between rectum maximum point dose and D0.1cc dose. 92

93 Figure 5.10: 3D view of HR-CTV, Bladder, Rectum and Sigmoid Figure 5.11: Manchester Point A, ABS Point A abs and HR-CTV on CT image 93

94 Distance in mm Translational and rotational motion between plans was recorded for 25 patients. The mean angle of rotation in X, Y and Z axis was found as 0.63 ± 1.85 deg, ± 1.30 deg and ± 2.44 deg, respectively. The mean translational motion between the plans in X, Y and Z axis were found as ± mm, ± 9.71 mm and ± mm, respectively. Figures shows the average rotational variation in X, Y and Z direction and Figures shows the average translational variation in X, Y and Z direction Average rotational variation in X axis Series Number of Patients Figure 5.12: Average rotational variation in X axis 94

95 Distance in mm Distance in mm 6.00 Average rotational variation in Y axis Number of Patients Series1 Figure 5.13: Average rotational variation in Y axis Average rotational variation in Z axis Series Number of patients Figure 5.14: Average rotational variation in Z axis 95

96 Distance in mm Distance in mm Average translational variation in X axis Number of patients Series1 Figure 5.15: Average translational variation in X axis Average translational variation in Y axis Number of patients Series1 Figure 5.16: Average translational variation in Y axis 96

97 Distance in mm Average translational variation in Z axis Number of patients Series1 Figure 5.17: Average translational variation in Z axis Figure 5.18 shows the point A dose difference when plan1 point A dose was compared on subsequent implants using fused image data set. Average point A dose varies from minimum 0.13% to Maximum 19.21% with an Average dose variation of 3.69% and standard deviation of Data shows that 60% of cases (15 out of 25 patients) the point A dose difference was less than 5%. 12% of plans have the point A dose difference between 5% - <10% and similar results (12%) were observed for point A dose difference between 10% - <15%. Only 4 (16%) plans have point A dose difference between 15% - 20%. 97

98 % dose difference 50.00% 40.00% 30.00% Point A dose difference on subsequent ICBT implants 20.00% 10.00% 0.00% % % % % Number of Patients Series1 Figure 5.18: Point A dose difference in subsequent ICBT implants Figure 5.19 shows the point Aabs dose difference when plan1 point Aabs dose was compared on subsequent implants using fused image data set. Average point Aabs dose was found to vary from minimum 0.10% to 19.19% with an average dose variation of 1.65% ± 0.08%. Data shows that 60% of cases (15 out of 25 patients) the point Aabs dose difference was less than 5%. 16% of patients have the point Aabs dose difference between 5% - <10% and similar results (16%) were observed for point Aabs dose difference between 10% - <15%. Only 2 (8%) patients have point Aabs dose difference between 15% - 20%. 98

99 % Dose difference 40.00% 30.00% Point Aabs dose difference on subsequent ICBT implants 20.00% 10.00% 0.00% % % % % Number of patients Series1 Figure 5.19: Point A abs dose difference in subsequent ICBT implants Figure 5.20 & 5.21 show relationship between HR-CTV verses ND90, and HR-CTV verses V100 for 25 patients. The mean values of HR-CTV, ND90 and V100 with standard deviation, were found to be ± cc, 1.18 ± 0.26 and ± cc, respectively. The mean of point A doses of each patient is compared with that of other patients using the method of the analysis of variance (ANOVA). The mean of all 5 plans of each patient do not have statistically significant difference (p=0.225) on the other hand, the difference between mean doses of all 25 patients (125 plan) at point Aabs (p=0.011), mean doses point A registered (p=0.005) and mean doses of point Aabs registered (p=0.0032) respectively, were statistically different. The comparison between the doses of the point As, defined using ICRU-38, ABS 2011 and computed by registering on plan of first implant, were statistically different (p <0.05). The mean HR-CTV of each patient were fitted with normalized D90 (ND90) and %IDL data using the method of least square fit. The ND90 data fits better with exponential 99

100 ND90 function and negative correlation with HR-CTV while 100% IDL have positive correlation with HR-CTV ND90 vs HR-CTV volume y = e -0.01x R² = Series1 Expon. (Series1) HR-CTV (cc) Figure 5.20: ND90 vs HR-CTV volume 100

101 100% IDL Vol (cc) V100 vs HR-CTV volume y = x R² = Series1 Linear (Series1) HR CTV Vol (cc) Figure 5.21: V100 vs. HR-CTV volume Data was also recorded for HR-CTV width for all the plans. HR-CTV data was correlated with patient pelvic cavity distance and femoral head distance. The maximum width of HR- CTV, in left - right directions, distance between femoral heads at the level of the mid femoral head and maximum width of the pelvic cavity at mid pelvis were measured for each plan, as shown in Fig The HR-CTV volume and D90 dose was also recorded for all plans from respective DVH. 101

102 Figure 5.22: Pelvic cavity width and femoral head distance. The values of D90, HR-CTV volume, HR - CTV width (in the left - right dimension), femoral head distance and pelvic cavity width were measured and averaged for the plans of 5 fractions of each patient. The D90 is normalized to the prescribed dose to eliminate prescription dose dependency of D90, i.e. normalized D90 (ND90) is defined as the ratio of D90 to the prescribed dose at point A. For testing the reliability of point A for dose prescription in the HDR intracavitary brachytherapy of carcinoma of the cervix, the HR- CTV coverage is examined. Figures 5.23 and 5.24 represent the plots of ND90 versus HR-CTV volume, and ND90 versus HR-CTV width (left - right), for each of the data sets referred above, respectively. Both of the data sets, plotted in these graphs appear to fit straight lines 102