UNIVERSITY OF WISCONSIN-LA CROSSE Graduate Studies

GASTROINTESTINAL TOXICITIES FOLLOWING RADIATION THERAPY FOR PROSTATE CANCER DELIVERED BY 3D-CRT OR IMRT

A Research Project Report Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in Medical Dosimetry

Krzysztof Karteczka

College of Science & Health Medical Dosimetry Program

June 2021

2 GASTROINTESTINAL TOXICITIES FOLLOWING RADIATIONN THERAPY FOR PROSTATE CANCER DELIVERED BY 3D-CRT OR IMRT

By Krzysztof Karteczka

We recommend acceptance of this project report in partial fulfillment of the candidate's requirements for the degree of Master of Science in Medical Dosimetry

The candidate has met all of the project completion requirements.

Nishele Lenards, M.S. Graduate Program Director

Date

The Graduate School University of Wisconsin-La Crosse La Crosse, WI

Author: Title:

Karteczka, Krzysztof. Gastrointestinal Toxicities Following Radiation Therapy for Prostate Cancer Delivered by 3D-CRT or IMRT

Graduate Degree/ Major: MS Medical Dosimetry Research Advisor: Nishele Lenards, M.S.

Month/Year: June/2012 Number of Pages: Style Manual Used: AMA, 10th edition Abstract Prostate cancer in men is comparable to breast cancer in women; both cancers are ranked first, respectively, in incidence and are generally responsive to radiation therapy. Additionally, advances in mammography help in early detection of breast cancers, and the advance and enhancement of prostatic specific antigen (PSA) has resulted in early detection of low-stage localized prostate cancers. This has created debate over the proper management of localized prostate cancer. While there have not been any controlled, prospective, randomized trials of sufficient power to compare the various local therapies, based on the current available data, the three commonly used local modalities, surgery, and external beam radiation therapy and brachytherapy (radioactive seed implant), ensure similar efficacy governing the disease up to 10 years in many patients. Technological advances in treatment delivery and planning have improved the treatment of prostate cancer with external-beam radiotherapy using threedimensional conformal radiotherapy (3D-CRT), or intensity-modulated radiation therapy (IMRT). The choice of the optimal RT treatment for the individual is still a topic of discussion, and the argument concentrates on two important outcomes namely, cancer control and reduction of side-effects. The aim of this paper is to compare acute and late GI toxicities

2 following radiation therapy for prostate cancer delivered either by conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT).

3 The Graduate School University of Wisconsin - La Crosse La Crosse, WI

Acknowledgments A special thanks to Guru Prasad, as well to Pawel Dudziak, and Yuri Tabrizzi from the Medical Physics Department of NorthShore University Health Systems for their knowledge, support, and patience.

Table of Contents .................................................................................................................................................... Page Abstract ............................................................................................................................................3 List of Tables ...................................................................................................................................7 List of Figures ..................................................................................................................................9 Chapter I: Introduction ..................................................................................................................10 Statement of the Problem ...................................................................................................10 Purpose of the Study ..........................................................................................................10 Assumptions of the Study ..................................................................................................10 Definition of Terms............................................................................................................10 Limitations of the Study.10 Methodology ......................................................................................................................10 Chapter II: Literature Review ........................................................................................................11 Chapter III: Methodology ..............................................................................................................12 Sample Selection and Description .....................................................................................12 Instrumentation ..................................................................................................................12 Data Collection Procedures................................................................................................12 Data Analysis .....................................................................................................................12 Limitations .........................................................................................................................12 Summary ............................................................................................................................12 Chapter IV: Results ........................................................................................................................13 Item Analysis ....................................................................................................................13 Chapter V: Discussion ...................................................................................................................14 Limitations ........................................................................................................................14 Conclusions ........................................................................................................................14 Recommendations ..............................................................................................................14 References ......................................................................................................................................15 Appendix A: An Introduction to AMA Style ...............................................................................16 Appendix B: How to Complete a Research Project .......................................................................17 Appendix C: Crediting Sources Quoting, Paraphrasing and Plagiarism ....................................19

List of Tables Table 1: Stats, Stats and More Stats..10 Table 2: Stats, Stats and More Stats. The title of this table is more than a single line; indent the second line just like this..13 If youve constructed more than a couple of tables and plan to place them in the body of your paper, include a list of them in a List of Tables. List the table number, name and page on which the table can be found (example above). The other option is to NOT include them within the paper, but to include them at the end (after references) as Tables and the place all of them in that location.

Note 1: Not all papers will have a List of Tables (see above). Note 2: Pay close attention to the purpose and format of your tables and figures. Tables and figures are meant to provide a quick graphical reference to the textual discussion within your paper; as such, they should be concise. For a quick visual reference for formatting a variety of tables consult the AMA manual (p. 97 - 98). On the next page youll find an example of a properly constructed table. Some of the lines may appear in green; if you print using grayscale (file, print, properties, color, check grayscale, ok) the green will not appear. Also, the light gray lines will not print out; they are there for your reference.

6 Table 4

I Am Equipped with the Computer Technology I Need To Work Efficiently in My Classroom

Response Disagree Neutral Agree

Frequency (N=143) 27 26 89

Percentage 18.9% 18.2% 62.3%

How to Make a Table Using Excel 2007 Insert your information into the cells in the way you would want it to appear in the table. Click on Home, then go to Format as Table. Click on New Table Style at the bottom . A window will pop up. Under the Table Elements click Whole Table, then click Format. A second window will pop up. You can control the font on the Excel sheet, so click on the table labeled Border. For the Line Style choose the single thin line on the bottom left. For the Border click the top horizontal line, the mid horizontal line, and the bottom horizontal line. Then choose the color green from the drop down box under the label Color. Click OK. Clicking ok will close the second window and take you back to the first. Click OK on this window. You have just created a custom table style. Now highlight the cells that contain your table data and click the Format as Table button again. This time select your custom style at the top. Save. Copy and paste into your Word document.

Response

Frequency (N=143)

Percentage

7
Disagree Neutral Agree 27 26 89 18.90% 18.20% 62.30%

Table formatting standard indicates that tables are to be double-spaced. However, if the table is longer than one page double-spaced, use 1.5 or single spacing. If your material is lengthy, consider including it in an appendix rather than in the body of the paper.

8 List of Figures Figures are graphical representations of data (not including tables). If youve included more than 1 or 2 figures in your paper, list them here. List the number, name and page on which the figure can be found (same format as for Tables). Same as tables, if you do NOT list them within your paper, you can list them at the end of the paper (after references) and title Figures and place all of your figures there.

Example Figure 1: List title here.14 Figure 2: List title here.18 Figure 3: List title here.19

Notes: Not all papers will have a List of Figures; consult the AMA Manual (p. 98).

Journal submissions typically require tables and figures to be placed in appendices. The publisher can then format them and place appropriately in the article for publishing. For this research project, you will include these tables, lists, or figures within your paper but refer to the AMA Manual for appropriate placement within the paper. You do not need to worry about text wrapping around these items, just include them on spaces/lines of their own and then continue your text on the next line available. It is very important that these tables, lists and figures are labeled appropriately per the AMA Manual.

Chapter I: Introduction Each year, the American Cancer Society evaluates the numbers of new cancer cases and deaths expected in the United States in the current year and collects the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in the United States in 2012.1 Prostate cancer is the most common cancer diagnosed in North American men, apart from skin cancers.2 It is projected that in 2012, approximately 241,740 new cases and 28,170 prostate cancer-related deaths will take place in the United States. Prostate cancer is now the second leading cause of cancer death in men, exceeded only by lung cancer. It accounts for 29% of all male cancers and 9% of male cancer-related deaths.3 The annual detection rate of prostate cancer increased then declined corresponding with the greater than before use of prostate-specific antigen (PSA) to screen for prostate cancer. For example, the estimated incidences were 99,000; 165,000; 334,500; and 179,300 in 1988, 1993, 1997 and 1999 respectively.2 Age-adjusted mortality rates have recently paralleled incidence rates, with an increase followed by a decrease in the early 1990s. It has been proposed that declines in mortality rates reveal the benefit of PSA screening, but others have suggested that these observations may be explained by independent phenomena such as improved treatment effects.3 Prostate cancer is a disease which only impacts men. Cancer originates to grow in the prostate - a gland in the male reproductive system. The word "prostate" derives from Medieval Latin prostate and Medieval French prostate. The ancient Greek word prostates means "one is standing in front", from proistanai meaning "set before". Therefore, the prostate is named because of its position - it lies at the base of the bladder.3 The prostate is an exocrine gland of the male reproductive system, and is located directly under the bladder, in front of the rectum. An exocrine gland is considered one whose secretions pass into a system of ducts that end up ultimately to the exterior of the body (like sweat glands or salivary glands). It is approximately the size of a walnut. The urethra - a tube that extends from the bladder to the end of the penis and transports urine and semen out of the body - goes through the prostate.3 There are thousands of tiny glands in the prostate - they all create a fluid that creates part of the semen. This fluid also protects and nurtures the sperm. When a male has an orgasm the seminal-vesicles discharge a milky liquid in which the semen travels. The liquid is

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made in the prostate gland, while the sperm is produced and stored in the testicles. When a male climaxes (has an orgasm) contractions force the prostate to secrete this fluid into the urethra and leave the body through the penis.3 The prostate gland is also engaged in urine control (continence) by the application of prostate muscle fibers. By contract and release, these muscle fibers control the flow of urine passing through the urethra.3 Figure 1 shows the location of the prostate gland and nearby organs. Figure 1 The location of the prostate gland and nearby organs.

The epithelial cells in the prostate gland manufacture a protein called PSA (prostatespecific antigen). The role of the PSA is to keep the semen in its liquid state. Some of the PSA leaks into the bloodstream and it can be measured by blood test. High levels of PSA can indicate either prostate cancer or some kind of prostate condition (e.g. Benign Prostatic Hyperplasia, when the prostate gland becomes too big; BPH is not cancer, but must be treated).3 In the past, most experts regarded PSA levels less than 4 nanogram per milliliter ng/mL as acceptable. Due to the outcomes of more recent studies, some suggested lowering the cutoff levels that defines if a PSA value is normal or elevated. Some researchers inspire using less than 2.5 or 3 ng/mL as a cutoff for normal values, especially for younger patients (younger than 50 year old). Younger patients are likely to to have smaller prostates and lower PSA values, so any elevation of the PSA in younger men above 2.5 ng/mL is a cause for concern.4

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In the vast majority of cases, the prostate cancer originates in the gland cells - this is called adenocarcinoma. Prostate cancer is generally a very slow progressing disease. In fact, many men die of old age, without ever knowing they had prostate cancer - it is only when an autopsy is done that doctors know it was there. Several studies have specified that about 80% of all men in their eighties had prostate cancer when they died, but, because of the lack of symptoms, nobody knew about their disease.5 Experts declare that prostate cancer starts with tiny alterations in the shape and size of the prostate gland cells - Prostatic Intraepithelial Neoplasia (PIN). Prostatic Intraepithelial Neoplasia means "dysplastic changes involving glands and ducts of the prostate that may be a precursor of adenocarcinoma.5 Low grade (PIN 1) is characterized by mild dysplasia with cell crowding, variation in nuclear size and shape, and irregular cell spacing. High grade (PIN 2 and 3) is described by moderate to severe dysplasia with cell crowding, nucleomegaly, and irregular cell spacing. Any man who scored high-grade PIN after a prostate biopsy is considered at a considerably greater risk of having cancer cells in his prostate.5 It is important to recognize the stage of the cancer, or how far it has spread. Knowledge of the cancers stage benefits the doctor in describing prognosis and assists in the selection of proper therapies. To date, the most common system for determining cancers stage is the TNM (Tumor/Nodes/Metastases) System. It includes defining the size of the tumor, how many lymph nodes are involved, and whether there is any other metastases.6 There are many ways to observe whether the cancer has spread. Computed Tomography (CT) can show for spread inside the pelvis, bone scan can display whether the cancer has spread to the bones, and endorectal coil magnetic resonance imaging will assess the prostatic capsule and the seminal vesicles.6 At present, there is no standard imaging modality that is reliable in demonstration of stage of prostate cancer. Prostate-specific antigen (PSA), digital rectal examination (DRE), transrectal ultrasound (TRUS) and TRUS-directed sextant biopsies remain currently the diagnostic procedures of choice for the clinical staging of patients with potentially organ-confined cancer of the prostate.6 Prostate cancer treatments are created based on PSA levels and the tumor grade. Eng et al6 suggest that prostate tumor grade is one of the most important prognosticators in treatment outcome. The most commonly used grading system is the Gleason score system. A pathologist will examine the biopsy samples under a microscope. If cancer tissue is identified, the

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pathologist then grades the tumor. The Gleason System of grading goes from 2 to 10. The higher the number, the more abnormal the tissues are compared to normal prostate tissue.6 Two numbers are added up to get a Gleason score: a number from 1 to 5 for the most common pattern observed under the microscope (this is the predominant grade and must be more than 51% of the sample), and another number from 1 to 5 for the second most common pattern (this is the secondary grade and must make up more than 5% but less than 50% of the sample).6 There is no standard single best treatment for localized prostate cancer, as each patient characteristic remains unique and diverse. The current treatment options for localized prostate cancer consist of surgery, radiation therapy (RT), hormonal manipulation, and observation as well as various combinations thereof. Radiation therapy treatment can be achieved by externalbeam or brachytherapy (radioactive seed implant).6 By far, external-beam radiation therapy remained the prevailing form of radiation treatment for adenocarcinoma of the prostate in the past 30 to 40 years. Recently, thanks to advancements in technology and treatment planning systems, rising number of patients have been treated with 3-D conformal radiation therapy (3DCRT) techniques.7 While the relative ratio of patients treated with radical prostatectomy has expanded over the past 10 years, the total number treated with radiation therapy also remains to rise. Possible causes for the persistent use of this modality are numerous but include medically non-surgical candidates, relatively low morbidity, cost, preservation of normal sexual function in some patients, less time lost from work, and patient preference.7 Three-dimensional conformal radiation therapy, or 3D-CRT, is a type of external beam radiation therapy that utilizes computers and special imaging techniques to accurately shape the radiation beams so that nearby normal tissue receives less radiation and is capable to repair more quickly. Intensity modulated radiation therapy, or IMRT, is a newer, specific form of 3D-CRT that permits radiation to be more exactly designed to fit the tumor and further limits the amount of radiation received by healthy tissue near the tumor. This can also safely permit a higher dose of radiation to be deposited in the tumor, and potentially enhance the chance of a cure.8 Treatment and screening studies mostly pay attention to their reports on survival outcomes, but to advise our patients, we must also acquire high-quality data regarding treatment related toxicities. Unwanted side-effects from radiation therapy to the prostate might be irreversible and reduce quality of life. Evaluating toxicity is therefore essential in evaluating the therapeutic benefit of radiation therapy and planning treatment for future patients.9 Common acute radiation related gastrointestinal (GI) toxicity includes bowel urgency, frequency, diarrhea,

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and presence of rectal blood. Late RT-generated GI toxicity consists of proctitis (manifested by rectal frequency, urgency, and bleeding), obstruction, and necrosis.9 It is acknowledged that radiotherapy dosimetric factors, such as total dose, dose per fraction, volume irradiated, irradiation site and dose inhomogeneity, effect the development of late radiation toxicity.9 Other factors, either environmental or genetic, can also influence the development of late toxicity. Examples of such factors involve additional treatment (e.g. the use of systemic treatment or surgery) and patient characteristics (age, smoking history, body mass index, hemoglobin level and co-morbid conditions, such as diabetes, hypertension, vascular and connective tissue diseases).9 It is significant to account for the effect of such factors in the analysis of all trials of radiotherapy. Initially it might help in the choice of treatment modality, e.g. radical prostatectomy, external beam radiotherapy, brachytherapy or active surveillance. For patients who receive radiation therapy, the likelihood of late toxicity may help in presenting planning corrections to better individualize RT treatments.9 Statement of the Problem There is no standard single best treatment for localized prostate cancer, as each patient characteristic remains unique and diverse. The current treatment options for localized prostate cancer consist of surgery, radiation therapy, hormonal manipulation, and observation as well as various combinations thereof. External-beam radiation therapy remained the prevailing form of radiation treatment for adenocarcinoma of the prostate in the past 30 to 40 years. However, unwanted side-effects from radiation therapy to the prostate might be irreversible and reduce quality of life. Evaluating toxicity is therefore essential in evaluating the therapeutic benefit of radiation therapy and planning treatment for future patients. Acute and late gastrointestinal (GI) toxicity rates after radiation therapy for prostate cancer are substantial and have been the topic of many studies. The continuing improvements in computer hardware, software and radiotherapy equipment have enabled the employment of sophisticated 3-D conformal treatment techniques permitting accurate delivery of higher doses of external beam radiation to the prostate with steep drop-off of the dose to adjacent organs. Thus the incidence of treatment related side effects stands lower with 3-D conformal techniques than with conventional techniques for the same given therapeutic doses of radiation to the tumor. To minimize some of the limitations of 3D-CRT, the more complex conformal therapy utilizes modulated beam intensity in addition to beam shaping to attain preferred dose distribution. This intensity modulated radiation therapy (IMRT) technique includes the use of non-uniform

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dynamic radiation beams of various intensities to reach conformal dose distributions. The dose conformity perceived with IMRT is considerably enhanced with better sparing of critical uninvolved surrounding structures contrasted with that seen with the 3D-CRT technique. IMRT may potentially be superior to 3D-CRT in permitting dose escalation without higher rates of morbidity. (primary radiation therapy article) Purpose of the Study The purpose of this study is to compare acute and late toxicities of high dose radiation therapy delivered either by conventional three-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT). The outcomes of this study may potentially help patients in the choice of treatment modality. Additionally, understanding the likelihood of late toxicity can help in presenting planning corrections to better individualize RT treatments. Assumptions of the Study From the literature review, the dose conformity perceived with IMRT is substantially better because of improved sparing of critical uninvolved surrounding structures compared with that established with the 3D-CRT technique. IMRT may potentially be superior to 3D-CRT in permitting dose escalation without higher rates of morbidity. Definition of Terms Biopsy. A medical test commonly performed by a surgeon or an interventional radiologist involving sampling of cells or tissues for examination. Benign Prostatic Hyperplasia (BHP). BHP is an increase in size of the prostate. Brachytherapy. It is a form of radiotherapy where a radiation source is positioned inside or next to the area requiring treatment. Computed Tomography (CT). Computed tomography scans, usually used for diagnostic purpose, are used in radiation therapy treatment planning to identify tumor and adjacent critical structures. CT planning refers to the process where a patient goes through simulation on a computed tomography simulator which is competent of scanning in the treatment position and linked to a radiotherapy treatment planning system. The final plan would incorporate all the 3-dimensional information obtained by the scan. Conformal radiation therapy. It is a procedure that utilizes computers to create a 3dimensional picture of the tumor in order to target the tumor as accurately as possible while sparing normal tissue. It is also known as 3-D or conformational radiation therapy.

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Digital Rectal Examination (DRE). A digital (finger) rectal examination is done for men as part of a complete physical examination to check the prostate gland. External Beam Radiation Therapy (EBRT). EBRT is a method for delivering a beam or several beams of high-energy x-rays to a patient's tumor site. Beams are produced outside the patient (usually by a linear accelerator) and are targeted at the tumor site. Endorectal coil magnetic resonance imaging. Endorectal coil MRI is a type of medical imaging in which MRI is used in conjunction with a coil placed into the rectum in order to acquire high quality images of the area surrounding the rectum. The technique has revealed higher accuracy than other modalities in assessing seminal vesicle invasion and extra-capsular extension (ECE) of prostate cancer. Exocrine glands. Exocrine glands are glands whose secretions pass into a system of ducts that lead ultimately to the exterior of the body. Gleason Score. Most pathologists grade prostate cancer according to the Gleason score, which assigns a grade from 1 to 5 based on how the cancerous cells look compared to normal prostate cells. The grade refers to the cancer's appearance and indicates how quickly a cancer is growing. Gray (Gy). Gray is an SI (International System of Units) unit of radiation that refers to the dose of ionizing radiation. One gray is equal approximately to the absorbed dose delivered when the energy per unit mass imparted to matter by ionizing radiation is one joule per kilogram. Histology. The study of the form of structures seen under the microscope. Heterogeneity. In radiation therapy, heterogeneity is referred as non-uniform tissue density. The heterogeneous composition of the human body presents numerous tissues types and cavities with widely differing radiologic properties. These include air cavities, lungs, bones, and fat, which attenuate and scatter the beam differently. Intensity-modulated radiation therapy (IMRT). IMRT is an advanced type of highprecision radiation therapy that uses computer-controlled linear accelerators to deliver highly conformal radiation doses to a malignant tumor or specific areas within the tumor. IMRT permits for the radiation dose to conform more precisely to the three-dimensional (3-D) shape of the tumor by modulatingor controllingthe intensity of the radiation beam in multiple small volumes. IMRT also lets higher radiation doses to be aimed to regions within the tumor while minimizing the dose to surrounding normal critical structures.

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Necrosis. Necrosis is death of body tissue. It occurs when there is not enough blood supplied to the tissue, whether from injury, radiation, or chemotherapy. Necrosis is not reversible. Prostatic Intraepithelial Neoplasia (PIN). PIN is a noncancerous growth of the cells lining the internal and external surfaces of the prostate gland. Having high-grade prostatic intraepithelial neoplasia may increase the risk of developing prostate cancer. Proctisis. Proctitis is inflammation of the lining of the rectum, the lower end of the large intestine leading to the anus. Prostate-specific antigen (PSA). PSA is a protein manufactured by the prostate gland that may be found in elevated levels in the blood when a person develops certain diseases of the prostate, notably prostate cancer. PSA is specific, because it is present only in prostate tissue. It is not specific for prostate cancer, however, as it may also be elevated in men with benign enlargement of this organ. Prostatectomy. Prostatectomy is a surgical removal of the prostate. TNM . TNM is a cancer staging system that describes the extent of cancer in a patients body. T describes the size of the tumor and whether it has invaded nearby tissue, N describes regional lymph nodes that are involved, and M describes distant metastasis (spread of cancer from one body part to another). Transrectal ultrasound (TRUS). TRUS, also called prostate ultrasound, provides images of the prostate and surrounding tissue and allows the physician to examine the gland for abnormalities. Limitations of the Study Limitations of this study are numerous. They include the absence of randomization of patients between the treatments techniques, the same planned target margins around the prostate for the 3D versus IMRT techniques, and limited DVH data. Another limitation is that majority of studied patients were between 65 and 85 year of age, so my results might not be entirely relevant to younger patients. Moreover, I did not have information on socio-economic statistics of studied population, if they are more or less frequently white, less poverty prone, more urban residence, and having lower rates of cancer mortality. Finally, since the extend of the majority of GI symptoms (e.g. rectal bleeding or rectal mucous) is difficult to quantify, the standards of reporting results without adequate assessment of baseline characteristics (patient reported vs. physician reported) were uneven.

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Methodology External-beam radiation therapy remains the prevailing form of radiation treatment for adenocarcinoma of the prostate. This study analyzed extends of gastrointestinal toxicities of patients treated with three-dimensional conformal radiation therapy or intensity modulated radiation therapy. This retrospective study will be based on studying results of treatments of patients between 65 and 85 year of age, treated with conformal fields (clinical target volumeplanning target volume margin of 10 millimeters for the first 68 Gy, margins of 0-5 millimeters for the last 10 Gy when applicable). The Radiation Therapy Oncology Group (RTOG) acute and late toxicity scales were used to score GI morbidity.

References: 1. American Cancer Society. Cancer Statistics, 2012. Available at: http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full. Accessed: June 9, 2012. 2. Washington C, Leaver D. Principles and Practice of radiation Therapy. 3rd ed. St. Louis, MO: Mosby/Elsevier; 2010. 3. National Cancer Institute. Prostate Cancer Screening. Available at: http://www.cancer.gov/cancertopics/pdq/screening/prostate/HealthProfessional/page2. Accessed June 9, 2012. 4. Filella X, J Alcover J, et al. Clinical evaluation of free PSA/Total PSA (Prostate-specific Antigen) ratio in the diagnosis of prostate cancer. European Journal of Cancer.1997; 33(8): 1226-1229. 5. Bostwick D, Eble J. Urological Surgical Pathology. 3rd ed. St. Louis, MO: Mosby/Elsevier; 2007. ISBN 0-323-01970-6. 6. Chao KSC, Perez CA, Brady LW. Radiation Oncology Management Decisions. 2nd Edition. Philadelphia PA. Lippincott Williams & Wilkins; 2002. 7. Eng T, Herman T. Primary radiation therapy for localized prostate cancer. Urologic Oncology. 2002. 20(2): 239-257.

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8. Badaus L, Bolla M, et al. Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of Literature. European Urology. 2012. 61(1): 112-117. 9. Zalefsky M, Fuks Z, et al. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiotherapy and Oncology. 2000. 55(3): 241-249. 10. Malone S, Croke J, et al. Postoperative Radiotherapy for Prostate Cancer: A Comparison of Four Consensus Guidelines and Dosimetric Evaluation of 3D-CRT Versus Tomotherapy IMRT. 11. Zelefsky M, Leibel S, Gaudin P, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys. 1998. 41 (3): 491500. 12. E.A el-Gabry, E.J Halpern, S.E Strup, L.G Gomella. Imaging prostate cancercurrent and future applications. Oncology, 15 (2001), pp. 325336 discussion 33942 13. J Scheidler, H Hricak, D.B Vigneron et al. Prostate cancerlocalization with threedimensional proton MR spectroscopic imagingclinicopathologic study. Radiol, 213 (1999), pp. 473480. 14. Bentel 15. Heemsbergen W, Peeters S, Koper P. et al. Acute and late gastrointestinal toxicity after Radiotherapy in prostate cancer patients: consequential late damage. Int J Radiat Oncol Biol Phys. 2006. 66(1): 3-10.

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Chapter II: Literature Review No sub-headings are indicated for this chapter because they will vary considerably from research paper to research paper. The format of headings and sub-headings depends upon the way you have organized your thoughts via the use of heading levels in your paper. Place headings in their appropriate spot on the page and use boldface formatting as indicated. See Appendix B for information about writing an effective literature review. Prostate cancer is the most common cancer diagnosed in North American men, apart from skin cancers.2 It is projected that in 2012, approximately 241,740 new cases and 28,170 prostate cancer-related deaths will take place in the United States. Although the introduction of prostate-specific antigen (PSA) testing has led to a stage migration toward less-advanced disease at presentation, men with locally advanced or high-risk prostate cancer still institute approximately 17% of all newly diagnosed cases.10 There is no standard single best treatment for localized prostate cancer, as each patient characteristic remains unique and diverse. The current treatment options for localized prostate cancer consist of surgery, radiation therapy (RT), hormonal manipulation, and observation as well as various combinations thereof.10 Recently, thanks to advancements in technology and treatment planning systems, rising number of patients have been treated with 3-D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) techniques.7 However, unwanted side-effects from radiation therapy to the prostate might be irreversible and reduce quality of life. This study will compare acute and late toxicities of high dose radiation therapy delivered either by conventional threedimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). To better understand these techniques and their outcome, it is important to become familiar with the fundamental principles and techniques that are presently being employed in treatment planning for patient diagnosed with a prostate cancer. Moreover, understanding the likelihood of late toxicity associated with radiation therapy treatment can potentially help patients in the choice of treatment modality and in presenting planning corrections to better individualize RT treatments.9 First of all, it is important to recognize the stage of the cancer, or how far it has spread. Knowledge of the cancers stage benefits the doctor in describing prognosis and assists in the selection of proper therapies. To date, the most common system for determining cancers stage is the TNM (Tumor/Nodes/Metastases) System. It includes defining the size of the tumor, how many lymph nodes are involved, and whether there is any other metastases.6

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The current staging system is based on the American Joint Committee on Cancer (AJCC) Staging System.6 Primary tumor (T) 1. Tx-Primary tumor cannot be assessed 2. Tx-Primary tumor cannot be assessed 3. T0-No evidence of primary tumor 4. T1-Clinically unapparent tumor not palpable on digital rectal examination or visible by radiological imaging. Tumor is confined to the prostate. 5. T1a-tumor incidental histological finding in <5% of resected tissue 6. T1b-tumor incidental histological finding in >5% of resected tissue 7. T2-Clinically palpable tumor confined within the prostate. 8. T2a-involves only one lobe 9. T2b-involves both lobes 10. T3-tumor extends through the prostate capsule 11. T3a-extracapsular extension (unilateral or bilateral) 12. T3b-seminal vesicle involvement 13. T4-Tumor fixation or tumor invades adjacent structures 14. T4a-tumor involves bladder neck 15. T4b-tumor involves external sphincter 16. T4c-tumor involves rectum 17. T4d-tumor involves levator muscles 18. T4e-tumor extends to pelvic sidewall Regional lymph nodes (N) 1. Nx regional lymph nodes cannot be assessed 2. N0-No regional lymph node metastasis 3. N1-metastasis in regional lymph nodes Distant metastasis (M) 1. Mx Distant metastasis cannot be assessed 2. M0-No distant metastasis 3. M1-distant metastasis 4. M1a-Nonregional lymph node(s) 5. M1b-Bone(s)

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6. M1c-Other site(s) Imaging Techniques Researchers have analyzed cancer staging based on imaging techniques. According to Tony Eng et al7, imaging techniques, like TRUS, CT, and MRI, have enhanced progressively and supplied useful information, each has specific restrictions by itself and precise diagnosis and staging of prostate cancer with any single imaging modality are still incomplete. TRUS is a lowcost simple procedure and continues to be one of the vital parts of prostate cancer evaluation. CT is less operator-dependent and provides size, density and symmetry information and is fairly cost effective in staging prostate cancer whereas MRI provides better specific detailed architectural information of the prostate gland, its border, in particular the prostatic apex, and adjacent organs.7 Some of the new emerging modalities, including color and power Doppler ultrasonography, ultrasound contrast agents, intermittent and harmonic ultrasound imaging, MR contrast imaging, MRI with fat suppression, MRI spectroscopy, three-dimensional MRI spectroscopy imaging (MRSI), elastography, and radioimmunoscintigraphy has been lately studied by el-Gabry and associates.12 Although most of these newer imaging techniques are restricted in availability and necessitate further confirmation, several studies have confirmed that combining conventional MRI findings with metabolic abnormalities provided by MR spectroscopic imaging (MRSI) is able to considerably enrich cancer localization and assessment of its spread outside the prostate, thus upgrade the chance diagnosis, staging, and treatment planning for patients with prostate cancer.13 At present, there is no standard imaging modality that is reliable in demonstration of stage of prostate cancer. Prostate-specific antigen (PSA), digital rectal examination (DRE), transrectal ultrasound (TRUS) and TRUS-directed sextant biopsies remain currently the diagnostic procedures of choice for the clinical staging of patients with potentially organ-confined cancer of the prostate.6 Gastrointestinal toxicity following radiation therapy Several studies have demonstrated that higher doses of RT improve local tumor control; however, dose escalation is ultimately limited by the occurrence of side-effects. According to Lars Budaus et al., Gastrointestinal (GI) complications are the most frequently considered end points in the published analyses, with rectal bleeding accounting for the majority of late GI toxicity.8 Because of its objectivity, rectal bleeding is sometimes the singular end point of the

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treatment, but the Radiation Therapy Oncology Group (RTOG) toxicity scale is also frequently used. Table 1 and 2 illustrates acute and late GI toxicity caused by radiation therapy treatment. Table 1 Acute gastrointestinal complications according to the Radiation Therapy Oncology Group (RTOG)

Grade 1 Increased G GI frequency or change in quality of bowel habits not requiring medication Rectal discomfort not requiring analgesics

Grade 2 Diarrhea requiring parasympatholytic drugs. Mucous discharge not necessitating sanitary pads Rectal or abdominal pain requiring analgesics

Grade 3 Diarrhea requiring parenteral support Severe mucous or blood discharge necessitating sanitary pads Abdominal distension (flat plate radiograph demonstrates distended bowel loops)

Grade 4 Obstruction, fistula, or perforation GI bleeding requiring transfusion; Abdominal pain or tenesmus requiring tube decompression or bowel diversion

Table 2 Late gastrointestinal and genitourinary complications according to the Radiation Therapy Oncology Group (RTOG)

Grade 1 Mild G diarrhea.

Grade 2 Moderate diarrhea.

Grade 3 Watery

Grade 4 Necrosis.

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Grade 1 GI Mild cramping. Bowel movements 25 per day. Slight rectal discharge or bleeding.

Grade 2 Intermittent, severe cramping. Bowel movements (5 per day). Moderate excessive, rectal discharge. Intermittent, frequent bleeding

Grade 3 diarrhea. Obstruction requiring surgery. Bleeding requiring surgery

Grade 4 Perforation. Fistula. Abdominal pain or tenesmus requiring tube decompression or bowel diversion.

As stated earlier the most commonly measured functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Recognized risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, and history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, hemorrhoids, and inflammatory bowel disease (IBD) .8 To provide an example of the relative frequency of these toxicities for a large series in the literature, Zelefsky et al. testified on 743 patients treated with EBRT and found 14% with grade 1; 8%, grade 2; 0.8%, grade 3; and only one patient with grade 4 GI toxicity.11 External Beam Radiation Therapy External beam radiation therapy (EBRT) includes immobilization, simulation, treatment planning, and sometimes verification before actual treatment. During a conventional simulation the patient lays down in a supine (or prone to push the small bowels upward out of the pelvic fields) position that is easily to reproduce. Sometimes, custom immobilization is necessary, especially if a small field is treated. Contrast media for urethra (retrograde urethrogram), bladder and rectum may be necessary to pinpoint the prostate radiographically. Typically, a 4-field box technique with two opposing lateral and two anterior-posterior fields is used.14 Even though conventional EBRT its not a subject of this study, it is important to describe it to have a broad understanding of this historic approach. According to Bentel14 the most customary modified pelvic fields include the lower pelvis, prostate, and seminal vesicles. In larger pelvic fields, regional lymph nodes are incorporated, such as iliac nodal chains. Average size of the fields vary from 10 to 11 cm2 followed by 8 to 9 cm2 for the boost part of treatment. The boost provides additional dose to the prostate. This allows increase of dose to the prostate

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with saving of the surrounding tissues and structures. The total dose of EBRT keeps changing, but usually ranges from 65 Gy to 72 Gy. The total dose is delivered within about 8 weeks, from Monday to Friday, and daily dose from 1.8 Gy to 2.0 Gy. The actual daily treatment takes about 5 minutes; however, patients can spend in the department about 30 minutes. 14 The inability of conventional EBRT to securely deliver doses over 70 Gy was subjects of many studies. Heemsbergen, Peeters, and Koper et al 15 discussed, that the ongoing improvements in computer hardware and software and radiotherapy equipment have enabled the application of sophisticated 3-D conformal treatment techniques permitting precise delivery of higher doses of external beam radiation to the prostate with steep drop-off of the dose to adjacent organs. Therefore, the possibility of treatment related side effects are lower with 3-D conformal techniques than with conventional techniques for the same given therapeutic doses of radiation to the tumor.15 The common techniques of 3D-CRT could include the use of multiple static fields, custom blocks, sophisticated patient immobilization devices, and CT-based simulation and 3Dtreatment planning systems with beam's eye view. The use of beam's eye view (BEV) permits discrete selection of beam directions, field sizes and shapes to conform to the shape of the target and minimize radiation dose to surrounding critical normal structures.15 To minimize some of the limitations of 3D-CRT, the more complex conformal therapy employs modulated beam intensity in addition to beam shaping to accomplish desired dose distribution. This intensity modulated radiation therapy (IMRT) was studied by Iwamoto and Maher 16, who described that IMRT involves the use of non-uniform dynamic radiation beams of various intensities to reach conformal dose distributions. The dose conformity perceived with IMRT is significantly improved with better sparing of critical uninvolved surrounding structures compared with that witnessed with the 3D-CRT technique. IMRT may potentially be superior to 3D-CRT in allowing dose escalation without increased morbidity. Similarly, Eng et al

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Chapter III: Methodology Begin with an introduction. Some suggestions include reiterating the statement of the problem and briefly discussing what this chapter will include. Sections to be addressed might include subject selection and description, instrumentation, data collection procedures, data analysis, and limitations. Subject Selection and Description Discuss the sample and population. Instrumentation Talk about the survey used, if applicable. Was it created for this purpose or did you find it somewhere? Data Collection Procedures A 57 question survey was administered. Data analysis. How was the data analyzed? Example: A number of statistical analyses were used in this study. The Statistical Program for Social Sciences version 10.0 (SPSS) was used to analyze the data. Independent T-Test analyses were conducted... Limitations Discuss methodological limitations or procedural weaknesses. Summary This is optional, but make sure it is in the table of contents if you use it.

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Chapter IV: Results Start with another introduction, you might briefly reiterate the purpose of the study and how it was conducted, e.g. a survey was given. Your sub-headings for this chapter also will vary considerably: some people use each question as a sub-heading and some dont. If you do use each question as a sub-heading, write out the question rather than just Question 1. The purpose is to provide the reader with at- a-glance information about the nature and scope of your paper. Item Analysis Use tables when appropriate, but dont overuse them or discuss the whole table in text. Discuss the high points in text, providing the table for further details. See pages 7 through 9 of this document for more information about tables as well as an example. Tables are different than figures, name and refer to them appropriately. There is no hard rule as to whether a summary at the end of this chapter should be provided since chapter 5 is often a summary. Discuss this with your advisor.

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Chapter V: Discussion Again, start with an introduction. Summarize what has happened in your paper so far. This chapter will also vary considerably in headings and organization; what follows is a suggestion or possibility. Limitations State them again. Conclusions Hit the high points of your findings. There should be a relationship to the literature review: did your study correlate with previous research or did you find something different? Recommendations Recommend some further research or a change in practices.

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References Make sure that everything you cite in text is also in the reference list and vice versa. The AMA Manual describes the correct format for each type of reference. Be especially careful about how you reference and format on-line sources. See examples of types of references below: 1. Travis, EL. Primer of Medical Radiobiology. 2nd edition. St. Louis, MO: Mosby; 2000:9. 2. Maxwell TW, Kupczyk-Romanczuk G. Producing the professional doctorate: the portfolio as a legitimate alternative to the dissertation. Innovations in Education & Teaching International. 2009;46(2):135-145. 3. Kavanagh, BD, Timmerman, RD. Stereotactic Body Radiation Therapy. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:34. 4. Coleman, AM, Zeidman, C. Electronic charting and image management. In: Washington, CM, Leaver, D, eds. Principles and Practice of Radiation Therapy. 3rd ed. St. Louis, MO: Mosby; 2010: 564-578. 5. Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 6. U.S. Department of Health and Human Services, National Institute of Health, and Centers for Disease Control and Prevention. Guiding Principles for Diabetes Care: For Health Care Professionals. Bethesda, MD: National Institutes of Health; 2009. NIH publication 09-4343. 7. Pujol, B, Zhou, S, Vilas, JS, Pannell, JR. Reduced inbreeding depression after species range expansion. Proc Natl Acad Sci U S A. 2009;106(36):15379-15383. doi:10.1073/pnas.0902257106.

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Appendix A: An Introduction to AMA Style Refer to Research Methods in Medical Dosimetry I, II, and III for resources to write your research paper.

Use the links page in the D2L courses to find resources for research papers and AMA Manual of Style.

Before typing your research paper, make sure your Word document has these format settings: Font: 12 pt, Times New Roman Line Spacing: 1.5 Margins: 1 inch all sides

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Appendix B: How to Complete a Research Project Complete a Research Project? Yes; you can do it! So now youre in graduate school and expected to engage in a culminating research project and write a paper; youre beginning to panic. We all know that stepping out of our comfort zone initiates a growth process and also increases our stress level. So how do you mitigate the amount of stress associated with the research project process? Here are some tips: Find comfort in knowing youre not alone and that scores of people just like you have successfully completed a research project/paper. Surround yourself with supportive colleagues classmates, faculty members, an adviser with whom you connect. You need a cadre of people to act as sounding boards, editors, word processing & statistical consultants, etc. If youre uncomfortable asking questions, conquer your fear; people become knowledgeable by asking questions its what a graduate student is supposed to do. After all, if you knew all the answers you wouldnt be in school! Enough of the warm, fuzzy stuff; its time to get busy on that project! ______________________________________________________________ Where do you start? First of all, understand WHY youre writing this paper . Why Complete a Research Project and Write A Research Paper? The point of this piece of formalized instruction is to help you to understand how: knowledge is created to find sources of scholarly information o (Contrary to popular opinion, its not all free and available on the web. In fact, access to many of the most reliable sources of information are available only in electronic databases purchased for large sums of money - by libraries for the use of faculty, students & staff at that institution) to evaluate the reliability of information, i.e., whether items reported as facts have actually been proven to be true to analyze and interpret literature to effectively express important ideas utilizing your insight and ability to analyze to contribute to a body of knowledge through research and presentation How to Begin the Project? Read, Question, Take Notes and Record Citations 1. As you progress through your coursework reading assignments including those in your textbook, start paying attention to the topics that pique your interest. 2. Begin to identify principal authors and reference works about that topic either by checking out the in-text citations, the references/bibliography section of the text youre

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reading or by using library tools to identify relevant materials. Make friends with a Reference Librarian! S/he can be helpful in directing you to relevant materials. How to Begin the Project? Read, Question, Take Notes and Record Citations (contd) 3. As you begin retrieving documents; read the abstracts, they will help you weed out the articles that are only peripherally related to your interest area. 4. Record the questions that come to you while reading. Read with a critical eye dont be afraid to question the points the researcher is making, the methodology, etc. 5. Notice how the paper is written. If you find a particularly good article in terms of style and structure, use it as a model for your own paper 6. After youve finished reading the article, make summary notes (in your own words including agreements/disagreements you might have with the author) and record citations! 7. Narrow your focus down to one question. A typical research project answers one very narrowly focused question How to Begin the Paper 1. Create an outline 2. Utilize writing guides to help focus your writing and develop your ability to produce an effective paper Numerous research paper writing guides are available. A helpful and practical guide that includes writing tips for all sections of the research paper, including tips for writing a quality literature review see: Brightwell, G. (1998). Writing up Research: The Guidebook. Retrieved February 8, 2010 from Asian Institute of Technology, Language Center website: http://www.ait.ac.th/education/LanguageCenter/ait-writing-services/guidebook/index.htm NOTES: 1. The guide referenced above should be used to assist you in writing your paper.

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Appendix C: Crediting Sources - Quoting, Paraphrasing and Plagiarism Building an accurate knowledge base is a labor-intensive, relatively slow process that relies on the ethics of each researcher involved. In this electronic era it is easy, accidently or purposefully, to cut and paste from the work of others and attribute those ideas to ones self. In order to avoid that, every researcher needs to be confident in the methods used to cite resources, i.e., giving credit to those who helped formulate the ideas outlined in a paper. Follow the guidelines and excerpts provided to you previously for AMA formatting and citing sources. You were provided examples of how to cite direct quotations and how to paraphrase properly.

Plagiarism Authors do not present the work of another as if it were their own work. Whether paraphrasing, quoting an author directly, or describing an idea that influenced your work, you must credit the source. To avoid charges of plagiarism, take careful notes as you research to keep track of your sources and cite those sources.