UNIVERSITY OF WISCONSIN-LA CROSSE Graduate Studies

UNIVERSITY OF WISCONSIN-LA CROSSE Graduate Studies AN ANALYSIS OF FOUR DIMENSIONAL STEREOTACTIC BODY RADIATION THERAPY FOR LUNG CANCER: ABDOMINAL COMPRESSION VERSUS FREE BREATHING A Research Project Report Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in Medical Dosimetry Robert Anthony Rostock Jr. College of Science & Health Medical Dosimetry Program May 2013

2 AN ANALYSIS OF FOUR DIMENSIONAL STEREOTACTIC BODY RADIATION THERAPY FOR LUNG CANCER: ABDOMINAL COMPRESSION VERSUS FREE BREATHING By Robert Anthony Rostock Jr. 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. April 30, 2013 Nishele Lenards, M.S. Date Graduate Program Director

3 Author: Rostock, Robert A. The Graduate School University of Wisconsin-La Crosse La Crosse, WI Title: An Analysis of Four Dimensional Stereotactic Body Radiation Therapy for Lung Cancer: Abdominal Compression versus Free Breathing Graduate Degree/ Major: MS Medical Dosimetry Research Advisor: Nishele Lenards, M.S. Month/Year: May 2013 Number of Pages: 54 Style Manual Used: AMA, 10 th edition Abstract Lung cancer can be particularly difficult to treat with radiation therapy due to the motion of the tumor inside the lungs during the respiratory cycle. Advanced treatment modalities such as stereotactic body radiation therapy (SBRT) allow a moving lung tumor to be treated accurately and precisely. Stereotactic body radiation therapy can be performed in a number of ways; with a linear accelerator, CyberKnife system, or helical TomoTherapy. Linear accelerator based SBRT requires the use of complex immobilization devices and advanced integrated imaging devices. Stereotactic body radiation therapy can be performed while the abdomen is compressed, while the patient breathes freely, or with respiratory gating. The aim of this study was to compare two linear accelerator based SBRT methods: SBRT with abdominal compression and SBRT with free breathing. The results of the study were inconclusive; one method did not outperform the other outright with regard to metrics provided in the Radiation Therapy Oncology Group (RTOG)-0236 protocol. 1

4 The Graduate School University of Wisconsin - La Crosse La Crosse, WI Acknowledgments I would like to thank the staff where I completed clinical internship affiliated with the University of Wisconsin - La Crosse Medical Dosimetry program. This research would not have been possible without their knowledge and support.

5 Table of Contents... Page Abstract...3 List of Tables...6 List of Figures...7 Chapter I: Introduction...8 Statement of the Problem...13 Purpose of the Study...13 Assumptions of the Study...14 Definition of Terms...14 Limitations of the Study.18 Methodology...18 Chapter II: Literature Review...20 Chapter III: Methodology...31 Sample Selection and Description...31 Instrumentation...31 Data Collection Procedures...32 Data Analysis...32 Limitations...32 Summary...33 Chapter IV: Results...34 Item Analysis...34 Chapter V: Discussion...38 Limitations...39 Conclusions...39 Recommendations...40 References...51

6 List of Tables Page Table 1: Percent volume of Total Lung without PTV receiving 20 Gy...41 Table 2: Total Lung without PTV Mean Dose...41 Table 3: Patient A treatment plan results...41 Table 4: Patient B treatment plan results...42 Table 5: Patient C treatment plan results...42 Table 6: Patient D treatment plan results...42 Table 7: Patient E treatment plan results...42 Table 8: Patient F treatment plan results...43 Table 9: Patient G treatment plan results...43 Table 10: Patient H treatment plan results...43 Table 11: Patient I treatment plan results...43 Table 12: Patient J treatment plan results...44 Table 13: Max dose 2 centimeters away from PTV (D2cm)...44 Table 14: Ratio of prescription isodose volume to the PTV...44 Table 15: Low Dose Spillage...45 Table 16: High Dose Spillage...45 Table 17: Prescription isodose surface coverage...46

7 List of Figures Figure 1: Ratio of prescription isodose volume to the PTV...47 Figure 2: High Dose Spillage...49 Figure 3: Low Dose Spillage...49 Figure 4: Prescription isodose surface coverage...50

8 Chapter I: Introduction For both men and women, lung cancer is the leading cause of mortality among all cancers. 2 It is estimated that in 2013, more than 225,000 new cases of lung cancer and 155,000 deaths due to lung cancer are expected in the United States. 3 Roughly 10% of all patients with lung cancer are expected to live for at least 5 years after their diagnosis. 4 It is assumed that the primary cause of lung cancer is cigarette smoking. Ninety percent of all patients diagnosed with lung cancer have a history of smoking. 4 There is evidence to support that the number of cigarettes smoked per day, the degree of inhalation, and the age of initiation of smoking are all directly related to an increased risk of lung cancer. 2 Roughly 10% of lung cancers are thought to be caused by carcinogens other than cigarette smoking. 2 Exposure to these carcinogens usually arises from occupational and residential hazards. Occupations that involve exposure to agents such as arsenic, asbestos, beryllium, chloromethylethers, chromium, hydrocarbons, mustard gas, nickel, and radiation (including radon) significantly increase the risk of developing lung cancer. 4 Although the relationship between residential radon exposure and lung cancer is uncertain, it is still a concern in the public eye. Increased risk of lung cancer has also been associated with diet, nutrition and genetic factors. 5 Adults with low fruit and vegetable intake are at a slightly higher risk for lung cancer than those who have a normal intake. 5 There are also genetic factors that help determine how an individual will respond to lung carcinogens. The most common genetic factor associated with an increased risk of lung cancer is mutation of the epidermal growth factor receptor (EGFR). 5 Other important genetic mutations associated with lung cancer include abnormalities in genes encoding the Ras family of proteins, as well as retinoblastoma protein (Rb), protein 53 (p53), protein kinase B (Akt), liver kinase B1 (LKB1), and proto oncogene B-Raf (BRAF). 5 There are two types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Historically, treatments for lung cancer have varied based on the type of cancer, stage of the tumor, and the patient s current medical condition. Treatment options include surgery, radiation therapy, chemotherapy, or a combined modality therapy. Small cell lung cancer is typically treated with chemotherapy and radiation therapy due to the responsiveness from both modalities. While NSCLC is curable, most patients die from disease progression due to rapid development of drug resistance. The development of chemotherapy resistance often causes NSCLC to metastasize to the central ipsilateral supraclavicular area. 3 Despite the

9 advancements in chemotherapy and radiation therapy, the survival rate for patients with NSCLC has not changed in the past two decades. 3 Radiation therapy is known to have great effect on SCLC, and is recommended to be used concomitantly early in the course of chemotherapy. The objective with radiation therapy is to treat all gross disease and possibly the ipsilateral hilum, bilateral mediastinal nodes, and the ipsilateral supraclavicular area. 4 Small cell lung cancer also has a tendency to metastasize to the central nervous system (CNS). Because of this, prophylactic cranial irradiation is recommended for patients with CNS metastases who have had a complete response to chemotherapy. 4 For patients with NSCLC, the preferred treatment of choice is surgery. If the patient is deemed inoperable or refuses surgery, then chemo-radiation is a potential curative alternative. Assuming the patient is assessed to have operable NSCLC, there are a number of preoperative and post-operative techniques involving radiation therapy and chemotherapy. Theoretically, preoperative radiation therapy may improve respectability of larger tumors, sterilize cells beyond the margins of resection, prevent dissemination by surgical manipulation, and allow the use of lower doses of radiation postoperatively if needed. 4 However, preoperative radiation alone is no longer studied consistently due to more effective chemotherapy agents. 4 The role of postoperative radiation therapy is controversial; it has been shown to improve local control in patients with residual disease, but has no proven benefit of increased survival rate for advanced stage NSCLC. 4 For inoperable locally advanced NSCLC, radical radiation therapy techniques with or without chemotherapy are the primary alternative. This includes radiation therapy alone, sequential chemotherapy and radiation, and concurrent chemoradiotherapy. Conventional radiation therapy produced limited results when compared with surgery. This is due to inaccurate tumor targeting and a lack of conformality of the dose distribution to the target volume. 4 With the advent of three dimensional conformal radiation therapy (3D-CRT), higher doses were achievable, but at the cost of inducing late toxicities. 4 For inoperable early-stage NSCLC, radical radiation therapy incorporating advanced modalities is the preferred method. Stereotactic body radiation therapy (SBRT) is a relatively new, radical radiation therapy technique that has proven effective in the treatment of early stage NSCLC. Stereotactic radiosurgery (SRS) is a radiation technique that delivers a single high dose of radiation with high accuracy and precision to a target. 6 The concept of SRS was developed in

10 1951 by Lars Leksell, and the first prototype of Gamma Knife was installed in Sophiahemet in 1968. 7 Stereotactic radiosurgery was first developed for intracranial lesions, and requires complex immobilization devices. Stereotactic body radiation therapy evolved from a similar concept as SRS, but was applied to lesions located outside of the brain. It was in the 1990s that groups around the world attempted to mimic SRS to extracranial sites. 7 From that point on, centers around the world have conducted research on SBRT. Stereotactic body radiation therapy has been found to largely exclude normal tissue in the high-dose region and optimize the therapeutic ratio by increasing the effective dose to the tumor while excluding the normal tissue. 6 Because of this, the number of fractions treated with SBRT can be limited to 5 or less. With the availability of high speed computing and advanced imaging techniques that allow for improved methods of dealing with respiratory motion, SBRT is becoming a growingly popular treatment for spinal tumors, lung cancer, pancreatic cancer, and liver malignancies. As mentioned previously, SBRT has become a promising treatment for early stage NSCLC for patients who are ineligible for surgery or cannot tolerate surgery. It is also popular for the avoidance of anesthesia and invasive procedures. Since NSCLC is predominantly a disease in elderly patients with a history of smoking, which generally makes these patients ineligible surgical candidates, SBRT can be particularly useful. 8 However, SBRT comes with considerable risk. The high dose of radiation given by SBRT can lead to severe toxicities. It is crucial to achieve high quality treatment through meticulous planning to attain adequate tumor coverage while avoiding organs-at-risk (OR) and maintaining reliable immobilization and accurate tumor targeting and verification of dose delivery. 8 And much like primary lung tumors, SBRT has also become a popular treatment for lung metastases. Similar to primary lung tumors, SBRT is very attractive as it avoids the risk of invasive procedures. 9 As mentioned previously, SBRT requires strict patient immobilization and respiratory motion control. It is imperative to minimize damage to OR by limiting the amount of tissue included the high dose region that SBRT can create. There are a number of commercially available immobilization devices, which include stereotactic body frames (with an additional abdominal compression device), body cradles and vacuum bags. For cases involving targets that are subject to respiratory motion, there are 3 methods of inducing motion control: motion dampening, motion gating, and motion tracking. 7

11 The use of an abdominal compression device and active breathing control (ABC) are examples of motion dampening. Abdominal compression is a method of inducing forced shallow breathing (FSB). 10 It is popular for SBRT of the lung because it reduces excursion of the diaphragm and movement of a tumor while breathing. If a lung tumor is located in the lower lobe, abdominal compression devices can reduce the excursion of the diaphragm by as much as 2 centimeters. 6 This method significantly reduces tumor motion, but at the cost of less lung sparing for tumors in the upper and middle lobe of the lung. 11 Abdominal compression devices can be uncomfortable for patients who already have a difficulties breathing due to lung cancer. In addition to abdominal compression, ABC is a method to create a reproducible breath hold. An ABC device is meant to suspend breathing at a predetermined position, but is normally used during inhalation. 10 An ABC system works by the patient breathing through an ABC device and the operator specifying the appropriate lung volume and breathing cycle stage at which the device will limit the patient s breathing. Once the patient reaches the specified stage, the ABC device activates and the patient can no longer inhale. In motion gating, also known as respiratory gating, a fixed radiation beam is activated only at a specific phase of the respiratory cycle. 7 Motion due to the respiratory cycle is normally tracked by a device placed on a patient s body, close to the diaphragm. Motion tracking is an invasive procedure where a fiducial marker is implanted within the target. A radiation beam then tracks the fiducial marker, which moves in conjunction with the respiratory cycle. Fourdimensional computed tomography (4DCT) can also be used with or without these methods of motion control. Four dimensional computed tomography is useful in evaluating the mobility of a tumor and can be used to generate an internal target volume (ITV) for treatment planning. 7 In the case that 4DCT is unavailable, CTs obtained at free breathing, deep inspiration, and deep expiration can be effective in generating an ITV. Along with the various immobilization devices and methods of motion control, there are a number of ways that SBRT can be delivered. The current commercially available treatment units that are able to deliver SBRT are all capable of image-guided radiation therapy (IGRT), which makes target localization possible prior to treatment delivery. 7 The most common form of SBRT is linear accelerator based. Stereotactic body radiation therapy began with groups employing frame-based immobilization techniques, but localization accuracy was extremely limited due to difficulties reproducing patient positioning between imaging sessions and

12 treatments. 12 Frame-based immobilization techniques improved however, with groups fixing patients to a frame with a vacuum pillow or body cast. These early frame-based approaches to SBRT prompted those who practiced SBRT to develop image-based methods for target verification. 12 Frame-based SBRT methods began to include daily CT imaging for localization, which eventually moved towards localization based on electronic portal imaging. Currently the most common image-based methods for SBRT are kv and MV cone-beam CT (CBCT). Stereotactic body radiation therapy requires that treatments be conducted using a fixed 3D coordinate system created by the use of fiducial markers. 13 The fiducial markers used in the treatments can vary, and may include markers on a stereotactic body frame or implanted in the tumor itself. Any immobilization device used during treatment must coincide and reference the stereotactic coordinate system created by the fiducial markers. 13 Most importantly, the coordinate system produced by the fiducial markers must correlate with the treatment machine and the target lesion within the patient in a reproducible and secure manner. Due to the motion of the lungs during the respiratory cycle, special techniques must be used to account for the effects of the motion. Such techniques include abdominal compression, free breathing and breath hold techniques, and respiratory gating. Most SBRT systems are linear accelerator based. These systems incorporate either digital x-ray or tomographic imaging to assist in localization, using CT-on-rails or on-board CBCT imaging. Current linear accelerator based SBRT systems include units made by Varian, BrainLab, and Elekta. Other SBRT capable systems include CyberKnife and helical TomoTherapy. CyberKnife began in 1994 as a modernized dedicated SRS system. 14 It initially was only able to treat brain tumors, but over time technological improvements allowed treatment of extracranial targets. The current CyberKnife system is an integrated image-guidance and treatment delivery device that incorporates a computer controlled robotic linear accelerator with an x-ray camera. 6 This system tracks the tumor in real time during treatment, and adjusts the position of the robotic arm to deliver the treatment. The advantage of this system is that it does not require stereotactic body frames or complex immobilization devices. Helical TomoTherapy involves a machine that uses a linear accelerator waveguide that rotates in a gantry around the patient as the treatment couch moves through the gantry bore during treatment, analogous to a CT unit. 15 Helical TomoTherapy can be thought of as a helical CT scanner equipped with a MV linear accelerator instead of a kv x-ray tube as a source of

13 radiation. 15 TomoTherapy is unique in that the operator no longer needs to be concerned with parameters such as gantry angle, field size, or collimator angle. The helical TomoTherapy system uses a ring gantry like a typical CT scanner to scan the patient and administer treatments. The downside to this delivery method is that it acts like a helical CT scanner; it requires a warm up and cool down before and after each treatment. 15 Regardless of the technique, SBRT is an increasingly popular treatment modality for treating lung cancer. Statement of the Problem The use of SBRT as a treatment method for primary and metastatic lung cancer has shown many benefits. Some of these benefits include an extremely precise and focused treatment, a reduced number of fractions, a highly conformal isodose distribution, and a very rapid dose fall off, which allows healthy tissue surrounding the tumor to be spared. 13 Strict immobilization procedures and advanced imaging technologies are used in order to keep tumor margin expansions as small as possible. Despite this, tumor motion brought on by the respiratory cycle is still a major concern. Motion control techniques such as respiratory gating and FSB brought on by abdominal compression may allow for a target to be treated more accurately. The use of abdominal compression in particular can reduce excursions of the diaphragm during breathing, theoretically reducing target motion and allowing for a target to be treated more accurately. This study analyzed the use of SBRT with free breathing compared to SBRT with abdominal compression to see which technique provided superior dosimetric outcomes. Purpose of the Study The purpose of this quantitative study was to compare 2 different methods of SBRT used at 2 different centers; Center A, which performs SBRT while the patient breathes freely, and Center B, which performs SBRT with abdominal compression. A total of 10 patients (5 from each center) treated from January 2012 through December 2012 were randomly selected with the purpose of analyzing their SBRT treatment plans. Dosimetric data from the treatment plans was collected in the Pinnacle 3 treatment planning system (TPS). The treatment plans were evaluated on target coverage and dose spillage metrics provided in RTOG-0236, 1 such as total lung volume without the PTV receiving 2000 cgy, the mean dose to the total lung volume without the PTV, the maximum dose 2 cm from the PTV, the ratio of prescription isodose volume to the PTV volume, high and low dose spillage, prescription isodose volume conformity, as well as

14 treatment planning results (OR minimum dose, maximum dose, mean dose, etc.) to determine if one method was superior to the other. Assumptions of the Study This study compared the treatment planning results of SBRT performed while free breathing and with abdominal compression. The use of abdominal compression limits the excursion of the diaphragm while breathing, and should reduce motion of tumors in lower lung lobes. For lower lung lobe tumors, it was assumed SBRT with the use of abdominal compression would have improved treatment planning results compared to SBRT with free breathing. For upper lung lobe tumors, it was assumed that SBRT with the use of abdominal compression would have similar treatment planning results to SBRT with free breathing. The overall assumption was that SBRT with abdominal compression would have slightly improved treatment planning results compared to SBRT with free breathing. Definition of terms Abdominal Compression. Abdominal compression reduces diaphragm excursion while still permitting limited normal respiration. 10 It can be applied in a number of ways, usually in conjunction with a stereotactic body frame. Accelerated Fractionation. Accelerated fractionation, or hypofractionation, provides similar radiation doses to conventional fractionation but in less time. 16 The total prescribed dose is divided into larger dose fractions. Alpha Cradle. An alpha cradle is an immobilization device and foaming agent used to immobilize practically any anatomical part. The foaming agent is set in a protective sheet and expands, contouring to the shape of a patient. 16 Biological Effective Dose Equivalent. The biological effective dose equivalent takes into account that different types of radiation cause different amounts of biological damage. 16 Centigray (cgy). Centigray is the unit of energy absorbed per unit mass of any material. 1 cgy = 1 rad. 16 Charlson Comorbidity Index. The Charlson Comorbidity Index is a test that predicts patient prognosis based on comorbid conditions. Clinical Target Volume (CTV). The CTV consists of the demonstrated tumor(s) if present and any other tissue with presumed tumor. 17

15 Computed Tomography (CT). A CT scan is an ionizing radiation-based technique in which x-rays interact with a highly sensitive scintillation crystal. Beams of radiation are sent through the body and tissues absorb small amounts of the radiation. The absorption of radiation in tissue allows for the production of images that show slices of the body. The result is a series of scans that allows for the examination of sections a patient anatomy. 16 Cone-Beam Computed Tomography (CBCT). Cone-beam computed tomography is a form of volumetric imaging using an integrated accelerator with an x-ray system. 16 It creates a 3D CT data set with the patient in treatment position. Conformal Radiation Therapy. Conformal radiation therapy is a radiation therapy technique that uses 3D images of the tumor so that multiple radiation beams can be shaped to conform to the contour of the tumor volume. 16 Conformity Index. A conformity index measures how well the volume of a dose distribution conforms to the shape of a target volume. Contouring. The act of contouring is delineating structures by outlining their anatomic borders. 16 Convolution Algorithm. A convolution algorithm is a dose calculation algorithm used in 3D planning systems. Dose to all points from primary radiation is computed, and then scattered radiation from the primary dose depositions is added to obtain the total dose; contour irregularities and tissue heterogeneities can be taken into account. 16 Critical Structures. Critical structures comprise normal tissues whose radiation tolerance limits the deliverable dose. 16 CT-on-Rails System. In the CT-on-Rails system, the linear accelerator treatment table is rotated 180 degrees and a CT unit moves on rails to image a patient while the table stays stationary. 16 CyberKnife. The CyberKnife system consists of a linear accelerator mounted on a robotic manipulator and an integrated image guidance system. 14 It is highly effective for SBRT delivery. Digitally Reconstructed Radiograph (DRR). A DRR replaces fluoroscopy and film with CT simulation. It is an image similar in appearance to a conventional radiograph, but digitally displayed on a video monitor. 16

16 Dose Rate. The dose rate is the amount of radiation exposure produced by a treatment machine or source as specified at a reference field size and at a specified reference distance. 16 Stereotactic body radiation therapy employs a high dose rate. Dose Volume Histogram. A dose volume histogram is a plot of target or normal structure volume as a function of dose. 16 External Beam Radiation Therapy. External beam radiation therapy is the use of external beam x-rays, electrons, protons, or gamma rays to be delivered to a tumor or lesion. 16 Four Dimensional Computed Tomography (4DCT). Each image obtained through 4D CT scan corresponds to a specific phase of the respiratory cycle at which the image was acquired. 16 The complete 4D CT data set displays the complete target motion during the breathing cycle. 16 Gross Tumor Volume (GTV). The GTV is the gross demonstrable extent and location of the tumor. 17 Image-Guided Radiation Therapy (IGRT). Image-guided radiation therapy is the use of imaging methods such electronic portal imaging devices, in-room CT scanner, kv CBCT, MV CBCT, or ultrasound to assist in targeting a lesion during radiation treatment. 16 Immobilization Device. An immobilization device is a custom-designed body mold fabricated to keep a patient in the same position. 16 Internal Target Volume (ITV). The ITV is created by adding an internal margin to the CTV, which takes into account variation in size, shape, position, and movement of the CTV during treatment. 17 Intensity-Modulated Radiation Therapy (IMRT). Intensity-modulated radiation therapy can deliver non-uniform exposure across a beam s eye view with a variety of techniques and equipment. 16 Areas of low dose in the target from one field are compensated by larger doses delivered through another gantry angle that does not intersect the protected structure. Several of these non-coplanar, intensity-modulated fields are produced, which results in high doses of radiation delivered to targets that are irregularly shaped or close to critical structures. These nonuniform exposures create even dose distribution to target volumes with steep dose gradients to adjacent normal tissue. Isodose Distribution. An isodose distribution is a 2D spatial representation of dose. 16

17 Linear Accelerator. A linear accelerator is a radiation therapy treatment machine that makes use of high-frequency electromagnetic waves to accelerate charged particles to high energies via a linear tube. 16 Localization. Localization in radiation therapy refers to geometric definition of the position and extent of a tumor or anatomic structure by reference of surface landmarks for treatment setup. 16 Maximum Intensity Projection (MIP). A MIP is a fusion of CT scans at full inhalation and full exhalation. This scan shows the maximum amount of tumor movement during the respiratory cycle. 16 Metastases. Metastases is defined as the spread of cancer beyond the primary site. 16 On-Board Imagers. An on-board imager is a portal imaging device built in to a linear accelerator, which takes kv images that resemble conventional simulation images and diagnostic-quality x-ray images. 16 Organs at Risk (OR). An organ at risk is an organ in proximity to a tumor where collateral damage done to the organ may put a patient at risk of serious injury or death. 16 Planning Target Volume (PTV). The PTV is the contoured volume that includes the CTV with an internal margin and setup margin for patient movement setup uncertainties. 17 Portal Imaging. Portal imaging is performed at the beginning of treatment and at regular intervals over the course of treatment to verify isocenter placement and beam position. 16 Positron Emission Tomography (PET). A PET scan creates digital images of chemical changes that take place in body tissue. 16 An injection of glucose and radioactive material causes the chemical changes. Radiation Pneumonitis (RP). Radiation pneumonitis is the inflammation of lung tissue caused by radiation therapy to the thorax. 16 Respiratory Cycle. The respiratory cycle is the process of breathing. A healthy, resting adult breathes in and out, one respiratory cycle, about 12 to 16 times per minute or approximately 1 cycle every 4 seconds. 16 Respiratory Gating. Respiratory gating is a method of treatment where the treatment machine can be programmed to turn on only during specific phases of the respiratory cycle. The respiratory cycle is tracked with an infrared camera and a marker placed on the chest or abdomen or other methods. 18 This allows the target to be treated at a specified position.

patient. 16 V x. V x stands for the volume of lung receiving at least x Gy. 16 For example, V 20 stands 18 Stereotactic Body Radiation Therapy (SBRT). Stereotactic body radiation therapy is a radiation therapy technique treatment method that can deliver a high dose of radiation to a target, utilizing either a single dose or a small number of fractional doses with a high degree of precision within the body. 12 Therapeutic Ratio. In radioimmunotherapy, the therapeutic ratio is a comparison of tumor dose to the dose to the most sensitive normal tissues. 6 Vac-Lok. Vac-Lok is an immobilization device that consists of a cushion and a vacuum compression pump used to vacuum the cushion until it is rigid, molding to the shape of a for the volume of lung receiving at least 20 Gy. Limitations of the Study The main limitation of this study was the difference in the amount of patients treated with 4D-SBRT with abdominal compression as opposed to free breathing. It was necessary to restrict the abdominal compression patient sample size to accommodate the free breathing patient sample size. There was also a problem with respect to treatment plans for the abdominal compression patients. The two types of SBRT were performed at different centers; some of the abdominal compression patients were treated on a linear accelerator, which was not available in the treatment planning system at the other center. Thus it was necessary to further restrict the abdominal compression patient sample size to patients with treatment plans compatible with linear accelerators at both centers. A higher sample size would have provided more data and an improved data analysis. Another limitation to this study was the various locations of tumors inside the lungs. It was difficult, if not impossible, to compare an individual patient plan to another, as certain organs may have received a higher dose based solely on tumor position. Another limitation to this study was the algorithm of the Pinnacle 3 TPS. Lax et al 19 concluded that this algorithm only gives a relatively accurate estimate of dose, compared to Monte Carlo algorithms, in the lung volume outside of the GTV. Methodology This quantitative study retrospectively analyzed two different techniques used in 4D- SBRT treatment of lung cancer. The first technique was to perform 4D-SBRT while the patient breathed freely, and the second technique was to perform 4D-SBRT while the patient underwent

19 abdominal compression to induce FSB. A total of 10 patients from January 2012 through December 2012 were selected (5 treated with each technique) for this study. Each patient underwent a 4DCT simulation scan. Once the scan was completed, the information was used to construct 10 different CT scans related to specific stages of the respiratory cycle. These scans were used to create a MIP dataset where the physician contoured an ITV. Once the ITV was contoured, treatment planning was performed on the average of the reconstructed 4DCT dataset in the Pinnacle 3 TPS. The treatment plans were copied to a test environment in the Pinnacle 3 TPS in order to study metrics provided in the RTOG-0236 1 protocol such as the total lung volume without the PTV receiving 2000 cgy, the mean dose to the total lung volume without the PTV, the maximum dose 2 cm from the PTV, the ratio of prescription isodose volume to the PTV volume, high and low dose spillage, prescription isodose volume conformity, and doses to OR.

20 Chapter II: Literature Review For both men and women, lung cancer is the leading cause of mortality among all cancers. 2 It is estimated that in 2013, more than 225,000 new cases of lung cancer and 155,000 deaths due to lung cancer are expected in the United States. 3 Radiation therapy can be particularly effective for lung cancer due to the response it evokes. Stereotactic body radiation therapy is a relatively new and effective treatment modality and is increasingly popular for small lung tumors. Stereotactic body radiation therapy provides an extremely precise and focused delivery of a small number of fractions of radiation, to an ablative dose, to extracranial targets. The treatment planning for SBRT requires a highly conformal isodose distribution with very rapid dose fall off, which makes it possible to spare surrounding healthy tissue or structures from collateral damage, even at an ablative dose. 6 In order to accomplish this, SBRT employs strict immobilization and advanced imaging technologies so that tumor margins of expansion can be kept to a minimum. 6 Stereotactic body radiation therapy requires advanced imaging and localization technologies during simulation and treatment. To aid in localization and immobilization, molded cradles, stereotactic body frames, and vacuum bag systems can be used in combination with abdominal compression or ABC to reduce tumor motion. 20 Murray et al 21 sought to outline the steps involved in the proper use of a rigid immobilization device for SBRT treatments. They claimed that there are 4 steps in the treatment process that are essential to ensure accurate SBRT treatments when using a stereotactic body frame. These steps included patient immobilization, motion control of tumors and organs, treatment and planning correlation, and daily targeting with pretreatment quality assurance. All patients in the study were simulated in a Vac-Lok bag, which attached to a stereotactic body frame, creating a rigid structure that conformed to the shape of the patient. Next, the patient was marked and tattooed at a point delineated by a laser positioning device; this point correlated to a coordinate system labeled on the body frame. Once the patient was immobilized in the frame, motion of the tumor and nearby organs was monitored under fluoroscopy. An abdominal compression plate was then placed just below the xiphoid process of the sternum. Once an acceptable tumor motion was observed, the abdominal compression plate parameters were recorded for reproducibility. A CT scan was then performed. A GTV was delineated and the physician placed the isocenter. The GTV was then expanded to a PTV according to specific institutional guidelines. At the institution where the study was conducted,

21 treatment planning was conducted with the Phillips Pinnacle TPS using non-coplanar beams uniformly distributed around the patient. Once planning was completed, the isocenter position with regard to the stereotactic body frame fiducials was identified. Before each treatment, the patient underwent a verification CT scan and a new isocenter was placed in the center of the GTV; the new isocenter was compared to that of the treatment planning CT. Once this was completed, the patients were transferred to the treatment room where a number of quality assurance double checks were performed to ensure proper patient positioning. The study concluded that frame-based SBRT prevented serious misadministration for those utilizing a conventional CT scanner for pretreatment imaging. While technologies such as on-board CBCT could allow for reduced setup margins and easier daily setup, it was still recommended that frame-based SBRT be used. Another example of a rigid immobilization technique was presented by Zhou et al, 22 who presented their clinical implementation of an immobilization and localization system, BodyLoc, combined with a TomoTherapy treatment unit to reduce set-up error and treatment time. For each patient in the study, a GTV was obtained from a PET-CT scan, and a patient-specific margin was added to create a PTV. The goal of treatment planning was to achieve 98% of the PTV volume receiving the prescribed dose of 3000-6000 cgy in 3-5 fractions. A BodyLoc system was used for patients for both a CT simulation and treatment. All patients underwent coached free breathing during the planning CT scan. Using software designed for the BodyLoc system, the isocenter was placed and verified using a fusion between a pretreatment CT and planning CT. The study concluded that rigid immobilization devices greatly improved set-up accuracy and reduced treatment time. However, in order to reduce set-up deviation and internal organ motions, a real-time tumor tracking and dose delivery system would be required. Not all SBRT treatments are performed with rigid immobilization devices. Frameless SBRT is also a safe and effective method of SBRT. 23, 24 Nath et al 23 conducted a study on frameless image-guided SBRT for the treatment of lung tumors with 4DCT and 4DPET/CT, and determined that it is an effective treatment. Over the course of 2.5 years, 85 lung tumors (35 lung metastases and 50 stage T1/T2 presumed NSCLC) were treated using SBRT with 3-5 fractions. 23 Patients were set up using customized vacuum bags, wings boards with arm handles, and respiratory position management blocks placed on the abdomen. Accompanying software for the block was used to obtain 4DCT scans where the patient was instructed to breathe freely and

22 normally. The 4DCT scans were fused with 4DPET images; these fused images were used for target contouring. Internal target volume contouring was performed on MIP images fused with their corresponding 4DPET images. The treatment margin from ITV to PTV was set to 5 mm uniform for tumors in the upper lobe and 5 millimeters in all directions except for 8 mm in the superior-inferior direction for tumors in the middle and lower lobes. All treatment plans were created in the Eclipse TPS using 3D conformal radiation therapy or sliding-window IMRT. The median dose prescribed was 4800 cgy in 4 fractions. Normal tissues monitored included lungs, aorta, spinal cord, brachial plexus, esophagus, heart, and ribcage. The results of the study showed a median overall survival for all patients of 31 months and a median local failure-free survival of 30 months. Local control at 2 years was 87%, which was within range of published studies. 23 A similar study conducted by Sonke et al 24 sought to quantify the localization accuracy and intrafraction stability of lung cancer patients treated with frameless 4D-CBCT guided SBRT. Sixty-five patients with medically inoperable early stage lung cancer qualified for the study. Each patient underwent a 4DCT scan in the supine position without a body frame or any other immobilization devices while free-breathing without abdominal compression. For each treatment, three 4D-CBCTs were acquired: before treatment to measure and correct the mean tumor position, after the correction to validate the correction applied, and after treatment to estimate intrafraction stability of the tumor. The study concluded that SBRT without a body frame could be administered safely using 4D-CBCT guidance. Regardless of the immobilization technique used, the addition of abdominal compression is popular for SBRT of the lung. In theory, the use of abdominal compression should limit target motion during the respiratory cycle. Heinzerling et al 25 analyzed tumor motion during stereotactic treatment with abdominal compression of lower lung and liver tumors with 4DCT scans. In this study 10 patients underwent three 4DCT scans; one while breathing freely and two at different levels of abdominal compression. The analysis found an average reduction of tumor motion in the superior and inferior directions by 37.5% with medium compression force, and 49.2% with heavy compression force. Further, the average overall reduction in tumor motion was 39% with medium compression force, and 47.1% with heavy compression force. The study concluded that abdominal compression can significantly reduce tumor motion in all directions, but more research is needed on the dosimetric effects that reducing tumor motion with abdominal compression has on tumor dose and dose to normal tissue. 25

23 A similar study conducted by Kontrisova et al 26 sought to evaluate the dosimetric consequences of irradiated lung tissue during different respiration conditions for hypofractionated SBRT. 26 This study compared a typical SBRT technique performed during free breathing while the patient was immobilized using a body frame. Treatments were performed in deep inspiration and expiration using standard and reduced margins, and during shallow breathing via abdominal compression with individual margins. Thirteen patients undergoing hypofractionated SBRT were included in the study. Two of the patients were treated for primary lung lesions, while the rest were treated for lung metastases; all tumors were located in different lobes of the lungs. The patients were immobilized with a stereotactic body frame with an individually adapted vacuum pillow attached. Every patient underwent a planning CT scan in treatment position breathing freely with abdominal compression. Additional multi-slice CT studies were performed during free breathing without abdominal pressure, deep inspiration hold, and deep expiration breath hold. All SBRT patients were treated with 3750 cgy in 3 fractions prescribed to the 65% isodose level. Along with the SBRT treatment plan, 6 additional treatment plans were created with free breathing, deep inhalation breath hold (2 plans with different margins), deep expiration breath hold (2 plans with different margins), and free breathing with abdominal compression. The study concluded that SBRT performed with a stereotactic body frame and free breathing with abdominal compression favorably compared with deep inhalation breath hold and deep expiration breath hold techniques. 26 Research conducted by Huang et al 27 sought to determine the dosimetric accuracy of SBRT of lung cancer using MIPs and average 4DCT images. A custom built motion platform and cubic lung phantom was used to simulate respiratory motion during SBRT. 27 This setup was able to recreate a number of superior-inferior motion patterns which included free breathing with maximum motion ranges of 21.5 mm, 10 mm, and 9.5 mm, and abdominal compression with a maximum motion range of 4.4 mm. Four dimensional computed tomography scans were taken of all breathing motions with a Phillips Big Bore CT scanner. The 4DCT data sets were reconstructed into composite MIP and average images and imported into the TPS. In the TPS, ITVs were contoured on the MIP images and expanded by 0.5 mm to generate a PTV. Treatment planning and dose calculations for the MIP based PTVs were performed on the average 4DCT images. The study found that the 4DCT generated MIP images did not accurately depict the maximum motion of the phantom with free breathing at a maximum motion range of 21.5 mm. It

24 was found that abdominal compression could limit the maximum range of motion of a target and could make targeting much more accurate. It was also recommended to obtain CBCT scans prior to SBRT to ensure accurate targeting and that target motion had not deviated away from the 4DCT defined PTV. Stereotactic body radiation therapy is a treatment modality known for a highly conformal isodose distribution with a very rapid dose-fall off which is equally effective for primary lung tumors as it is metastatic lung tumors. Guckenberger et al 28 evaluated the outcome of treatment following image-guided SBRT for early stage NSCLC and pulmonary metastases. The study was retrospective and included 124 patients treated for 159 pulmonary target volumes between 1997 and 2007. Forty of these patients were treated for inoperable early-stage NSCLC, while 84 were treated for pulmonary metastases. All patients were simulated and treated in a stereotactic body frame or BodyFix system. All patients were treated while breathing freely, with abdominal compression being added if tumor motion exceeded 5 mm in the superoinferior direction. A GTV was delineated on a CT scan, expanded to a CTV without additional margins, and further expanded to an ITV by adding the CTVs at inhalation and exhalation. A PTV was generated by expanding the ITV by 5 mm in all dimensions. The treatment dose was prescribed to the PTV surrounding isodose of 65% or 80%, depending on target location. The study concluded that doses greater than 1000 cgy biologic effective dose to the CTV, based on 4D dose calculation, resulted in exceptional local control rates for image-guided SBRT of primary early-stage NSCLC and pulmonary metastasis. 28 It has already been discussed that SBRT can be performed for both primary and metastatic lung tumors, but SBRT is also commonly used for the treating early-stage NSCLC regardless of the amount of primary lung tumors. Creach et al 29 retrospectively analyzed the clinical outcomes of patients with multiple primary lung cancers treated with SBRT. In this study, patients were immobilized using either the Elekta Stereotactic Body Frame, the BodyFix system, or an Alpha cradle. 29 Abdominal compression was applied if a tumor moved more than 1 cm in any direction as shown by a 4DCT scan. Maximum intensity projection images from the 4DCT scan were registered to a helical CT scan for treatment planning. An ITV was defined on the MIP images, which represented the complete motion of the GTV throughout the respiratory cycle. The PTV was expanded from the ITV by adding a 0.5 cm margin in all dimensions. Treatment plans were created using 7-11 non-coplanar, non-opposing beams. Treatment dose

25 was prescribed to the 80% isodose line and covered more than 95% of the PTV. Typical dose fractionation schemes included 5000 cgy in 5 fractions and 5400 cgy in 3 fractions depending on tumor location. Patients were monitored with physical examinations and alternating chest x- ray or CT scans every 3 months for 2 years following treatment. The overall survival and progression-free survival rates of the population were monitored. The results of the study showed that patients with metachronous (two nodules appearing at different times) lung tumors had high survival rates, and local therapy was justified. However, patients with synchronous (two nodules at the same time) tumors displayed poor survival rates despite having exceptional local control. The study concluded that SBRT is an effective alternative local treatment to surgery for medically inoperable patients with multiple primary lung cancers. 29 A similar study conducted by Norihisa et al 30 sought to retrospectively analyze SBRT outcomes for oligometastatic lung tumors. Oligometastases refer to a small number of metastatic lesion limited to a particular organ. 30 All patients in this study met the following criteria: 1 or 2 pulmonary metastases, tumor diameter of less than 4 cm, a primary tumor that was locally controlled, and no other metastatic sites. A total of 34 patients were treated over a period of 6 years; 25 of which had a single pulmonary tumor (the rest had two). All patients were simulated with a combined x-ray and CT simulator in a stereotactic body frame. Treatment planning was performed using CADPLAN and Eclipse. The ITV was delineated on the CT images and was expanded by 5 mm in all dimensions to a PTV. Another 5 mm margin was added to the PTV, which extended to the edge of the multileaf collimator for penumbra. A total of 5 to 7 noncoplanar static 6-MV photon beams were used for each plan, irradiating 1200 cgy in each fraction (4-5 fractions) at the isocenter for a total dose of 4800 cgy or 6000 cgy. The study concluded that a 6000 cgy fractionation scheme was superior to 4800 cgy for local control at 2 years. The study further concluded that SBRT for oligometastatic lung tumors was comparable to surgical metastasectomy with regard to the 2-year overall survival rate. 30 Stereotactic body radiation therapy is an alternative to surgery for those unfit for surgery and has generally minor side effects. Widder et al 31 sought to investigate survival and local recurrence rate after SBRT or 3D CRT administered for early stage primary lung cancer and to investigate changes of health-related quality of life (HRQOL) parameters after either treatment. 31 Over the course of 3 years, 202 consecutive patients with medically inoperable early stage primary lung tumors were treated with SBRT. The treatment results were compared to a control

26 group of patients treated with 3D CRT. This control group exhibited characteristics similar to those treated with SBRT, which included: medically inoperable early stage primary lung cancer with a maximum tumor diameter of 5 cm and a World Health Organization Score (WHO) of 0 to 2. All patients treated with SBRT were positioned in a vacuum-mattress and underwent a 4DCT scan. The ITV was derived by delineating the visible GTV on a MIP reconstructed from 4-6 respiratory phases. A PTV was created by adding a 5 mm margin in all dimensions. Three different fractionation schedules were used and were determined by tumor location in the lung. All patients received a total dose of 6000 cgy, which was prescribed at the margin of the PTV, constituting 80% of the dose at the isocenter. Treatments were delivered using 4 non-coplanar dynamic arcs. The results of the study showed improved HRQOL and overall survival rates for SBRT over 3D CRT. The study concluded that SBRT should be preferred over conventional radiotherapy for inoperable patients with early stage NSCLC. 31 Stereotactic body radiation therapy may prove to be an effective treatment for lung cancers, but high dose fractionations used in SBRT can cause radiation-induced toxicities. The chance of radiation induced toxicities increases when the target volume is located close to an OR. 32 A study conducted by Song et al 33 assessed the results and toxicity of body frame SBRT for medically inoperable early stage lung cancer adjacent to the central large bronchus. The results were compared with survival rates and SBRT-related toxicities of SBRT in peripheral lung tumors. 33 All patients within the study met the eligibility criteria, meaning: all were diagnosed with NSCLC, confirmed to be stage 1 according to the American Joint Committee on Cancer, had tumor sizes that were less than 5 cm in longest diameter, and Eastern Cooperative Oncology Group performance status 2 or below. The technique used for the SBRT treatments included a vacuum-fitted stereotactic body frame. Tumor motion was assessed fluoroscopically. Tumor motion was minimized by ABC, abdominal compression, or respiratory gating. All patients in the study underwent a CT simulation with contrast enhancement. A CTV was delineated on axial CT images and was expanded to a PTV by adding a 5 mm margin to the axial plane and a 10 mm margin to the longitudinal direction of the CTV. Daily setup accuracy and tumor motion were checked via on-board CBCT. The treatment dose was prescribed such that 85% of the isodose would cover 95% of the PTV volume. Stereotactic body radiation therapy was performed in 3 or 4 fractions, with doses of 1000, 1200, or 2000 cgy. Following treatment, 96.9% of the patients experienced pulmonary toxicities, with most patients showing only mild