UNIVERSITY OF WISCONSIN-LA CROSSE Graduate Studies

VOLUMETRIC MODULATED ARC THERAPY VERSUS DYNAMIC CONFORMAL ARC STEREOTACTIC RADIOSURGERY FOR INTRACRANIAL LESIONS

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

Angela Marie Kempen

College of Science & Health Medical Dosimetry Program

May 2013

2 VOLUMETRIC MODULATED ARC THERAPY VERSUS DYNAMIC CONFORMAL ARC STEREOTACTIC RADIOSURGERY FOR INTRACRANIAL LESIONS

By Angela Marie Kempen

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

April 30, 2013 Date

3 The Graduate School University of Wisconsin-La Crosse La Crosse, WI Author: Title: Kempen, Angela M. Volumetric Modulated Arc Therapy versus Dynamic Conformal Arc Stereotactic Radiosurgery for Intracranial Lesions Graduate Degree/ Major: MS Medical Dosimetry Research Advisor: Month/Year: Number of Pages: Nishele Lenards, M.S. May 2013 58

Style Manual Used: AMA, 10th edition Abstract The aim of this study is to dosimetrically evaluate dynamic conformal arc therapy (DCAT) and volumetric modulated arc therapy (VMAT) via frameless, linear accelerator based stereotactic radiosurgery (SRS) for the treatment of brain metastases. Dosimetric evaluation parameters included the target coverage, conformity index (CI), homogeneity index (HI), gradient index (GI), and the volume of the normal brain tissue receiving doses of 12 and 5 Gray (Gy). Two plans were developed per each patient, with a total of ten patients, utilizing DCAT and VMAT. Results of this research outline which planning method may provide benefits or lack thereof depending on the brain metastases location and size, thus providing data in terms of conformity of target coverage as well as lower dose spillage to the rest of the brain. This study also provides dosimetric results regarding advantages and disadvantages of forward versus inverse planning, in addition to the impact of a multi-leaf collimator (MLC) width size. The results of this study showed the superiority of DCAT when compared to 2 coplanar arc VMAT treatment plans.

The Graduate School University of Wisconsin - La Crosse La Crosse, WI Acknowledgments I would like to give special thanks to the Gundersen Lutheran Medical Center physics staff for teaching me so much about medical dosimetry, in addition to all their help 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 ...................................................................................................12 Purpose of the Study ..........................................................................................................13 Assumptions of the Study ..................................................................................................13 Definition of Terms............................................................................................................13 Limitations of the Study.17 Methodology ......................................................................................................................17 Chapter II: Literature Review ........................................................................................................19 Chapter III: Methodology ..............................................................................................................32 Sample Selection and Description .....................................................................................32 Instrumentation ..................................................................................................................32 Data Collection Procedures................................................................................................33 Data Analysis .....................................................................................................................34 Limitations .........................................................................................................................34 Summary ............................................................................................................................35 Chapter IV: Results ........................................................................................................................36 Item Analysis .....................................................................................................................36 Chapter V: Discussion ...................................................................................................................39 Limitations .........................................................................................................................39 Conclusions ........................................................................................................................39 Recommendations ..............................................................................................................40 References ......................................................................................................................................55

6 List of Tables .................................................................................................................................................... Page Table 1: Patients, tumor and treatment parameters ........................................................................42 Table 2: Description of treatment planning techniques .................................................................42 Table 3: SRS plan evaluation data for DCAT and VMAT ............................................................43 Table 4: SRS Plan Comparison .....................................................................................................43 Table 5: Volume of normal brain tissue at V12 and V5 doses for DCAT and VMAT .................44

7 List of Figures .................................................................................................................................................... Page Figure 1: 3D views of the planning or gross target volumes for patients #2 and #10 ...................45 Figure 2: Dose distribution of the DCAT plan on the top and the VMAT plan on the bottom for (a) patient #2, and (b) for patient #10 taken at similar 3D views. Isodose lines are scaled at the same levels of dose to indicate plan comparisons visually.. ....................46 Figure 3: Dose distribution for (a) patient #2 and (b) patient #10 for DCAT plans on the top and VMAT on the bottom showing 100%, 95% and 50% isodose levels on axial slices. ...48 Figure 4: Dose-volume histograms for target "R Temporal Lobe GTV", and "Brain-GTV" which is the only OR structure for patient #2. Data on the top (a) is for the DCAT plan while the bottom one (b) is for the VMAT plan. ....................................................................50 Figure 5: Dose-volume histograms for target "GTV", and "Brain-GTV", "Brain Stem" and "OpticNerveChiasm" which are the OR structures for patient #10. Data on the top (a) is for the DCAT plan while the bottom one (b) is for the VMAT plan.........................51 Figure 6: RTOG Conformity index as a function of target volume for DCAT and RapidArc (VMAT) plans ...............................................................................................................52 Figure 7: Paddick Conformity index as a function of target volume for DCAT and RapidArc (VMAT) plans ...............................................................................................................52 Figure 8: Gradient index as a function of target volume for DCAT and RapidArc plans .............53 Figure 9: Homogeneity index as a function of target volume for DCAT and RapidArc plans .....53 Figure 10: Normal brain tissue minus target volume receiving 12 Gy dose .................................54 Figure 11: Normal brain tissue minus target volume receiving 5 Gy dose ...................................54

8 Chapter I: Introduction Brain tumors account for 1.5% of all malignancies diagnosed annually in the United States.1 Approximately, 85-90% of central nervous system (CNS) tumors involve the brain, whereas the spinal cord is involved in 20% of cases.2 According to the National Cancer Institute, 22,910 new cases of brain and other CNS tumors were diagnosed leading to 13,700 deaths in 2010.2 Brain tumors are the second leading cause of death in children, trailing behind leukemia.1 There are different classifications of tumors of the CNS; gliomas (including astrocytoma, glioblastoma, glioblastoma multiforme, brainstem and thalamus tumors), in addition to pituitary, medulloblastoma, oligodendroglioma, ependymoma, meningioma, lymphoma and schwannoma.1 Primary brain tumors are moderately uncommon; however, cerebral metastases occurs in approximately one third of those diagnosed with cancer; therefore, making them the most common brain lesion.1 The prognosis for brain tumors is generally poor. However, the 5-year survival rates for patients with primary tumors has risen over the past couple decades to an overall survival of 35%.1 Treatment for primary and metastatic brain tumors includes surgery, chemotherapy, radiation therapy, immunotherapy and vaccine therapy.2 The options for radiation therapy and chemotherapy vary depending on histology and anatomic location of the brain lesion.2 Radiation therapy plays a major role in the treatment of patients diagnosed with high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, as well as those with brain metastases. The origin of primary CNS tumors is currently unknown.1 Occupational and environmental exposures, lifestyle and dietary factors, medical conditions and genetic factors are all thought to perhaps have an association with brain tumors.1 The three most important prognostic factors include age, performance status and tumor type. The incidence rate for CNS tumors is 5 per 100,000 people.1 While age is the dominant variable in the occurrence of these tumors, race and gender also play a significant role. An increase in the incidence of CNS tumors diagnosed in the elderly population has been noted.1 An increase in age expectancy, improved availability and use of computed tomography (CT) and magnetic resonance imaging (MRI), as well as increased knowledge and interest in improving quality of life in the elderly contribute to the rise in incidence.1 The average age at diagnosis is 50 to 80. In 2008, approximately 21,810 CNS tumors were diagnosed, with 16,400 of them being in the cerebrum. Of those, half were diagnosed as gliomas, and 75% were high-grade gliomas.1

9 During recent years, radiation therapy has played a significant role in the treatment of CNS tumors; therefore, increasing survival rates and improving quality of life.1 Patients diagnosed with malignant tumors that cannot be surgically removed, are only partially excised, or are associated with metastatic disease should undergo radiation therapy. Tumor type, tumor grade, patterns of recurrence, and radio-responsiveness are important factors to consider in determining the doses for radiation treatment. When determining total doses, the progression of the tumor in addition to the potential risk of radiation necrosis of normal tissues, must be taken into consideration. Radiation therapy used in the treatment of brain tumors can be delivered in multiple approaches. Consideration for the type of disease, tumor location and extent are essential. Not only is a total resection of a brain tumor challenging, but also obtaining adequate resection margins in brain tissue is almost impossible with surgery alone. Therefore, radiation therapy can be utilized after surgical procedures in an effort to prevent tumor recurrence.1 The most common treatment technique is whole brain radiation therapy (WBRT), where the entire brain is treated via opposing lateral fields. Additionally, this technique is commonly used in the presence of brain metastases as well. Currently, standard treatment in the United States is 30 Gy of WBRT delivered in 10 fractions.3 A rapidly growing, important treatment option for patients with CNS tumors is stereotactic radiosurgery (SRS).4 Stereotactic radiosurgery is a technique utilizing radiation treatments in a single, high-dose fraction of ionizing radiation that conforms to the shape of the lesion.5 Radiobiology of such high dose fraction(s) needs to be well understood in terms of its differences regarding toxicities and side effects, as well as the possible benefits when compared to conventional fractionation of 1.8 to 2.0 Gy per fraction. As previously mentioned, radiobiology is an important component in treating cancer with radiation. Throughout history, accepted radiobiology has relied on the linear quadratic (LQ) model which evaluates the effectiveness of radiation delivery treatments by comparing daily doses.6 Currently, typical clinical daily doses range from 1.2-2.5 Gy. Puck and Marcus7 showed that fractional cell surviving radiation is equal to S.F. = e- (+2). This formula takes into account the alpha/beta (/) ratio, which demonstrates differentiated dose response of late and acute responding tissues. The ratio is low for late responding tissues and high for acute responding tissues. Conventionally, it is the tolerance of late responding tissues within the field that limits the radiation dose.6 For tumor cells where the / ratio is low, such as 2 Gy for melanoma, soft tissue sarcoma, liposarcoma, prostate and breast, shortening the treatment time

10 through hypofractionation may be beneficial. In terms of radiobiology of hypofractionation, which is a dose of 12-20 Gy per single fraction, the traditional behavior of the radiobiology fractionation is altered.6 Radiobiology fractionation principles include repair, re-assortment, reoxygenation, and re-population. The new dominating role players become bystander/abscopal factors, immune activation and tumor endothelium cell deaths.6 Bystander/abscopal effects occur when unirradiated tumor cells behave as if irradiated due to the messages being carried out by irradiated cells.6 High dose radiotherapy may help activate immune system response, which does not occur with conventional fractionation. Such immune system response can help fight against the primary tumor as well as potentially prevent distant metastases.6 At fractional doses of 10 Gy or higher, animal studies showed endothelial cell death by activation of acidsphingomyelinase (ASMase) and ceramide generation.6 It is important to note that endothelium in brain, lung and stomach are radio-resistant in the absence of ASMase.6 With the radiobiology of SRS proven to be successful, various clinical studies have been conducted to evaluate the efficacy of SRS for intracranial lesions. The most commonly treated lesions with SRS include arteriovenous malformations (AVMs), vestibular schwannomas, acoustic schwannomas, meningiomas, gliomas and metastatic brain tumors.5 Recently, there have been studies showing strong evidence of the efficacy of SRS. University of Pittsburgh Medical Center (UPMC) reported a study including 829 patients with vestibular schwannoma who were treated with SRS to dose of 12-13 Gy.6 The results showed a 10 year control rate as high as 97%.6 Studies performed evaluating SRS treatment of brain metastases either alone or in addition to whole brain irradiation have shown improved local control. A trial conducted by Radiation Therapy Oncology Group (RTOG) 09-58 randomized 333 patients with 1-3 brain metastases (< 4 centimeter diameter) and Karnofsky Performance Status (KPS) 70 to either WBRT alone versus WBRT followed by an SRS boost.6 The results demonstrated significant improvement in local control for all patients, in addition to improved survival rates for patients with a single brain metastasis with WBRT followed by an SRS boost.6 There were two studies conducted by UPMC evaluating treatment of meningiomas. The first study included 159 patients treated with a median margin dose of 13 Gy.6 The results showed tumor control rates at 5 and 10 years both to be 93.1%.6 The second trial included 168 patients with petroclival meningiomas.6 The 5 and 10 year survival rates were 91% and 86% respectively.6

11 Stereotactic radiosurgery has become a routine approach over the past couple decades. To effectively acquire the benefits of SRS, high precision is vital. The treatment requires an overall accuracy of approximately 1 mm.4 Historically, SRS has referred to targeting intracranial lesions. Stereotactic radiosurgery can be delivered using multiple modalities and has been applied to a number of various benign and malignant malformations. Different specialized approaches for radiosurgery include Elektas GammaKnife, which utilizes a live Cobalt-60 source inside a gamma-ray treatment device, Accurays CyberKnife that is a particle beam accelerator, or a medical linear accelerator with either a frame or frameless system using BrainLabs Novalis system.6 GammaKnife uses 201 very small well-collimated beams of gamma radiation that focus precisely on the tumor. The patient has a stereotactic frame attached to his or her skull, which is then attached to the automatic positioning system. The patient is advanced into the machine and the shielded vault is closed for treatment. CyberKnife utilizes a linear accelerator attached to a robotic arm with 6-degrees of freedom, each of which delivers pencil beams of radiation. A medical linear accelerator can be adapted to deliver SRS treatment. A linear accelerator system involves a gantry, which rotates around an axis of the machine in space, to vary the delivery angle of a photon beam used for treatment. A stereotactic frame can be used; however, more recently with the linear accelerator coupled with improved real-time imaging methods, frameless systems have emerged. With MLC advancements and imageguidance capabilities, linear accelerator based SRS has dramatically improved its accuracy and viability. There are a few systems, from various manufacturers, being used in clinical application such as Novalis (BrainLab, Heimstetten, Germany), Varian Medical Systems, and Xknife (Radionics, Burlington, MA, USA). For any type of SRS treatment, a vigorous immobilization is mandated. Historically, linear accelerator based SRS required a stereotactic head frame, or halo, with a rigid fixation to the skull. With recent advances in imaging modalities, more centers are utilizing the noninvasive approach for patient comfort while maintaining similar accuracy as the rigid fixation systems. Often, an aquaplast mask is used with a bite block for a non-invasive approach to immobilization. An optical positioning system or image guidance tools such as on-board imaging, cone beam CT, Tomotherapy, or Novalis ExacTrac may be used for position accuracy.6 The new dose delivery technologies, in addition to improved imaging capabilities, have increased the use of precise stereotactic treatment delivery instead of conventional fractionation.

12 Image guided radiation therapy (IGRT) techniques are required in order to achieve stereotactic localization of the tumor.4 Linear accelerator based systems use secondary collimation close to the patient that shapes the beam while reducing penumbra.4 Penumbra is analogous to radiation beam width; therefore, as penumbra becomes smaller, the dose falls off quicker. Ideally, the smaller the penumbra, the more conformal the radiation field size becomes. Multi-leaf collimators can create off-axis beams. The MLC, with narrow leaves, is used in a tertiary device even closer to the patient to further reduce penumbra.4 Dynamic delivery is typically used with a large number of beams to irradiate the target. Intensity modulated radiation therapy (IMRT), VMAT and DCAT are most commonly used with single isocenter, frameless, linear accelerator based systems. Over time, great advances have been made in regards to treatment techniques used to deliver SRS. Non-invasive, frameless SRS has been implemented in many clinics and allows patients to receive the benefits of SRS treatment without the invasive component. Multiple studies have proven the efficacy for this method of radiation treatment. With the promise of SRS becoming such a prominent role in increasing overall survival rates, it is essential to continue to study and evaluate the various treatment techniques in order to continually improve treatment of brain lesions. Statement of the Problem Studies have been done to evaluate the dosimetric differences between treatment techniques used to deliver SRS for intracranial tumors.(8-16) Stereotactic radiosurgery is becoming a widely accepted treatment approach for intracranial tumors; therefore, further research is essential to provide data on various treatment techniques for SRS. The popularity of non-invasive brain surgery is on the rise due to significantly improved imaging technologies. There are multiple treatment techniques that can be utilized for non-invasive linear accelerator based SRS, namely cone-based, DCAT, IMRT, Tomotherapy and VMAT. The specific problem is determining which method will yield superior planning, resulting in improved treatment for the patient. One main difference between these delivery methods is the planning, consisting of forward versus inverse. Secondly, with the advent of smaller MLC leaf widths, it is expected that DCAT or VMAT may yield better dosimetric results.16 Knowledge gained between these two planning techniques would enable clinics to deliver SRS for intracranial tumors utilizing techniques with dosimetric advantages.

13 Purpose of the Study The purpose of this research is to evaluate the dosimetric differences between treatment plans using DCAT and VMAT. The plan comparisons of 20 treatment plans include target coverage, conformity and homogeneity index, GI and dose fall-off or spillage. Between DCAT and VMAT, the study aims to determine which technique offers a better planning evaluation index depending on the brain metastases location, shape and size. This will in turn provide data in terms of conformity of target coverage, in addition to lower doses to the normal brain tissue. Potentially the results of the study will indicate the most beneficial technique for delivery of SRS treatments for intracranial tumors. Assumptions of the Study The volume of normal brain tissue receiving doses of 12 and 5 Gy was tracked per the radiation oncologists. This is an assumption in terms of clinical patient outcome. Another assumption is in terms of the results of this research study. It is assumed that the DCAT technique will produce slightly better results than VMAT due to the use of non-coplanar beams, which was concluded from multiple literature reviews.(8-19) Otherwise, this research does not have any other assumptions. Definitions of the Terms Acidsphingomyelinase (ASMase). This is a type of enzyme that hydrolyse certain types of lipids to yield ceramide.6 Alpha/beta ratio. The ratio is a term used in the LQ model. It is the dose where the number of cells killed by the linear component is equal to the cell kill from the quadratic component . Early responding tissues have a high ratio, whereas late responding tissues have a low ratio.20 Analytical Anisotropic Algorithm (AAA). A convolution-superposition algorithm used to calculate radiation dose distribution in a treatment planning system computer. Aquaplast mask. A trade name for a thermoplastic that is used frequently as an immobilization device of the head and neck region.1 Astrocytoma. Low grade or anaplastic tumors of the CNS. They originate from the non-neuronal supporting cells.1

14 Bite block. An object placed between the patients teeth to assist in immobilization. It also aids in placement of the tongue. It can be made of various materials including dental wax and Aquaplast pellets.1 Ceramide generation. The generation of ceramides is a family of lipid molecules, which are found in high concentrations within the cell membrane of cells. They are signalcarrying molecules, which function and regulate programmed cell death and apoptosis of cells.6 Clinical Target Volume (CTV). Per ICRU Report 62, this volume indicates the gross palpable or visible tumor volume (GTV) and a surrounding volume of tissue that may contain subclinical or microscopic disease.21 Computed tomography (CT) simulator. A diagnostic imaging modality, used in radiation therapy treatment planning, that provides accurate information on tumor localization and identifying dose-limiting structures. Conformity index (CI). The volume enclosed by the prescription isodose surface divided by the target volume.22 The index is a dosimetric tool that attributes a score to a treatment plan that can compare several treatment plans. CyberKnife. A robotic radiosurgery system designed by Accuray that delivers pencil beams of radiation via a linear accelerator attached to a robotic arm with 6-degrees of freedom. Dynamic conformal arc therapy (DCAT). A treatment technique in which MLC leaves move to dynamically conform to the tumor volume during gantry rotation. Ependymoma. Low or high grade tumors arising from the ependymal cells lining the brain ventricles and central spinal canal.1 GammaKnife. A treatment machine utilizing Cobalt-60 gamma radiation for use in radiosurgery of the head only. It is designed by Elekta. Glioblastoma. A fast-growing type of CNS tumor. It arises from glial (supportive) tissue of the brain and spinal cord and the cells have an appearance quite different from normal cells. Also known as Glioblastoma Multiforme or grade IV astrocytoma.2 Gradient Index (GI). A treatment planning index used to measure the dose gradient or dose fall-off, which complements the conformity index when comparing several plans. Gray (Gy). A unit of measured radiation dose. It is the absorption of one Joule (J) of energy, in the form of ionizing radiation, per kilogram of matter. (J/kg)

15 Gross Tumor Volume (GTV). Per ICRU Report 62, this volume indicates the gross palpable or visible tumor.21 Homogeneity index (HI). This is defined by the target dose maximum divided by the volume of reference isodose. The index is a dosimetric tool that attributes a score to a treatment plan that can compare several treatment plans. Histology. The study of tissues and cells under a microscope.2 Hypofractionation. This term describes a dosage of radiation that is divided into several large doses given every few days.6 Image Guided Radiation Therapy (IGRT). A device used to image the patient immediately before treatment in order to compare the position of the external set-up and internal anatomy to the treatment plan.1 Image registration. Process where the images of the patient are aligned with respect to the isocenter of the accelerator.1 Integral dose. The total energy absorbed by an organ(s) in terms of ionizing radiation, expressed in gram-rads, also called volume dose, e.g. integral brain dose. Intensity Modulated Arc Therapy (IMAT). A form of radiation treatment, where the radiation field is divided into small beamlets via the aid of blocks/MLCs, and the intensity of the beamlets are determined by planning optimization in the form of arc-rotation. Intensity Modulated Radiation Therapy (IMRT). A form of radiation treatment, where the radiation field is divided into small beamlets via the aid of blocks/MLCs, and the intensity of the beamlets are determined by planning optimization. Tomotherapy utilizes IMRT methods and delivers radiation slice by slice in a rotating fashion. Isocenter. The isocenter is the point of intersection of the three axes of rotation (gantry, collimator, and couch) of the treatment machine.1 Isodose lines. Isodose lines are connecting points of equivalent relative radiation dose.1 A radiation dose of equal intensity, e.g. 80% isodose line. Karnofsky Performance Status (KPS). A scale, ranging from 1 to 100, which measures the neurological and functional status of a person. Karnofsky Performance Scale allows measuring of the quantity and quality of neurological defects.1 Linear accelerator. This is a radiation therapy treatment machine that accelerates electrons and produces x-rays or electrons for treatment.1

16 Linear quadratic (LQ) model. This is a method of demonstrating cell survival following radiation with an equation. The equation approximates clonogenic survival data with a truncated power series (second order polynomial) expansion of natural log of S (surviving proportion) as follows: lnS = - x d x d2, where d = dose, and = expansion parameters.23 Lymphoma. A cancer that originates in cells of the immune system.2 Medulloblastoma. A highly malignant cerebellar tumor with the tendency to spread via the cerebrospinal fluid.1 Magnetic resonance imaging (MRI). A diagnostic, non-ionizing way to visualize internal anatomy through a noninvasive technique. Imaging is based on the magnetic properties of the hydrogen nuclei.1 Meningioma. A type of slow-growing tumor that forms in the meninges, which are the thin layers of tissue covering the brain and spinal cord.2 Metastases. The spread of cancer beyond the primary site of origin.1 Monitor Unit (MU). A measurement of output on a linear accelerator used to deliver radiation treatments. Multileaf collimator (MLC). A secondary part of the linear accelerator that allows treatment field shaping and blocking through the use of motorized leaves in the head of the machine.1 Oligodendroglioma. A type of slow-growing tumor that forms in the oligodendrocytes, which are the cells that cover and protect nerve cells in the brain and spinal cord.2 Penumbra. The region near the edge of the field margin where the dose falls off rapidly. The width of the penumbra depends on the size of the radiation source, the distance from the source to the distal part of the collimator, and the source-to-skin distance (SSD).24 Photon. A small packet of electromagnetic energy, such as x-rays or gamma rays.1 Pituitary tumor. Being mostly benign, it is a cancer that forms in the pituitary gland, which is a pea-sized organ at the base of the brain.2 Planning target volume (PTV). Per ICRU Report 62, this volume indicates the clinical target volume (CTV) plus margins for geometric uncertainties, such as patient motion, beam penumbra, and treatment setup differences.21

17 Radiobiology. The study of the sequence of events following the absorption of energy from ionizing radiations, the efforts of the organism to compensate and the damage to the organism that may be produced.1 Radiation Therapy Oncology Group (RTOG). This is a nationally recognized research group funded by the National Cancer Institute to improve quality of care in radiation oncology. Schwannoma. Usually benign tumors of the peripheral nervous system that originate in the nerve sheath, which is a protective covering.2 Stereotactic radiosurgery (SRS). The use of a high-energy photon beam with multiple ports of entry convergent on the target volume.1 Usually high doses of 10 Gy or more are delivered in a single fraction. Thalamus. An area of the brain that helps process information from the senses and transmit it to other areas of the brain.2 Target volume (TV). The area of a known and presumed tumor.1 This may be a GTV or PTV depending on the patient and immobilization methods used. Volumetric modulated radiation therapy (VMAT). An innovative approach to delivering IMRT via arcs where the gantry, MLC speed, and dose rate of the linear accelerator may be modified via optimization. Limitations A limitation to this study includes the number of patients. A small volume of patients was studied therefore the data collected is limited. Optimization parameters may be a limitation if the same optimization objectives are used for each case. To date, most of the treatment planning algorithms for SRS are still pencil-beam calculations (PBC) that do a very poor job for heterogeneous mediums, such as brain tissue. Therefore, it is a limitation that the study utilizes analytical anisotropic algorithm (AAA), as other algorithms will produce slightly different results. Lastly, all plans were calculated with a 1 mm grid size. The results may significantly change, especially for target volumes less than 5 cc if a courser grid size were used; albeit the course grid size would not yield the correct data. Methodology This research compares and evaluates two separate linear accelerator based SRS treatment techniques for intracranial lesions. The two treatment techniques that were compared include DCAT and VMAT. The study compares a variety of dosimetric parameters. The

18 parameters analyzed are target coverage of the GTV or PTV, CI, HI, GI and the integral brain dose by determining the volume of normal brain tissue receiving doses of 12 and 5 Gy. Ten patients were included in this retrospective study. These patients were planned utilizing the Eclipse treatment planning system (TPS) (v10, Varian Medical Systems). Two treatment plans were created for each patient, one plan using VMAT, or RapidArc, and another plan using DCAT. The plans were constructed using the RTOG 95-08 guidelines for total dose, dependent on maximum tumor diameter. The goal of the study is to determine whether or not the treatment techniques generate comparable plans, in addition to potential dosimetric advantages.

19 Chapter II: Literature Review Brain tumors account for 1.5% of all malignancies diagnosed annually in the United States.1 Primary brain tumors are moderately uncommon; however, cerebral metastases occurs in approximately 1/3 of those diagnosed with cancer; therefore, making them the most common brain lesion.1 The prognosis for brain tumors is generally poor. However, the 5-year survival rates for patients with primary brain tumors has risen over the past couple decades to an overall survival of 35%.1 Treatment for primary and metastatic brain tumors includes surgery, chemotherapy, radiation therapy, immunotherapy and vaccine therapy.2 The options for radiation therapy and chemotherapy vary depending on histology and anatomic location of the brain lesion.2 Radiation therapy plays a major role in the treatment of patients diagnosed with high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, as well as those with brain metastases. Stereotactic radiosurgery is a treatment technique growing in popularity for the treatment of brain tumors. There have been multiple studies done on increased survival and local control rates with SRS in addition to external beam radiation therapy.6 Since studies are showing the efficacy of SRS, it is important to understand the multiple modalities used to deliver these treatments, in addition to possible dosimetric advantages of certain techniques. This review of literature will cover topics such as a variety of dosimetric parameters used to analyze multiple treatment planning techniques, effects of radiobiology, conformity index and effects of calculation grid sizes. Pollack and Ahmed6 described multiple intracranial tumors treated with SRS and the advantages of this type of treatment. Additionally, the dose selections and tumor control rates were studied and reported. With SRS, delivering high doses and conformity is possible while effectively sparing critical structures adjacent to a tumor volume from radiation-induced toxicities. Pollack and Ahmed6 mentioned several specific studies and RTOG protocols specific to meningioma, vestibular schwannoma (VS), glomus tumor, pituitary adenoma, craniopharyngioma, chordoma, chondrosarcoma, and brain metastases. Regarding meningiomas, studies were conducted at Mayo Clinic and UPMC, which showed increased tumor control rates with 12-18 Gy SRS. Studies done with VS at UPMC giving 12-13 Gy SRS yielded 10-year tumor control rates of 97%. A UCSF study treated glomus jugulare with SRS and had a tumor control rate of 95% with a mean follow-up of 71 months. Johns Hopkins found linac-based SRS

20 to have the same control rate of 95%. Pituitary ademonas treated with SRS had excellent tumor control rates of 92-100%; however, endocrine cure rates were reported lower. There were inconsistencies of the endpoints used in varying studies, but an average endocrine cure rate was approximately 20-30%. In a study from Japan, tumor control rates were reported at 79.6% for patients with craniopharyngiomas treated with 11.5 Gy SRS. The University of Pittsburgh Medical Center treated with 13 Gy SRS and found the 1, 3, and 5-year overall local control rates were 91%, 81%, and 68% respectively. Mayo Clinic studies involving skull base chordomas treated with SRS to a marginal dose of 15 Gy had 2 and 5-year survival rates of 89% and 32% respectively, with a follow-up time of 4.8 years. A dose of 16 Gy SRS was reported at UPMC to yield a 5-year actuarial local tumor control rate of 62.9%.6 Brain metastases have historically been treated with WBRT; however, numerous RTOG protocols and randomized trials have utilized SRS for selected patients with brain metastasis. A trial at the University of Pittsburg showed the median survival for WBRT + SRS increased to 11 months versus 7.5 months for WBRT alone. A phase III study from MD Anderson showed patients with SRS + WBRT also demonstrating increased survival rates, but unfortunately found patients were significantly more likely to show decline than patients assigned to SRS alone.6 One of the most feared complications of brain radiotherapy is optic neuropathy. Utilizing SRS to treat skull base tumors has shown a low incidence of this occurrence. Mayo Clinic showed that the risk of developing clinically significant radiation-induced optic neuropathy was 1.1% for patients receiving a single SRS dose of 12 Gy or less. In addition, vascular damage from SRS is rare as well. In order to decrease vascular damage, it is recommended that the prescribed dose cover less than 50% of the diameter of the internal carotid artery or the maximum dose to the internal carotid artery be limited to 30 Gy or less. Damage to the brainstem has low occurrence also. According to Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC), the tolerance of the brainstem to a single dose of radiation, based on a maximum dose, is 12.5 Gy.6 A study similar to those reviewed in the book by Pollack and Ahmed6 was conducted by Mehta, et al.20 The researchers systematically reviewed evidence for the use of SRS in patients diagnosed with brain metastases. Key clinical questions were addressed comparing a radiosurgery boost with WBRT to WBRT alone. The outcomes considered overall survival, quality of life or symptom control, brain tumor control or response, and toxicity. Multiple

21 databases were searched and reviewed from 1990-2004 to collect data regarding the role of radiosurgery for brain metastases. The data was tabulated to create an evidence-based review, which included an assessment of the level of evidence. The review evaluated 3 randomized trials regarding newly diagnosed brain metastases. Level I evidence indicated that overall survival does improve for patients with a single brain metastasis, and that local brain control was significantly improved in those patients with 1 to 4 metastases. Six months after treatment, one trial demonstrated decreased steroid dosage and improvement of KPS; however, a nonsignificant increase in the risk of toxicity was noted. Evidence from 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series indicated that radiosurgery alone as the initial treatment did not alter overall survival in patients. It was noted that utilizing radiosurgery at the time of progressive or recurrent brain metastases requires stronger evidence.20 Similar to the evidence-based reviews conducted by Mehta et al,20 data was collected from 10 different institutions by Sneed et al.25 The researchers quantitatively compared survival probabilities for 569 patients with newly diagnosed brain metastases. Initially, 268 patients underwent radiosurgery alone, which was assessed in comparison to 301 patients who were managed with radiosurgery plus whole brain irradiation. One of the trials completed reviewed 236 patients with 1-3 brain metastases and KPS 50. The trial demonstrated that patients with no known extracranial disease had a median survival time of 15.4 months when managed with radiosurgery plus whole brain irradiation versus 8.3 months survival time when treated with radiosurgery alone. However, a similar study looking at 105 patients showed no survival difference. Regarding salvage therapy, it was determined that more data needs to be collected from prospective trials following patients being treated with salvage therapy.25 In addition to the previous articles, the American College of Radiology conducted a study looking at multiple trials and clinical scenarios regarding treatment for brain metastases.26 It was found that the median survival for a patient with brain metastases varies between 4 to 6 months after WBRT, which is an established standard of care for most patients diagnosed with brain metastases. Many different dose schemes and fractionations, as well as various total doses have been studied. However, none of the regimens have proven better than another in terms of survival or efficacy. The most commonly used prescriptions include 30 Gy in 10 fractions or 37.5 Gy in 15 fractions and have proven to be an effective palliative treatment for brain metastases. A majority of patients who receive WBRT do not receive local control, although

22 approximately half of these patients do experience an improvement in neurologic symptoms. The multiple studies reviewed did show the effectiveness of SRS, however, this may be related to choosing an appropriate patient selection. It was also stated that SRS alone probably could not replace the benefits of WBRT.26 Treating with high dose schemes requires careful consideration since the risk of damage to normal tissues associated with this type of treatment increases with increased dose. Nedzi27 reviewed radiation treatment courses using dose per fraction schemes of 10 Gy or above. He evaluated the efficacy and safety of such high doses, also known as ablative therapy. Many disease sites were reviewed, including trigeminal neuralgia, epilepsy, arteriovenous malformations, acoustic neuromas, meningiomas, pituitary adenomas, malignant tumors including early stage lung cancer, brain metastases, and liver and spine metastases. High rates of recurrence are noted if complete resection of meningiomas is not achieved and unfortunately a variety of meningiomas can be challenging to completely surgically resect due the location of the tumor. In a situation such as this, SRS can be extremely effective. Retrospective data of small meningiomas that could not undergo surgery supported an 89% - 94% progression-free effect for patients treated with 15 - 16 Gy radiosurgery. Prospective trials are needed to evaluate the efficacy of SRS with pituitary adenomas. Evaluation of 2 retrospective studies identifying patients with multiple brain metastases treated with WBRT SRS showed that SRS added to WBRT has benefits. The addition of SRS improves performance status and survival; however, because these patients do not have long-term survival, more data is required on the patients quality of life. Liver and spine metastases have been studied with stereotactic radiation therapy, a promising treatment method requiring extra precise planning due to the proximity to crucial adjacent structures.27 Certain critical organ dose tolerances specific to ablative therapies must be carefully followed in any radiosurgery treatment. The decision to treat a patient diagnosed with brain metastases is often influenced by a variety of considerations. One factor frequently considered is whether a SRS program is readily available to the institution where a patient is treated. A multi-institutional study of factors influencing the use of SRS for brain metastases was recently conducted by Hodgson et al.28 Because the implementation of SRS is technically complex, this study chose to look at how local availability of SRS affected how patients diagnosed with brain metastases were treated. Logistic regression analyses were performed on 973 randomized patients. This analysis indicated factors

23 associated with using SRS as a boost treatment in combination with WBRT. Of these patients, SRS was given as a boost treatment to 70 Gy, which accounted for approximately 7.8% of the randomized population. The analysis showed the factors most significantly influencing the use of SRS treatment were fewer brain metastases, controlled extracranial disease, age, and the availability of an onsite SRS program at the hospital or clinic where the patient was being treated. Results showed that whether or not the institution offered SRS changed the percentage of patient receiving SRS drastically, especially for patients with 1-3 brain metastases, good performance status, and no evidence of extracranial disease. For facilities that did not have a SRS program, 3.0% of patients underwent SRS treatment, versus 40.3% of patients who were treated at a facility with an onsite SRS program.28 With multiple factors influencing treatment decisions for patients diagnosed with brain metastases as mentioned above, Sperduto et al29 conducted a study to introduce a new prognostic index for patients with brain metastases. They looked at 1,960 patients in the RTOG database and compared the new prognostic index with 3 other indices. Advantages and disadvantages were found with all 4 indices compared. However, Recursive Partitioning Analysis (RPA) and the new Graded Prognostic Assessment (GPA) had the most statistically significant differences, with the GPA being the least subjective and most quantitative. Graded Prognostic Assessment along with Score Index for Radiosurgery (SIR) incorporated the number of brain metastases, whereas RPA and Basic Score for Brain Metastases (BSBM) did not include this parameter. Score Index for Radiosurgery requires calculation of the volume of the largest lesion, which varies depending on the treatment system used. With varying systems, it is often only assessed at the time of treatment planning.29 This study was important in determining which treatment approach is most appropriate for a given patient. Determining the appropriate treatments are crucial to a patients outcome, and a useful prognostic index could guide the decisions made and presented by physicians and their colleagues. Stereotactic radiosurgery is becoming more and more utilized in the treatment of intracranial tumors because of its precision and high dosage. Researchers have conducted several studies, which have compared and evaluated the dosimetric differences between linear accelerator based stereotactic radiosurgery techniques.(8-19) The various techniques included three dimensional conformal radiation therapy (3D-CRT), IMRT, DCAT, and VMAT (RapidArc), in addition to CyberKnife and GammaKnife. The dosimetric comparisons included

24 target coverage of the GTV and PTV, CI, HI, and dose received by critical structures proximal to the tumor. (8-19) Ding et al8 looked at dosimetric comparisons of different treatment techniques, including 3D-CRT, DCAT, and IMRT for the treatment of brain tumors. In this study, 15 patients were selected who had been treated with Novalis. For all patients, 3D-CRT, DCAT and IMRT plans were done. A standard margin of 1 mm was used for the planning target volume (PTV) and 90% was used as the prescription isodose line for all plans. In order to quantify comparisons made in the study, the target coverage at the prescription dose, conformity index (CI), and heterogeneity index (HI) were analyzed. For PTVs ranging in size from 2 cm3 to 100 cm3, IMRT plans yielded a high CI. Plans utilizing IMRT had better target coverage at the prescription dose, in addition to a better HI for medium sized tumors. For large tumors with PTV >100 cm3, the Intensity modulated radiation therapy plans demonstrated good target coverage at the prescription dose and HI and CI values were comparable to those values found with the 3D-CRT and DCAT plans. Intensity modulated radiation therapy utilizes inverse planning, which is better for overlapping of the target and critical structures. It also lends the ability to decrease the dose to normal brain tissue. Intensity Modulated Radiation Therapy was not recommended for small tumors; however, for large tumors IMRT was superior. Dynamic conformal arc therapy was found suitable for most treatments of brain tumors, and showed improved coverage of the treatment volume when used for larger tumors. The plans produced high conformity, and the treatment could be delivered in less time than 3D-CRT treatment plans. Three-dimensional conformal radiation therapy was useful for small tumors because it demonstrated increased ability to conform the dose distribution to irregular target shapes.8 Solberg et al9 compared absolute dose distributions from 3 radiosurgery delivery techniques, including conventional approach using non-coplanar circular arcs, static field conformal treatment, and dynamic arc field shaping. A simulated target with 3 overlapping spheres was used for straightforward planning. The tumors ranged in size and required different numbers of isocenters. The study found that circular arc techniques required multiple isocenters for the treatment of large tumors, which in this case was 9.79 cm3, or irregularly shaped tumors resulting in very low homogeneity within the target volume. The single isocenter approach used with both the static fields and dynamic conformal arcs, increased the homogeneity within the target volume and decreased the dose to surrounding critical structures.9

25 Hazard et al10 assessed the conformity of DCAT treatments for SRS delivered on a linear accelerator. One hundred and seventy four cases were studied and quantitatively compared to evaluate the target volume, and prescription isodose volume, which is defined as the total volume encompassed by the prescription isodose surface. The 3 mm MLC improved conformity by the ability to shape the MLC pattern to the beams eye view of the target volume for each 10 degrees of the arc. The resulting CIs were similar to that of GammaKnife treatment plans. Treatment times with DCAT are less than with GammaKnife as well. In addition, because conformity varies with different prescription isodose surfaces, the researchers chose a uniform method for selection of this surface. It was required that 95% of the target volume receive 100% of the dose, in addition to 99% of the target volume receiving 95% of the dose.10 It is crucial to achieve high dose coverage to the target volume by the prescription isodose surface, as well as decrease complications by minimizing the volume of normal tissue receiving minimal dose. Wang et al11 analyzed coplanar and non-coplanar arc treatments using intensity modulated arc therapy (IMAT). Patients included in the study were diagnosed with 2 - 5 lesions. A Novalis TX linear accelerator with high-definition MLC was used to deliver the treatments. The MLC leaf width was 2.5 mm at isocenter. Treatment planning was done utilizing RapidArc and the study compared the effects of a single arc versus 5-arcs on IMAT SRS treatment plans. The target coverage, CI and volume of tissue within the low dose isodose line of 5 Gy were compared. It was concluded that 5-arc non-coplanar treatment plans were superior regarding CI and volume of tissue within the 5 Gy isodose line. The 5-arc plans produced a smaller volume within the 5 Gy isodose line in addition to higher conformality.11 Lo,12 at Stanford University Medical Center, evaluated the quality of brain SRS treatment plans between Accuray CyberKnife and Varian RapidArc. CyberKnife is a non-isocentric, conebased SRS system utilizing 6 MV, which has the ability to generate isodose distributions with a high conformity index and rapid dose fall off. RapidArc is MLC based VMAT. With 2.5 mm high-definition (HD) MLC, the treatment planning system can design the potential isodose distributions required for brain SRS. CyberKnife treatment plans were recreated using RapidArc with the same target coverage and dose constraints. The results of the study yielded superior plans created when using CyberKnife. The RapidArc treatment plans were found to have higher CI by 10%, a 70% higher ratio of volume receiving 50% of the prescription dose to a volume

26 receiving the prescription dose, 50% of the brainstem receiving more than 8 Gy, and 45% higher dose 2 cm from the target on average.12 A study reviewing the feasibility of single-isocenter VMAT SRS for multiple brain metastases was reported by Clark et al.13 The study looked at the plan quality of single versus multiple isocenter VMAT planning technique using Varian RapidArc technology. The treatment plans were created using single-arc/single isocenter, triple-arc (non-coplanar)/single isocenter, and triple-arc (coplanar)/triple isocenter arrangements. Each patient had 3 brain metastases. In using Paddick and RTOG evaluation tools, plans were quantitatively evaluated with dosimetric parameters including CI scores, GI scores and 12 Gy isodose volumes. As a result, all 3 plans were clinically acceptable; however, non-coplanar arcs demonstrated small improvements in the CI as well as decreased 12 Gy isodose volumes when the 3 metastases were in close proximity to each other. When the lesions increased distance between them, only small differences were observed. The study concluded that a single isocenter could be used to deliver plans with equivalent conformity to the multiple isocenter plans.13 A study was conducted by Mayo et al14 evaluating intracranial SRT. This study was the researchers initial experience delivering linear accelerator based, frameless SRT with RapidArc. The treatment plans were created using 2-3 arcs per isocenter, in addition to at least one of the arcs being non-coplanar. The study compared a few dosimetric parameters including conformity, homogeneity within the tumor volume, dose gradient and treatment times. The results showed comparable outcomes with other treatment techniques such as CyberKnife, Tomotherapy and static-beam IMRT. In addition, treatment times ranged from 4-7 minutes, which is considerably shorter than other techniques. Therefore, it was concluded that SRT using volumetric IMRT with RapidArc is a viable alternative.14 Similar to the study conducted by Mayo et al,14 Yang et al15 investigated the feasibility of RapidArc for SRS and SRT for the treatment of intracranial lesions. Ten patients were studied that had previously been treated with conventional DCAT plans. The patients were replanned with RapidArc utilizing multiple non-coplanar arcs along with a single arc. The plan quality was evaluated by comparing conformity and homogeneity indexes as well as the volumes of normal tissue receiving low doses (V50, V25 and V10) of radiation between the RapidArc linear accelerator based with DCAT. The volumes of normal brain receiving 50%, 25% and 10% of the dose increased with the single arc RapidArc treatment plans. Increased MUs were found

27 with the RapidArc plans; however, treatment time was comparable to DCAT. The results yielded RapidArc superior when multiple arcs were implemented.15 Lagerwaard et al17 conducted a study evaluating a single arc utilizing RapidArc treatment for SRS. A single arc can be delivered in less than 10 minutes, which is beneficial to both patients and the staff in radiation therapy departments. Stereotactic radiosurgery in addition to WBRT is an established treatment option for patients who are diagnosed with a limited number of brain metastases. Most SRS treatments are delivered in a time frame of 20 minutes up to an hour depending on the number of lesions. The researchers evaluated whether one arc using RapidArc could possibly lessen the treatment duration. For this study, RapidArc treatments were created for 6 patients with between 2 and 8 brain lesions. The volumes of these lesions ranged from 1.0 to 37.5 cm3. All the lesions were treated to 18 Gy and prescribed to the 80% isodose line. The single arc RapidArc plans were compared to 4-5 conventional dynamic conformal arcs using CI and dose volume histograms (DVH). The results of the study found the CI of the RapidArc plans to be superior to the dynamic conformal arcs. RapidArc yielded a CI of 1.5 0.6 versus 2.1 0.7 for dynamic conformal arcs. The RapidArc plans also had a decreased volume of normal brain tissue encompassed in the 80% isodose surface. In addition, the RapidArc plans resulted in a drastic decrease in treatment delivery times, averaging 8 minutes to deliver each treatment. In conclusion, RapidArc can be regarded as an effective way to deliver SRS treatments in addition to WBRT.17 A few studies focused on specific intracranial lesions and compared different treatment techniques using SRS. Lee et al18 conducted a study on vestibular schwannomas using DCAT with the Novalis system and Tomotherapy. They compared the dosimetric results of these treatment methods using CI, HI, comprehensive quality index for 9 critical structures, gradient score index, and plan quality index. Ten to 16 Gy was prescribed to PTV volumes ranging from 0.27 19.99 cm3. The study found Tomotherapy conformed better to the PTV but had a decreased gradient score index. Tomotherapy also showed an advantage over DCAT with a better plan quality index; however, the radiation beam was on longer and more monitor units were used to deliver the treatment. The study confirmed more research should be conducted to determine whether the dosimetric advantage of Tomotherapy confirms a clinical benefit as well.18

28 Grabenbauer et al19 evaluated different techniques for SRS of pituitary adenomas. Out of 152 SRS procedures, 10 patients with pituitary adenomas were compared using conformal, DCAT with a micro multi-leaf collimator (mMLC), circular collimators, and 8-10 conformal static mMLC beams with and without IMRT. The prescribed total dose used was 18 Gy, with Dmax of the optic chiasm < 8 Gy, and < 10 mL of the temporal lobe receiving 10 Gy. The dosimetric parameters the researchers chose to compare the plans were coverage, CI, HI, and the volume of the temporal lobe receiving 10 Gy. Intensity Modulated Radiation Therapy had better coverage in 5 out of 10 patients over DCAT. In addition, IMRT had a smaller volume of tissue outside the PTV receiving > 18 Gy in 9 of 10 patients. One patient had better conformity with circular collimators. Circular arcs, however, yielded the highest maximum dose of 39.8 Gy, which produced a HI of 2.2 versus HI of 1.13-1.2 for the other treatment techniques. The study concluded that IMRT techniques are safe and appropriate for SRS of pituitary adenomas.19 The treatment modalities mentioned previously have been compared in many of the studies quantitatively by utilizing a variety of dosimetric parameters. Conformity Index was a common parameter assessed; however, there are multiple formulas used to calculate CI. Feuvret et al30 analyzed and evaluated conformity indices based on their field of application. Medical Dosimetry treatment planning systems provide dose distribution for each CT slice and a DVH to aid in analyzing treatment plans, but there is no indication of conformity. A CI can be helpful by providing a quantitative score in order to compare several treatment plans for the same patient. The CI was primarily developed for SRS treatment plans, and integrates multiple parameters. There were several volume-based conformity indices in various clinical settings. For SRS, RTOG based its CI on several parameters, including reference isodose values of the treatment plan, reference isodose volume or prescription isodose, and the target volume. Ideal CI equals 1, while an index greater than 1 indicates the irradiated volume is greater than the target volume and extends into normal structures. A CI less than 1 indicates the target volume is only partially irradiated. As defined by RTOG, when a CI value is between 1 and 2, the treatment complies with guidelines, if the index falls between 2 and 2.5, or 0.9 and 1 it is a minor violation, and values less than 0.9 or greater than 2.5 are considered major violations. The disadvantage to this CI is it does not consider the degree of spatial intersection of two volumes or their shape. An ideal CI is yet to be determined in order to achieve the desired objective of the CI, which is to quantify the quality of treatment with 100% specificity and sensitivity.30

29 The conformity of linear accelerator-based SRS using DCAT was assessed by Hazard et al31 in a research study. In addition, the researchers also evaluated and described a standardized method of isodose surface selection. The CI at the prescription isodose surface of 174 targets was calculated. A prescription dose was chosen using the following criteria: 95% of the target volume encompassed by the prescription isodose volume and 99% of the target volume encompassed by 95% of the prescription dose. It was found that median CI was 1.63 at the prescription isodose surface and 1.47 at the standardized prescription isodose surface. The CI values previously reported for GammaKnife SRS were similar to the CI found in this study looking at linear accelerator-based SRS. A standardized prescription isodose surface may aid physicians in choosing a prescription isodose surface that takes into consideration coverage and conformity, thus helping with CI comparison.31 Wagner et al32 presented a simple way to compare SRS plans. The purpose of the index evaluated was to gauge multiple competing SRS plans, but not necessarily to assess the superiority of one method of treatment delivery over another. The researchers provided a combined conformity/gradient index (CGI), which is an average of a conformity score and gradient score. Only 3 pieces of data were required to compute this relatively simple index. This includes the total volume irradiated to the prescription isodose level, the target volume, and the total volume irradiated at 50% of the prescription isodose level. A limitation of the CGI score is its inability to consider the issue of dose inhomogeneity within the tumor volume. Another limitation is that the CGI does not assess radiation dose to radiosensitive structures beyond normal brain tissue. Therefore, it is concluded that the CGI is a very simple tool to calculate for homogenous lesions that are located away from radiosensitive structures. The CGI tool was proven useful as a simple, quick calculation for forward planning as well as inverse radiosurgery planning.32 The studies reviewed previously included multiple treatment techniques including GammaKnife and CyberKnife, in addition to techniques utilized for non-invasive linear accelerator based SRS, namely cone-based, DCAT, IMRT, Tomotherapy and VMAT. One main difference between these delivery methods was the planning, which was forward versus inverse. Another comparison that has been analyzed includes the MLC utilized in treatment delivery. With the introduction of smaller MLC leaf widths, it is expected that DCAT or VMAT may yield better dosimetric results.16 Chern et al16 performed a dosimetric comparison of BrainLAB

30 micro-MLC with the leaf widths being 3 mm, 4.5 mm and 5.5 mm and Varian Millennium MLC with leaf widths of 5 mm and 10 mm. For dynamic conformal arc SRS for treatment of intracranial lesions, it was assumed that the micro-MLC would yield further improvement in target conformity and normal tissue sparing. Two plans were done for each of the 23 patients in the study, one using the minimal 3 mm MLC and one using the minimal 5mm MLC, while keeping all parameters the same except for collimator angle, which were optimized for each arc in the separate plans. In order to evaluate the normal tissue sparing in close proximity to the target volume, a peritumoral rind structure of 1 cm was created. The CI used was an equation described by Paddick, as used in a few other studies. The CI and normal tissue sparing was found to be slightly improved with the minimal 3 mm MLC. In conclusion, the 3 mm microMLC provided small improvements with better target coverage and increased normal tissue sparing with SRS utilizing DCAT.16 Similarly, a dosimetric study was completed by Jin et al33 using different leaf-width MLCs for treatment planning with DCAT and IMRT. Three mm micro MLC, 5 mm MLC, and a 10 mm MLC were evaluated for SRS using the Brainscan treatment planning system. The dosimetric analysis used for comparison of the treatment techniques, target volumes, and treatment sites included CI, DVH for organs at risk (OR), and the percentage target coverage. When using DCAT, significant differences were found between the different leaf-width MLCs. The CI ratio depends on the size of the target volume, and targets approximately 1 cm3 showed a large variation between CI, however, for relatively large targets over 8 cm3, the variation decreased. For IMRT plans, the results demonstrated the CI with minimal difference between different MLC leaf widths. For both treatment planning techniques, the 3 mm MLC showed improved OR DVHs, more notable with the OR with smaller volumes. The study concluded that narrower leaf-width MLC could have some advantages over wider leaf-width MLC.33 Monk et al34 conducted a study comparable to Jin et al33 regarding a comparison of different leaf-width MLCs. Three mm MLC and 5 mm MLC were dosimetrically compared on a linear accelerator for SRT treatment of intracranial lesions. Fourteen patients diagnosed with brain metastases who had been treated with BrainLABs 3 mm micro MLC were replanned using the 5 mm Varian Millennium MLC. The same target coverage was achieved by adjusting the MLC shape to conform around the PTV; however, noncoplanar beam arrangements were used. The results demonstrated that the 5 mm Varian Millennium MLC provided an increase in the CI.

31 The DVH curves showed an increase in the volume of normal tissues receiving low dose radiation, but the maximum dose to critical structures did not significantly increase with the 5 mm MLC. It was concluded that the 3 mm micro MLC does consistently improve PTV conformity and achieves decreased low dose spillage to surrounding normal tissues. However, quantitatively the improvements are not significant enough to give evidence of one leaf-width MLC to be more beneficial than the other.34 Another principal component to consider when planning and evaluating SRS is proper calculation of the dose distribution. Ong et al35 investigated the impact of calculation resolution using anisotropic analytical algorithms (AAA). They were looking specifically at 3D-CRT utilizing small fields in homogeneous and heterogeneous mediums and with the use of RapidArc plans. Dose distributions were calculated utilizing AAA version 8.6.15 and 10.0.25. These distributions were compared with measurements performed using GafChromic film on phantoms made of polystyrene. They evaluated the accuracy of the algorithms calculated using grid resolution sizes of 2.5 and 1.0 mm. Both AAA versions demonstrated lower peak doses and broader penumbra widths than the measured. However, using AAA version 10.0.25 with a 1.0 mm calculation grid improved the dose distribution. It was found that 1.0 mm was superior to 2.5 mm and was recommended. However, when using the smaller dose grid at 1.0 mm, the calculation times were longer.35 In conclusion, several studies have indicated the use of SRS, in addition to external beam radiation therapy, can provide increased survival and local control rates.6 There are multiple modalities used to deliver these treatments and the possible dosimetric advantages of certain techniques are advantageous in treatment planning of SRS. The variety of dosimetric parameters used to analyze multiple treatment planning techniques, effects of radiobiology, and the effects of calculation grid sizes is important when determining the most effective way to plan and deliver SRS in the treatment of brain lesions. Dynamic conformal arc therapy and VMAT are two commonly used methods in planning and delivery of SRS treatment. This study aimed to quantify the dosimetric indicies utilized in evaluating SRS treatment plans and indicate a superior planning method between DCAT and VMAT.

32 Chapter III: Methodology Patients diagnosed with primary brain tumors or brain metastases may be candidates for radiation therapy. Traditionally, 3D-CRT or WBRT have been used as the treatment technique for these lesions. However, SRS has been rapidly growing in popularity and can be applied to a number of various benign and malignant intracranial lesions. There are multiple treatment techniques that can be utilized for non-invasive linear accelerator based SRS, namely conebased, DCAT, IMRT, Tomotherapy and VMAT. Prior research has proven the efficacy of SRS in conjunction with WBRT for brain metastases.20 Stereotactic radiosurgery delivered via DCAT or VMAT has the ability to increase local control and survival rates. The specific problem is determining which method will yield superior planning, resulting in improved treatment for the patient. Knowledge gained between these 2 planning techniques would enable clinics to deliver SRS for intracranial tumors utilizing techniques with dosimetric advantages. The purpose of this research is to evaluate a variety of dosimetric parameters between treatment plans using DCAT and VMAT. Subject Selection and Description For this retrospective research study, 10 patients were selected using a purposive sampling method; therefore, the study will involve a deliberate selection of individuals. By using this method of sampling, it will be ensured that the patients included in the study meet specific, pre-determined criteria. The patients selected will have intracranial tumors and meet requirements for SRS treatment. The patients included in this research study will meet the requirements of RTOG 95-08, which allowed a maximum tumor diameter of 4.0 cm. All patients included have received previous radiation treatment for brain metastases. Figure 1 displays the location and size of the brain metastases for all 10 patients included in the study. The patients included have a single lesion metastasis. The patients were all treated at Gundersen Lutheran Medical Center in La Crosse, Wisconsin. Instrumentation A variety of different equipment was needed for this research study. A treatment planning computed tomography (TPCT) scan was obtained using a GE lightspeed R16. The precision of SRS requires the patients to have extensive immobilization. The patients included in the study each had a custom, reinforced Orfit facemask, in addition to an S frame. This frame extends over the edge of the treatment couch allowing for increased couch treatment

33 angles, as well as less attenuation, during treatment delivery. Image fusion of MRI and the TPCT was required in order for the physician to accurately delineate the tumor volume, as well as critical structures in proximity to the tumor volume. The treatment plans created for the patients in this study were developed through the use of the Eclipse treatment planning system (TPS) (v10, Varian Medical Systems). Two treatment plans were created for each patient; one using VMAT RapidArc, in addition to another plan using DCAT. The plans were developed following RTOG 95-08 guidelines. Per the protocol, total dose is dependent on the size of the lesion.3 An assigned total dose of 24 Gy was prescribed for planning a maximum tumor diameter of 2 cm, 18 Gy was prescribed for a maximum tumor diameter of 2.1-3.0 cm, and 12 Gy was prescribed for a maximum tumor diameter of 3.1-4.0 cm.3 The MLC dimensions varied for each treatment technique. Volumetric modulated radiation therapy utilized two full optimized, coplanar arcs around the patient with 120-leaf millennium MLC (Varian Medical Systems), which project 5 mm width from isocenter in each direction for the inner 10 cm. In contrast, DCAT used seven non-coplanar arcs with micro (m3) MLC (BrainLAB) that project 3 mm out to 2.1 cm on either side of isocenter, 4 mm for 3.3 cm on either side of isocenter and 5 mm out to 4.5 cm on either side of isocenter. For the above DCAT technique, a standard table arrangement was used setting the table approximately 27 degrees apart for each non-coplanar arc delivered (90, 63, 36, 10, 350, 323 and 296). The treatment planning calculations were done using AAA due to its ability to accurately calculate heterogeneous mediums. For field sizes of < 3x3 cm2, a recent publication indicated the significant improvement of dose calculation accuracy using AAA v10 when the calculation grid size was reduced from 2.5 mm to 1.0 mm.35 Therefore, for this study the calculation grid size was set to 1.0 mm. Data Collection Data collection for this research study consisted of multiple steps. The 10 patients that were chosen for this retrospective study had previously been treated for SRS; therefore, MRI/TPCT fusion had already been completed. The physician previously contoured GTV and PTV volumes, in addition to critical structures. Upon review of the previous planning, some modifications were made in order to standardize the planning criteria of the patient population included. The next step in the process was to re-plan utilizing the Eclipse TPS. Each patient had two plans developed, one using DCAT and the other using VMAT or RapidArc. Seven non-

34 coplanar arcs with various table angles were created for DCAT and two full coplanar arcs were used for VMAT. Dynamic conformal arc therapy uses forward planning methods versus VMAT using inverse planning optimization. Once optimal treatment plans were created, the next step was gathering the dosimetric parameters including target coverage, CI, HI, GI, and the volume of the normal brain tissue receiving doses of 12 Gy and 5 Gy. Data Analysis Data collection was analyzed utilizing descriptive statistical analysis. This type of analysis allowed the large amount of data generated from the treatment plans to condense into a comprehensible and interpretable form. A DVH was utilized to determine target coverage. Additionally, the mean, range and standard deviations were calculated. To determine isodose volumes, which are required to calculate the conformity and homogeneity indexes, the convert isodose level to structure tool was used. In order to evaluate CI, the formula created by RTOG and Paddick36 was utilized, PITV = VRI/TV and CIPaddick = TV2RI/TVxVRI, respectively. PITV is defined as the RTOG conformity index where VRI is the reference isodose volume and TV is the target volume. TVRI is the target volume covered by the reference isodose.37 Two conformity indexes were calculated because the RTOG index does not penalize for the prescription isodose line that does not cover the target. For evaluation of homogeneity index, HI = Dmax/VRI, where Dmax is the maximum dose to the target will be used.37 The GI was evaluated using a formula created by Paddick;38 GI = V50%RI/VRI, where V50%RI is defined as the volume of 50% of the reference isodose. A DVH was utilized to determine the volume of normal brain tissue receiving doses of 12 Gy and 5 Gy. Limitations A limitation to this study includes the number of patients. A small volume of patients was studied therefore the data collected is limited. Optimization parameters may be a limitation if the same optimization objectives are used for each case. To date, most of the treatment planning algorithms for SRS are still pencil-beam calculations (PBC) that do a very poor job for heterogeneous mediums, such as brain tissue. Therefore, it is a limitation that the study utilizes analytical anisotropic algorithm (AAA), as other algorithms will produce slightly different results. Lastly, all plans were calculated with a 1 mm grid size. The results may significantly change, especially for target volumes less than 5 cc if a courser grid size were used; albeit the course grid size would not yield the correct data.

35

Summary Ten patients were included in this study that met specific, pre-determined criteria. Two plans were developed per patient, with a total of ten patients, utilizing DCAT and VMAT. Data was collected and analyzed utilizing descriptive statistical analysis. Measures of central tendency and variability including the mean, range and standard deviation were used. Dosimetric evaluation parameters included the target coverage, CI, HI, GI, and the volume of the normal brain tissue receiving doses of 12 and 5 Gy.

36 Chapter IV: Results The purpose of this research was to evaluate the dosimetric differences between treatment plans using DCAT and VMAT. The plan comparisons included target coverage, conformity and homogeneity index, GI and normal brain tissue doses. Between DCAT and VMAT, the study aimed to determine which technique offers a better planning evaluation index for 10 metastatic brain SRS patients outlined in Table 1. Treatment plans were optimized using 7 non-coplanar DCAT and 2 coplanar VMAT fields as outlined in Table 2. Target coverage to the GTV or PTV, according to the indices, as well as normal brain tissue doses were used to evaluate the treatment plans. The results of this study showed the superiority of DCAT when compared to 2 coplanar arc VMAT treatment plans. Item Analysis The results section is divided into 2 comparisons. Comparison 1 analyzed the treatment planning efficacy in terms of the RTOG and Paddick36 conformity indices, Paddick38 gradient index, and HI between DCAT and VMAT. A total of 20 plans, 10 each per planning modality, indices were compared. Stereotactic radiotherapy plan evaluation data for DCAT and VMAT is summarized in Table 3 for the patient pool. In addition, the mean values for each index were calculated along with the standard deviation in order to differentiate the target coverage between DCAT and VMAT. Table 4 provides the mean data for comparison of treatment plan indices. Comparison 2 looked at the dose to critical structures. Since all 10 patients lesions were not located near the optical or auditory apparatus, brain stem, spinal cord, or pituitary gland, normal brain tissue doses were analyzed. Moreover, V12, which is the absolute volume of normal brain tissue in ccs receiving 12 Gy of dose, and V5, were cumulated demonstrating that DCAT provided a statistical advantage over VMAT at either dose level. Comparison 1 The first comparison between DCAT and VMAT treatment plans looked at treatment plan indices for target coverage and dose fall-off. All 20 of the treatment plans were normalized as 99% of the target volume receiving 100% of the prescription dose. While RTOG and Paddick36 conformity indices, along with HI provided how well the target was covered, Paddick38 GI provided valuable information regarding how fast the dose fall-off occurred beyond the target. The index specifically compared the ratio of 50% of the reference isodose volume to the prescription isodose volume. As outlined in Table 3, the target volumes ranged from 0.13 cc

37 10.24 cc. Radiation Therapy Oncology Group CI for the targets ranged from 0.85 1.33 for DCAT, and 1.08 1.44 for VMAT, mostly increasing with target volume. Similar results were seen studying the Paddick36 CI, which takes the target volume covered by the referenced isodose. Thus Paddick36 CI ranged from 0.45 0.78 for DCAT and 0.45 0.83 for VMAT, increasing in number with increasing target volume. In terms of homogeneity of the plans, the HI values for DCAT ranged from 1.17 1.22, and VMAT values ranged from 1.05 1.21. In terms of mean values, the PITV was 1.18 0.13 for DCAT and 1.27 0.11 for VMAT. Paddick36 CI mean results were 0.68 0.11 for DCAT and 0.69 0.11 for VMAT. Lastly, HI means were 1.20 0.02 for DCAT and 1.12 0.06 for VMAT. Therefore, the HI was slightly better for VMAT. However, the PITV and Paddick36 CI mean results showed DCAT as slightly superior. Plots for RTOG and Paddick36 conformity indices can be seen on Figure 6 and 7 respectively, while Figure 9 shows the plot of the HI as a function of tumor volume. In terms of dose fall-off or spillage, the GI values ranged from 2.65 8.45 for DCAT and 4.25 18.21 for VMAT. The mean Paddick38 GI values were 3.99 1.76 for DCAT versus 7.55 4.17 for VMAT. The GI as a function of target volume for each treatment plan modality was plotted in figure 8. Comparison 2 Along similar lines of evaluating dose spillage and its effects on OR structures, normal brain tissue volumes receiving 12 and 5 Gy of dose were compared for DCAT and VMAT plans. V12 for normal brain tissue is outlined in the QUANTEC report and suggests that such volume be less than 5-10 cc for symptomatic necrosis avoidance. V5 was added as a parameter to track based on clinical discussions with the physicians, in order to evaluate lower dose spillage volumes. Table 5 outlines the volume of normal brain tissue receiving 12 and 5 Gy doses for DCAT and VMAT. V12 Brain Target values ranged from 0.9 13.8 cc for DCAT, and 2.4 22.3 cc for VMAT. V5 Brain Target volumes for DCAT were 3.7 68.7 cc, and 9.9 124.8 cc for VMAT. This demonstrated that the volume of brain receiving 12 and 5 Gy was less with the DCAT plans. The plots for V12 comparison between treatment plans for DCAT and VMAT can be seen in figure 10, while V5 values are plotted in figure 11. Results of this study can be analyzed in two parts: i) Target coverage in terms of treatment plan evaluation indices including CI and HI, and ii) Dose fall-off in terms of gradient index, and absolute normal brain tissue volumes receiving 12 and 5 Gy doses. In terms of target

38 coverage DCAT has a slightly better RTOG defined conformity, however Paddick CI and HI values indicate that VMAT provides comparable coverage to the target as DCAT within statistical error margins. Therefore, unless the tumor volumes are very small, as is the case of 0.13 cc for patient 1, both DCAT and VMAT can cover the target similarly. In the case of such small target volumes, caution regarding the prescription isodose should be applied. A lower prescription isodose would have increased both plans to a better index coverage. Analyzing the dose fall-off showed that DCAT plans completed with 7 non-coplanar arcs provided a statistically superior GI and normal brain tissue volumes receiving 12 and 5 Gy dose when compared to the VMAT plans completed using 2 full coplanar arcs. Two coplanar arc, VMAT plans yielded nearly twice the values seen for DCAT in terms of GI as well as normal brain tissue volumes receiving 12 and 5 Gy.

39 Chapter V: Discussion Stereotactic radiosurgery is a treatment technique growing in popularity for the treatment of brain tumors. There have been multiple studies done on increased survival and local control rates with SRS in addition to external beam radiation therapy.6 Since studies are showing the efficacy of SRS in addition to external beam radiation therapy, it is important to understand the possible dosimetric advantages of certain techniques. The purpose of this study was to compare SRS treatment plans, namely DCAT and VMAT, based upon plan evaluation tools including indices and dose to normal brain tissue. Ten patients were included in this study that met specific, pre-determined criteria. Two plans were developed per patient, with a total of ten patients, utilizing DCAT and VMAT. Data was collected and various dosimetric evaluation parameters were analyzed including the target coverage, CI, HI, GI, and the volume of the normal brain tissue receiving doses of 12 and 5 Gy. These dosimetric parameters were evaluated to determine a superior treatment technique for SRS delivery. The results of this study showed the superiority of DCAT when compared to 2 coplanar arc VMAT treatment plans. Limitations A limitation to this study includes the number of patients. A small volume of patients was studied therefore the data collected is limited. Optimization parameters may be a limitation if the same optimization objectives are used for each case. To date, most of the treatment planning algorithms for SRS are still pencil-beam calculations (PBC) that do a very poor job for heterogeneous mediums, such as brain tissue. Therefore, it is a limitation that the study utilizes analytical anisotropic algorithm (AAA), as other algorithms will produce slightly different results. Lastly, all plans were calculated with a 1 mm grid size. The results may significantly change, especially for target volumes less than 5 cc if a courser grid size were used; albeit the course grid size would not yield the correct data. Conclusions This study concluded that VMAT plans compared to DCAT for SRS treatment plans produced similar results in terms of target coverage; however, produced almost twice the dose spillage, which in turn doubles the 12 and 5 Gy dose to the healthy brain tissue. In addition, in terms of RTOG and Paddick36 conformity indices, and HI, both treatment plan modalities produced similar coverage to the target volume. However, in terms of Paddick38 GI, and normal brain tissue receiving doses of 5 and 12 Gy, DCAT was superior. The plans utilizing VMAT

40 were 1.9 times the average GI to DCAT. Furthermore, VMAT plans would have irradiated twice the amount of normal brain tissue compared to DCAT. These findings are consistent with various studies previously conducted and outlined in the literature review. Monk et al34 concluded that RapidArc plans had an increased CI and higher dose spillage to normal brain tissue. Additionally, Mayo et al14 and Yang et al15 yielded similar results. The researchers conducting these studies found increased volumes of normal brain tissue when treating with VMAT (RapidArc). However, Clark et al13 demonstrated an improved CI with VMAT using non-coplanar arcs, as well as a decreased volume of normal brain tissue receiving 12 Gy. This could be clinically very significant in order to avoid symptomatic necrosis to the brain, as VMAT V12 volumes were greater than 10 cc on 4 out of the 10 patients planned, while DCAT plans produced only a single patient that went over this QUANTEC threshold. If such a threshold were to be reduced to 5 cc, then 6 out of 10 VMAT plans did not meet this criterion while only 4 out of 10 DCAT plans did not. These findings strongly agree with published results of IMRT as well as VMAT studies when a smaller number of coplanar fields or arcs were used. Though previous research did look at normal brain tissue dose, this study expands on the previous data by providing 12 and 5 Gy dose volumes in hopes to identify dose/volume parameters for symptomatic necrosis of the healthy brain tissue. Laangerward et al17 had findings slightly different from this study whereas RapidArc decreased the volume of brain encompassed by the 80% isodose line. Finally, the current research study concluded that treatment plan evaluation using indices is a great tool comparing SRS plans. Recommendations Although this study conclusively states 7 non-coplanar DCAT plans are better than 2 coplanar RapidArc (VMAT) plans in terms of target coverage as well as dose spillage, a more extensive study is needed. A more extensive study would need to increase the number of arcs for VMAT planning to 3, and then to 4 or 5 with a non-coplanar approach. These VMAT plans may reduce dose spillage, thus reducing the volumes of brain tissue getting 5 and 12 Gy dose and still maintain excellent target coverage. In addition, dose objectives for RapidArc were not modified for each plan to maintain plan development consistency; however, a more active optimization role may help produce statistically better results depending on the target location. Additionally, this study involved a limited number of patients. An increased patient population could enhance the results of this study and may certainly prove to have more comprehensive findings. Finally,

41 the VMAT plans used 5 mm width MLCs while the DCAT used 3 mm microMLCs. An additional study could be done utilizing the 2.5 mm HD MLC set that is available with Varian linear accelerators. Reducing the MLC width to 2.5 mm may produce comparable dose fall-off as seen on DCAT plans due to reduction in penumbra. Utilizing conformity, homogeneity, and gradient index is extremely important in evaluating patient plans and should be used during SRS planning.

42 Tables Table 1. Patients, tumor, and treatment parameters Patient 1 2 3 4 5 6 7 8 9 10 Sex F F M F F M F F F F Age (y) 70 42 59 62 76 63 73 50 61 47 ICD9 / Diagnosis 198.5 Lung Met 174.9 Breast Met 162.9 Lung Met 198.3 Renal Cell Met 174.9 Breast Met 198.3 Parotid Met 182.0 Uterine Met 198.3 Breast Met 198.3 Colon Met 198.3 Lung Met Tumor Location R frontal lobe R temporal lobe R sup frontal lobe R midline sup frontal/parietal lobe R parietal lobe R occipital lobe L parietal lobe L occipital lobe R frontal lobe L parietal lobe Prescription Dose (Gy) 24 24 24 24 24 24 24 18 18 18 Target Diameter (cm) 0.6 0.8 0.8 1.0 1.3 1.6 1.9 2.1 2.3 2.7

Abbreviations: M = male, F = female, y = years, Gy = Gray, cm = centimeters Table 2. Description of treatment planning techniques Radiosurgery Dynamic Conformal Arcs Technique Description 7 non-coplanar rotations, mMLC positions according to shape of PTV/GTV and ORs, monoisocentric

IMRT 2 coplanar RapidArc (VMAT) rotations, Millenium MLC optimized, monoisocentric

Abbreviations: IMRT = intensity-modulated radiation therapy; mMLC = micromultileaf collimator; PTV = planning target volume; GTV = gross tumor volume; OR = organs-at-risk; VMAT = volumetric-modulated arc therapy

43 Table 3. SRS plan evaluation data for DCAT and VMAT DCAT VMAT Patient TV (cc) PITV CIPaddick GIPaddick HI PITV CIPaddick GIPaddick HI 1 0.13 0.85 0.45 8.45 1.18 1.08 0.45 18.21 1.10 2 0.27 1.26 0.58 4.68 1.20 1.44 0.55 7.85 1.19 3 0.27 1.15 0.63 5.00 1.17 1.19 0.72 9.53 1.09 4 0.58 1.22 0.68 3.68 1.20 1.33 0.68 8.83 1.09 5 1.26 1.15 0.78 3.57 1.20 1.30 0.72 6.65 1.05 6 2.21 1.19 0.71 3.26 1.19 1.32 0.66 4.79 1.21 7 3.75 1.15 0.78 2.92 1.18 1.28 0.75 5.47 1.05 8 4.15 1.33 0.71 2.99 1.21 1.37 0.71 5.29 1.13 9 6.20 1.22 0.78 2.75 1.22 1.14 0.83 4.63 1.18 10 10.24 1.29 0.75 2.65 1.21 1.23 0.79 4.25 1.13 Abbreviations: SRS = stereotactic radiosurgery; DCAT = dynamic conformal arc therapy; PITV = RTOG conformity index; CIpaddick = Paddick conformity index; GI = gradient index; HI = homogeneity index Table 4. SRS Plan Comparison Patient PITV CIPaddick GIPaddick HI DCAT 1.18 0.13 0.68 0.11 3.99 1.76 1.20 0.02 SD VMAT 1.27 0.11 0.69 0.11 7.55 4.17 1.12 0.06 SD Abbreviations: SRS = stereotactic radiosurgery; DCAT = dynamic conformal arc therapy; SD = standard deviation; PITV = RTOG conformity index; CIpaddick = Paddick conformity index; GI = gradient index; HI = homogeneity index

44 Table 5. Volume of normal brain tissue at V12 and V5 doses for DCAT and VMAT DCAT VMAT V12 Brain - V5 Brain - V12 Brain - V5 Brain Patient TV (cc) Target (cc) Target(cc) Target (cc)2 Target(cc)2 1 0.13 0.9 3.7 2.4 14.1 2 0.27 1.1 4.1 2.1 9.9 3 0.27 1.3 5.6 2.8 15.6 4 0.58 1.3 5.2 4.1 18.8 5 1.26 3.9 17.4 9.6 50.0 6 2.21 3.9 14.2 5.7 30.6 7 3.75 8.9 35.3 22.3 103.3 8 4.15 6.9 30.0 12.6 60.3 9 6.20 8.1 37.4 26.1 88.9 10 10.24 13.8 68.7 21.6 124.8 Abbreviations: DCAT = dynamic conformal arc therapy; TV = Target volume; V12 = Volume (cc) of tissue that receives 12 Gy dose; V5 = Volume (cc) of tissue that receives 5 Gy dose.

45 Figures Figure 1. 3D views of the planning or gross tumor volumes (PTV or GTV) for (a) patient #2 and (b) patient #10. (a).

(b).

46 Figure 2. Dose distribution of the DCAT plan on the top and the VMAT plan on the bottom for (a) patient #2, and (b) for patient #10 taken at similar 3D views. Isodose lines are scaled at the same levels of dose to indicate plan comparisons visually. (a).

47 (b).

48 Figure 3. Dose distribution for (a) patient #2 and (b) patient #10 for DCAT plans first and VMAT plans second showing 100%, 95% and 50% isodose levels on axial slices. (a).

49 (b).

50 Figure 4. Dose-volume histograms for target "R Temporal Lobe GTV", and "Brain-GTV" which is the only OR structure for patient #2. Data on the top (a) is for the DCAT plan while the bottom one (b) is for the VMAT plan. (a).

(b).

51 Figure 5. Dose-volume histograms for target "GTV", and "Brain-GTV", "Brain Stem" and "OpticNerveChiasm" which are the OR structures for patient #10. Data on the top (a) is for the DCAT plan while the bottom one (b) is for the VMAT plan. (a).

(b).

52 Figure 6. RTOG Conformity index as a function of target volume for DCAT and RapidArc (VMAT) plans

Figure 7. Paddick Conformity index as a function of target volume for DCAT and RapidArc (VMAT) plans

53 Figure 8. Gradient index as a function of target volume for DCAT and RapidArc (VMAT) plans

Figure 9. Homogeneity index as a function of target volume for DCAT and RapidArc (VMAT) plans

54

Figure 10. Normal brain tissue minus target volume receiving 12 Gy dose

Figure 11. Normal brain tissue minus target volume receiving 5 Gy dose

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