Kerstin Müntzing, Caroline Adestam Minnhagen. total body irradiation, TBI, treatment planning system, TPS, Eclipse

SAHLGRENSKA ACADEMY EVALUATION OF ECLIPSE TREATMENT PLANNING SYSTEM FOR CALCULATION OF RADIATION DOSES TO PATIENTS TREATED WITH TOTAL BODY IRRADIATION AT EXTENDED TREATMENT DISTANCE Linnéa Karlsson Thesis: 30 hp Program: Medical Physics Programme Level: Second Cycle Semester/year: Autumn 2018 Supervisors: Roumiana Chakarova, Kerstin Müntzing, Caroline Adestam Minnhagen Examiner: Magnus Båth

Abstract Thesis: 30 hp Program: Medical Physics Level: Second Cycle Semester/year: Autumn 2018 Supervisors: Roumiana Chakarova, Kerstin Müntzing, Caroline Adestam Minnhagen Examiner: Magnus Båth Keyword: total body irradiation, TBI, treatment planning system, TPS, Eclipse Purpose: Theory: Method: The aim of this study was to evaluate the current treatment planning system (TPS) for external radiotherapy at Sahlgrenska University Hospital (SU), Eclipse, for total body irradiation (TBI) at extended treatment distance. External radiotherapy is used for treatment of different cancer diseases. High energy photons are usually directed towards the tumour. When planning for the radiotherapy treatment, most commonly, a computer-based TPS is used. Situations, where the whole body needs to be irradiated, are called total body irradiation. There are many parameters that differ between each hospital performing TBI. For example, prescribed dose, number of fractions, dose rate, source-to-skin distance (SSD) and delivery technique. The TPS used at SU is not validated for TBI, which is performed at extended treatment distance. Absolute doses, percental depth dose (PDD), profiles, off-axis values and transmission at two different SSDs (350 cm and 460 cm) for two linear accelerators, TrueBeam and Clinac ix were studied in phantom geometries created in Eclipse version 13.6.23. The clinical field currently used, as well as other field setups, was investigated, including multileaf collimator (MLC) fields and fields defined by jaws, smaller than the clinical field. Results from earlier measurements and Monte Carlo simulations of the clinical field were compared with the results from Eclipse. Additional measurements were performed in a solid water phantom for different field sizes and corresponding Eclipse data were evaluated. Dose distribution comparisons between Monte Carlo simulations and Eclipse for patients previously treated with TBI in Gothenburg were performed. The possibility to improve the homogeneity of the dose distribution in patients was investigated by implementing the field-in-field technique in Eclipse.

Results: The absolute doses for the clinical field, determined in Eclipse, at 10 cm depth were up to 4.3 % higher than the measured at SSD = 460 cm and 0.1 % higher than measured at SSD = 350 cm. The PDD in Eclipse compared to measured PDD was in good agreement. The cross-section area of the phantom, perpendicular to the beam axis, had a larger effect on the dose deviation at 10 cm depth, than the depth of the phantom. Profiles at extended SSD > 275 cm showed oscillations with increased amplitude related to increased SSD. For smaller fields defined by jaws, the doses differences were 1.9 % higher in Eclipse than the corresponding measurements. If the fields were defined by MLCs instead, the deviations increased to 3.0 % at SSD = 350 cm and to 4.5 % at SSD = 460 cm. Patient doses calculated in Eclipse varied compared to the Monte Carlo calculated doses. Both higher and lower deviations were observed up to 4 % for Dmean when dose-volume-histogram for the body was studied. The field-in-field technique was feasible, but the planning strategy was highly dependent on the individual patient size and anatomy features. Conclusion: Eclipse overestimates the dose at SSD = 460 cm and shows good agreement with the expected dose at SSD = 350 cm. The profiles in Eclipse show oscillations for SSDs larger than 275 cm, which implies that the dose distribution in a patient at extended SSD in Eclipse is not correct. The difference between calculated and measured doses is affected by the definition of the fields and the SSD used. Further investigations are needed before Eclipse can be used for treatment planning at extended treatment distance.

Populärvetenskaplig sammanfattning Ungefär 50 % av de cancerdrabbade patienterna i Sverige får någon gång strålbehandling. Extern strålbehandling innebär i de flesta fall att högenergetiska fotoner riktas mot områdena som ska behandlas. Vid helkroppsbestrålning (TBI) är målet att ge stråldos till hela kroppen. Syften med TBI är bland annat att undertrycka kroppens egna immunförsvar och skada de elakartade tumörcellerna. Tillfällen då TBI kan användas är inför stamcellstransplantationer, för patienter med olika typer av blodcancer och vid vissa immunologiska sjukdomar. Det finns olika tekniker att genomföra extern strålbehandling och TBI, beroende på vilka resurser och kunskaper som finns på respektive sjukhus. En vanlig teknik för TBI är att ha ett längre avstånd mellan behandlingsmaskinen och patienten, source-to-skin distance (SSD), än för patienter som behandlas med konventionell strålbehandling. Patienten kan då stå upp eller ligga ner under behandlingen. Det finns en rad olika parametrar som måste väljas vid TBI, till exempel vilken doshastighet och hur behandlingen ska delas upp i fraktioner. Dessa val baseras på vilken biologisk effekt som ska uppnås i patienten. Dosplanering inför strålbehandling kan göras manuellt eller med ett dosplaneringssystem (TPS), ett program som används för beräkning av stråldos. Eclipse, det system som används på Sahlgrenska Universitetssjukhus, fungerar för SSD upp till 130 cm, vid längre avstånd är det ännu inte validerat. Syftet med denna studie var att utvärdera Eclipse, för beräkning av stråldoser till patienter som behandlas med TBI. För att göra detta studerades dosplaneringssystemet med förlängt SSD då det är den teknik som används. Två olika typer av linjäracceleratorer användes med var sitt SSD, 460 cm och 350 cm. I Eclipse skapades fantomgeometrier med olika storlekar. Resultat från Eclipse jämfördes med tidigare mätningar som genomförts. Mätningar i olika fältgeometrier genomfördes med syftet att kunna förbättra den metod för TBI som används nu och fälten jämfördes mot Eclipse. Dessutom analyserades Monte Carlo-simuleringar av patienter som fått TBI på Sahlgrenska och dessa jämfördes med det aktuella dosplaneringssystemet. Vid studie av dosen på 10 cm djup sågs en variation beroende på fantomgeometri som använts i Eclipse samt även vilket SSD som används. Vid jämförelse mellan procentuella djupdoskurvor (PDD) ser de ut på samma sätt i Eclipse som vid mätningar. Dosprofilen längs med fantomet hade en oscillerande form som inte var förväntad. Det blev mer markant med ökat avstånd och berodde även på vilka metoder som fältet formats på. Mätningarna gav lägre doser än Eclipse. Skillnaden i medeldos till patienten mellan Eclipse och Monte Carlo-simuleringar varierade från patient till patient men var för det flesta inom ± 4 %. Undersökningen med tilläggsfält resulterade för vissa patienter i en mer homogen dosfördelning, för andra var det svårare att uppnå en homogen dosfördelning med denna metod. Patientens kroppsform spelade roll för hur bra dosfördelningen blev.

Table of content Background and Theory... 1 1.1 Techniques of performing total body irradiation... 2 1.2 Treatment planning and evaluation... 4 1.3 Aims... 4 Methods and Material... 4 2.1 The current TBI method in Gothenburg... 4 2.2 Dose calculations in Eclipse... 6 2.3 Previous measurements and Monte Carlo calculation... 7 2.4 Validation measurements... 7 2.5 Studies of Eclipse accuracy in phantom geometry... 9 2.5.1 Absolute doses... 10 2.5.2 PDD... 10 2.5.3 Profiles and off-axis values... 10 2.5.4 Monte Carlo comparison... 11 2.5.5 Other studies of Eclipse... 11 2.6 Retrospective dose distribution... 11 2.7 Dose planning... 11 Results... 12 3.1 Validation measurements... 12 3.2 Studies of Eclipse accuracy in phantom geometry... 13 3.2.1 Absolute doses... 13 3.2.2 PDD... 14 3.2.3 Profiles and off-axis values... 16 3.2.4 Monte Carlo comparison... 18 3.2.5 Other studies of Eclipse... 19 3.3 Retrospective dose distribution... 19 3.4 Dose planning... 21 Discussion... 22 4.1 Measurements... 22 4.2 Eclipse accuracy... 22 4.3 Patient cases and dose planning... 23 4.4 Limitations... 23 Conclusion... 24 Acknowledgement... 24 References... 25 Appendix...

Background and Theory The knowledge about radiation and its applications in medicine has been used since Wilhelm Röntgen took an x-ray image of his wife s hand in 1895 by letting her hold the hand in front of a photographic plate and then irradiating it [1]. Applications have included both to diagnose and to treat patients. External radiotherapy treatment (RT) with photons is a sort of therapy with ionizing radiation, where high energy photons are used to irradiate malignant cells in order to kill them. The radiation is damaging the DNA in the cells either directly or indirectly by generating free radicals [2]. Almost fifty percent of patients diagnosed with cancer are being treated with external RT either to cure, reduce pain or to increase the survival time [3]. The treatment goal is to deliver the prescribed dose to the tumour target while sparing normal tissue and organs at risk (OAR). Therefore a patient specific treatment plan is designed. [4]. Total body irradiation (TBI) is a technique and a type of external RT, where the whole body is the target. Purposes of TBI are immunosuppression and/or to kill malignant cells. In 1990 Joseph E. Murray and E. Donnall Thomas received the Noble Prize in Physiology or Medicine for their research in organ and cell transplantations. One of their discoveries was that total body irradiation reduced the probability to reject the transplanted organ [5]. An early, unethical study on the effects of TBI was made in the 1960s by Defence Atomic Support Agency in the United States of America. The purpose of this study was to investigate the acute effects of radiation and the effects for their army troops [6]. Diseases, where TBI is a possible treatment method, include myeloma, leukaemia, Hodgins s lymphoma and immunodeficiency. TBI is widely used prior to bone marrow transplantation and stem cell transplantation. Bone marrow is soft tissue in bone cavities. Its functions are to produce blood cells and store fat. There are two types of bone marrows, red (blood-producing stem cells) and yellow (fat, bone and cartilage-producing cells). With increasing age, the red bone marrow is replaced with yellow fat tissue [7]. Stem cells in the bone marrow and other blood production sites in the body, divide themselves into one of the three types of blood cells in the body, leukocytes, erythrocytes and thrombocytes [8]. Cancers that originate from the bone marrow are for example myeloma, lymphoma and leukaemia [7]. In many of the above-mentioned cancer types, stem cell transplantation can be an optional treatment. Alternatively, bone marrow transplantation can be used, depending on where the cells are taken from. Stem cells can be taken either from the patient or from a donor. Before receiving the transplanted cells, the patient must undergo a pre-treatment. This can be done either by chemotherapy and/or by irradiation. The purpose of the pre-treatment is immunosuppression and sometimes to kill the malignant cells, which is called conditioning in medicine [9]. Graft-versus-host disease (GVHD) can be a severe complication to bone marrow transplantation and other types of transplantations. The cause of GVHD is immuno-cells of the transplanted organ which attack cells in the body they have been transplanted to [10]. TBI may be combined with chemotherapy. Studies have shown that this combination is more efficient than each of them separately, for instance, in treatment for leukaemia. One advantage of TBI compared to chemotherapy is that it affects the central nervous system where the chemotherapy is ineffective [11, 12]. 1

Although advantageous, there are risks and complications with the TBI treatment. Acute effects include nausea, skin irritation and interstitial pneumonitis (IP). Long-term effects may be cataract and thyroid complications [13]. Long-term complications can appear some months after treatment up to several years later, depending on dose, other medication and the type of complication. For example, secondary cancer has a latency period of many years [14]. Complications related to the lungs are mainly IP and increases in risk if GVHD occurs. Cataract is common but can be reduced with fractionated treatment [13]. Both in men and women, TBI has been shown to affect the gonad function. Most common is total or partial gonad failure but in a few cases, the gonads are not affected at all [15]. To reduce the risk of acute effects, such as IP, the dose rate is usually low and commonly under 10 cgy/min. The treatment is fractionated to increase the total dose and reduce the risk of complications. Total doses are usually in the range of 8 and 12 Gy [16]. According to Swedish studies from 2003, there are about sixty people each year in Sweden treated with TBI [17]. 1.1 Techniques of performing total body irradiation There are numerous methods that can be used for TBI. Early techniques for TBI included a sweeping field or multiple radiation sources. For example, Co-60 or Cs-137 was placed around the patient, to create a homogenous dose distribution. Standing position with irradiation posterior and then anterior (AP/PA technique) or lateral irradiation from both sides (standing, sitting or lying) with extended source-to-skin distance (SSD) has for a long time been the most common ways to perform TBI. Energies can be in the range of 0.6 MV to 25 MV depending on photon source and treatment setup [16]. Figure 1 is presenting many of the early and traditional setups of performing TBI or half body irradiation. a. b. c. d. e. f. Figure 1. Some possible ways to deliver TBI. Redrawn from [16]. a. Four sources. b. Two horizontal beams. c. Two vertical beams. d. Source scans horizontally. e. Half body, direct and oblique fields. f. Direct horizontal, long SSD. 2

In the standing AP/PA position, lung blocks as compensators, are commonly used to shield the lungs. Usually, an immobilization stance is used to support the patient and to guarantee the same position every treatment. In the lateral technique, the patient can either lay on the back with the arms used as lung shields, or on the side. Otherwise, lung blocks can be used [16]. A schematic picture of TBI with linear accelerator and standing position is presented in Figure 2. To create a long SSD the gantry is tilted down, or the couch is removed, and the patient is placed on the floor. With an extended SSD the total body are being covered with one static field. If the energy is above 1,25 MeV, a screen is used in front of the patient as an electron generator to increase the superficial dose [16]. A common treatment method to achieve a more uniform dose distribution is the field-infield technique. This has also been suggested for TBI to create a more uniform dose to the whole body [18]. Figure 2. Schematic picture of TBI with standing technique at extended SSD. As the techniques for external RT evolves, so does the range of TBI techniques. Intensitymodulated radiotherapy and volumetric arc therapy have the benefits of giving a conform dose to the target volume and reduce the dose to surrounding tissues and are alternatives for TBI in some cases. One technique with rotating and modulated delivery is helical tomographic RT, where a linear accelerator mounted on a helical computed tomography (CT)-gantry is used. The patient is lying on a moving couch that travels along the machine. The field of view in helical tomographic RT is less than the volume to cover with TBI. Therefore, adjacent fields are used and this needs to be done with high precision [19]. One main concern about the use of techniques where fields are not covering the whole patient at the same time, i.e. intensity modulated, spliced or sweeping fields, are circulating cells. This means that cells may escape from the irradiation and are therefore at risk of not receiving the prescribed dose [16]. Many of these new techniques may be used to specifically deliver the dose to the bone marrow and/or to the lymphatic system, such as total marrow irradiation (TMI), total lymphatic irradiation or total marrow and lymphatic irradiation. The main advantage with these new techniques is the ability to reduce the dose to OAR, such as lungs and eyes. TMI may be an alternative method prior to bone marrow transplantation in the cases where modulated RT is available for TBI [19]. All modalities are not clinically relevant to all types of TBI since they serve different purposes and require different apertures and knowledge. 3

1.2 Treatment planning and evaluation Treatment planning and dose calculation, i.e. defining fields and calculating monitor units (MU) for a particular dose distribution can be performed in different ways. In general, a plan is generated, and the corresponding dose distributions are calculated in a treatment planning system (TPS). One of the ways of determining the quality of the treatment plan is calculating the dose homogeneity. Accepted values of dose variations in the target region for external radiotherapy, are 5 % to +7 % of the prescribed dose [4]. In TBI, the recommended dose homogeneity in the body can be up to ±10 % [4, 20]. Evaluation of the treatment plan can be done by using a dose-volume-histogram (DVH). Dose distribution both to OAR and target can be evaluated [21]. A TPS is usually configured to reproduce the accelerator beam at isocentre distances (up to 130 cm from the accelerator target). The ability to perform dose calculations in TPS Eclipse (Varian Medical System, Inc. Palo Alto) with extended SSD has recently become available. A study by Lamichhane et al. on the use of Eclipse calculations for SSD longer than 3 m indicated that the dose distribution agreed well compared to measured values. However, they did not recommend Eclipse for absolute dose or MU calculations [20]. Studies of TPS based planning and field-in-field for TBI or TMI have shown better dose homogeneity and reduced dose to OAR [18, 22]. The accuracy of dose calculations at long treatment distance needs to be further studied. 1.3 Aims The ultimate goal is to improve dose determination and dose homogeneity for TBI at Sahlgrenska University hospital (SU). The aims of this study were experimental and theoretical validation of the accuracy of the Eclipse TPS in phantom and patient geometries for TBI geometry. Furthermore, to investigate the possibilities to improve the current TBI technique. Methods and Material 2.1 The current TBI method in Gothenburg The current TBI method used at SU in Gothenburg, is the lateral technique with two lateral 15 MV fields applied to a patient lying on a couch designed for TBI geometry at extended SSD. Before treatment, a planning CT is performed with 8 mm resolution. The dose is prescribed to a reference point defined in the centre of the patient, at the widest point of the hips. The patient width is calculated from the planning CT. Water tanks are placed above the head and under the feet to compensate for the loss of scattering which would occur otherwise, as displayed in Figure 3.a and b. Water tanks are also placed on the sides of the head, and in between the legs, to create a rectangular shape around the body, with the tissue equivalent density. The size of the rectangle is matched with the width that corresponds to the reference point. A bolus may be used to compensate for the different widths around the patient, for instance around the throat, to produce a more uniform dose. Styrofoam, with the thickness measured from the couch to the bottom of the lung, shown in Figure 4.a, is placed under the shoulders, to prevent the shoulders and upper arms from shielding the spinal cord. The arms are kept together on the stomach to shield the lungs and reduce the lung dose. Since the dose maximum is reached a few centimetres inside of the skin a plexiglass screen with a thickness of 1.6 cm is used in 4

front of the patient, placed in a fix holder at the long axis of the couch, to generate electrons and improve the superficial dose. The distance from the source to the centre of the patient, source-axis distance (SAD), is 480 cm, represented by the laser in Figure 3.b. The gantry is rotated towards the patient and the collimator head is rotated to produce the largest possible field diagonally with the jaws at 38 38 cm 2. Multi-leaf collimators (MLCs) and blocks of lead are used to form a maximum field size, seen in Figure 4.b, which is 15 43 cm 2 at isocentre, at extended SSD the field is covering the total patient. All patients are treated with the same field size and 15 MV photons. The number of MU per field for the treatment is calculated using the equation MU = K td 2 100 PDD pm SSD corr (Equation 1) where K is the number of monitor units (MU) required to deliver 1 Gy at 10 cm depth, td is the dose prescribed for one fraction, PDD pm is the percentage depth dose curve measured behind the plexiglass normalized at 10 cm depth, and SSD corr is the correction factor for SSD, dependent on the patients width compared to the reference of 40 cm. The number of MU that is calculated correlates to the deposited dose to water, not dose to tissue or media. a. b. Figure 3. Patient positioning during TBI and with the lasers shown in red. a. The green part represents the Styrofoam. b. The positioning compared to the laser through the patient centre, also called SAD. The figures are from SU and have been approved for use in this publication. A Monte Carlo (MC) simulation is performed with the number of MU and the planning CT, to visualize the dose distribution and dose homogeneity. If the simulation indicates dose inhomogeneities, these are reduced before treatment with additional water equivalent material. Lasers customized for treatment at extended SSD are used to position the centre of the patient at SAD, going through the nose and umbilical plane. An additional laser is used for the reference point to verify the position in craniocaudal-direction. Lasers and patient positioning are shown in Figure 3.a and b. The dose rate is set to 300 MU per minute on the machine, which corresponds to a dose rate of 11 cgy/min at 10 cm depth in the patient. The extended SSD reduces the dose rate, due to the inverse square law, and enlarges the field size. The most common fractionation scheme is 2.75 Gy per fraction, one fraction per day and four fractions in total. 5

An in-vivo dosimetry system is used to monitor the delivered dose to the patient each fraction. In Gothenburg, diodes are used, and their places are shown in Figure 5. These points are the reference point, at the neck and auditory canal. The above-described method is used at a Varian TrueBeam (TB) linear accelerator (Varian Medical Systems Inc). At SU there is also a possibility to use a Varian Clinac ix linear accelerator (Varian Medical Systems Inc) with SSD = 350 cm, SAD = 365 cm, reference width 30 cm and dose rate 19 cgy/min at 10 cm depth. When using a shorter SSD the field becomes shorter and the technique, in that case, is limited to shorter patients. a b Figure 4. a. The thickness required of the Styrofoam is shown with the red line [23]. b. The clinically used field. The collimator is rotated to create the longest possible field. The MLCs are shown in green and blocks in the darker shade of grey. The figures are from SU and have been approved for use in this publication. Figure 5. The red lines are showing the left and right position of the diodes during the first treatment fraction. The lowest line is in this case also used as the reference plane. The figure is from SU and has been approved for use in this publication. 2.2 Dose calculations in Eclipse In Eclipse, different calculation algorithms may be used to determine the dose. The Analytic Anisotropic Algorithm (AAA) is a convolution/superposition method that is currently used for clinical calculations at SU. The patient is represented as water with different densities and the 6

calculated dose is given as dose to water. Beam characteristics consist of analytical sources with parameters fitted to Monte Carlo simulations and measurements for a specific machine. Contributions from primary photons, extra-focal photons, electron contamination and scattered photons are calculated separately [24]. Optional in Eclipse is also Acuros XB as a calculation algorithm, which uses a model-based algorithm that analytically solves the linear Boltzmann transport equation. It takes into account the tissue composition and calculates doses to media and water [25]. Acuros XB has superior accuracy compared to AAA in heterogeneous geometries, such as lungs [26]. For calculations and comparisons, it is important to understand how the grid size in the calculation matrix is defined by the different algorithms. The AAA uses a grid that is divergent perpendicular to the beam axis. The grid size is specified at SAD = 100 cm. Therefore, the grid size at an extended SSD will be expanded perpendicular to the beam axis and will remain constant in beam direction. The grid size chosen in Acuros XB is the size that will be calculated in the volume and does not diverge [24]. 2.3 Previous measurements and Monte Carlo calculation Measured data obtained previously during TBI commissioning at SU have been used in the current work. The data include a calibration factor (number of MU for 1 Gy at 10 cm depth along beam axis), depth dose distributions along the beam axis as well as off-axis doses. All values were obtained behind plexiglass with the 15 MV clinical field. From these measurements, the factors; K, PDD pm and SSD corr in Equation 1 were determined. The phantom for these measurements was a water-filled phantom of size 20 20 20 cm 3 used with additional water cans placed on the sides of the phantom. For TrueBeam at SSD 460 cm, an electrometer from Janus Engineering (Sindelfingen, Germany) together with PTW-Freiburg Semiflex ionization chambers TB31010, and ionization chamber NE2571 (Phoenix Dosimetry Ltd, Sandhurst, United Kingdom) were used. At the Clinac ix, electrometer from Janus Engineering, ionization chamber NE2571 and SSD 350 cm were used. Dose distributions obtained earlier by the Monte Carlo method were used to evaluate the accuracy of the dose distribution in patient geometry. The MC simulations were based on the BEAMnrc/DOSXYZnrc code package. MC accelerator model was validated for 15 MV Clinac ix at extended treatment distance for the clinical field. The patient was represented by nine tissues. The dose distribution was given in term of dose-to-medium and was imported in Eclipse [27]. 2.4 Validation measurements The measurements were performed with a solid water phantom of size 24 30 30 cm 3 at both Varian Clinac ix linear accelerator and Varian TrueBeam (TB). For the ix machine, an initial measurement in the reference geometry with 120 MU at SSD 90 cm, field-size 10x10 cm 2 and 300 MU/min, was performed to receive a value from the electrometer that correlated to the reference calibration setup 1 Gy at 10 cm depth, with gantry and collimator rotation 0. Correction for daily output was performed based on dosimetry measurements that were performed two weeks before and after this study. The rest of the measurements were performed at SSD 350 cm, SAD = 365 cm, with the plexiglass placed 10 cm in front of the phantom, 900 MU and same dose rate as before. All values were collected 10 cm in the phantom. The setup is presented in Figure 6. 7

The clinically used field with MLCs and blocks was measured. Three fields formed by the jaws with sizes 15 40; 5.5 40 and 2.7 40 cm 2 at isocentre, were measured. The first field had the same size as the clinical field but was created by jaws. The latter two fields correspond to field-sizes of 20 cm and 10 cm at SAD = 365 cm in the anterior-posterior (AP) direction, schematically presented in Figure 7. MLC fields with sizes 2.7 40; 2.7 10 and 2.7 19 cm 2, were also investigated. These fields corresponded to field-lengths 36.5 cm and 69 cm at SAD in craniocaudal direction and 10 cm in AP direction, as in Figure 8. Off-axis values were studied with the jaw field size 15 40 cm 2, by moving the phantom 5, 10 and 15 cm in the gantry-target direction. Figure 6. Placement of the phantom and ionization chamber at the TBI setup. The green laser indicates the SAD length. Figure 7. Schematic picture of the fields that were 20 cm and 10 cm high in SAD. Note the direction of the field compared to the gantry and patient placement. Figure 8. Schematic picture of the fields that were 10 cm high in SAD and with varying length in the craniocaudal direction. Note the direction of the field compared to the gantry and patient placement 8

The detector was a Farmer ionization chamber (PTW Freiburg) and used without build-up material. For read-out, an electrometer (Fluke Biomedical, Advanced Therapy Dosimeter) was used. Measurements were also performed at TB but with SSD = 460 cm and SAD = 480 cm. To correlate the electrometer readout for these measurements to the dose, an initial measurement was performed with the gantry rotated 270 and dose rate 300 MU/min, collected at SSD = 90 cm. Jaw shaped fields were 15 40; 4.2 40 and 2 40 cm 2. In similarity to measurements at the ix machine the latter two fields are corresponding to 20 cm and 10 cm high fields in AP direction, at SAD. MLC shaped fields were 2 40; 2 14.3; 2 10 and 2 5 cm 2. Their lengths in craniocaudal direction were 69 cm, 48 cm, and 24 respectively at SAD. Also measured at TB was a field 9.6 cm high and 24 cm long at SAD. The off-axis measurements for TrueBeam were performed at 5, 10, 15, 20, 30 and 40 cm. Water cans were placed on both sides of the phantom, with the size 22 cm high, 12 cm wide and 18 cm deep. The setup is presented in Figure 9. The equipment used at the TrueBeam was a Farmer ionization chamber (PTW Freiburg) and electrometer E5 (Newport). The analysis was performed by comparing the mean of the collected values (nc) for each field relative to each geometry and settings in Eclipse with AAA, version 13.6.23 (Varian Medical System, Inc. Palo Alto) and with a grid size of 0.25 cm. When the off-axis at SSD = 460 cm was studied, an additional phantom was created with the additional scattering material included. To correlate the measured values to the dose, the daily output was measured at the TB right before the study. Figure 9. Measurement setup when measuring off-axis values at SSD 460 cm. 2.5 Studies of Eclipse accuracy in phantom geometry Phantoms were created with a CT value of -7 HU (defined as water) together with an additional plexiglass wall with a CT value of 330 HU in Eclipse TPS version 13.6.23. The plexiglass was defined as support material and placed 10 cm in front of the phantom or, as close to 10 cm as possible. Figure 10 demonstrates the representation of the coordinates x, y and z. 9

Figure 10. Definition of the parameters used when the phantoms were created. Two different machine set-ups were used: Varian TB linear accelerator and Varian Clinac ix linear accelerator. Their calibration factors were 2703 MU/Gy for TB with SSD 460 cm and 1545 MU/Gy for Clinac ix with SSD 350 cm commissioned with the clinically used field. The clinical field and its settings at SU were used for all phantom sizes at both machines, including SSD, dose rate and MU for 1 Gy at 10 cm depth according to Equation 1. The algorithm used was AAA (grid size of 0.25 cm), the doses at 10 cm depth were also calculated with Acuros XB (grid size 0.3 cm), dose to media. All calculations ran with heterogeneity corrections on. The analysis was performed in Excel 2013 (Microsoft Office). 2.5.1 Absolute doses For the study of absolute doses phantoms of sizes 20 20 20; 30 30 30; 40 40 40 and 40 40 150 cm 3 were created. Doses were collected at 10 cm depth in the central beam axis for the above-mentioned phantoms, for both SSDs with the clinical settings. Doses without plexiglass were calculated. To determine the impact of the distance between the source and the phantom, the phantoms were calculated with SAD = 365 cm and SAD = 480 cm. Doses were collected at 10 cm depth. A more precise impact of the dose due to phantom sizes was studied by creating additional phantoms with the sizes 20 30 30; 24 30 30; 20 40 40 and 30 40 40 cm 3. Their doses were calculated for the two SSDs with AAA grid size of 0.25 cm. 2.5.2 PDD The PDDs were obtained along the beam axis for the phantoms. The values were normalized at 10 cm depth. Values for the PDDs at six different depths (0.5 cm; 2 cm; 5 cm; 10 cm; 15 cm and 20 cm) were also collected in the phantoms. 2.5.3 Profiles and off-axis values Off-axis values were collected in a phantom of size 20 20 40 cm 3 with the same CT values as before and with plexiglass, by moving the phantom 10; 20; 30 and 40 cm laterally (plus 60 cm at SSD = 460 cm) and compared with previous measurements. All values were normalized at the phantom centre for the comparisons. Profiles were collected at the different SSDs and phantoms. A more detailed study of the profiles was performed since the profiles appeared to behave in an unexpected way. The phantom of size 40 40 150 cm 3 at the TB machine, with different SSDs of 250 cm, 275 cm, 350 cm, 460 cm and 500 cm was used. All profiles were normalized to the centre of the phantom and calculated with AAA and a grid size of 0.25 cm. The profile at SSD = 460 cm was also 10

calculated with AAA, of 0.1 cm grid size and studied with fields determined by jaws and blocks separately. A profile with Acuros XB and a grid size of 0.3 cm was collected for the phantom size 40 40 40 cm 3. This was the largest phantom that could be calculated with Acuros XB and for comparison, that field was also calculated with AAA with grid sizes of 0.1 cm and 0.25 cm. 2.5.4 Monte Carlo comparison The PDD curve and profile at SSD = 460 cm was also compared with a previous MCsimulation with a phantom of size 46 21 150 cm 3. The MC-simulation was performed with the purpose to validate MC as a method for TBI compared with commissioning data. Therefore, the plexiglass was taken into account in the phase space. This phantom was also created in Eclipse and simulated with the ix machine. The profile of the phantom was studied at 10 cm depth. The profile from Monte Carlo simulations was generated by dividing the phantom into two equally sized sections and taking the mean values of each section. The profile was normalized at the phantom centre. Differences in the fluctuations were investigated by calculating the deviation of the dose and the fluctuation in each point. Fields in Eclipse were created by blocks to make the situation most similar to the Monte Carlo created beam configuration. For comparison, a profile from a field shaped by jaws with the same field size as the clinical field was studied. 2.5.5 Other studies of Eclipse The transmission at extended SSD was studied in Eclipse by closing all MLC leaves in one bank, outside the field, then closing them in the other bank. The mean dose from both these calculations was divided with the dose from an open field of size 10 10 cm 2. The phantom was 20 20 20 cm 3. Doses with different distances between the plexiglass and the phantom were also calculated. These plexiglass to phantom distances were 2 cm, 4 cm, 10 cm and 15 cm. The phantom of size 20x20x20 cm 3 and the clinical field was used. 2.6 Retrospective dose distribution Dose distributions calculated with AAA, were used for retrospective dose distribution of nine patients who already had undergone TBI at SU. Their treatment plans were also simulated by the MC technique described earlier. These patients were of different age, gender and body shape. The ix machine was the most similar to the MC-code, therefore these were compared. The AAA with a grid size of 0.25 cm and an automatic segmentation method for defining the lungs was used. The DVH parameters studied were Dmean (mean dose to the patient), Dmax (maximum dose to the patient), and V95% for the total body (the volume of the body that receives 95 % of the prescribed dose). For the lungs, Dmean and Dmax were evaluated. A visual comparison of the dose distribution of different anatomical locations in the body was performed. 2.7 Dose planning Minor investigations of individual treatment planning for patients who have been treated with TBI at SU were performed. The goal was to find a method with a dose homogeneity within ±10 %. The treatment planning was performed in Eclipse and results from this study were considered. Therefore, additional plans with fields defined only by jaws and fields defined by 11

MLCs were used. The evaluation was performed by studying the dose distribution within ±10 %. Results 3.1 Validation measurements Measurements with the currently used treatment setup and with different field-sizes are shown in Table 1 and Table 2. The measured values are corrected for dose output which was 1.001 on the ix machine and 1.008 on the TB. The mean difference between calculated and measured doses were 1.8 % higher at SSD = 350 cm, and 2.0 % higher at SSD = 460 cm, if the fields were created by jaws. The mean difference for fields created by MLCs at SSD = 350 cm was 3.0 % and at SSD = 460 cm 4.4 %. Table 1. Doses from Eclipse and measurements for s.w phantom of size 24 30 30 cm, 3 SSD = 460 cm, TrueBeam, and 900 MU. The doses were collected at 10 cm depth at the central axis. Field size Dose with AAA (Gy) Measured (Gy) 15 43 cm 2 - blocks and MLC 0.355 0.3475 2.1 15 40 cm 2 - jaws 0.359 0.3544 1.3 4.2 40 cm 2 - jaws 0.34 0.3303 2.9 2 40 cm 2 - jaws 0.318 0.3127 1.7 2 40 cm 2 - MLC 0.335 0.3202 4.6 2 14.3 cm 2 - MLC 0.334 0.3200 4.4 2 10 cm 2 - MLC 0.333 0.3194 4.2 2 5 cm 2 - MLC 0.331 0.3168 4.5 Difference (%) Table 2. Doses from Eclipse and measurements for s.w phantom of size 24 30 30 cm 3, SSD = 350 cm, Clinac ix, and 900 MU. The doses were collected at 10 cm depth at the central axis. Field size Dose with AAA (Gy) Measured (Gy) 15 43 cm 2 - blocks and MLC 0.597 0.5834 2.3 15 40 cm 2 - jaws 0.604 0.5988 0.9 5.5 40 cm 2 - jaws 0.587 0.5738 2.3 2.7 40 cm 2 - jaws 0.558 0.5456 2.3 2.7 40 cm 2 - MLC 0.575 0.5573 3.2 2.7 19 cm 2 - MLC 0.572 0.5550 3.1 2.7 10 cm 2 - MLC 0.572 0.5562 2.9 Difference (%) Values off-axis for SSD = 460 cm are presented in Figure 11, where extra scattering material was added on the sides of the phantom, both when measured and evaluated in Eclipse. Off-axis measurements for SSD = 350 were performed without adding extra scattering material and are shown in Figure 12. 12

Relative dose compared to the centre Relative dose compared to the centre Off-axis at SSD = 460 cm Measured Eclipse 109 107 105 103 101 99 0 5 10 15 20 25 30 35 40 45 50 Distance off-axis [cm] Figure 11. Off-axis values measured with TrueBeam at SSD = 460 cm and calculated values in Eclipse for the same distances. Doses were collected at 10 cm depth and normalized at central beam axis. Off-axis at SSD = 350 cm Eclipse Measured 104 103 102 101 100 0 2 4 6 8 10 12 14 Distance off-axis [cm] Figure 12. Off-axis values measured with Clinac ix at SSD = 350 cm and calculated values in Eclipse for the same distances. Doses were collected at 10 cm depth and normalized at central beam axis. 3.2 Studies of Eclipse accuracy in phantom geometry 3.2.1 Absolute doses Doses calculated in Eclipse for different phantoms at SSD = 460 cm are presented in Table 3. For SSD = 350 cm the doses are presented in Table 4. The doses were collected at 10 cm depth and the number of MU that was used is for 1 Gy at 10 cm depth. Doses were also calculated with Acuros XB if possible. The dose to water gave the same results as the calculated dose to media. The tables are also presenting the impact of using plexiglass in front of the phantom. 13

Phantom Table 3. Doses at SSD = 460 cm, calculated by Eclipse with AAA and Acuros XB dose to medium, 2703 MU. Dose with AAA (grid size 0.25 cm) Dose with Acuros XB (grid size 0.3 cm) Dose with AAA (grid size 0.25 cm) without plexiglass Difference in dose between plexiglass compared to without plexiglass 40 40 150 cm 3 1.085 Gy - 1.128 Gy - 4.0 % 40 40 40 cm 3 1.078 Gy 1.065 Gy 1.119 Gy - 3.8 % 30 30 30 cm 3 1.066 Gy 1.059 Gy 1.108 Gy - 3.9 % 20 20 20 cm 3 1.043 Gy 1.040 Gy 1.090 Gy - 4.5 % 20 40 40 cm 3 1.077 Gy 1. 069 Gy 1.120 Gy - 4.0 % 30 40 40 cm 3 1.077 Gy 1.071 Gy 1.121 Gy - 4.1 % 20 30 30 cm 3 1.064 Gy 1.054 Gy 1.109 Gy - 4.2 % Phantom Table 4. Doses at SSD = 350 cm, calculated by Eclipse with AAA and Acuros XB dose to medium, 1545 MU. Dose with AAA (grid size 0.25 cm) with plexiglass Dose with Acuros XB (grid size 0.3 cm) with plexiglass Dose with AAA (grid size 0.25 cm) without plexiglass Difference in dose between plexiglass compared to without plexiglass 40 40 150 cm 3 1.044 Gy - 1.085 Gy - 3.9 % 40 40 40 cm 3 1.037 Gy - 1.076 Gy - 3.8 % 30 30 30 cm 3 1.025 Gy 1.015 Gy 1.066 Gy - 4.0 % 20 20 20 cm 3 1.001 Gy 0.998 Gy 1.045 Gy - 4.5 % 20 40 40 cm 3 1.035 Gy 1.022 Gy 1.076 Gy - 4.0 % 30 40 40 cm 3 1.036 Gy 1.028 Gy 1.077 Gy - 4.0 % 20 30 30 cm 3 1.022 Gy 1.010 Gy 1.066 Gy - 4.3 % Calculated doses with fixed SADs are presented in Table 5. All phantoms were calculated with plexiglass and AAA with grid size of 0.25 cm and the number of MU for 1 Gy in the reference geometry. Table 5. Doses at 10 cm in the phantom calculated with Eclipse AAA, for the two SADs used a SU. Phantom SAD = 365 cm. Dose at 10 cm depth. SAD = 480 cm. Dose at 10 cm depth. 40 40 150 cm 3 1.073 Gy 1.085 Gy 40 40 40 cm 3 1.066 Gy 1.078 Gy 30 30 30 cm 3 1.025 Gy 1.046 Gy 20 20 20 cm 3 0.974 Gy 1.002 Gy 3.2.2 PDD PDD curves for SSD = 460 cm and SSD = 350 cm are presented in Figure 13 and Figure 14, normalized at 10 cm depth, both with and without plexiglass in front. In these figures, the 14

Relative dose distribution [%] Relative dose distribution [%] phantom of size 40 40 150 cm is used. The PDD for all other phantom sizes can be studied in Appendix A. The PDDs are collected with Eclipse, AAA with a grid size of 0.25 cm and compared with previous measurements. Values for PDD were also collected at six points in the phantoms with normalization at 10 cm shown in Table 6 and Table 7. 120 100 80 60 40 20 PDD normalized at 10 cm. SSD = 460 cm 0 0 5 10 15 20 25 30 35 40 Depth in the phantom [cm] With plexiglass Without plexiglass Measured Figure 13. PDD for the phantom with size 40 40 150 cm 3. Both with and without plexiglass and measured data with plexiglass. PDD normalized at 10 cm. SSD = 350 cm Measured With Plexiglas Without Plexiglas 120 100 80 60 40 20 0 0 5 10 15 20 25 30 35 40 Depth in the phatnom [cm] Figure 14. PDD for the phantom with size 40 40 150 cm 3. Both with and without plexiglass and measured data with plexiglass. 15

Relative dose off axis Table 6. Comparison of PDD values at six depths in the phantoms in Eclipse with measured values at SSD = 460 cm. PDD comparison, normalized at 10 cm [%]. SSD = 460 cm. Phantoms in Eclipse 0.5 cm 2 cm 5 cm 10 cm 15 cm 20 cm 20 20 20 122.21 121.57 113.75 100 86.66 30 30 30 119.13 120.10 113.10 100 87.74 76.33 40 40 40 118.13 119.30 112.60 100 87.98 76.90 40 40 150 118.37 118.73 112.18 100 88.35 77.50 Measured values 117.66 118.9 111.32 100 86.83 75.45 Table 7.Comparison of PDD values at six depths in the phantoms in Eclipse with measured values at SSD = 350 cm. PDD comparison, normalized at 10 cm depth [%]. SSD = 350cm. Phantoms in Eclipse 0.5 cm 2 cm 5 cm 10 cm 15 cm 20 cm 20 20 20 cm 3 123.07 122.63 114.38 100 86.26 46.71 30 30 30 cm 3 119.90 121.00 113.59 100 87.26 75.50 40 40 40 cm 3 118.91 120.30 112.12 100 87.61 76.22 40 40 150 cm 3 118.81 119.54 112.70 100 87.96 76.78 Measured values 118.50 120.50 113.60 100 88.10 76.40 3.2.3 Profiles and off-axis values Off-axis values for each of the two used SSDs compared with commissioning data is presented in Figure 15 and Figure 16. All values were normalized to 100 % at off-axis value = 0 cm. Off-axis at SSD = 460 cm Measured Eclipse 106 105 104 103 102 101 100 0 10 20 30 40 50 60 70 Distance off-axis [cm] Figure 15. Off-axis values for TB with SSD 460 cm compared with previous measurements. 16

Relative dose off axis Relative dose off axis Off axis at SSD = 350 cm Measured Eclipse 106 105 104 103 102 101 100 0 5 10 15 20 25 30 35 40 Distance off-axis [cm] Figure 16. Off-axis values for Clinac ix with SSD = 350 cm compared with previous measurements. Profiles for different SSDs are presented in Figure 17 with phantom 40 40 150 cm 3. All profiles are normalized at the centre of the phantom, beam axis at 75 cm and produced with 2703 MU, Eclipse AAA with the grid size of 0.25 cm. For SSD = 460 cm, the largest dose difference due to the amplitude was 3.8 % and with SSD = 350 cm around 1 %. Profiles with different field configurations are presented in Figure 18. If the grid size = 0.1 cm was used, the dose variation was 4.5 %. The dose variation if only jaws were used was 2.5 %. If only blocks were used to create the field the amplitude was 4.3 %. Profiles collected from Eclipse with the same phantom size are also presented, collected at 10 cm depth, with fields defined only by jaws and by blocks together with MLCs. The influence of different algorithms is shown in Figure 19, with both Acuros XB and AAA for the phantom of size 40 40 40 cm 3. Profiles for different SSDs SSD= 250 cm SSD= 350 cm SSD= 460 cm SSD= 500 cm 1.09 1.07 1.05 1.03 1.01 0.99 0.97 0.95 0 20 40 60 80 100 120 140 Off axis distance [cm] Figure 17. Profiles collected with different SSDs for TB. All values are normalized to the centre of the phantom. Beam axis at 75 cm. 17

Relatie dose compared to the centre of the phatnom Profiles with different field definitions SSD= 460 cm, grid size 0.1 cm SSD= 460 cm, jaws only SSD=460 cm, ordinary field SSD=460 cm, block only 1.09 1.07 1.05 1.03 1.01 0.99 0.97 0.95 0 20 40 60 80 100 120 140 Off axis distance[cm] Figure 18. Profiles collected with different field definitions for TB. All values are normalized to the centre of the phantom. Beam axis at 75 cm. Profile with different calculation algorithms at SSD = 460 cm Relative dose of the prescribed [%] AAA- grid 0.25 cm AAA- grid 0.1 cm Acuros XB- grid 0.3 cm 112 110 108 106 104 102 100 0 5 10 15 20 25 30 35 40 Off axis distance [cm] Figure 19. Profiles with different calculation models in Eclipse. Beam axis at 20 cm. 3.2.4 Monte Carlo comparison For SSD = 460 cm, the MC-simulated PDD is presented in Figure 20 and compared to PDD with Clinac ix. Calculations with Monte Carlo generated the profile presented in Figure 21. The statistical fluctuations of the Monte Carlo simulation were within ± 2 %. Geometrical symmetry was used to improve the statistical accuracy by taking mean values of the dose for the voxels on both sides of the beam axis. 18

Relative dose compared to the centre of the phantom Relative absorbed dose [%] PDD, Eclipse compared to Monte Carlo. Normalized at 10 cm. 120 Monte Carlo Eclipse 100 80 60 40 20 0 0 50 100 150 200 250 300 350 400 Depth in water or phantom [mm] Figure 20. PDD curves from Monte Carlo simulations and Eclipse at SSD = 460 cm Profiles from Monte Carlo simulations and Eclipse 1.09 Eclipse jaws Eclipse MLC and block Monte Carlo 1.07 1.05 1.03 1.01 0.99 0.97 0.95 0 20 40 60 80 100 120 140 Lenght of the phantom [cm] Figure 21. Profiles determined from Monte Carlo simulation and Eclipse with two different field definitions. Beam axis at 75 cm. 3.2.5 Other studies of Eclipse The MLC transmission in Eclipse for SSD = 460 cm was 1.66 % and the previously measured was 1.69 % (SSD = 90) at commissioning. For SSD = 350 cm the transmission in Eclipse was 1.42 % and measured at SSD = 90 cm 1.4 %. This means that even if calculations are performed at extended SSD, the transmission factor is constant. The distance between the plexiglass and the phantom did not influence the dose at 10 cm depth in Eclipse (presented in Appendix B). 3.3 Retrospective dose distribution Differences in dose distribution between Eclipse calculations and MC-simulations were visible in some anatomical locations but not in others. The most common region of agreement was the reference plane, as shown in Figure 22. Differences were noticeable in other locations, 19

for example, the lungs, stomach and shoulders, as shown in Figure 23. The dose distributions calculated by Eclipse and Monte Carlo are shown to the left and right respectively. In these figures green is representing good agreement with the prescribed dose. Figure 22. Dose distributions calculated by Eclipse (left) and Monte Carlo (right) for a child at the reference plane. The range of the colour scale is ± 15 % of the prescribed dose. Figure 23. Dose distributions calculated by Eclipse (left) and Monte Carlo (right) for a child in the stomach. The range of the colour scale is ± 15 % of the prescribed dose. The DVHs for each patient, are presented in Table 8. Values labelled 1 are collected for the whole body and values labelled 2 are for the lungs. The mean difference in the mean dose to the body between AAA and MC for all patients was 1.86 %, which is within the statistical fluctuations of MC. The mean difference in mean lung doses was 0.2 % lower with AAA than with MC. Maximum doses were in general higher with MC compared to Eclipse. The differences in V95% doses were between 1 % and 13 %. 20

Table 8. DVH parameters for the total body (1) and lungs (2) calculated with Eclipse and Monte Carlo simulations. Doses are presented in Gy. Patient D prescribed V 95% 1 AAA V 95% 1 MC D mean 1 AAA D mean 1 MC D max 1 AAA D max 1 MC D mean 2 AAA D mean 2 MC D max 2 AAA D max 2 MC Man 1 2.75 95% 92% 3.04 3.04 4.04 4.86 2.74 2.74 2.39 3.66 Man 2 2.75 92% 80% 2.91 2.79 3.87 4.19 2.87 2.82 3.33 3.41 Man 3 2.0 90% 93% 2.15 2.17 3.04 3.37 2.00 2.07 2.38 2.75 Woman 1 2.75 96% 91% 3.05 2.95 4.16 4.14 2.99 2.92 4.01 4.08 Woman 2 2.0 97% 96% 2.29 2.20 3.25 3.39 2.27 2.26 2.64 2.62 Child 1 2.75 92% 82% 2.94 2.91 3.76 4.18 2.93 2.92 3.38 3.71 Child 2 Child 3 Child 4 2.75 87% 77% 2.87 2.80 3.63 3.77 2.80 2.79 3.02 3.15 2.75 92% 87% 2.77 2.72 3.23 3.46 2.78 2.75 3.10 3.11 2.75 86% 87% 2.75 2.75 3.24 3.51 2.68 2.72 3.02 3.25 3.4 Dose planning For small size patients, homogeneous dose distributions were created with fields defined by jaws and MLC fields separately. For patients with wide shoulders or variations in width, it was more difficult to create homogeneous dose plans, especially if only jaws were used. The most apparent problem was to deliver the prescribed dose to the spine without receiving too high doses (more than 15 %) in the lungs or to the skin. Example of one additional field is shown in Figure 24. Figure 24. One example of an additional field, suitable for the field-in-field technique, that was studied in Eclipse. 21