OVERVIEW OF PROTON THERAPY

Since the discovery of the Xrays on November 8,1895,Radiotherapy has become one of the most important methods of cancer treatment.A few year later, Marie Curie and the discovery of Radium (in 1898) has opened up new horizons for radiotherapy and brought several new hopes for patients.

VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF PHYSICS NGUYEN THE BON OVERVIEW OF PROTON THERAPY Submitted in partial fulfillment of the requirements for the degree of Bachelor of Science in Physics (Advanced Program) Hanoi - 2017 VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF PHYSICS NGUYEN THE BON OVERVIEW OF PROTON THERAPY Submitted in partial fulfillment of the requirements for the degree of Bachelor of Science in Physics (Advanced Program) Supervisor: NGUYEN VAN HUNG, MSc Hanoi - 2017 ACKNOWLEDGEMENTS This work would not have been possible without the dedication and endeavour of all people who were involved in it, and the collaboration between institutions was determinant for accomplishing the initial goals I would like to express my deep gratitude to Master Nguyen Xuan Ku who showed me the road and helped to get me start on the path to this thesis and much more in the future Also, his enthusiasm and dedication were remarkable and an actual example to me I also would like to thank Master Nguyen Van Hung for the information shared and for the availability shown for collaborating with this work I truly thank the teachers at the Faculty of Physics - VNU University of Sciences in general, at the Department of Nuclear Physics in particular, who helped enthusiastically in the process of learning and researching I am thankful for all the companions in the team of Medical Physicists especially Nguyen Ngoc Chien for helping and contributing many valuable comments in the period of implementing the experimental subjects Finally, but no less important, special thanks to my family and friends, who stood by and motivated and dedicated to many good feelings to overcome all difficulties in my study duration Hanoi, June 2017 Students, Nguyen The Bon Nguyen The Bon – Overview of Proton Therapy LIST OF ABBREVIATION ASB Actively Scanned Beam BTS Beams Transport System CTV Clinical Target Volume CT Computed Tomography DRR Digitally Reconstruction Radiograph DVH Dose-Volume Histogram DNA Deoxyribo Nucleic Acid GTV Gross Target Volume ITV Internal Target Volume IMPT Intensity Modulate Proton Therapy IMRT Intensity Modulated Radiation Therapy LET Linear Energy Transfer NPTC Northeast Proton Therapy Center OAR Organ at Risk PSB Passively Scattered Beam PSI Paul Scherrer Institute PTV Planning Target Volume RBE Relative Biological Effectiveness RF Radio Frequency SOBP Spread-out Bragg Peak TPS Treatment Planning System Nguyen The Bon – Overview of Proton Therapy TABLE OF CONTENTS CHAPTER 1: RADIOTHERAPY IN TREATING CANCER PATIENTS 1.1 Introduction 1.2 Types Of Radiation Therapies 1.3 Biological Effects Of Radiation CHAPPER PROTON THERAPY .6 2.1 Proton Therapy History 2.2 Basic Physics Of Proton .7 2.2.1 Nature of the particle 2.2.2 Proton Interactions Mechanisms 2.2.3 Bragg peak 2.3 Biological Effectiveness 11 2.3.1 Relative Biological Effectiveness (RBE) 11 2.3.2 Secondary radiation 12 2.4 Equipment For Proton Therapy 12 2.4.1 Proton accelerators 12 2.4.2 Beam line 16 2.4.3 Gantry/ fixed beam .16 2.4.4 Beam delivery system 18 2.4.5 Patient positioning and immobilization issues, motion 23 Nguyen The Bon – Overview of Proton Therapy 2.5 Treatment Planning In Proton Therapy 24 2.5.1 Principles 24 2.5.2 Treatment beam parameters 25 CHAPTER PROTON THERAPY IN CLINICAL APPLICATION 27 3.1 Principles 27 3.2 The Clinical Cases Use Of Proton Therapy .28 3.2.1 Prostate cancer 28 3.2.2 Brain tumors 29 3.2.3 Head and neck cancers 30 3.2.4 Lung cancer .31 3.2.5 CNS tumors 31 CONCLUSION 32 REFERENCES 33 Nguyen The Bon – Overview of Proton Therapy LIST OF FIGURES Figure Cure rate for different cancer treatment strategies [6] .2 Figure Damage to DNA by direct and indirect mechanisms [10] Figure The first working cyclotron from 1929 with a diameter of inches producing 80 keV protons [17] Figure Schematic illustration of proton interaction mechanisms [11] Figure Central axis depth dose distribution for an unmodulated 250-MeV proton beam, showing a narrow Bragg peak [11] 10 Figure 6.Comparison of typical cell survival curves for low linear energy transfer X-rays and high LET radiation such as heavy charged particles [11] 11 Figure Plan view of the classical cyclotron accelerator [9] .13 Figure 8: Proton therapy cyclotron offered by Varian [11] 14 Figure 9: Schematic diagram illustrating the principle of proton acceleration in a synchrotron [11] .15 Figure 10 Floor plan of the Northeast Proton Therapy Center [20] 16 Figure 11 One of the gantries at the Northeast Proton Therapy Center [20] 17 Figure 12 The nozzle at the NPTC [20] 18 Figure 13 A final aperture and a patient-specific range compensator [20] 19 Figure 14 Three types of range modulation wheels [20] 20 Figure 15 The principle of passive beam spreading 20 Figure 16 The principle of beam scanning[20] .22 Figure 17 Proton therapy requires, like all highly conformal treatment modalities, a significant effort in patient setup and immobilization This figure shows the setup using orthogonal x-rays (one x-ray source is integrated into the nozzle) and flat panel detectors [20] 23 Nguyen The Bon – Overview of Proton Therapy Figure 18 Spread-out Bragg peak (SOBP) depth dose distribution [11] 26 Figure 19 Comparison of photon intensity-modulated radiation therapy (IMRT) plan (left) and proton therapy plan (right) [15] 27 Figure 20 Comparison of dose distribution for IMRT and IMPT (right) [21] 28 Figure 21 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] .29 Figure 22 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] .30 Figure 23 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] .31 Nguyen The Bon – Overview of Proton Therapy LIST OF TABLES Table Summary of proton interaction types, targets, ejectiles, influence on projectile, and selected dosimetric manifestrtions [19] .9 Table Accelerator technology comparisons for some parameters [20] 15 Nguyen The Bon – Overview of Proton Therapy INTRODUCTION Since the discovery of the X-rays on November 8, 1895, Radiotherapy has become one of the most important methods of cancer treatment A few years later, Marie Curie and the discovery of Radium (in 1898) has opened up new horizons for radiotherapy and brought several new hopes for patients Nowadays, in traditional radiotherapy X-rays are still used and it is also the most common type of radiation in a medical context The basic principle of radiotherapy is to use ionizing radiation (internal or/and external) to deposit energy in a tumor to kill the cancer cells The current cancer therapy methods mainly include surgery, chemotherapy, radiotherapy or a combination of these The techniques in radiotherapy have evolved during the century, all with the same goals, i.e to concentrate the dose to the target tissue and spare as much as possible of the healthy organs and tissues Despite the new advanced technologies in radiotherapy there is still need to improve radiation treatment methods In this thesis, I will introduce an emerging radiation treatment tool – proton therapy, which is call ―the state of the art‖ technique in radiation therapy Besides, this special technique have been presented to point out advantages as well as disadvantages so that we can make decision to use in clinical applications The contents of my thesis are represented in chapters as follows: Chapter 1: Radiotherapy in Treating Cancer Patients Chapter 2: Overview of Proton Therapy Chapter 3: Proton Therapy in Clinical Application Nguyen The Bon – Overview of Proton Therapy Figure 14 Three types of range modulation wheels [20] Figure 15 The principle of passive beam spreading 20 Nguyen The Bon – Overview of Proton Therapy 2.4.4.2 Scanning Because protons can be deflected magnetically, an alternative to the use of a broad beam is to generate a narrow mono-energetic ―pencil‖ beam and to scan it magnetically across the target volume Typically, the beam is scanned in a zigzag pattern in the x–y plane perpendicular to the beam direction This is in close analogy to how a conventional television works (in which, of course, an electron beam is scanned) The depth scan is done by means of energy variation The method requires neither a collimator nor a compensator In practice, it works as follows: one starts with the deepest layer (highest energy) and does one x–y scan The energy is then reduced, the next layer is painted, and so forth until all 20–30 layers have been delivered Due to density variations in the patient, the Bragg peaks of one layer are not generally in a plane Also, it is useful to keep in mind that the distal layers deliver various amounts of dose (depending on the curvature of the distal target surface) to the more proximal regions, such that each layer needs to be intensity modulated in order to generate a uniform target dose Each layer may be delivered multiple times to reduce delivery errors and uncertainties Various modes of particle scanning techniques have been devised, just like different modes of photon IMRT exist:  Discrete spot scanning: This is a step-and-shoot approach in which the predetermined dose is delivered to a given spot at a static Then the beam is switched off and the magnet settings are changed to target the next spot, dose is delivered to the next spot, and so forth (see Fig 16) This approach is practically implemented at PSI in Switzerland There the magnetic scan is performed in one direction only, and the position in the orthogonal direction is changed through a change of the table position Because the table motion is the slowest motion, it is the last and least often used: first the magnetic scan is performed to create one line of dose (along discrete steps), then the depth is varied by changing the energy, and another line of dose is ―drawn‖ at a more shallow depth This is repeated until dose is delivered at all relevant depths Finally, the table is moved to the next position, and the process is repeated  Raster scanning: This method, which is practically realized for heavy ions at the GSI in Darmstadt, Germany (Kraft 2000), is very similar to discrete spot 21 Nguyen The Bon – Overview of Proton Therapy scanning, but the beam is not switched off while it moves to the next position Practically, the dose distributions are equivalent for the two methods as long as the scan time from spot to spot is small compared with the treatment time per spot In general, this is not fulfilled if the scan is done with the treatment table  Dynamic spot scanning: Here the beam is scanned fully continuously across the target volume This method will be used at the NPTC Intensity (or rather, fluence) modulation can be achieved through a modulation of the output of the source, or the speed of the scan, or both The combination of the two reduces the required dynamic range of the source output but puts higher demands on the control system [20] Figure 16 The principle of beam scanning[20] One advantage of scanning is that arbitrary shapes of uniform high-dose regions can be achieved with a single beam With the broad-beam technique, on the other hand, the SOBP is constant across the treatment field and typically delivers some unnecessary amount of dose proximal to the target volume Another advantage of the scanning approach is that, due to the avoidance of first and second scatterers, the beam has less nuclear interactions outside the patient, and therefore the neutron contamination is smaller The biggest advantage might be the great flexibility, which can be fully utilized in intensity-modulated proton therapy (IMPT), as we explain below However, a disadvantage is the technical difficulty to generate very narrow pencil beams that result in an optimal lateral dose fall-off The scanning approach can also be more sensitive to organ motion than passive scattering Another variant of scanning is called ―wobbling.‖ Here a relatively broad 22 Nguyen The Bon – Overview of Proton Therapy beam (diameter of the order of cm) is magnetically scanned across the target volume Because this would result in a broad penumbra, collimators are still required The main advantage is that field sizes larger than those with passive scattering are easily achievable 2.4.5 Patient positioning and immobilization issues, motion Proton therapy is, like all highly target-conformal treatment modalities, susceptible to geographical misses Considerable effort is therefore necessary to position and immobilize the patient For example, at the NPTC orthogonal X-ray projections are used to detect both translational and rotational positioning errors and correct those errors using a six-axes table within mm or 0.5° (Fig 17) For the most part, positioning and immobilization issues are identical for proton therapy and, for example, IMRT However, there are a few issues that are specific to protons and other charged particles They have to with the simple fact that the range is affected by structures moving in and out of the beam For example, in prostate treatments the position of the Bragg peak may be significantly altered if parts of the pelvic bone move into the beam, which can happen if on one treatment day the pelvis is rotated compared with the planned position Similar problems can affect treatments in the skull (Fig 17) Figure 17 Proton therapy requires, like all highly conformal treatment modalities, a significant effort in patient setup and immobilization This figure shows the setup using orthogonal x-rays (one x-ray source is integrated into the nozzle) and flat panel detectors [20] 23 Nguyen The Bon – Overview of Proton Therapy Therefore, in particle therapy it is not only important to ensure that the target volume is always at the same position, but the surrounding structures and especially bony structures should also be at their planned position The detrimental effect of misalignments can be mitigated to some degree in treatment planning A common approach in passive scattering proton therapy is to "smear" (thin) the range compensator such that target coverage is ensured even if the position is slightly off However, this will push the dose into the normal tissues distal to the target volume and the smearing radius is therefore limited to about mm Bigger errors cannot be compensated with this method Besides alignment errors, proton (and charged particle) therapy is also uniquely affected by internal organ motion, especially in the case of lung tumors The dose distribution is deformed by the motion of the tumor in the low density lung tissue Unless methods such as gating are used to "freeze" the motion, this effect must be carefully considered at treatment planning stage This is doable but it is fair to say the proton treatments of lung tumors have not fully come of age yet [20] 2.5 TREATMENT PLANNING IN PROTON THERAPY 2.5.1 Principles Basic principles of radiotherapy treatment planning for protons are essentially the same as for photons and electrons These include:  Acquisition of three-dimensional imaging data set  Delineation of target volumes and organs at risk  Setting up of one or more beams  Selection of beam angles and energies  Design of field apertures  Optimization of treatment parameters  Display of isodose distributions and dose volume histograms (DVHs) and so on, depending on the complexity of a given case The planning system output for the selected plan includes the necessary treatment parameters to implement the plan (e.g., beam coordinates, angles, energies, patient setup parameters, isodose curves, DVHs, and digitally reconstructed radiographs) In the case of protons, additional data are provided for the construction of range compensators and other devices, depending on the type of accelerator and the beam delivery system 24 Nguyen The Bon – Overview of Proton Therapy Because of the very sharp dose drop-off at the end of the beam range and laterally at the field edges and uncertainties in the computed tomography–based waterequivalent depths, calculated beam ranges, patient setup, target localization, and target motion assume greater importance for protons than for photons So a major part of the treatment-planning process for protons consists of taking into account these uncertainties For example, dose distributions are often computed at both the upper and the lower end of these uncertainties Also, corrective techniques, such as ―smearing‖ the range compensator, may be used to counteract the effects of some of the uncertainties The smearing procedure consists of adjusting the compensator dimensions within the smearing distance, based on the geometric and target motion uncertainties, and thereby shifting its range profile to ensure target volume coverage during treatment (even at the expense of target volume conformality) The need and complexity of this procedure require that the proton beam treatment-planning systems must incorporate a smearing algorithm and provide details for the fabrication of the ―smeared‖ range compensator A combination of suitable margins around the clinical target volume (CTV) and range smearing is essential to ensure target volume coverage at each treatment session 2.5.2 Treatment beam parameters The proton beam is mono-energetic as it enters the treatment head or nozzle The Bragg peak of such a beam, called the pristine peak, is very narrow in depth and is not clinically useful The nozzle is equipped with a range modulation system that creates an SOBP by combining pristine peaks of reduced ranges and intensity (Fig 18) Modulation of the proton beam in range and intensity is accomplished by a rotating modulation wheel (also called ―propeller‖) The wheel consists of varying thicknesses of plastic (e.g., polystyrene) with varying angular widths The thickness is constant in a given segment but successively increases from one segment to the other Whereas the water-equivalent range of the pristine peak is reduced by an amount equal to the water-equivalent thickness of the plastic in a segment, its intensity is reduced because of the increasing width of the segment (i.e., increasing beam-on time at that range position) As the wheel rotates, the combination of pristine peaks with successively reduced range and intensity creates the desired SOBP [11] A modern nozzle consists of many components for creating and monitoring a clinically useful beam (e.g., rotating range-modulator wheel, range-shifter plates to 25 Nguyen The Bon – Overview of Proton Therapy bring the SOBP dose distribution to the desired location in the patient, scattering filters to spread and flatten the beam in the lateral dimensions, dose-monitoring ion chambers, and an assembly to mount patient-specific field aperture and range compensator) These nozzle components are not standard and may vary between different accelerators Figure 18 Spread-out Bragg peak (SOBP) depth dose distribution [11] The SOBP is specified by its modulation width, measured as the width between the distal and proximal 90% dose values relative to the maximum dose (indicated by vertical dashed lines in Fig 18), and its range, measured at the distal 90% dose position SOBP beam parameters are generated by the treatment-planning system for each treatment field Lateral dimensions of the SOBP beam are shaped by a field aperture (corresponding to beam’s-eye-view projection of the field to cover the target), typically constructed from brass with equivalent wall thickness exceeding the maximum possible SOBP range by cm Thus, all the treatment beam parameters for each field, namely, beam energy, SOBP range and modulation, range compensator, field aperture, and dose, are designed by the treatment-planning system 26 Nguyen The Bon – Overview of Proton Therapy CHAPTER PROTON THERAPY IN CLINICAL APPLICATION 3.1 PRINCIPLES Proton beam therapy has been used to treat almost all tumors that are traditionally treated with x-rays and electrons (e.g., tumors of the brain, spine, head and neck, breast, and lung; gastrointestinal malignancies; and prostate and gynecologic cancers) Because of the ability to obtain a high degree of conformity of dose distribution to the target volume with practically no exit dose to the normal tissues, the proton radiotherapy is an excellent option for tumors in close proximity of critical structures such as tumors of the brain, eye, and spine Also, protons give significantly less integral dose than photons and, therefore, should be a preferred modality in the treatment of pediatric tumors where there is always a concern for a possible development of secondary malignancies during the lifetime of the patient For the same reasons, namely dose conformity and less integral dose, lung tumors are good candidates for proton therapy provided the respiratory tumor motion is properly managed (Fig 19) Figure 19 Comparison of photon intensity-modulated radiation therapy (IMRT) plan (left) and proton therapy plan (right) [15] Although single and multiple static beams are often used in proton therapy, there is a trend toward adopting IMPT Proton dose distributions can be optimized by the use of IMPT, achieving dose conformity comparable to IMRT but with much less 27 Nguyen The Bon – Overview of Proton Therapy integral dose However, as discussed earlier, IMPT is very sensitive to target motion Therefore, in cases where target motion is a problem, image guidance is essential to track target motion and ensure target coverage during each treatment 3.2 THE CLINICAL CASES USE OF PROTON THERAPY 3.2.1 Prostate cancer There have been no clinical trials showing that PT has fewer side effects or is more effective compared to IMRT treatments The proton dose distribution is sensitive to uncertainties in the particle range in the tissue The day to day variation in rectal and bladder filling not allow use of oblique fields that pass through the bladder and rectum as in the 3D conformational or IMRT in the treatment of prostate cancer Proton therapy is planned with two lateral opposed beams while IMRT spreads out the dose with several beams, results in a high dose region in the anterior rectum wall and/or bladder, and less gain than expected Trofimov from Boston reported that IMRT achieved significantly better sparing of the bladder regarding higher than 60 Gy(RBE), while rectal sparing was similar with 3D proton planning A does lower than 50% of the target prescription to healthy tissues was lower with proton therapy Figure 20 Comparison of dose distribution for IMRT and IMPT (right) [21] 28 Nguyen The Bon – Overview of Proton Therapy 3.2.2 Brain tumor The brain is the most complex and important organ within the human body It is the source of our thoughts, feelings and senses It is this complexity that makes the treatment of brain tumours the most difficult and dangerous because of the high risk of damaging sensitive structures Figure 21 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] Proton therapy is suitable for:  Low Grade Gliomas -Pilocytic Astrocytoma -Nonpilocytic Gliomas (astrocytoma, oligodendroglioma, oligoastrocytoma)  Meningiomas  Pituitary Adenomas  Chordomas & Chondrosarcomas Proton therapy reduces radiation exposure to surrounding tissue by 50% which helps to preserve:  Vision  Hearing  Intellectual ability  Endocrine functions 29 Nguyen The Bon – Overview of Proton Therapy 3.2.3 Head and neck cancers Proton therapy gains importance especially in the case of sinonasal malignancies in the head and neck region A combination of radical surgery and postoperative radiation is the treatment of choice for most of the sinonasal malignancies, however due to the proximity of critical structures, radiation induced late toxicity is common Conformal RT or Intensity Modulated Radiation Therapy (IMRT) have reduced toxicity, however, local control and overall survival were more favorable with Proton Beam Therapy Figure 22 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] Advantages of proton therapy:  Enables dose escalation in compliance with dose limits for critical organs in treatment of paranasal sinuses and nasopharyngeal carcinoma  Lower irradiation of salivary glands compared to IMRT with consequent lower risk of xerostomia Proton therapy is suitable for:  Tumors of the sinuses  Nasopharyngeal carcinoma 30 Nguyen The Bon – Overview of Proton Therapy 3.2.4 Lung cancer Local control (and chances of survival) depends on the dose applied in the case of lung tumors Small lung tumors (T1, T2) can be successfully cured by surgery Radical radiotherapy seems to achieve results comparable to Radiotherapy is a necessary part of progressing lung carcinoma However, the dose of radiation is limited by possible damage to structures sensitive to radiation with unacceptable risk of progressing postradiation pneumonitis, oesophagitis and myelitis Figure 23 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] 3.2.5 CNS tumors Proton therapy is suitable for: Malignant CNS disease:  Skull base tumors (chordomas, chondrosarkomas)  Paraspinal tumors  Low grade glioma(especially situated close to structures sensitive to radiation)  High grade glioma  Specific types of brain metastasis Benign CNS tumors:  A-V malformations  Acute vascular malformations  Acoustic neurinoma 31 Nguyen The Bon – Overview of Proton Therapy CONCLUSION In summary, the main points of my research are: understanding and giving a review of proton therapy:  Currently the proton accelerators for use in radiotherapy are cyclotrons and synchrotrons Cyclotrons operate at a fixed energy, which can be modulated by the use of energy degraders to create SOBP at any depth Synchrotrons produce beams of variable energy and can generate any desired energy without the use of energy degraders  RBE depends on LET which increases with decrease in proton energy and is greatest at the Bragg peak However, a universal RBE of 1.1 for proton beams has been adopted for practical reasons  Beam delivery systems to produce uniform fields of any size vary between different accelerators and are mainly of two types: passive beam spreading and pencil beam scanning  Proton beam therapy has been used to treat almost all kinds of tumors that are traditionally treated with x-rays and electrons Most useful applications are in the treatment of tumors in close vicinity of critical normal structures (e.g., tumors of the brain, eye, and spine) These promising results help me to continue studying practical application of proton therapy in clinical 32 Nguyen The Bon – Overview of Proton Therapy REFERENCES Vietnamese [1] Nguyễn Xuân Kử, “Cơ sở vật-lý & tiến xạ trị ung thư.” Nhà xuất Y Học, 2010 [2] Nguyễn Xuân Kử, ―Cone Beam ứng dụng lâm sàng” Tạp chí Y học thực hành, HT PCUT-Huế, tháng 9-2013 [3] Nguyễn Xuân Kử, “Giới thiệu máy Gia tốc Xạ trị Ung thư, Hội thảo Quốc tế Phòng chống Ung thư, Hà nội 2000 [4] Nguyễn Xuân Kử, “Những tiến kỹ thuật xạ trị ung thư” Tạp chí Y học thực hành, HT PCUT- thành phố HCM, tháng 9-2013 [5] Nguyễn Xuân Kử, “Quy trình đảm bảo chất lượng Xạ trị Ung thư”, Hội thảo Quốc tế Điều trị Phóng xạ Ion hoá ứng dụng Y-học, Hà nội 42000 English [6] Andrew Maier (1998) “Passive beam spreading systems and light-weight gantries for synchrotron base Hardon Therapy”, Dissertation for obtaining the academic degree University of Wien [7] Daniel W.Miller “ A review of proton 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