Proton therapy physics (series in medical physics and biomedical engineering)

It also examines computerized treatment plan optimization, methods for in vivo dose or beam range verification, the safety of patients and operating personnel, and the biological implic

PROTON THERAPY

PHYSICS

SerieS editorS: John G WebSter, Slavik tabakov, kWan-hoonG nG

Edited by Harald Paganetti

provide an in-depth overview of the physics aspects of this radiation therapy

modality, eliminating the need to dig through information scattered in the

medical physics literature

After tracing the history of proton therapy, the book summarizes the atomic and

nuclear physics background necessary for understanding proton interactions

with tissue It describes the physics of proton accelerators, the parameters

of clinical proton beams, and the mechanisms to generate a conformal dose

distribution in a patient The text then covers detector systems and measuring

techniques for reference dosimetry, outlines basic quality assurance and

commissioning guidelines, and gives examples of Monte Carlo simulations in

proton therapy

The book moves on to discussions of treatment planning for single- and

multiple-field uniform doses, dose calculation concepts and algorithms, and

precision and uncertainties for nonmoving and moving targets It also examines

computerized treatment plan optimization, methods for in vivo dose or beam

range verification, the safety of patients and operating personnel, and the

biological implications of using protons from a physics perspective The final

chapter illustrates the use of risk models for common tissue complications in

treatment optimization

Along with exploring quality assurance issues and biological considerations,

this practical guide collects the latest clinical studies on the use of protons

in treatment planning and radiation monitoring Suitable for both newcomers

in medical physics and more seasoned specialists in radiation oncology, the

book helps readers understand the uncertainties and limitations of precisely

shaped dose distribution

Physics

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A TAY L O R & F R A N C I S B O O K

CRC Press is an imprint of the

Taylor & Francis Group, an informa business

Boca Raton London New York

Edited by Harald Paganetti

Massachusetts General Hospital and Harvard Medical School, Boston, USA

Proton Therapy

Physics

© 2012 by Taylor & Francis Group, LLC

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About the Series vii

The International Organization for Medical Physics ix

Introduction xi

Editor xvii

Contributors xix

1 Proton Therapy: History and Rationale 1

Harald Paganetti 2 Physics of Proton Interactions in Matter 19

Bernard Gottschalk 3 Proton Accelerators 61

Marco Schippers 4 Characteristics of Clinical Proton Beams 103

Hsiao-Ming Lu and Jacob Flanz 5 Beam Delivery Using Passive Scattering 125

Roelf Slopsema 6 Particle Beam Scanning 157

Jacob Flanz 7 Dosimetry 191

Hugo Palmans 8 Quality Assurance and Commissioning 221

Zuofeng Li, Roelf Slopsema, Stella Flampouri, and Daniel K Yeung 9 Monte Carlo Simulations 265

Harald Paganetti 10 Physics of Treatment Planning for Single-Field Uniform Dose 305

Martijn Engelsman 11 Physics of Treatment Planning Using Scanned Beams 335

Antony Lomax

Peter van Luijk and Marco Schippers

The Series in Medical Physics and Biomedical Engineering describes the

applica-tions of physical sciences, engineering, and mathematics in medicine and clinical research

The series seeks (but is not restricted to) publications in the following topics:

The Series in Medical Physics and Biomedical Engineering is an international

series that meets the need for up-to-date texts in this rapidly developing field Books in the series range in level from introductory graduate textbooks and practical handbooks to more advanced expositions of current research

The Series in Medical Physics and Biomedical Engineering is the official book

series of the International Organization for Medical Physics

The International Organization for Medical Physics (IOMP), founded in

1963, is a scientific, educational, and professional organization of 76 national adhering organizations, more than 16,500 individual members, several cor-porate members, and four international regional organizations

IOMP is administered by the Council, which includes delegates from each

of the Adhering National Organizations Regular meetings of the Council are held electronically as well as every three years at the World Congress

on Medical Physics and Biomedical Engineering The president and other officers form the Executive Committee, and there are also committees cover-ing the main areas of activity, including education and training, scientific, professional relations, and publications

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• To contribute to the advancement of medical physics in all its aspects

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in developing countries

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of medical physics in those countries that lack such organizations

Activities

Official journals of the IOMP are Physics in Medicine and Biology, Medical Physics , and Physiological Measurement The IOMP publishes a bulletin Medical Physics World twice a year that is distributed to all members

A World Congress on Medical Physics and Biomedical Engineering is held every three years in cooperation with IFMBE through the International Union for Physics and Engineering Sciences in Medicine A regionally based International Conference on Medical Physics is held between World Congresses IOMP also sponsors international conferences, workshops, and courses IOMP representatives contribute to various international commit-tees and working groups

The IOMP has several programs to assist medical physicists in developing countries The joint IOMP Library Programme supports 69 active libraries in

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Information on the activities of the IOMP can be found on its website at http://www.iomp.org

According to the World Health Organization, cancer is the leading cause of death worldwide A large portion of cancer patients (e.g., more than half of all cancer patients in the United States) receive radiation therapy during the course of treatment Radiation therapy is used either as the sole treatment or, more typically, in combination with other therapies, including surgery and chemotherapy

Radiation interacts with tissue via atomic and nuclear interactions The energy transferred to and deposited in the tissue in such interactions is quantified as “absorbed dose” and expressed in energy (Joules) absorbed per unit mass (kg), which has the units of Gray (Gy) Depending on the number and spatial correlation of such interactions, mainly with cellular DNA, they can result in mutations or complete functional disruption (i.e., cell death) Assessing radiation damage is a complex problem because the cell typically does have the limited ability to repair certain types of lesions

There are many degrees of freedom when administering radiation, for example, different radiation modalities, doses, and beam directions The main focus in research and development of radiation therapy is on eradicat-ing cancerous tissue while minimizing the irradiation of healthy tissue The ideal scenario would be to treat the designated target without damaging any healthy structures This is not possible for various reasons such as uncertain-ties in defining the target volume as well as delivering the therapeutic dose

as planned Furthermore, applying external beam radiation therapy typically requires the beam to penetrate healthy tissue in order to reach the target.Treatment planning in radiation therapy uses mathematical and physical formalisms to optimize the trade-off between delivering a high and con-formal dose to the target and limiting the doses to critical structures The dose tolerance levels for critical structures, as well as the required doses for various tumor types, are typically defined on the basis of decades of clinical experience

When considering the trade-off between administering the prescribed get dose and the dose to healthy tissue, the term “therapeutic ratio” is often used The therapeutic ratio can be defined as the ratio of the probabilities for tumor eradication and normal tissue complication Technological advances

tar-in beam delivery and treatment modality focus matar-inly on tar-increastar-ing the therapeutic ratio Improvements can be achieved, for example, by applying advanced imaging techniques leading to improved patient setup or tumor localization

A gain in the therapeutic ratio can also be expected when using proton therapy instead of conventional photon or electron therapy The rationale for using proton beams instead of photon beams is the feasibility of delivering

higher doses to the tumor while maintaining the total dose to critical tures or maintaining the target dose while reducing the total dose to critical structures.

struc-The most prominent difference between photon and proton beams is the finite range of a proton beam After a short build-up region, photon beams show an exponentially decreasing energy deposition with increasing depth in tissue Except for superficial lesions, a higher dose to the tumor compared with the organ at risk can only be achieved by using multiple beam directions Furthermore, a homogenous dose distribution can only

be achieved by utilizing various different beam angles, not by delivering

a single field In contrast, the energy transferred to tissue by protons is inversely proportional to the proton velocity as protons lose their energy mainly in electromagnetic interactions with orbital electrons of atoms The more the protons slow down, the higher the energy they transfer to tissue per track length, causing the maximum dose deposition at a certain depth

in tissue For a single proton, the peak is very sharp For a proton beam,

it is broadened into a peak of typically a few millimeters width because

of the statistical distribution of the proton tracks The peak is called the Bragg peak (Figure 1) This feature allows pointing a beam toward a criti-cal structure The depth and width of the Bragg peak is a function of the beam energy and the material (tissue) heterogeneity in the beam path The peak depth can be influenced by changing the beam energy and can thus be positioned within the target for each beam direction Although protons from a single beam direction are able to deliver a homogeneous dose throughout the target (by varying the beam energy), multiple beam angles are also used in proton therapy to even further optimize the dose distribution with respect to organs at risk Note that there is also a slight difference between photon and proton beams when considering the lateral penumbra For large depths (more than ~16 cm), the penumbra for proton beams is slightly wider than the one for photon beams by typically a few millimeters Depending on the site, this can be a slight disadvantage of proton beams

Depth in tissue

Bragg peak Dose

FIGURE 1

Energy deposition as a function of depth for a proton beam leading to the Bragg peak.

The physical characteristic of proton beams—their finite range—can be used in radiation therapy for increasing the dose to the target or decreas-ing the dose to organs at risk Treatment plan comparisons show that protons offer potential gains for many sites In some cases, the dose con-formity that can be reached with intensity-modulated photon therapy might be comparable to one that can be achieved with proton techniques However, because of the difference in physics between photon beams and proton beams as outlined above, the total energy deposited in the patient for any treatment will always be higher with photons than with protons The use of protons leads to a reduction of the total energy when treating

a given target by a factor of about three compared to standard photon techniques and by a factor of about two compared to intensity- modulated photon plans The irradiation of a smaller volume of normal tissues compared to conventional modalities allows higher doses to the tumor, leading to an increased tumor control probability Furthermore, proton therapy allows a smaller dose to critical structures while maintaining the target dose compared to photon techniques Benefits can thus be expected particularly for pediatric patients where the irradiation of large volumes are particularly critical in terms of long-term side effects

The share of patients treated with proton therapy compared with photon therapy is currently still low but is expected to increase significantly in the near future, as evidenced by the number of facilities currently planned or under construction With the increasing use of protons as radiation therapy modality comes the need for a better understanding of the characteristics

of protons Protons are not just heavy photons when it comes to treatment planning, quality assurance, delivery uncertainties, radiation monitor-ing, and biological considerations To fully utilize the advantages of pro-ton therapy and, just as importantly, to understand the uncertainties and limitations of precisely shaped dose distribution, proton therapy physics needs to be understood Furthermore, the clinical impact and the evidence for improved outcomes need to be studied Proton therapy research has increased significantly in the last few years Figure 2 shows how the number

of proton therapy–related publications in most relevant scientific journals has increased over the years

This book starts with an overview about the history of proton therapy

in Chapter 1 The pioneering work done at a few institutions in the early days of proton therapy is acknowledged, and the main developments up

to the first hospital-based facilities are outlined The chapter concludes with comments about the original and current clinical rationale for proton therapy

The atomic and nuclear physics background necessary for understanding proton interactions with tissue is summarized in Chapter 2 The chapter cov-ers the basic physics of protons slowing down in matter independent of their medical use The ways in which protons can interact with materials/tissue

is described from both macroscopic (e.g., dose) and microscopic (energy loss

kinematics) points of view Furthermore, Chapter 2 presents equations that can be used for estimating many characteristics of proton beams.

Chapter 3 describes the physics of proton accelerators, including currently used techniques (cyclotrons and synchrotrons) and a brief discussion of new developments The chapter goes beyond simply summarizing the charac-teristics of such machines for proton therapy and also describes some of the main principles of particle accelerator physics

Chapter 4 outlines the characteristics of clinical proton beams and how the clinical parameters are connected to the design features and the operational settings of the beam delivery system Parameters such as dose rate, beam intensity, beam energy, beam range, distal falloff, and lateral penumbra are introduced

The next two chapters describe in detail how to generate a conformal dose distribution in the patient Passive scattered beam delivery systems are dis-cussed in Chapter 5 Scattering techniques to create a broad beam as well

as range modulation techniques to generate a clinically desired depth–dose distribution are outlined in detail Next, Chapter 6 focuses on magnetic beam scanning systems Scanning hardware as well as parameters that determine the scanning beam characteristics (e.g., its time structure and performance) are discussed The chapter closes with a discussion of safety and quality assurance aspects

Chapter 7 focuses on dosimetry and covers the main detector systems and measuring techniques for reference dosimetry as well as beam profile measurements The underlying dosimetry formalism is reviewed as well

as the basic aspects of microdosimetry Chapter 8 expands on this topic by

apy” in the title or abstract () Also shown is an exponential fit of the form Publications =

a × e b[year-1970] (solid line).

outlining the basic quality assurance and commissioning guidelines, ing acceptance testing The quality assurance guidelines focus on dosimetry

includ-as well includ-as mechanical and safety issues

One aspect of increasing importance in the field of medical physics is the use of computer simulations to replace or assist experimental methods After

an introduction to the Monte Carlo particle-tracking method, Chapter  9 demonstrates how Monte Carlo simulations can be used to address various clinical and research aspects in proton therapy Examples are treatment head design studies as well as the simulation of scattered radiation for radiation protection or dose deposition characteristics for biophysical modeling.Next, treatment planning is outlined The treatment planning process is largely modality independent Consequently, Chapter 10 covers only proton-specific aspects of treatment planning for passive scattering and scanning delivery for single-field uniform dose (i.e., homogeneous dose distributions

in the target from each beam direction) Proton-specific margin ations and special treatment techniques are discussed

consider-Chapter 11 describes treatment planning for multiple-field uniform dose and intensity-modulated proton therapy using beam scanning The chal-lenges and the potential of intensity-modulated treatments are described, including uncertainties and optimization strategies A few case studies con-clude this chapter

One of the key methods used in treatment planning is the dose calculation method Chapter 12 does focus on dose calculation concepts and algorithms The formalism for pencil beam algorithms is reviewed from a theoretical and practical implementation point of view Further, the Monte Carlo dose calculation method and hybrid methods are outlined

One of the advantages of proton therapy is the ability to precisely shape dose distributions, in particular using the distal falloff due to the finite beam range Uncertainties in the proton beam range limit the use of the finite range

of proton beams in the patient because more precise dose distributions are less forgiving in terms of errors and uncertainties Chapter 13 discusses pre-cision and uncertainties for nonmoving targets Special emphasis is on the dosimetric consequences of heterogeneities Chapter 14 deals with precision and uncertainties for moving targets, such as when treating lung cancer with proton beams The clinical impact of motion as well as methods of motion management for minimizing motion effects are outlined

Computerized treatment planning relies on optimization algorithms to generate a clinically acceptable plan Chapter 15 reviews some of the main aspects of treatment plan optimization including the consideration of some

of the uncertainties discussed in Chapters 13 and 14 Robust and dimensional optimization strategies are described

four-Chapter 16 discusses methods for in vivo dose or beam range verification These include the detection of photons caused by nuclear excitations and of annihilation photons created after the generation of positron emitters by the primary proton beam

The safety of patients as well as operating personnel has to be ensured by proper shielding of a treatment beam In proton therapy the main concerns are secondary neutrons Shielding considerations and measurement meth-ods are covered in Chapter 17.

The consequences of scattered or secondary radiation that a patient receives during treatment of the primary cancer could include long-time side effects such as a second cancer This aspect is outlined in Chapter 18 Secondary doses are quantified, and methods to estimate the risks for radiation-induced cancers are presented

Although this book is concerned mainly with proton therapy physics, logical implications are discussed briefly as they relate directly to physics aspects The biological implications of using protons are outlined from a physics perspective in Chapter 19

bio-Finally, outcome modeling is summarized in Chapter 20 This final ter illustrates the use of risk models for normal tissue complications in treat-ment optimization Proton beams allow precise dose shaping, and thus, personalized treatment planning might become particularly important for proton therapy in the future

chap-The goal of this book is to offer a coherent and instructive overview of proton therapy physics It might serve as a practical guide for physicians, dosimetrists, radiation therapists, and physicists who already have some experience in radiation oncology Furthermore, it can serve graduate stu-dents who are either in a medical physics program or are considering a career in medical physics Certainly it is also of interest to physicians in their last year of medical school or residency who have a desire to under-stand proton therapy physics There are some overlaps between different chapters that could not be avoided because each chapter should be largely independent Overall, the book covers most, but certainly not all, aspects of proton therapy physics

Dr Harald Paganetti is currently Director of Physics Research at the Department of Radiation Oncology at Massachusetts General Hospital in Boston and Associate Professor of Radiation Oncology at Harvard Medical School

He received his PhD in experimental nuclear physics in 1992 from the Rheinische-Friedrich-Wilhelms University in Bonn, Germany, and has been working in radiation therapy research on experimental as well as theoretical projects since 1994 He has authored and coauthored more than 100 peer-reviewed publications, mostly on proton therapy Dr Paganetti has been awarded various research grants from the National Cancer Institute in the United States He serves on several editorial boards and is a member of numerous task groups and committees for associations such as the American Association of Physicists in Medicine, the International Organization for Medical Physics, and the National Institutes of Health/National Cancer Institute

Dr Paganetti teaches regularly worldwide on different aspect of proton therapy physics

Department of Radiation Oncology

Massachusetts General Hospital

and Harvard Medical School

Proton Therapy Center

Boston, Massachusetts

David Craft

Department of Radiation Oncology

Massachusetts General Hospital

and Harvard Medical School

Proton Therapy Center

Boston, Massachusetts

Martijn Engelsman

Department of Radiation Oncology

Massachusetts General Hospital

and Harvard Medical School

Proton Therapy Center

Department of Radiation Oncology

Massachusetts General Hospital

and Harvard Medical School

Proton Therapy Center

Massachusetts General Hospital and Harvard Medical SchoolProton Therapy Center

Boston, Massachusetts

Zuofeng Li

University of Florida Proton Therapy InstituteJacksonville, Florida

Antony Lomax

Center for Proton TherapyPaul Scherrer InstituteVilligen, Switzerland

Hsiao-Ming Lu

Department of Radiation Oncology

Massachusetts General Hospital and Harvard Medical SchoolProton Therapy Center

Boston, Massachusetts

Department of Radiation Oncology

Massachusetts General Hospital

and Harvard Medical School

Proton Therapy Center

Boston, Massachusetts

Hugo Palmans

National Physical Laboratory

Acoustics and Ionising Radiation

Teddington, United Kingdom

Heidelberg Ion Beam Therapy

Center and Department of

Massachusetts General Hospital and Harvard Medical SchoolProton Therapy Center

Boston, Massachusetts

Jan H Unkelbach

Department of Radiation Oncology

Massachusetts General Hospital and Harvard Medical SchoolProton Therapy Center

Boston, Massachusetts

Peter van Luijk

Department of Radiation Oncology

University Medical Center Groningen

University of GroningenGroningen, The Netherlands

Daniel K Yeung

University of Florida Proton Therapy Institute

Jacksonville, FloridaDepartment of Radiation Oncology

University of FloridaGainesville, Florida

Proton Therapy: History and Rationale

Harald Paganetti

1.1 The Advent of Protons in Cancer Therapy

The first medical application of ionizing radiation, using x-rays, occurred in

1895 (1, 2) In the following decades, radiation therapy became one of the main treatment options in oncology (3) Many improvements have been made with

CONTENTS

1.1 The Advent of Protons in Cancer Therapy 11.2 History of Proton Therapy Facilities 21.2.1 Early Days: Lawrence Berkeley Laboratory, Berkeley,

California 21.2.2 Early Days: Gustav Werner Institute, Uppsala, Sweden 31.2.3 Early Days: Harvard Cyclotron Laboratory,

Cambridge, Massachusetts 31.2.4 Second Generation: Proton Therapy in Russia 41.2.5 Second Generation: Proton Therapy in Japan 41.2.6 Second Generation: Proton Therapy Worldwide 51.2.7 Hospital-Based Proton Therapy 51.2.8 Facilities and Patient Numbers 51.3 History of Proton Therapy Devices 71.3.1 Proton Accelerators 71.3.2 Mechanically Modulating Proton Beams 71.3.3 Scattering for Broad Beams 71.3.4 Magnetic Beam Scanning 71.3.5 Impact of Proton Technology in Other Areas of

Radiation Therapy 81.4 The Clinical Rationale for Using Protons in Cancer Therapy 91.4.1 Dose Distributions 91.4.2 Early Clinical Implications 101.4.3 Current Clinical Implications 111.4.4 Economic Considerations 11Acknowledgments 12References 12

respect to how radiation is administered considering biological effects, for example, the introduction of fractionated radiation therapy in the 1920s and 1930s Technical advances have been aimed mainly at reducing dose to healthy tissue while maintaining prescribed doses to the target or increasing the dose

to target structures with either no change or a reduction of dose to normal sue Computerized treatment planning, advanced imaging and patient setup, and the introduction of mega-voltage x-rays are examples of new techniques that have impacted beam delivery precision during the history of radiation therapy Another way of reducing dose to critical structures is to take advan-tage of dose deposition characteristics offered by different types of particles.The advantages of proton radiation therapy, compared with “conventional” photon radiation therapy, were first outlined by Wilson in 1946 (4) He pre-sented the idea of utilizing the finite range and the Bragg peak of proton beams for treating targets deep within healthy tissue and was thus the first

tis-to describe the potential of protis-ton beams for medical use Wilson’s tion to use protons (in fact he also extended his thoughts to heavy ions) was based on the well-known physics of protons as they slowed down during penetration of tissue

sugges-1.2 History of Proton Therapy Facilities

1.2.1 Early Days: Lawrence Berkeley Laboratory, Berkeley, California

The idea of proton therapy was not immediately picked up at Wilson’s home institution, Harvard University, but was adopted a couple of years later by the Lawrence Berkeley Laboratory (LBL) in California Pioneering the medi-cal use of protons, Tobias, Anger, and Lawrence (5) in 1952 published their work on biological studies on mice using protons, deuterons, and helium beams Many experiments with mice followed at LBL (6), and the first patient was treated in 1954 (7)

The early patients had metastatic breast cancer and received proton ation of their pituitary gland for hormone suppression The bony landmarks made targeting of the beam feasible The Bragg peak itself was not utilized Instead, using a 340-MeV proton beam, patients were treated with a cross-firing technique (i.e., using only the plateau region of the depth dose curve) This approximated a rotational treatment technique to concentrate the dose

irradi-in the target Protons as well as helium beams were applied Between 1954 and 1957, 30 patients were treated with protons Initially large single doses were administered (7), and later fractionated delivery treatment three times

a week was applied (8) The first patient using the Bragg peak was treated in

1960 for a metastatic lesion in the deltoid muscle, using a helium beam (9) The LBL program moved to heavier ions entirely in 1975, resulting in several developments that also benefited proton therapy

1.2.2 Early Days: Gustav Werner Institute, Uppsala, Sweden

In 1955, shortly after the first proton treatments at LBL, radiation oncologists

in Uppsala, Sweden, became interested in the medical use of protons Initially,

a series of animal (rabbits and goats) experiments were performed to study the biological effect of proton radiation (10–12) The first patient was treated

in 1957 using a 185-MeV cyclotron at the Gustav Werner Institute (12–14) Subsequently, radiosurgery beams were used to treat intracranial lesions, and

by 1968, 69 patients had been treated (15, 16) Because of limitations in beam time at the cyclotron, high doses per fraction were administered Instead of the cross-firing technique, the use of the Bragg peak was adopted early on by using large fields and range-modulated beams (14, 17, 18) In fact, the Gustav Werner Institute was the first to use range modulation using a ridge filter, that is, a spread-out Bragg peak (SOBP) with a homogeneous dose plateau at

a certain depth in tissue (14), based on the original idea of Robert Wilson, in which various mono-energetic proton beams resulting in Bragg peaks were combined to achieve a homogeneous dose distribution in the target The pro-ton therapy program ran from 1957 to 1976 and reopened in 1988 (19)

1.2.3 Early Days: Harvard Cyclotron Laboratory,

Cambridge, Massachusetts

Preclinical work on proton therapy at Harvard University (Harvard Cyclotron Laboratory [HCL]) started in 1959 (20) The cyclotron at HCL had sufficient energy (160 MeV) to reach the majority of sites in the human body

up to a depth of about 16 cm The relative biological effectiveness (RBE) of proton beams was studied in the 1960s using experiments on chromosome aberrations in bean roots (21), mortality in mice (22), and skin reactions on primates (23) Subsequently, the basis for today’s practice of using a clinical RBE (see Chapter 19) was established (24–27)

The clinical program was based on a collaboration between HCL and the neurosurgical department of Massachusetts General Hospital (MGH) The first patients were treated in 1961 (28) Intracranial targets needed only a small beam, which could be delivered using a single scattering technique

to broaden the beam As at LBL, pituitary irradiation was one of the main targets Because of the maximum beam energy of 160 MeV, it was decided

to focus on using the Bragg peak instead of applying a crossfire technique Until 1975, 732 patients had undergone pituitary irradiation at HCL (29) On the basis of the growing interest in biomedical research and proton ther-apy, the facility was expanded by constructing a biomedical annex in 1963 This was funded by NASA to examine the medical effects of protons When the research program funded by the U.S Office of Naval Research, which originally funded the cyclotron, was shut down in 1967, the proton therapy project was in danger of being terminated Extensive negotiations between MGH  and HCL, as well as small grants by the National Cancer Institute

(NCI) in 1971 and the National Science Foundation (NSF) in 1972 helped, thus saving the program.

In 1973, the radiation oncology department commenced an extensive proton therapy program The first patient was a four-year-old boy with a posterior pelvic sarcoma Subsequently, the potential of the HCL proton beam for treat-ment of skull-base sarcomas, head-and-neck region carcinomas, and uveal melanomas was identified, and several studies on fractionated proton therapy were performed (30) Furthermore, a series of radiobiological experiments was done (25) On the basis of the development of a technique to treat choroidal melanomas at MGH, the Massachusetts Eye and Ear Infirmary, and HCL, mel-anoma treatments started in 1975 (31) after tests had been done using monkeys (32, 33) The first treatments for prostate patients were in the late 1970s (34)

A milestone for the operation at HCL as well as for proton therapy research

in general was a large research grant by the NCI awarded in 1976 to MGH Radiation Oncology to allow extensive studies on various aspects of proton therapy The HCL facility treated a total of 9116 patients until 2002

1.2.4 Second Generation: Proton Therapy in Russia

Proton therapy began early at three centers in Russia Research on using ton beams in radiation oncology had been started in Dubna (Joint Institute for Nuclear Research [JINR]) and at the Institute of Theoretical and Experimental Physics (ITEP) in Moscow in 1967 The Dubna facility started treatments in April 1967, followed by ITEP in 1968 (35–39) A joint project between the Petersburg Nuclear Physics Institute and the Central Research Institute of Roentgenology and Radiology (CRIRR) in St Petersburg launched a proton therapy program in 1975 in Gatchina, a nuclear physics research facility near

pro-St Petersburg The latter treated intracranial diseases using Bragg curve teau irradiation with a 1-GeV beam (40)

pla-The program at ITEP was the largest of these programs and was based

on a 7.2-GeV proton synchrotron with a medical beam extraction of up to

200 MeV Patients were treated with broad beams and a ridge filter to create depth–dose distributions Starting in 1972, the majority of treatments irradi-ated the pituitary glands of breast cancer and prostate cancer patients using the plateau of the Bragg curve (35, 41) By the end of 1981, 575 patients with various indications had been treated with Bragg peak dose distributions (35)

1.2.5 Second Generation: Proton Therapy in Japan

The history of proton therapy treatments in Japan goes back to 1979 when the National Institute of Radiological Sciences (NIRS) at Chiba started treat-ments at a 70-MeV facility (42) Of the 29 patients treated between 1979 and

1984, only 11 received proton therapy alone and 18 received a boost tion of protons after either photon beam or fast neutron therapy The effort was followed by the use of a 250-MeV beam at the Particle Radiation Medical

irradia-Science Center in Tsukuba in 1983 using a 250-MeV proton beam obtained

by degrading a 500-MeV beam from a booster synchrotron of the National Laboratory for High Energy Physics (KEK) (43) Japan has since emerged as one of the main users of proton and heavy ion therapy

1.2.6 Second Generation: Proton Therapy Worldwide

The late 1980s and early 1990s saw a number of initiatives starting proton therapy programs on several continents, for example, at the Paul Scherrer Institute (PSI) (Switzerland) in 1984, Clatterbridge (U.K.) in 1989, Orsay (France) in 1991, and iThemba Laboratory for Acclerator Based Sciences (iThemba LABS) (South Africa) in 1993 In particular the activities at PSI, starting with a 72-MeV beam for ocular melanoma treatments (44) and after

1996 using a 200-MeV beam, have lead to many technical and treatment planning improvements in proton therapy

1.2.7 Hospital-Based Proton Therapy

By the early 1990s, proton therapy was based mainly in research tions and was used on a modest number of patients, in part because of very restricted beam time availability at some centers Then, in 1990, the first hospital-based facility was built and started operation at the Loma Linda University Medical Center (LLUMC) in California (45) The accelerator system, based on a synchrotron (46), was developed in collaboration with Fermilab The gantries were designed by the HCL group (47) By July 1993, 12,914 patients had been treated with protons worldwide—still roughly half

institu-of those at HCL and 25% in Russia (48) Roughly 50% were radiosurgery patients treated with small fields However, the facility at Loma Linda would soon treat the biggest share of proton therapy patients

It took another few years before the first commercially available equipment was installed and in operation at MGH, which transferred the program from the HCL to its main hospital campus in 2001 At the time when the facility was purchased, proton therapy was still considered mainly experimental as part of a research effort In fact, the construction project was in part funded

by the NCI The commercial equipment sold to MGH started the interest

of different companies to offer proton therapy solutions and the interest of major hospitals to buy proton therapy facilities Many other hospital-based facilities have been opened since then

1.2.8 Facilities and Patient Numbers

Table 1.1 lists the facilities and the number of patients treated with protons as of December 2010 On the basis of the increasing interest in proton therapy and the number of additional facilities under construction, one can assume that roughly

6000 patients will be treated with protons in 2011 in the United States alone

First Patient

Last Patient

Number

of Patients

Facilities in operation: 27 Total number of patients treated: 73,804

Source: The Particle Therapy Co-Operative Group (PTCOG) (http://ptcog.web.psi.ch).

1.3 History of Proton Therapy Devices

1.3.1 Proton Accelerators

The concept of accelerating particles in a repetitive way with time- dependent varying potentials led to the invention of the cyclotron by Lawrence in 1929 (49) Cyclotrons accelerate particles while they are circulating in a mag-netic field and pass the same accelerating gap several times (see Chapter 3) Gaining energy, the particles are traveling in spirals and are eventually extracted To overcome the energy limitation of a cyclotron, the principle

of phase stability was invented in 1944 (50) One was now able to accelerate particles of different energy on the same radius, leading to the synchrotron (see Chapter 3) The synchrotron concept was suggested first by Oliphant in

1943 (51) Thus, both accelerator types were available when proton therapy was first envisaged

1.3.2 Mechanically Modulating Proton Beams

In his 1946 paper, Wilson introduced the idea of using a rotating wheel of variable thickness to cover an extended volume with an SOBP (although

he did not define this term) (4, 52) This technique to produce an SOBP (see Chapter 5) was adopted by proton facilities such as the HCL (53–55) Others have used a ridge filter design to shape an SOBP (14, 56, 57)

1.3.3 Scattering for Broad Beams

For treatment sites other than very small targets (e.g., in radiosurgery) ton beams produced by accelerators result in “pencil” beams that are too small to cover an extended target Thus, scattering foils had to be used to increase their width To produce a flat dose distribution in lateral direction,

pro-it was inefficient to use a single-scattering foil because only a small area in the center of the beam would suffice beam flatness constraints The double-scattering system, using two scatterers to achieve a parallel beam producing

a flat dose distribution with high efficiency, was developed at the HCL in the late 1970s (58) The idea was based on similar systems previously designed for heavy ion and electron beams (59) The double-scattering concept was later improved using a contoured scatterer system (see Chapter 5) (60)

1.3.4 Magnetic Beam Scanning

The development of beam scanning was a major milestone in proton apy The clinical implications of beam scanning were analyzed in the late 1970s and early 1980s (61, 62) The advantage of scanning is not only the need for fewer beam shaping absorbers in the treatment head (increasing the

ther-efficiency) but also the potential of delivering variable modulation and thus sparing structures proximal to the SOBP (61).

The concept of using magnets to deflect a proton beam (dynamic beam delivery) is as old as the double-scattering scattering system The idea to magnetically deflect proton beams for treatment was first published by Larsson in 1961 (14) Continuous scanning using an aperture was done in the 1960s in Uppsala (14) The aim was not to scan the tumor with individual pencil beams but to replace the scattering system using a sweeping mag-netic field A method using rotating dipoles instead of a scattering system

in order to produce a uniform dose distribution was considered by Koehler, Schneider, and Sisterton (58) It can be considered as intermediate between double-scattered broad beam delivery and beam scanning Similarly, a tech-nique called wobbling, using magnetic fields to broaden the beam without a double-scattering system, was developed at Berkeley for heavy ion therapy because here the material in the beam path when using a double scattering system produces too much secondary radiation (63)

Full-beam scanning uses small proton beams of variable energy and sity that are magnetically steered to precisely shape of dose around critical structures (see Chapter 6) This concept of using beam scanning in three dimensions for clinical proton beam delivery was developed by Leemann et al (64) Many different flavors of beam scanning exist Typical terms are spot, pixel, voxel, dynamic, and raster scanning The terminology is not consistent The main differences between scanning systems are whether the delivery

inten-is done in a step-and-shoot mode or continuously Spot scanning, where the beam spots are delivered one by one with beam off-time in between, covering the target volume instead of delivering a rectangular scanned field that has to

be shaped by an aperture, was first introduced at NIRS using a 70-MeV beam Scanning was mainly done to improve the range of the beam by removing a scattering system At first, two-dimensional scanning was applied in combi-nation with a range-modulating wheel (42) Later, three-dimensional beam scanning was introduced by using a system with two scanning magnets and

an automatic range degrader to change the spot energy (42, 65–68)

Many studies on different scanning techniques (spot scanning, continuous scanning) were done in the early 1980s at LBL, and continuous scanning in three dimensions without collimator was first done in the early 1990s (69).Beam scanning can be used in passive scattered proton therapy, but it also allows creating fields delivering inhomogeneous dose distributions where only a combination of several fields yields the desired dose distribution in the target (see Chapter 11) This intensity-modulated proton therapy is cur-rently on the verge of finding its way into the clinical routine

1.3.5 Impact of Proton Technology in Other Areas of Radiation Therapy

Some of the developments in proton therapy have influenced the way ation therapy is being conducted also in conventional radiation therapy

radi-External beam radiation therapy requires a geometric description of the nal patient anatomy Until the advent of computed tomography (CT) this could only be obtained from x-ray images, which project the anatomy on a planar film Because conventional radiation therapy uses photons, the imaging x-ray modality basically just replaces the treating photons In the case of protons, which stop in the patient, this method does not suffice for treatment planning When proton treatment of cancer patients began at the HCL, positioning of the target for each treatment field for each fraction was readily achieved by the simple use of bi-planar radiographs The information was used to decide

inter-on potential beam approaches that covered the target in the lateral dimensiinter-on for each beam path Pituitary adenomas and arteriovenous malformation were the initial targets for proton therapy (16, 70) These lesions could be visualized

on x-rays using contrast material to visualize the vasculature and thus could

be treated without the use of CT imaging It became clear that in order to lize the superior dose distribution of proton beams one needed to understand the impact of density variations for each beam path (30, 71, 72) Thus, the treat-ment of other sites in the very heterogeneous head and neck region (e.g., para-nasal sinus or nasopharynx) required additional research on accurate imaging

uti-to visualize the patient’s geometry and densities in the beam path (71)

When CT imaging became available, proton radiation therapy was the early adaptor, that is, using CT for treatment planning (73–75) The proton therapy program at HCL, the heavy ion program at LBL, and the pi-meson program at the University of New Mexico were the first radiation therapy programs to install dedicated CT scanners Some were modified to allow imaging in a seated position to mimic the treatment geometry

Proton therapy paved the way for many other advances in radiation apy The proton therapy group at MGH developed the first computerized treatment planning program in the early 1980s, which was subsequently used clinically (76–79) Other developments included the innovative con-cepts of beam’s eye view and dose-volume histograms, features that have become standard in radiation therapy today Sophisticated patient position-ing was developed first in proton therapy because the finite range of proton beams required a more precise setup than in photon therapy (80)

distribution is a distribution that is more closely confined to the tumor ume This allows reducing the dose to normal structures (decreasing the normal tissue complication probability) or increasing the dose to the tumor (increasing the tumor control probability) or both When proton therapy became available, it was of interest mainly because it showed dose confor-mity far superior to any type of conventional photon radiation therapy at that time (72, 81) Nowadays, it is quite feasible for some tumor shapes to reach dose conformity to the target with photons that is comparable to the one achievable with protons, albeit at the expense of using a larger number of beams The difference in dose conformity between protons and photons has certainly decreased since the early days of proton therapy (at least for regu-lar shaped targets), mainly due to the development of intensity- modulated photon therapy.

vol-There is a limit to further improving and shaping photon generated dose distributions because the total energy deposited in the patient and thus to critical structures cannot be reduced but only distributed differently Proton radiation therapy, on the other hand, can achieve significant further physical improvements through the use of scanning-beam technology and intensity-modulated proton therapy This will increase the advantage of proton ther-apy due to advanced dose sculpting potential

1.4.2 Early Clinical Implications

Target dose distributions can typically be shaped with proton beams by applying fewer beams than with photons Proton therapy is of particular interest for tumors located close to serially organized tissues where a small local overdose can cause significant complications Protons are ideal for many targets, specifically if they are concave-shaped or are close to criti-cal structures The advantages of proton therapy could not be utilized right from the start because of limitations in patient imaging and beam delivery (e.g., the absence of gantry systems) Proton treatments started with the cross firing technique and the irradiation of pituitary targets The proton therapy program at the HCL began with single fraction treatments of intracranial lesions (28) In the early 1960s the program of fractionated irradiation was commenced by the radiation oncologists at HCL and was used for a greatly expanded number of anatomic sites such as skull base sarcomas, choroidal melanomas, head and neck carcinomas, and others Choroidal melanomas quickly became the most commonly treated tumor at HCL (82) Starting in

1973, all treatments for cancer patients was done by fractionated dose ery (30) By the mid-1980s roughly one-third of the treated patients received intracranial radiosurgery treatments (e.g., arterioveneous maformations) (83, 84)

deliv-Even with a limited number of indications, the distinct advantages of proton treatments compared to photon treatments were seen early on (85) One was able to demonstrate clinical efficacy of proton radiation therapy in

otherwise poorly manageable diseases such as for chordoma and sarcoma of the skull base and the spine (86, 87) These present significant treatment challenges as they are often very close to critical structures (e.g., the brain stem, spinal cord, or optic nerves).

chondro-1.4.3 Current Clinical Implications

Today proton therapy is a well-established treatment option for many tumor types and sites Advantages when using protons in favor of photons have been shown in terms of tumor control probability and/or normal tissue com-plications probability Various dosimetric studies clearly demonstrate supe-rior normal tissue sparing with protons (88–99) It is well recognized that protons are extremely valuable to treat tumors close to critical structures (e.g., for head-and-neck treatments) (100) However, there are circumstances and treatment sites where the advantage appears to be marginal at best (101)

In the pediatric patient population the impact of the decreased total absorbed energy in the patient [by a factor of 2–3 (92)] with protons is most significant The overall quality-of-life and reduction of secondary effects is of great importance and the reduction in overall normal tissue dose is proven

to be relevant (91) Using protons for cranio-spinal cases can reduce the dose

to the thyroid glands significantly One prime example is the treatment of medulloblastoma, a malignant tumor that originates in the medulla and extends into the cerebellum Treatment with photon radiation therapy invari-ably causes significant dose to the heart, lung, and abdominal tissues as well

as organs at risk in the cranium, something that can largely be avoided using protons These facts have boosted proton therapy in particular for pediatric patients For example, at MGH about 90% of the pediatric patient population

in radiation oncology is treated with proton therapy About 60% of those treated have brain tumors

Although the dose distributions achievable with protons are superior to those achievable with photons, it is debatable whether the advantages of pro-ton therapy are clinically significant for all treatment sites There is an ongo-ing discussion about the necessity for randomized clinical trials to show a significant advantage in outcome by using protons (102–105) Note that data

on late morbidity are still scarce because of the follow-up of less than 20 years for most patients

1.4.4 Economic Considerations

Related to the question of clinical trials mentioned above is the cost of health care, that is, whether the gain in tumor control or reduced tissue complication

is substantial enough to warrant the additional cost of proton therapy This

is one of the reasons why the treatment of prostate cancer with protons has been criticized (105, 106), and it has been argued that because of the limited availability of proton beams, proton therapy might be used predominantly

for such cases where protons are believed to make the biggest difference (e.g., for the pediatric patient population) (107).

Goitein and Jerman (108) estimated that the cost of a proton treatment is about double the cost of a photon treatment, considering the initial invest-ment and the operation of a facility The cost of a proton treatment is expected

to decrease with the advent of more and more facilities A detailed sion on the economic aspects of proton therapy is beyond the scope of this book, and the reader may be referred to publications on this subject (108–111)

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