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

PROTON THERAPY
PHYSICS

Edited by

Harald Paganetti

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


Proton Therapy
Physics


Series in Medical Physics and Biomedical Engineering
Series Editors: John G Webster, Slavik Tabakov, Kwan-Hoong Ng
Other recent books in the series:
Practical Biomedical Signal Analysis Using MATLAB®
K J Blinowska and J Zygierewicz
Physics for Diagnostic Radiology, Third Edition
P P Dendy and B Heaton (Eds.)
Nuclear Medicine Physics
J J Pedroso de Lima (Ed)
Handbook of Photonics for Biomedical Science
Valery V Tuchin (Ed)
Handbook of Anatomical Models for Radiation Dosimetry
Xie George Xu and Keith F Eckerman (Eds)
Fundamentals of MRI: An Interactive Learning Approach
Elizabeth Berry and Andrew J Bulpitt
Handbook of Optical Sensing of Glucose in Biological Fluids and Tissues
Valery V Tuchin (Ed)

Intelligent and Adaptive Systems in Medicine
Oliver C L Haas and Keith J Burnham
A Introduction to Radiation Protection in Medicine
Jamie V Trapp and Tomas Kron (Eds)
A Practical Approach to Medical Image Processing
Elizabeth Berry
Biomolecular Action of Ionizing Radiation
Shirley Lehnert
An Introduction to Rehabilitation Engineering
R A Cooper, H Ohnabe, and D A Hobson
The Physics of Modern Brachytherapy for Oncology
D Baltas, N Zamboglou, and L Sakelliou
Electrical Impedance Tomography
D Holder (Ed)


Series in Medical Physics and Biomedical Engineering

Proton Therapy
Physics

Edited by

Harald Paganetti

Massachusetts General Hospital and
Harvard Medical School, Boston, USA

Boca Raton London New York

CRC Press is an imprint of the
Taylor & Francis Group, an informa business

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


CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2012 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 2011912
International Standard Book Number-13: 978-1-4398-3645-3 (eBook - PDF)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts
have been made to publish reliable data and information, but the author and publisher cannot assume
responsibility for the validity of all materials or the consequences of their use. The authors and publishers
have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
copyright holders if permission to publish in this form has not been obtained. If any copyright material has
not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented,
including photocopying, microfilming, and recording, or in any information storage or retrieval system,
without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.
com ( or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood
Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and
registration for a variety of users. For organizations that have been granted a photocopy license by the CCC,
a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used

only for identification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at

and the CRC Press Web site at



Contents
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

v


vi

Contents

12. Dose Calculation Algorithms................................................................... 381
Benjamin Clasie, Harald Paganetti, and Hanne M. Kooy
13. Precision and Uncertainties in Proton Therapy for
Nonmoving Targets..................................................................................... 413
Jatinder R. Palta and Daniel K. Yeung
14. Precision and Uncertainties in Proton Therapy for
Moving Targets............................................................................................435
Martijn Engelsman and Christoph Bert
15. Treatment-Planning Optimization.......................................................... 461
Alexei V. Trofimov, Jan H. Unkelbach, and David Craft
16. In Vivo Dose Verification.......................................................................... 489
Katia Parodi
17. Basic Aspects of Shielding........................................................................ 525
Nisy Elizabeth Ipe
18. Late Effects from Scattered and Secondary Radiation........................ 555
Harald Paganetti
19. The Physics of Proton Biology.................................................................. 593

Harald Paganetti
20. Fully Exploiting the Benefits of Protons: Using Risk Models for
Normal Tissue Complications in Treatment Optimization................ 627
Peter van Luijk and Marco Schippers


About the Series
The Series in Medical Physics and Biomedical Engineering describes the applications of physical sciences, engineering, and mathematics in medicine and
clinical research.
The series seeks (but is not restricted to) publications in the following topics:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

•
•
•

Artificial organs
Assistive technology
Bioinformatics
Bioinstrumentation
Biomaterials
Biomechanics
Biomedical engineering
Clinical engineering
Imaging
Implants
Medical computing and mathematics
Medical/surgical devices
Patient monitoring
Physiological measurement
Prosthetics
Radiation protection, health physics, and dosimetry
Regulatory issues
Rehabilitation engineering
Sports medicine
Systems physiology
Telemedicine
Tissue engineering
Treatment

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.
vii



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 corporate 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 covering the main areas of activity, including education and training, scientific,
professional relations, and publications.

Objectives
• To contribute to the advancement of medical physics in all its aspects
• To organize international cooperation in medical physics, especially
in developing countries
• To encourage and advise on the formation of national organizations
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 committees and working groups.
ix


x

The International Organization for Medical Physics

The IOMP has several programs to assist medical physicists in developing
countries. The joint IOMP Library Programme supports 69 active libraries in
42 developing countries, and the Used Equipment Programme coordinates
equipment donations. The Travel Assistance Programme provides a limited
number of grants to enable physicists to attend the World Congresses.
The IOMP website is being developed to include a scientific database of
international standards in medical physics and a virtual education and
resource center.
Information on the activities of the IOMP can be found on its website at
.


Introduction
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 eradicating 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 uncertainties 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 conformal 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 target 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
in beam delivery and treatment modality focus mainly on increasing 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
xi


xii

Introduction

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

Bragg peak

Depth in tissue
FIGURE 1
Energy deposition as a function of depth for a proton beam leading to the Bragg peak.


Introduction

xiii

The physical characteristic of proton beams—their finite range—can be
used in radiation therapy for increasing the dose to the target or decreasing the dose to organs at risk. Treatment plan comparisons show that
protons offer potential gains for many sites. In some cases, the dose conformity 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 monitoring, and biological considerations. To fully utilize the advantages of proton 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 covers 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


xiv

Introduction

160

Number of publications

140

Proton therapy research publications

120
100
80
60
40
20
0
1970

1980

1990
Year

2000

2010

FIGURE 2
The number of publications listed in PubMed (a free database of citations on life sciences
and biomedical topics) per year with the phrase equal or similar to “proton radiation therapy” in the title or abstract (). Also shown is an exponential fit of the form Publications =
a × eb[year-1970] (solid line).

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 characteristics 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 discussed 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


Introduction

xv

outlining the basic quality assurance and commissioning guidelines, including acceptance testing. The quality assurance guidelines focus on dosimetry
as well 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 protonspecific 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 considerations and special treatment techniques are discussed.
Chapter 11 describes treatment planning for multiple-field uniform dose
and intensity-modulated proton therapy using beam scanning. The challenges and the potential of intensity-modulated treatments are described,
including uncertainties and optimization strategies. A few case studies conclude 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 precision 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 fourdimensional optimization strategies are described.
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.


xvi

Introduction

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 methods 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, biological 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.
Finally, outcome modeling is summarized in Chapter 20. This final chapter illustrates the use of risk models for normal tissue complications in treatment optimization. Proton beams allow precise dose shaping, and thus,
personalized treatment planning might become particularly important for
proton therapy in the future.
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 students 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 understand 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.


Editor
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 peerreviewed 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.

xvii



Contributors
Christoph Bert
GSI Helmholtzzentrum für
Schwerionenforschung GmbH
Abteilung Biophysik
Darmstadt, Germany

Bernard Gottschalk
Laboratory for Particle Physics and
Cosmology
Harvard University
Cambridge, Massachusetts

Benjamin Clasie
Department of Radiation Oncology
Massachusetts General Hospital
and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts

Nisy Elizabeth Ipe
Shielding Design, Dosimetry, and
Radiation Protection
San Carlos, California

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
Boston, Massachusetts
Stella Flampouri
University of Florida
Proton Therapy Institute
Jacksonville, Florida
Jacob Flanz
Department of Radiation Oncology
Massachusetts General Hospital
and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts

Hanne M. Kooy
Department of Radiation

Oncology
Massachusetts General Hospital
and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts
Zuofeng Li
University of Florida
Proton Therapy Institute
Jacksonville, Florida
Antony Lomax
Center for Proton Therapy
Paul Scherrer Institute
Villigen, Switzerland
Hsiao-Ming Lu
Department of Radiation
Oncology
Massachusetts General Hospital
and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts

xix


xx

Harald Paganetti
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
Jatinder R. Palta
Department of Radiation Oncology
University of Florida
Gainesville, Florida
Katia Parodi
Heidelberg Ion Beam Therapy
Center and Department of
Radiation Oncology
Heidelberg University Clinic
Heidelberg, Germany
Marco Schippers
Paul Scherrer Institut
Villigen, Switzerland
Roelf Slopsema
University of Florida
Proton Therapy Institute
Jacksonville, Florida

Contributors

Alexei V. Trofimov
Department of Radiation
Oncology
Massachusetts General Hospital

and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts
Jan H. Unkelbach
Department of Radiation
Oncology
Massachusetts General Hospital
and Harvard Medical School
Proton Therapy Center
Boston, Massachusetts
Peter van Luijk
Department of Radiation
Oncology
University Medical Center
Groningen
University of Groningen
Groningen, The Netherlands
Daniel K. Yeung
University of Florida Proton
Therapy Institute
Jacksonville, Florida
Department of Radiation
Oncology
University of Florida
Gainesville, Florida


1
Proton Therapy: History and Rationale
Harald Paganetti

CONTENTS
1.1 The Advent of Protons in Cancer Therapy.................................................1
1.2 History of Proton Therapy Facilities............................................................2
1.2.1 Early Days: Lawrence Berkeley Laboratory, Berkeley,
California............................................................................................. 2
1.2.2 Early Days: Gustav Werner Institute, Uppsala, Sweden............... 3
1.2.3 Early Days: Harvard Cyclotron Laboratory,
Cambridge, Massachusetts��������������������������������������������������������������� 3
1.2.4 Second Generation: Proton Therapy in Russia...............................4
1.2.5 Second Generation: Proton Therapy in Japan................................. 4
1.2.6 Second Generation: Proton Therapy Worldwide...........................5
1.2.7 Hospital-Based Proton Therapy........................................................5
1.2.8 Facilities and Patient Numbers.........................................................5
1.3 History of Proton Therapy Devices.............................................................. 7
1.3.1 Proton Accelerators............................................................................. 7
1.3.2 Mechanically Modulating Proton Beams........................................ 7
1.3.3 Scattering for Broad Beams............................................................... 7
1.3.4 Magnetic Beam Scanning.................................................................. 7
1.3.5Impact of Proton Technology in Other Areas of
Radiation Therapy�����������������������������������������������������������������������������8
1.4 The Clinical Rationale for Using Protons in Cancer Therapy.................. 9
1.4.1 Dose Distributions..............................................................................9
1.4.2 Early Clinical Implications.............................................................. 10
1.4.3 Current Clinical Implications......................................................... 11
1.4.4 Economic Considerations................................................................ 11
Acknowledgments................................................................................................. 12
References................................................................................................................ 12

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
1


2

Proton Therapy Physics

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 tissue. 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 advantage 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 presented 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
to describe the potential of proton beams for medical use. Wilson’s suggestion 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.

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 medical 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 irradiation 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 crossfiring technique (i.e., using only the plateau region of the depth dose curve).
This approximated a rotational treatment technique to concentrate the dose
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.


Proton Therapy: History and Rationale

3

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 proton 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 therapy, 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

4

Proton Therapy Physics

(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 treatment 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, melanoma 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 proton 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
St. Petersburg. The latter treated intracranial diseases using Bragg curve plateau irradiation with a 1-GeV beam (40).
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 irradiated 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 treatments 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 irradiation 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