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
1.3.5 Impact 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 tis-
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
to describe the potential of proton beams for medical use. Wilson’s sugges-
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.

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 irradi-
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
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 pro-
ton therapy program ran from 1957 to 1976 and reopened in 1988 (19).

1.2.3  E arly 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
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 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 pro-
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
St. Petersburg. The latter treated intracranial diseases using Bragg curve pla-
teau 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 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 irradia-
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
Proton Therapy: History and Rationale 5

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 institu-
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
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.
6 Proton Therapy Physics

TABLE 1.1
Total Years of Operation and Patients Treated with Protons. Worldwide (as of
12/2010)
Ocular Number
Tumors First Last of
Facility Only Patient Patient Patients
Berkeley 184, California 1954 1957 30
Uppsala_1, Sweden 1957 1976 73
Cambridge (Harvard), Massachusetts 1961 2002 9116
Dubna (JINR_1), Russia 1967 1996 124
Chiba (NIRS), Japan • 1979 2002 145
Tsukuba (PMRC_1), Japan 1983 2000 700
Louvain-la-Neuve, Belgium • 1991 1993 21
Bloomington (MPRI_1), Indiana • 1993 1999 34
Moscow (ITEP), Russia 1969 4246
St. Petersburg, Russia 1975 1362
Villigen (PSI_1, 72 MeV), Switzerland • 1984 2010 5458
Uppsala_2, Sweden 1989 1000
Clatterbridge, England • 1989 2021
Loma Linda (LLUMC), California 1990 15000
Nice (CAL), France • 1991 4209
Orsay (CPO), France 1991 5216
iThemba LABS, Somerset West, South Africa 1993 511
UCSF – CNL, California • 1994 1285
Vancouver (TRIUMF), Canada • 1995 152
Villigen (PSI_2, 230 MeV), Switzerland 1996 772
Dubna (JINR_2), Russia 1999 720
Kashiwa (NCC), Japan 1998 772
Berlin (HMI), Germany • 1998 1660
Hyogo (HIBMC), Japan 2001 2382
Tsukuba (PMRC_2), Japan 2001 1849
Boston (MGH-FHBPTC), Massachusetts 2001 4967
Catania (INFN-LNS), Italy • 2002 174
Wakasa Bay (WERC), Japan 2002 2009 62
Shizuoka, Japan 2003 986
Wanjie (WPTC), China 2004 1078
Bloomington (MPRI_2), Indiana 2004 1145
Houston, Texas 2006 2700
Jacksonville, Florida 2006 2679
Ilsan (NCC), South Korea 2007 648
Munich (RPTC), Germany 2009 446
Oklahoma City (ProCurePTC), Oklahoma 2009 21
Heidelberg (HIT), Germany 2010 40
Facilities in operation: 27 Total number of patients treated: 73,804
Source: The Particle Therapy Co-Operative Group (PTCOG) ([Link]
Proton Therapy: History and Rationale 7

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) pro-
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,
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 ther-
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
8 Proton Therapy Physics

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 inten-
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
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 radi-
ation therapy is being conducted also in conventional radiation therapy.
Proton Therapy: History and Rationale 9

External beam radiation therapy requires a geometric description of the inter-

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
on potential beam approaches that covered the target in the lateral dimension
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 uti-
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
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 ther-
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).

1.4 The Clinical Rationale for Using

Protons in Cancer Therapy
1.4.1  Dose Distributions
Any new radiation treatment technology has to find acceptance amongst
clinicians, for example, by demonstrating improved dose distributions and
suggesting a more favorable treatment outcome (30). A more favorable dose
10 Proton Therapy Physics

distribution is a distribution that is more closely confined to the tumor vol-

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.
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 deliv-
ery (30). By the mid-1980s roughly one-third of the treated patients received
intracranial radiosurgery treatments (e.g., arterioveneous maformations)
(83, 84).
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
Proton Therapy: History and Rationale 11

otherwise poorly manageable diseases such as for chordoma and chondro-

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).

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
12 Proton Therapy Physics

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 discus-
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).

Acknowledgments
The author thanks Dr. Herman Suit and Jocelyn Woods for proofreading.

References
1. Roentgen WC. Über eine neue Art von Strahlen. Sitzungsberichte der
Würzburger Physikalischmedicinischen Gesellschaft. 1895;137:41.
2. Roentgen WC. On a new kind of rays. Nature. 1896;53(1369):274–276.
3. Hewitt HB. Rationalizing radiotherapy: some historical aspects of the endeav-
our. Br J Radiol. 1973 Oct;46(550):917–926.
4. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491.
5. Tobias CA, Anger HO, Lawrence JH. Radiological use of high energy deu-
terons and alpha particles. Am J Roentgenol Radium Ther Nucl Med. 1952
Jan;67(1):1–27.
6. Ashikawa JK, Sondhaus CA, Tobias CA, Kayfetz LL, Stephens SO, Donovan
M. Acute effects of high-energy protons and alpha particles in mice. Radiat Res
Suppl. 1967;7:312–324.
7. Lawrence JH. Proton irradiation of the pituitary. Cancer. 1957 Jul-Aug;10(4):795–798.
8. Tobias CA, Lawrence JH, Born JL, McCombs R, Roberts JE, Anger HO, et al.
Pituitary irradiation with high energy proton beams: a preliminary report.
Cancer Res. 1958;18:121–134.
9. Lawrence JH, Tobias CA, Born JL, Wangcc, Linfoot JH. Heavy-particle irradia-
tion in neoplastic and neurologic disease. J Neurosurg. 1962 Sep;19:717–722.
10. Falkmer S, Larsson B, Stenson S. Effects of single dose proton irradiation of
normal skin and Vx2 carcinoma in rabbit ears: a comparative investigation with
protons and roentgen rays. Acta Radiol. 1959 Sep;52:217–234.
11. Larsson B, Leksell L, Rexed B, Sourander P. Effect of high energy protons on the
spinal cord. Acta Radiol. 1959 Jan;51(1):52–64.
12. Leksell L, Larsson B, Andersson B, Rexed B, Sourander P, Mair W. Lesions in
the depth of the brain produced by a beam of high energy protons. Acta Radiol.
1960 Oct;54:251–264.
Proton Therapy: History and Rationale 13

13. Larsson B. Blood vessel changes following local irradiation of the brain with
high-energy protons. Acta Soc Med Ups. 1960;65:51–71.
14. Larsson B. Pre-therapeutic physical experiments with high energy protons. Br J
Radiol. 1961 Mar;34:143–-151.
15. Larsson B, Leksell L, Rexed B. The use of high-energy protons for cerebral sur-
gery in man. Acta Chir Scandinavia. 1963;125:1–7.
16. Larsson B, Leksell L, Rexed B, Sourander P, Mair W, Andersson B. The high-energy
proton beam as a neurosurgical tool. Nature. 1958 Nov 1;182(4644):1222–1223.
17. Falkmer S, Fors B, Larsson B, Lindell A, Naeslund J, Stenson S. Pilot study on
proton irradiation of human carcinoma. Acta Radiol. 1962 Feb;58:33–51.
18. Fors B, Larsson B, Lindell A, Naeslund J, Stenson S. Effect of high energy protons
on human genital carcinoma. Acta Radiol Ther Phys Biol. 1964 Oct;2:384–398.
19. Montelius A, Blomquist E, Naeser P, Brahme A, Carlsson J, Carlsson A-C, et al.
The narrow proton beam therapy unit at the Svedberg Laboratory in Uppsala.
Acta Oncol. 1991;30:739–745.
20. Kjellberg RN, Koehler AM, Preston WM, Sweet WH. Stereotaxic instrument for
use with the Bragg peak of a proton beam. Confin Neurol. 1962;22:183–189.
21. Larsson B, Kihlman BA. Chromosome aberrations following irradiation with
high-energy protons and their secondary radiation: a study of dose distribu-
tion and biological efficiency using root-tips of Vicia faba and Allium cepa. Int
J Radiat Biol. 1960;2:8–19.
22. Dalrymple GV, Lindsay IR, Hall JD, Mitchell JC, Ghidoni JJ, Kundel HL,
et al. The relative Biological effectiveness of 138-MeV protons as compared to
cobalt-60 gamma radiation. Radiat Res. 1966;28:489–506.
23. Dalrymple GV, Lindsay IR, Ghidoni JJ, Hall JD, Mitchell JC, Kundel HL, et al.
Some effects of 138-Mev protons on primates. Radiat Res. 1966 Jun;28(2):471–488.
24. Hall EJ, Kellerer AM, Rossi HH, Yuk-Ming PL. The relative biological effective-
ness of 160 MeV protons. II. Biological data and their interpretation in terms of
microdosimetry. Int J Radiat Oncol Biol Phys. 1978;4:1009–1013.
25. Robertson JB, Williams JR, Schmidt RA, Little JB, Flynn DF, Suit HD.
Radiobiological studies of a high-energy modulated proton beam utilizing cul-
tured mammalian cells. Cancer. 1975;35:1664–1677.
26. Tepper J, Verhey L, Goitein M, Suit HD. In vivo determinations of RBE in a high
energy modulated proton beam using normal tissue reactions and fractionated
dose schedules. Int J Radiat Oncol Biol Phys. 1977;2:1115–1122.
27. Todd P. Radiobiology with heavy charged particles directed at radiotherapy.
Eur J Cancer. 1974 Apr;10(4):207–210.
28. Kjellberg RN, Sweet WH, Preston WM, Koehler AM. The Bragg peak of a proton
beam in intracranial therapy of tumors. Trans Am Neurol Assoc. 1962;87:216–218.
29. Kjellberg RN, Kliman B. Bragg peak proton treatment for pituitary-related con-
ditions. Proc R Soc Med. 1974 Jan;67(1):32–33.
30. Suit HD, Goitein M, Tepper J, Koehler AM, Schmidt RA, Schneider R. Exploratory
study of proton radiation therapy using large field techniques and fractionated
dose schedules. Cancer. 1975;35:1646–1657.
31. Gragoudas ES, Goitein M, Koehler AM, Verhey L, Tepper J, Suit HD, et al.
Proton irradiation of small choroidal malignant melanomas. Am J Ophthalmol.
1977 May;83(5):665–673.
32. Constable IJ, Goitein M, Koehler AM, Schmidt RA. Small-field irradiation of
monkey eyes with protons and photons. Radiat Res. 1976;65:304–314.
14 Proton Therapy Physics

33. Constable IJ, Roehler AM. Experimental ocular irradiation with accelerated pro-
tons. Invest Ophthalmol. 1974 Apr;13(4):280–287.
34. Shipley WU, Tepper JE, Prout GR, Jr, Verhey LJ, Mendiondo OA, Goitein M,
et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA.
1979 May 4;241(18):1912–1915.
35. Chuvilo IV, Goldin LL, Khoroshkov VS, Blokhin SE, Breyev VM, Vorontsov IA,
et al. ITEP synchrotron proton beam in radiotherapy. Int J Radiat Oncol Biol
Phys. 1984 Feb;10(2):185–195.
36. Khoroshkov VS, Goldin LL. Medical proton accelerator facility. Int J Radiat
Oncol Biol Phys. 1988 Oct;15(4):973–978.
37. Dzhelepov VP, Komarov VI, Savchenko OV. [Development of a proton beam
synchrocyclotron with energy from 100 to 200MeV for medico-biological
research]. Med Radiol (Mosk). 1969 Apr;14(4):54–58.
38. Khoroshkov VS, Barabash LZ, Barkhudarian AV, Gol’din LL, Lomanov MF,
Pliashkevich LN, et al. [A proton beam accelerator ITEF for radiation therapy].
Med Radiol (Mosk). 1969 Apr;14(4):58–62.
39. Dzhelepov VP, Savchenko OV, Komarov VI, Abasov VM, Goldin LL, Onossovsky
KK, et al. Use of USSR proton accelerators for medical purposes. IEEE Trans
Nucl Sci. 1973;20:268–2670.
40. Abrosimov NK, Gavrikov YA, Ivanov EM, Karlin DL, Khanzadeev AV, Yalynych
NN, et al. 1000 MeV Proton beam therapy facility at Petersburg Nuclear Physics
Institute Synchrocyclotron. J Phys Conf Ser. 2006;41:424–432.
41. Savinskaia AP, Minakova EI. [Proton hypophysectomy and the induction of
mammary cancer]. Med Radiol (Mosk). 1979 Feb;24(2):53–57.
42. Kanai T, Kawachi K, Kumamoto Y, Ogawa H, Yamada T, Matsuzawa H, et al.
Spot scanning system for proton radiotherapy. Med Phys. 1980;7:365–369.
43. Kurihara D, Suwa S, Tachikawa A, Takada Y, Takikawa K. A 300-MeV pro-
ton beam line with energy degrader for medical science. Jpn J Appl Phys.
1983;22:1599–1605.
44. Zografos L, Perret C, Egger E, Gailloud C, Greiner R. Proton beam irradiation
of uveal melanomas at Paul Scherrer Institute (former SIN). Strahlenther Onkol.
1990 Jan;166(1):114.
45. Slater JM, Archambeau JO, Miller DW, Notarus MI, Preston W, Slater JD. The
proton treatment center at Loma Linda University Medical Center: rationale for
and description of its development. Int J Radiat Oncol Biol Phys. 1992;22:383–389.
46. Cole F, Livdahl PV, Mills F, Teng L. Design and application of a proton therapy
accelerator. Proc 1987 IEEE Particle Accelerator Conference. 1987;Piscataway,
NJ: IEEE Press. 1985–1987 (Lindstrom ER, Taylor LS, eds.).
47. Koehler AM. Preliminary design study for a corkscrew gantry. Harvard
Cyclotron Laboratory Report. 1987.
48. Raju MR. Proton radiobiology, radiosurgery and radiotherapy. Int J Radiat Biol.
1995;67:237–259.
49. Lawrence EO, Edlefson NE. On the production of high speed protons. Science.
1930;72:376–377.
50. Veksler V. Concerning some new methods of acceleration of relativistic parti-
cles. Doklady Acad Sci. USSR 1944;43:444.
51. Oliphant MO. The acceleration of particles to very high energies. Classified
memo submitted to DSIR, United Kingdom; now in the University of
Birmingham Archive. 1943.
Proton Therapy: History and Rationale 15

52. Wilson RR. Range, straggling, and multiple scattering of fast protons. Phys Rev.
1947;74:385–386.
53. Koehler AM. Dosimetry of proton beams using small silicon detectors. Radiat
Res. 1967;7:s53–s63.
54. Koehler AM, Preston WM. Protons in radiation therapy. Radiology.
1972;104:191–195.
55. Koehler AM, Schneider RJ, Sisterson JM. Range modulators for protons and
heavy ions. Nucl Instr Methods. 1975;131:437–440.
56. Blokhin SI, Gol’din LL, Kleinbok Ia L, Lomanov MF, Onosovskii KK, Pavlonskii
LM, et al. [Dose field formation on proton beam accelerator ITEF]. Med Radiol
(Mosk). 1970 May;15(5):64–68.
57. Karlsson BG. [Methods for calculating and obtaining some favorable dosage
distributions for deep therapy with high energy protons]. Strahlentherapie.
1964 Aug;124:481–492.
58. Koehler AM, Schneider RJ, Sisterson JM. Flattening of proton dose distributions
for large-field radiotherapy. Med Phys. 1977;4:297–301.
59. Sanberg G. Electron beam flattening with an annular scattering foil. IEEE Trans
Nucl Sci. 1973;20:1025.
60. Gottschalk B, Wagner M. Contoured scatterer for proton dose flattening.
Harvard Cyclotron Laboratory Report. 1989.
61. Goitein M, Chen GTY. Beam scanning for heavy charged particle radiotherapy.
Med Phys. 1983;10:831–840.
62. Grunder HA, Leemann CW. Present and future sources of protons and heavy
ions. Int J Radiat Oncol Biol Phys. 1977;3:71–80.
63. Chu WT, Curtis SB, Llacer J, Renner TR, Sorensen RW. Wobbler facility for biomed-
ical experiments at the BEVALAC. IEEE Trans Nucl Sci. 1985;NS-32:3321–3323.
64. Leemann C, Alonso J, Grunder H, Hoyer E, Kalnins G, Rondeau D, et al.
A  3-dimensional beam scanning system for particle radiation therapy. IEEE
Trans Nucl Sci. 1977;NS-24:1052–1054.
65. Kanai T, Kawachi K, Matsuzawa H, Inada T. Three-dimensional beam scanning
for proton therapy. Nucl Instr Methods. 1983;214:491–496.
66. Kawachi K, Kanai T, Matsuzawa H, Inada T. Three dimensional spot beam scan-
ning method for proton conformation radiation therapy. Acta Radiol Suppl.
1983;364:81–88.
67. Kawachi K, Kanai T, Matsuzawa H, Kutsutani-Nakamura Y, Inada T. [Proton
radiotherapy facility using a spot scanning method]. Nippon Igaku Hoshasen
Gakkai Zasshi. 1982 May 25;42(5):467–475.
68. Hiraoka T, Kawashima K, Hoshino K, Kawachi K, Kanai T, Matsuzawa H. [Dose
distributions for proton spot scanning beams: effect by range modulators].
Nippon Igaku Hoshasen Gakkai Zasshi. 1983 Oct 25;43(10):1214–1223.
69. Chu WT, Ludewigt BA, Renner TR. Instrumentation for treatment of cancer
using proton and light-ion beams. Rev Sci Instrum. 1993;64:2055–2122.
70. Kjellberg RN, Nguyen NC, Kliman B. [The Bragg Peak proton beam in stereo-
taxic neurosurgery]. Neurochirurgie. 1972 May-Jun;18(3):235–265.
71. Goitein M. The measurement of tissue heterodensity to guide charged particle
radiotherapy. Int J Radiat Oncol Biol Phys. 1977;3:27–33.
72. Suit HD, Goitein M, Tepper JE, Verhey L, Koehler AM, Schneider R, et al. Clinical
experience and expectation with protons and heavy ions. Int J Radiat Oncol Biol
Phys. 1977;3:115–125.
16 Proton Therapy Physics

73. Goitein M. Compensation for inhomogeneities in charged particle radio-

therapy using computed tomography. Int J Radiat Oncol Biol Phys. 1978
May-Jun;4(5-6):499–508.
74. Goitein M. Computed tomography in planning radiation therapy. Int J Radiat
Oncol Biol Phys. 1979 Mar;5(3):445–447.
75. Munzenrider JE, Pilepich M, Rene-Ferrero JB, Tchakarova I, Carter BL. Use of
body scanner in radiotherapy treatment planning. Cancer. 1977 Jul;40(1):170–179.
76. Goitein M, Abrams M, Gentry R, Urie M, Verhey L, Wagner M. Planning
treatment with heavy charged particles. Int J Radiat Oncol Biol Phys. 1982;8:
2065–2070.
77. Goitein M, Abrams M. Multi-dimensional treatment planning: I. Delineation of
anatomy. Int J Radiat Oncol Biol Phys. 1983 Jun;9(6):777–787.
78. Goitein M, Abrams M, Rowell D, Pollari H, Wiles J. Multi-dimensional treat-
ment planning: II. Beam’s eye-view, back projection, and projection through CT
sections. Int J Radiat Oncol Biol Phys. 1983 Jun;9(6):789–797.
79. Goitein M, Miller T. Planning proton therapy of the eye. Med Phys. 1983;
10:275–283.
80. Verhey LJ, Goitein M, McNulty P, Munzenrider JE, Suit HD. Precise positioning
of patients for radiation therapy. Int J Radiat Oncol Biol Phys. 1982;8:289–294.
81. Suit HD, Goitein M. Dose-limiting tissues in relation to types and location of
tumours: implications for efforts to improve radiation dose distributions. Eur
J Cancer. 1974 Apr;10(4):217–224.
82. Gragoudas ES, Seddon JM, Egan K, Glynn R, Munzenrider J, Austin-Seymour
M, et al. Long-term results of proton beam irradiated uveal melanomas.
Ophthalmology. 1987 Apr;94(4):349–353.
83. Kjellberg RN, Davis KR, Lyons S, Butler W, Adams RD. Bragg peak proton
beam therapy for arteriovenous malformation of the brain. Clin Neurosurg.
1983;31:248–290.
84. Kjellberg RN, Hanamura T, Davis KR, Lyons SL, Adams RD. Bragg-peak pro-
ton-beam therapy for arteriovenous malformations of the brain. N Engl J Med.
1983 Aug 4;309(5):269–274.
85. Suit H, Goitein M, Munzenrider J, Verhey L, Blitzer P, Gragoudas E, et al.
Evaluation of the clinical applicability of proton beams in definitive fraction-
ated radiation therapy. Int J Radiat Oncol Biol Phys. 1982;8:2199–2205.
86. Suit HD, Goitein M, Munzenrider J, Verhey L, Davis KR, Koehler A, et al.
Definitive radiation therapy for chordoma and chondrosarcoma of base of skull
and cervical spine. J Neurosurg. 1982 Mar;56(3):377–385.
87. Austin-Seymour M, Munzenrieder JE, Goitein M, Gentry R, Gragoudas E,
Koehler AM, et al. Progress in low-LET heavy particle therapy: intracranial and
paracranial tumors and uveal melanomas. Radiat Res. 1985;104:S219–226.
88. Archambeau JO, Slater JD, Slater JM, Tangeman R. Role for proton beam irradia-
tion in treatment of pediatric CNS malignancies. Int J Radiat Oncol Biol Phys.
1992;22:287–294.
89. Fuss M, Hug EB, Schaefer RA, Nevinny-Stickel M, Miller DW, Slater JM, et al.
Proton radiation therapy (PRT) for pediatric optic pathway gliomas: compari-
son with 3D planned conventional photons and a standard photon technique.
Int J Radiat Oncol Biol Phys. 1999;45:1117–1126.
90. Fuss M, Poljanc K, Miller DW, Archambeau JO, Slater JM, Slater JD, et al. Normal
tissue complication probability (NTCP) calculations as a means to compare
Proton Therapy: History and Rationale 17

proton and photon plans and evaluation of clinical appropriateness of calcu-

lated values. Int J Cancer (Radiat Oncol Invest). 2000;90:351–358.
91. Lin R, Hug EB, Schaefer RA, Miller DW, Slater JM, Slater JD. Conformal pro-
ton radiation therapy of the posterior fossa: a study comparing protons with
three-dimensional planned photons in limiting dose to auditory structures. Int
J Radiat Oncol Biol Phys. 2000;48:1219–1226.
92. Lomax AJ, Bortfeld T, Goitein G, Debus J, Dykstra C, Tercier P-A, et al. A treat-
ment planning inter-comparison of proton and intensity modulated photon
radiotherapy. Radiother Oncol. 1999;51:257–271.
93. St. Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM, et al.
Advantage of protons compared to conventional X-ray or IMRT in the treatment
of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys. 2004
Mar 1;58(3):727–734.
94. Suit HD, Goldberg S, Niemierko A, Trofimov A, Adams J, Paganetti H, et al.
Proton beams to replace photon beams in radical dose treatments. Acta Oncol.
2003;42:800–808.
95. Yock T, Schneider R, Friedmann A, Adams J, Fullerton B, Tarbell N. Proton
radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosi-
metric comparison with photons. Int J Radiat Oncol Biol Phys. 2005 Nov
15;63(4):1161–1168.
96. Isacsson U, Hagberg H, Johansson K-A, Montelius A, Jung B, Glimelius B.
Potential advantages of protons over conventional radiation beams for paraspi-
nal tumours. Radiother Oncol. 1997;45:63–70.
97. Isacsson U, Montelius A, Jung B, Glimelius B. Comparative treatment planning
between proton and X-ray therapy in locally advanced rectal cancer. Radiother
Oncol. 1996;41:263–272.
98. Miralbell R, Lomax A, Russo M. Potential role of proton therapy in the
treatment of pediatric medulloblastoma/primitive neuro-ectodermal
tumors: spinal theca irradiation. Int J Radiat Oncol Biol Phys. 1997;38:
805–811.
99. Weber DC, Trofimov AV, Delaney TF, Bortfeld T. A treatment plan comparison
of intensity modulated photon and proton therapy for paraspinal sarcomas. Int
J Radiat Oncol Biol Phys. 2004;58:1596–1606.
100. Chan AW, Liebsch NJ. Proton radiation therapy for head and neck cancer. J Surg
Oncol. 2008 Jun 15;97(8):697–700.
101. Lee M, Wynne C, Webb S, Nahum AE, Dearnaley D. A comparison of pro-
ton and megavoltage X-ray treatment planning for prostate cancer. Radiother
Oncol. 1994;33:239–253.
102. Glimelius B, Montelius A. Proton beam therapy do we need the randomised
trials and can we do them? Radiother Oncol. 2007 May;83(2):105–109.
103. Goitein M, Cox JD. Should randomized clinical trials be required for proton
radiotherapy? J Clin Oncol. 2008 Jan 10;26(2):175–176.
104. Goitein M. Trials and tribulations in charged particle radiotherapy. Radiother
Oncol. 2010 Apr;95(1):23–31.
105. Brada M, Pijls-Johannesma M, De Ruysscher D. Current clinical evidence for
proton therapy. Cancer J. 2009 Jul-Aug;15(4):319–324.
106. Konski A, Speier W, Hanlon A, Beck JR, Pollack A. Is proton beam therapy cost
effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007
Aug 20;25(24):3603–3608.
18 Proton Therapy Physics

107. Jagsi R, DeLaney TF, Donelan K, Tarbell NJ. Real-time rationing of scarce
resources: the Northeast Proton Therapy Center experience. J Clin Oncol.
2004;22:2246–2250.
108. Goitein M, Jermann M. The relative costs of proton and X-ray radiation therapy.
Clin Oncol. 2003;15:S37–S50.
109. Lundkvist J, Ekman M, Ericsson SR, Jonsson B, Glimelius B. Proton therapy
of cancer: potential clinical advantages and cost-effectiveness. Acta Oncol.
2005;44(8):850–861.
110. Peeters A, Grutters JP, Pijls-Johannesma M, Reimoser S, De Ruysscher D,
Severens JL, et al. How costly is particle therapy? Cost analysis of external beam
radiotherapy with carbon-ions, protons and photons. Radiother Oncol. 2010
Apr;95(1):45–53.
111. Lodge M, Pijls-Johannesma M, Stirk L, Munro AJ, De Ruysscher D, Jefferson T.
A systematic literature review of the clinical and cost-effectiveness of hadron
therapy in cancer. Radiother Oncol. 2007 May;83(2):110–122.