An evidence based review of proton beam therapy: The report of ASTRO’s
emerging technology committee
Aaron M. Allena,⇑, Todd Pawlickib, Lei Dongc, Eugene Fourkald, Mark Buyyounouskid, Keith Cengele,
John Plastarase, Mary K. Buccic, Torunn I. Yockf, Luisa Bonillaa, Robert Priced, Eleanor E. Harrisg,
Andre A. Konskih
aDavidoff Center, Tel Aviv University, Israel;bUniversity of California, San Diego, La Jolla, USA;cM.D. Anderson Cancer Center, University of Texas, Houston, USA;dFox Chase
Cancer Center, Philadelphia, USA;eUniversity of Pennsylvania, Philadelphia, USA;fMassachusetts General Hospital, Boston, USA;gH. Lee Moffit Cancer Center, Tampa, USA;hWayne
State University Medical Center, Detroit, USA
a r t i c l ei n f o
Received 4 October 2011
Received in revised form 30 January 2012
Accepted 4 February 2012
Available online 9 March 2012
Proton beam therapy
Evidence based guidelines
a b s t r a c t
Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. The pur-
pose of this work was to evaluate the state of the science of PBT and arrive at a recommendation for the
use of PBT. The emerging technology committee of the American Society of Radiation Oncology (ASTRO)
routinely evaluates new modalities in radiotherapy and assesses the published evidence to determine
recommendations for the society as a whole. In 2007, a Proton Task Force was assembled to evaluate
the state of the art of PBT. This report reflects evidence collected up to November 2009. Data was
reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck,
prostate, and pediatric tumors. Current data do not provide sufficient evidence to recommend PBT in lung
cancer, head and neck cancer, GI malignancies, and pediatric non-CNS malignancies. In hepatocellular
carcinoma and prostate cancer and there is evidence for the efficacy of PBT but no suggestion that it is
superior to photon based approaches. In pediatric CNS malignancies PBT appears superior to photon
approaches but more data is needed. In large ocular melanomas and chordomas, we believe that there
is evidence for a benefit of PBT over photon approaches. PBT is an important new technology in radiother-
apy. Current evidence provides a limited indication for PBT. More robust prospective clinical trials are
needed to determine the appropriate clinical setting for PBT.
? 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 8–11
This report summarizes the past, present and future of proton
beam therapy for malignant disease. Overall, hundreds of patients
have been treated worldwide with proton therapy for a variety of
different diseases. Two questions remain: Is proton therapy better
than the current standard of care with photon treatment? Should it
be adopted as the standard of care?
We are not the first to attempt to answer these important ques-
tions. In 2007, two systematic reviews of the literature were per-
formed in Europe and published in Radiotherapy and Oncology.
Olsen et al. summarized that in all disease sites including pediatric,
ocular, GI, lung, base of skull that the evidence for the efficacy of
proton therapy is low . They did comment that there is more
support for its use in prostate cancer as a method of dose escala-
tion, but no conclusions could be drawn regarding the preference
of protons over photons as a method of dose escalation. Lodge et
al. similarly reviewed the literature in addition to studies of ion
therapy. They concluded that there is no evidence for the use of
protons in GI, pelvis, head and neck, lung, and sarcoma. They con-
clude that in prostate cancer, protons are an option but not supe-
rior to photons. In opposition to Olsen et al., they conclude that
there is evidence for the use of protons in chordomas and large
ocular tumors. They did not review the role of protons in pediatric
patients . Another review by Brada et al. published in 2007 con-
cluded that there is insufficient evidence at the present to recom-
mend the use of proton therapy in any of the disease sites .
This review focuses specifically on the use of PBT to treat CNS
malignancies, lung cancer, gastrointestinal malignancies, ocular
melanoma, prostrate cancer, head and neck cancer, and pediatric
Central nervous system
CNS tumors are treated with ionizing radiation in definitive,
post-operative and palliative clinical settings. Unfortunately, the
radiotherapy dose necessary to achieve long term local control of
CNS tumors often exceeds the tolerance doses of critical structures,
including the spinal cord, brain stem, optic nerves, pituitary gland,
vertebral bodies, and eyes. As a result, difficult clinical choices
0167-8140/$ - see front matter ? 2012 Elsevier Ireland Ltd. All rights reserved.
⇑Corresponding author. Address: Davidoff Center, Rabin Medical Center, Tel Aviv
University, Petach Tikvah, Israel.
E-mail addresses: Aarona2@clalit.org.il, firstname.lastname@example.org (A.M. Allen).
Radiotherapy and Oncology 103 (2012) 8–11
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must be made between risking damage to these structures and fail-
ing to deliver sufficient radiotherapy doses to attain local control of
the tumor. Even while maintaining dose constraints to critical
structures, CNS radiotherapy can lead to undesirable neurocogni-
tive deficits that may be either temporary or permanent in adults
and are often permanent in children. Therefore, any advance in
dose conformity to the target volume and avoidance of critical
structures either with IMRT (photons) or PBT (scanning or scat-
tered beam) or certainly IMPBT is welcomed.
Planning studies that have compared conformal photon and PBT
CNS radiotherapy techniques have, in general, found that the cov-
erage of the PTV is either similar or slightly better with PBT, but
that the avoidance of critical structures and the total integral dose
were substantially improved with PBT . One site where PBT has
been extensively used is chordomas. In a number of studies the lo-
cal control of chordomas has approached 80%, better than a series
of treatment with conventional photon therapy [5–7]. Other cen-
ters using either combinations of photons with PBT or PBT alone
have found similar results and attributed the success of this ther-
apy to the increased ability to safely deliver higher doses of radio-
therapy using PBT techniques as compared to photons [8–10]. In
other series using PBT to treat meningiomas, 91.7–100% local con-
trol was achieved at 3 years with rates of grade 3 or greater toxicity
of 0–12.5% [11,5].
PBT has multiple theoretical advantages over photon radiother-
apy for CNS tumors due to the ability of PBT to deliver high dose
radiotherapy with steeper dose gradients to proximal critical struc-
tures than can be achieved with photon radiotherapy. Clinical data
from PBT or mixed photon/PBT for base of skull tumors appear
superior to previously published series of conformal photon radio-
therapy; however, stereotactic photon radiosurgery may provide a
significant dosimetric and clinical advantage to standard confor-
mal (3D or IMRT) radiotherapy techniques. Overall, more clinical
data (published clinical trials) are needed to fully establish the role
of PBT in CNS tumors.
The most lethal malignancy in the world today, lung cancer rep-
resents a very large group of patients treated each year with radi-
ation therapy . Radiation is used as a sole modality to treat
stage I NSCLC in the medically inoperable settings. In stage III
NSCLC radiation is used in combination with chemotherapy and
sometimes surgery to provide definitive treatment. It is also used
in limited stage SCLC in combination with systemic therapy and
for palliation of obstructive disease in stage IV lung cancer. Major
treatment related toxicities include pneumonitis and esophagitis.
For stage III or higher lung cancers, PBT has unique advantages in
sparing lung volumes from receiving low dose irradiations from
the exiting photon beams. Contralateral lung volume may be com-
pletely spared with PBT.
PBT has been shown in a limited number of patients to produce
80–90% local control rate with hypofractionated radiation in early
stage lung cancer [13–16]. However, a recent meta-analysis
showed no difference between photon based SBRT to PBT .
Very little published data exists for locally advanced lung cancer.
It is important to note that for all moving tumors, certainly for
lung cancer, challenges exist in the accuracy and planning of PBT.
Because of organ motion as well as changes in lung density during
respiration, PBT in the lung requires significantly more work in
planning and dose verification.
PBT has been used in the treatment of stage I NSCLC although
no clear clinical benefit over photon therapy has currently been
shown. Data regarding the use of PBT in other clinical scenarios re-
main limited and do not provide sufficient evidence to recommend
PBT for lung cancer outside of clinical trials. In addition, unlike in
some other disease sites, the issue of organ motion in lung cancer
is critical and adds an additional challenge to the use of PBT.
Radiotherapy plays a role in two different settings in GI malig-
nancies. For diseases in which surgery plays a primary role in the
treatment (rectum, gastric, and esophagus), radiotherapy provides
either neoadjuvant or an adjuvant role delivering moderate dose
treatment (45 Gy) to a large volume to provide downstaging and
microscopic coverage . For other diseases in which radiation
plays the primary role in therapy (hepatocellular, esophagus, and
pancreas), dose escalation and normal tissue avoidance become
more important and thus a role for PBT may be more relevant.
The only area where PBT has been extensively studied is HCC. In
a number of studies from the Asia, fractionated PBT has been used
in HCC with good success providing a local control rate of between
70% and 85% [19–28].
PBT is mostly untested in GI malignancies, and the number of
patients with GI malignancies who are eligible for PBT will be very
small until indications for its use become clearer. In rectal and gas-
tric cancers there appears to be little role for PBT. In esophageal
and pancreatic cancers there may be a rationale for PBT, as these
are two sites often with localized unresectable disease near critical
organs at risk, but almost no clinical data exist. In hepatocellular
cancer there appears to be the most data and perhaps promise
for PBT as an alternative to photon based approaches, but more rig-
orous study and prospective clinical trials are necessary to define
the differences in toxicity and efficacy between protons and
Ocular melanoma can threaten vision and is potentially fatal
when it disseminates . Advances in the treatment of ocular
melanoma have been aimed at preservation of the eye and ideally
vision while maintaining high cure rates. Therapeutic options
range from local ablative treatments to enucleation of the eye,
depending on the size and location of the tumor.
PBT has been reported in the literature in thousands of cases for
ocular melanoma. Combined results of leading centers in the U.S.
and Europe have shown a 95% local control rate and a 90% eye
retention rate [30–34]. This technique is especially useful in large
and posteriorly located melanomas that are unapproachable by
PBT has been shown to be effective in the treatment of large
ocular melanomas not approachable via brachytherapy. In the
group of intermediate tumors that has been well studied by the
COMS (Collaborative Ocular Melanoma Study) group, there is evi-
dence for efficacy of both PBT and brachytherapy. Further compar-
ative studies will help select patients for the appropriate therapy.
In the U.S. in 2010 alone, there were 217,000 estimated new
cases of prostate cancer, the most common malignancy (excluding
skin cancer) in males . IMRT produces excellent local control
rates and genitourinary and gastrointestinal toxicity are present
but manageable in most patients with low rates of long-term dys-
function. Therefore, the bar is set high for a new technique such as
proton beam therapy (PBT) to deliver either improved tumor
control or reduced toxicity over IMRT.
Approximately 2000 prostate cancer patients treated with
proton therapy have been reported in the literature. Toxicity so
A.M. Allen et al./Radiotherapy and Oncology 103 (2012) 8–11
far has been acceptable while dose escalation utilizing a PBT boost
has improved outcome. Preliminary results with PBT only therapy
are also available and similar to proton/photon results. Dosimetric
studies suggest the greatest benefit for conformal proton therapy is
reducing the mean integral dose to normal tissue, which may
translate into fewer secondary malignancies. Sparing of normal tis-
sues in the low to moderate range (<60–70 Gy) is superior with
conformal proton therapy compared to photon therapy. Normal
tissue sparing of high doses appears possible with IMPBT.
Prostate cancer has the most patients treated with PBT (confor-
mal proton therapy) of any other disease site. The outcome is sim-
ilar to IMRT therapy however, with no clear advantage from
clinical data for either technique in disease control or prevention
of late toxicity. This is a site where further head to head clinical tri-
als may be needed to determine the role of PBT. In addition, careful
attention must be paid to the role of dosimetric issues including
correction for organ motion in this disease. Based on current data,
proton therapy is an option for prostate cancer, but no clear benefit
over the existing therapy of IMRT photons has been demonstrated.
Head and neck
The term ‘‘head and neck cancer’’ encompasses a variety of car-
cinomas from multiple subsites in the upper aerodigestive tract
from the nasopharynx through the hypopharynx. Treatment out-
comes often involve significant treatment-related morbidities from
both radiation doses to delivered targeted tissue as well as from
radiation entrance and exit doses unavoidably deposited in normal
tissue. The majority of clinical experience in head and neck cancer
is with a combination of traditional photon therapy and passive
scatter PBT [35–39].
Despite monumental progress in treatment, many patients con-
tinue to experience acute- and late-term toxicities from radiation
delivered to normal tissue, even with optimal IMRT plans. While
PBT, even with passive scattering, decreases the volume of normal
tissue receiving a low dose of radiation, the more complex issue in
head and neck cancer is the very small volume of a critical struc-
ture, especially a serial structure such as an optic nerve or the
spinal cord, receiving a high dose. A second complicating issue in
head and neck cancer is the potentially magnified effect of inter-
fraction or inter-field variation due to the effects of sinus filling
and the use of modulated proton therapy (IMPBT).
PBT has been shown to be well suited to treat targets near crit-
ical structures, especially at the base of the skull. Data for sinonasal
tumors specifically are encouraging, but further data are needed.
However, until IMPBT is more fully developed and tested, it will
be difficult to establish whether PBT may be equivalent to photon
IMRT in treating full head and neck plans. At this time, further clin-
ical data through prospective clinical trials are needed regarding
cases in which the target is the primary volume located near crit-
ical structures. Currently, there are insufficient data to recommend
PBT for routine head and neck radiation therapy outside of clinical
There are 8600 new cases of pediatric cancer each year . Of
these cases, many solid tumors are treated with radiation therapy
for a portion of their management. However, radiotherapy causes a
disproportionate share of the adverse late effects of treatment
[40,41]. In addition to the same side effects that adults experience
 radiotherapy in children impairs growth and development of
soft tissue, bone, and nerve. Brain tumors account for over 50% of
pediatric solid tumors. Radiotherapy has a profound effect on the
developing brain with younger patients faring worse .
PBT has the ability to significantly limit the low dose radiation
beyond the treatment target volume. There have been multiple
dosimetric studies clearly demonstrating superior normal tissue
sparing and decreased integral dose with protons [44–48]. In orbi-
tal rhabdomyosarcoma, MGH reported seven clinical cases with
excellent outcome (85% local control) and sparing of both ipsilat-
eral and contralateral optic structures when compared to the pho-
ton late effects of historical controls in the same population .
MacDonald et al. published a study showing excellent outcome
in ependymomas with PBT while sparing cochlea, hypothalamus,
and temporal lobes . Second malignancies are a major source
of morbidity and mortality in pediatric cancer survivors. Protons
decrease the volume and dose to normal tissues compared with
photon techniques. An early report from MGH described a cohort
of 1450 adult patients (median age 56 years) treated with protons
at their institution from 1974 to 2001. They found a 6.4% rate of
second malignancy as compared with a matched cohort from a
SEER database of 12%. Of the 15 pediatric patients in this cohort
none developed second malignancies.
PBT has perhaps its most developed place in pediatric brain tu-
mors. Although the clinical evidence is lacking, the rationale for
using PBT in posterior fossa tumors, optic pathway tumors, and
brainstem lesions is compelling. Future clinical studies reporting
on the outcome of patients treated with protons will decide how
widespread protons become for pediatric CNS tumors. There does
not appear to be sufficient evidence at this time to recommend
treatment with protons for non-CNS pediatric malignancies.
In our report, we feel that there is reason to be optimistic about
the potential developments in proton therapy, especially as the
delivery and planning techniques such as active scanning beams
and IMPBT become more prevalent and the prospective research
that is ongoing at centers worldwide. Current data do not provide
sufficient evidence to recommend PBT outside of clinical trials in
lung cancer, head and neck cancer, GI malignancies (with the
exception of HCC) and pediatric non-CNS malignancies. In hepato-
cellular carcinoma and prostate cancer and there is evidence for
the efficacy of PBT but no suggestion that it is superior to photon
based approaches. In pediatric CNS malignancies there is a sugges-
tion from the literature that PBT is superior to photon approaches
but there is currently insufficient data to support a firm recom-
mendation for PBT. In the setting of craniospinal irradiation for
pediatric patients protons appear to offer a dosimetric benefit over
photons but more clinical data are needed. In large ocular melano-
mas and chordomas, we believe that there is evidence for a benefit
of PBT over photon approaches. In all fields, however, further clin-
ical trials are needed and should be encouraged.
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