Curr Treat Options Neurol (2017) 19: 12

DOI 10.1007/s11940-017-0447-4

Neuro-oncology (R Soffietti, Section Editor)

Does Proton Therapy Have

a Future in CNS Tumors?
Stephanie E. Combs, Prof Dr
Address
Department of Radiation Oncology, Technical University of Munich (TUM),
Ismaninger Straße 22, 81675, Munich, Germany
Email: Stephanie.combs@tum.de
2
Institute of Innovative Radiotherapy (iRT), Helmholtz Zentrum München,
Ingolstädter Landstraße 1, Neuherberg, Germany

Published online: 1 April 2017

* Springer Science+Business Media New York 2017

This article is part of the Topical Collection on Neuro-oncology

Keywords Brain tumors I Skull base tumors I Radiotherapy I Particle therapy I Protons

Opinion statement
Proton therapy is characterized by certain physical properties leading to a reduction in
integral dose. As proton therapy becomes more widely available, the ongoing discussion
on the real indications for proton therapy becomes more important. In the present article,
data on proton therapy for tumors of the central nervous system (CNS) is summarized and
discussed in view of modern photon treatments. Still today, no randomized controlled
trials are available confirming any clinical benefit of protons in CNS tumors. For certain
skull base lesions, such as chordomas and chondrosarcomas, dose escalation is possible
with protons thus patients should be referred to a proton center if readily available. For
vestibular schwannoma, at present, proton data are inferior to advanced photons. For
glioma patients, early data is present for low-grade gliomas, presenting comparable
results to photons; dose escalation studies for high-grade gliomas have led to significant
side effects, thus strategies of dose-escalation need to rethought. For skull base menin-
giomas, data from stereotactic series and IMRT present excellent local control with
minimal side effects, thus any improvement with protons might only be marginal. The
largest benefit is considered in pediatric CNS tumors, due to the intricate radiation
sensitivity of children’s normal tissue, as well as the potential of long-term survivorship.
Long-term data is still lacking, and even recent analyses do not all lead to a clear reduction
in side effects with improvement of outcome; furthermore, clinical data seem to be
comparable. However, based on the preclinical evidence, proton therapy should be
evaluated in every pediatric patient. Protons most likely have a benefit in terms of
reduction of long-term side effects, such as neurocognitive sequelae or secondary malig-
nancies; moreover, dose escalation can be performed in radio-resistant histologies.
Clinical data with long-term follow-up is still warranted to prove any superiority to
advanced photons in CNS tumors. If available, protons should be evaluated for chordoma
or chondrosarcoma of the skull base and pediatric tumors. However, many factors are
important for excellent oncology care, and no time delay or inferior oncological care
should be accepted for the sake of protons only.
12 Page 2 of 14
Introduction
Radiation therapy (RT) is an essential component in the
interdisciplinary treatment of brain tumors. Indepen-
dently of histology, radiation plays a central role and
has shown to increase local tumor control.
Developments in radiation oncology are always
aiming at an increased precision of dose delivery: More
conformal coverage of target volumes, steep dose gradi-
ents to surrounding tissues, and sparing of organs at risk
(OAR). In photon therapy, based on 3D-RT, stereotactic
radiotherapy was a big step in the direction of more
precision. Tightly conformal dose distributions and a
sharp dose fall-off to normal tissue were the main ben-
efits. With this, high single doses can be applied in a
single fraction as radiosurgery, or, in larger volumes as
fractionated stereotactic radiotherapy (FSRT) [1]. The
search for increased conformality in more complex-
shaped volumes and the need to spare specific regions,
such as parotid glands or other functional organs, have
facilitated the development of intensity-modulated ra-
diotherapy (IMRT). Therefore, broadening of the thera-
peutic window has taken place, and for certain indica-
tions, such as skull base tumors, head-and-neck tumors
or prostate cancers, this technique can be considered the
treatment standard [1–4]. Taken both techniques to-
gether, RT has gained a central role in the treatment of
CNS tumors. Both benign and malignant lesions can be
treated with excellent long-term results associated with
few side effects. Especially for benign lesions such as
skull base meningioma or vestibular schwannoma, ex-
cellent clinical data are present, even arguing for equiv-
alent outcome compared to neurosurgery [2, 5–9].
Treating patients with particle therapy has a long
history—in the 50s and 60s, first, patients were treated
mostly with heavy charged particles, namely, radiation-
resistant lesions such as sarcomas [10–14]. The benefit
of charged particles lies firstly in the physical properties:
Within the entry channel of the particle beam, very low
dose deposition takes place; as particles slow down with
depth, dose deposition takes place and climaxes in the
so called Bragg Peak [1]. Thereafter, a steep dose fall-off
Low-grade glioma
Years ago, the indication for RT in low-grade gliomas (LGGs) was seen critically.
Early RT after diagnosis did not prolong overall survival; only progression-free
Curr Treat Options Neurol (2017) 19: 12
spares normal tissue behind the target volume. Regard-
ing biology, a distinction must be made between pro-
tons and heavier charged particles. With protons, biolo-
gy is approximately comparable to photons, and a rela-
tive biological effectiveness (RBE) of 1.1 is thought to be
correct. Although recently, an ongoing discussion on
variable RBEs in protons is underway [15]. A higher
RBE is present for carbon ions, oxygen, and other heavier
charge particles. For brain tumors, a preclinical benefit
or a higher RBE has been demonstrated; however, clin-
ical evidence still remains sparse [16–18].
Considering the reduction of dose to normal tissue
in conjunction with a comparable RBE to photons, pro-
ton therapy might be the ideal modality to treat patients
with brain tumors. The strongest rationale lies not pri-
marily in increase in local tumor control but in reduc-
tion of side effects, i.e., neurocognitive side effects or
secondary malignancies. Albeit many calculations have
demonstrated the potential of protons to meet these
criteria, generation of evidence is still underway; the
end points however are intricate to meet, and long-
term follow-up in large populations may be necessary
to demonstrate the hypothetical benefits with clinical
data.
Currently, the number of centers available for proton
therapy is increasing; the development of smaller facili-
ties with one or two treatment gantries will provide the
capacities to increase availability in many centers where
also all other modern radiation techniques are available.
This will be an optimal situation, offering proton thera-
py to patients who benefit from particles.
In neuro-oncology, radiation is a central pillar in
multimodal treatment and is offered after neurosurgical
resection, as an additive or adjuvant treatment, as pri-
mary definitive treatments as an alternative to resection,
or for treatment recurrences. The present manuscript
summarizes the most recent data on proton therapy
for CNS tumors and reflects on the limitations and
potentials (summary of selected publications on CNS
indications are seen in Table 1).
Table 1. Selected clinical data on proton therapy for meningiomas, chordomas (CH) and chondrosarcoma (CS), and vestibular schwannoma

Authors Year Indication No. of Local control Toxicity

patients
Wenkel et al. 2000 Meningioma 46 100 at 5 and 88% at 10 years 11/46 ≥ Grade III toxicity (brains tem necrosis,
opthalmologic, neurologic, otologic)
Vernimmen et al. 2001 Meningioma 23 100% for conventional fractionation, 13% permanent neurological deficits
88% for hypofractionation
Noel et al. 2005 Meningioma 51 98% at 4 years 2/51 severe side effects (hearing loss, complete
pituitary insufficiency)
Boskos et al. 2009 High-grade meningioma 24 82.9% at 3 and 61.3% at 5 years 1 patient with radiation necrosis
Halasz et al. 2011 Meningioma 50 94% at 3 years 5.9% late toxicity
Slater et al. 2012 Meningioma 72 96% at 5 years 11% (optic neuropathy, edema, panhypopituitarism)
Curr Treat Options Neurol (2017) 19: 12

Weber et al. 2012 Meningioma 99 84.8% at 5 years 84.5% late-toxicity free survival at 5 years
McDonald et al. 2015 Atypical meningioma 22 71.1% at 5 years 1/22 temporal lobe necrosis
Munzenrider et al. 1999 CH and CS 290 CH, 229 CS 73% at 5 years for CH, 80% at 5 years for CS 3 brainstem injury; 8 temporal lobe injury; 12 optic
neuropathy
Hug et al. 1999 CH and CS 33 CH, 25 S 59% at 5 years CH, 75% for CS 7% late toxicity
Igaki et al. 1999 CH 13 CH 46% at 5 years 3 patients (brain necrosis, oral mucosa ulceration)
Noel et al. 2005 CH and CS 100 CH (88 skull 86% at 2 and 54% at 4 years 42 patients with late toxicity (optic neuropathy,
base CH) neuropsychological disorder, hearing deficiency,
pituitary dysfunction)
Ares et al. 2009 CH and CS 41CH, 22 CS 81% CH and 94% CS at 5 years 94% freedom from high-grade toxicity
Bush et al. 2002 Vestibular schwannoma 30 100% 69% loss of useful hearing
Vernimmen et al. 2009 Vestibular schwannoma 51 98% at 5 years Hearing preservation of 42%, a facial
nerve preservation of 90.5% and a trigeminal
nerve preservation of 93%
Page 3 of 14 12
12 Page 4 of 14 Curr Treat Options Neurol (2017) 19: 12

survival and weighting of potential side effects of early RT against a benefit in

only PFS was in focus. Only recently, long-term data of prospective studies
showed that even LGG patients can benefit from combined chemoradiation
[19]. Thus, the importance of RT in this context is emerging. All the more safe
and well-tolerable RT treatments are important. Considering the long-term
outcome in LGG, the potential benefit of neurocognitive function preservation
is a strong rationale. Still today, no large series on protons for LGG are available.
Early data have shown safety and low toxicity but overall comparable to
advanced photons [20]. A consort analysis of several proton centers reported no
side effects ≥grade III; however, 81% of alopecia, 78% dermatitis, 47% fatigue,
and 40% headache as grades I and II toxicities in patients with LGG [21].
Considering neurocognitive assessment, only sparse data is available. A
small group of 20 patients treated with protons underwent a comprehensive
neuropsychological battery testing at baseline and follow-up including intellec-
tual, attention, executive, visuospatial, and memory functions as well as mood
and functional status; overall, patients exhibited stability in cognitive function-
ing, and the most important prognostic factor was tumor location [22]. Addi-
tionally, QOL assessment revealed no changes over time. The progression-free
survival rate at 3 years was 85%, but it dropped to 40% at 5 years [23].
High-grade glioma
Due to the aggressive nature of high-grade gliomas, the potential of particle RT
might be more in dose-escalation strategies compared to the reduction of long-
term side effects. Early activities in this regard included a mono-institutional
trial on photon and proton dose escalation up to 90 Gy E in an early trial,
including 23 patients with GBM [24]; median survival time was 20 months, and
in comparison with photon, data demonstrated a 5- to 11-month increase in
median survival time over those of comparable conventionally treated patients.
However, all patients developed new areas of gadolinium enhancement during
the follow-up period, and histological examination of tissues obtained at
biopsy, resection, or autopsy was conducted in 15 of 23 patients. Seven patients
developed radiation necrosis; also, this group has significantly longer survival
times compared to patients with pure recurrences. Reflecting the known dose-
response relationship for glioma, the study showed that recurrences developed
predominantly in areas treated with 60 to 70 Gy E or less, not in the volumes
treated with 90 Gy E.
In a phase I/II trial from the same group on 20 patients with grade II and III
gliomas, the prescribed doses to the target volumes were 68.2 Gy E to WHO
grade II and 79.7 Gy E to grade III tumors with conventional fractionation [25].
Actuarial 5-year survival rate for grade II lesions was 71 and 23% for grade III
lesions. Compared to photons, this study of dose escalation did not increase
outcome.

Meningioma
Radiation therapy for benign meningiomas has emerged to a valid treatment
alternative. In skull base lesions, where surgical resection can be difficult and
complete resections would be associated with severe and vital dysfunctioning,
Curr Treat Options Neurol (2017) 19: 12 Page 5 of 14 12

high-precision radiotherapy leads to high local tumor control with very low rates of
side effects. Several series on photon radiotherapy are available with local control
rates between 80 and 100% [2, 26–31]. With FSRT or radiosurgery, not only long-
term local control is excellent but also treatment-related side effects are very low
and quality of life (QOL) can be preserved [2]. Therefore, it will be difficult to show
that proton therapy will be superior to photons. However, in terms of local control,
comparable results for protons have been reported with low rated sorts of side
effects, however, potentially distinct response patterns in terms of volume reduc-
tion [16, 32]. Most series include small patient numbers: Wenkel et al. treated 46
patients with benign meningiomas, local control was 100% at 5 and 88% at
10 years; 8 of 36 patients developed side effects ≥grade III, mostly ophthalmologic,
neurologic, or otologic, and one patient died from brainstem necrosis [33]. A dose
of 59 Gy E was applied. Vernimmen published data about 23 patients, local
control was 100% for fractionated and 88% for hypofractionated proton therapy
[34]. Median doses of 20.3 Gy E for hypofractionated and 57.9 Gy E for fraction-
ated regimens were prescribed. A larger series by Noel and colleagues included
photons and a proton boost; out of 51 patients, 45 presented with benign
histology [35]; local control at 4 years was 98% and tumor stabilization was
observed in 38 cases (72%), volume reduction in 10 cases (20%), and intratumor
necrosis in 3 cases. Two patients complained of grade III side effects: 1 unilateral
hearing loss requiring aid and 1 case of complete pituitary deficiency. In 2012, PSI
reported their outcome in 39 patients with meningiomas treated with protons [36].
In patients with histological confirmation, 24 patients had a diagnosis of World
Health Organization (WHO) grade I and 10 of a WHO grade II/III meningioma,
respectively. The median total dose was 56.0 Gy E in single fractions of 1.8–2.0 Gy
E. Five-year actuarial local control and overall survival rates were 84.8 and 81.8%,
respectively, for the entire cohort and 100% for benign histology. Late toxicity-free
survival (≥grade III) was 84.5% at 3 years.
For atypical meningiomas, there is an ongoing discussion whether RT
should be applied directly postoperatively or if RT can be deferred; moreover,
there is controversy on the optimal target volume (resection cavity vs. tumor
residuals only). These questions are currently being evaluated in prospective
trials [37, 38, 39•]. Thus, high-grade meningiomas should play a separate role
with respect of indication for RT: Smaller series have reported on protons, with
comparable data to photons. For example, 22 patients with atypical meningi-
omas reported by MacDonald et al. were treated to a median dose of 63 Gy E
using proton therapy, as an adjuvant therapy after surgery (n = 12) or for
recurrence or progression of residual tumor (n = 10). Local control at 5 years
was significantly different at 87.5% with a radiation dose 960 Gy E, compared
to 50.0% for = 60 Gy E [40]. In France, 7/24 patients with atypical/malignant
meningiomas were treated with protons, again as a boost in conjunction with
photons [41]: Mean local progression-free survival was 27.2 months for all
patients and 28.3 months for atypical meningiomas and 23 months for ma-
lignant meningiomas. One patient developed symptomatic necrosis after
treatment. A mean local dose of 65.01 Gy E with a mean proton total dose of
34.05 Gy E and a mean photon total dose 30.96 Gy E were applied.
In conclusion, there is a rationale that proton therapy might optimize the
therapeutic window in skull base meningiomas. Respecting the excellent local
control of modern photon treatments in benign lesions, the benefit would be in
terms of neurocognitive detriments or secondary malignancies, for both of
12 Page 6 of 14 Curr Treat Options Neurol (2017) 19: 12

which preclinical hypotheses exist. For high-risk meningiomas, dose-escalation

strategies might be beneficial to increase local tumor control and due to the
physical properties, protons might offer more beneficial dose distributions.
However, these benefits have yet to be confirmed.
Vestibular schwannoma
For vestibular schwannoma, clinical data from FSRT or radiosurgery are excel-
lent; local control rates are between 80 and 100%, and hearing preservation is
high, especially using fractionated regimens [8, 9, 42–52]. For smaller lesions,
both FSRT and radiosurgery may be considered equally effective; however,
pretreatment characteristics significantly influence outcome. Cranial toxicity,
especially using fractionated regimens, is well below 5%, generally around 1–
3% [8, 9, 50, 52]. Only scarce data is available on protons; due to the small
treatment volumes, depending on the volume and anatomy characteristics,
dose distributions with protons might even be inferior to those of highly
advanced photons. Vernimmen et al. reported on 51 patients treated with
hypofractionated proton therapy, 51 Gy E in three fractions. Local control was
98% at 5 years; however, hearing preservation was only 42%, and facial and
trigeminal nerve preservation rates were as low as 90.5 and 93%, respectively
[53]. Bush et al. reported on 30 patients treated for 31 vestibular schwannoma
with 54 Gy E protons in 30 fractions. Patients without useful hearing were
treated with 60 Gy E in 30–33 fractions. No patient demonstrated tumor
progression; however, useful hearing preservation was only 31%. No transient
or permanent treatment-related trigeminal or facial nerve dysfunction was
observed [54].
Taken together, the few data on proton therapy for vestibular schwannoma
compare unfavorably to advanced photons, either with radiosurgery or FSRT.
Thus, currently, no clear role of protons in this indication can be seen.

Chordoma and chondrosarcoma

For chordoma (CH) and chondrosarcoma (CS) of the skull base, local doses
beyond 70 Gy are necessary for long-term local control as they are radiation-
resistant tumors. Due to the intricate anatomy with proximity to sensitive OAR
with relevant physiological functions, such as the brain stem, cranial nerves,
temporal lobes, optic apparatus, inner and middle ear, major vessels, pituitary
gland, or other. Data from photon radiotherapy have shown rather disap-
pointing long-term local control between 15 and 65% for CH, however be-
tween 80 and 100% for CS [31, 55–63]. Based on early data on proton therapy
results seem superior which has established protons to be a certain gold
standard [64], if readily available. Thus, if possible, the availability of proton
therapy should be considered. Early studies from Boston have reported local
failure rate of 31% in 204 CH patients, of which 95% were local recurrences
[64]. In France, Noel and colleagues treated 67 patients with CH and CS with
photons and a proton boost [65]; the 3-year local control rates were 71 and
85% for CH and CS, respectively. Updated results for CH confirmed the local
control rates of 86% at 2 and 54% at 4 years [66]. However, only doses of 67 Gy
were applied, which is substantially less than in series treating with protons
Curr Treat Options Neurol (2017) 19: 12 Page 7 of 14 12

only. Newer series have employed full courses of proton therapy. While overall
tolerability of such high doses is reported, including tumors of varying histol-
ogies, few series on pure CH or CS are available with long-term follow up [67].
Weber et al. reported on proton therapy delivered with spot-scanning at PSI in
Switzerland. They treated 151 (68%) CH and 71 (32%) CS patients; the median
dose was 72.5 ± 2.2 Gy RBE. Local control at 7 years for CH was 71 and 94% for
CS patients. Prognostic factors were optic apparatus and/or brainstem com-
pression, histology and tumor volume. High-grade toxicities were observed in
13% of the patients at 7 years. Detailed analyses on toxicity, predominantly
temporal lobe toxicity, have shown no differences in dose-response relation-
ships between photons and protons, however with proton data originating
from high-dose treatment concepts. Mainly tissue volume included into high-
dose regions is predictive for toxicities [68, 69]; treatment planning must take
into account not only maximal doses but especially volume relationships which
(D(max, V—1 cm)3) are considered to be most relevant. In summary, albeit few
large and randomized data on protons for skull base CH and CS are available,
all data from proton therapy confirm that even high local doses beyond 74 Gy
can be applied safely with protons; direct comparison with photon therapy
confirms the dose-response relationship for chordomas, and only few series
with photons have delivered such high doses as required for long-term tumor
control [70]. Thus, patients with skull base CH or CS should be treated either in
a center with high expertise in skull base lesions with modern photon equip-
ment with IMRT and IGRT, or with proton therapy, if readily available in a
center offering high-quality treatments [71•].

Pediatric oncology: largest margin of benefit and potential cost-

effectiveness
In pediatric patients, proton therapy probably offers the greatest margin of
benefit. Especially small children are sensitive to radiation-related changes.
Also, long-term survivorship can be achieved in many indications, thus children
will live to the long-term side effects, such as secondary malignancies, growth
reduction, deformities, or neurocognitive sequelae.
Still today, few datasets are available, especially for long-term outcome.
Many smaller series on proton treatment for low-grade gliomas, sarcomas, or
other pediatric tumors are available, all reporting excellent tolerability and
comparable outcome to photons [72–88]. Prospective studies with long-term
follow-up are currently underway. Only recently, several articles evaluated
craniospinal irradiation (CSI), which is indicated, e.g., in medulloblastoma.
With CSI, large volumes of bone marrow are included into the treatment field,
and due to the long treatment volumes, OAR in the whole body are exposed to
radiation. Therefore, proton therapy seems to contribute beneficially in this
indication [77, 81, 82, 84, 89]. IQ scores from 150 patients treated with
photons (n = 60) or protons (n = 90) were compared [85]. While the proton
group did not show IQ changes over time, the IQ declined at 1.1 points per year
in the photon group. However, IQ slopes were comparable: For CSI, IQ
remained stable in both groups, whereas slight changes were observed in the
focal RT group, however again without differences in IQ slopes. The authors
12 Page 8 of 14 Curr Treat Options Neurol (2017) 19: 12

conclude that it still remains unclear if protons will provide the anticipated
benefits in terms of neurocognition thus providing a meaningful preservation
of IQ or other measures.
Eaton et al. compared local and locoregional control as well as survival in
pediatric patients with medulloblastoma treated with protons versus photons
[82, 84]. Disease control with both modalities was equivalent for standard risk
medulloblastoma after a median follow-up time of 6.2 years. Patterns of failure
are comparable between protons and photons [89]. Previously, smaller single-
arm studies had reported on safety of proton radiation even in very young
children with medulloblastoma and PNET [77]. Extensive neurocognitive as-
sessment is still to be reported, especially in long-term follow up; however, in
accordance with the calculations, early data have shown no significant changes
in different neuropsychological assessments after proton therapy in pediatric
patients with CNS tumors, which compared favorably to published photon
data [81].
Especially in pediatric patients, however, reduction of long-term side effects
can foster the economic argument for proton therapy [90]: Because generally,
investment costs are significantly higher compared to photons and operating
costs for especially large centers are very high, and treatment costs are a multiple
of any photon treatment. Due to increasing healthcare costs, there is an urgent
need to examine whether the benefits of new technologies are worth any extra
cost; for proton therapy, unfortunately, to date, clinical studies are lacking that
demonstrate any meaningful benefit for especially larger population groups
[91]. In pediatrics, the rationale for protons clinically seems to be well in line
with cost effectivity. Preservation of hormonal function in children with brain
tumors treated with protons can substantially reduce follow-up cost in terms of
dietary supplements, medication or other; thus, proton therapy may be more
cost-effective for scenarios in which radiation dose to the hypothalamus can be
spared, but protons may not be cost-effective when tumors are involving or
directly adjacent to the hypothalamus if there is a high dose to this structure
[92]. For other indications, such as medulloblastoma, simulation data also
suggest a benefit in terms of very low cost per quality-adjust life year gained,
compared to photons [93]. However, most data are calculations and model
studies; in pediatrics, if protons are available in a timely fashion and high-end
radio-oncological care is offered, it will be hard to argue for any randomized
trials. And, if proton treatment cost would be comparable to photons, would we
ask for clinical data?

Discussion and ongoing research

Proton therapy offers unique physical properties: Due to the inverted dose
profile, dose to normal tissue can be reduced and dose to the target can
potentially be increased, if needed clinically. Compared to photons, the bio-
logical effect is thought to be comparable, and a RBE of 1.1 is generally used in
clinical applications. As treatment centers are increasing around the world,
clinical data are gradually evolving. For CNS tumors, there is a strong rationale
for proton therapy: Normal tissue can be spared much better, thus side effects,
even if intricate and difficult to measure, can be reduced. Clinical trials are
currently underway, although it may be difficult to prove small changes in long-
Curr Treat Options Neurol (2017) 19: 12 Page 9 of 14 12

term outcome. In certain indications, such as CH and CS of the skull base,

proton therapy can be considered the gold standard, and patients should be
evaluated for proton therapy. However, no prolongation in treatment schedules
or inferior oncological quality should be accepted for the price of protons only.
The overall benefit of any oncology treatment is based on excellent expertise
and interdisciplinary discussion and treatments, which should not be com-
promised for any new technology.
For gliomas, clinical data is still to be generated however, and especially in
low-grade gliomas, the idea of sparing normal tissue seems promising. It should
be kept in mind, however, that ALSS photon techniques can reduce dose to
OAR. Moreover, selective sparing of eloquent regions, such as the hippocam-
pus, is also possible with photons [94].
In pediatric patients with CNS tumors, protons should be evaluated. Due to
the reduction in integral dose, the risk for secondary malignancies is thought to
be lower with protons. The total lifetime attributable risks of the incidence of
second cancer considered after proton CSI and photon CSI were 7.7 and 92%,
respectively, and the ratio of lifetime risk was 0.083 [95•]. Uncertainty analysis
revealed that the qualitative findings of this study were insensitive to any
plausible changes of dose-risk models and mean radiation weighting factor for
neutrons. Proton therapy confers lower predicted risk of second cancer than
photon therapy for the pediatric medulloblastoma patient.
Uncertainties in biology as well as specifics of the particle beam have
raised concern about potential side effects: Preclinical as well as clinical
reports have postulated that the RBE may be higher than 1.1. Moreover, in
the distal edge of the Bragg Peak, an increase in LET is present. Therefore,
this could lead to substantial dose increase in areas which are at high risk
for radiation-related side effects, such as the brainstem, temporal lobe,
optic chiasm, or other. Especially in cases where the benefit of protons is
considered to be highest, for example, radiation-resistant lesions in close
vicinity to sensitive OAR, this might become critical. Recent data from
Boston have correlated LET and RBE with morphological changes observed
after treatment of patients with medulloblastoma with proton therapy
[83]: A rate of CNS injury of 3.6% was observed, which is comparable to
photons; no correlations with RBE was observed, but the regions with
tissue changes were associated with a higher LET in 80%. Currently,
multicenter analysis are ongoing, to describe toxicity profiles with protons
compared to photons and to generated evidence in relation to RBE and
LET. Preclinical work is underway to further describe the RBE for protons,
most likely moving away from a fixed RBE for variable and dose, volume,
and tissue-dependent RBE values [96].
Conclusion
Proton therapy is an essential component in modern radiation oncology. To
date, however, no clinical data have shown superiority over advanced photon
radiotherapy. Thus, two hypotheses supporting proton therapy still need to be
confirmed—namely, the benefit in terms of reduction of integral dose, i.e.,
secondary malignancies, neurocognitive sequelae, and the potential to dose
escalation due to the physical properties of charged particles.
12 Page 10 of 14
Compliance with Ethical Standards
Conflict of Interest
Stephanie E. Combs is member of advisory board for BMS.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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