BJR © 2020 The Authors.

Published by the British Institute of Radiology

https://​doi.​org/​10.​1259/​bjr.​20190291
Received: Revised: Accepted:
24 March 2019 16 August 2019 19 August 2019

Cite this article as:

Friedrich T. Proton RBE dependence on dose in the setting of hypofractionation. Br J Radiol 2020; 93: 20190291.

Proton therapy special feature: Review Article

Proton RBE dependence on dose in the setting

of hypofractionation
Thomas Friedrich, PhD
GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany

Address correspondence to: Dr Thomas Friedrich

E-mail: ​t.​friedrich@​gsi.​de

Abstract
Hypofractionated radiotherapy is attractive concerning patient burden and therapy costs, but many aspects play a role
when it comes to assess its safety. While exploited for conventional photon therapy and carbon ion therapy, hypofrac-
tionation with protons is only rarely applied. One reason for this is uncertainty in the described dose, mainly due to the
relative biological effectiveness (RBE), which is small for protons, but not negligible. RBE is generally dose-­dependent,
and for higher doses as used in hypofractionation, a thorough RBE evaluation is needed. This review article focuses on
the RBE variability in protons and associated issues or implications for hypofractionation.

Introduction experiments including murine skin reactions and survival

In contrast to conventional photon therapy modalities
like conformal radiotherapy or volumetric arc therapy, the
inverted dose profile of accelerated protons allows a highly
conformal irradiation of solid tumours, while at the same
time the dose to the normal tissue is reduced. The sparing
of the normal tissue suggests that the fraction number in
fractionated therapy could be lowered, keeping the level of
side-­effects balanced.
While so far most proton therapy courses are designed
according to the corresponding photon therapy schedules,
few attempts have been made for hypofractionated proton
therapy within clinical studies, in particular for hepatocel-
lular carcinoma and non-­small cell lung cancer.1–3 Some
follow-­up results are available but do not allow general
conclusions about the proton RBE at high doses. Further
results can be expected throughout the next years.
The enhanced effect of particle irradiation is reasoned in a
higher linear energy transfer (LET), resulting in larger local
energy concentrations. The DNA damage is augmented in
amount and/or complexity, representing a higher burden
for the cell’s repair system. This enhanced efficacy of ion
radiation is quantized as the relative biological effectiveness
(RBE). While for heavier particles like carbon ions the RBE
is large in the Bragg peak and can be beneficially exploited
in treatment planning, for protons it appears to be rather
moderate and uniform almost anywhere across the irradi-
ated field, including entrance channels. Inspired by early
of jejunal crypts4 and tumour cell survival in lung colony
formation,5 ICRU recommended a constant RBE of 1.1
for proton fields at all depths and doses.6 While this recipe
is broadly accepted for clinical practice as well as simple
and unambiguous to report, many studies demonstrated a
clear increase of the RBE towards the Bragg peak, where
protons stop and their LET is comparably high. However,
only few possibly related clinical observations have been
reported and discussed.7–9 There is a vivid ongoing discus-
sion about the impact of such deviation from the ICRU
recommendation.10–16
For hypofractionated regimens, where fraction doses are
considerably higher than delivered conventionally, two
main questions arise in that perspective:
• Does the RBE for protons vary with dose? What is the
experimental or clinical evidence and the theoretical
support?
• If so, does it matter? How large is the expected effect
modification and what is its clinical relevance for
hypofractionated regimens?
This review addresses these questions, approaching them
by considering both experimental and theoretical find-
ings. Along this line, also contributions to a mechanistic
understanding of such proposed effect modifications are
reviewed. Particularly as protons are ions, although with
small charge and moderate LET, also knowledge gained
from other, heavier ion species is considered.
 BJR
Basics
RBE in ion radiobiology
Despite its simple definition as the dose ratio of ion and photon
reference radiation to induce the same radiobiological effect, the
RBE shows complex dependencies. The systematics of RBE were
extensively studied in in vitro experiments for the end point of
clonogenic cell survival and related cellular end points. The studies
established that RBE depends on physical aspects (LET, particle
species) which determine the track structure, i.e. the local energy
distribution pattern. Furthermore, RBE depends on biological
factors (repair capability of the cells and cell cycle phase). In in
vivo experiments and preclinical investigations, most of these
dependencies turned out to hold: the RBE systematics seem to be
generic, exhibiting the same qualitative behaviour for many end
points and experimental/clinical settings. Many of these findings
have been gathered in studies with clinical neutrons and later
with heavy ions such as carbon.17–19
For protons, due to the anyway smaller LET and RBE values, inves-
tigations of the RBE characteristics are much more demanding,
both in terms of experimental technique, e.g. concerning sample
positioning in Bragg peaks, as well as data analysis.20 Hence, in
line with the RBE systematics also the uncertainty of RBE values
has to be considered.21,22
Dose-dependence of RBE
In most ion experiments a reduction of RBE with increasing
dose is observed. This appears as the ion dose–response curves
typically start with a higher slope, while the photon reference
curves begin shallower but with larger curvature. As a result of
that nonlinearity, often referred to as "shoulder shape", photon
and ion dose–response curves approach more at higher doses,
suppressing the RBE. In most mechanistic models, the nonlinear
contribution in the dose–response is interpreted as the self-­
interaction of radiation.23 Motivated by the quadratic depen-
dence on dose, it reflects the combination of multiple sublethal
damage sites to lethal damage, committing cell inactivation.
The biological nature of such sublethal damage is still not fully
exploited. The linear-­quadratic (LQ) model provides a simple
parameterization of the dose–response curves by the linear and
quadratic coefficients α and β, respectively, the latter of which
represents the combined action. Regimens with high fraction
doses provoke, in particular for low LET radiation, additional
damage resulting from sublethal damage interaction. As this
appears less expressed at higher LET, RBE is maximized in the
low dose limit and decreases with increasing dose.
In the case of protons, the dose–response curves only differ
moderately to the photon reference curves in the initial slope and
curvature. This is because even in the Bragg peak region proton
tracks induce on average less than one double strand break (DSB)
to the cell nucleus,24 and the combined action of different tracks
in proximity gives rise to the formation of lethal lesions,25 which
implies a strong β term similar as for photon radiation. Even if
the generic trends of a decreasing RBE with dose persist, it is a
challenge to unveil it given the considerable level of RBE uncer-
tainty observed in experiments and clinical findings.
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Friedrich
Hypofractionation
The goal of radiotherapy is to inactivate the tumour while sparing
the surrounding normal tissue. Hence, a widening of the ther-
apeutic window can be reached by either increasing the effect
on tumour cells, or by sparing or protecting normal tissue from
damage. If the repair capability of normal cells is larger than
that of tumour cells, fractionated regimens will be favourable.
However, if also the tumour has a considerable repair capability
it will react to fractionation in the same way as the normal tissue
in the field margin of the high dose region. In that situation frac-
tionation may be less beneficial, and larger fraction sizes become
attractive, lowering patient burdens and therapy costs.
For heavy ion therapy, the good tumour conformity and sparing
of normal tissue allow the transition to hypofractionated regi-
mens. Indeed, numerous approaches have shown that hypof-
ractionation is well tolerated in carbon ion therapy for several
tumour types.26 In proton therapy, hypofractionation has only
been applied in few studies so far. Besides limitations in tumour
conformity due to the scattering properties of protons, but also
because of the uncertainties in the optimum fractional dosage,
establishing fractionated proton therapy regimens is an ongoing
challenge.
It is useful to distinguish between moderate and extreme hypof-
ractionation, where in the latter case at most a few fractions are
given at a high fractional dose typically larger than 10 Gy. In that
case, the clinical outcome is modified also by other factors than
RBE, e.g. by a less important impact of tumour repopulation due
to low overall treatment times.
Experimental findings
Based on a set of various radiobiological data gathered with
neutron radiation at high LET, Kellerer27 realized a common
decrease of RBE with dose D according to the functional depen-
dence ‍ RBE ∝ D−1/2‍ . This observation provoked extensive
attempts to model and understand the RBE on a mechanistic
basis, including explicit hypotheses of damage induction and
repair.
Many in vitro studies with heavy ions confirmed a decrease of
RBE with dose. For protons, numerous studies of cell survival in
proton Bragg peaks or towards the distal end of extended Bragg
peaks as exploited in the clinics revealed the same systematics as
summarized in a in a review article.20 The authors often calcu-
lated the maximum RBE for vanishing dose and the RBE at
10% survival or for some fixed dose, and the latter value often
appeared to be reduced compared to the former one, although
this reduction is not significant in individual experiments. Inves-
tigating the RBE dependence on dose in in vivo experiments
delivered an even less obvious trend, including cases of no or
opposed RBE dependence on dose.
While individual experiments make often contradicting state-
ments about the course of RBE with dose or provide limited
significance in the reported decrease of RBE with dose, a more
global view at data from multiple studies allows deriving trends
and systematics on a statistically more sound basis, resulting in a
Br J Radiol;93:20190291
 RBE dependence on dose for proton hypofractionation
comprehensive picture of RBE systematics. Gerweck and Kozin28
considered a collection of both in vitro and in vivo experiments
and confirmed the impression of a decreasing RBE with dose,
as well as no significant change for in vivo experiments. The
authors conjectured that this is not necessarily a contradiction,
as (i) the in vivo results addressed mostly tissues with a larger α/β
for which RBE effects are known to appear less evident28 and (ii)
in vivo endpoints are usually associated intrinsically with higher
doses, where RBE is already reduced and the gradient is not
exhibited. In the data collection of Paganetti,20 a larger database
impressively confirmed this picture. Considering not only the
determined RBE values but also their uncertainties it was found
that for in vivo systems the RBE values in general are smaller than
for in vitro experiments, and there is a weaker decrease of RBE
with dose which, however, is still significant. Using an update
of these data collection,29 Paganetti confirmed the apparent
decrease of RBE. Recent comprehensive in vitro data sets30–32
support the findings, while encompassing preclinical studies
of rat spinal cord injury33 and skin reactions34 do not show a
clear dose-­dependence of RBE, albeit this finding is expected
for suppressed RBE at high fraction doses. While databases are
useful for unveiling general trends that multiple RBE experi-
ments under not exactly identical conditions share, the differ-
ences of considered experiments impose a limitation as well.
Hence individual experiments and data collections are comple-
mentary, trading-­off between a high discrimination power in the
former under exactly defined conditions and a high statistical
power in the latter. Hence, there is further room for investigating
RBE dependence, e.g. on α/β values by considering mutants of
the same cell line,35,36 which supports the conjecture that resis-
tant cell lines with a small α/β ratio show typically larger RBE
values than sensitive cell lines with a straighter dose–response
curve. To project out such dependence of RBE on α/β, it is of
importance to keep other impacting factors such as the choice
of the photon reference radiation, the sample positioning depth,
the mode of beam delivery (monoenergetic beam or within an
extended Bragg peak) and the survival level for RBE determina-
tion identical or at least comparable.
The course of the RBE decrease was analyzed by Paganetti et al29
for cell survival experiments in various ranges of the α/β ratio
and the dose averaged LET. As expected from the general RBE
characteristics, RBE and its decrease with dose appeared most
pronounced for small α/β values and for larger LET values.
Grün et al37 used another database restricted to data gathered
from extended Bragg peak experiments and confirmed the RBE
decrease with dose in particular for higher LET values and low
α/β values. They moreover assessed that the dose-­dependence of
RBE is most pronounced below 3 Gy (RBE), i.e. in the conven-
tional clinical region, while for larger doses the dependence
becomes less expressed.
The uncertainty of proton RBE turned out to be considerable in
relative proportion to its absolute value. In individual cell survival
experiments error bars are typically 10% in survival, mainly
reflecting the Poissonian uncertainty in the observed number
of surviving cell colonies (including >50 cells), when about 100
surviving colonies are expected in the cell dishes by appropriate
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BJR
seeding.38 This uncertainty propagates into the RBE.22,39 It was
shown at hand of the PIDE database which comprises a large set
of survival data for various ion species, that the RBE uncertainty
stems primarily from the photon reference curve uncertainty38
while ion dose–response curves at high LET appear rather stable
and less sensitive to determining factors like LET and α/β ratio.
For protons instead, in view of the rather moderate RBE, uncer-
tainties remain large, making experimental observations of RBE
evolution with dose a demanding task.
A further complication is that reported experimental RBE results
are mostly model-­dependent, because the LQ model is used for
calculating it. By means of fit methods, the parameters α and β
are correlated, i.e. if α is by chance evaluated too high, this is
typically compensated by a lower β.38–41 The anticorrelated
fluctuations of α and β lead to a compensation at intermediate
doses, which is why RBE at intermediate survival levels appears
much more stable and less affected by uncertainty than for low
doses. In addition, Paganetti16 brought up the issue that in the
individual studies only few data points are available at low doses
< 2 Gy, further enhancing RBE uncertainty via LQ parameters.
Hence, an observed decrease of RBE with dose might hardly be
inferred by curve fitting in individual experiments. Only large
data sets providing numerous independent experiments can
overcome this bias.
For large doses, the β term of the LQ model for both the proton
and photon dose–response curve plays a pronounced role in RBE
evaluation: if the β term for ions is sufficiently small, this implies
a RBE reduction towards high doses. Despite of the large amount
of in vitro data collected over the decades, it is still under debate
how the β term evolves with LET.42,43 Again, with a large data-
base it was demonstrated that a drop of β down to 0 towards
higher LET values seems evident.38 For protons, not much can
be said about the RBE for very high doses where clonogenic cell
survival assays reach their limit: even if there is a decreasing RBE,
it cannot be decided whether it drops down to one or to some
larger limiting value above 1. A potential existence of subpop-
ulations, e.g. due to a cell cycle distribution of cultured cells,44
might result in further complications of the parameter derivation
at high doses.
Theoretical consideration
Evaluating and reporting RBE employs the LQ model in most
experimental studies. Thereby RBE values are calculated quanti-
ties rather than experimental data. The RBE results from a typi-
cally steeper ion dose–response curve with modified curvature
(expressed by a larger α and varying β) as compared to the refer-
ence radiation. Concerning hypofractionation, this once more
underlines the importance of knowing the course of the β term
with LET.
Notably, the dose-­dependence of RBE must be reflected in the
model used to parameterize the dose–response curves. Blom-
quist et al45 pointed out that RBE values vary depending on
whether the LQ model or the multi target—single hit model is
used to parameterize the underlying dose–response curves. An
inspection of the mathematical expression of the latter model
Br J Radiol;93:20190291
 BJR
implies that—for a fixed number of sensitive targets—the RBE is
a fixed value independent on dose.
Inspired by this insight and in perspective of regimens with high
fractional doses exceeding a few Gy one may question whether
the linear quadratic model provides a reliable parameteriza-
tion of dose–response curves. Indeed deviations from the LQ
formalism have been reported at high doses,46–48 and possible
mechanistic reasons49 and alternatives50–52 have been proposed,
although the relevance is disputable.53
For more conservative fractionation regimens with smaller frac-
tion sizes, the LQ model conveniently describes cell survival
curves in experiments and the fractionation sensitivity in clinical
settings. The dose–response curves of both ions (protons) and
the reference radiation can be inverted, and the RBE at arbitrary
dose be expressed in terms of the maximum RBE at vanishing
dose, ‍RBEmax ‍ , and the minimum RBE at the high dose limit,
‍RBEmin‍:
αI √ This reflects the nonlinearity of dose–response and results in the
RBEmax = α ; RBEmin = βI /βX
‍ X ‍
( ( ) ) The most important parameter for the dose-­dependence is—
RBE RBEmax , RBEmax , α again—the bending of dose–response curves, i.e. the β term.
β X ,D =
(√
( )2 ( ) ( )
) Although the different model approaches share many similari-
1 α α 2 2 α
2D β X + 4D β X RBEmax + 4D RBEmin − β X
‍ ‍
Here, the dose D is the particle (proton) dose, and the indices
refer to ion (I) or photon reference (X) radiation. An inspection
of the equation shows that the RBE drops √ with dose if and only
αI
if ‍RBEmax , > RBEmin‍ , implying α > βI /βX . This inequality
‍ X ‍
shows that the course of α and β with LET decides about whether
RBE decreases with dose or not.
Noteworthy, this is a functional description of the RBE evolution
with dose, but not a RBE prediction, as the limiting RBE values
are free unknown parameters. Here, practically the problem of
retrieving the high dose limit RBE emerges, given that the β term
is usually uncertainty prone.
To predict the RBE based on low LET properties of dose–re-
sponse only, several approaches have been developed. A class of
phenomenological RBE models uses the discussed LQ parame-
terization and impose simple empirical approaches for ‍RBEmax ‍
and ‍RBEmin‍. Often ‍RBEmax ‍is chosen as
( )
RBEmax = c1 + c2 LET/ α β ,‍ where the LET is adapted as the dose
‍ or non-­small cell lung cancer.1–3 To determine appropriate doses
average of the LET distribution, and the constants c1 and c2 for the
limiting RBE values are fixed by fits to experimental data. Similar
parameterizations are employed for ‍RBEmin‍ . While for heavier
particles the assumption of a linear course of the maximum RBE
with LET and the use of the dose average LET are not valid, these
assumptions may approximately hold for protons.54 Remarkably,
such parametrization has some mechanistic rationale within an
approximative microdosimetric cell survival model.55 Rørvik
et al56 investigated thoroughly the performance of numerous
empirical RBE models for protons. In almost all parameteriza-
tions, the RBE decreased with dose, reflecting the indications
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Friedrich
observed in the experimental data. Roughly, the more ‍RBEmax ‍
and ‍RBEmin‍ differ, the larger will be the impact of dose changes
on RBE, in particular for small α/β values.
Phenomenological models are simple and quite accurate as they
are directly gauged to experimental data, but lack of a mecha-
nistic underpinning and do hardly allow model extensions.
Moreover, as they use the pure LQ model and are gauged based
on data usually obtained at lower doses, their use for extreme
hypofractionated regimens is questionable.
In contrast to empirical models, mechanistic-­based models for
high LET dose–response explain the RBE based on the induc-
tion and processing of DNA damage induced to the cell nuclei.
The general approaches strongly differ and include microdosi-
metric,27,57 statistics58 or amorphous track structure consider-
ations59,60 which may include explicit lesion simulations.61 In all
models, usually the concerted action of sublethal DNA lesions
gives rise to an enhancement of the damage level at high doses.
dose–dependence of RBE.
ties, they differ considerably in predicting β as a function of LET
and in the dose-­dependence of RBE.62 As experimental data for
several particle species strongly indicate a drop of the β term
with LET,38 recent modifications of the microdosimetric model-
ling63 and a revision of a lesion statistics model62 were triggered.
The theoretic reasoning of the decrease of β with LET is a less
probable intertrack effect, i.e. less sublethal damage combination
leading to lethal damage, at higher LET due to narrower tracks
and due to less tracks needed for a given dose. This argumenta-
tion points towards a RBE decrease with dose, where, however,
its strength depends on model details.
Clinical relevance
To recall, RBE appears anyway small in radiobiology experi-
ments, and small RBE changes with dose are likely to be covered
by a large RBE uncertainty. So far, only a few clinical studies on
hypofractionated proton therapy have been running or are on
the way. They all assume 1.1 as proton RBE—just as do all clin-
ical studies using conventional fractionation schedules. For deep
seated tumours, they mostly focus on hepatocellular carcinoma
in hypofractionated regimens, a possible approach is to step-
wise escalate the dose towards the tolerable limit of side-­effects
as applied in a recent study,64 circumventing the issue of RBE
uncertainty at high doses.
Although the conventional RBE estimate of 1.1 is a practical
approximation, in locations where a higher LET and therefore a
higher RBE is expected usually no enhanced toxicity is observed.
There are only few publications which report on tissue modifica-
tions that could be associated with an elevated RBE7–9 in partic-
ular at the distal margins of the irradiated target volumes. The
Br J Radiol;93:20190291
 RBE dependence on dose for proton hypofractionation
lack of clinical evidence for proton RBE exceeding 1.1 is not fully
understood and may find its explanation in biological aspects
like tissue organization and associated repair mechanisms, given
that the affected high LET regions usually cover small volumes
only. As discussed above, in hypofractionated proton therapy
RBE effects are expected to be rather suppressed than amplified.
Consequently, even less clinical manifestation is expected.
For extreme hypofractionation some models expect considerably
lower RBE values close to 1.0. The assumption of 1.1 might lead
to an underdosage, in particular for low α/β. At high doses, the
LQ formalism allows for a flip of the known dependence of RBE
on the α/β ratio, i.e. tissues with a higher fractionation sensitivity
(lower α/β) show a lower RBE65,66 because of their pronounced
drop of RBE with dose. Moreover, in regimens with few frac-
tions the overall therapy time is considerably lowered. To inter-
pret clinical effectiveness, other aspects have to be considered in
addition to the pure LQ formalism, e.g. temporal effects such as
tumour repopulation or tumour cell heterogeneity requiring for
distributions of LQ parameters rather than fixed values.67
In that regard, the use of empirical RBE models may be
misleading as they assume the LQ model to describe dose–re-
sponse adequately at arbitrary high doses, which is poorly justi-
fied. However, this does not necessarily exclude the application
of empirical models for hypofractionation. The RBE at high
doses could be eventually unveiled in a comparative analysis
of dose escalation studies. More preclinical data are needed to
approach this path and to facilitate model benchmarking, that in
turn could justify model approaches at large doses. Notably such
data will be affected by large fluctuations, which will hamper the
evaluation of RBE characteristics and question the relevance of
the discussed RBE effects.
Recently, as a practical approach to avoid potential impact of
regions with larger RBE, the dose averaged LET is considered
as a surrogate for the RBE. Steps to avoid high LET regions are
included in treatment planning.68–70 The rationale is that empir-
ical RBE models provide a linear dependence of ‍RBEmax ‍ with
dose average LET. However, although this might be justified for
protons, for higher doses this linearity might not be preserved.
Jones argues that the product of LET and dose as effect surrogate
will not fully appreciate changes in the biologic effective dose.71
Limitations are expected as such models do not consider the ions’
track structure beyond LET, while LET alone does not uniquely
define RBE. Moreover, a model calibration assessing the radia-
tion action based on LET needs to be repeated whenever going
over to other tissue types that respond differently to radiation.
Currently, the discussion on potential impact of a variable proton
RBE is rather model driven. With respect to hypofractionation
several investigations have been carried out: using one of the
phenomenological model approaches, Dasu et al72 found that
the assumption of a variable RBE leads to predictions of a lower
effect at high doses in normal tissue within the target volume
than the conventional fixed value RBE = 1.1 approach. This is
explained as in their model RBE typically exceeds 1.1 at low
doses, but decreases to 1 towards the high dose limit. Chen et
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BJR
al73 considered hypofractionated proton therapy of liver cancer
patients with a similar empirical model.74 They found that in the
normal liver tissue outside the target volume, where dose levels
are moderate compared to the tumour, a higher RBE weighted
dose and normal tissue toxicity are expected as compared to the
1.1 assumption, and that difference decreases with the number
of fractions. They report predicted differences of complication
rates values of up to 25%, although this number is usually smaller
and depends strongly on the individual patient geometry. Carabe
et al75 pointed out that for hypofractionated regimens the RBE
weighted dose given to normal tissues gets modified within a
variable RBE model as compared to the conventional RBE = 1.1
assumption, whereas the direction of RBE alteration depends on
details of the patient plan and irradiation geometry. The uncer-
tainty of the dose predictions was observed to decrease with the
number of fractions, which might facilitate a more robust plan-
ning at higher doses.
The flip of RBE dependence on the α/β ratio mentioned above65,66
and the convergence towards a common limit in the high dose
limit suggest an optimum fractionation scheme depending on
the particular combination of a high α/β ratio of tumour and a
lower one for surrounding organs. For carbon ions with stronger
RBE effects such optimization has been attempted at hand of
preclinical data,76 but for protons where differential RBE effects
are hardly observable, rather tolerance doses of normal tissue in
the irradiation field are considered for finding tolerable hypof-
ractionation schedules.
Another important consequence of proton RBEs is that the
effective range of proton beams, i.e. the Bragg peak position of
the RBE-­weighted dose profile, is enhanced compared to the
absorbed dose–depth distribution.77–79 Therefore, modifications
in RBE will result in changes of the effective range. Paganetti
concluded that the RBE uncertainty contributes to a non-­
negligible extent to about a third to the total range uncertainty
in the patient.80
Summary and outlook
Despite the favourable dose deposition properties in proton
therapy, an improved efficacy was not always observed in compar-
ison to photon therapy.81 Here, hypofractionation might extend
the spectrum of therapeutic outcome. A decrease of the clinical
RBE towards higher doses for protons is likely. This is based on
evidence in radiobiology experiments with protons and heavier
particles, and is supported by theoretic arguments. In thera-
peutic settings—with few exceptions—normal tissue complica-
tions associated with an elevated RBE are usually not observed.
In hypofractionated schedules, an attribution of side-­effects with
RBE might thus even be harder. For moderate hypofractionated
regimens, the clinical relevance of RBE variations is expected to
be small. However, the RBE is expected to drop below 1.1, and
the high dose limit is unclear, eventually leading to the danger of
an underdosage in the tumour region. Consequences of "missing
RBE" might become detectable at very high doses, in particular in
view of the expected reduced uncertainty of RBE. More dedicated
radiobiological in vivo experiments in combination with theoretic
considerations may gather a better quantitative insight.
Br J Radiol;93:20190291
 BJR Friedrich

Currently, a number of technical and biological advances open
up new options for radiation therapy. Their application in the
context of proton therapy involves the delivery of extremely
high doses. For instance, in analogy to stereotactic body radi-
ation therapy with photons, the treatment of small fields with
high proton doses was considered, where a potential trigger
of additional damage pathways like vascular damage is under
discussion.49,82,83 In minibeam or microbeam therapy (also
termed grid therapy or spatial fractionation), multiple small
separated beams are coupled into the body at extremely high
doses, which overlap in the target volume due to lateral scat-
tering.84–86 Recent findings on FLASH irradiations with ultra-
high dose rates demonstrated a selective effect on the tumour
tissue, while normal tissue is spared, so that hypofractionation
becomes feasible.87,88 These examples have in common, that a
widening of the therapeutic window is associated to or allows
the application of high doses to the target volume. Albeit RBE
effects expected irrelevant at such high doses, the observed
strong effect modifications indicate processes not captured
by the conventional RBE concept: in addition to schedule and
dose, spatial and temporal aspects of dose delivery within frac-
tions become important. Further preclinical studies promise
more insight in high dose action.
An important aspect discussed concerning the RBE in hypofrac-
tionated regimens is the RBE uncertainty, which might prevent
the observation of significant RBE effects. In the clinical context,
this is complicated by another source of uncertainty, which is the
limited knowledge on volume effects.89 Understanding the effects
of partial organ irradiation in terms of inflicted normal tissue
complication is crucial for a predictive assessment of treatment
outcome. In combination, the effect prediction within voxelized
models becomes vague. In vivo experiments at high doses may be
helpful to discriminate between these sources of uncertainty due
to smaller confidence intervals of RBE.
Besides the "classical" end points in cancer therapy like toxicity,
local control and overall survival, also the risk of radiation
induced second cancers is of interest.90 Particle therapy may
perform better than photons, as the irradiated field including
entrance channels is much smaller.91,92 Hypofractionation
is expected to modify the expectations, as at high doses cell
kill prevents the induction of heritable mutations as potential
starting point for cancer evolution. For a detailed analysis, RBE
values for the carcinogenic potential would have to be consid-
ered in a high-­dose voxel plan.
Finally, we can gain much knowledge from studies using
heavier ions, where RBE effects are more prominent and
hypofractionation is more common. Since protons and heavier
ions are massive particles that primarily differ in mass and
charge, the general mechanisms from damage induction to the
manifestation of biological and clinical effects should remain
the same, while only amount and quality of inflicted damage
vary. Investigating hypotheses and models applicable consis-
tently to arbitrary radiation qualities will be helpful to derive
further insight in RBE at high doses, as well as the design of
dedicated experiments and clinical studies.

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