Content uploaded by Karoline Faust
Author content
All content in this area was uploaded by Karoline Faust on Oct 28, 2015
Content may be subject to copyright.
Advances in Radiotherapy for Head and Neck Cancer
Vincent Grégoire, Jan A. Langendijk, and Sandra Nuyts
Vincent Grégoire, Institut de Recherche
Clinique, Université Catholique de
Louvain, St-Luc University Hospital,
Brussels; Sandra Nuyts, Katholieke
Universiteit Leuven–University of
Leuven, University Hospitals Leuven,
Leuven Cancer Institute, Leuven,
Belgium; and Jan A. Langendijk,
University Medical Center Groningen,
University of Groningen, Groningen,
the Netherlands.
Published online ahead of print at
www.jco.org on September 8, 2014.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Vincent
Grégoire, MD, PhD, FRCR (hon),
Department of Radiation Oncology,
St-Luc University Hospital, Brussels,
Belgium; e-mail: vincent.gregoire@
uclouvain.be.
© 2015 by American Society of Clinical
Oncology
0732-183X/14/3399-1/$20.00
DOI: 10.1200/JCO.2015.61.2994
ABSTRACT
Over the last few decades, significant improvements have been made in the radiotherapy (RT)
treatment of head and neck malignancies. The progressive introduction of intensity-modulated RT
and the use of multimodality imaging for target volume and organs at risk delineation, together
with the use of altered fractionation regimens and concomitant administration of chemotherapy or
targeted agents, have accompanied efficacy improvements in RT. Altogether, such improvements
have translated into improvement in locoregional control and overall survival probability, with a
decrease in the long-term adverse effects of RT and an improvement in quality of life. Further
progress in the treatment of head and neck malignancies may come from a better integration of
molecular imaging to identify tumor subvolumes that may require additional radiation doses (ie,
dose painting) and from treatment adaptation tracing changes in patient anatomy during treat-
ment. Proton therapy generates even more exquisite dose distribution in some patients, thus
potentially further improving patient outcomes. However, the clinical benefit of these approaches,
although promising, for patients with head and neck cancer need to be demonstrated in
prospective randomized studies. In this context, our article will review some of these advances,
with special emphasis on target volume and organ-at-risk delineation, use of molecular imaging for
tumor delineation, dose painting for dose escalation, dose adaptation throughout treatment, and
potential benefit of proton therapy.
J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
INTRODUCTION
Over the last few decades, significant improvements
have been made in radiotherapy (RT) for the treat-
ment of cancer in general and of head and neck
malignancies in particular. From Cobalt-60 ma-
chines to modern linear accelerators, from x-rays
to particles, from two-dimensional techniques to
intensity-modulated RT (IMRT), and from planar
x-ray films to full three-dimensional computed
tomography (CT), magnetic resonance imaging
(MRI), or positron emission tomography (PET) im-
ages for target volume (TV) visualization, tremen-
dous technical progress has accompanied efficacy
improvements in RT. Along with this technical
progress, an increasing understanding of the molec-
ular mechanisms of interactions between radiation
and tumors and normal tissues has been obtained,
leading to the development of altered fractionation
regimens, concomitant use of RT with chemother-
apy or targeted agents, and heterogeneous dose pre-
scription, also called dose painting.
Altogether, it can be estimated that today, ap-
proximately 75% of patients with head and neck
squamous cell carcinoma (HNSCC) will benefit
from RT as part of their primary treatment or as
adjuvant treatment modality after surgery.
1
In Den-
mark, for example, locoregional control has im-
proved from approximately 27% some 30 years ago
to figures approaching 80% in 2014, and these im-
provements have translated into gains in overall sur-
vival.
2
As a consequence of these improvements, a
progressive shift has been observed in major can-
cer centers from primary surgery to function-
preservation RT, at least for pharyngolaryngeal SCC.
In addition, although patients live longer free of
disease, significant progress has been made in im-
proving the quality of their survival by decreasing
the long-term adverse effects of RT, such as xerosto-
mia or swallowing difficulties.
3,4
In the following sections, some of these ad-
vances will be reviewed, with special emphasis on TV
and organ-at-risk (OAR) delineation, use of molec-
ular imaging for TV delineation, dose painting for
dose escalation, dose adaptation throughout treat-
ment, and potential benefit of proton therapy.
DELINEATION OF CLINICAL TVS AND OARS
Because IMRT typically creates sharp dose gradients
between the TV and surrounding OARs, precise de-
lineation of these structures to which dose-volume
constraints will be applied is required to run the dose
JOURNAL OF CLINICAL ONCOLOGY REVIEW ARTICLE
© 2015 by American Society of Clinical Oncology 1
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.61.2994The latest version is at
Published Ahead of Print on September 8, 2015 as 10.1200/JCO.2015.61.2994
Copyright 2015 by American Society of Clinical Oncology
optimizer.
5
Guidelines for the delineation of the primary tumor clin-
ical TV (CTV) have been published, but none have gained worldwide
acceptance. The Danish Head and Neck Cooperative Group has pro-
posed margin-based guidelines, by which a security margin is applied
around the primary tumor gross TV (GTV), with corrections for bony
structures, air cavities, or other normal structures where applicable (C.
Grau, personal communication, July 2013). These guidelines have the
advantage of being easily implementable, but they do not take into
account the fact that tumor-cell infiltration is not isotropic and clearly
depends on the surrounding normal tissues; cells may easily infiltrate
fatty tissues, whereas they are confined to some extent by ligaments or
bone cortex. Anatomy-driven guidelines bypass these shortcomings;
they are justified by the general principle that the microscopic spread
of SCCs around the primary tumor GTV follows anatomic compart-
ments (eg, paralaryngeal, parapharyngeal, and pre-epiglottic spaces)
bounded by anatomic barriers (eg, bone cortex, muscular fascia, and
ligaments).
6
Such guidelines are intrinsically more adequate, but they
require a much broader knowledge of the complex head and neck
anatomy and are probably more time consuming to develop. When
there are no anatomic barriers (eg, muscles at base of tongue), both
sets of guidelines agree on the use of a fixed margin from the GTV.
Margins of approximately 10 mm for the so-called prophylactic CTV
and of 5 mm for the so-called therapeutic CTV have been recom-
mended based on microscopic assessment of surgical specimens.
7
It is
likely that when used by experienced physicians, both sets of guide-
lines will converge in close CTV delineation. In contrast, conformal
avoidance IMRT, by which only GTVs and OARs are delineated, is not
a recommended method, because it translates into much larger irra-
diated volumes, sparing only a few OARs.
8
Regarding the delineation of the neck node CTV, in collabora-
tion with representatives of the major European and North American
clinical cooperative groups, an international set of guidelines was
published in the early 2000s for the node-negative neck.
9
In the late
2000s, a few amendments were proposed to take into account the
specific situation of a node-positive and postoperative neck.
10
More
recently, in 2013, a task force comprising opinion leaders in the field of
head and neck RT oncology from European, Asian, Australian and
New Zealand, and North American clinical research organizations
(Danish Head and Neck Cooperative Group, European Organisation
for Research and Treatment of Cancer, Hong Kong Nasopharyngeal
Carcinoma Study Group, National Cancer Institute of Canada Clini-
cal Trials Group, National Cancer Research Institute, Radiation Ther-
apy Oncology Group, and Trans Tasman Radiation Oncology Group)
was formed to review and update the previously published guidelines
on nodal level delineation (Fig 1).
11
It is beyond the scope of this article
to discuss in depth these guidelines. The reader is referred to the
original publication. In short, based on the nomenclature proposed by
the American Head and Neck Society and the American Academy of
Otolaryngology–Head and Neck Surgery, and in line with the TNM
atlas for lymph nodes in the neck, 10 nodal groups (corresponding to
17 levels) were defined, with concise descriptions of their main ana-
tomic boundaries, the normal structures juxtaposed to these nodes,
and the main tumor sites at risk for harboring metastases at those
levels. Emphasis was placed on those levels not adequately considered
previously (or not addressed at all); these included the lower neck (eg,
supraclavicular nodes [levels IVb and Vc]), scalp (eg, retroauricular
and occipital nodes [levels Xa and Xb, respectively]), and face (eg,
parotid and buccofacial nodes [levels VIII and IX, respectively]).
Translation from the nodal levels to CTV delineation may need some
adjustment as a function of the nodal status setting. In node-negative
patients and in patients with a single small lymph node or with several
small lymph nodes not abutting one of the surrounding structures (eg,
muscle or salivary gland), the CTV will be defined by the association of
one or several of the nodal levels. For larger lymph nodes abutting or
infiltrating one of the surrounding structures (eg, sternocleidomas-
toid muscle, paraspinal muscle, or parotid gland), CTV delineation
may need to take into account macroscopic and microscopic tumor
infiltration outside of the node. On the basis of expert opinion, an
isotropic expansion by 10 to 15 mm into these structures from the
visible edge of the node seems reasonable, excluding bone and airway.
Finally, for the delineation of the high-dose CTV (ie, therapeutic-dose
CTV), it is typically recommended that a 5- to 8-mm margin be added
around the nodal GTV.
Adequate sparing of OARs requires delineation of anatomic re-
gions considered relevant for the development of acute and late
radiation-induced adverse effect. However, so far, there is no consen-
sus on the exact definition of OARs in the head and neck region. The
use of uniform guidelines for OAR delineation is becoming increas-
ingly important, because nearly all new RT technologies in head and
neck cancer have been clinically introduced to decrease the radiation
dose to healthy tissues to prevent radiation-induced adverse effects.
For example, IMRT was first implemented to reduce xerostomia.
12
To
further optimize IMRT, detailed information on the relationships
between the radiation dose metric in various OARs and the risk of
adverse effects is required to derive normal tissue complication prob-
ability models. However, marked differences with regard to risk esti-
mates for similar end points have been reported when different
definitions of the same OAR were used.
13
This lack of uniformity may
hamper the clinical utility of normal tissue complication probability
models in routine practice, because they may result in over- or under-
estimation of the risk of adverse effects. Moreover, it could jeopardize
the comparison of radiation-induced adverse effects between institu-
tions. Therefore, in this context, the same committee of experts that
Level Ib
Level II
Level VIII
Level VIIa
Level IX
Level Xb
Left submandibular
gland
Mandible
Spinal cord
Oral cavity
Constrictor muscle
Left parotid
Fig 1. Computed tomography slide illustrating international consensus guide-
lines for delineation of clinical target volume and organs at risk in neck.
Grégoire, Langendijk, and Nuyts
2© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
published the international guidelines for CTV delineation in the neck
is now producing international guidelines for delineation of OARs as
well (Fig 1). These guidelines should be published in 2015.
MOLECULAR IMAGING FOR RADIATION DOSE PLANNING
For pharyngolaryngeal and oral cavity SCCs, delineation of target
volumes for treatment planning is routinely performed on contrast-
enhanced axial CT slices and/or on coregistered MRI sections after
comprehensive clinical examination, including examination under
general anesthesia. This latter examination remains crucial to detect
mucosal spread typically not visible on any imaging modalities. For
delineation of the primary tumor, MRI has been shown to be comple-
mentary to CT, improving tumor delineation in the oral cavity or the
oropharynx, in case of dental artifacts, and decreasing interobserver
variation, especially for tumors near the base of skull (eg, nasopharyn-
geal carcinoma).
14-16
For delineation of nodal disease, CT and MRI
have similar diagnostic accuracy, and no advantage of one over the
other is expected.
17,18
The role of [
18
F]fluorodeoxyglucose (FDG) –PET (or PET-CT)
for TV delineation and its added value in dose distribution have been
extensively studied. Despite claims by some authors, FDG-PET (or
PET-CT) has no added value for TV delineation in the neck, because it
has no more sensitivity or specificity for neck-node detection in com-
parison with CT or MRI.
17-22
However, the use of FGD-PET (or
PET-CT) substantially influences primary tumor delineation, at least
for locally advanced tumors, with FDG-PET– based TV being typically
smaller compared with CT or MRI.
20,22-25
When compared with the
pathologic specimen taken as the ground truth, GTV delineation
based on FDG uptake has been shown to be closer to the pathologic
specimen, and changes in GTV delineation translated into differences
in CTV, planning TV, and dose distribution.
24-26
However, PET (or
PET-CT) image acquisition in the treatment position with an immo-
bilization mask is required; if available, the use of combined PET-CT
camera with intravenous contrast enhancement is preferred, because
it allows an all-in-one examination, decreasing the uncertainties of
image registration between PET and CT. For PET image segmenta-
tion, observer-independent automatic methods, which can cope with
noise, low resolution, and partial volume effect of PET images, should
be used.
27
Suboptimal FDG-PET segmentation methods (eg, based on
visual segmentation or on fixed standardized uptake value) have been
reported and may explain some of the discrepancies reported when
comparing different imaging modalities for TV delineation.
28,29
How-
ever, no PET segmentation method has identified small macroscopic
mucosal infiltration, highlighting once more the importance of clini-
cal examination for GTV determination and the use of proper margins
when delineating the CTV. No randomized study has ever been con-
ducted to compare FGD-PET (or PET-CT) – based dose distribution
and patient outcome, but a few prospective studies have demonstrated
that PET planning translated into more conforming dose distribution
and fewer late adverse effects, without compromising treatment effi-
cacy.
30,31
In the study by Leclerc et al,
30
the advantage of FDG-PET was
mainly observed for oropharyngeal tumors, allowing for lower doses
to the parotid glands and oral cavity.
In addition to PET, newer MRI techniques have been evaluated
for their added value in TV delineation. Diffusion-weighted (DW)
MRI detects differences in the tissue microenvironment resulting
from random displacement of water molecules. This movement be-
tween pairs of opposing magnetic field gradients is detectable as a
signal loss proportional to the amount of movement and the strength
of the gradient. These differences are quantified as apparent diffusion
coefficients (ADCs), which are inversely correlated with tissue cellu-
larity. In contrast to FDG-PET, DW-MRI shows a potential role for
TV delineation in the neck, with special promise in the detection of
subcentrimetric nodal metastases (Fig 2). In a study of surgically
treated patients, DW-MRI showed higher sensitivity and specificity to
detect nodal metastases in the neck, leading to a 91% accuracy, com-
pared with 83% for 1.5-T turbo-spin echo MRI. Neither MRI protocol
could detect lymph node metastases smaller than 4 mm. The ADC was
significantly lower for metastatic than for benign lymph nodes, likely
because of hypercellularity, cellular polymorphism, and increased mi-
totic activity in metastatic nodes.
32
Furthermore, an RT planning
study based on DW-MRI showed a better correlation of the nodal
CTV to the gold standard (ie, pathologic findings) when contouring
ABCD
Fig 2. (A) Computed tomography and (B) gadolinium-enhanced T1-weighted fat-suppressed turbo-spin echo magnetic resonance imaging scans obtained in
62-year-old woman diagnosed with large tumor of tongue showing normally shaped lymph node (arrows) with regular contours, shortest transverse diameter of 0.5
cm, and homogeneous contrast enhancement; this node was considered normal. (C) However, lymph node (arrow) is hyperintense on transverse b ⫽1,000
seconds/mm
2
diffuse-weighted image, corresponding to lymph node with apparent diffusion coefficient (ADC) of 0.76 ⫻10
⫺3
mm
2
/seconds on transverse ADC map,
findings of which are suggestive of metastatic adenopathy. (D) Corresponding pathology shows metastatic deposit infiltrating node. (Original magnification, ⫻100;
courtesy of V. Vandecaveye and E. Hauben.)
Advances in RT for Head and Neck Cancer
www.jco.org © 2015 by American Society of Clinical Oncology 3
was performed based on DW-MRI findings in comparison with con-
touring based on CT and conventional MRI findings.
33
The high
negative predictive value of DW-MRI for metastatic disease may help
in decision making regarding determination of RT treatment volume
and dose. Today, no imaging technique allows the complete sparing of
at-risk clinically negative nodal levels from prophylactic irradiation,
but the question arises if lower doses could be considered for these
small, yet undetectable, tumor deposits in lymph nodes.
Primary tumor delineation based on DW-MRI is still under
investigation. A comparison between CT, FDG-PET, and DW-MRI
was performed by Dirix et al.
34
The GTV
PET
was automatically seg-
mented based on source-to-background ratio, whereas the GTV
MRI
was manually delineated by a radiation oncologist and a radiologist in
consensus. Both the GTV
PET
and GTV
DW-MRI
were significantly
smaller than the GTV
CT
. Over a median follow-up of 30.7 months,
seven patients had recurrent disease; all recurrences were located
within the area of overlap between the GTV
CT
, GTV
MRI
, and GTV
PET
.
It is evident that considerable further research and development are
necessary before DW-MRI can be routinely used for contouring of
HNSCC. Interpretation of DW images is not straightforward, making
the use of quantitative measurements (ie, ADC values) absolutely
necessary. However, this is also one of the strengths of the technique,
because a straightforward cutoff value would allow simple and reliable
differentiation, potentially eliminating both intra- and interobserver
variability. Also, DW images have a non-negligible distortion, which
makes image fusion with planning CT images difficult. Because of the
low signal-to-noise ratio and the high level of deformation, automatic
nonrigid coregistration algorithms based on mutual information do
not provide enough information for accurate coregistration. There-
fore, semiautomatic alterations of this algorithm have to be developed
to provide the additional information required.
35
DOSE PAINTING AND DOSE ESCALATION
Imaging-based dose painting (ie, prescription and delivery of nonuni-
form dose to CTV) is a different paradigm for prescribing RT.
36
The
basic idea is to steer dose distribution on the spatial distribution of a
specific tumor phenotype that is hypothesized or has been shown to be
related to local tumor control after RT. In this framework, dose paint-
ing by volume refers to the delivery of an additional boost dose to a
subvolume within the GTV, whereas in dose painting by number, the
dose is prescribed at the voxel level.
37
Hybrids between the two strat-
egies use a series of nested volumes, with a prescribed dose assigned to
each of them.
The dose-painting paradigm is supported by several clinicobio-
logic hypothesis: first, local recurrences arise from cellular or microen-
vironmental niches that are (relatively) resistant at the radiation-dose
level that can safely be routinely delivered using a uniform dose distri-
bution
38
; second, molecular imaging will allow spatiotemporal map-
ping of these regions of relative radioresistance; and third, advances in
RT planning and delivery technologies facilitate delivery of a graded
boost to such regions, which in turn should lead to improved local
tumor control with acceptable adverse effects. Support for the dose-
painting hypothesis comes in part from mathematic modeling studies
showing that in case of nonuniform radiosensitivity distribution, a
uniform dose distribution is inferior to a distribution that delivers a
relatively higher proportion of the integral dose to the more resistant
regions of the tumor (ie, by dose painting).
39
Current developments in dose painting focus on the three main
causes of RT failure in the clinic: tumor burden, tumor cell prolifera-
tion, and tumor hypoxia. Regarding tumor burden, FDG uptake is
commonly considered a good surrogate for tumor-cell density. A
modeling study based on retrospective clinical data on the prognostic
significance of FDG uptake in HNSCC estimated that a 10% to 30%
higher dose was required in an FDG-avid tumor to reach similar local
tumor control than in a non–FDG-avid tumor.
40
Proof-of-concept
planning studies have shown the feasibility of selective dose escalation
based on FDG distribution (Fig 3) and have justified a dose-searching
phase I trial in patients with locally advanced HNSCC
41,42
; in the latter
study, a median dose of 86 Gy to the FDG-avid sub-GTV was associ-
ated with late mucosal necrosis in five of 14 patients, and the
maximum-tolerated median dose was set at 80.9 Gy. A multicentric
randomized study comparing a standard dose of 70 Gy with FDG-
PET– based dose redistribution up to a maximum dose of 84 Gy is
ongoing.
43
DW-MRI is a complementary imaging method to visualize
tumor-cell density, but no clinical dose-painting study has been re-
ported yet.
44,45
86 Gy
81.7 Gy
74.4 Gy
66.5 Gy
63 Gy
58.8 Gy
53.2 Gy
50.4 Gy
35 Gy
BA
Fig 3. Example of [
18
F]fluorodeoxyglu-
cose (FDG) –positron emission tomogra-
phy (PET) – based dose painting by
numbers. (A) Axial section of FDG-PET/
computed tomography of patient with T4-
N2c-M0 oropharyngeal squamous cell
carcinoma; FDG-PET image was seg-
mented into levels, which were used for
dose escalation from 70 to 86 Gy. (B)
Corresponding dose distribution obtained
with TomoTherapy (Accuray, Sunnyvale,
CA). Volumes of interest: planning target
volume (PTV)
70 Gy
(red), PTV
56 Gy
(deep
blue), PTV
PET
(light blue).
Grégoire, Langendijk, and Nuyts
4© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Regarding tumor-cell proliferation, a planning study investi-
gated the use of 3=-deoxy-3=-
18
F-fluorothymidine (FLT) –PET to steer
dose escalation on proliferative subvolumes within the GTV, but in
the absence of a clear association between expression of FLT and
tumor failure, the biologic rationale for this boosting strategy needs
further investigation.
46
Finally, regarding tumor hypoxia, few clinical studies have
used specific PET-labeled tracers to detect and quantify the presence
of hypoxia in patients with HNSCC or shown its prognostic
significance.
47-50
Preclinical studies with [
18
F]misonidazole- or
[
18
F]fluoroazomycinarabinofuranoside-PET have also validated the
concept of selective radiation dose escalation in hypoxic tumors to
improve local control.
51-53
In patients, planning studies have shown
that radiation dose escalation was possible without exceeding the
tolerance dose to the surrounding normal tissues,
54-56
and according
to the ClinicalTrials.gov database, a randomized clinical study to val-
idate dose escalation in hypoxic subvolumes in patients with locally
advanced HNSCC is planned or ongoing. However, the magnitude of
the required dose to maximize local tumor control in PET-positive
hypoxic regions is still not settled. Calculation of the additional radia-
tion dose required to achieve local control of hypoxic tumors based on
oxygen-enhancement ratios derived from in vitro experimental data is
likely too simplistic. In a proof-of-concept planning study using
[
18
F]misonidazole-derived sub-GTV, it was calculated that a 10%
dose escalation (⬎70 Gy) with dose redistribution would be associ-
ated with a significant increase in tumor control probability.
54
Thus, it
is likely that dose-painting prescription in hypoxia-driven treatment
will be based on the concept of dose redistribution, which allows both
dose increase and dose decrease to generate a similar integral dose, as if
the dose were homogeneously distributed throughout the TV.
57
ADAPTIVE TREATMENT
Current RT treatments are planned using a CT scan at a single pre-
treatment time point to delineate the TV and OARs, without taking
into account the occurrence of anatomic changes during the course of
fractionated RT. With current concomitant chemo-RT schedules, the
limits of acceptable toxicity have been reached, and therefore, more
personalized treatment delivery is needed to increase the therapeutic
ratio for patients. In this context, considerable efforts have been made
in adaptive RT (ie, adapting treatment delivery based on changes in
tumor and/or normal tissues during course of RT).
It is common for tumors, and to some extent for OARs, to change
over the course of curative RT. Tumor and nodal volumes shrink by up to
3.0% per day, changing size, shape, and position, sometimes asymmetri-
cally.
58
Modifications in patient outlines are observed as a consequence of
weight and muscle mass loss. This further alters the anatomy and geom-
etry of the tumor in relation to critical normal structures. Geets et al
59
showed reductions of 51% in the CTV and of 48% in the planning TV
after a partial course (45 Gy) of RT. Regarding normal tissues, parotid
glands not only shrink but also shift medially into the high-dose region
during treatment.
58,60
Spatiotemporal instability of the tumor and nor-
mal structures and/or geometric uncertainty in patient positioning are
critical in IMRT because of the sharp dose gradients involved.
58
The
consequence of all these changes is that the dose distribution may differ
significantly from what was planned, calling for adaptive replanning dur-
ing treatment. Schwartz et al
61
investigated the concept of adaptive RT in
a prospective trial including 22 patients with oropharyngeal cancer. The
study showed superior dosimetric results using adaptive RT over IMRT,
with no affect on locoregional control. Similar data have been reported in
Organs at Risk Dose Distribution, IMRT (photons) Dose Distributions, IMPT (protons)
Dose Difference Map
V5
V10
V15
V20
V25
V30
V35
V40
V45
V50
V55
V60
V65
V70
V5
V10
V15
V20
V25
V30
V35
V40
V45
V50
V55
V60
V65
V70
V5
V10
V15
V20
V25
V30
V35
V40
V45
V50
V55
V60
V65
V70
Esophagus inlet
Brain stem
Spinal cord
Parotid gland right
Cricopharyngeus
Submandibular gland R
Carotid artery
Glottis
Thyroid gland
Middle PCM
Inferior PCM
Supraglottis
Parotid gland left
Superior PCM
Submandibular gland L
Body volume (scan)
Fig 4. Comparison of dose distributions between intensity-modulated radiation therapy (IMRT) photon plan and intensity-modulated proton therapy (IMPT) plan in
patient with T4-N0-M0 oropharyngeal squamous cell carcinoma. Green shades in dose-difference map indicate difference in favor of protons. Figure shows that with
protons, dose can be significantly reduced in all organs at risk, which is expected to result in more favorable toxicity risk profile as compared with that obtained with
IMRT. L, left; PCM, pharyngeal constrictor muscle; R, right.
Advances in RT for Head and Neck Cancer
www.jco.org © 2015 by American Society of Clinical Oncology 5
patients treated by IMRT for nasopharyngeal carcinoma; replanning was
associated with improved quality of life and efficacy compared with no
replanning.
62
Finally, in parallel to adaptive RT based on anatomy varia-
tion, adaptive replanning may also be envisaged on the basis of tumor
response assessed with molecular imaging. This is a relatively new area of
investigation, which should remain in the realm of clinical research.
Although a potential advantage of adaptive RT is the compensa-
tion for underdosage of TVs or overdosage of OARs, because of extra
workload and cost, the optimal implementation strategy remains to be
defined. Further development in computational power, image guid-
ance, autocontouring, dose verification, and plan adaptation is crucial.
It is widely accepted that deformable image registration plays a vital
role in adaptive RT.
In summary, although adaptive RT is an appealing concept, it is
currently not used on a routine basis for all patients; rather, it is performed
at the discretion of the treating physician. It is hoped that questions re-
garding selection of patients and timing of imaging and replanning will be
resolved by well-designed prospective and/or randomized studies.
PROTON THERAPY
In external photon (x-ray) beam RT, because of the exponential depth-
energy deposition curve, a substantial amount of the dose will be depos-
ited in the normal tissues upstream and downstream of the tumor. The
beam properties of protons are fundamentally different. They release the
greatest part of their energy at a defined depth (ie, so-called Bragg peak),
which depends on the energy of the incident beam; no dose will be
deposited downstream of the Bragg peak. When a number of beams with
different energies are combined, a so-called spread-out Bragg peak can be
produced, leading to homogeneous dose distribution in the tumor, with
less dose delivered to the normal tissues located upstream of the target and
still no dose to the tissues downstream of the Bragg peak. When different
beam angles are combined, and when the intensities of these various
beams are carefully modulated (ie, so-called intensity-modulated proton
therapy [IMPT]), an advantageous dose distribution can be produced
compared with photons. The physical advantages of IMPT over IMRT
can be used either to escalate the dose to the tumor without exceeding
(and even with decreasing) the radiation dose delivered to the surround-
ing normal tissues and/or to significantly reduce the normal tissue irradi-
ation while delivering a similar dose to the tumor.
63
With the currently available photon technology, further spar-
ing of nontarget tissues is frequently difficult, because target vol-
umes in HNSCC are generally large, complex in shape, and
surrounded by critical normal tissues. With IMRT, attempts to
optimize the dose to one OAR frequently increases the dose to
other structures, which may lead to higher incidence of toxicities,
some of which are apparently unique to IMRT (eg, higher rates of
acute oral mucositis and transient tube feeding dependence,
64
higher rates of nausea and vomiting, occipital alopecia, and ante-
rior oral mucositis,
65
higher rates of acute fatigue,
12
and higher
rates of hypothyroidism
66
).
Proton therapy technology is developing rapidly. In particular,
the introduction of pencil-beam scanning and the introduction of
IMPT are relevant for patients with HNSCC. Numerous in-silico
planning comparative studies have indeed shown that with IMPT, the
dose to OARs related to salivary dysfunction and swallowing can be
reduced significantly, which in turn is expected to result in lower rates
of acute and late adverse effects
67-69
(Fig 4). However, given the rela-
tive novelty of IMPT, clinical data on the efficacy of IMPT to reduce
adverse effects are scarce. At present, there is only one ongoing phase
III study at the MD Anderson Cancer Center in Houston, Texas, in
which patients with human papillomavirus–positive oropharyngeal
SCC are being randomly assigned to receive concurrent chemo-RT
with IMRT versus IMPT.
Given their beam properties, protons are more sensitive to geo-
metric variations during treatment than photons, because of setup
inaccuracies, tumor shrinkage, weight loss, and organ motion, which
over the course of a fractionated treatment may lead to underdosage in
the tumor and overdosage in the OARs. Different strategies can be
applied to account for these uncertainties, such as robust treatment
planning techniques, multicriteria optimization, CT-based image
guidance, adaptive proton therapy, and online verification techniques
(eg, prompt gamma). Given its superior beam properties and the
increasing availability of proton facilities with IMPT integrated into
existing radiation oncology departments, we expect that RT with
protons will open unique opportunities to broaden the therapeutic
window for patients with head and neck cancer.
In conclusion, over the last decade, we have witnessed the progres-
sive routine use of IMRT for the treatment of HNSCC. Together with the
use of guidelines for TV and OAR delineation, it has translated into dose
reductions to OARs, with significant reduction in radiation-induced
complications such as xerostomia, without compromising treatment ef-
ficacy. Further progress in the treatment of HNSCC may come from a
better integration of molecular imaging to identify tumor subvolumes
that may require additional radiation doses and from treatment adapta-
tion, tracing changes in patient anatomy during treatment. Finally, proton
therapy generates even more exquisite dose distribution in some patients
and thus has the potential to further improve patient outcomes. However,
prospective randomized studies are needed to demonstrate the clinical
benefit of these approaches for patients with HNSCC.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Vincent Grégoire
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
REFERENCES
1. Barton MB, Jacob S, Shafiq J, et al: Estimat-
ing the demand for radiotherapy from the evidence:
A review of changes from 2003 to 2012. Radiother
Oncol 112:140-144, 2014
2. Overgaard J: Improving radiotherapy of squa-
mous cell carcinoma of the head and neck (HNSCC)
through a continuous process of biological based
clinical trials: A 30 year experience from the Danish
head and neck group. JAMA 140:S397, 2014 (suppl)
3. Langendijk JA, Doornaert P, Verdonck-de
Leeuw IM, et al: Impact of late treatment-related
toxicity on quality of life among patients with head
Grégoire, Langendijk, and Nuyts
6© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
and neck cancer treated with radiotherapy. J Clin
Oncol 26:3770-3776, 2008
4. O’Sullivan B, Rumble RB, Warde P: Intensity-
modulated radiotherapy in the treatment of head
and neck cancer. Clin Oncol (R Coll Radiol) 24:474-
487, 2012
5. Brahme A: Optimization of stationary and
moving beam radiation therapy techniques. Ra-
diother Oncol 12:129-140, 1988
6. Eisbruch A, Gregoire V: Balancing risk and
reward in target delineation for highly conformal
radiotherapy in head and neck cancer. Semin Radiat
Oncol 19:43-52, 2009
7. Campbell S, Poon I, Markel D, et al: Evaluation
of microscopic disease in oral tongue cancer using
whole-mount histopathologic techniques: Implica-
tions for the management of head-and-neck can-
cers. Int J Radiat Oncol Biol Phys 82:574-581, 2012
8. Harari PM, Song S, Tomé WA: Emphasizing
conformal avoidance versus target definition for
IMRT planning in head-and-neck cancer. Int J Radiat
Oncol Biol Phys 77:950-958, 2010
9. Grégoire V, Levendag P, Ang KK, et al:
CT-based delineation of lymph node levels and re-
lated CTVs in the node-negative neck: DAHANCA,
EORTC, GORTEC, NCIC,RTOG consensus guide-
lines. Radiother Oncol 69:227-236, 2003
10. Grégoire V, Eisbruch A, Hamoir M, et al:
Proposal for the delineation of the nodal CTV in the
node-positive and the post-operative neck. Ra-
diother Oncol 79:15-20, 2006
11. Grégoire V, Ang K, Budach W, et al: Delinea-
tion of the neck node levels for head and neck
tumors: A 2013 update—DAHANCA, EORTC, HKN-
PCSG, NCIC CTG, NCRI, RTOG, TROG consensus
guidelines. Radiother Oncol 110:172-181, 2014
12. Nutting CM, Morden JP, Harrington KJ, et al:
PARSPORT trial management group. Parotid-
sparing intensity modulated versus conventional ra-
diotherapy in head and neck cancer (PARSPORT): A
phase 3 multicentre randomised controlled trial.
Lancet Oncol 12:127-136, 2011
13. Brouwer CL, Steenbakkers RJ, Gort E, et al:
Differences in delineation guidelines for head and
neck cancer result in inconsistent reported dose and
corresponding NTCP. Radiother Oncol 111:148-152,
2014
14. Geets X, Daisne JF, Arcangeli S, et al: Inter-
observer variability in the delineation of pharyngo-
laryngeal tumor, parotid glands and cervical spinal
cord: Comparison between CT-scan and MRI. Ra-
diother Oncol 77:25-31, 2005
15. Rasch C, Steenbakkers R, van Herk M: Target
definition in prostate, head, and neck. Semin Radiat
Oncol 15:136-145, 2005
16. Thiagarajan A, Caria N, Schöder H, et al:
Target volume delineation in oropharyngeal cancer:
Impact of PET, MRI, and physical examination. Int J
Radiat Oncol Biol Phys 83:220-227, 2012
17. Kyzas PA, Evangelou E, Denaxa-Kyza D, et al:
18F-fluorodeoxyglucose positron emission tomogra-
phy to evaluate cervical node metastases in patients
with head and neck squamous cell carcinoma: A
meta-analysis. J Natl Cancer Inst 100:712-720, 2008
18. Liao LJ, Lo WC, Hsu WL, et al: Detection of
cervical lymph node metastasis in head and neck
cancer patients with clinically N0 neck-a meta-
analysis comparing different imaging modalities.
BMC Cancer 12:236, 2012
19. Gardner M, Halimi P, Valinta D, et al: Use of
single MRI and 18F-FDG PET-CT scans in both
diagnosis and radiotherapy treatment planning in
patients with head and neck cancer: Advantage on
target volume and critical organ delineation. Head
Neck 31:461-467, 2009
20. Delouya G, Igidbashian L, Houle A, et al:
18
F-FDG-PET imaging in radiotherapy tumor volume
delineation in treatment of head and neck cancer.
Radiother Oncol 101:362-368, 2011
21. Schinagl DA, Span PN, van den Hoogen FJ, et
al: Pathology-based validation of FDG PET segmen-
tation tools for volume assessment of lymph node
metastases from head and neck cancer. Eur J Nucl
Med Mol Imaging 40:1828-1835, 2013
22. Chatterjee S, Frew J, Mott J, et al: Variation in
radiotherapy target volume definition, dose to organs
at risk and clinical target volumes using anatomic
(computed tomography) versus combined anatomic
and molecular imaging (positron emission tomogra-
phy/computed tomography): Intensity-modulated ra-
diotherapy delivered using a tomotherapy Hi Art
machine—Final results of the VortigERN study. Clin
Oncol (R Coll Radiol) 24:e173-e179, 2012
23. Guido A, Fuccio L, Rombi B, et al: Combined
18F-FDG-PET/CT imaging in radiotherapy target de-
lineation for head-and-neck cancer. Int J Radiat
Oncol Biol Phys 73:759-763, 2009
24. inelevel0Daisne JF, Duprez T, Weynand B, et
al: Tumor volume in pharyngolaryngeal squamous
cell carcinoma: comparison at CT, MR imaging, and
FDG PET and validation with surgical specimen.
Radiology 233:93-100, 2004
25. Caldas-Magalhaes J, Kasperts N, Kooij N, et
al: Validation of imaging with pathology in laryngeal
cancer: Accuracy of the registration methodology.
Int J Radiat Oncol Biol Phys 82:e289-e298, 2012
26. Geets X, Daisne JF, Tomsej M, et al: Impact
of the type of imaging modality on target volumes
delineation and dose distribution in pharyngo-
laryngeal squamous cell carcinoma: Comparison be-
tween pre- and per-treatment studies. Radiother
Oncol 78:291-297, 2006
27. Lee JA: Segmentation of positron emission
images: Some recommendations for target delinea-
tion in radiation oncology. Radiother Oncol 96:302-
307, 2010
28. Murphy JD, Chisholm KM, Daly ME, et al:
Correlation between metabolic tumor volume and
pathologic tumor volume in squamous cell carci-
noma of the oral cavity. Radiother Oncol 101:356-
361, 2011
29. Schinagl DA, Vogel WV, Hoffmann AL, et al:
Comparison of five segmentation tools for 18F-fluoro-
deoxy-glucose-positron emission tomography-based tar-
get volume definition in head and neck cancer. Int J
Radiat Oncol Biol Phys 69:1282-1289, 2007
30. Leclerc M, Lartigau E, Lacornerie T, et al:
Target volume delineation based on 18FDG-PET for
locally advanced head and neck cancer treated by
chemo-radiotherapy. Radiother Oncol 103:S175-
S176, 2012 (suppl 1)
31. Wang D, Schultz CJ, Jursinic PA, et al: Initial
experience of FDG-PET/CT guided IMRT of head-
and-neck carcinoma. Int J Radiat Oncol Biol Phys
65:143-151, 2006
32. Vandecaveye V, De Keyzer F, Vander Poorten
V, et al: Head and neck squamous cell carcinoma:
Value of diffusion-weighted MR imaging for nodal
staging. Radiology 251:134-146, 2009
33. Dirix P, Vandecaveye V, De Keyzer F, et al:
Diffusion-weighted MRI for nodal staging of head
and neck squamous cell carcinoma: Impact on radio-
therapy planning. Int J Radiat Oncol Biol Phys 76:
761-766, 2010
34. Dirix P, Vandecaveye V, De Keyzer F, et al: Dose
painting in radiotherapy for head and neck squamous cell
carcinoma: Value of repeated functional imaging with
F-18-FDG PET, F-18-fluoromisonidazole PET, diffusion-
weighted MRI, and dynamic contrast-enhanced MRI. J
Nucl Med 50:1020-1027, 2009
35. Lambrecht M, Van Herck H, De Keyzer F, et
al: Can we visualize regional differences within the
target volume using sequential diffusion weighted
MRI? Radiother Oncol 110:329-334, 2014
36. Ling CC, Humm J, Larson S, et al: Towards
multidimensional radiotherapy (MD-CRT): Biological
imaging and biological conformality. Int J Radiat
Oncol Biol Phys 47:551-560, 2000
37. Bentzen SM, Gregoire V: Molecular imaging-
based dose painting: A novel paradigm for radiation
therapy prescription. Semin Radiat Oncol 21:101-
110, 2011
38. Due AK, Vogelius IR, Aznar MC, et al: Recur-
rences after intensity modulated radiotherapy for
head and neck squamous cell carcinoma more likely
to originate from regions with high baseline [18F]-
FDG uptake. Radiother Oncol 111:360-365, 2014
39. Brahme A, Agren AK: Optimal dose distribu-
tion for eradication of heterogeneous tumours. Acta
Oncol 26:377-385, 1987
40. Jeong J, Setton JS, Lee NY, et al: Estimate of
the impact of FDG-avidity on the dose required for
head and neck radiotherapy local control. Radiother
Oncol 111:340-347, 2014
41. Schwartz DL, Ford EC, Rajendran J, et al:
FDG-PET/CT-guided intensity modulated head and
neck radiotherapy: A pilot investigation. Head Neck
27:478-487, 2005
42. Madani I, Duprez F, Boterberg T, et al: Maxi-
mum tolerated dose in a phase I trial on adaptive
dose painting by numbers for head and neck cancer.
Radiother Oncol 101:351-355, 2011
43. Heukelom J, Hamming O, Bartelink H, et al:
Adaptive and Innovative Radiation Treatment for Improv-
ing Cancer Treatment Outcome (ARTFORCE): A ran-
domized controlled phase II trial for individualized
treatment of head and neck cancer. BMC Cancer 13:84,
2013
44. Houweling AC, Wolf AL, Vogel WV, et al:
FDG-PET and diffusion-weighted MRI in head-and-
neck cancer patients: Implications for dose painting.
Radiother Oncol 106:250-254, 2013
45. Dirix P, Haustermans K, Vandecaveye V: The
value of magnetic resonance imaging for radiother-
apy planning. Semin Radiat Oncol 24:151-159, 2014
46. Troost EG, Bussink J, Hoffmann AL, et al:
18
F-FLT PET/CT for early response monitoring and
dose escalation in oropharyngeal tumors. J Nucl
Med 51:866-874, 2010
47. Mortensen LS, Johansen J, Kallehauge J, et al:
FAZA PET/CT hypoxia imaging in patients with squa-
mous cell carcinoma of the head and neck treated with
radiotherapy: Results from the DAHANCA 24 trial. Ra-
diother Oncol 105:14-20, 2012
48. Servagi-Vernat S, Differding S, Hanin FX, et al:
A prospective clinical study of
18
F-FAZA PET-CT
hypoxia imaging in head and neck squamous cell
carcinoma before and during radiation therapy. Eur J
Nucl Med Mol Imaging 41:1544-1552, 2014
49. Komar G, Lehtiö K, Seppänen M, et al: Prog-
nostic value of tumour blood flow, [
18
F]EF5 and
[
18
F]FDG PET/CT imaging in patients with head and
neck cancer treated with radiochemotherapy. Eur J
Nucl Med Mol Imaging 41:2042-2050, 2014
50. Zips D, Zöphel K, Abolmaali N, et al: Explor-
atory prospective trial of hypoxia-specific PET imag-
ing during radiochemotherapy in patients with
locally advanced head-and-neck cancer. Radiother
Oncol 105:21-28, 2012
51. Tran LB, Bol A, Labar D, et al: Potential role of
hypoxia imaging using (18)F-FAZA PET to guide
Advances in RT for Head and Neck Cancer
www.jco.org © 2015 by American Society of Clinical Oncology 7
hypoxia-driven interventions (carbogen breathing or
dose escalation) in radiation therapy. Radiother On-
col 113:204-209, 2014
52. Clausen MM, Hansen AE, Af Rosenschold
PM, et al: Dose escalation to high-risk sub-volumes
based on non-invasive imaging of hypoxia and gly-
colytic activity in canine solid tumors: A feasibility
study. Radiat Oncol 8:262, 2013
53. Schütze C, Bergmann R, Brüchner K, et al:
Effect of [(18)F]FMISO stratified dose-escalation on
local control in FaDu hSCC in nude mice. Radiother
Oncol 111:81-87, 2014
54. Thorwarth D, Eschmann SM, Paulsen F, et al:
Hypoxia dose painting by numbers: A planning
study. Int J Radiat Oncol Biol Phys 68:291-300, 2007
55. Grosu AL, Souvatzoglou M, Röper B, et al: Hyp-
oxia imaging with FAZA-PET and theoretical consider-
ations with regard to dose painting for individualization of
radiotherapy in patients with head and neck cancer. Int J
Radiat Oncol Biol Phys 69:541-551, 2007
56. Servagi-Vernat S, Differding S, Sterpin E, et al:
Hypoxia-guided adaptive radiation dose escalation in
head and neck carcinoma: A planning study. Acta
Oncol 6:1-9, 2015
57. Søvik A, Malinen E, Bruland ØS, et al: Optimi-
zation of tumour control probability in hypoxic tu-
mours by radiation dose redistribution: A modelling
study. Phys Med Biol 52:499-513, 2007
58. Castadot P, Geets X, Lee JA, et al: Assess-
ment by a deformable registration method of the
volumetric and positional changes of target volumes
and organs at risk in pharyngo-laryngeal tumors
treated with concomitant chemo-radiation. Ra-
diother Oncol 95:209-217, 2010
59. Geets X, Tomsej M, Lee JA, et al: Adaptive
biological image-guided IMRT with anatomic and
functional imaging in pharyngo-laryngeal tumors:
Impact on target volume delineation and dose dis-
tribution using helical tomotherapy. Radiother Oncol
85:105-115, 2007
60. Barker JL Jr, Garden AS, Ang KK, et al:
Quantification of volumetric and geometric changes
occurring during fractionated radiotherapy for head-
and-neck cancer using an integrated CT/linear accel-
erator system. Int J Radiat Oncol Biol Phys 59:960-
970, 2004
61. Schwartz DL, Garden AS, Thomas J, et al:
Adaptive radiotherapy for head-and-neck cancer: Ini-
tial clinical outcomes from a prospective trial. Int J
Radiat Oncol Biol Phys 83:986-993, 2012
62. Yang H, Hu W, Wang W, et al: Replanning during
intensity modulated radiation therapy improved quality of
life in patients with nasopharyngeal carcinoma. Int J
Radiat Oncol Biol Phys 85:e47-e54, 2013
63. Suit H, Urie M: Proton beams in radiation
therapy. J Natl Cancer Inst 84:155-164, 1992
64. Garden AS, Morrison WH, Wong PF, et al:
Disease-control rates following intensity-modulated
radiation therapy for small primary oropharyngeal
carcinoma. Int J Radiat Oncol Biol Phys 67:438-444,
2007
65. Rosenthal DI, Chambers MS, Fuller CD, et al:
Beam path toxicities to non-target structures during
intensity-modulated radiation therapy for head and
neck cancer. Int J Radiat Oncol Biol Phys 72:747-
755, 2008
66. Murthy V, Narang K, Ghosh-Laskar S, et al:
Hypothyroidism after 3-dimensional conformal ra-
diotherapy and intensity-modulated radiotherapy for
head and neck cancers: Prospective data from 2
randomized controlled trials. Head Neck 36:1573-
1580, 2014
67. van de Water TA, Bijl HP, Schilstra C, et al:
The potential benefit of radiotherapy with protons in
head and neck cancer with respect to normal tissue
sparing: A systematic review of literature. Oncolo-
gist 16:366-377, 2011
68. van der Laan HP, van de Water TA, van Herpt
HE, et al: The potential of intensity-modulated pro-
ton radiotherapy to reduce swallowing dysfunction
in the treatment of head and neck cancer: A plan-
ning comparative study. Acta Oncol 52:561-569,
2013
69. Kandula S, Zhu X, Garden AS, et al: Spot-
scanning beam proton therapy vs intensity-
modulated radiation therapy for ipsilateral head and
neck malignancies: A treatment planning compari-
son. Med Dosim 38:390-394, 2013
■■■
Grégoire, Langendijk, and Nuyts
8© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Advances in Radiotherapy for Head and Neck Cancer
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽Immediate Family Member, Inst ⫽My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Vincent Grégoire
No relationship to disclose
Jan A. Langendijk
Research Funding: Philips (Inst), RaySearch (Inst), Mirada Medical
(Inst)
Sandra Nuyts
No relationship to disclose
Advances in RT for Head and Neck Cancer
www.jco.org © 2015 by American Society of Clinical Oncology
